JP6677775B2 - Muscle builders - Google Patents
Muscle builders Download PDFInfo
- Publication number
- JP6677775B2 JP6677775B2 JP2018161076A JP2018161076A JP6677775B2 JP 6677775 B2 JP6677775 B2 JP 6677775B2 JP 2018161076 A JP2018161076 A JP 2018161076A JP 2018161076 A JP2018161076 A JP 2018161076A JP 6677775 B2 JP6677775 B2 JP 6677775B2
- Authority
- JP
- Japan
- Prior art keywords
- muscle
- lactic acid
- muscles
- present
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
本発明は、筋肉増強剤に関し、より詳細には、乳酸及び／又はその塩を有効成分として含有してなる筋肉増強剤に関する。 The present invention relates to a muscle-building agent, and more particularly, to a muscle-building agent containing lactic acid and / or a salt thereof as an active ingredient.
定期的に運動を行うことが健康を維持するために重要であることは広く認識されている。しかし、定期的に運動を実施するスポーツ人口の割合は、全国の人口から見れば未だ低いレベルにとどまっており、運動が不足しがちな成人においては、加齢による影響と相俟って、筋肉量の顕著な減少が見受けられる。筋肉量の減衰は、日常生活におけるエネルギー代謝量を減少させ、生活習慣病の原因となるばかりでなく、日常生活における思わぬけがの原因ともなりうる。 It is widely recognized that regular exercise is important for maintaining good health. However, the proportion of the sports population who regularly exercises is still low when viewed from the population of the whole country, and in adults who tend to lack exercise, the effects of aging, combined with the effects of aging, There is a noticeable decrease in volume. Decreased muscle mass reduces energy metabolism in daily life and may not only cause lifestyle-related diseases but also cause injuries in daily life.
手術後や病気療養などで長期の安静が必要な場合には、急激な筋萎縮や筋量減少が起きることがあり、治癒後の日常生活への早期復帰の妨げとなる。また、高齢者は一般に筋肉量が少なく、安全に生活するために筋量低下の抑制が望まれる場合がある。さらに、スポーツ選手は必要な筋肉の増強のために、効果的な栄養補給を心掛け、サプリメントを使用する場合もある。 When long-term rest is required after surgery or medical treatment, sudden muscle atrophy or loss may occur, which hinders an early return to daily life after healing. In addition, elderly people generally have low muscle mass, and there is a case where suppression of muscle mass reduction is desired in order to live safely. In addition, athletes may seek effective nutrition and use supplements to build the necessary muscle.
筋肉増強剤としては、一般にステロイド剤や成長ホルモンが使用されることが知られており、例えば、シピオン酸テストステロンやメチルテストステロン等のアナボリックステロイド（蛋白同化ステロイド）が使用されている。しかしながら、そのような筋肉増強剤は筋肉以外の部分に作用するおそれもあり、血圧・コレステロール値の上昇や肝障害等の副作用の問題も同時に有している。そのため、特に安全性に焦点が当てられた筋肉増強剤についても多くの研究開発が行われており、例えば筋肉の材料となり得るタンパク質及びアミノ酸の利用や、植物抽出物の利用が報告されている（特許文献１〜３）。 It is known that steroids and growth hormones are generally used as muscle-building agents. For example, anabolic steroids (anabolic steroids) such as testosterone sipionate and methyltestosterone are used. However, such a muscle-building agent may act on parts other than muscle, and also has side effects such as an increase in blood pressure and cholesterol and liver damage. Therefore, a great deal of research and development has been carried out on muscle-building agents that are particularly focused on safety. For example, the use of proteins and amino acids that can be used as muscle materials and the use of plant extracts have been reported ( Patent Documents 1 to 3).
一方、乳酸は、急激な運動（無酸素運動）を行った際、体内においてグルコースから一過性にＡＴＰを取得するために乳酸代謝される結果として合成される物質である。安静時の乳酸の血中濃度は０．５〜２．０ｍＭ程度であるが、運動の結果として生じる乳酸の血中濃度は４〜５ｍＭ程度になる。また、吐き気を催すほどの極めて激しい運動をした場合は、乳酸の血中濃度は２０ｍＭ程度まで上昇することが知られている。 On the other hand, lactic acid is a substance that is synthesized as a result of lactic acid metabolism in order to temporarily obtain ATP from glucose in the body when a rapid exercise (anaerobic exercise) is performed. The blood concentration of lactic acid at rest is about 0.5 to 2.0 mM, but the blood concentration of lactic acid resulting from exercise is about 4 to 5 mM. Also, it is known that the blood concentration of lactic acid rises to about 20 mM when exercise is extremely intense enough to cause nausea.
体内で合成された乳酸は、血液循環によって肝臓に運搬され、乳酸デヒドロゲナーゼによってピルビン酸に変換され、その後、糖新生によってグルコースが再生される。この一連の回路は、乳酸回路又はコリ回路と言われる。酸素供給不足を伴う運動時、乳酸の代謝除去を乳酸蓄積が上回る限界点があり、血中乳酸濃度が急速に増加を開始する時点を乳酸蓄積閾値と呼んでいる。有酸素運動のトレーニングでは、この乳酸蓄積閾値を酸素供給の指標として利用し、運動強度の設定に利用することがある。 Lactic acid synthesized in the body is transported to the liver by blood circulation, converted to pyruvate by lactate dehydrogenase, and then glucose is regenerated by gluconeogenesis. This series of circuits is called a lactic acid circuit or a Kori circuit. When exercising with a lack of oxygen supply, there is a limit point where lactate accumulation exceeds metabolic elimination of lactate, and the point in time when the blood lactate concentration starts to increase rapidly is called the lactate accumulation threshold. In aerobic exercise training, the lactate accumulation threshold is used as an index of oxygen supply, and may be used to set exercise intensity.
乳酸は、このように体内で合成されている一方で、一般の食品にも含まれており、とりわけ発酵食品には多く含まれていることが知られている。そのような発酵食品としては、ヨーグルトや漬物などが挙げられる。また、飲料中に含まれることもあり、飲料への酸味付与物質として使用されることが開示されている（特許文献４〜６）。しかしながら、乳酸摂取によって筋肉増強効果が得られることは知られておらず、乳酸が筋肉増強剤として利用されることはこれまで報告されていない。むしろ、乳酸は運動によって合成されて体内に蓄積されることから、一般に疲労原因物質であると理解されており、乳酸の体内濃度を下げることが疲労回復や筋肉回復に有効であると考えられている。 While lactic acid is synthesized in the body as described above, it is known that lactic acid is also contained in general foods, especially in fermented foods. Such fermented foods include yogurt and pickles. Further, it is disclosed that it may be contained in a beverage and is used as a substance imparting acidity to a beverage (Patent Documents 4 to 6). However, it is not known that a muscle-building effect is obtained by ingesting lactic acid, and it has not been reported that lactic acid is used as a muscle-building agent. Rather, since lactic acid is synthesized by exercise and accumulated in the body, it is generally understood that it is a substance causing fatigue, and it is considered that lowering the concentration of lactic acid in the body is effective for recovery from fatigue and muscle recovery. I have.
継続的な運動を必要とせずとも筋肉量を増大又は維持することができ、特に、高齢者や療養中の患者を含めて幅広い対象に利用することができる剤は、極めて価値の高い発明であるといえる。そのため、本発明の目的は、安全であり、且つ効率的に筋肉量を増大又は維持することのできる剤及び組成物を提供することにある。 Agents that can increase or maintain muscle mass without the need for continuous exercise, and that can be used in a wide range of subjects, including the elderly and recuperating patients, are extremely valuable inventions. It can be said that. Therefore, an object of the present invention is to provide an agent and a composition that are safe and can efficiently increase or maintain muscle mass.
本発明者は、上記課題を解決すべく鋭意検討した結果、驚くべきことに乳酸及び／又はその塩に筋肉増強作用があることを見出した。かかる知見に基づき、本発明者らは、さらに研究を重ねることによって本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have surprisingly found that lactic acid and / or its salt have a muscle-building action. Based on such knowledge, the present inventors have completed further research and completed the present invention.
即ち、本発明は以下に関する。
〔１〕乳酸及び／又はその塩を有効成分として含有してなる、筋肉増強剤。
〔２〕カフェインをさらに含有する、〔１〕に記載の剤。
〔３〕乳酸及び／又はその塩とカフェインとの含有比が、重量比として（ただし、乳酸塩の重量においては、乳酸としての重量に換算された値が用いられる）、０．９：１〜１０００：１である、〔２〕に記載の剤。
〔４〕乳酸及び／又はその塩を有効成分として含有してなる、筋肉増強作用を有する組成物。
〔５〕カフェインをさらに含有する、〔４〕に記載の組成物。
〔６〕乳酸及び／又はその塩とカフェインとの含有比が、重量比として（ただし、乳酸塩の重量においては、乳酸としての重量に換算された値が用いられる）、０．９：１〜１０００：１である、〔５〕に記載の組成物。
That is, the present invention relates to the following.
