JP2005247841A - Anti-anxiety agent - Google Patents
Anti-anxiety agent Download PDFInfo
- Publication number
- JP2005247841A JP2005247841A JP2005029114A JP2005029114A JP2005247841A JP 2005247841 A JP2005247841 A JP 2005247841A JP 2005029114 A JP2005029114 A JP 2005029114A JP 2005029114 A JP2005029114 A JP 2005029114A JP 2005247841 A JP2005247841 A JP 2005247841A
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- Prior art keywords
- serine
- cysteine
- phosphatidylserine
- glycine
- produced
- 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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Abstract
Description
本発明は抗不安剤に関するものである。 The present invention relates to an anxiolytic agent.
不安症は精神疾患の１種であり、発病原因がかなり複雑である。不安症は症状により更にパニック障害、全般性不安障害、恐怖、強迫性障害、外傷後ストレス障害などに分類される。不安症の主な症状は精神障害、気分障害、人格障害、行動障害、睡眠障害などに代表され、これらの‘不安’を適応症に含む医薬品はベンゾジアゼピン系、チエノジアゼピン系、カルバメート系などの５０余りの品目にのぼる。 Anxiety is a type of psychiatric disorder and the cause of its onset is quite complex. Anxiety is further classified into panic disorder, generalized anxiety disorder, fear, obsessive-compulsive disorder, and post-traumatic stress disorder according to symptoms. The main symptoms of anxiety are represented by psychiatric disorders, mood disorders, personality disorders, behavioral disorders, sleep disorders, etc., and there are more than 50 drugs such as benzodiazepines, thienodiazepines, carbamates etc. The number of items.
これらの医薬品は不安、焦燥、イライラ、抑うつ、不眠、緊張、恐怖感などの症状に適用されるが、症状を完全に改善、安定させるために何れも長期間に渡って服用する必要がある。この様な、大量、且つ連続的な摂取により薬依存症、興奮、錯乱など重大な副作用が引起される。或いは少量、短期間の使用でも眠気、めまい、脱力、便秘、食欲不振、肝機能障害など‘軽度な’副作用が発生する。何れにしても従来の抗不安剤は副作用を起こし易い欠点を有する。これら抗不安剤による副作用の欠点を改善するために新たな医薬品及び機能性食品などの開発が必要とされる。 These drugs are applied to symptoms such as anxiety, irritability, irritation, depression, insomnia, tension, fear, etc., but all of them need to be taken for a long time in order to completely improve and stabilize the symptoms. Such large and continuous ingestion causes serious side effects such as drug dependence, excitement and confusion. Alternatively, even in small doses, short-term use can cause 'mild' side effects such as sleepiness, dizziness, weakness, constipation, loss of appetite, and liver dysfunction. In any case, conventional anti-anxiety agents have the drawback of easily causing side effects. In order to improve the disadvantages of side effects caused by these anxiolytic agents, it is necessary to develop new pharmaceuticals and functional foods.
セリンは１８６５年にCramerにより絹の表面蛋白質（セリシン）の加水分解によって得られた新しいアミノ酸で、甘味を有することで知られている。１９０２年、Fischer及びSkitaがセリシンの加水分解物から分離し、更に合成によりその構造を明らかにした。過去に蛋白質の加水分解物から抽出したり、他のアミノ酸より合成したりしていたが、近年では酵素法、発酵法などの工業的手法により生産されている。 Serine is a new amino acid obtained by hydrolysis of silk surface protein (sericin) by Cramer in 1865 and is known to have sweetness. In 1902, Fischer and Skita separated from the sericin hydrolyzate and further revealed its structure by synthesis. In the past, it has been extracted from protein hydrolysates or synthesized from other amino acids, but in recent years it has been produced by industrial methods such as enzymatic methods and fermentation methods.
セリンは非必須アミノ酸であり、生体内でグリシンと相互変換し、また、細胞内でプリン、クレアチン、ポルフィンなど重要な生体成分の合成にも関与し、蛋白質やその他の様々な生体機能にとって重要な化合物の先駆体であることが知られている。特に近年、セリンは神経栄養因子として注目されている。研究によると、セリンは神経細胞の神経栄養支持作用を媒介する重要な因子の１つであり、神経細胞での脂質合成に必要である。しかも、この神経細胞生存促進活性は既知の蛋白質性神経栄養因子よりも強力であり、小脳プルキンエ細胞の樹状突起上に形成されるシナプス終末の数を増加させ、成熟した細胞に特徴的な反複型の膜電位応答の出現も促進する
（非特許文献１：Furuya S. et al, Brain Res. Protoc., 3, 192, 1998；
非特許文献２：Mitoma, M. et al. Neurosei. Res., 30, 195, 1998；
非特許文献３：Furuya, S. et al. Proc. Natl. Acad. Sci. USA, 97, 11528, 2000；
非特許文献４：Yamasaki M. et al, J. Neurosci. Res., 21, 7691, 2001）。
Serine is a non-essential amino acid, interconverts with glycine in vivo, and is also involved in the synthesis of important biological components such as purine, creatine and porphine in the cell, and is important for proteins and various other biological functions. It is known to be a precursor of compounds. In recent years, serine has attracted attention as a neurotrophic factor. Studies show that serine is one of the important factors that mediate neurotrophic support of neurons and is required for lipid synthesis in neurons. Moreover, this neuronal survival promoting activity is more potent than known protein neurotrophic factors, increasing the number of synaptic terminals formed on the dendrites of cerebellar Purkinje cells, which is characteristic of mature cells. The appearance of a type of membrane potential response is also promoted (Non-Patent Document 1: Furuya S. et al, Brain Res. Protoc., 3, 192, 1998;
Non-Patent Document 2: Mitoma, M. et al. Neurosei. Res., 30, 195, 1998;
Non-Patent Document 3: Furuya, S. et al. Proc. Natl. Acad. Sci. USA, 97, 11528, 2000;
Non-Patent Document 4: Yamasaki M. et al, J. Neurosci. Res., 21, 7691, 2001).
セリンはアストロサイトなどグリア細胞で合成され、グリア細胞は常にセリンを一定の濃度を保つように迅速に分泌して、濃度を調節している。しかし、非必須アミノ酸であるセリンが神経細胞に対し神経栄養活性をもち、アストロサイトがセリンを供給している理由は不明であった。この疑問に対する回答の糸口はセリンを前駆体として必要とする膜構成脂質ホスファチジルセリン及びスフィンゴ脂質の生合成が細胞外から供給されるセリンに依存しているという現象の解析から得られた。従って、神経細胞膜に多く含まれるホスファチジルセリン及びスフィンゴ脂質も神経機能と何らかの関係を有することと考えられる（非特許文献５：Mitoma, M. et al. J. Biol. Chem., 273, 19363, 1998）。 Serine is synthesized in glial cells such as astrocytes, and the glial cells always secrete serine rapidly so as to maintain a constant concentration and regulate the concentration. However, the reason why serine, which is a non-essential amino acid, has neurotrophic activity on nerve cells and astrocytes supply serine is unknown. The clue to answering this question was derived from an analysis of the phenomenon that the biosynthesis of the membrane-constituting lipids phosphatidylserine and sphingolipid, which require serine as a precursor, depends on serine supplied from the outside of the cell. Therefore, it is considered that phosphatidylserine and sphingolipids contained in a large amount in nerve cell membranes also have some relationship with nerve function (Non-patent Document 5: Mitoma, M. et al. J. Biol. Chem., 273, 19363, 1998). ).
