JP6710733B2 - Lipid metabolism promoter - Google Patents
Lipid metabolism promoter Download PDFInfo
- Publication number
- JP6710733B2 JP6710733B2 JP2018179409A JP2018179409A JP6710733B2 JP 6710733 B2 JP6710733 B2 JP 6710733B2 JP 2018179409 A JP2018179409 A JP 2018179409A JP 2018179409 A JP2018179409 A JP 2018179409A JP 6710733 B2 JP6710733 B2 JP 6710733B2
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- Prior art keywords
- lactic acid
- present
- weight
- caffeine
- composition
- 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、脂質代謝促進剤に関し、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脂質代謝促進剤に関する。 The present invention relates to a lipid metabolism promoter, and more particularly to a lipid metabolism promoter containing lactic acid and/or a salt thereof as an active ingredient.
肥満は現代社会における最も重大な疾患の一つであるが、その主たる要因は脂肪の過剰摂取である。脂肪の過剰摂取は、肥満のみならず、肥満に起因してメタボリックシンドローム、糖尿病、高脂血症、高血圧、動脈硬化などの生活習慣病を発症させることが知られている。 Obesity is one of the most serious diseases in modern society, but the main factor is overdose of fat. It is known that excessive intake of fat causes not only obesity but also lifestyle-related diseases such as metabolic syndrome, diabetes, hyperlipidemia, hypertension, and arteriosclerosis due to obesity.
肥満に対する治療薬としては、食欲抑制剤であるマジンドールや、リパーゼ阻害剤であるオルリスタットなどが使用されている。しかしながら、これらの医薬では、口渇、便秘、吐き気、不眠、頭痛及び動悸など、並びにオイルスポット、鼓腸、急な便意、排便の増加、便失禁、直腸からの漏れ、上部呼吸器感染及び脂肪便などの副作用がそれぞれ報告されており、必ずしも安全性は十分であるとは言えない。 As a therapeutic drug for obesity, mazindol, which is an appetite suppressant, orlistat, which is a lipase inhibitor, and the like are used. However, with these medicines, thirst, constipation, nausea, insomnia, headache and palpitation, etc., as well as oil spots, flatulence, sudden bowel movements, increased bowel movements, incontinence, rectal leakage, upper respiratory infection and steatorrhea. The side effects such as are reported respectively, and it cannot be said that the safety is necessarily sufficient.
肥満を予防するためには、食事制限により摂取カロリーを減らすことが有効な手段である。しかしながら、そのためには十分な栄養指導を受けなければならず、実質的に日常生活での実施は困難である場合が多い。そのため、十分な安全性を有し、且つ効率的に肥満を解消することのできる物質が強く求められている。 In order to prevent obesity, reducing calorie intake by dietary restriction is an effective means. However, in order to do so, it is necessary to receive sufficient nutritional guidance, and it is often difficult in practice to practice it in daily life. Therefore, there is a strong demand for a substance that has sufficient safety and can effectively eliminate obesity.
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 the body to transiently obtain ATP from glucose when performing rapid exercise (anoxic exercise). The blood concentration of lactic acid at rest is about 0.5 to 2.0 mM, but the blood concentration of lactic acid produced as a result of exercise is about 4 to 5 mM. It is also known that the blood concentration of lactic acid rises to about 20 mM when exercise is carried out extremely intensely 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。 Lactate synthesized in the body is transported to the liver by the blood circulation, converted to pyruvate by lactate dehydrogenase, and then glucose is regenerated by gluconeogenesis. This series of circuits is called a lactate circuit or a coli circuit. There is a limit point where lactic acid accumulation exceeds the metabolic elimination of lactic acid during exercise accompanied by insufficient oxygen supply, and the point when the blood lactate concentration starts to increase rapidly is called the lactate accumulation threshold. In aerobic exercise training, this lactate accumulation threshold value may be used as an index of oxygen supply and may be used to set exercise intensity.
このように体内で合成され、代謝される乳酸であるが、食品中にも含まれており、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。かかる発酵食品としては、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１〜３）。しかしながら、このような乳酸を肥満の解消のために使用することは知られておらず、また脂質代謝促進剤として利用することはこれまでに報告されていない。 It is known that lactic acid, which is synthesized and metabolized in the body as described above, is also contained in foods, especially in fermented foods. Examples of such fermented foods include yogurt and pickles. In addition, it may be contained in a beverage and is disclosed to be used as a sourness imparting substance for a beverage (Patent Documents 1 to 3). However, the use of such lactic acid for obesity relief has not been known, and its use as a lipid metabolism promoter has not been reported so far.