[1] A muscle-building agent comprising lactic acid and / or a salt thereof as an active ingredient.
[2] The agent of [1], further comprising caffeine.
[3] The content ratio of lactic acid and / or its salt to caffeine is 0.9: 1 as weight ratio (in the case of lactate, the value converted to the weight as lactic acid is used), 0.9: 1 The agent according to [2], wherein the ratio is up to 1000: 1.
[4] A composition having a muscle-building action, comprising lactic acid and / or a salt thereof as an active ingredient.
[5] The composition according to [4], further comprising caffeine.
[6] The content ratio of lactic acid and / or its salt to caffeine is 0.9: 1 by weight ratio (however, in the case of lactate weight, a value converted to the weight as lactic acid is used). The composition according to [5], wherein the composition ratio is 1000: 1.
本発明によれば、効率的に筋肉量を増大又は維持することのできる剤及び組成物を提供することができる。また、本発明で用いられる乳酸及び／又はその塩は、体内で合成される物質であるばかりでなく、国内では食品添加物に指定されており、飲食品の酸味料やｐＨ調整剤としても使用可能であることから、本発明の剤及び組成物は、ヒト等の動物に対して十分な安全性を有しているといえる。 ADVANTAGE OF THE INVENTION According to this invention, the agent and composition which can increase or maintain muscle mass efficiently can be provided. Lactic acid and / or its salt used in the present invention is not only a substance synthesized in the body, but is also designated as a food additive in Japan and used as an acidulant and pH adjuster for food and drink. Since it is possible, it can be said that the agent and the composition of the present invention have sufficient safety for animals such as humans.
本発明者は、乳酸の生理機能を研究する過程において、乳酸をモデル動物に投与した場合に、驚くべきことに、乳酸が動物の筋肉を増強する作用を有することを見出した。すなわち、この知見に基づいて、本発明は、一つの態様として、乳酸及び／又はその塩を有効成分として含有してなる筋肉増強剤を提供する（以下、「本発明の剤」と称する）。 In the course of studying the physiological function of lactic acid, the present inventors have surprisingly found that when lactic acid is administered to a model animal, the lactic acid has an effect of enhancing muscles of the animal. That is, based on this finding, the present invention provides, as one embodiment, a muscle-building agent containing lactic acid and / or a salt thereof as an active ingredient (hereinafter, referred to as “agent of the present invention”).
本発明において用いられる乳酸とは、化学式ＣＨ３−ＣＨ（ＯＨ）−ＣＯＯＨで表される化合物である。乳酸は、Ｄ体（Ｄ−乳酸）、Ｌ体（Ｌ−乳酸）及びＤＬ体（ＤＬ−乳酸）のいずれもが使用可能であるが、本発明では、好ましくはＬ体及びＤＬ体、より好ましくはＬ体が使用される。尚、Ｄ体のＣＡＳ登録番号は７９−３３−４であり、Ｌ体のＣＡＳ登録番号は１０３２６−４１−７であり、ＤＬ体のＣＡＳ登録番号は５９８−８２−３又は５０−２１−５である。 The lactic acid used in the present invention is a compound represented by the chemical formula CH 3 -CH (OH) -COOH. As lactic acid, any of D-form (D-lactic acid), L-form (L-lactic acid) and DL-form (DL-lactic acid) can be used, but in the present invention, L-form and DL-form are more preferable. Is L-form. The CAS registration number of the D-form is 79-33-4, the CAS registration number of the L-form is 10326-41-7, and the CAS registration number of the DL-form is 598-82-3 or 50-21-5. It is.
また、乳酸の塩としては、特に制限されないが、たとえば、ナトリウムやカリウムなどのアルカリ金属塩（具体的には、乳酸ナトリウム、乳酸カリウムなど）、カルシウムやマグネシウムなどのアルカリ土類金属塩（具体的には、乳酸カルシウム、乳酸マグネシウムなど）、乳酸アルミニウム、乳酸亜鉛、乳酸マンガン及び乳酸鉄などを挙げることができる。本発明における乳酸の塩は、好ましくは乳酸ナトリウム、乳酸カルシウムである。尚、本発明において乳酸の塩は水和物であってもよい。 The salt of lactic acid is not particularly limited. For example, alkali metal salts such as sodium and potassium (specifically, sodium lactate, potassium lactate, and the like), and alkaline earth metal salts such as calcium and magnesium (specifically, Examples thereof include calcium lactate and magnesium lactate), aluminum lactate, zinc lactate, manganese lactate and iron lactate. The salt of lactic acid in the present invention is preferably sodium lactate or calcium lactate. In the present invention, the salt of lactic acid may be a hydrate.
本発明において用いられる乳酸及びその塩は、それらの入手方法については特に限定されず、動物や植物に由来する天然のもの、或いは化学合成法や発酵法などにより得られるもののいずれであってもよい。得られる乳酸及びその塩の純度及び製造コスト等に基づき、好適な乳酸及びその塩の製造方法を適宜選択することができる。本発明においては、市販されている乳酸及びその塩を使用することができる。そのような市販品としては、例え
ば、株式会社武蔵野化学研究所、扶桑化学工業株式会社、株式会社内藤商店、和光純薬工業株式会社等で製造又は販売されている商品が挙げられる。また、本発明では、発酵法を利用して細菌（乳酸菌等）を培養しながら得られた乳酸又は乳酸を含む組成物（飲食品等）をそのまま、或いは加工して使用することもできる。
Lactic acid and salts thereof used in the present invention are not particularly limited with respect to the method of obtaining them, and may be any of natural ones derived from animals or plants, or ones obtained by chemical synthesis or fermentation. . A suitable method for producing lactic acid and its salt can be appropriately selected based on the purity and production cost of the obtained lactic acid and its salt. In the present invention, commercially available lactic acid and salts thereof can be used. Examples of such commercially available products include products manufactured or sold by Musashino Chemical Laboratory Co., Ltd., Fuso Chemical Co., Ltd., Naito Shoten Co., Ltd., Wako Pure Chemical Industries, Ltd., and the like. In the present invention, lactic acid or a composition containing lactic acid (such as food and drink) obtained by culturing bacteria (such as lactic acid bacteria) using a fermentation method can be used as it is or after processing.
生体内において覚醒作用や興奮作用等の生理的機能を発揮する物質としてカフェインが存在する。カフェインによる筋肉増強効果は明らかではないが、本発明者は、乳酸の生理的機能に対する効果を研究する過程においてカフェインとの併用を試みたところ、驚くべきことに乳酸の筋肉増強効果が顕著に向上することを見出した。すなわち、この知見に基づいて、本発明の剤は、上記乳酸に加えてカフェインをさらに含有することができる。 Caffeine exists as a substance that exerts physiological functions such as an arousal action and an excitatory action in a living body. Although the muscle-building effect of caffeine is not clear, the inventor of the present invention attempted to use lactic acid in combination with caffeine in the course of studying its effect on physiological functions. Was found to improve. That is, based on this finding, the agent of the present invention can further contain caffeine in addition to the lactic acid.
カフェインは、プリン環を有するプリンアルカロイドの一種であり、コーヒー豆、緑茶、紅茶などに含まれる成分である。カフェインのＩＵＰＡＣ名は、１，３，７−トリメチルキサンチンであり、そのＣＡＳ登録番号は５８−０８−２である。 Caffeine is a kind of purine alkaloid having a purine ring, and is a component contained in coffee beans, green tea, black tea, and the like. The IUPAC name for caffeine is 1,3,7-trimethylxanthine, and its CAS registry number is 58-08-2.
本発明におけるカフェインには、無水物（「無水カフェイン」とも称される）及び水和物（例えば、一水和物）の両方の態様が包含される。本発明ではいずれの態様も使用することができるが、好ましくは無水物が使用される。 Caffeine in the present invention encompasses both anhydrous (also referred to as “anhydrous caffeine”) and hydrate (eg, monohydrate) embodiments. In the present invention, any of the embodiments can be used, but an anhydride is preferably used.
