JP2014208598A - Lipid metabolism promoting agent - Google Patents
Lipid metabolism promoting agent Download PDFInfo
- Publication number
- JP2014208598A JP2014208598A JP2013201151A JP2013201151A JP2014208598A JP 2014208598 A JP2014208598 A JP 2014208598A JP 2013201151 A JP2013201151 A JP 2013201151A JP 2013201151 A JP2013201151 A JP 2013201151A JP 2014208598 A JP2014208598 A JP 2014208598A
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- Prior art keywords
- lactic acid
- present
- lipid metabolism
- 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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- 230000001737 promoting effect Effects 0.000 title claims abstract description 17
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- A23L1/30—
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
Landscapes
- Health & Medical Sciences (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Non-Alcoholic Beverages (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
Abstract
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 comprising 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 its main factor is fat overdose. 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 agent for obesity, mazindol, an appetite suppressant, orlistat, a lipase inhibitor, and the like are used. However, these medications include dry mouth, constipation, nausea, insomnia, headaches and palpitations, as well as oil spots, flatulence, sudden constipation, increased defecation, fecal incontinence, rectal leakage, upper respiratory infections and fatty stools Such side effects have been reported, and safety is not 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, sufficient nutritional guidance is required for this purpose, and it is often difficult to implement 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 synthesized as a result of lactic acid metabolism in order to obtain ATP from glucose transiently in the body when a rapid exercise (anoxic 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 generated as a result of exercise is about 4 to 5 mM. In addition, it is known that the blood concentration of lactic acid rises to about 20 mM when exercise is performed so as 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 into pyruvate by lactate dehydrogenase, and then glucose is regenerated by gluconeogenesis. This series of circuits is called a lactic acid circuit or a coli circuit. There is a limit point where lactic acid accumulation exceeds the metabolic removal of lactic acid during exercise accompanied by insufficient oxygen supply, and the point at which blood lactic acid concentration starts to increase rapidly is called the lactic acid accumulation threshold. In aerobic exercise training, the lactic acid accumulation threshold is sometimes used as an oxygen supply index to be used for setting 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。 Thus, it is lactic acid synthesized and metabolized in the body, but it is also contained in foods, and it is known that it is contained in fermented foods in particular. Examples of such fermented foods include yogurt and pickles. Moreover, it is contained in a drink and it is disclosed that it is used as a sourness imparting substance to a drink (patent documents 1-3). However, it is not known that such lactic acid is used for relieving obesity, and 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。 The objective of this invention is providing the agent and composition which can accelerate | stimulate a lipid metabolism safely and efficiently as a substance useful for elimination of 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 a salt thereof has an action of promoting lipid metabolism. Based on this finding, 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 comprising 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 a salt thereof 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 agent according to [2], which is ˜1000: 1.
[4] The agent according to any one of [1] to [3], wherein the lipid metabolism promotion is a reduction in body fat.
[5] A composition having a lipid metabolism promoting action, comprising lactic acid and / or a salt thereof as an active ingredient.
[6] The composition according to [5], further comprising caffeine.