ホスファチジルセリンは、動物や植物中に広く分布するリン脂質の１種である。ホスファチジルセリンは、生体において、主にその細胞の細胞膜、特に神経細胞膜に多く存在し、細胞膜の重要な成分として知られている。また、ホスファチジルセリンはホスファチジン酸とアミノ酸の１種であるセリンが結合しているという化学構造的な特徴を有するリン脂質であるため、生体内において様々な重要な役割を担っており、生体の生理機能に深く関与している。臨床研究により、ホスファチジルセリンを100〜500mg/日摂取することによる、脳機能改善をはじめとする様々な生理活性が報告された（非特許文献６：Bruni A. et al. Nature, 260, 331, 1976； 非特許文献７：Amaducci T. et al. Psychopharmacol. Bull., 24, 130, 1988； 非特許文献８：Crook T. et al. Neurology, 41, 644, 1991）。 Phosphatidylserine is a kind of phospholipid widely distributed in animals and plants. In the living body, phosphatidylserine exists in a large amount mainly in the cell membrane of the cell, particularly the nerve cell membrane, and is known as an important component of the cell membrane. In addition, phosphatidylserine is a phospholipid having a chemical structural feature in which phosphatidic acid and serine, which is one of amino acids, are combined, and thus plays various important roles in vivo. Deeply involved in the function. Clinical studies have reported various physiological activities including brain function improvement by ingesting phosphatidylserine at 100 to 500 mg / day (Non-patent Document 6: Bruni A. et al. Nature, 260, 331, Non-patent document 7: Amaducci T. et al. Psychopharmacol. Bull., 24, 130, 1988; Non-patent document 8: Crook T. et al. Neurology, 41, 644, 1991).
しかし、ホスファチジルセリンの摂取量は、西洋型の肉食を中心にした食事でも１日平均数十mg程度であり、普段の食事によって生理機能を発揮させるために十分な量のホスファチジルセリンを摂取することは困難である（非特許文献９：Heywood R. et al. Clin. Trials., 24, 25, 1987）。したがって、生理機能を発揮できる十分な量のホスファチジルセリンを摂取するためには、ホスファチジルセリンを高含有する組成物、又はホスファチジルセリンの体内生成に必要とされるものを補助的に摂取すること、例えば健康食品や特定保健用食品などとして摂取することが、有効な方法である。
本発明は従来の抗不安剤が有する副作用を発現しない抗不安剤を提供するものである。 The present invention provides an anxiolytic agent that does not exhibit the side effects of conventional anxiolytic agents.
本発明者は、抗不安剤など精神疾患に対応する医薬品、食品、特定保健用食品、栄養機能食品、又は健康食品を開発するために鋭意検討を重ねた結果、セリン又はホスファチジルセリンに抗不安効果があることを見出した。更に、研究開発を継続した結果、セリン類及び類似の化合物についても抗不安効果があることを見出した。すなわち、本発明は、次のような手段による。
１．セリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）から選択される１種又は２種以上を含有することを特徴とする抗不安剤。
２．セリンが蛋白質加水分解法、化学合成法、酵素法、発酵法、又は動物、植物などから抽出・精製のいずれかの方法によって製造されたものであることを特徴とする１．記載の抗不安剤。
３．ホスファチジルセリンが天然原料から抽出されたもの、或いは酵素による塩基転換反応によって製造されたものであることを特徴とする１．記載の抗不安剤。
４．ホスホセリン、アセチルセリン、システイン、グリシンの各化合物が蛋白質加水分解法、化学合成法、酵素法、又は動物、植物などから抽出・精製のいずれかの方法によって製造されたものであることを特徴とする１．記載の抗不安剤。
５．リゾホスファチジルセリンが天然原料から抽出されたもの、或いは酵素による塩基転換反応又はホスファチジルセリンの脂肪酸解離によって製造されたものであることを特徴とする１．記載の抗不安剤。
６．ホスファチジン酸が天然原料から抽出されたもの、或いは酵素や化学反応による解離反応によって製造されたものであることを特徴とする１．記載の抗不安剤。
７．セリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）から選択される１種又は２種以上の含有量が５質量％以上であることを特徴とする１．〜６．のいずれかに記載の抗不安剤。
８．１．〜７．のいずれかに記載の抗不安剤を含有することを特徴とする抗不安用医薬品。
９．１．〜７．のいずれかに記載の抗不安剤を含有することを特徴とする抗不安用食品、特定保健用食品、栄養機能食品、又は健康食品。
１０．１．〜７．のいずれかに記載の抗不安剤を含有する飼料。
As a result of intensive investigations to develop pharmaceuticals, foods, foods for specified health use, foods with nutrient function claims, or health foods that respond to mental illnesses such as anti-anxiety agents, the present inventor has found an anti-anxiety effect on serine or phosphatidylserine. Found that there is. Furthermore, as a result of continuing research and development, it was found that serines and similar compounds also have anxiolytic effects. That is, the present invention is based on the following means.
1. An anxiolytic agent comprising one or more selected from a compound having a serine unit, cysteine (Cysteine), phosphatidic acid, and glycine (Glycine).
2. 1. Serine is produced by a protein hydrolysis method, a chemical synthesis method, an enzyme method, a fermentation method, or an extraction / purification method from animals, plants, etc. The anxiolytic agent described.
3. 1. Phosphatidylserine extracted from natural raw materials or produced by enzymatic base conversion reaction The anxiolytic agent described.
4). Each compound of phosphoserine, acetylserine, cysteine, and glycine is produced by a protein hydrolysis method, a chemical synthesis method, an enzymatic method, or an extraction / purification method from animals, plants, etc. 1. The anxiolytic agent described.
5. 1. Lysophosphatidylserine extracted from natural raw materials, or produced by enzymatic base conversion or phosphatidylserine fatty acid dissociation. The anxiolytic agent described.
6). 1. A phosphatidic acid extracted from a natural raw material or produced by a dissociation reaction by an enzyme or a chemical reaction. The anxiolytic agent described.
7). The content of one or more selected from a compound having a serine unit, cysteine (Cysteine), phosphatidic acid, and glycine is 5% by mass or more. 1. ~ 6. The anxiolytic agent according to any one of the above.
8.1. ~ 7. An anti-anxiety pharmaceutical comprising the anti-anxiety agent according to any of the above.
9.1. ~ 7. An anti-anxiety food, a specific health food, a nutritional functional food, or a health food, comprising the anxiolytic agent according to any one of the above.
10.1. ~ 7. A feed containing the anxiolytic agent according to any one of the above.
１．セリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）には、抗不安効果があることが確認できた。
２．本発明により副作用を起こさず安全な抗不安剤を提供することができる。
３．人以外に家畜、ペットを対象とすることができる。
1. It was confirmed that compounds having a serine unit, cysteine (Cysteine), phosphatidic acid, and glycine have an anxiolytic effect.
