WO2009096505A1 - Agent for improving attention and concentration powers - Google Patents

Agent for improving attention and concentration powers Download PDF

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WO2009096505A1
WO2009096505A1 PCT/JP2009/051535 JP2009051535W WO2009096505A1 WO 2009096505 A1 WO2009096505 A1 WO 2009096505A1 JP 2009051535 W JP2009051535 W JP 2009051535W WO 2009096505 A1 WO2009096505 A1 WO 2009096505A1
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citrulline
salt
concentration
attention concentration
agent
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PCT/JP2009/051535
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French (fr)
Japanese (ja)
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Masayuki Ochiai
Koji Morishita
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Kyowa Hakko Bio Co., Ltd.
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Priority to JP2009551590A priority Critical patent/JP5931325B2/en
Publication of WO2009096505A1 publication Critical patent/WO2009096505A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • 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
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an attention concentration improving agent containing citrulline or a salt thereof as an active ingredient.
  • Attention and concentration are necessary abilities in various scenes of daily life. For example, it can be said that it is indispensable for improving performance and learning in exercise and maximizing work efficiency in work.
  • Various training methods such as mental training and mind control have been established in order to enhance these capabilities.
  • food materials that increase attention concentration by promoting anti-stress and relaxation effects are also known (Patent Document 1).
  • L-citrulline is a kind of amino acid that is not used as a raw material for protein synthesis in vivo but exists in a free state. In the body, it plays an important role as a component of the NO cycle related to arginine biosynthesis and supply of nitric oxide (NO) as an arginine precursor. It is known that when citrulline is orally ingested, most of the citrulline is converted into arginine in the kidney and arginine is efficiently supplied to the whole body (Non-patent Document 1). In addition, ingestion of citrulline and arginine has been reported to improve blood flow through the production of NO which is a vasodilator (Non-patent Document 2).
  • Ginkgo biloba extract one of the herbs, is known as a material that improves brain function by improving cerebral blood flow, improving dementia (Non-Patent Document 3) and improving brain function disorder due to ischemia (Non-Patent Document) 4), but there is no known relevance to attention concentration.
  • arginine has been reported to promote cerebral blood flow, the effect on attention concentration is not clear.
  • Amino Acids 2005, Vol. 29, pp. 177-205.
  • PNAS 2005, Volume 102, pp. 13681-13686 “JA MA”, 1997, Vol. 278, p. 1327-1332 “Journal of Neurosciense Research”, 2002, Vol. 68, p. 636-645 JP 2005-232045 A
  • An object of the present invention is to provide an agent for improving attention concentration for those who have subjective symptoms such as unthinkable thoughts, distractions, and little thoughts.
  • the present invention relates to the following (1) to (4).
  • An attention concentration improving agent containing citrulline or a salt thereof as an active ingredient (2) A method for improving attention concentration, comprising administering an effective amount of citrulline or a salt thereof to a subject in need thereof. (3) Use of citrulline or a salt thereof for the production of an attention concentration improving agent. (4) Citrulline or a salt thereof for use as an attention concentration improving agent.
  • FIG. 1 is a graph showing the effect of citrulline to improve attention concentration.
  • the vertical axis represents the average value of the body sensation index.
  • Citrulline used in the present invention includes L-citrulline and D-citrulline, with L-citrulline being preferred.
  • Citrulline can be obtained by a chemical synthesis method, a fermentation production method, or the like.
  • Citrulline can also be obtained by purchasing a commercial product. Examples of methods for chemically synthesizing citrulline include the methods described in J. Biol. Chem., 122 , 477 (1938), J. Org. Chem., 6 , 410 (1941).
  • L-citrulline examples include the methods described in JP-A-53-075387 and JP-A-63-068091.
  • L-citrulline and D-citrulline can also be purchased from Sigma-Aldrich.
  • citrulline salts include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • Acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, malate, lactate, ⁇ -ketoglutarate And organic acid salts such as gluconate and caprylate.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt.
  • ammonium salts include salts such as ammonium and tetramethylammonium.
  • organic amine addition salt include salts of morpholine, piperidine and the like.
  • amino acid addition salts include salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like.
  • citrulline salts malate is preferably used, but other salts or two or more salts may be used in appropriate combination.