本発明の目的は、肥満の解消に有用な物質として、安全で、且つ効率的に脂質代謝を促進することのできる剤及び組成物を提供することにある。 An object of the present invention is to provide an agent and a composition that are capable of promoting lipid metabolism safely and efficiently as a substance useful for eliminating obesity.
本発明者らは、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／又はその塩に脂質代謝を促進する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 has an action of promoting lipid metabolism. Based on such findings, the present inventors have completed the present invention through further research.
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、脂質代謝促進剤。
〔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〕脂質代謝促進が体脂肪減少である、〔１〕〜〔３〕のいずれかに記載の剤。
〔５〕乳酸及び／又はその塩を有効成分として含有してなる、脂質代謝促進作用を有する組成物。
〔６〕カフェインをさらに含有する、〔５〕に記載の組成物。
〔７〕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、〔６〕に記載の組成物。
〔８〕脂質代謝促進作用が体脂肪減少作用である、〔５〕〜〔７〕のいずれかに記載の組成物。
〔９〕医薬である、〔５〕〜〔８〕のいずれかに記載の組成物。
〔１０〕飲食品である、〔５〕〜〔８〕のいずれかに記載の組成物。
That is, the present invention relates to the following.
[1] A lipid metabolism promoter containing lactic acid and/or a salt thereof as an active ingredient.
[2] The agent according to [1], further containing caffeine.
[3] The content ratio of lactic acid and/or its salt and caffeine is 0.9:1 as a weight ratio (however, in the weight of lactate, a value converted into the weight as lactic acid is used). The agent according to [2], which is about 1000:1.
[4] The agent according to any one of [1] to [3], wherein promotion of lipid metabolism is reduction of body fat.
[5] A composition having a lipid metabolism promoting action, which comprises lactic acid and/or a salt thereof as an active ingredient.
[6] The composition according to [5], further containing caffeine.
[7] The content ratio of lactic acid and/or its salt and caffeine is 0.9:1 as a weight ratio (however, in the weight of lactate, a value converted to the weight as lactic acid is used). The composition according to [6], which is about 1000:1.
[8] The composition according to any one of [5] to [7], wherein the lipid metabolism promoting action is a body fat reducing action.
[9] The composition according to any one of [5] to [8], which is a medicine.
[10] The composition according to any one of [5] to [8], which is a food or drink.
本発明によれば、効率的に脂質代謝を促進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 promote lipid metabolism efficiently can be provided. The lactic acid and/or its salt used in the present invention is not only a substance synthesized in the body but also designated as a food additive in Japan, and is also used as a sour agent for foods and drinks and a pH adjuster. Since it is possible, it can be said that the agent and composition of the present invention have sufficient safety for animals such as humans.
本願発明者は、乳酸の生理機能を研究する過程において、乳酸を添加した条件下で細胞を培養した場合に、驚くべきことに、乳酸が脂質代謝を促進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、乳酸及び／又はその塩を有効成分として含有してなる脂質代謝促進剤を提供する（以下、「本発明の剤」と称する）。 In the process of studying the physiological function of lactic acid, the present inventor has surprisingly found that lactic acid has an action of promoting lipid metabolism when cells are cultured under conditions in which lactic acid is added. That is, based on this finding, the present invention provides a lipid metabolism promoter comprising 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。 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 preferred, and more preferred L body is used. The CAS registration number of the D body is 79-33-4, the CAS registration number of the L body is 10326-41-7, and the CAS registration number of the DL body is 598-82-3 or 50-21-5. 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 lactic acid salt is not particularly limited, but examples thereof include alkali metal salts such as sodium and potassium (specifically, sodium lactate and potassium lactate), alkaline earth metal salts such as calcium and magnesium (specifically, Can include calcium lactate, magnesium lactate, etc.), aluminum lactate, zinc lactate, manganese lactate, iron lactate, and the like. The salt of lactic acid in the present invention is preferably sodium lactate or calcium lactate. In the present invention, the lactic acid salt 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。 The lactic acid and its salt used in the present invention are not particularly limited as to how to obtain them, and may be natural ones derived from animals or plants, or those obtained by a chemical synthesis method or a fermentation method. .. 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 its salt 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. Further, in the present invention, lactic acid or a composition containing lactic acid (food and drink, etc.) obtained by culturing bacteria (lactic acid bacteria, etc.) using a fermentation method can be used as it is or after being processed.