本発明において用いられるカフェインは、特に限定されず、例えば、化学合成などによって得られる結晶物であってもよく、或いはカフェインを含有する植物抽出物をそのまま、又は濃縮若しくは精製したもの（即ち、カフェインを含む植物抽出物からカフェイン以外の成分を選択的に除去してカフェインの含有率を高めたもの）であってもよい。得られるカフェインの純度及び製造コスト等に基づき、好適なカフェインの製造方法を適宜選択することができる。カフェインを含む植物抽出物は、特に限定されないが、例えば、コーヒー豆、コーラの実、茶葉、カカオ等から水（又は熱水）、メタノール、エタノール、イソプロパノール、酢酸エチル等の溶媒で自体公知の方法を用いて抽出することにより製造される。 The caffeine used in the present invention is not particularly limited, and may be, for example, a crystalline product obtained by chemical synthesis or the like, or a plant extract containing caffeine as it is, or a concentrated or purified plant extract (ie, And those in which the components other than caffeine are selectively removed from the plant extract containing caffeine to increase the content of caffeine). A suitable method for producing caffeine can be appropriately selected based on the purity and production cost of the obtained caffeine. Although the plant extract containing caffeine is not particularly limited, for example, water (or hot water) from coffee beans, cola seeds, tea leaves, cocoa, etc., a solvent such as water, methanol, ethanol, isopropanol, or ethyl acetate is known per se. It is produced by extraction using a method.
本発明においては、市販されているカフェインを使用することができる。そのような市販品としては、例えば、白鳥製薬株式会社、和光純薬工業株式会社等で製造又は販売されている商品が挙げられる。 In the present invention, commercially available caffeine can be used. Examples of such commercially available products include products manufactured or sold by Shiratori Pharmaceutical Co., Ltd., Wako Pure Chemical Industries, Ltd., and the like.
本発明の剤における乳酸及び／又はその塩とカフェインとの含有比（乳酸及び／又はその塩：カフェイン）は、重量比として、通常０．９：１〜１０００：１である。また、上記含有比は、好ましくは２：１〜５００：１であり、より好ましくは４：１〜１４０：１であり、さらに好ましくは４：１〜５６：１である。両者の比が上記範囲内であることにより、効率的に筋肉増強作用を発揮することが可能となる。尚、乳酸の塩を用いる場合は、乳酸の遊離体（フリー体）に換算した上で上記重量比を算出するものとする。本発明では、このように換算された重量が「乳酸としての重量に換算された値」として取り扱われる。また、各有効成分が水和物を形成している場合は、水分子を除いた遊離体（無水物）に換算した上で上記重量比を算出するものとする。 The content ratio of lactic acid and / or a salt thereof to caffeine (lactic acid and / or a salt thereof: caffeine) in the agent of the present invention is usually 0.9: 1 to 1000: 1 as a weight ratio. The content ratio is preferably from 2: 1 to 500: 1, more preferably from 4: 1 to 140: 1, and further preferably from 4: 1 to 56: 1. When the ratio between the two is within the above range, it is possible to efficiently exert a muscle enhancing action. When a salt of lactic acid is used, the weight ratio is calculated after conversion to a free form (free form) of lactic acid. In the present invention, the weight converted in this way is treated as “a value converted to the weight as lactic acid”. When each active ingredient forms a hydrate, the above weight ratio is calculated after conversion into a free form (anhydride) excluding water molecules.
本発明において、「筋肉増強剤」とは、動物の筋肉を増強するために使用される剤を意味する。また、本発明における筋肉の増強は、結果的に筋肉が増強される限り特に限定されるわけではないが、主に筋肉量の増加に基づいて筋肉が増強されることを意味する。そのため、本発明の剤は筋肉増加剤と称することもできる。本発明の筋肉増強剤は、筋肉を増強するため、又は筋肉量を増加するために使用されることは勿論であるが、その目的のみならず、筋肉量維持の観点から、筋肉の減衰を抑制（防止）するため、又は筋肉量の低減を抑制（防止）するためにも使用されることができる。また、本発明の筋肉増強剤は、
筋肉の萎縮（例えば、廃用性筋萎縮等）等により減少又は減衰した筋肉（筋肉量、筋力等）を回復させるためにも使用されることができる。
In the present invention, “muscle-enhancing agent” means an agent used to enhance muscle of an animal. Further, the muscle enhancement in the present invention is not particularly limited as long as the muscle is eventually enhanced, but means that the muscle is enhanced mainly based on the increase in the muscle mass. Therefore, the agent of the present invention can also be referred to as a muscle building agent. The muscle-building agent of the present invention is used not only for the purpose of building muscle or for increasing muscle mass, but also for the purpose of maintaining muscle mass. It can also be used to (prevent) or suppress (prevent) loss of muscle mass. Further, the muscle-building agent of the present invention,
It can also be used to recover muscles (muscle mass, muscle strength, etc.) that have been reduced or attenuated due to muscle atrophy (eg, disuse muscle atrophy, etc.).
本発明で対象とされる筋肉は、特に限定されないが、主に骨格筋（随意筋）である。本発明における筋肉は、頭部から下肢までの全身に及ぶことができる（具体的には、頭部、頸部、胸部、腹部、背部、上肢、下肢）。各部における筋肉の中から、本発明における筋肉として、例えば抗重力筋（脊柱起立筋、腹直筋、大臀筋、大腿四頭筋等）を挙げることができる。本発明においては、特に限定されないが、下肢の筋肉が好ましい。下肢の筋肉としては、下肢帯筋、大腿筋、下腿筋、足筋等が挙げられるが、これらの中では下腿筋が好ましい。下腿筋としては、下腿伸筋群の筋肉、腓骨筋、下腿屈筋群の筋肉等が挙げられるが、これらの中では、下腿伸筋群の筋肉及び下腿屈筋群の筋肉が好ましい。下腿伸筋群の筋肉としては、前頸骨筋、長趾伸筋（長指伸筋）、第三腓骨筋、長母趾伸筋等が挙げられる。下腿屈筋群の筋肉としては、足底筋（足底屈筋）、膝窩筋、下腿三頭筋（腓腹筋、ヒラメ筋等）、長趾屈筋、後頸屈筋、長母趾屈筋等が挙げられる。 The muscle targeted in the present invention is not particularly limited, but is mainly skeletal muscle (voluntary muscle). The muscle in the present invention can extend to the whole body from the head to the lower limb (specifically, the head, neck, chest, abdomen, back, upper limb, and lower limb). Among the muscles in each part, examples of the muscle according to the present invention include antigravity muscles (erector spinae, rectus abdominis, gluteus maximus, quadriceps, etc.). In the present invention, although not particularly limited, lower limb muscles are preferred. Examples of lower limb muscles include lower limb girdle muscles, thigh muscles, lower leg muscles, foot muscles, and the like. Examples of the leg muscles include the muscles of the extensor leg group, the peroneal muscle, the muscles of the flexor leg group, and among these, the muscles of the extensor leg group and the muscles of the flexor leg group are preferable. Examples of the muscles of the extensor leg muscles include the anterior tibialis muscle, the extensor digitorum longus (extensor digit longus), the third peroneal muscle, the extensor pollicis longus, and the like. The muscles of the lower leg flexors include plantar muscles (plantar flexors), popliteal muscles, triceps surae muscles (gastrocnemius muscles, soleus muscles, etc.), flexor long toes, posterior cervical flexors, flexor pollicis longus, and the like.
本発明の剤は、筋肉増強作用を通じて以下の用途にも有用である：骨折関節損傷、肉離れ、捻挫等の負傷時のリハビリテーション用；加齢による（高齢者の）筋力低下の改善用；加齢による（高齢者の）筋肉量減少の改善用；寝たきり状態の改善用；運動選手の筋肉増強用など。また、本発明の剤は、筋力低下又は筋肉量減少に関連する疾患（例えば、筋肉減少症）の改善用として使用することもできる。尚、本発明において「改善」とは、現在の状態をより良い状態にすることと現在の状態よりも悪い状態になることを防ぐこととの両方の概念を包含することを意味し、「治療又は予防」と読み替えてもよい。 The agents of the present invention are also useful through muscle-building action in the following applications: for rehabilitation in the event of injuries such as fractured joint injuries, loosening, sprains, etc .; for improving aging-related (elderly) muscle weakness; To improve muscle mass loss (of the elderly); to improve bedridden status; to increase muscle strength in athletes. In addition, the agent of the present invention can also be used for ameliorating a disease associated with muscle weakness or muscle loss (eg, sarcopenia). Note that, in the present invention, “improvement” means to include both concepts of making the current state better and preventing it from becoming worse than the current state. Or prevention ".