  • Citrulline or a salt thereof can be administered as it is as the attention concentration improving agent of the present invention, but it is usually desirable to provide it as various preparations.
  • the preparation can be produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers.
  • the preparation may further contain any other active ingredient for treatment.
  • additives such as excipients, binders, disintegrants, lubricants, dispersants, suspending agents, emulsifiers, diluents, buffers, antioxidants, and bacterial inhibitors should be used. it can.
  • dosage forms include tablets, powders, granules, pills, suspensions, emulsions, soaking and decoction, capsules, syrups, solutions, elixirs, extracts, tinctures, fluid extracts, and other oral preparations. Any of parenteral preparations such as injections, infusions, creams, suppositories, etc. may be used, but they are preferably used as oral preparations.
  • the dosage forms suitable for oral administration are tablets, powders and granules, sugars such as lactose, glucose, sucrose, mannitol, sorbitol, starches such as potato, wheat, corn, calcium carbonate, calcium sulfate , Inorganic substances such as sodium bicarbonate, sodium chloride, excipients such as crystalline cellulose, licorice powder, gentian powder, etc., starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, Disintegrants such as sodium bicarbonate and sodium alginate, magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil and other lubricants, polyvinyl alcohol, hydroxypropylcellulose, methylcellulose, ethylcellulose, carmellose, gelatin Binders starch glue solution and the like, surfactants such as fatty acid esters can be formulated by adding a plasticizer such as glycerin.
  • a plasticizer
  • the dosage form suitable for oral administration is a liquid preparation such as syrup, water, sucrose, sorbitol, sugars such as fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil, etc. Oils, p-hydroxybenzoates and other preservatives, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint. can do.
  • a liquid preparation such as syrup, water, sucrose, sorbitol, sugars such as fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil, etc.
  • Oils, p-hydroxybenzoates and other preservatives, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint. can do.
  • a dosage form suitable for parenteral administration in the case of injections, preferably comprises a sterile aqueous preparation containing citrulline or a salt thereof that is isotonic with the blood of the recipient.
  • a solution for injection can be prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
  • preparations suitable for oral administration include additives generally used in foods and drinks such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, color formers, bleaches, fungicides, gum bases. Bitterings, enzymes, brighteners, acidulants, seasonings, emulsifiers, fortifiers, manufacturing agents, fragrances, spice extracts and the like may be added.
  • Formulations suitable for oral administration may be as they are or in the form of, for example, powdered foods, sheet foods, bottled foods, canned foods, retort foods, capsule foods, tablet foods, liquid foods, drinks, etc. .
  • the dosage form of the preparation is preferably the most effective in improving attention concentration, and can be given by oral administration or parenteral administration such as intravenous, intraperitoneal or subcutaneous administration. Is preferred.
  • the concentration of citrulline or a salt thereof in the attention concentration improving agent of the present invention is appropriately selected according to the type of the preparation, the effect expected by ingestion or administration of the preparation, etc. It is 0.1 to 100% by weight, preferably 0.5 to 80% by weight, particularly preferably 1 to 70% by weight.
  • the dose and frequency of administration in the case of administering the attention concentration improving agent of the present invention vary depending on the administration form, the age, weight, etc. of the recipient, but usually from 50 mg to citrulline or a salt thereof usually per adult day. It is administered once to several times a day so as to be 30 g, preferably 100 mg to 10 g, particularly preferably 200 mg to 3 g.
  • the administration period is not particularly limited, but is usually 1 day to 1 year, preferably 1 week to 3 months.
  • test example for examining the effect of citrulline on improving attention concentration.
  • a test was conducted in which the capsules containing these were ingested for 3 weeks.
  • the attention concentration of the subjects at the start of the test and 3 weeks after the start of the test was evaluated using a line segment scale (VAS) method.
  • VAS line segment scale
  • the reference expression was written at both ends of the line segment, and the subjects were asked to check which line segment corresponded to the contents of the question items shown in Table 1.
  • the distance (mm) from the left end of the line segment to the checked part was measured with the left end of the line segment as a bodily sensation index of 0 and the right end as a bodily sensation index of 10, and this was converted into a bodily sensation index. This operation was performed before and after the test, and the difference (change in sensory index) was measured to determine the average value and standard deviation for each group. The greater the change in the body sensation index, the greater the effect of improving attention concentration. It was confirmed that there was no difference between the two groups at the start of the study.