生体内において、たとえば運動などによる生理的な現象として筋肉細胞などの細胞内カルシウム濃度が上昇することが知られている。生体内において、運動によらずに筋肉細胞などの細胞内カルシウム濃度を上昇させることを目的として、食品中にて一般的に使用されておりかつ細胞内カルシウム濃度の上昇をもたらすことができる物質として、カフェインを追加的に使用することができる。すなわち、本発明の剤は、カフェインをさらに含有することができる。 It is known that intracellular calcium concentration in muscle cells and the like increases in a living body as a physiological phenomenon due to, for example, exercise. As a substance that is commonly used in foods and that can increase the intracellular calcium concentration in the living body for the purpose of increasing the intracellular calcium concentration of muscle cells and the like without depending on exercise , Caffeine can be used additionally. That is, the agent of the present invention can further contain caffeine.
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 type 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 of caffeine is 1,3,7-trimethylxanthine and its CAS registration 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 includes both anhydrous (also referred to as “anhydrous caffeine”) and hydrate (eg, monohydrate) embodiments. Either aspect can be used in the present invention, but preferably an anhydride is 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。
Caffeine used in the present invention is not particularly limited, for example, it may be a crystalline substance obtained by chemical synthesis or the like, or a plant extract containing caffeine as it is, or concentrated or purified (ie , A plant extract containing caffeine to selectively remove components other than caffeine to increase the caffeine content). A suitable caffeine production method can be appropriately selected based on the purity and production cost of the obtained caffeine. Caffeine-containing plant extract is not particularly limited, for example, coffee beans, cola fruits, tea leaves, cacao and the like, water (or hot water), methanol, ethanol, isopropanol, ethyl acetate and the like known per se. It is produced by extraction using the 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 Shirotori 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０．９：１〜５００：１であり、より好ましくは０．９２８：１〜１００：１であり、さらに好ましくは０．９２８：１〜２２．３２：１である。両者の比が上記範囲内であることにより、効率的に脂質代謝を促進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 its salt and caffeine (lactic acid and/or its salt: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 0.9:1 to 500:1, more preferably 0.928:1 to 100:1, and further preferably 0.928:1 to 22.32:1. Is. When the ratio of the both is within the above range, lipid metabolism can be efficiently promoted. When a salt of lactic acid is used, the weight ratio is calculated after converting it into the free form of lactic acid. In the present invention, the weight thus converted is treated as a “value converted into the weight of lactic acid”. When each active ingredient forms a hydrate, the above weight ratio is calculated after converting to the free form (anhydrate) excluding water molecules.
本発明において、「脂質代謝促進剤」という場合、本発明の剤が「脂質代謝促進」の作用を有しており、ここで「脂質代謝促進」とは、生体内の脂質の代謝を促進する作用を有することを意味する。ここで、本明細書において「脂質」とは、生体内に存在する水不溶性の物質の総称である。本発明において、脂質は、常温で固体であってもよく、或いは液体であってもよいが、固体であることが好ましい。尚、常温とは、第十六改正日本薬局方の通則に従い、通常１５〜２５℃であることを示す。脂質には、例えば、単純脂質（中性脂肪、蝋など）、複合脂質（リン脂質、糖脂質など）、誘導脂質などが含まれる。これらのうち本発明で対象とされる脂質は、単純脂質が好ましく、その中でも中性脂肪がより好ましく、最も好ましくはトリアシルグリセロール（トリグリセリド）である。また、本明細書において脂質の「代謝」とは、主に脂質を分解することを示すが、脂質の量を減少することができる限り、特にこれに限定されるわけではない。 In the present invention, when the term “lipid metabolism promoter” is used, the agent of the present invention has a “lipid metabolism promoting” action, and the term “lipid metabolism promoting” as used herein refers to promoting lipid metabolism in a living body. It means having an action. As used herein, the term "lipid" is a general term for water-insoluble substances existing in the living body. In the present invention, the lipid may be solid at room temperature or liquid, but is preferably solid. In addition, the normal temperature means that the temperature is usually 15 to 25° C. according to the general rule of the 16th revised Japanese Pharmacopoeia. Lipids include, for example, simple lipids (neutral fats, waxes, etc.), complex lipids (phospholipids, glycolipids, etc.), derived lipids, and the like. Of these, the lipids targeted by the present invention are preferably simple lipids, more preferably neutral fats, and most preferably triacylglycerols (triglycerides). Further, in the present specification, “metabolism” of a lipid refers to mainly degrading a lipid, but is not particularly limited as long as the amount of the lipid can be reduced.