本発明の剤は、医薬及び食品などとして有用であり、その適用対象は哺乳動物であり得る。このような哺乳動物としては、例えば、霊長類（例えば、ヒト、サル、チンパンジー）、げっ歯類（例えば、マウス、ラット、モルモット）、ペット（例、イヌ、ネコ、ウサギ）、使役動物又は家畜（例えば、ウシ、ウマ、ブタ、ヒツジ、ヤギ）が挙げられるが、本発明ではヒトが好ましい。尚、ヒト以外の哺乳動物に適用する場合、本発明の剤の投与量（摂取量）は、動物の体重又は大きさに応じて適宜加減すればよい。 The agent of the present invention is useful as a medicament, food, and the like, and its application target may be a mammal. Such mammals include, for example, primates (eg, humans, monkeys, chimpanzees), rodents (eg, mice, rats, guinea pigs), pets (eg, dogs, cats, rabbits), working animals or livestock. (Eg, cows, horses, pigs, sheep, goats), but humans are preferred in the present invention. When applied to mammals other than humans, the dose (intake) of the agent of the present invention may be appropriately adjusted according to the weight or size of the animal.
本発明はまた、更なる一つの態様として、乳酸及び／又はその塩を含有してなる組成物を提供する（以下、「本発明の組成物」と称する）。本発明の組成物は、上記の本発明の剤により発揮される効果をすべて有することができる。すなわち、本発明の組成物は、筋肉増強作用を有することができる。ここで、本発明の組成物における筋肉の増強は、主に筋肉量の増加に基づいており、本発明の組成物は筋肉増加作用も合わせて有することが意図される。また、本発明の組成物は、筋肉を増強するため、又は筋肉量を増加するために使用されることは勿論であるが、その目的のみならず、筋肉の減衰を抑制（防止）するため、又は筋肉量の低減を抑制（防止）するためにも使用されることができる。また、本発明の組成物は、筋肉の萎縮（例えば、廃用性筋萎縮等）等により減少又は減衰した筋肉（筋肉量、筋力等）を回復させるためにも使用されることができる。尚、本発明の組成物は、本発明の剤を含有しているということもできる。 The present invention also provides, as a further embodiment, a composition containing lactic acid and / or a salt thereof (hereinafter, referred to as “the composition of the present invention”). The composition of the present invention can have all the effects exhibited by the above-mentioned agent of the present invention. That is, the composition of the present invention can have a muscle-building action. Here, the muscle building in the composition of the present invention is mainly based on the increase in muscle mass, and it is intended that the composition of the present invention also has a muscle building action. In addition, the composition of the present invention is used not only for the purpose of building muscle or for increasing muscle mass, but also for the purpose as well as for suppressing (preventing) muscle attenuation. Alternatively, it can also be used to suppress (prevent) loss of muscle mass. The composition of the present invention can also be used to restore muscle (muscle mass, muscle strength, etc.) that has been reduced or attenuated due to muscle atrophy (eg, disuse muscle atrophy, etc.). In addition, it can be said that the composition of the present invention contains the agent of the present invention.
本発明の組成物が対象とする筋肉は、本発明の剤と同様に、特に限定されないが、主に骨格筋（随意筋）である。その対象とされる筋肉は、頭部から下肢までの全身に及ぶことができる（具体的には、頭部、頸部、胸部、腹部、背部、上肢、下肢）。各部における筋肉の中から、本発明における筋肉として、例えば抗重力筋（脊柱起立筋、腹直筋、大臀筋、大腿四頭筋等）を挙げることができる。本発明においては、特に限定されないが、下肢の筋肉が好ましい。下肢の筋肉としては、下肢帯筋、大腿筋、下腿筋、足筋等が挙げられるが、これらの中では下腿筋が好ましい。下腿筋としては、下腿伸筋群の筋肉、腓骨筋、下腿屈筋群の筋肉等が挙げられるが、これらの中では、下腿伸筋群の筋肉及び下腿屈筋群
の筋肉が好ましい。下腿伸筋群の筋肉としては、前頸骨筋、長趾伸筋（長指伸筋）、第三腓骨筋、長母趾伸筋等が挙げられる。下腿屈筋群の筋肉としては、足底筋（足底屈筋）、膝窩筋、下腿三頭筋（腓腹筋、ヒラメ筋等）、長趾屈筋、後頸屈筋、長母趾屈筋等が挙げられる。
The muscle targeted by the composition of the present invention is not particularly limited, as in the case of the agent of the present invention, but is mainly skeletal muscle (voluntary muscle). The muscles of interest can span the entire body from the head to the lower limbs (specifically, head, neck, chest, abdomen, back, upper limbs, lower limbs). Among the muscles in each part, examples of the muscle according to the present invention include antigravity muscles (erector spinae, rectus abdominis, gluteus maximus, quadriceps, etc.). In the present invention, although not particularly limited, lower limb muscles are preferred. Examples of lower limb muscles include lower limb girdle muscles, thigh muscles, lower leg muscles, foot muscles, and the like. Among these, the lower leg muscles are preferred. Examples of the leg muscles include the muscles of the extensor leg group, the peroneal muscle, the muscles of the flexor leg group, and among these, the muscles of the extensor leg group and the muscles of the flexor leg group are preferable. Examples of the muscles of the extensor leg muscles include the anterior tibialis muscle, the extensor digitorum longus (extensor digit longus), the third peroneal muscle, the extensor pollicis longus, and the like. Muscles of the flexor leg muscles include plantar muscles (plantar flexor muscles), popliteal muscles, triceps surae muscles (gastrocnemius muscles, soleus muscles, etc.), flexor long toes, posterior cervical flexors, flexor pollicis longus, and the like.
本発明の組成物は、担体を含有することができる。当該担体としては、例えば、薬学的に許容される担体、及び飲食品に許容される担体（飲食品の分野において通常使用される担体）等が使用される。本発明の組成物に含まれる担体は、組成物の形態により適宜選択することができ、特に限定されないが、例えば、賦形剤、結合剤、滑沢剤、崩壊剤、溶剤、安定化剤、溶解補助剤、酸化防止剤、着色剤、着香剤、甘味剤等の添加剤が挙げられる。 The composition of the present invention can contain a carrier. As the carrier, for example, a pharmaceutically acceptable carrier, a carrier acceptable for food and drink (a carrier usually used in the field of food and drink) and the like are used. The carrier contained in the composition of the present invention can be appropriately selected depending on the form of the composition, and is not particularly limited. For example, excipients, binders, lubricants, disintegrants, solvents, stabilizers, Additives such as dissolution aids, antioxidants, coloring agents, flavoring agents, sweeteners and the like can be mentioned.
賦形剤としては、糖類（白糖、乳糖、ブドウ糖、マンニトール等）、デンプン（コーンスターチ等）、結晶セルロース、リン酸カルシウム、硫酸カルシウム、硫酸マグネシウムなどが、結合剤としては、α化デンプン、ゼラチン、トラガントガム、アラビアゴム、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、結晶セルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコールなどが、滑沢剤としては、ステアリン酸マグネシウム、タルク、ポリエチレングリコール、シリカ、硬化植物油などが、崩壊剤としては、デンプン、結晶セルロース、カルボキシメチルセルロース、寒天、クエン酸カルシウム、炭酸カルシウム、炭酸水素ナトリウム、デキストリンなどが、溶剤としては、水、エタノール、グリセロール、生理食塩水、大豆油などが、安定化剤としては、安息香酸、安息香酸ナトリウム、パラオキシ安息香酸エチル、プロピレングルコールなどが、溶解補助剤としては、フマル酸、コハク酸、リンゴ酸などが、酸化防止剤としては、アスコルビン酸、トコフェロール、亜硫酸水素ナトリウム、チオ硫酸ナトリウム、ピロ亜硫酸ナトリウム、クエン酸などが、着色剤、着香剤、甘味剤としては、医薬及び食品分野において通常添加することが許容されているものがそれぞれ挙げられる。 As excipients, sugars (sucrose, lactose, glucose, mannitol, etc.), starch (corn starch, etc.), crystalline cellulose, calcium phosphate, calcium sulfate, magnesium sulfate, etc., as binders, pregelatinized starch, gelatin, tragacanth gum, Gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc., as lubricants, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil But disintegrants include starch, crystalline cellulose, carboxymethyl cellulose, agar, calcium citrate, calcium carbonate, charcoal Sodium hydrogen, dextrin, etc., as a solvent, water, ethanol, glycerol, physiological saline, soybean oil, etc., as a stabilizer, benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, propylene glycol, etc. As dissolution aids, fumaric acid, succinic acid, malic acid, etc., as antioxidants, ascorbic acid, tocopherol, sodium hydrogen sulfite, sodium thiosulfate, sodium pyrosulfite, citric acid, etc., coloring agents, flavors Examples of agents and sweeteners include those which are generally permitted to be added in the fields of medicine and food.
