JP6964635B2 - Orientation composition - Google Patents
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- JP6964635B2 JP6964635B2 JP2019161249A JP2019161249A JP6964635B2 JP 6964635 B2 JP6964635 B2 JP 6964635B2 JP 2019161249 A JP2019161249 A JP 2019161249A JP 2019161249 A JP2019161249 A JP 2019161249A JP 6964635 B2 JP6964635 B2 JP 6964635B2
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Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
本発明は、特定のペプチドを含有する、見当識改善用組成物に関する。 The present invention relates to an orientation-improving composition containing a specific peptide.
国際アルツハイマー病協会によると、２０１５年に新たに９９０万人が認知症と診断され、３秒に１人の割合で増加している（非特許文献１）。また、世界の認知症患者は２０１５年時点で４６８０万人であるが、２０５０年には１億３１５０万人に達すると予測されている。認知症の約７割がアルツハイマー病であることが知られており、アルツハイマー病をはじめとした認知症対策は世界中で喫緊の課題となっている。認知症の進行を遅延させる薬はいくつかあるものの、現状では根治薬は知られていない。したがって、脳機能障害を呈する前、すなわち認知症を発症する前に、脳機能を予防的に改善することの重要性が指摘されている（非特許文献２、３）。
脳機能障害を呈する前段階を対象とし、予防的方法であることから、安全性に優れ、継続的に取り組むことができる手段であることが望ましいと考えられる。
According to the International Alzheimer's Disease Association, 9.9 million people were newly diagnosed with dementia in 2015, increasing at a rate of 1 in 3 seconds (Non-Patent Document 1). In addition, the number of dementia patients in the world is 46.8 million as of 2015, but it is predicted to reach 131.5 million by 2050. It is known that about 70% of dementia is Alzheimer's disease, and measures against dementia including Alzheimer's disease are urgent issues all over the world. Although there are several drugs that slow the progression of dementia, no curative drug is currently known. Therefore, it has been pointed out that it is important to preventively improve brain function before exhibiting brain dysfunction, that is, before developing dementia (Non-Patent Documents 2 and 3).
Since it is a preventive method for the pre-stage of brain dysfunction, it is considered desirable to have a means that is highly safe and can be continuously tackled.
見当識は、場所、時間、人の名前など、自分の置かれた状況を正しく認識する能力をいう。見当識が低下すると、アルツハイマー病に進展しやすいことが知られている（非特許文献４）。
そのため、脳機能障害を有さない人において、見当識を改善することは、現在の生活を健やかに送ることに加え、将来におけるアルツハイマー病などの認知症の発症を予防することにもつながると考えられる。
Orientation refers to the ability to correctly recognize one's situation, such as place, time, or person's name. It is known that when orientation is reduced, Alzheimer's disease is likely to develop (Non-Patent Document 4).
Therefore, in people without brain dysfunction, improving orientation will lead to a healthy life today and prevent the onset of dementia such as Alzheimer's disease in the future. Be done.
これまでに、カゼイン加水分解物やこれに含まれるＭｅｔ−Ｌｙｓ−Ｐｒｏからなるペプチドを有効成分として含有する、高齢者用アルツハイマー型認知症改善剤が知られている（特許文献１）。また、カゼイン加水分解物やこれに含まれるＭｅｔ−Ｌｙｓ−Ｐｒｏからなるペプチドがアミロイド・ベータタンパク質に起因する脳機能障害の改善作用を有することが見出されている（特許文献２）。カゼイン加水分解物やＭｅｔ−Ｌｙｓ−Ｐｒｏからなるペプチドは、副作用が少なく安全性に優れ、血圧の変動を生じさせないことも確認されている。
しかしながら、カゼイン加水分解物やこれに含まれるＭｅｔ−Ｌｙｓ−Ｐｒｏからなるペプチドの作用効果として、見当識の改善、特に脳機能障害を有さない人における見当識の改善については、知られていない。
So far, an Alzheimer-type dementia improving agent for the elderly containing a casein hydrolyzate and a peptide consisting of Met-Lys-Pro contained therein as an active ingredient has been known (Patent Document 1). Further, it has been found that a casein hydrolyzate and a peptide composed of Met-Lys-Pro contained therein have an effect of improving brain dysfunction caused by amyloid beta protein (Patent Document 2). It has also been confirmed that peptides composed of casein hydrolysate and Met-Lys-Pro have few side effects, are excellent in safety, and do not cause fluctuations in blood pressure.