本発明において、「脂質代謝促進」には、生体内の脂質を減少する（「脂質の燃焼」と称する場合もある）概念と、体外より摂取される脂質を低減するなどして生体内への脂質の蓄積を抑制する概念とが包含される。本発明では、特に限定されないが、脂質代謝促進は、好ましくは生体内の脂質を減少することを意味する。本発明における脂質としては、体脂肪（皮下脂肪、内臓脂肪など）及び血中脂質などが例示されるが、好ましくは体脂肪である。 In the present invention, “facilitation of lipid metabolism” includes the concept of reducing lipids in the body (sometimes referred to as “lipid burning”), and reducing lipids ingested from outside the body. The concept of suppressing lipid accumulation is included. In the present invention, although not particularly limited, promotion of lipid metabolism preferably means reduction of lipid in vivo. Examples of the lipid in the present invention include body fat (subcutaneous fat, visceral fat, etc.), blood lipid, and the like, but body fat is preferable.
本発明の剤は、脂質代謝促進作用を通じて、肥満（「肥満症」とも称する）の予防及び治療を行うことができる。さらに、本発明の剤は、肥満に起因して発症する疾患の予防及び治療も行うことができる。そのような疾患としては、特に限定されないが、例えば、メタボリックシンドローム、糖尿病（２型糖尿病を含む）、高脂血症、高血圧症、動脈硬化症などが挙げられる。これにより、本発明はまた、上記疾患の予防及び治療剤を提供することもできる。 The agent of the present invention can prevent and treat obesity (also referred to as "obesity") through its lipid metabolism promoting action. Furthermore, the agent of the present invention can also prevent and treat diseases caused by obesity. Examples of such diseases include, but are not limited to, metabolic syndrome, diabetes (including type 2 diabetes), hyperlipidemia, hypertension, arteriosclerosis, and the like. Thereby, the present invention can also provide a preventive and therapeutic agent for the above-mentioned diseases.
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 medicine, food, etc., and its application target may be a mammal. Examples of such mammals include primates (eg, humans, monkeys, chimpanzees), rodents (eg, mice, rats, guinea pigs), pets (eg, dogs, cats, rabbits), working animals or livestock. (For example, cow, horse, pig, sheep, goat) can be mentioned, but human is preferable in the present invention. When applied to mammals other than humans, the dose (intake) of the agent of the present invention may be adjusted appropriately according to the body weight or size of the animal.
本発明の剤は、製剤上の必要に応じて、薬学的に許容される担体を適宜用いて常法により製剤化し、組成物とすることができる（以下、「本発明の組成物」と称する）。これにより、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ができる。本発明の組成物は、本発明の剤を含むことから、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、脂質代謝促進作用を有することを特徴とし、ここで「脂質代謝促進」とは、生体内の脂質の代謝を促進する作用を有することを意味し、本発明では、特に限定されないが、脂質代謝促進は、好ましくは生体内の脂質を減少することを意味する。本発明における脂質としては、体脂肪（皮下脂肪、内臓脂肪など）及び血中脂質などが例示されるが、好ましくは体脂肪である。 The agent of the present invention can be formulated into a composition by a conventional method using a pharmaceutically acceptable carrier as needed according to the need of the formulation (hereinafter, referred to as “composition of the present invention”). ). From this, it can be said that the composition of the present invention contains the agent of the present invention. Since the composition of the present invention contains the agent of the present invention, it can have all the effects exhibited by the agent of the present invention. That is, the composition of the present invention is characterized by having an action of promoting lipid metabolism, where "promoting lipid metabolism" means having an action of promoting the metabolism of lipids in a living body. Although not particularly limited, promotion of lipid metabolism preferably means reduction of lipids in the body. Examples of the lipid in the present invention include body fat (subcutaneous fat, visceral fat, etc.), blood lipid, and the like, but body fat is preferable.
上記担体は、製剤（組成物）の剤形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 above-mentioned carrier can be appropriately selected depending on the dosage form of the preparation (composition) and is not particularly limited, and examples thereof include excipients, binders, lubricants, disintegrants, solvents, stabilizers, solubilizing agents. , Antioxidants, coloring agents, flavoring agents, sweeteners and other additives.