本発明の組成物は、本発明の剤の場合と同様に、カフェインをさらに含有することができ、そして本発明の組成物における乳酸及び／又はその塩とカフェインとの含有比（乳酸及び／又はその塩：カフェイン）もまた、本発明の剤の場合と同様に、重量比として、通常０．９：１〜１０００：１、好ましくは２：１〜５００：１であり、より好ましくは４：１〜１４０：１であり、さらに好ましくは４：１〜５６：１である。両者の比が上記範囲内であることにより、効率的に筋肉増強作用を発揮することが可能となる。尚、乳酸の塩を用いる場合は、乳酸の遊離体（フリー体）に換算した上で上記重量比を算出するものとする。本発明では、このように換算された重量が「乳酸としての重量に換算された値」として取り扱われる。また、各有効成分が水和物を形成している場合は、水分子を除いた遊離体（無水物）に換算した上で上記重量比を算出するものとする。 The composition of the present invention can further contain caffeine, as in the case of the agent of the present invention, and the content ratio of lactic acid and / or a salt thereof to caffeine (lactic acid and // salt thereof: caffeine) is also, as in the case of the agent of the present invention, usually in a weight ratio of 0.9: 1 to 1000: 1, preferably 2: 1 to 500: 1, more preferably Is from 4: 1 to 140: 1, and more preferably from 4: 1 to 56: 1. When the ratio between the two is within the above range, it is possible to efficiently exert a muscle enhancing action. When a salt of lactic acid is used, the weight ratio is calculated after conversion to a free form (free form) of lactic acid. In the present invention, the weight converted in this way is treated as “a value converted to the weight as lactic acid”. When each active ingredient forms a hydrate, the above weight ratio is calculated after conversion into a free form (anhydride) excluding water molecules.
上述した乳酸、乳酸の塩及びカフェインは、単一の組成物に同時に調製されていてもよく、或いはそれぞれ別個の組成物に調製されていてもよい。別個の組成物とする場合には、各組成物を併用する態様で用いられる。本発明では、投与又は摂取の簡便性から、乳酸及び／又はその塩とカフェインとは単一の組成物に調製して使用することが好ましい。 The lactic acid, lactic acid salt and caffeine described above may be prepared simultaneously in a single composition, or may be prepared in separate compositions. When separate compositions are used, each composition is used in a combined mode. In the present invention, lactic acid and / or a salt thereof and caffeine are preferably prepared and used as a single composition from the viewpoint of easy administration or ingestion.
本発明の組成物における乳酸及び／又はその塩の含有量は、本発明の組成物の全重量に対し、通常０．１０〜９９．９９重量％であり、好ましくは０．６０〜９９．９０重量％であり、より好ましくは１．００〜９９．９０重量％である。また、本発明の組成物におけるカフェインの含有量は、本発明の組成物の全重量に対し、通常０．０１〜３３．３３重量％であり、好ましくは０．０２〜３３．３０重量％であり、より好ましくは０．０４〜３３．３０重量％である。上記重量比と同様に、乳酸の塩を用いる場合は、乳酸の遊離
体（フリー体）に換算した上で上記含有量を算出し、各有効成分が水和物を形成している場合は、水分子を除いた遊離体（無水物）に換算した上で上記含有量を算出するものとする。上記の含有量範囲は、乳酸及び／又はその塩及びカフェインをそれぞれ別個の組成物に調製した場合も採用されることができる。
The content of lactic acid and / or a salt thereof in the composition of the present invention is usually 0.10 to 99.99% by weight, preferably 0.60 to 99.90, based on the total weight of the composition of the present invention. %, More preferably 1.00 to 99.90% by weight. The content of caffeine in the composition of the present invention is usually 0.01 to 33.33% by weight, preferably 0.02 to 33.30% by weight, based on the total weight of the composition of the present invention. And more preferably 0.04 to 33.30% by weight. Similarly to the above weight ratio, when a salt of lactic acid is used, the content is calculated after conversion to a free form of lactic acid (free form), and when each active ingredient forms a hydrate, The above content is calculated after conversion to a free form (anhydride) excluding water molecules. The above content range can also be adopted when lactic acid and / or a salt thereof and caffeine are prepared in separate compositions.
本発明の組成物は、医薬（即ち、医薬組成物）として使用することができる。この場合、本発明の医薬組成物は、筋力低下又は筋肉量減少に関連する疾患の予防又は治療薬として取り扱うことが可能であり、かかる疾患の具体例は上述したとおりである。 The composition of the present invention can be used as a medicine (that is, a pharmaceutical composition). In this case, the pharmaceutical composition of the present invention can be used as a prophylactic or therapeutic agent for a disease associated with muscle weakness or muscle loss, and specific examples of such a disease are as described above.
本発明の医薬組成物の投与方法としては、特に限定されるものではなく、一般に経口投与による投与方法が挙げられるが、対象患者の状態、重症度等に応じて、非経口投与（血管内（静脈内、動脈内）投与、皮下投与、経皮投与、直腸内投与等）を適宜選択してもよい。有効成分である乳酸及び／又はその塩及びカフェインはいずれも飲食可能であることから、本発明では経口投与を採用することが好ましい。 The administration method of the pharmaceutical composition of the present invention is not particularly limited, and generally includes an administration method by oral administration. Parenteral administration (intravascular (intravascular) administration) is performed depending on the condition, severity, and the like of the target patient. Intravenous, intraarterial) administration, subcutaneous administration, transdermal administration, rectal administration, etc.) may be appropriately selected. Since the active ingredient lactic acid and / or its salt and caffeine are all edible, it is preferable to employ oral administration in the present invention.
本発明の医薬組成物の形態は、特に限定されず、投与方法に適した形態にすることができる。経口投与に適した形態としては、例えば、錠剤、ロゼンジ、硬質又は軟質カプセル、水性又は油性懸濁液、乳液、分散性粉末又は顆粒、シロップ又はエリキシルなどが挙げられる。非経口投与に適した形態としては、例えば、非経口注射に適した形態として、静脈内、皮下、筋肉内、血管内又は注入投与のための滅菌溶液、懸濁液、乳液などが、経皮投与に適した形態として、クリーム、軟膏、ゲル、水性又は油性の液剤（懸濁液を含む）などが挙げられる。 The form of the pharmaceutical composition of the present invention is not particularly limited, and can be a form suitable for an administration method. Forms suitable for oral administration include, for example, tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs. Suitable forms for parenteral administration include, for example, sterile solutions, suspensions, emulsions and the like for intravenous, subcutaneous, intramuscular, intravascular or infusion administration, suitable for parenteral injection, Suitable forms for administration include creams, ointments, gels, aqueous or oily solutions (including suspensions) and the like.
本発明の組成物はまた、飲食品（即ち、飲食品組成物）として使用することもできる。この場合、本発明の飲食品組成物は、上述した担体等を用いて常法により調製することができる。 The composition of the present invention can also be used as a food or drink (that is, a food or drink composition). In this case, the food and drink composition of the present invention can be prepared by a conventional method using the above-mentioned carrier and the like.
本発明における飲食品は、飲食品全般を意味するが、いわゆる健康食品を含む一般食品の他、消費者庁に規定されている特別用途食品（特定保健用食品、病者用食品、えん下困難者用食品など）や栄養機能食品をも含むものであり、さらにサプリメント、飼料等も本発明の飲食品に包含される。 The food and drink in the present invention means general food and drink, but includes general foods including so-called health foods, as well as special-use foods specified by the Consumer Affairs Agency (foods for specified health use, foods for the sick, difficulties in swallowing Foods for the elderly) and nutritionally functional foods, and supplements, feeds and the like are also included in the food and drink of the present invention.
本発明の飲食品組成物は、その形態は特に限定されず、細粒剤、顆粒剤、丸剤、錠剤（タブレット）（コーティング錠、糖衣錠を含む）、カプセル剤（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）、飲料、ドリンク剤、液剤（シロップ剤、乳剤、懸濁剤を含む）、粉末食品、ゼリー、飴等の形態とすることができる。 The form of the food and drink composition of the present invention is not particularly limited, and includes fine granules, granules, pills, tablets (tablets) (including coated tablets and sugar-coated tablets), capsules (hard capsules, soft capsules, and microcapsules). ), Beverages, drinks, liquids (including syrups, emulsions, and suspensions), powdered foods, jellies, candies, and the like.