  • citrulline significantly improved subjective symptoms such as unthinkable thoughts, little reminders, many mistakes to do, and distractions. From this result, it was shown that citrulline has an effect of improving attention concentration.
  • Example 1 Production of enteric tablet containing citrulline
  • the surface of the tablet produced in Example 1 is coated with a shellac solution to produce an enteric tablet.
  • enteric capsule containing citrulline 120 kg of L-citrulline (manufactured by Kyowa Hakko Kogyo Co., Ltd.), 19 kg of cyclic oligosaccharide, 57 kg of cellulose, 3 kg of calcium stearate and 1 kg of pullulan are mixed in a conical blender.
  • a mixture obtained by mixing and stirring 20 kg of the obtained mixture and 0.2 kg of silicon dioxide is put into a capsule filling machine and filled into hard capsules to obtain hard capsules.
  • the surface of the resulting hard capsule is coated with a zein solution to produce an enteric capsule.
  • a safe and effective attention concentration improving agent containing citrulline or a salt thereof as an active ingredient can be provided.

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Abstract

There have been required drugs, health foods and so on whereby subjective symptoms, for example, decline in clear thinking, defocusing and decline in memory of trivial matters can be reduced and the quality of life of people having these symptoms can be improved. Provided is an agent for improving attention and concentration powers. An agent for improving attention and concentration powers which contains citrulline or a salt thereof as the active ingredient can be provided.

Description

注意集中力向上剤Attention concentration improver
　本発明は、シトルリンまたはその塩を有効成分として含有する注意集中力向上剤に関する。 The present invention relates to an attention concentration improving agent containing citrulline or a salt thereof as an active ingredient.
　注意力および集中力は日常生活の様々な場面において必要な能力である。例えば、運動でのパフォーマンス向上や学習、仕事における作業効率の最大化を図る上では欠かすことのできない能力と言える。こうした能力を高めるために、メンタルトレーニングやマインドコントロールといった種々のトレーニング方法が確立されている。また、最近では抗ストレスやリラックス効果を促すことにより注意集中力を高めるといった食品素材なども知られている（特許文献1）。 注意 Attention and concentration are necessary abilities in various scenes of daily life. For example, it can be said that it is indispensable for improving performance and learning in exercise and maximizing work efficiency in work. Various training methods such as mental training and mind control have been established in order to enhance these capabilities. In addition, recently, food materials that increase attention concentration by promoting anti-stress and relaxation effects are also known (Patent Document 1).
　Ｌ－シトルリンは、生体内でタンパク質の合成原料としては使われず、遊離の状態で存在するアミノ酸の一種である。体内ではアルギニン前駆体としてアルギニン生合成や、一酸化窒素（ＮＯ）の供給に関わるＮＯサイクルの構成因子として重要な役割を果たしている。シトルリンを経口摂取すると大部分が腎臓でアルギニンに変換され、全身に効率よくアルギニンが供給されることが知られている（非特許文献１）。また、シトルリンやアルギニンの摂取により、血管拡張因子であるＮＯ産生を介した血流改善効果が報告されている（非特許文献２）。 L-citrulline is a kind of amino acid that is not used as a raw material for protein synthesis in vivo but exists in a free state. In the body, it plays an important role as a component of the NO cycle related to arginine biosynthesis and supply of nitric oxide (NO) as an arginine precursor. It is known that when citrulline is orally ingested, most of the citrulline is converted into arginine in the kidney and arginine is efficiently supplied to the whole body (Non-patent Document 1). In addition, ingestion of citrulline and arginine has been reported to improve blood flow through the production of NO which is a vasodilator (Non-patent Document 2).