[7] The content ratio of lactic acid and / or a salt thereof 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 ˜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 accelerate | stimulate lipid metabolism efficiently can be provided. In addition, lactic acid and / or a salt thereof used in the present invention is not only a substance synthesized in the body but also designated as a food additive in Japan, and used as an acidulant and pH adjuster for foods and drinks. 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 the condition of adding lactic acid. 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 “the 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. In the present invention, L-form and DL-form are preferred, and more preferred L-form is used. The CAS registration number for D-form is 79-33-4, the CAS registration number for L-form is 10326-41-7, and the CAS registration number for 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。 Moreover, the salt of lactic acid is not particularly limited. For example, alkali metal salts such as sodium and potassium (specifically, sodium lactate and potassium lactate), 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 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 salts thereof used in the present invention are not particularly limited as to how to obtain them, and may be any of those derived from animals or plants, or those obtained by chemical synthesis or fermentation. . Based on the purity and production cost of the obtained lactic acid and its salt, a suitable method for producing lactic acid and its salt can be appropriately selected. 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, Inc., Fuso Chemical Industry 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 a food or drink) obtained while culturing bacteria (lactic acid bacteria or the like) 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。 In vivo, it is known that the concentration of intracellular calcium such as muscle cells increases as a physiological phenomenon caused by exercise or the like. As a substance that is commonly used in foods and can increase intracellular calcium concentration in the living body for the purpose of increasing intracellular calcium concentration such as muscle cells without exercising. 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 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 includes both anhydrous (also referred to as “anhydrous caffeine”) and hydrate (eg, monohydrate) embodiments. Any embodiment 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。 The caffeine used in the present invention is not particularly limited, and may be, for example, a crystal obtained by chemical synthesis or the like, or a plant extract containing caffeine as it is or after being concentrated or purified (ie, In addition, a component other than caffeine may be selectively removed from a 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. The plant extract containing caffeine is not particularly limited. For example, it is known per se in solvents such as coffee beans, cola fruits, tea leaves, cacao, etc., water (or hot water), methanol, ethanol, isopropanol, ethyl acetate and the like. It is manufactured by extracting 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. As such a commercial item, the goods manufactured or sold by Shiratori Pharmaceutical Co., Ltd., Wako Pure Chemical Industries, Ltd., etc. are mentioned, for example.
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 salt thereof to caffeine in the agent of the present invention (lactic acid and / or salt thereof: caffeine) 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 still more preferably 0.928: 1 to 22.32: 1. It is. When the ratio between the two is within the above range, lipid metabolism can be efficiently promoted. In addition, when using the salt of lactic acid, the said weight ratio shall be calculated after converting into the free body (free body) of lactic acid. In the present invention, the weight converted in this way is handled as “a value converted into the weight as lactic acid”. Moreover, when each active ingredient forms the hydrate, the said weight ratio shall be calculated after converting into the free body (anhydride) except the water molecule.
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 referred to as “lipid metabolism promoter”, the agent of the present invention has an action of “facilitating lipid metabolism”, where “facilitating lipid metabolism” refers to promoting lipid metabolism in vivo. It means having an action. As used herein, “lipid” is a general term for water-insoluble substances existing in a living body. In the present invention, the lipid may be solid at room temperature or liquid, but is preferably solid. In addition, normal temperature shows that it is 15-25 degreeC normally according to the 16th revision Japanese Pharmacopoeia general rule. Lipids include, for example, simple lipids (neutral fats, waxes, etc.), complex lipids (phospholipids, glycolipids, etc.), derived lipids and the like. Among these, the lipid targeted in the present invention is preferably a simple lipid, more preferably a neutral fat, and most preferably triacylglycerol (triglyceride). In the present specification, “metabolism” of lipid mainly indicates degradation of lipid, but is not particularly limited as long as the amount of 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 lipid in the living body (sometimes referred to as “burning of lipid”) and reducing the amount of lipid ingested from outside the body. And the concept of inhibiting lipid accumulation. In the present invention, although not particularly limited, promotion of lipid metabolism preferably means reducing lipids in the living body. Examples of the lipid in the present invention include body fat (subcutaneous fat, visceral fat, etc.) and blood lipid, but body fat is preferred.
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 the action of promoting lipid metabolism. Furthermore, the agent of the present invention can also prevent and treat diseases that develop due to 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, this invention can also provide the preventive and therapeutic agent of the said disease.
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 and food, and the application target thereof can 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, cows, horses, pigs, sheep, goats) can be mentioned, but humans are preferred in the present invention. When applied to mammals other than humans, the dose (intake amount) of the agent of the present invention may be appropriately adjusted depending on 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 an appropriate pharmaceutically acceptable carrier as necessary in the formulation (hereinafter referred to as “the composition of the present invention”). ). Thereby, it can be said that the composition of this invention contains the agent of this invention. Since the composition of this invention contains the agent of this invention, it can have all the effects exhibited by the agent of this invention. That is, the composition of the present invention is characterized by having an action of promoting lipid metabolism, wherein “facilitating lipid metabolism” means having an action of promoting lipid metabolism in a living body. Although not particularly limited, promoting lipid metabolism preferably means reducing lipids in the living body. Examples of the lipid in the present invention include body fat (subcutaneous fat, visceral fat, etc.) and blood lipid, but body fat is preferred.