本発明の剤及び組成物の投与量（摂取量）は、特に限定されず、体内において筋肉増強作用が発現することができる有効量の範囲内であればよく、対象の個人差、症状、投与方法等に応じて適宜設定することができる。例えば、上記投与量（摂取量）は、乳酸の重量として、体重６０ｋｇの成人１日あたり４０〜１０，０００ｍｇであり、好ましくは１００〜５，０００ｍｇであり、より好ましくは５００〜３，５００ｍｇである。また、上記投与量（摂取量）は、カフェインの重量として、例えば、体重６０ｋｇの成人１日あたり１０〜１０００ｍｇであり、好ましくは１０〜５００ｍｇであり、より好ましくは１５〜２００ｍｇである。上記１日あたりの投与量（摂取量）は、一度にもしくは数回（例えば、２、３回）に分けて投与（摂取）することができる。本発明の剤及び組成物の投与（摂取）は、食前、食後及び食間を問わず、またその期間は、本発明の効果が奏される限りにおいて特に限定されない。以下、本明細書において用語「投与」が使用される場合は、該用語は「摂取」の概念も包含することを意味する。 The dosage (intake) of the agent and composition of the present invention is not particularly limited, and may be within an effective amount capable of exhibiting a muscle enhancing action in the body. It can be set appropriately according to the method and the like. For example, the above-mentioned dose (intake amount) is 40 to 10,000 mg, preferably 100 to 5,000 mg, more preferably 500 to 3,500 mg per day of an adult weighing 60 kg as lactic acid. is there. In addition, the above-mentioned dose (intake amount) is, for example, 10 to 1000 mg, preferably 10 to 500 mg, more preferably 15 to 200 mg per day for an adult weighing 60 kg as a weight of caffeine. The daily dose (intake) can be administered (taken) at once or divided into several times (for example, two or three times). Administration (ingestion) of the agent and composition of the present invention is not limited to before, after and between meals, and the period is not particularly limited as long as the effects of the present invention are exerted. Hereinafter, when the term “administration” is used herein, it is meant that the term also encompasses the concept of “ingestion”.
上述したとおり、乳酸及び／又はその塩及びカフェインは別個の組成物に調製することができ、その場合、本発明において両組成物は併用されることができる。乳酸及び／又はその塩及びカフェインは同時に投与されてもよく、或いはいずれかの順序で逐次的に投与されることもできる。 As mentioned above, lactic acid and / or its salt and caffeine can be prepared in separate compositions, in which case both compositions can be used together in the present invention. Lactic acid and / or its salt and caffeine may be administered simultaneously, or they may be administered sequentially in any order.
本発明の剤及び組成物を使用する場合はまた、筋肉増強作用を有する既存の成分と併用することも可能である。そのような場合、本発明の剤及び組成物と上記既存の成分とを投与する順序は、同時又は別々であってもよい。別々の場合、本発明の剤及び組成物の投与は、上記既存の成分の前又は後のいずれでもよい。 When the agents and compositions of the present invention are used, they can also be used in combination with existing ingredients having a muscle-building action. In such cases, the order of administration of the agents and compositions of the present invention and the existing components may be simultaneous or separate. When separate, administration of the agents and compositions of the present invention may be before or after the above-mentioned existing components.
上記既存の成分としては、例えば、バリン、ロイシン、イソロイシン、グルタミン、グルタミン酸等のアミノ酸、ペプチド、成長ホルモン、加味四物湯等の漢方、サラシア等の植物若しくはその抽出物又はこれらの組み合わせ等が挙げられるが、特にこれらに限定されない。 Examples of the existing components include, for example, valine, leucine, isoleucine, glutamine, amino acids such as glutamic acid, peptides, growth hormone, Kampo such as kamishimotsuto, plants such as salasia, extracts thereof, and combinations thereof. However, the present invention is not particularly limited to these.
以下に実施例を挙げて本発明をさらに具体的に説明するが、これらは単なる例示であって、本発明の範囲を何ら限定するものではない。 Hereinafter, the present invention will be described more specifically with reference to examples. However, these are merely examples, and do not limit the scope of the present invention.
実施例１．動物試験における乳酸及びカフェインの効果
１．試験材料および方法
１．１．被験物質及び媒体
１．１．１．被験物質
乳酸ナトリウム（和光純薬工業株式会社製）及びカフェイン（和光純薬工業株式会社製）を使用した。入手後は、いずれも試験施設の被験物質保管室の保管庫内に室温（設定温度：２３℃、許容範囲：１８．０〜２８．０℃）の条件下で保管した。
Embodiment 1 FIG. Effect of lactic acid and caffeine in animal tests Test materials and methods 1.1. Test substance and vehicle 1.1.1. Test substances Sodium lactate (manufactured by Wako Pure Chemical Industries, Ltd.) and caffeine (manufactured by Wako Pure Chemical Industries, Ltd.) were used. After the acquisition, all were stored in a storage in a test substance storage room of a test facility at room temperature (set temperature: 23 ° C, allowable range: 18.0 to 28.0 ° C).
１．１．２．媒体
注射用水（株式会社大塚製薬工場製）を使用した。入手後は、試験施設の被験物質保管室内に室温（設定温度：２３℃、実測値：１８．０〜２８．０℃）の条件下で保管した。
1.1.2. Medium Water for injection (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) was used. After the acquisition, it was stored in a test substance storage room of a test facility at room temperature (set temperature: 23 ° C, measured value: 18.0 to 28.0 ° C).
１．２．投与検体
乳酸ナトリウム及びカフェインの必要量を秤量後、注射用水を用いて、それぞれ最終濃度が２００ｍｇ／ｍＬ及び７．２ｍｇ／ｍＬとなるように混合して溶解した（混合したものを被験物質ＬＣとした）。
1.2. Administration Sample After weighing the required amounts of sodium lactate and caffeine, they were mixed and dissolved using water for injection so that the final concentrations would be 200 mg / mL and 7.2 mg / mL, respectively (the mixed substance was used as the test substance LC And).
１．３．試験系
１．３．１．試験動物および飼育条件
試験には、薬効薬理試験に一般的に用いられている動物種で、その系統維持が明らかな雄性Ｆ３４４ラット（ＳＰＦ、日本エスエルシー株式会社）を使用した。
動物は、設定温度：２３℃、明暗各１２時間（照明：午前８時〜午後８時）、に設定された動物飼養施設で飼育した。ケージ及び給餌器の交換は１週間に１回以上行った。
飼料は、製造後５ヵ月以内の固形高脂肪飼料（ＨＦＤ−６０、オリエンタル酵母工業株式会社）を給餌器に入れて自由に摂取させた。
1.3. Test system 1.3.1. Test Animals and Breeding Conditions For the test, male F344 rats (SPF, Japan SLC, Inc.), an animal species generally used for pharmacological tests and whose strain was clearly maintained, were used.
The animals were bred in an animal breeding facility set at a set temperature of 23 ° C. and light and dark for 12 hours each (lighting: 8:00 am to 8:00 pm). The cage and feeder were replaced at least once a week.
As the feed, a solid high-fat feed (HFD-60, Oriental Yeast Co., Ltd.) within 5 months after production was put in a feeder and fed freely.
１．３．２．群分け
５週齢のラットに対し、６週間、高脂肪食ＨＦＤ−６０を自由摂取させた。１１週齢の時点で、ラットをランダムに運動群（ｎ＝９）、運動＋Ｌ群（ｎ＝９）、運動＋Ｃ群（ｎ＝９）、運動＋ＬＣ群（ｎ＝９）に分類した。
1.3.2. Grouping Five-week-old rats were allowed to freely take a high-fat diet HFD-60 for 6 weeks. At the age of 11 weeks, rats were randomly divided into exercise group (n = 9), exercise + L group (n = 9), exercise + C group (n = 9), and exercise + LC group (n = 9).
１．３．３．個体識別法及びケージラベル
動物は、入手日に油性インクを用いた尾への記入法及び油性インクを用いて四肢への色素塗布法を併用して識別した。群分け後は、油性インクを用いて尾への動物番号（下３桁）の記入により識別した。各ケージには、予備飼育期間中は試験番号、入手年月日、予備飼育動物番号を記入したラベルを、群分け後は、試験番号、群名称及び動物番号を記入し、群ごとに色分けしたラベルを取り付けた。
1.3.3. Individual Identification Method and Cage Label Animals were identified on the day of acquisition using a tail filling method using oil-based ink and a pigment application method on limbs using oil-based ink. After the grouping, the animals were identified by entering the animal number (last 3 digits) on the tail using an oil-based ink. In each cage, during the preliminary breeding period, a label with the test number, date of acquisition, and pre-breeding animal number was entered, and after grouping, the test number, group name and animal number were entered, and each group was color-coded. Label attached.
１．３．４．運動負荷
運動負荷は自発性走運動を週３回、２日に１回の頻度で行った。自発性走運動は回転運動機（Ｌａｆａｙｅｔｔｅ Ｉｎｓｔｒｕｍｅｎｔ、型番８０８５９）を用いた。
1.3.4. Exercise load The exercise load was spontaneous running exercise performed three times a week and once every two days. The spontaneous running motion used a rotary exercise machine (Lafayette Instrument, model number 80859).