　脳血流の改善により脳機能を改善する素材としてハーブの１つであるイチョウ葉エキスが知られており、痴呆の改善（非特許文献３）や虚血による脳機能障害の改善（非特許文献４）などの報告があるが、注意集中力との関連性は知られていない。また、アルギニンには脳血流を促進するとの報告があるが、注意集中力に対する効果は明らかではない。
「アミノ　アシッズ（Amino Acids）」、２００５年、第２９巻、ｐ.１７７－２０５ 「ピー　エヌ　エー　エス（PNAS）」２００５年、第１０２巻、ｐ.１３６８１－１３６８６ 「ジェー　エー　エム　エー（JAMA）」、１９９７年、第２７８巻、ｐ．１３２７－１３３２ 「ジャーナル　オブ　ニューロサイエンス　リサーチ（Journal of Neurosciense Research）」、２００２年、第６８巻、ｐ．６３６－６４５ 特開２００５－２３２０４５号公報 Ginkgo biloba extract, one of the herbs, is known as a material that improves brain function by improving cerebral blood flow, improving dementia (Non-Patent Document 3) and improving brain function disorder due to ischemia (Non-Patent Document) 4), but there is no known relevance to attention concentration. Although arginine has been reported to promote cerebral blood flow, the effect on attention concentration is not clear.
"Amino Acids", 2005, Vol. 29, pp. 177-205. "PNAS" 2005, Volume 102, pp. 13681-13686 "JA MA", 1997, Vol. 278, p. 1327-1332 "Journal of Neurosciense Research", 2002, Vol. 68, p. 636-645 JP 2005-232045 A
　本発明の目的は、考えがまとまらない、気が散る、ちょっとしたことが思い出せない等の自覚症状を持つ者に対して、注意集中力向上剤を提供することにある。 An object of the present invention is to provide an agent for improving attention concentration for those who have subjective symptoms such as unthinkable thoughts, distractions, and little thoughts.
　本発明は、下記の（１）～（４）に関する。
（１）シトルリンまたはその塩を有効成分として含有する注意集中力向上剤。
（２）シトルリンまたはその塩の有効量を、必要とする対象に投与することを含む、注意集中力向上方法。
（３）注意集中力向上剤の製造のための、シトルリンまたはその塩の使用。
（４）注意集中力向上剤として使用するためのシトルリンまたはその塩。 The present invention relates to the following (1) to (4).
(1) An attention concentration improving agent containing citrulline or a salt thereof as an active ingredient.
(2) A method for improving attention concentration, comprising administering an effective amount of citrulline or a salt thereof to a subject in need thereof.
(3) Use of citrulline or a salt thereof for the production of an attention concentration improving agent.
(4) Citrulline or a salt thereof for use as an attention concentration improving agent.
図１は、シトルリンの注意集中力向上効果を表すグラフである。縦軸は体感指数の変化の平均値を示す。FIG. 1 is a graph showing the effect of citrulline to improve attention concentration. The vertical axis represents the average value of the body sensation index.
　本発明で用いられるシトルリンとしては、Ｌ－シトルリンおよびＤ－シトルリンがあげられるが、Ｌ－シトルリンが好ましい。
　シトルリンは、化学的に合成する方法、発酵生産する方法等により取得することができる。また、シトルリンは、市販品を購入することにより取得することもできる。
　シトルリンを化学的に合成する方法としては、例えば、J. Biol. Chem., 122, 477(1938)、J.Org.Chem., 6, 410(1941)に記載の方法があげられる。 Citrulline used in the present invention includes L-citrulline and D-citrulline, with L-citrulline being preferred.
Citrulline can be obtained by a chemical synthesis method, a fermentation production method, or the like. Citrulline can also be obtained by purchasing a commercial product.
Examples of methods for chemically synthesizing citrulline include the methods described in J. Biol. Chem., 122 , 477 (1938), J. Org. Chem., 6 , 410 (1941).
　Ｌ-シトルリンを発酵生産する方法としては、例えば、特開昭５３－０７５３８７号公報、特開昭６３－０６８０９１号公報に記載の方法があげられる。
　また、Ｌ-シトルリンおよびＤ-シトルリンは、シグマ－アルドリッチ社等より購入することもできる。
　シトルリンの塩としては、酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩、アミノ酸付加塩等があげられる。 Examples of the method for fermentative production of L-citrulline include the methods described in JP-A-53-075387 and JP-A-63-068091.
L-citrulline and D-citrulline can also be purchased from Sigma-Aldrich.
Examples of citrulline salts include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
　酸付加塩としては、塩酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸塩、酢酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、リンゴ酸塩、乳酸塩、α－ケトグルタル酸塩、グルコン酸塩、カプリル酸塩等の有機酸塩があげられる。
　金属塩としては、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩、亜鉛塩等があげられる。 Acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, malate, lactate, α-ketoglutarate And organic acid salts such as gluconate and caprylate.