However, as the action and effect of casein hydrolyzate and the peptide consisting of Met-Lys-Pro contained therein, improvement of orientation, especially improvement of orientation in people without brain dysfunction, is not known. ..
本発明は、安全性に優れ、継続可能な、見当識を改善するための技術を提供することを課題とする。 An object of the present invention is to provide a technique for improving orientation, which is excellent in safety and can be continued.
本発明者らは、上記の課題を解決すべく鋭意研究を行った結果、アミノ酸配列としてＭｅｔ−Ｌｙｓ−Ｐｒｏを有するペプチドが、見当識を改善することを見出し、本発明を完成するに至った。 As a result of diligent research to solve the above problems, the present inventors have found that a peptide having Met-Lys-Pro as an amino acid sequence improves orientation, and have completed the present invention. ..
すなわち、本発明は、Ｍｅｔ−Ｌｙｓ−Ｐｒｏからなるペプチド、又は前記アミノ酸配列を含むペプチドを含有する、見当識改善用組成物である。
本発明の組成物は、好ましくは、認知症ではない対象に摂取又は投与される。
本発明の組成物は、好ましくは、年、月、日、曜日、時間、季節、場所、及び人物からなる群から選択される１又は２以上の項目を認識する能力を改善するために用いられる。
本発明の組成物は、好ましくは、飲食品である。
本発明の組成物は、好ましくは、医薬品である。
That is, the present invention is a composition for improving orientation, which contains a peptide consisting of Met-Lys-Pro or a peptide containing the amino acid sequence.
The compositions of the present invention are preferably ingested or administered to a non-demented subject.
The compositions of the present invention are preferably used to improve the ability to recognize one or more items selected from the group consisting of year, month, day, day of the week, time, season, place, and person. ..
The composition of the present invention is preferably a food or drink.
The composition of the present invention is preferably a pharmaceutical product.
本発明によれば、摂取者（被投与者）の見当識を改善することができる。また、本発明の組成物は、副作用が少なく、安全性に優れるため、継続的に摂取可能である。本発明の組成物は、認知症ではない対象に適用でき、より好ましくは脳機能障害を有さない対象に適用できる。 According to the present invention, the orientation of the ingestor (administrator) can be improved. In addition, the composition of the present invention has few side effects and is excellent in safety, so that it can be continuously ingested. The composition of the present invention can be applied to a subject who does not have dementia, and more preferably to a subject who does not have brain dysfunction.
次に、本発明を詳細に説明する。ただし、本発明は以下の実施形態に限定されず、本発明の範囲内で自由に変更することができるものである。 Next, the present invention will be described in detail. However, the present invention is not limited to the following embodiments, and can be freely changed within the scope of the present invention.
本発明の組成物は、Ｍｅｔ−Ｌｙｓ−Ｐｒｏからなるペプチド、又は前記アミノ酸配列を含むペプチド（総称して「ＭＫＰペプチド」という）を含有する。
ここで、Ｍｅｔ（Ｍ）はメチオニン残基を、Ｌｙｓ（Ｋ）はリジン残基を、Ｐｒｏ（Ｐ）はプロリン残基を、それぞれ示す。いずれのアミノ酸も、Ｌ−型アミノ酸であることが好ましい。
The composition of the present invention contains a peptide consisting of Met-Lys-Pro or a peptide containing the amino acid sequence (collectively referred to as "MKP peptide").
Here, Met (M) indicates a methionine residue, Lys (K) indicates a lysine residue, and Pro (P) indicates a proline residue. All amino acids are preferably L-type amino acids.
ＭＫＰペプチドは、その塩の形態であってもよい。塩としては、例えば、カリウム、ナトリウム等のアルカリ金属類；カルシウム、マグネシウム等のアルカリ土類金属類等が挙げられる。 The MKP peptide may be in the form of a salt thereof. Examples of the salt include alkali metals such as potassium and sodium; alkaline earth metals such as calcium and magnesium.