１．３．５．投与
投与は、試験施設で用いている通常の方法に従って、ラット用金属製胃ゾンデを取り付けたポリプロピレン製ディスポーザブル注射筒（テルモ株式会社製）を用いて強制的に経口投与した。投与操作時には、投与検体を転倒混和により撹拌しながら注射筒に必要量を吸引した。
自発性走運動終了後３０分以内に（午前１０時から）、投与日に最も近い測定日の体重値より投与液量を５ｍＬ／ｋｇで算出し、１日１回、５週間投与した。
1.3.5. Administration The administration was forcibly administered orally using a polypropylene disposable syringe (manufactured by Terumo Corporation) equipped with a metal gastric tube for rats in accordance with the usual method used in the test facility. At the time of the administration operation, the required amount was aspirated into the syringe while stirring the administration sample by inversion mixing.
Within 30 minutes after the end of the spontaneous running exercise (from 10:00 am), the administered liquid amount was calculated at 5 mL / kg from the weight value on the measurement day closest to the administration day, and administered once a day for 5 weeks.
１．３．６．群構成 1.3.6. Group composition
１．４．試験方法
１．４．１．一般状態
一般状態及び死亡の有無を１日１回暗期（投与日については投与前）に観察した。
1.4. Test method 1.4.1. General condition The general condition and the presence or absence of death were observed once a day in the dark period (on the administration day, before administration).
１．４．２．体重測定
１週間に１回投与前及び剖検日に測定した。
1.4.2. Body Weight Measurements were taken once a week before dosing and on the day of necropsy.
１．４．３．摂餌量の測定
１週間に１回投与前に測定した。
1.4.3. Measurement of food consumption Measured once a week before administration.
１．４．４．剖検
投与してから３５日目に４％ペントバルビタールナトリウム麻酔下で翼付静注針を用いて腹部大動脈から採血を行った。そのまま麻酔下で骨格筋（腓腹筋、ヒラメ筋、前頸骨筋、長趾伸筋、足底屈筋）を摘出した。そして、動物をペントバルビタールナトリウムの過剰投与により安楽死させた後に、脂肪（副精巣周囲脂肪及び皮下脂肪）及び心臓、肝臓、副腎、脳、を摘出した。また、副腎、脂肪及び筋肉は重量を測定した。
採取した血液は遠心機を用いて遠心分離［設定温度：４℃、３０００ｒｐｍ（２１５０×ｇ）、１５分間］した。得られた血清は、委託者送付用にチューブに分取し、超低温フリーザーに凍結保管した。
筋肉は左右別々に重量を測定し、右の筋肉は液体窒素で冷やしたイソペンタンを用いて凍結保存（−８０℃）した。摘出した右の筋肉以外の臓器（左の筋肉も含む）は液体窒素を介して瞬間凍結させてから凍結保存（−８０℃）した。
1.4.4. Necropsy On day 35 after administration, blood was collected from the abdominal aorta using a winged intravenous needle under 4% pentobarbital sodium anesthesia. Under anesthesia, skeletal muscles (gastrocnemius muscle, soleus muscle, anterior tibialis muscle, extensor digitorum longus, plantar flexor muscle) were removed as they were. After the animals were euthanized by pentobarbital sodium overdose, the fat (peri-testicular fat and subcutaneous fat) and the heart, liver, adrenal gland, and brain were removed. The adrenal gland, fat and muscle were weighed.
The collected blood was centrifuged using a centrifuge [set temperature: 4 ° C., 3000 rpm (2150 × g), 15 minutes]. The obtained serum was separated into tubes for sending to a contractor, and stored frozen in an ultra-low temperature freezer.
The muscles were weighed separately on the left and right, and the right muscle was frozen (-80 ° C) using isopentane cooled with liquid nitrogen. The removed organs other than the right muscle (including the left muscle) were flash-frozen via liquid nitrogen and then cryopreserved (−80 ° C.).
２．結果
重量測定を行った腓腹筋、ヒラメ筋、前頸骨筋、長趾伸筋（長指屈筋）及び足底屈筋について、運動群の各筋肉量を１００％として、それに対する運動＋Ｌ群、運動＋Ｃ群及び運動＋ＬＣ群の各筋肉量の割合を求めた。尚、測定された筋肉重量（ｍｇ）はラット個体の体重（ｇ）で除し、個体間の体重差の影響を無くすようにした。
その結果、運動＋Ｌ群では、前頸骨筋、長趾伸筋及びヒラメ筋において筋肉増強効果が見られた。一方、運動＋Ｃ群では、いずれの筋肉においても筋肉増強効果は見られなかった。これらの結果に対し、運動＋ＬＣ群では、全ての筋肉において著しい筋肉増強効果が見られ、その効果は運動＋Ｌ群で得られた結果をさらに上回るものであった。
2. Results Regarding the gastrocnemius muscle, soleus muscle, anterior tibialis muscle, extensor longator longus (extensor digitorum longus), and plantar flexor muscles whose weights were measured, exercise + L group and exercise + C group corresponding to each muscle mass of the exercise group as 100% And the percentage of each muscle mass in the exercise + LC group. In addition, the measured muscle weight (mg) was divided by the weight (g) of a rat individual so as to eliminate the influence of the weight difference between individuals.
As a result, in the exercise + L group, a muscle enhancing effect was observed in the anterior tibial muscle, the extensor digitorum longus, and the soleus muscle. On the other hand, in the exercise + C group, no muscle enhancing effect was observed in any muscle. In contrast, in the exercise + LC group, a remarkable muscle-building effect was observed in all muscles, and the effect was even higher than the result obtained in the exercise + L group.
実施例２．乳酸及びカフェインの用量及び配合割合検討
（１）用量設定試験１
［被験動物］
５週齢のＳｌｃ：ＳＤラット（ＳＰＦ）を使用した。
［被験試料］
下記の試料を、水を用いて調製した（Ａ群は水のみ）。尚、表中の「Ｌ：Ｃ」は乳酸とカフェインとの比を示している（以下に記載のＬ：Ｃも同様である）。
Embodiment 2. FIG. Investigation of dose and combination ratio of lactic acid and caffeine (1) Dose setting test 1
[Test animal]
Five-week old Slc: SD rats (SPF) were used.
[Test sample]
The following samples were prepared using water (Group A only water). "L: C" in the table indicates the ratio of lactic acid to caffeine (the same applies to L: C described below).
［方法］
ラットを飼料ＣＥ−２で７日間馴化させた後、ラットの体重に基づいて群分けを行った（各群：ｎ＝６）。各ラットに対して経口投与（強制経口投与：０．０１ｍＬ／ｇ／ｄａｙ）を２日間実施し、翌日剖検を行った。剖検は、麻酔下で腹腔大動脈から採血した後、下肢の筋肉を摘出して行った。対象とする筋肉は実施例１の結果に基づいてヒラメ筋とし、ヒラメ筋の重量を測定してラット体重における割合を求めた。
[Method]
After the rats were acclimated to diet CE-2 for 7 days, groups were divided based on the weight of the rats (each group: n = 6). Each rat was orally administered (gavage administration: 0.01 mL / g / day) for 2 days, and necropsy was performed the next day. Necropsy was performed by extracting blood from the abdominal aorta under anesthesia and then removing muscles of the lower limbs. The target muscle was the soleus muscle based on the results of Example 1, and the weight of the soleus muscle was measured to determine the ratio to the rat body weight.
［結果］
図６に示されるように、Ｂ群において筋肉量増加（筋肉増強）の傾向が確認された。ま
た、Ｂ２群においてもＡ群（コントロール）よりも筋肉量が増加していた。
以上の結果より、乳酸Ｎａ及びカフェインは、乳酸Ｎａ：３５．１４ｍｇ／ｍｌ以上、カフェイン：１．１５２ｍｇ／ｍｌ以上の濃度において筋肉を増強することが示唆された。
[result]
As shown in FIG. 6, a tendency of an increase in muscle mass (muscle enhancement) was confirmed in group B. Also, the muscle mass was increased in the B2 group as well as in the A group (control).
The above results suggest that Na lactate and caffeine enhance muscle at concentrations of Na lactate: 35.14 mg / ml or more and caffeine: 1.152 mg / ml or more.
（２）用量設定試験２
下記の被験試料を使用した以外は全て上記用量設定試験１と同一の内容で、用量設定試験２を実施した。
［被験試料］
下記の試料を、水を用いて調製した（Ａ群は水のみ）。
(2) Dose setting test 2
The dose setting test 2 was performed in the same manner as the dose setting test 1 except that the following test samples were used.
[Test sample]
The following samples were prepared using water (Group A only water).