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 carrier can be appropriately selected depending on the dosage form of the preparation (composition), and is not particularly limited. For example, the excipient, binder, lubricant, disintegrant, solvent, stabilizer, solubilizer And additives such as antioxidants, coloring agents, flavoring agents, sweetening agents and the like.
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.), starches (corn starch, etc.), crystalline cellulose, calcium phosphate, calcium sulfate, magnesium sulfate, etc., and binders include pregelatinized starch, gelatin, tragacanth gum, Gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc., lubricants include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil As disintegrants, starch, crystalline cellulose, carboxymethylcellulose, agar, calcium citrate, calcium carbonate, charcoal Sodium hydrogen, dextrin, etc., the solvent is water, ethanol, glycerol, physiological saline, soybean oil, etc., and the stabilizer is benzoic acid, sodium benzoate, ethyl paraoxybenzoate, propylene glycol, etc. Examples of solubilizers include fumaric acid, succinic acid, and malic acid, and examples of antioxidants include ascorbic acid, tocopherol, sodium bisulfite, sodium thiosulfate, sodium pyrosulfite, and citric acid. Examples of the agent and sweetener include those that are normally allowed 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。 As in the case of the agent of the present invention, the composition of the present invention can further contain caffeine, and the content ratio of lactic acid and / or a salt thereof to caffeine in the composition of the present invention (lactic acid and (Or salt thereof: caffeine) is also generally in a weight ratio of 0.9: 1 to 1000: 1, preferably 0.9: 1 to 500: 1, as in the case of the agent of the present invention. More preferably, it is 0.928: 1-100: 1, More preferably, it is 0.928: 1-22.32: 1. When the ratio between the two is within the above range, lipid metabolism can be efficiently promoted. In addition, when using the salt of lactic acid, the said weight ratio shall be calculated after converting into the free body (free body) of lactic acid. In the present invention, the weight converted in this way is handled as “a value converted into the weight as lactic acid”. Moreover, when each active ingredient forms the hydrate, the said weight ratio shall be calculated after converting into the free body (anhydride) except the water molecule.
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 formulated simultaneously in a single formulation, or may be formulated in separate formulations. When separate preparations are used, the preparations are used in combination. In the present invention, it is preferable to use lactic acid and / or a salt thereof and caffeine in a single preparation for 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 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. % By weight, more preferably 1.00 to 99.90% by weight. In addition, 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. More preferably, it is 0.04 to 33.30% by weight. As with the above weight ratio, when using a salt of lactic acid, the content is calculated after conversion to a free form of lactic acid, and when each active ingredient forms a hydrate, The 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 formulated in 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 medicament (ie, a pharmaceutical composition). In this case, the pharmaceutical composition of the present invention can be handled as a preventive or therapeutic agent 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 administration method of the pharmaceutical composition of the present invention is not particularly limited, and generally includes an oral administration method. Depending on the condition, severity, etc. of the subject patient, parenteral administration (intravascular ( (Intravenous, intraarterial) administration, subcutaneous administration, transdermal administration, intrarectal administration, etc.) may be appropriately selected. Since any of lactic acid and / or a salt thereof and caffeine, which are active ingredients, can be consumed, it is preferable to employ 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 can be in a form suitable for the 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, and the like. Suitable forms for parenteral administration include, for example, sterile solutions, suspensions, emulsions, and the like for intravenous, subcutaneous, intramuscular, intravascular or infusion administration as forms 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 (ie, a food or drink composition). In this case, the food / beverage composition of the present invention can be formulated by a conventional method using a carrier usually used in the field of food / beverage products in addition to the pharmaceutically acceptable carrier described above.