2. The present invention can provide a safe anxiolytic agent without causing side effects.
3. Livestock and pets can be targeted in addition to humans.
本発明に関わる抗不安作用に有効な化合物は、セリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）を確認することができた。
本発明でいうセリンユニット（Serine Unit）とは、次の一般式１に示される（Serine Unit）「−Ｏ−ＣＨ（ＮＨ２）ＣＯＯＨ」をいう。
このセリンユニットを有する化合物としては、セリン（Serine（Ser.））、ホスファチジルセリン（Phosphatidyl-Serine（PS））、ホスホセリン（Phospho-Serine（Phos-S））、アセチルセリン（Acetyl-Serine（Ace-S））、リゾホスファチジルセリン（Lyso Phosphatidyl Serine（Lyso-PS） ）を挙げることができる。このセリンユニット（Serine Unit）に接続するＲ基が、リン酸基である場合は、より強い活性が得られる。
As the compounds effective for the anxiolytic action according to the present invention, compounds having a serine unit, cysteine (Cysteine), phosphatidic acid, and glycine (Glycine) could be confirmed.
The serine unit referred to in the present invention refers to (Serine Unit) “—O—CH (NH 2 ) COOH” represented by the following general formula 1.
Compounds having this serine unit include serine (Serine (Ser.)), Phosphatidylserine (Phosphatidyl-Serine (PS)), phosphoserine (Phospho-Serine (Phos-S)), acetylserine (Acetyl-Serine (Ace-) S)) and lysophosphatidylserine (Lyso-Phosphatidyl Serine (Lyso-PS)). When the R group connected to this serine unit is a phosphate group, stronger activity is obtained.
本発明に関わるセリンは蛋白質加水分解法、化学合成法、酵素法、発酵法の何れかの方法によって製造することができる。また、セリンは組織の構成成分であることから、収率は低いものの動物、植物などから抽出・精製して製造することもできる。さらに、動物、植物など由来成分から、例えばホスホセリンやホスビチンなどから化学処理により生成・抽出・精製して製造することもできる。本発明に関わるセリンは特に製造方法を限定するものではない。 Serine according to the present invention can be produced by any of protein hydrolysis method, chemical synthesis method, enzyme method and fermentation method. In addition, since serine is a structural component of tissue, it can be produced by extraction and purification from animals, plants, etc., although the yield is low. Furthermore, it can also be produced from components derived from animals, plants, etc., for example, from phosphoserine or phosvitin by chemical treatment, extraction and purification. The serine according to the present invention does not particularly limit the production method.
各化合物の構造の例を図２２〜２９に記載する。
図２２はＬ-セリン（L-Serine（Ser.））、図２３はＬ-アセチルセリン（L-Acetyl-Serine（Ace-S））、図２４はＯ−ホスホセリン（O-Phospho-Serine（Phos-S））、図２５はホスファチジルセリン（Phosphatidyl-Serine（PS））、図２６はリゾホスファチジルセリン（Lyso Phosphatidyl Serine（Lyso-PS） ）、図２７はL-システイン（L-Cysteine）、図２８はグリシン（Glycine）、図２９はホスファチジン酸（Phosphatidic Acid(PA)）である。
システイン（Cysteine）は、化学式「Ｈ−Ｓ−ＣＨ（ＮＨ２）ＣＯＯＨ」で示される。セリンユニットの「−Ｏ−」が属性の近い「−Ｓ−」に置換されて、その活性が維持されている。
Examples of the structure of each compound are shown in FIGS.
22 shows L-serine (L-Serine (Ser.)), FIG. 23 shows L-acetylserine (L-Acetyl-Serine (Ace-S)), and FIG. 24 shows O-phosphoserine (O-Phospho-Serine (Phos). -S)), FIG. 25 is phosphatidylserine (PS), FIG. 26 is lysophosphatidylserine (Lyso-PS), FIG. 27 is L-cysteine (L-Cysteine), FIG. Is Glycine, and FIG. 29 is Phosphatidic Acid (PA).
Cysteine is represented by the chemical formula “HS—CH (NH 2 ) COOH”. The “—O—” of the serine unit is replaced with “-S—” having a close attribute, and the activity is maintained.
本発明に関わるホスファチジルセリンは、天然物である、大豆、綿実などの植物種子や卵黄、魚介類、鳥獣肉類などから抽出により製造することができる。又は、これらから製造されたレシチンを用いてホスファチジル基転移反応を行うことにより、ホスファチジルセリン高含有リン脂質原料が製造できる。本発明に関わるホスファチジルセリンは特に製造方法を限定するものではない。 The phosphatidylserine according to the present invention can be produced by extraction from natural plant seeds such as soybeans and cottonseed, egg yolk, seafood, and animal meat. Or the phosphatidylserine high content phospholipid raw material can be manufactured by performing phosphatidyl group transfer reaction using the lecithin manufactured from these. The production method of phosphatidylserine according to the present invention is not particularly limited.
本発明に関わるホスホセリンは蛋白質加水分解法、化学合成法、酵素法の何れかの方法によって製造することができる。ホスホセリンはセリンの生合成の中間体として知られる。リン酸を含まれる蛋白質の構成成分であることから、収率は低いものの動物、植物などから抽出・精製して製造することもできる。ホスホセリンを多く含む蛋白質として、カゼイン、ホスビチンなどがある。さらに、動物、植物など由来成分から、例えばカゼインやホスビチンなどから化学処理により生成・抽出・精製して製造することもできる。本発明に関わるホスホセリンは特に製造方法を限定するものではない。 The phosphoserine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods. Phosphoserine is known as an intermediate of serine biosynthesis. Since it is a component of a protein containing phosphoric acid, it can be produced by extraction and purification from animals, plants, etc., although the yield is low. Examples of proteins rich in phosphoserine include casein and phosvitin. Furthermore, it can also be produced from components derived from animals, plants, etc., for example, from casein or phosvitin through chemical treatment, extraction and purification. The production method of phosphoserine according to the present invention is not particularly limited.
本発明に関わるアセチルセリンは蛋白質加水分解法、化学合成法、酵素法の何れかの方法によって製造することができる。アセチルセリンは微生物におけるシステインの生合成の中間体として知られる。本発明に関わるアセチルセリンは特に製造方法を限定するものではない。 Acetylserine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods. Acetylserine is known as an intermediate of cysteine biosynthesis in microorganisms. The production method of acetylserine according to the present invention is not particularly limited.
本発明に関わるシステインは蛋白質加水分解法、化学合成法、酵素法の何れかの方法によって製造することができる。また、システインは組織の構成成分であることから、収率は低いものの動物、植物などから抽出・精製して製造することもできる。さらに、システインはセリンのヒドロキシル基酸素原子を硫原子に置換されたものであるので、セリンから化学処理により生成・抽出・精製して製造することもできる。本発明に関わるシステインは特に製造方法を限定するものではない。 Cysteine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods. Cysteine is a structural component of tissue, and thus can be produced by extraction and purification from animals, plants, etc., although the yield is low. Furthermore, since cysteine has a hydroxyl group oxygen atom of serine substituted with a sulfur atom, it can be produced from serine by chemical treatment, extraction and purification. The production method of cysteine related to the present invention is not particularly limited.