なお、本発明において、所定のアミノ酸配列「を含むペプチド」とは、該所定のアミノ酸配列のＮ末端又はＣ末端にペプチド残基が１又は複数個の任意のアミノ酸が付加したものをいい、より具体的には１〜１０残基、望ましくは１〜５残基、さらに望ましくは１〜３残基付加したペプチドであって、かつ見当識改善作用を有する配列が望ましい。 In the present invention, the term "peptide containing" a predetermined amino acid sequence means a peptide in which one or more arbitrary amino acids having a peptide residue are added to the N-terminal or C-terminal of the predetermined amino acid sequence. Specifically, a peptide having 1 to 10 residues, preferably 1 to 5 residues, and more preferably 1 to 3 residues added, and having an insight-improving action is desirable.
本発明の組成物は、本発明の効果を妨げない限りにおいて、他のペプチドが併存してもかまわない。 In the composition of the present invention, other peptides may coexist as long as the effects of the present invention are not impaired.
ＭＫＰペプチドは、例えば、（１）Ｍｅｔ−Ｌｙｓ−Ｐｒｏのアミノ酸配列を含むタンパク質やペプチドを加水分解酵素等にて分解し、得られた分解物から分離精製して得る方法、（２）ペプチドの合成法によってＭＫＰペプチドを合成した後、得られた合成物から所望のＭＫＰペプチドを分離精製して得る方法、（３）本発明に係るＭＫＰペプチドを含むペプチド等を生産する植物、動物又は微生物から抽出し、得られた抽出物から分離精製する方法等により得ることができる。
以下に（１）及び（２）の方法について具体的に説明する。
The MKP peptide is, for example, (1) a method obtained by decomposing a protein or peptide containing the amino acid sequence of Met-Lys-Pro with a hydrolyzing enzyme or the like, and separating and purifying the obtained degradation product, (2) the peptide. A method for obtaining a desired MKP peptide by separating and purifying the desired MKP peptide from the obtained synthesis after synthesizing the MKP peptide by a synthetic method, (3) from a plant, animal or microorganism producing a peptide containing the MKP peptide according to the present invention. It can be obtained by a method of extracting and separating and purifying from the obtained extract.
The methods (1) and (2) will be specifically described below.
（１）加水分解により得る方法
ＭＫＰペプチドは、Ｍｅｔ−Ｌｙｓ−Ｐｒｏのアミノ酸配列を含むタンパク質やペプチドをタンパク質加水分解酵素や、酸・アルカリ等により加水分解し、得られた加水分解物からＭＫＰペプチドを分離精製して得ることができる。原料となるタンパク質やペプチドを含むものとしては、例えば、乳、大豆、卵、小麦、大麦、米、じゃが芋、さつま芋、えんどう豆、トウモロコシ、畜肉、魚肉、魚介などに由来するタンパク質などが挙げられ、これらのうち乳タンパク質であるカゼインが特に好ましい。
(1) Method obtained by hydrolysis The MKP peptide is obtained by hydrolyzing a protein or peptide containing the amino acid sequence of Met-Lys-Pro with a protein hydrolyzing enzyme, an acid, an alkali, or the like, and the MKP peptide is obtained from the obtained hydrolyzate. Can be obtained by separating and purifying. Examples of those containing proteins and peptides as raw materials include proteins derived from milk, soybeans, eggs, wheat, barley, rice, potatoes, sweet potatoes, pea, corn, livestock meat, fish meat, seafood and the like. Of these, casein, which is a milk protein, is particularly preferable.
以下にカゼインを原料として用いる場合を例に挙げて、加水分解酵素による処理によってＭＫＰペプチドを得る方法を説明する。
カゼインタンパク質は、ＭＫＰペプチドを一次構造中に含むタンパク質であって、適宜加水分解酵素で消化したときにＭＫＰペプチドが生成可能なものである。
まず、酵素で加水分解する前に、原料タンパク質を水又は温湯に分散し、溶解してタンパク質水溶液を調製する。当該タンパク質水溶液の濃度は、特に限定されないが、通常、タンパク質濃度として２質量％以上、さらに好ましくは５〜１５質量％程度の濃度範囲に設定するのが好適である。
さらに、前記タンパク質水溶液を、ナトリウム型又はカリウム型陽イオン交換樹脂（好適には強酸性陽イオン交換樹脂）を用いたイオン交換法、電気透析法、限界ろ過膜法、ルーズ逆浸透膜法等で脱塩し、適宜ｐＨ調整やカルシウム濃度調整を行うのが好適である。脱塩の際には、カラム式やバッチ式の何れを採用してもよい。また、タンパク質水溶液を、脱塩前等に適宜、加熱殺菌をおこなってもよい。
Hereinafter, a method for obtaining an MKP peptide by treatment with a hydrolase will be described by taking the casein as a raw material as an example.