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 food and drink, but in addition to general foods including so-called health foods, special-purpose foods specified by the Consumer Affairs Agency (specific health foods, sick foods, difficult to swallow) Foods for consumers, etc.) and 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 / beverage composition of the present invention is not particularly limited. Fine granules, granules, pills, tablets (including coated tablets and dragees), capsules (including hard capsules, soft capsules, and microcapsules) , Beverages, drinks, liquids (including syrups, emulsions, suspensions), powdered foods, jellies, rice cakes 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。 The dose (intake) of the agent and composition of the present invention is not particularly limited as long as it is within the effective amount range in which the lipid metabolism promoting action can be expressed in the body. It can be set appropriately according to the administration method and the like. Further, the daily dose (intake) can be administered (intake) at one time or divided into several times (for example, two or three times). Administration (intake) of the agent and composition of the present invention is not particularly limited as long as the effect of the present invention is exhibited, regardless of whether it is before, after, or between meals. Hereinafter, when the term “administration” is used herein, the term is meant to encompass 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 described above, lactic acid and / or a salt thereof and caffeine can be formulated into separate formulations, in which case both formulations can be used in combination in the present invention. Lactic acid and / or its salt and caffeine may be administered simultaneously or 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、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 using the agent and composition of the present invention, it can also be used in combination with existing components having a lipid metabolism promoting action. In such a case, the order of administering the agent and composition of the present invention and the existing component 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 existing components.
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 procyanidins, transglycosyl hesperidin, resveratrol, green citrus extract, citrus nalidinine, glucosamine, mushroom chitosan, chitosan, diacyl. Glycerol, medium chain fatty acid, EPA, DHA, soybean protein, plant sterol (β-sitosterol, etc.), psyllium seed coat-derived dietary fiber, low molecular weight sodium alginate, guarana, ginger, garcinia, globin proteolysate, carnitine, α- Examples include lipoic acid, plant stanol esters, phospholipid-bound soybean peptides, or 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。 The present invention will be described more specifically with reference to the following examples. However, these are merely examples and do not limit the scope of the present invention.
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.1. Effects of lactic acid and caffeine in cell tests (in vitro)
Mouse preadipocytes 3T3-L1 (purchased from ATCC) are differentiated with 12 well-dish, and then lactic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and caffeine (concentrated in units of mmol) shown in Table 1 The medium was changed to 10% serum-containing DMEM medium (Wako Pure Chemical Industries, Ltd.) supplemented with Wako Pure Chemical Industries, Ltd., and static 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 washed with 1 mL of DMEM medium containing 2% BSA (no fatty acid), 20 mM HEPES, 0.5 mM IBMX, 10 μM isoprotenol at 37 ° C. For 6 hours. Thereafter, the culture supernatant was collected, and the amounts of glycerol and free fatty acids in the supernatant were measured. The amount of glycerol and fatty acid was determined using an absorbance method (measurement wavelength glycerol: 600 nm, Triglyceride E-test kit (manufactured by Wako Pure Chemical Industries, Ltd.) and NEFA C-test kit (manufactured by Wako Pure Chemical Industries, Ltd.), respectively. Free fatty acid: 550 nm, measuring instrument: xMark (manufactured by BIO-RAD)). The measurement results and the relative values with the comparative examples are shown in Tables 2 and 3.
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 larger than those in Comparative Examples. Further, in Examples 5 and 6 in which lactic acid and caffeine were combined, it was shown that the amount of glycerol released and the amount of released free fatty acid were higher than those 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 all examples.
From the above results, it was suggested that lactic acid and the combination of lactic acid and caffeine degrade fat in cells, that is, have 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 lactic acid and caffeine in animal studies (in vivo)
1. Test materials and methods 1.1. Test substance and medium 1.1.1. Test substances Sodium lactate (Wako Pure Chemical Industries, Ltd.) and caffeine (Wako Pure Chemical Industries, Ltd.) were used. After acquisition, all were stored in the storage of the test substance storage room of the 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) was used. After acquisition, it was stored in the test substance storage room of the test facility under conditions of room temperature (set temperature: 23 ° C., actual measurement: 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 to be administered Weighed the required amounts of sodium lactate and caffeine, and then mixed and dissolved with water for injection so that the final concentrations were 200 mg / mL and 7.2 mg / mL, respectively (the mixture was the test substance LC )
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 rearing conditions In the test, male F344 rats (SPF, Japan SLC Co., Ltd.), which is an animal species generally used in pharmacological pharmacological tests and whose lineage is clearly maintained, were used.