Examples of the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt.
　アンモニウム塩としては、アンモニウム、テトラメチルアンモニウム等の塩があげられる。
　有機アミン付加塩としては、モルホリン、ピペリジン等の塩があげられる。
　アミノ酸付加塩としては、グリシン、フェニルアラニン、リジン、アスパラギン酸、グルタミン酸等の塩があげられる。 Examples of ammonium salts include salts such as ammonium and tetramethylammonium.
Examples of the organic amine addition salt include salts of morpholine, piperidine and the like.
Examples of amino acid addition salts include salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like.
　上記のシトルリンの塩のうち、リンゴ酸塩が好ましく用いられるが、他の塩、または２以上の塩を適宜組み合わせて用いてもよい。
　本発明の注意集中力向上剤としては、シトルリンまたはその塩をそのまま投与することも可能であるが、通常各種の製剤として提供するのが望ましい。
　製剤は、有効成分を薬理学的に許容される一種またはそれ以上の担体と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造することができる。また、該製剤は更に任意の他の治療のための有効成分を含有していてもよい。 Of the above citrulline salts, malate is preferably used, but other salts or two or more salts may be used in appropriate combination.
Citrulline or a salt thereof can be administered as it is as the attention concentration improving agent of the present invention, but it is usually desirable to provide it as various preparations.
The preparation can be produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers. The preparation may further contain any other active ingredient for treatment.
　製剤化する際には、賦形剤、結合剤、崩壊剤、潤沢剤、分散剤、懸濁剤、乳化剤、希釈剤、緩衝剤、抗酸化剤、細菌抑制剤等の添加剤を用いることができる。
　剤形としては、例えば錠剤、散剤、顆粒剤、丸剤、懸濁剤、乳剤、浸剤・煎剤、カプセル剤、シロップ剤、液剤、エリキシル剤、エキス剤、チンキ剤、流エキス剤等の経口剤、注射剤、点滴剤、クリーム剤、坐剤等の非経口剤のいずれでもよいが、経口剤として好適に用いられる。 When formulating, additives such as excipients, binders, disintegrants, lubricants, dispersants, suspending agents, emulsifiers, diluents, buffers, antioxidants, and bacterial inhibitors should be used. it can.
Examples of dosage forms include tablets, powders, granules, pills, suspensions, emulsions, soaking and decoction, capsules, syrups, solutions, elixirs, extracts, tinctures, fluid extracts, and other oral preparations. Any of parenteral preparations such as injections, infusions, creams, suppositories, etc. may be used, but they are preferably used as oral preparations.
　例えば、経口投与に適当な剤形が、錠剤、散剤および顆粒剤等の場合には、乳糖、ブドウ糖、蔗糖、マンニトール、ソルビトール等の糖類、バレイショ、コムギ、トウモロコシ等の澱粉、炭酸カルシウム、硫酸カルシウム、炭酸水素ナトリウム、塩化ナトリウム等の無機物、結晶セルロース、カンゾウ末、ゲンチアナ末等の植物末等の賦形剤、澱粉、寒天、ゼラチン末、結晶セルロース、カルメロースナトリウム、カルメロースカルシウム、炭酸カルシウム、炭酸水素ナトリウム、アルギン酸ナトリウム等の崩壊剤、ステアリン酸マグネシウム、タルク、水素添加植物油、マクロゴール、シリコーン油等の滑沢剤、ポリビニールアルコール、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、カルメロース、ゼラチン、澱粉のり液等の結合剤、脂肪酸エステル等の界面活性剤、グリセリン等の可塑剤などを添加して製剤化することができる。 For example, when the dosage forms suitable for oral administration are tablets, powders and granules, sugars such as lactose, glucose, sucrose, mannitol, sorbitol, starches such as potato, wheat, corn, calcium carbonate, calcium sulfate , Inorganic substances such as sodium bicarbonate, sodium chloride, excipients such as crystalline cellulose, licorice powder, gentian powder, etc., starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, Disintegrants such as sodium bicarbonate and sodium alginate, magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil and other lubricants, polyvinyl alcohol, hydroxypropylcellulose, methylcellulose, ethylcellulose, carmellose, gelatin Binders starch glue solution and the like, surfactants such as fatty acid esters can be formulated by adding a plasticizer such as glycerin.