The casein protein is a protein containing an MKP peptide in its primary structure, and can produce an MKP peptide when appropriately digested with a hydrolase.
First, before being hydrolyzed by an enzyme, the raw material protein is dispersed in water or warm water and dissolved to prepare an aqueous protein solution. The concentration of the aqueous protein solution is not particularly limited, but it is usually preferable to set the protein concentration in the concentration range of 2% by mass or more, more preferably about 5 to 15% by mass.
Further, the protein aqueous solution is subjected to an ion exchange method using a sodium-type or potassium-type cation exchange resin (preferably a strongly acidic cation exchange resin), an electrodialysis method, a limit filtration membrane method, a loose reverse osmosis membrane method, or the like. It is preferable to desalt and adjust the pH and calcium concentration as appropriate. At the time of desalting, either a column type or a batch type may be adopted. Further, the aqueous protein solution may be appropriately sterilized by heating before desalting.
次いで、前記タンパク質水溶液を、加水分解処理する。当該加水分解処理として、例えば酵素処理、酸処理、アルカリ処理、熱処理等が挙げられ、これらの２種以上の処理を適宜組み合わせてもよい。
本開示のタンパク質分解酵素は、例えば、植物由来、動物由来、微生物由来等が挙げられ、これらから１種又は２種以上組み合わせて使用できる。当該タンパク質分解酵素としては、エンドプロテアーゼが好適である。
前記エンドプロテア−ゼとしては、例えば、セリンプロテアーゼ、メタロプロテアーゼ、システインプロテアーゼ、アスパラギン酸プロテアーゼが挙げられ、これらを１種又は２種以上選択して用いることができる。このうち、セリンプロテアーゼ及び/又はメタロ
プロテアーゼを用いるのが好適である。
また、プロテアーゼは、アルカリ性プロテアーゼ、中性プロテアーゼ及び酸性プロテアーゼに分類される。このうち中性プロテアーゼを用いるのが好適である。
Next, the aqueous protein solution is hydrolyzed. Examples of the hydrolysis treatment include enzyme treatment, acid treatment, alkali treatment, heat treatment and the like, and two or more of these treatments may be appropriately combined.
Examples of the proteolytic enzyme of the present disclosure include plant-derived, animal-derived, and microbial-derived, and one or a combination of two or more of these can be used. Endoproteases are suitable as the proteolytic enzyme.
Examples of the endoprotease include serine protease, metalloprotease, cysteine protease, and aspartic protease, and one or more of these can be selected and used. Of these, it is preferable to use serine protease and / or metalloprotease.
In addition, proteases are classified into alkaline proteases, neutral proteases and acidic proteases. Of these, it is preferable to use a neutral protease.