本発明に関わるグリシンは蛋白質加水分解法、化学合成法、酵素法の何れかの方法によって製造することができる。また、グリシンは動物性蛋白質、特に絹フィブロイン、ゼラチン、エラスチンなどに多量に含まれるので、収率は低いものの動物から抽出・精製して製造することもできる。さらに、グリシンはセリンの脱炭酸代謝体であるから、セリンから化学処理により生成・抽出・精製して製造することもできる。本発明に関わるグリシンは特に製造方法を限定するものではない。 Glycine according to the present invention can be produced by any of protein hydrolysis, chemical synthesis, and enzymatic methods. In addition, glycine is contained in a large amount in animal proteins, particularly silk fibroin, gelatin, elastin and the like, so that it can be produced by extraction and purification from animals although the yield is low. Furthermore, since glycine is a decarboxylated metabolite of serine, it can also be produced from serine by chemical treatment, extraction and purification. The production method of glycine according to the present invention is not particularly limited.
本発明に関わるリゾホスファチジルセリンは、天然物である、大豆、綿実などの植物種子や卵黄、魚介類、鳥獣肉類などから抽出により製造することができる。又は、これらから製造されたリゾレシチンを用いてホスファチジル基転移反応を行うことにより、リゾホスファチジルセリン高含有リン脂質原料が製造できる。リゾホスファチジルセリンはホスファチジルセリンの脂肪酸部分が解離されたものであるから、ホスファチジルセリンから酵素や化学的処理により生成・抽出・精製して製造することもできる。本発明に関わるリゾホスファチジルセリンは特に製造方法を限定するものではない。 The lysophosphatidylserine according to the present invention can be produced by extraction from natural plant seeds such as soybeans and cotton seeds, egg yolk, seafood, and animal meat. Alternatively, a lysophosphatidylserine-rich phospholipid raw material can be produced by carrying out a phosphatidyl group transfer reaction using lysolecithin produced therefrom. Since lysophosphatidylserine is obtained by dissociating the fatty acid part of phosphatidylserine, it can also be produced from phosphatidylserine by enzyme, chemical treatment, extraction and purification. The production method of lysophosphatidylserine according to the present invention is not particularly limited.
本発明に関わるホスファチジン酸は、天然物である、大豆、綿実などの植物種子や卵黄、魚介類、鳥獣肉類などから抽出により製造することができる。また、ホスファチジン酸はリン脂質の塩基部分が解離されたものであるから、各種リン脂質、例えばレシチン（ホスファチジルコリン）、ホスファチジルセリン、ホスファチジルエタノールアミン、ホスファチジルイノシトールの１種、或いは数種を高含有する原料から酵素や化学的処理により生成・抽出・精製して製造することもできる。本発明に関わるホスファチジン酸は特に製造方法を限定するものではない。 The phosphatidic acid according to the present invention can be produced by extraction from plant seeds such as soybeans and cotton seeds, egg yolks, seafood, poultry meat, and the like, which are natural products. In addition, since phosphatidic acid is obtained by dissociating the base part of phospholipid, it is a raw material containing a high content of various phospholipids such as lecithin (phosphatidylcholine), phosphatidylserine, phosphatidylethanolamine, or phosphatidylinositol. It can also be produced, extracted and purified by enzyme or chemical treatment. The production method of the phosphatidic acid according to the present invention is not particularly limited.
本発明に関わる抗不安剤を製造するには、上記の方法で製造したセリン、ホスファチジルセリン、ホスホセリン、アセチルセリン、システイン、グリシン、リゾホスファチジルセリン、ホスファチジン酸を有効成分とするもの又は市販のセリン、ホスファチジルセリン、ホスホセリン、アセチルセリン、システイン、グリシン、リゾホスファチジルセリン、ホスファチジン酸を有効成分とするものを原料として用いることができ、常法に従って公知の医薬用無毒性担体と組み合わせて製剤化すればよい。 In order to produce an anxiolytic agent related to the present invention, serine, phosphatidylserine, phosphoserine, acetylserine, cysteine, glycine, lysophosphatidylserine, phosphatidic acid produced by the above method or commercially available serine, Those containing phosphatidylserine, phosphoserine, acetylserine, cysteine, glycine, lysophosphatidylserine, phosphatidic acid as active ingredients can be used as raw materials, and may be formulated in combination with known non-toxic pharmaceutical carriers according to conventional methods. .
本発明に関わる抗不安剤は、種々の剤型での投与が可能であり、例えば、経口投与剤としては錠剤、顆粒剤、散剤、カプセル剤、ソフトカプセル剤等の固形剤、溶液剤、懸濁剤、乳剤等の液剤、凍結乾燥製剤等が挙げられ、非経口投与剤としては、注射剤のほか、坐剤、噴霧剤、経皮吸収剤等が挙げられ、これらの製剤は製剤上の常套手段により調製することができる。上記の医薬用無毒性担体としては、例えば、グルコース、乳糖、ショ糖、澱粉、マンニトール、デキストリン、脂肪酸グリセリド、ポリエチレングリコール、ヒドロキシエチルデンプン、エチレングリコール、ポリオキシエチレンソルビタン脂肪酸エステル、アミノ酸、アルブミン、水、生理食塩水等が挙げられる。また、必要に応じて、安定化剤、滑剤、湿潤剤、乳化剤、結合剤等の慣用の添加剤を適宜添加することができる。 The anxiolytic agent according to the present invention can be administered in various dosage forms. For example, as an orally administered agent, a solid agent such as a tablet, granule, powder, capsule, soft capsule, solution, suspension Liquids such as suppositories and emulsions, lyophilized preparations, and the like, and parenteral administration agents include suppositories, sprays, transdermal absorption agents, etc., in addition to injections. It can be prepared by means. Examples of the non-toxic pharmaceutical carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, amino acid, albumin, water And physiological saline. If necessary, conventional additives such as stabilizers, lubricants, wetting agents, emulsifiers, binders and the like can be appropriately added.
本発明に関わる抗不安剤において、セリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）の投与量は、患者の年齢、体重、症状、疾患の程度、投与スケジュール、製剤形態等により、適宜選択・決定されるが、例えば、１日あたり0.01〜10g/kg体重程度とされ、１日１〜数回に分けて投与してもよい。 In the anti-anxiety agent according to the present invention, the dosage of a compound having a serine unit (Serine Unit), cysteine (Cysteine), phosphatidic acid (Glycine), the patient's age, weight, symptoms, disease The dose is appropriately selected and determined according to the degree, administration schedule, formulation form, etc., but is, for example, about 0.01 to 10 g / kg body weight per day, and may be divided into 1 to several times a day.
また、本発明に関わるセリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）は、生体生成又は構成成分であり、食品中にも微量ながら普遍的に含まれている成分であることから安全性が高いと考えられ、不安の予防・改善を目的として、抗不安機能性食品として摂取することもできる。 In addition, compounds having serine units related to the present invention, cysteine (Cysteine), phosphatidic acid, and glycine (Glycine) are biologically produced or constituting components, and even in food, they are universal in small quantities. It is considered to be highly safe because it is contained in the food, and can be taken as an anxiolytic functional food for the purpose of preventing or improving anxiety.