　経口投与に適当な剤形が、シロップ剤のような液体調製物である場合は、水、蔗糖、ソルビトール、果糖等の糖類、ポリエチレングリコール、プロピレングリコール等のグリコール類、ごま油、オリーブ油、大豆油等の油類、ｐ－ヒドロキシ安息香酸エステル類等の防腐剤、パラオキシ安息香酸メチル等のパラオキシ安息香酸誘導体、安息香酸ナトリウム等の保存剤、ストロベリーフレーバー、ペパーミント等のフレーバー類などを添加して製剤化することができる。 If the dosage form suitable for oral administration is a liquid preparation such as syrup, water, sucrose, sorbitol, sugars such as fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil, etc. Oils, p-hydroxybenzoates and other preservatives, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint. can do.
　非経口投与に適当な剤形が、注射剤の場合には、好ましくは受容者の血液と等張であるシトルリンまたはその塩を含む滅菌水性剤からなる。例えば、塩溶液、ブドウ糖溶液または塩溶液とブドウ糖溶液の混合物からなる担体等を用いて注射用の溶液を調製することができる。
　また、経口投与に適当な製剤には、一般に飲食品に用いられる添加剤、例えば甘味料、着色料、保存料、増粘安定剤、酸化防止剤、発色剤、漂白剤、防かび剤、ガムベース、苦味料、酵素、光沢剤、酸味料、調味料、乳化剤、強化剤、製造用剤、香料、香辛料抽出物等が添加されてもよい。 A dosage form suitable for parenteral administration, in the case of injections, preferably comprises a sterile aqueous preparation containing citrulline or a salt thereof that is isotonic with the blood of the recipient. For example, a solution for injection can be prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
In addition, preparations suitable for oral administration include additives generally used in foods and drinks such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, color formers, bleaches, fungicides, gum bases. Bitterings, enzymes, brighteners, acidulants, seasonings, emulsifiers, fortifiers, manufacturing agents, fragrances, spice extracts and the like may be added.
　経口投与に適当な製剤は、そのまま、または例えば粉末食品、シート状食品、瓶詰め食品、缶詰食品、レトルト食品、カプセル食品、タブレット状食品、流動食品、ドリンク剤等の形態のものであってもよい。また、注意集中力向上用の健康食品、機能性食品、栄養補助食品、特定保健用食品等の飲食品として用いてもよい。
　製剤の摂取形態は、注意集中力向上に際し最も効果的なものを使用するのが望ましく、経口投与または、例えば静脈内、腹膜内もしくは皮下投与等の非経口投与をあげることができるが、経口投与が好ましい。 Formulations suitable for oral administration may be as they are or in the form of, for example, powdered foods, sheet foods, bottled foods, canned foods, retort foods, capsule foods, tablet foods, liquid foods, drinks, etc. . Moreover, you may use as food-drinks, such as a health food for attention concentration improvement, a functional food, a dietary supplement, and a food for specified health.
The dosage form of the preparation is preferably the most effective in improving attention concentration, and can be given by oral administration or parenteral administration such as intravenous, intraperitoneal or subcutaneous administration. Is preferred.
　本発明の注意集中力向上剤中のシトルリンまたはその塩の濃度は、製剤の種類、当該製剤の摂取または投与により期待する効果等に応じて適宜選択されるが、シトルリンまたはその塩として、通常は０．１～１００重量％、好ましくは０．５～８０重量％、特に好ましくは１～７０重量％である。
　本発明の注意集中力向上剤を投与する場合の投与量および投与回数は、投与形態、被投与者の年齢、体重等により異なるが、通常、成人一日当り、シトルリンまたはその塩として通常は５０ｍｇ～３０ｇ、好ましくは１００ｍｇ～１０ｇ、特に好ましくは２００ｍｇ～３ｇとなるように一日一回ないし数回投与する。 The concentration of citrulline or a salt thereof in the attention concentration improving agent of the present invention is appropriately selected according to the type of the preparation, the effect expected by ingestion or administration of the preparation, etc. It is 0.1 to 100% by weight, preferably 0.5 to 80% by weight, particularly preferably 1 to 70% by weight.