前記タンパク質分解酵素は、市販品を用いることができる。前記タンパク質分解酵素として、例えば、ビオプラーゼ（ナガセケムテックス社製）、プロレザー（天野エンザイム社製）、プロテアーゼＳ（天野エンザイム社製）、ＰＴＮ６．０Ｓ（ノボザイムズ社製）、サビナーゼ（ノボザイムズ社製）、ＧＯＤＯ Ｂ．Ａ．Ｐ（合同酒精社製）、プロテア
ーゼＮ（天野エンザイム社製）、ＧＯＤＯ Ｂ．Ｎ．Ｐ（合同酒精社製）、ニュートラー
ゼ（ノボザイムズ社製）、アルカラーゼ（ノボザイムズ社製）、トリプシン（ノボザイムズ社製）、キモトリプシン（ノボザイムズ社製）、スブチリシン（ノボザイムズ社製）、パパイン（天野エンザイム社製）、ブロメライン（天野エンザイム社製）等が挙げられ、これらから１種又は２種以上の酵素を選択して用いてもよい。
これらのうち、スブチリシン（subtilisin：例えば、ビオプラーゼ）、トリプシン（trypsin：例えばＰＴＮ６．０Ｓ）、及びバシロリシン（bachillolysin：例えばプロテアーゼＮ）から選ばれる１種又は２種以上の中性プロテアーゼが好ましく、より好ましくはこれら３種を組み合わせて用いる。
A commercially available product can be used as the proteolytic enzyme. Examples of the proteolytic enzyme include bioprase (manufactured by Nagase ChemteX), proleather (manufactured by Amano Enzymes), protease S (manufactured by Amano Enzymes), PTN6.0S (manufactured by Novozymes), and sabinase (manufactured by Novozymes). , GODO B. A. P (manufactured by Joint Sake Seisha), Protease N (manufactured by Amano Enzyme), GODO B. N. P (manufactured by Joint Sake Seisha), Neutrase (manufactured by Novozymes), Alcalase (manufactured by Novozymes), Trypsin (manufactured by Novozymes), Chymotrypsin (manufactured by Novozymes), Subtilisin (manufactured by Novozymes), Papain (manufactured by Amano Enzymes) ), Bromelain (manufactured by Amano Enzymes), etc., and one or more enzymes may be selected and used from these.
Of these, one or more neutral proteases selected from subtilisin (eg, bioplase), trypsin (eg, PTN6.0S), and bachillolysin (eg, protease N) are preferred and more preferred. Uses these three types in combination.
前記タンパク質に対するエンドプロテア−ゼの使用量は、特に限定されず、基質濃度、酵素力価、反応温度及び反応時間等により適宜調整すればよいが、一般的には、タンパク質中のタンパク質１ｇ当り２，０００〜１１，０００活性単位の割合で添加することが好ましい。
前記タンパク質分解酵素による加水分解条件を適宜調整することにより、所望のペプチドを得ることができる。
The amount of endoprotease used for the protein is not particularly limited and may be appropriately adjusted according to the substrate concentration, enzyme titer, reaction temperature, reaction time, etc., but in general, 2 per 1 g of protein in the protein. It is preferable to add in a ratio of 1,000 to 11,000 active units.
A desired peptide can be obtained by appropriately adjusting the hydrolysis conditions of the proteolytic enzyme.
前記タンパク質分解酵素による加水分解前に、前記原料タンパク質溶液のｐＨを、炭酸カリウム、水酸化ナトリウム等の食品上使用可能な塩類を用いて、使用酵素の至適ｐＨに調整することもできる。前記原料タンパク質溶液のｐＨは、好ましくは５〜１０、より好ましくは７〜１０に調整する。 Prior to hydrolysis by the proteolytic enzyme, the pH of the raw material protein solution can be adjusted to the optimum pH of the enzyme used by using food-grade salts such as potassium carbonate and sodium hydroxide. The pH of the raw material protein solution is preferably adjusted to 5 to 10, more preferably 7 to 10.
前記タンパク質分解酵素の反応温度は、使用酵素の最適温度の範囲で行うことが望ましく、好ましくは３０〜６０℃、より好ましくは４０〜６０℃で行う。
前記タンパク質分解酵素の反応保持時間は、酵素反応の分解率をモニターしながら、好ましい分解率に達するまで反応を続ければよく例えば０．５〜２４時間で行うことが可能であり、好ましくは１〜１５時間、より好ましくは３〜１０時間である。特に、原料に前記カゼインタンパク質を用いた場合の分解率は２０〜３０％であることが好ましい。
The reaction temperature of the proteolytic enzyme is preferably in the optimum temperature range of the enzyme to be used, preferably 30 to 60 ° C, more preferably 40 to 60 ° C.
The reaction retention time of the proteolytic enzyme may be, for example, 0.5 to 24 hours, preferably 1 to 1, as long as the reaction is continued until a preferable decomposition rate is reached while monitoring the decomposition rate of the enzyme reaction. It is 15 hours, more preferably 3 to 10 hours. In particular, when the casein protein is used as a raw material, the decomposition rate is preferably 20 to 30%.