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。 Excipients include sugars (sucrose, lactose, glucose, mannitol, etc.), starch (corn starch, etc.), crystalline cellulose, calcium phosphate, calcium sulfate, magnesium sulfate, etc., and binders include pregelatinized starch, gelatin, tragacanth gum, Gum arabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc., lubricants include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oils. As disintegrants, starch, crystalline cellulose, carboxymethyl cellulose, agar, calcium citrate, calcium carbonate, sodium bicarbonate, dextrin, etc., and as solvents, water, ethanol, glycerol, physiological saline, soybean oil, etc. However, as the stabilizer, benzoic acid, sodium benzoate, ethyl paraoxybenzoate, propylene glycol, etc., as the solubilizer, fumaric acid, succinic acid, malic acid, etc., as the antioxidant, ascorbine Acids, tocopherols, sodium bisulfite, sodium thiosulfate, sodium pyrosulfite, citric acid and the like, as coloring agents, flavoring agents, sweeteners, those which are generally allowed to be added in the pharmaceutical and food fields, respectively. Can be mentioned.
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０．９：１〜５００：１であり、より好ましくは０．９２８：１〜１００：１であり、さらに好ましくは０．９２８：１〜２２．３２：１である。両者の比が上記範囲内であることにより、効率的に脂質代謝を促進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 its salt to caffeine in the composition of the present invention (lactic acid and / Or its salt: caffeine) is also usually 0.9:1 to 1000:1, preferably 0.9:1 to 500:1 as a weight ratio, as in the case of the agent of the present invention, It is more preferably 0.928:1 to 100:1, and even more preferably 0.928:1 to 22.32:1. When the ratio of the both is within the above range, lipid metabolism can be efficiently promoted. When a salt of lactic acid is used, the weight ratio is calculated after converting it into the free form of lactic acid. In the present invention, the weight thus converted is treated as a “value converted into the weight of lactic acid”. When each active ingredient forms a hydrate, the above weight ratio is calculated after converting to the free form (anhydrate) excluding water molecules.
上述した乳酸、乳酸の塩及びカフェインは、単一の製剤に同時に製剤化されていてもよく、或いはそれぞれ別個の製剤に製剤化されていてもよい。別個の製剤とする場合には、各製剤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製剤に製剤化して使用することが好ましい。 The above-mentioned lactic acid, lactic acid salt and caffeine may be simultaneously formulated into a single preparation, or may be separately formulated into separate preparations. In the case of separate preparations, the preparations are used in combination. In the present invention, lactic acid and/or a salt thereof and caffeine are preferably formulated into a single preparation for use because of the ease of 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製剤に製剤化した場合も採用されることができる。
The content of lactic acid and/or its salt 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. Similar to the above weight ratio, when using a salt of lactic acid, the above content is calculated after converting to the free form of lactic acid, and when each active ingredient forms a hydrate, The above content should be calculated after converting to the free form (anhydrate) excluding water molecules. The above content range can also be adopted when lactic acid and/or its salt and caffeine are formulated into separate formulations.
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、脂質代謝異常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 treated as a prophylactic or therapeutic drug for diseases associated with abnormal lipid metabolism, and such diseases 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 method of administration of the pharmaceutical composition of the present invention is not particularly limited, and generally includes an administration method by oral administration. However, parenteral administration (intravascular (intravascular ( (Intravenous, intraarterial) administration, subcutaneous administration, transdermal administration, intrarectal administration, etc.) may be appropriately selected. Since lactic acid and/or its salt and caffeine which are active ingredients can all be eaten and drinked, it is preferable to adopt oral administration in the present invention.
本発明の医薬組成物の剤形は、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 dosage form of the pharmaceutical composition of the present invention is not particularly limited, and may be in a form suitable for the administration method. Suitable forms for oral administration include, for example, tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs and the like. Suitable forms for parenteral administration include, for example, sterilized solutions, suspensions, emulsions for intravenous, subcutaneous, intramuscular, intravascular or infusion administration, as transdermal forms. 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、上述した薬学的に許容される担体に加えて、飲食品の分野において通常使用される担体を用いて常法により製剤化することができる。 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 or drink composition of the present invention can be formulated by a conventional method using, in addition to the above-mentioned pharmaceutically acceptable carrier, a carrier usually used in the field of food and drink.
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 all foods and drinks, but in addition to general foods including so-called health foods, special-purpose foods specified by the Consumer Affairs Agency (foods for specified health use, foods for patients, difficult to swallow) Foods for persons) and foods with nutritional function, and supplements, feeds, etc. are also included in the food and drink of the present invention.