本発明に関わるセリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）を含有することを特徴とする抗不安機能性食品は、特定保健用食品、栄養機能食品、又は健康食品として位置付けることができる。機能性食品としては、例えば、これらの化合物に適当な助剤を添加した後、慣用の手段を用いて、食用に適した形態、例えば、顆粒状、粒状、錠剤、カプセル剤、ソフトカプセル剤、ペースト状等に形成したものを用いることができる。この抗不安機能性食品は、そのまま食用に供してもよく、また種々の食品（例えばハム、ソーセージ、かまぼこ、ちくわ、パン、バター、粉乳、菓子など）に添加して使用したり、水、酒類、果汁、牛乳、清涼飲料水等の飲物に添加して使用してもよい。かかる食品の形態における本発明のセリン又はホスファチジルセリンの摂取量は年齢、体重、症状、疾患の程度、食品の形態等により適宜選択・決定されるが、例えば、１日あたり0.01〜10g/kg体重程度とされる。 An anxiolytic functional food characterized by containing a compound having a serine unit according to the present invention, cysteine (Cysteine), phosphatidic acid, glycine (Glycine) is a food for specified health use, It can be positioned as a nutritional functional food or a health food. As a functional food, for example, after adding an appropriate auxiliary agent to these compounds, using a conventional means, a form suitable for food, for example, granular, granular, tablet, capsule, soft capsule, paste What was formed in the shape etc. can be used. This anti-anxiety functional food may be used for food as it is, or added to various foods (for example, ham, sausage, kamaboko, chikuwa, bread, butter, milk powder, confectionery, etc.), water, alcoholic beverages It may be used by adding to drinks such as fruit juice, milk, and soft drinks. The intake of serine or phosphatidylserine of the present invention in such a food form is appropriately selected and determined according to age, body weight, symptoms, disease level, food form, etc., for example, 0.01 to 10 g / kg body weight per day It is said to be about.
上述のセリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）を含有する抗不安を目的とした医薬品、食品、特定保健用食品、栄養機能食品、又は健康食品中のこれらの各化合物の含有量の合計は組成物全量中５質量％以上にすることが望ましい。さらに望ましいのはこれら各化合物の含有量の合計が組成物全量中20質量％以上にすることである。 Drugs, foods, foods for specified health use, foods for nutritional function, foods for the purpose of anxiety containing the above-mentioned compounds having serine units (Cysteine), phosphatidic acid, glycine (Glycine), Alternatively, the total content of these compounds in the health food is desirably 5% by mass or more based on the total amount of the composition. It is further desirable that the total content of these compounds is 20% by mass or more based on the total amount of the composition.
さらに、セリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）を含有する抗不安剤を飼料として家畜、ペットに与えることにより、家畜の情緒が安定し、成長を促進することができる。特に、生後間もなく、親から離されて飼育される幼齢のペットや家畜に有効である。 In addition, by giving anxiolytics containing serine units, cysteine (Cysteine), phosphatidic acid, and glycine (Glycine) as feed to livestock and pets, the emotions of the livestock are stabilized. And can promote growth. In particular, it is effective for young pets and livestock that are bred away from their parents soon after birth.
セリンユニット（Serine Unit）を有する化合物、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）を有効成分とする組成物の抗不安機能を検証することに当たって、本発明者はまず新生ニワトリヒナの脳室内に直接セリン（Serine（Ser.））、ホスファチジルセリン（Phosphatidyl-Serine（PS））、ホスホセリン（Phospho-Serine（Phos-S））、アセチルセリン（Acetyl-Serine（Ace-S））、リゾホスファチジルセリン（Lyso Phosphatidyl Serine（Lyso-PS） ）、システイン（Cysteine）、ホスファチジン酸（Phosphatidic Acid）、グリシン（Glycine）、ホスファチジルコリン（Phosphatidyl-choline（PC））、ホスファチジルエタノールアミン（Phosphatidyl-ethanolamin（PE））及びホモセリン（Homo- Serine（HS））を投与し、その後ニワトリヒナの行動を観察し、さらに血中コルチコステロン濃度を比較した。
以下に実施例を挙げて本発明を具体的に説明するが、本発明はこれらに限定されるものではない。
In examining the anti-anxiety function of a composition comprising a compound having a serine unit, cysteine (Cysteine), phosphatidic acid, and glycine (Glycine) as an active ingredient, the present inventor firstly developed a newborn chicken. Serine (Serine (Ser.)), Phosphatidylserine (Phosphatidyl-Serine (PS)), phosphoserine (Phospho-Serine (Phos-S)), acetylserine (Acetyl-Serine (Ace-S)) , Lysophosphatidylserine (Lyso Phosphatidyl Serine (Lyso-PS)), cysteine (Cysteine), phosphatidic acid (Glycine), phosphatidylcholine (Phosphatidyl-choline (PC)), phosphatidylethanolamine (Phosphatidyl-ethanola (Phosphatidyl-ethanola) PE)) and homoserine (HS), followed by chick behavior and blood Medium corticosterone concentrations were compared.
EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
〔試験条件１〕
試験条件１は、実施例１〜３に適用する。
試験動物：卵用種雄ニワトリヒナ（Julia、４又は５日齢）を試験に使用した。試料を投与する前に、試験動物は体重に応じて群分けを行い、６羽を一組にした。
飼育条件：29±1℃の条件下で、市販飼料（豊橋飼料社製、AX）と水を自由摂食させた。
試験試料：次の試薬はそれぞれ0.1%のエバンスブルーを含むTris-HCl Buffer中に懸濁し、調製した。
大豆由来のホスファチジルセリン（ＳＩＧＭＡ、98％、牛脳由来）
ホスファチジルコリン（ＳＩＧＭＡ、99％、大豆由来）
ホスファチジルエタノールアミン（ＳＩＧＭＡ、98％、牛脳由来）、
Ｌ−セリン（和光純薬工業、99％）
試験方法： マイクロシリンジを用いて210mmolの試験試料をニワトリヒナの脳室に投与した。
また、Control群には0.1%のエバンスブルーを含むTris-HCl Bufferを10μl脳室投与した。
行動観察：投与から10分後、各ニワトリヒナを群飼育ケージから行動観察用分離飼育ケージに移し、ニワトリヒナの鳴き回数と自発運動量を記録した。
血液測定：行動観察が終了したニワトリヒナから直ちに採血を行い、血漿中のコルチコステロン濃度をコルチステロンキット（ＳＣＥＴＩ社製、Rat Corticosterone RIA Kit）で測定した。
[Test condition 1]
Test condition 1 applies to Examples 1-3.
Test animals: Egg breed male chicks (Julia, 4 or 5 days old) were used in the test. Prior to sample administration, the test animals were grouped according to body weight, with 6 birds in groups.
Breeding conditions: Under the condition of 29 ± 1 ° C., commercial feed (Toyohashi Feed Co., Ltd., AX) and water were freely fed.
Test sample: The following reagents were each prepared by suspending in Tris-HCl Buffer containing 0.1% Evans blue.