The animals were bred in an animal breeding facility set at a preset temperature: 23 ° C. and light and dark for 12 hours each (lighting: 8 am to 8 pm). Cages and feeders were changed at least once a week.
For the feed, a solid high-fat feed (HFD-60, Oriental Yeast Co., Ltd.) within 5 months after production was placed in a feeder and allowed to feed 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＋ＬＣ群（ｎ＝９）に分類した。
1.3.2. Grouping High-fat diet HFD-60 was ad libitum for 6 weeks to 5-week-old rats. At the age of 11 weeks, the rats were randomly classified into exercise group (n = 9), exercise + L group (n = 9), 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 date of acquisition by combining the method of filling the tail with oil-based ink and the method of applying dye to the limbs using oil-based ink. After grouping, it was identified by entering the animal number (last 3 digits) on the tail using oil-based ink. Each cage is labeled with the test number, date of acquisition, and the number of the pre-reserved animal during the pre-breeding period. After the grouping, the test number, group name, and animal number are entered, and each group is color-coded. A label was 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 a voluntary running exercise with a frequency of three times a week and once every two days. For the spontaneous running exercise, a rotary exercise machine (Lafayette Instrument, model No. 80859) was used.
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 Administration was forcibly orally administered using a disposable syringe (made by Terumo Corporation) made of polypropylene with a metal gastric sonde for rats attached in accordance with the usual method used in the test facility. During the administration operation, the required amount was aspirated into the syringe while stirring the administration specimen by inversion mixing.
Within 30 minutes after the end of spontaneous running (from 10:00 am), the liquid volume was calculated at 5 mL / kg from the body 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 (the day of administration 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 measurement It was measured once a week before administration 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 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 needle under anesthesia with 4% sodium pentobarbital. The animals were then euthanized by pentobarbital sodium overdose, and the fat (peri-testicular fat and subcutaneous fat) and the 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 The body weight in the exercise group, the weight of the built-in fat and the weight of the subcutaneous fat were taken as 100%, and the ratios in the exercise + L group and exercise + LC group were calculated respectively, and the rat's body weight and weight were measured around the accessory testicular fat ( Visceral fat) and subcutaneous fat were evaluated for reduction in each group.
As a result, in the exercise + L group, the body weight of the rats was decreased as compared with the exercise group, and the amounts of visceral fat and subcutaneous fat were also decreased as compared with the exercise group. Similarly, in the exercise + LC group, the body weight of the rat and the amounts of visceral fat and subcutaneous fat were decreased from those in the exercise group, but the decreased amounts were more than those in the exercise + L group. From these results, it was suggested that lactic acid has a lipid metabolism improving action in vivo, and the 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。
Formulation example:
Based on the results of Example I and Example II, the following formulation examples are presented.
処方例１
表５に示した組成で飲料を製造した。
Formulation Example 1
Beverages were produced with the compositions shown in Table 5.
処方例２
表６に示した組成で飲料を製造した。
Formulation example 2
Beverages were produced with the compositions shown in Table 6.
処方例３
表７に示した組成で飲料を製造した。
Formulation 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。
Formulation Example 4
Beverages were produced with the compositions shown in Table 8.
処方例５
表９に示した組成で飲料を製造した。
Formulation Example 5
Beverages were produced with the compositions 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。
Formulation 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。
Formulation 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。
Formulation 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。
Formulation 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。
Formulation 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 have a lipid metabolism promoting action and are useful in the pharmaceutical field, and from the viewpoint of extremely high safety, they are useful not only in the pharmaceutical field but also in the food field.
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