本発明の飲食品組成物は、その剤形は特に限定されず、細粒剤、顆粒剤、丸剤、錠剤（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、飴等の剤形とすることができる。 The dosage form of the food and drink composition of the present invention is not particularly limited, and it includes fine granules, granules, pills, tablets (including coated tablets and sugar-coated tablets), capsules (including hard capsules, soft capsules, and microcapsules). , Beverages, drinks, liquids (including syrups, emulsions and suspensions), powdered foods, jellies, candy 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、体内において脂質代謝促進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。また、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。 Dosage (intake) of the agent and composition of the present invention is not particularly limited, as long as it is within the range of an effective amount capable of expressing lipid metabolism promoting action in the body, individual differences of the subject, symptoms, It can be appropriately set according to the administration method and the like. Further, the daily dose (intake) can be administered (ingested) at once or divided into several times (for example, two or three times). Administration (ingestion) of the agent and composition of the present invention may be performed before, after, or between meals, and the period thereof is not particularly limited as long as the effects of the present invention are exhibited. Hereinafter, when the term "administration" is used in the present specification, the term is meant to include 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製剤に製剤化することができ、その場合、本発明において両製剤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 formulated in separate formulations, in which case both formulations can be used in combination in the present invention. Lactic acid and/or its salts and caffeine may be administered simultaneously, or may be administered sequentially in either order.
本発明の剤及び組成物を使用する場合はまた、脂質代謝促進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 components having a lipid metabolism promoting action. In such cases, the order of administering the agents and compositions of the present invention and the existing ingredients described above may be simultaneous or separate. In separate cases, administration of the agents and compositions of the present invention may be either before or after the above existing ingredients.
上記既存の成分としては、例えば、茶抽出物、カカオ抽出物、コーヒー豆マンノオリゴ糖、りんご由来プロシアニジン、糖転移ヘスペリジン、レスベラトロール、グリーンシトラスエキス、シトラスナリジニン、グルコサミン、キノコキトサン、キトサン、ジアシルグリセロール、中鎖脂肪酸、ＥＰＡ、ＤＨＡ、大豆蛋白、植物ステロール（β−シトステロール等）、サイリウム種皮由来食物繊維、低分子化アルギン酸ナトリウム、ガラナ、ショウキョウ、ガルシニア、グロビン蛋白分解物、カルニチン、α−リポ酸、植物スタノールエステル、リン脂質結合大豆ペプチド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 tea extract, cacao extract, coffee bean manno-oligosaccharide, apple-derived procyanidin, transglycosyl hesperidin, resveratrol, green citrus extract, citrus naridinine, glucosamine, mushroom chitosan, chitosan, diacyl. Glycerol, medium chain fatty acids, EPA, DHA, soybean protein, plant sterols (β-sitosterol etc.), dietary fiber derived from psyllium seed, low molecular weight sodium alginate, guarana, ginger, garcinia, globin proteolysate, carnitine, α- Examples thereof include lipoic acid, plant stanol ester, phospholipid-bound soybean peptide, and combinations thereof, but are not particularly limited thereto.
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 in more detail with reference to Examples, but these are merely examples and do not limit the scope of the present invention in any way.
実施例Ｉ．細胞試験における乳酸及びカフェインの効果（ｉｎ ｖｉｔｒｏ）
マウス前駆脂肪細胞３Ｔ３−Ｌ１（ＡＴＣＣより購入）を１２ｗｅｌｌ−ｄｉｓｈで分化させ、その後、表１に示した濃度（単位：ｍｍｏｌ）となるよう乳酸（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）を添加した１０％血清含有ＤＭＥＭ培地（和光純薬工業株式会社製）に培地交換を行い、３７℃で１８時間静置培養を行った。
Example I. Effects of lactate and caffeine on cell tests (in vitro)
Mouse preadipocyte 3T3-L1 (purchased from ATCC) was differentiated by 12-well-dish, and then lactic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and caffeine (concentration: mmol) shown in Table 1 were prepared. The medium was exchanged for a 10% serum-containing DMEM medium (manufactured by Wako Pure Chemical Industries, Ltd.) supplemented with Wako Pure Chemical Industries, Ltd., and stationary culture was performed at 37° C. for 18 hours.