なお、原料タンパク質の分解率の算出方法は、ケルダール法（日本食品工業学会編、「食品分析法」、第１０２頁、株式会社光琳、昭和５９年）により試料の全窒素量を測定し、ホルモール滴定法（満田他編、「食品工学実験書」、上巻、第５４７ページ、養賢堂、１９７０年）により試料のホルモール態窒素量を測定し、これらの測定値から分解率を次式により算出する。
分解率（％）＝（ホルモール態窒素量／全窒素量）×１００
The method for calculating the decomposition rate of the raw material protein is to measure the total nitrogen content of the sample by the Kjeldahl method (edited by the Japan Food Industry Association, "Food Analysis Method", p. 102, Korin Co., Ltd., 1984) and formol. The amount of formol nitrogen in the sample was measured by the titration method (Mitsuda et al., "Food Engineering Experiment Book", Volume 1, page 547, Yokendo, 1970), and the decomposition rate was calculated from these measured values by the following formula. do.
Decomposition rate (%) = (formole nitrogen amount / total nitrogen amount) x 100
前記タンパク質分解酵素による加水分解は、当該酵素を加熱して失活させて終了させればよい。加熱失活処理の加熱温度と保持時間は、使用した酵素の熱安定性を考慮し、十分に失活できる条件を適宜設定することができる。例えば、１００℃以上（好適には１１０〜１３０℃）で失活させる場合には１〜３秒間、１００℃未満６０℃以上で失活させる場合には３〜４０分間で行うことが好適である。
加熱処理の方式としては、バッチ方式、連続方式のいずれの方式も可能であり、連続方式として、プレート熱交換方式、インフュージョン方式、インジェクション方式等の方式を用いることができる。
なお、前記の加熱失活処理は、加水分解物の殺菌処理として併用することも可能であり、常法による加熱処理方法等を用いることができる。
加水分解終了後、必要に応じて分解液のｐＨを、好ましくは６〜８、より好ましくは７．０±０．５、さらに好ましくは７．０±０．３とするのが好適である。
Hydrolysis by the proteolytic enzyme may be terminated by heating the enzyme to inactivate it. The heating temperature and holding time of the heat deactivation treatment can be appropriately set under conditions that allow sufficient deactivation in consideration of the thermal stability of the enzyme used. For example, it is preferable to inactivate at 100 ° C. or higher (preferably 110 to 130 ° C.) for 1 to 3 seconds, and to inactivate at 60 ° C. or higher below 100 ° C. for 3 to 40 minutes. ..
As the heat treatment method, either a batch method or a continuous method can be used, and as the continuous method, a plate heat exchange method, an injection method, an injection method, or the like can be used.
The heat deactivation treatment can be used in combination as a sterilization treatment for the hydrolyzate, and a conventional heat treatment method or the like can be used.
After completion of hydrolysis, the pH of the decomposition solution is preferably 6 to 8, more preferably 7.0 ± 0.5, and even more preferably 7.0 ± 0.3, if necessary.
なお、本発明に係るタンパク質分解物の製造において、カルシウム濃度未調整の溶液を
加水分解した場合には、得られた分解液を、前記のような脱塩処理し、カルシウム濃度を調整してもよい。次いで、常法により加熱して酵素を失活させる。反応加熱温度と反応保持時間は使用した酵素の熱安定性を配慮し、十分に失活できる条件を適宜設定することができる。加熱失活後、常法により冷却し、そのまま利用することもでき、必要に応じて濃縮して濃縮液を得ることもでき、更に濃縮液を乾燥し、粉末製品を得ることも可能である。
In the production of the proteolytic product according to the present invention, when the solution whose calcium concentration has not been adjusted is hydrolyzed, the obtained decomposition solution may be desalted as described above to adjust the calcium concentration. good. Then, it is heated by a conventional method to inactivate the enzyme. The reaction heating temperature and the reaction holding time can be appropriately set under conditions that allow sufficient deactivation in consideration of the thermal stability of the enzyme used. After heat deactivation, it can be cooled by a conventional method and used as it is, and if necessary, it can be concentrated to obtain a concentrated solution, and the concentrated solution can be further dried to obtain a powder product.