Soybean-derived phosphatidylserine (SIGMA, 98%, derived from bovine brain)
Phosphatidylcholine (SIGMA, 99%, derived from soybeans)
Phosphatidylethanolamine (SIGMA, 98%, derived from bovine brain),
L-serine (Wako Pure Chemical Industries, 99%)
Test Method: 210 mmol test sample was administered into the chick ventricle using a microsyringe.
In addition, 10 μl of the Tris-HCl Buffer containing 0.1% Evans Blue was administered to the Control group.
Behavioral observation: Ten minutes after administration, each chick was transferred from the group cage to a separate cage for behavioral observation, and the number of chicks squealed and the amount of spontaneous exercise were recorded.
Blood measurement: Blood was immediately collected from chicks whose behavior was observed, and the corticosterone concentration in the plasma was measured with a cortisosterone kit (Rat Corticosterone RIA Kit, manufactured by SCETI).
各試験動物を体重に応じて６羽ずつintact群（脳室投与の注射行為をしない群）、コントロール群（脳室に0.1％のエバンスブルーを含むTris-HCl Bufferを投与する群）、ホスファチジルセリン投与群とホスファチジルコリン投与群に分け、それぞれの群飼育ケージに入れ、飼育した。その後、コントロール群、ホスファチジルセリン群、ホスファチジルコリン群にそれぞれの試験試料を投与し、その10分後にニワトリヒナを群飼育ケージから分離飼育ケージに移し、不安と感じたヒナの鳴き回数を10分間記録し、その結果は図１、図２に示した。
また、鳴き回数を測定する間のニワトリヒナの動きを自発運動量として記録し、そのカウントした結果は図３、図４に示した。
これらの結果からセリン(Ser．)とホスファチジルセリン(PS)は、不安によるニワトリヒナの鳴き回数と自発運動量を共に有意に抑えたことが示された。一方、ホスファチジルコリン(PC)にはこの様な結果が示されなかった。
Each test animal has 6 intact animals (groups that do not undergo ventricular injection), control group (group that receives Tris-HCl Buffer containing 0.1% Evans blue in the ventricle), phosphatidylserine. They were divided into administration groups and phosphatidylcholine administration groups, placed in their respective cages and reared. Then, each test sample was administered to the control group, the phosphatidylserine group, and the phosphatidylcholine group. Ten minutes later, the chicks were transferred from the group cage to a separate cage, and the number of chicks felt anxious was recorded for 10 minutes. The results are shown in FIGS.
In addition, the movement of the chicken chick during the measurement of the number of calls was recorded as the amount of spontaneous movement, and the counted results are shown in FIGS.
These results showed that serine (Ser.) And phosphatidylserine (PS) significantly suppressed both the number of chicks squeaking and locomotor activity due to anxiety. On the other hand, phosphatidylcholine (PC) did not show such results.
上述試験を終えたコントロール群、ホスファチジルセリン群、ホスファチジルコリン群及びintact群の各ニワトリヒナから直ちに採血を行い、血漿中のコルチコステロン濃度を測定した（図５）。
この結果からホスファチジルセリンとセリンは、不安による血中コルチコステロン濃度の上昇を抑え、正常時のレベル近くまで回復する傾向が示された。一方、ホスファチジルコリンにはこの様な結果が示されなかった。
Blood was immediately collected from chicks in the control group, phosphatidylserine group, phosphatidylcholine group, and intact group after the above test, and the corticosterone concentration in plasma was measured (FIG. 5).
The results showed that phosphatidylserine and serine suppressed the increase in blood corticosterone concentration due to anxiety and tended to recover to near normal levels. On the other hand, phosphatidylcholine did not show such results.
コルチコステロンは副腎皮質にて合成される物質である。不安（ストレス）時に血中に多く分泌される特徴を有することにより不安（ストレス）ホルモンと呼ばれ、不安（ストレス）の指標として利用されている。今回の試験は試料がニワトリヒナの脳室内に直接投与することであるため、セリン及びホスファチジルセリンの抗不安効果は通常の中枢神経系から脳下垂体へ転達した不安（ストレス）情報により副腎皮質ホルモンが刺激され、そしてコルチコステロンの生成に至る過程の何処かに阻害したのではないかと推測される。 また、この効果は少なくともムスカリン性アセチルコリン受容体（M-AchR）を部分的に介していることが別の試験（試験部分を省略する）により明らかとなった。 Corticosterone is a substance synthesized in the adrenal cortex. It is called an anxiety (stress) hormone because it has a characteristic of being secreted in the blood during anxiety (stress), and is used as an index of anxiety (stress). In this study, the sample was administered directly into the chick cerebral ventricle, so the anxiolytic effects of serine and phosphatidylserine were determined by the anxiety (stress) information that was transferred from the normal central nervous system to the pituitary gland. It is speculated that the hormone was stimulated and inhibited somewhere in the process leading to the production of corticosterone. In addition, it was revealed by another test (the test part is omitted) that this effect is at least partially mediated by the muscarinic acetylcholine receptor (M-AchR).
セリンとホスファチジルセリンがほぼ同様な結果を示したことは、この２つの成分に共通点を有することを示唆した。つまり、セリンとホスファチジルセリンに共有する「−Ｏ−ＣＨ（ＮＨ２）ＣＯＯＨ」の様なセリンユニット（Serine Unit）が不安に対して抑制効果を有することを示唆した。この点については、ホスファチジルセリンと脂質部分に共通な構造を持つホスファチジルコリンにこの様な抗不安効果を全く示していなかったことにより、裏付けを得た。さらに裏付けるために、ホスファチジルセリンの脱炭酸生成物であるホスファチジルエタノールアミンを用いて上述の試験と同じ様にニワトリヒナの鳴き回数と自発運動量においてホスファチジルセリンと比較した。 The fact that serine and phosphatidylserine showed almost similar results suggested that these two components had something in common. That is, it was suggested that a serine unit (Serine Unit) such as “—O—CH (NH 2 ) COOH” shared by serine and phosphatidylserine has an inhibitory effect on anxiety. This was supported by the fact that phosphatidylcholine having a structure common to phosphatidylserine and the lipid portion did not show such an anxiolytic effect at all. For further support, phosphatidylserine was compared with phosphatidylserine using the phosphatidylethanolamine, which is a decarboxylation product of phosphatidylserine, in the number of chicks squeezed and the amount of locomotion.
各試験動物を体重に応じて６羽ずつに分け、コントロール群、ホスファチジルセリン群とホスファチジルエタノールアミン群とし、それぞれの試験試料を投与した。その後、実施例１と同様にニワトリヒナの鳴き回数と自発運動量を記録した。
図６〜９に示したように、ホスファチジルセリン(PS)は実施例１と同様な抗不安効果を示したのに対して、セリンユニットを持っていないホスファチジルエタノールアミン(PE)は全くこの様な結果を示さなかった。
Each test animal was divided into 6 birds according to body weight, and each test sample was administered as a control group, a phosphatidylserine group, and a phosphatidylethanolamine group. Thereafter, the number of chicks squeezed and the amount of spontaneous exercise were recorded in the same manner as in Example 1.