上記の通り処理した脂肪細胞をＨａｎｋ’ｓバッファーで２回洗浄し、２％ＢＳＡ（脂肪酸不含有）、２０ｍＭ ＨＥＰＥＳ、０．５ｍＭ ＩＢＭＸ、１０μＭイソプロテノールをそれぞれ含有する１ｍＬのＤＭＥＭ培地で、３７℃で６時間静置培養を行った。その後、培養上清を回収し、上清中のグリセロール及び遊離脂肪酸の量を測定した。グリセロール及び脂肪酸の量は、Ｔｒｉｇｌｙｃｅｒｉｄｅ Ｅ−ｔｅｓｔ ｋｉｔ（和光純薬工業株式会社製）及びＮＥＦＡ Ｃ−ｔｅｓｔ ｋｉｔ（和光純薬工業株式会社製）をそれぞれ用いて、吸光度法（測定波長 グリセロール：６００ｎｍ、遊離脂肪酸：５５０ｎｍ、測定機器：ｘＭａｒｋ（ＢＩＯ−ＲＡＤ社製））により測定した。その測定結果及び比較例との相対値を表２及び表３に示す。 The adipocytes treated as described above were washed twice with Hank's buffer, and then added with 1 mL of DMEM medium containing 2% BSA (without fatty acid), 20 mM HEPES, 0.5 mM IBMX, and 10 μM isoprotenol at 37° C. C., and static culture was performed for 6 hours. Then, the culture supernatant was collected, and the amounts of glycerol and free fatty acid in the supernatant were measured. The amounts of glycerol and fatty acid were measured using a Triglyceride E-test kit (manufactured by Wako Pure Chemical Industries, Ltd.) and a NEFA C-test kit (manufactured by Wako Pure Chemical Industries, Ltd.) by an absorbance method (measurement wavelength glycerol: 600 nm, Free fatty acid: 550 nm, measuring instrument: xMark (manufactured by BIO-RAD)). Table 2 and Table 3 show the measurement results and the relative values to the comparative examples.
表２及び表３に示された通り、実施例１〜７におけるグリセロール放出量及び遊離脂肪酸放出量は、比較例での量よりも多いことが明らかになった。また、乳酸とカフェインとを組み合わせた実施例５及び６では、乳酸のみ添加された実施例１〜４よりもグリセロール放出量及び遊離脂肪酸放出量は多いことが示された。さらに、グリセロール放出量の相対値と遊離脂肪酸放出量の相対値とは、いずれの実施例においても同等であった。
以上の結果より、乳酸、及び乳酸とカフェインとの組み合わせは細胞中の脂肪を分解する、即ち、体脂肪の減少作用を有することが示唆された。
As shown in Table 2 and Table 3, it was revealed that the glycerol release amount and the free fatty acid release amount in Examples 1 to 7 were higher than those in the comparative example. Further, it was shown that in Examples 5 and 6 in which lactic acid and caffeine were combined, the glycerol release amount and the free fatty acid release amount were larger than in Examples 1 to 4 in which only lactic acid was added. Furthermore, the relative value of the glycerol release amount and the relative value of the free fatty acid release amount were the same in any of the examples.
From the above results, it was suggested that lactic acid or a combination of lactic acid and caffeine decomposes intracellular fat, that is, has a body fat reducing action.
実施例ＩＩ．動物試験における乳酸及びカフェインの効果（ｉｎ ｖｉｖｏ）
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。
Example II. Effects of lactate and caffeine in animal studies (in vivo)
1. 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 of them were stored in the storage room of the test substance storage room of the test facility under the conditions of 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) was used. After the acquisition, it was stored in the test substance storage room of the test facility under the conditions of 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. Samples for administration After weighing the necessary amounts of sodium lactate and caffeine, they were mixed and dissolved using water for injection so that the final concentrations were 200 mg/mL and 7.2 mg/mL, respectively (the mixture was tested 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 Animal and Breeding Conditions For the test, a male F344 rat (SPF, Japan SLC, Inc.), which is an animal species generally used in the pharmacological and pharmacological tests and whose strain maintenance is clear, was used.
The animals were bred in an animal feeding facility set at a set temperature of 23° C. and 12 hours of light and dark (lighting: 8 am to 8 pm). The cages and feeders were changed 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 allowed to freely ingest.
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＋ＬＣ群（ｎ＝９）に分類した。
1.3.2. Grouping Five-week-old rats were allowed to freely take the high-fat diet HFD-60 for 6 weeks. At 11 weeks of age, the rats were randomly classified into an exercise group (n=9), an exercise+L group (n=9), and an 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 by using the method of filling in the tail with oil-based ink and the method of applying dye to the extremities with oil-based ink. After grouping, identification was performed by writing an animal number (last 3 digits) on the tail using an oil-based ink. Each cage was labeled with the test number, the date of acquisition, and the animal number for preliminary breeding during the preliminary breeding period, and after grouping, the test number, group name, and animal number were entered, and each group was color-coded. I attached the label.
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 Spontaneous running was performed three times a week and once every two days. A rotation exercising machine (Lafayette Instrument, model number 80859) was used for the spontaneous running motion.