［結果］
図７に示されるように、Ｇ群及びＧ２群のいずれにおいてもＡ群（コントロール）より筋肉量が増加していた。以上の結果より、乳酸Ｎａ：３５．１４ｍｇ／ｍｌ以上の濃度において筋肉を増強することが示唆された。
[result]
As shown in FIG. 7, the muscle mass was increased in both the G group and the G2 group as compared with the A group (control). From the above results, it was suggested that muscle was enhanced at a concentration of Na lactate: 35.14 mg / ml or more.
（３）配合割合検討１
［被験動物］
５週齢のＳｌｃ：ＳＤラット（ＳＰＦ）を使用した。
［被験試料］
下記の試料を、水を用いて調製した（Ａ群は水のみ）。
(3) Examination of mixing ratio 1
[Test animal]
Five-week old Slc: SD rats (SPF) were used.
[Test sample]
The following samples were prepared using water (Group A only water).
［方法］
ラットを飼料ＣＥ−２で７日間馴化させた後、ラットの体重に基づいて群分けを行った（各群：ｎ＝６）。各ラットに対して経口投与（強制経口投与：０．０１ｍＬ／ｇ／ｄａｙ）を２日間実施し、翌日剖検を行った。剖検は、麻酔下で腹腔大動脈から採血した後、下肢の筋肉を摘出して行った。対象とする筋肉は実施例１の結果に基づいてヒラメ筋とし
、ヒラメ筋の重量を測定してラット体重における割合を求めた。
[Method]
After the rats were acclimated to diet CE-2 for 7 days, groups were divided based on the weight of the rats (each group: n = 6). Each rat was orally administered (gavage administration: 0.01 mL / g / day) for 2 days, and necropsy was performed the next day. Necropsy was performed by extracting blood from the abdominal aorta under anesthesia and then removing muscles of the lower limbs. The target muscle was the soleus muscle based on the results of Example 1, and the weight of the soleus muscle was measured to determine the ratio to the rat body weight.
［結果］
図８に示されるように、Ｂ群、Ｅ２群及びＦ２群において有意な筋肉量の増加（筋肉増強）が確認された。Ｂ２群においても、Ａ群（コントロール）より筋肉量が増加していた。以上の結果より、乳酸Ｎａ：３５．１４ｍｇ／ｍｌ以上の投与は筋肉を増強させ、その効果はカフェイン量を増加させることで高められることが示唆された。
[result]
As shown in FIG. 8, a significant increase in muscle mass (muscle enhancement) was confirmed in the groups B, E2, and F2. Also in group B2, the muscle mass was higher than in group A (control). The above results suggest that administration of Na lactate: 35.14 mg / ml or more strengthens muscles, and that the effect is enhanced by increasing the amount of caffeine.
（４）配合割合検討２
下記の被験試料を使用した以外は全て上記配合割合検討１と同一の内容で、配合割合検討２を実施した。
［被験試料］
下記の試料を、水を用いて調製した（Ａ群は水のみ）。
(4) Mixing ratio study 2
Except that the following test samples were used, the mixing ratio study 2 was carried out in the same manner as in the above mixture ratio study 1.
[Test sample]
The following samples were prepared using water (Group A only water).
［結果］
図９に示されるように、Ｂ群において有意な筋肉量の増加（筋肉増強）が確認された。また、Ｃ群及びＤ群においてもＡ群（コントロール）より筋肉量が増加していた。
[result]
As shown in FIG. 9, a significant increase in muscle mass (muscle enhancement) was confirmed in group B. Also, the muscle mass was increased in the group C and the group D as compared with the group A (control).
実施例３．廃用性筋萎縮に対する乳酸及びカフェインの有用性検討
ギブス固定による筋肉量減少からの回復について乳酸及びカフェインが有効であるかどうかを調べるため、以下の試験を実施した。
Embodiment 3 FIG. Examination of the usefulness of lactic acid and caffeine for disuse muscular atrophy In order to investigate whether lactic acid and caffeine are effective in recovering from muscle loss caused by casting, the following test was conducted.
［被験動物］
１０週齢のＳＤラットを使用した（ｎ＝６）。
［被験試料］
下記の試料を、水を用いて調製した（コントロール群は水のみ）。
[Test animal]
Ten-week-old SD rats were used (n = 6).
[Test sample]
The following samples were prepared using water (the control group was water only).
［方法］
ラットの左足をギブスで固定し、１０日後にギブスを解除した。１１日目〜１７日目の７日間ラットに対して経口投与（強制経口投与：０．０１ｍＬ／ｇ／ｄａｙ）を実施し、翌日（１８日目）に剖検（筋肉及び血液の採取）を行った。採取した筋肉は、重量測定後
イソペンタンを用いて凍結し、血液は血清にして凍結保管した。
採取した筋肉の重量を測定し、非固定筋（右足の筋肉）重量に対する固定筋（左足の筋肉）重量の割合を求めた。また、対象とする筋肉は、腓腹筋、ヒラメ筋、足底筋、長指伸筋及び前頚骨筋とした。
[Method]
The left foot of the rat was fixed with a cast, and the cast was released 10 days later. Rats were orally administered (gavage administration: 0.01 mL / g / day) for 7 days from day 11 to day 17 and necropsy (collection of muscle and blood) was performed on the following day (day 18). Was. The collected muscle was frozen using isopentane after the weight measurement, and blood was stored as frozen serum.
The weight of the collected muscle was measured, and the ratio of the weight of the fixed muscle (the muscle of the left foot) to the weight of the non-fixed muscle (the muscle of the right foot) was determined. The target muscles were gastrocnemius, soleus, plantar, extensor digitorum, and tibialis anterior.
［結果］
図１０に示されるように、いずれの筋肉においても、回復した筋肉の割合（固定／非固定）が乳酸及びカフェインの投与により増加した。この結果より、乳酸及びカフェインの投与は、筋肉の回復（特に、萎縮した筋肉の回復）を促進する作用があることが示唆された。
[result]
As shown in FIG. 10, the ratio of the recovered muscle (fixed / non-fixed) was increased by administration of lactic acid and caffeine in all muscles. These results suggested that administration of lactic acid and caffeine had an effect of promoting muscle recovery (particularly, recovery of atrophied muscle).
処方例：
実施例１〜３の結果に基づいて、以下の処方例を提示する。
Prescription example:
The following formulation examples are presented based on the results of Examples 1 to 3.
処方例１
表７に示した組成で飲料を製造した。
Formulation Example 1
A beverage was manufactured with the composition shown in Table 7.
処方例２
表８に示した組成で飲料を製造した。
Formulation Example 2
A beverage was manufactured with the composition shown in Table 8.
処方例３
表９に示した組成で飲料を製造した。
Formulation Example 3
A beverage was manufactured with the composition shown in Table 9.
処方例４
表１０に示した組成で飲料を製造した。
Formulation Example 4
A beverage was manufactured with the composition shown in Table 10.
処方例５
表１１に示した組成で飲料を製造した。
Formulation Example 5
A beverage was manufactured with the composition shown in Table 11.
処方例６
表１２に示した組成でハードカプセルを製造した。
Formulation Example 6
Hard capsules were manufactured with the compositions shown in Table 12.
処方例７
表１３に示した組成でハードカプセルを製造した。
Formulation Example 7
Hard capsules were manufactured with the compositions shown in Table 13.
処方例８
表１４に示した組成でハードカプセルを製造した。
Formulation Example 8
Hard capsules were manufactured with the compositions shown in Table 14.
処方例９
表１５に示した組成で飲料を製造した。
Formulation Example 9
A beverage was manufactured with the composition shown in Table 15.
処方例１０
表１６に示した組成で飲料を製造した。
Formulation Example 10
A beverage was manufactured with the composition shown in Table 16.
処方例１１
表１７に示した組成で錠剤（タブレット）を製造した。
Tablets (tablets) were produced with the compositions shown in Table 17.
本発明の剤及び組成物は、筋肉増強作用を有する上で医薬分野において有用であり、またその極めて高い安全性の観点から、医薬分野のみならず食品分野においても有用である。 The agent and the composition of the present invention are useful in the pharmaceutical field because they have a muscle-building action, and from the viewpoint of extremely high safety, are useful not only in the pharmaceutical field but also in the food field.
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| JP2013047192A (en) * | 2011-08-29 | 2013-03-07 | Meiji Co Ltd | Lactobacillus promoting physical activity |
| JP6453534B2 (en) * | 2012-09-28 | 2019-01-16 | 小林製薬株式会社 | Lipid metabolism promoter |
| JP6429478B2 (en) * | 2013-03-28 | 2018-11-28 | 小林製薬株式会社 | Muscle enhancer |
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| JP6429478B2 (en) | 2018-11-28 |
| JP2014208638A (en) | 2014-11-06 |
| JP2014208637A (en) | 2014-11-06 |
| JP6345960B2 (en) | 2018-06-20 |
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