As shown in FIGS. 6 to 9, phosphatidylserine (PS) showed an anxiolytic effect similar to that of Example 1, whereas phosphatidylethanolamine (PE) having no serine unit is completely like this. Results were not shown.
また、上述の試験は検体がニワトリヒナの脳室に投与後直ちに行われたものであるので、これら抗不安効果は、セリン又はホスファチジルセリンそのものに由来すると推測できる。つまり、少なくとも単体であるセリン又はホスファチジルセリンを有効成分とするものには抗不安効果があると言える。 In addition, since the above-mentioned test was performed immediately after administration of the specimen into the chick ventricle, it can be assumed that these anxiolytic effects are derived from serine or phosphatidylserine itself. That is, it can be said that what has serine or phosphatidylserine which is a simple substance as an active ingredient has an anxiolytic effect.
更に、研究を継続した結果、本発明者は、上述に提案したセリンユニットに抗不安効果を有することについて、セリン類及び類似の化合物についても抗不安効果があることを見出し、より具体的にセリンユニットの特徴を定義できた。
以下に追加実施例を挙げて本発明を具体的に説明するが、本発明はこれらに限定されるものではない。
Furthermore, as a result of continuing research, the present inventor found that the serine unit proposed above has an anxiolytic effect, and that serine compounds and similar compounds also have an anxiolytic effect. The characteristics of the unit could be defined.
The present invention will be specifically described below with reference to additional examples, but the present invention is not limited thereto.
〔試験条件２〕
試験条件２は、実施例４〜６に適用する。各実施例は、時期と化合物を変えて実験を行った。
試験動物：卵用種雄ニワトリヒナ（Julia、５又は６日齢）を試験に使用した。試料を投与する前に、試験動物は体重を応じて群分けを行い、７〜９羽を一組にして、化合物数に相当する組数を用いた。
飼育条件：29±1℃の条件下で、市販飼料（豊橋飼料社製、AX）と水を自由摂食させた。
試験試料：次の試薬はそれぞれ0.1%のエバンスブルーを含む0.85%の生理食塩水に溶かし、調製した。
[Test condition 2]
Test condition 2 applies to Examples 4-6. In each example, the experiment was performed at different times and compounds.
Test animals: Egg chicks (Julia, 5 or 6 days old) were used for the test. Prior to sample administration, the test animals were grouped according to body weight, with 7-9 birds in one set, and the number of pairs corresponding to the number of compounds was used.
Breeding conditions: Under the condition of 29 ± 1 ° C., commercial feed (Toyohashi Feed Co., Ltd., AX) and water were freely fed.
Test sample: The following reagents were each prepared by dissolving in 0.85% physiological saline containing 0.1% Evans blue.
実施例４〜６に用いる試薬：
Ｌ−セリン（和光純薬工業社製、99％）
ホスホセリン（ＳＩＧＭＡ社製、98％）
アセチルセリン（和光純薬工業社製、99％）
リゾホスファチジルセリン（フナコシ社製、98％、牛脳由来）
Ｌ-システイン（和光純薬工業社製、99％）
ホスファチジン酸（フナコシ社製、98％、大豆由来）
グリシン（和光純薬工業社製、99％）
Reagents used in Examples 4 to 6:
L-serine (Wako Pure Chemical Industries, 99%)
Phosphoserine (SIGMA, 98%)
Acetylserine (Wako Pure Chemical Industries, 99%)
Lysophosphatidylserine (Funakoshi, 98%, derived from bovine brain)
L-Cysteine (Wako Pure Chemical Industries, 99%)
Phosphatidic acid (Funakoshi, 98%, derived from soybeans)
Glycine (Wako Pure Chemical Industries, 99%)
試験方法：マイクロシリンジを用いて一羽あたりに0.84mmolをニワトリヒナの脳室に投与した。また、Control群には0.1%のエバンスブルーを含む0.85%の生理食塩水を10μl 脳室投与した。
行動観察：投与から10分後、各ニワトリヒナを群飼育ケージから行動観察用分離飼育ケージに移した脳室投与の直後に単離ストレス状況下で10分間の行動観察を行い、鳴声と自発運動量の測定を行った。ニワトリヒナの鳴き回数と自発運動量を記録した。10分間の経過と10分間の総数を１羽当たりの平均としてグラフを図１０〜２１に示した。
試料投与確認観察：麻酔後に断頭し、脳を観察して試薬が側脳室に正しく注入されているか観察した。
Test method: 0.84 mmol per bird was administered to the chick ventricle using a microsyringe. In the Control group, 10 μl of ventricle was administered with 0.85% physiological saline containing 0.1% Evans blue.
Behavioral observation: 10 minutes after administration, each chick was transferred from the group cage to a separate cage for behavioral observation Immediately after the ventricular administration, the behavioral observation was performed for 10 minutes under isolated stress conditions. The momentum was measured. The number of chicks squeezed and the amount of spontaneous movement were recorded. The graphs are shown in FIGS. 10 to 21 with the 10-minute progress and the total number of 10-minutes as the average per bird.
Sample administration confirmation observation: The patient was decapitated after anesthesia, and the brain was observed to observe whether the reagent was correctly injected into the lateral ventricle.
実施例４は次の化合物を試験試料として用いた。鳴き回数を測定する間のニワトリヒナの動きを自発運動量として記録し、そのカウントした結果は図１０〜１３に示した。
（１）Control群
（２）Ｌ-セリン（L-Serine（Ser.））投与群
（３）ホスホセリン（Phospho-Serine（Phos-S））投与群
（４）アセチルセリン（Acetyl-Serine（Ace-S））投与群
（５）ホモセリン（Homo- Serine（HS））投与群
In Example 4, the following compounds were used as test samples. The movement of chicks during the measurement of the number of calls was recorded as the amount of spontaneous movement, and the counted results are shown in FIGS.
(1) Control group (2) L-serine (L-Serine (Ser.)) Administration group (3) Phosphoserine (Phospho-Serine (Phos-S)) administration group (4) Acetyl-Serine (Ace-) S)) administration group (5) homoserine (Homo- Serine (HS)) administration group
これらの結果からＬ-セリン（L-Serine（Ser.））、ホスホセリン（Phospho-Serine（Phos-S））、アセチルセリン（Acetyl-Serine（Ace-S））には、不安によるニワトリヒナの鳴き回数と自発運動量を共に有意に抑えたことが示された。一方、ホモセリン（Homo- Serine（HS））には効果が示されなかった。最も効果が得られた物質は、ホスホセリン（Phospho-Serine（Phos-S））であった。 From these results, L-serine (L-Serine (Ser.)), Phosphoserine (Phospho-Serine (Phos-S)), and acetylserine (Acetyl-Serine (Ace-S)) are squeezed by chicks due to anxiety. It was shown that both the frequency and the amount of spontaneous exercise were significantly suppressed. On the other hand, homoserine (Homo- Serine (HS)) showed no effect. The most effective substance was phosphoserine (Phospho-Serine (Phos-S)).