The dose and frequency of administration in the case of administering the attention concentration improving agent of the present invention vary depending on the administration form, the age, weight, etc. of the recipient, but usually from 50 mg to citrulline or a salt thereof usually per adult day. It is administered once to several times a day so as to be 30 g, preferably 100 mg to 10 g, particularly preferably 200 mg to 3 g.
　投与期間は、特に限定されないが、通常は１日間～１年間、好ましくは１週間～３ヶ月間である。
　本発明の注意集中力向上剤を摂取または投与することにより、運動でのパフォーマンス向上や学習、仕事における作業効率の最大化等、注意集中力を高めることで期待される効果を得ることができる。 The administration period is not particularly limited, but is usually 1 day to 1 year, preferably 1 week to 3 months.
By ingesting or administering the attention concentration improving agent of the present invention, it is possible to obtain the expected effects by increasing attention concentration, such as performance improvement and learning in exercise, maximizing work efficiency at work.
　以下に、シトルリンの注意集中力向上効果を調べた試験例を示す。
試験例
　健常な45歳から64歳までの男女36名を18名ずつ2つの群に分け、一日当たりシトルリン800mg（266.6mg/カプセル×3粒）もしくはコーンスターチ800mg（266.6mg/カプセル×3粒）を含むカプセルを3週間摂取させる試験を行った。試験開始時および試験開始３週間後の被験者の注意集中力について、線分スケール（ＶＡＳ）法を用いて評価した。すなわち線分の両端に基準となる表現を記し、被験者に表1に示される質問項目の内容に関して線分のどのあたりに相当するかをチェックしてもらった。線分の左端を体感指数０、右端を体感指数１０として、線分の左端からチェックした部分までの距離（mm）を測定し、これを体感指数に換算した。この作業を試験前および試験後に実施し、その差（体感指数の変化）を測定して、群毎の平均値および標準偏差を求めた。体感指数の変化が大きいほど、注意集中力向上効果が大きいことを表す。なお、試験開始時に2群間で差がないことを確認している。 The following is a test example for examining the effect of citrulline on improving attention concentration.
Test example 36 healthy men and women aged between 45 and 64 were divided into two groups of 18 each, and citrulline 800mg (266.6mg / capsule x 3 capsules) or corn starch 800mg (266.6mg / capsule x 3 capsules) per day. A test was conducted in which the capsules containing these were ingested for 3 weeks. The attention concentration of the subjects at the start of the test and 3 weeks after the start of the test was evaluated using a line segment scale (VAS) method. In other words, the reference expression was written at both ends of the line segment, and the subjects were asked to check which line segment corresponded to the contents of the question items shown in Table 1. The distance (mm) from the left end of the line segment to the checked part was measured with the left end of the line segment as a bodily sensation index of 0 and the right end as a bodily sensation index of 10, and this was converted into a bodily sensation index. This operation was performed before and after the test, and the difference (change in sensory index) was measured to determine the average value and standard deviation for each group. The greater the change in the body sensation index, the greater the effect of improving attention concentration. It was confirmed that there was no difference between the two groups at the start of the study.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　また、試験は無作為割付とし、二重盲検並行群間比較を行った。2群間の統計学的有意差検定は、試験開始時と試験終了時の差から、両側分布のunpaired-t検定を行った。結果を図１に示す。
　シトルリン摂取により、考えがまとまらない、ちょっとしたことが思い出せない、やることに間違いが多い、および気が散るといった自覚症状が顕著に改善した。この結果から、シトルリンの注意集中力向上効果が示された。 The study was randomized and compared between double-blind parallel groups. The statistically significant difference test between the two groups was an unpaired-t test with a two-sided distribution based on the difference between the start and end of the test. The results are shown in FIG.
Citrulline significantly improved subjective symptoms such as unthinkable thoughts, little reminders, many mistakes to do, and distractions. From this result, it was shown that citrulline has an effect of improving attention concentration.
　以下に、本発明の実施例を示す。 Examples of the present invention are shown below.