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 forcedly orally using a polypropylene disposable syringe (made by Terumo Corp.) equipped with a metal stomach tube for rats according to the usual method used in the test facility. During the administration operation, the required amount was sucked into the syringe while stirring the administered sample by inversion mixing.
Within 30 minutes after the end of the spontaneous running motion (from 10:00 am), the amount of the administration liquid was calculated at 5 mL/kg from the body weight value of the measurement day closest to the administration day, and the solution was 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 during the dark period (before the administration on the administration day).
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 measurement It was measured once a week before administration and on the day of autopsy.
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 intake It was 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。その後、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、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。そして、脂肪の重量を測定した。
1.4.4. Necropsy On day 35 after administration, blood was collected from the abdominal aorta using a winged intravenous injection needle under 4% pentobarbital sodium anesthesia. Then, the animals were euthanized by sodium pentobarbital sodium overdose, and the fat (peritudinal fat and subcutaneous fat), heart, liver, adrenal gland, and brain were removed. Then, the weight of fat was measured.
２．結果
運動群での体重、内蔵脂肪の重量及び皮下脂肪の重量を１００％として、それに対する運動＋Ｌ群及び運動＋ＬＣ群での割合をそれぞれ算出し、ラットの体重並びに重量測定した副精巣周囲脂肪（内臓脂肪）及び皮下脂肪について、各群での減少量を評価した。
その結果、運動＋Ｌ群では、ラットの体重が運動群よりも減少しており、内臓脂肪及び皮下脂肪の量も運動群より減少していた。また、運動＋ＬＣ群でも同様に、ラットの体重並びに内臓脂肪及び皮下脂肪の量が運動群より減少していたが、その減少量は、運動＋Ｌ群の結果をさらに上回るものであった。これらの結果より、乳酸はｉｎ ｖｉｖｏにおいても脂質代謝改善作用を有しており、その作用はカフェインと併用することによりさらに増強されることが示唆された。
2. Results Taking the body weight, visceral fat weight and subcutaneous fat weight in the exercise group as 100%, the proportions in the exercise+L group and the exercise+LC group were calculated respectively, and the rat body weight and the weight around the epididymis (weighed) were measured. For visceral fat) and subcutaneous fat, the reduction amount in each group was evaluated.
As a result, in the exercise+L group, the body weight of the rat was lower than in the exercise group, and the amounts of visceral fat and subcutaneous fat were also lower than in the exercise group. Similarly, in the exercise+LC group, the body weight of rats and the amounts of visceral fat and subcutaneous fat were decreased as compared with the exercise group, but the decrease amount was even higher than that of the exercise+L group. From these results, it was suggested that lactic acid has a lipid metabolism improving action also in vivo, and its action is further enhanced by using it together with caffeine.
処方例：
実施例Ｉ、実施例ＩＩの結果に基づいて、以下の処方例を提示する。
Prescription example:
The following prescription examples are presented based on the results of Example I and Example II.
処方例１
表５に示した組成で飲料を製造した。
Prescription example 1
Beverages were produced with the composition shown in Table 5.
処方例２
表６に示した組成で飲料を製造した。
Prescription example 2
Beverages were produced with the composition shown in Table 6.
処方例３
表７に示した組成で飲料を製造した。
Prescription example 3
Beverages were produced with the compositions shown in Table 7.
処方例４
表８に示した組成で飲料を製造した。
Prescription example 4
Beverages were produced with the composition shown in Table 8.
処方例５
表９に示した組成で飲料を製造した。
Prescription example 5
Beverages were produced with the composition shown in Table 9.
処方例６
表１０に示した組成でハードカプセルを製造した。
Prescription example 6
Hard capsules were produced with the compositions shown in Table 10.
処方例７
表１１に示した組成でハードカプセルを製造した。
Prescription example 7
Hard capsules were produced with the compositions shown in Table 11.
処方例８
表１２に示した組成でハードカプセルを製造した。
Prescription example 8
Hard capsules were produced with the compositions shown in Table 12.
処方例９
表１３に示した組成で飲料を製造した。
Prescription example 9
Beverages were produced with the compositions shown in Table 13.
処方例１０
表１４に示した組成で飲料を製造した。
Prescription example 10
Beverages were produced with the compositions shown in Table 14.
本発明の剤及び組成物は、脂質代謝促進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 composition of the present invention are useful in the field of medicine because they have a lipid metabolism promoting action, and from the viewpoint of their extremely high safety, they are useful not only in the field of medicine but also in the field of food.
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