実施例５は次の化合物を試験試料として用いた。鳴き回数を測定する間のニワトリヒナの動きを自発運動量として記録し、そのカウントした結果は図１４〜１７に示した。 （１）Control群
（２）Ｌ-セリン（L-Serine（Ser.））投与群
（３）ホスホセリン（Phospho-Serine（Phos-S））投与群
（４）アセチルセリン（Acetyl-Serine（Ace-S））投与群
（５）Ｌ-システイン（L-Cysteine）投与群
In Example 5, the following compounds were used as test samples. The movement of the chicken chick during the measurement of the number of calls was recorded as the amount of spontaneous movement, and the counted results are shown in FIGS. (1) Control group (2) L-serine (L-Serine (Ser.)) Administration group (3) Phosphoserine (Phospho-Serine (Phos-S)) administration group (4) Acetyl-Serine (Ace-) S)) administration group (5) L-cysteine (L-Cysteine) administration group
これらの結果からＬ-セリン（L-Serine（Ser.））、ホスホセリン（Phospho-Serine（Phos-S））、アセチルセリン（Acetyl-Serine（Ace-S））に抗不安効果を有することを再度確認できたと共にＬ-システイン（L-Cysteine）にも、不安によるニワトリヒナの鳴き回数と自発運動量を共に有意に抑えたことが分った。この試験においても最も効果が得られた物質は、ホスホセリン（Phospho-Serine（Phos-S））であった。 From these results, it has been confirmed that L-serine (L-Serine (Ser.)), Phosphoserine (Phospho-Serine (Phos-S)), and acetylserine (Acetyl-Serine (Ace-S)) have an anxiolytic effect. It was confirmed that L-cysteine (L-Cysteine) also significantly suppressed both the number of chicks squeaking due to anxiety and the amount of spontaneous movement. The substance that was most effective in this test was phosphoserine (Phospho-Serine (Phos-S)).
実施例６は次の化合物を試験試料として用いた。鳴き回数を測定する間のニワトリヒナの動きを自発運動量として記録し、そのカウントした結果は図１４〜１７に示した。 （１）Control群
（２）Ｌ-セリン（L-Serine（Ser.））投与群
（３）グリシン（Glycine）投与群
（４）ホスファチジン酸（Phosphatidic Acid(PA)）投与群
（５）リゾホスファチジルセリン（Lyso Phosphatidyl Serine（Lyso-PS） ）投与群
In Example 6, the following compounds were used as test samples. The movement of the chicken chick during the measurement of the number of calls was recorded as the amount of spontaneous movement, and the counted results are shown in FIGS. (1) Control group (2) L-Serine (Ser.) Administration group (3) Glycine administration group (4) Phosphatidic acid (PA) administration group (5) Lysophosphatidyl Serine (Lyso Phosphatidyl Serine (Lyso-PS)) administration group
これらの結果からＬ-セリン（L-Serine（Ser.））、グリシン（Glycine）、ホスファチジン酸（Phosphatidic Acid(PA)）、リゾホスファチジルセリン（Lyso Phosphatidyl Serine（Lyso-PS） ）には、不安によるニワトリヒナの鳴き回数と自発運動量を共に有意に抑えたことが示された。 From these results, L-serine (L-Serine (Ser.)), Glycine (Glycine), phosphatidic acid (PA), lysophosphatidylserine (Lyso Phosphatidyl Serine (Lyso-PS)) are caused by anxiety. It was shown that both the number of chicks squeezed and the amount of spontaneous movement were significantly suppressed.
〔処方例１〕
抗不安効果を持つセリンとホスファチジルセリンを含有することを特徴とする健康食品用ソフトカプセル剤の製造
セリン、ホスファチジルセリン25％含有液体大豆レシチン、ビタミンEオイル、ビタミンB1（チアミン硝酸塩）、ビタミンB6（ピリドキシン塩酸塩）、ビタミンB12（シアノコバラミン）、ミツロウとパーム油は表１に示した様な配合量となるように混合し、30分間撹拌した。80メッシュで篩過した後、真空撹拌機で脱泡処理を行った。ソフトカプセル充填機により内容量が250mgとなるように充填した。皮膜は通常用いられるゼラチン、グリセリン混合物を用いた。乾燥後、液漏れ検査、形状選別検査、目視検査を合格した粒について規格試験を行った結果、カプセル長径、カプセル短径、カプセル総重量、カプセル皮膜重量、カプセル内容物重量、皮膜水分含有量、崩壊時間、酸価、過酸化物価、一般生菌数、大腸菌群等の諸規格を満たす製剤であることが確認された。
[Prescription Example 1]
Manufacture of soft capsule for health food characterized by containing serine and phosphatidylserine with anti-anxiety effect Serine, liquid soybean lecithin containing 25% phosphatidylserine, vitamin E oil, vitamin B1 (thiamine nitrate), vitamin B6 (pyridoxine) Hydrochloric acid salt), vitamin B12 (cyanocobalamin), beeswax and palm oil were mixed so as to have the blending amounts shown in Table 1, and stirred for 30 minutes. After sieving with 80 mesh, defoaming was performed with a vacuum stirrer. The inner volume was filled with a soft capsule filling machine to 250 mg. For the coating, a commonly used gelatin and glycerin mixture was used. After drying, as a result of conducting a standard test for grains that passed liquid leakage inspection, shape selection inspection, visual inspection, capsule long diameter, capsule short diameter, capsule total weight, capsule film weight, capsule content weight, film moisture content, It was confirmed that the preparation satisfies various standards such as disintegration time, acid value, peroxide value, general viable cell count, coliform group and the like.
〔処方例２〕
抗不安効果を持つセリンを含有することを特徴とする健康食品用飲料の製造
セリン、クエン酸、マルチトール、エリスリトール、トレハロース、オレンジ果汁、ラカンカエキス、香料は表１に示した様な配合量で配合し、最後に水を50mlになるように加え、原料を水に混合・溶解させ、容器に充填を行い、85℃10分の殺菌を行った。殺菌後冷却し、本飲料を完成させた。処方例１及び２を表１に、処方例３及び４を表２に示す。
[Prescription Example 2]
Manufacture of beverages for health food characterized by containing serine with anxiolytic effect Serine, citric acid, maltitol, erythritol, trehalose, orange juice, rakanka extract, fragrance are blended as shown in Table 1. After mixing, water was finally added to 50 ml, the raw materials were mixed and dissolved in water, filled into a container, and sterilized at 85 ° C. for 10 minutes. After sterilization and cooling, the beverage was completed. Formulation Examples 1 and 2 are shown in Table 1, and Formulation Examples 3 and 4 are shown in Table 2.
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| WO2008070994A1 (en) * | 2006-12-14 | 2008-06-19 | Nps Pharmaceuticals, Inc. | Use of d-serine derivatives for the treatment of anxiety disorders |
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| WO2003013549A2 (en) * | 2001-08-09 | 2003-02-20 | Degussa Food Ingredients Gmbh | Formulation containing (lyso-) phosphatidylserine for the prevention and treatment of stress states in warm-blooded animals |
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| WO2003013549A2 (en) * | 2001-08-09 | 2003-02-20 | Degussa Food Ingredients Gmbh | Formulation containing (lyso-) phosphatidylserine for the prevention and treatment of stress states in warm-blooded animals |
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