　シトルリンを含有する錠剤の製造
　Ｌ－シトルリン（協和発酵工業社製）120kg、環状オリゴ糖19kg、セルロース57kgおよびプルラン1kgを流動層造粒乾燥機で造粒した。得られた造粒物とステアリン酸カルシウム3kgとをコニカルブレンダーで混合した後、ロータリー圧縮成形機で圧縮成形して錠剤を製造した。 Production of tablets containing citrulline 120 kg of L-citrulline (manufactured by Kyowa Hakko Kogyo Co., Ltd.), 19 kg of cyclic oligosaccharide, 57 kg of cellulose and 1 kg of pullulan were granulated with a fluidized bed granulation dryer. The obtained granulated product and 3 kg of calcium stearate were mixed with a conical blender, and then compressed with a rotary compression molding machine to produce a tablet.
　シトルリンを含有する腸溶錠剤の製造
　実施例１で製造する錠剤の表面をシェラック溶液でコーティングして腸溶錠剤を製造する。 Production of enteric tablet containing citrulline The surface of the tablet produced in Example 1 is coated with a shellac solution to produce an enteric tablet.
　シトルリンを含有する腸溶カプセルの製造
　Ｌ－シトルリン（協和発酵工業社製）120kg、環状オリゴ糖19kg、セルロース57kg、ステアリン酸カルシウム3kgおよびプルラン1kgを、コニカルブレンダーで混合する。得られる混合物20ｋｇと0.2ｋｇの二酸化ケイ素とを混合攪拌して得られる混合物をカプセル充填機に投入、ハードカプセルに充填してハードカプセルを得る。得られるハードカプセルの表面をツェイン溶液でコーティングして腸溶カプセルを製造する。 Production of enteric capsule containing citrulline 120 kg of L-citrulline (manufactured by Kyowa Hakko Kogyo Co., Ltd.), 19 kg of cyclic oligosaccharide, 57 kg of cellulose, 3 kg of calcium stearate and 1 kg of pullulan are mixed in a conical blender. A mixture obtained by mixing and stirring 20 kg of the obtained mixture and 0.2 kg of silicon dioxide is put into a capsule filling machine and filled into hard capsules to obtain hard capsules. The surface of the resulting hard capsule is coated with a zein solution to produce an enteric capsule.
　シトルリンを含有する飲料の製造
　Ｌ－シトルリン（協和発酵工業社製）1.28ｋｇ、エリスリトール3ｋｇ、クエン酸0.05ｋｇ、人工甘味料3ｇ、香料0.06ｋｇを液温70℃で水50Ｌに攪拌溶解し、クエン酸でｐＨを3.3に調整後、プレート殺菌を用いて滅菌して瓶に充填後、パストライザー殺菌し、飲料を製造する。 Manufacture of beverages containing citrulline 1.28 kg of L-citrulline (manufactured by Kyowa Hakko Kogyo Co., Ltd.), 3 kg of erythritol, 0.05 kg of citric acid, 3 g of artificial sweetener and 0.06 kg of fragrance are stirred and dissolved in 50 L of water at a liquid temperature of 70 ° C. After adjusting the pH to 3.3 with acid, sterilize using plate sterilization, fill the bottle, sterilize with pasteurizer, and produce a beverage.
　本発明により、シトルリンまたはその塩を有効成分として含有する、安全で効果的な注意集中力向上剤を提供することができる。 According to the present invention, a safe and effective attention concentration improving agent containing citrulline or a salt thereof as an active ingredient can be provided.

Claims (4)

  1. 　シトルリンまたはその塩を有効成分として含有する注意集中力向上剤。 Attention concentration improver containing citrulline or a salt thereof as an active ingredient.
  2. 　シトルリンまたはその塩の有効量を、必要とする対象に投与することを含む、注意集中力向上方法。 A method for improving attention concentration, including administering an effective amount of citrulline or a salt thereof to a subject in need thereof.
  3. 　注意集中力向上剤の製造のための、シトルリンまたはその塩の使用。 ¡Use of citrulline or its salt for the production of attention concentration improvers.
  4. 　注意集中力向上剤として使用するためのシトルリンまたはその塩。 ¡Citrulline or its salt for use as a concentration-enhancing agent.
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JP2013060406A (en) * 2011-09-15 2013-04-04 Kyowa Hakko Bio Co Ltd Oral agent for brain fatigue improvement
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