また、前記タンパク質水溶液を酸処理又はアルカリ処理にて加水分解する際には、タンパク質水溶液のｐＨを調整して処理すればよい。当該ｐＨ調整による処理の場合には、タンパク質水溶液のｐＨが、好ましくはｐＨ５以下又はｐＨ９以上であり、より好ましくはｐＨ４以下又はｐＨ１０以上である。このようにｐＨ処理された水溶液は、室温にて数分以上、好ましくは５分〜１時間、放置又は撹拌することによって、酸処理又はアルカリ処理の加水分解物を得ることができる。ここで、「室温」とは、４〜４０℃程度であるが、１０〜３０℃が好適である。
また、前記タンパク質水溶液を、熱処理にて加水分解してもよい。このタンパク質水溶液は、ｐＨ未調整でもよく、またｐＨ調整（具体的には、酸性（ｐＨ５以下）、中性（ｐＨ６〜８）、アルカリ性（ｐＨ８以上））してもよい。熱処理は、４〜１００℃程度で、上記酸アルカリ処理のような条件にて行えばよい。
Further, when the aqueous protein solution is hydrolyzed by acid treatment or alkaline treatment, the pH of the aqueous protein solution may be adjusted for the treatment. In the case of the treatment by the pH adjustment, the pH of the aqueous protein solution is preferably pH 5 or less or pH 9 or more, and more preferably pH 4 or less or pH 10 or more. The pH-treated aqueous solution can be left or stirred at room temperature for several minutes or longer, preferably 5 minutes to 1 hour to obtain an acid-treated or alkaline-treated hydrolyzate. Here, "room temperature" is about 4 to 40 ° C, but 10 to 30 ° C is preferable.
Further, the aqueous protein solution may be hydrolyzed by heat treatment. The aqueous protein solution may be pH-adjusted, or may be pH-adjusted (specifically, acidic (pH 5 or less), neutral (pH 6 to 8), alkaline (pH 8 or more)). The heat treatment may be performed at about 4 to 100 ° C. under the conditions such as the above acid-alkali treatment.
上記のようにしてカゼイン等のタンパク質加水分解物を取得できるが、市販のカゼイン加水分解物を用いてもよい。通常、市販のカゼイン加水分解物は、ＭＫＰペプチドを含むことが確認されている。 A protein hydrolyzate such as casein can be obtained as described above, but a commercially available casein hydrolyzate may be used. Generally, commercially available casein hydrolysates have been confirmed to contain MKP peptides.
タンパク質加水分解物中のＭＫＰペプチドの含有率は特に限定されないが、その下限値は、本発明の効能をより良好に発揮させる観点から、好ましくは０．００１質量％以上であり、０．００５質量％以上であり、より好ましくは０．０１質量％以上であり、その上限値は、本発明の分解物の製造効率の観点から、好ましくは１質量％以下であり、より好ましくは０．５質量％以下であり、さらに好ましくは０．４質量％以下であり、よりさらに好ましくは０．３質量％以下である。 The content of MKP peptide in the protein hydrolyzate is not particularly limited, but the lower limit thereof is preferably 0.001% by mass or more, and 0.005% by mass, from the viewpoint of better exerting the efficacy of the present invention. % Or more, more preferably 0.01% by mass or more, and the upper limit thereof is preferably 1% by mass or less, more preferably 0.5% by mass, from the viewpoint of the production efficiency of the decomposition product of the present invention. % Or less, more preferably 0.4% by mass or less, and even more preferably 0.3% by mass or less.
なお、本発明において、対象のペプチド含有量は、下記の方法にて測定できる。
（ａ）試料粉末を、１．０ｍｇ／ｍＬとなるように、０．２％ギ酸水溶液に希釈溶解し、１０分間超音波破砕したのち、０．２２μｍ口径のＰＶＤＦフィルター（Ｍｉｌｌｉｐｏｒｅ社製）でろ過して粉末溶液を調製し、下記測定条件によるＬＣ／ＭＳ分析を実施する。一方、測定対象のペプチドの化学合成標準ペプチド（ペプチド研究所社製）の溶解液を濃度別に数点調製し、下記測定条件によるＬＣ／ＭＳ分析を実施し、検量線を作成する。
前記粉末溶液の分析におけるピークのうち、標準ペプチドと分子量及びリテンションタイムが一致するものを、標準ペプチドと同一の配列として同定する。標準ペプチドのピーク面積と資料粉末のピーク面積を対比することにより、前記粉末溶液中に対象ペプチドの含有量を求める。
In the present invention, the peptide content of the target can be measured by the following method.
(A) The sample powder is diluted and dissolved in a 0.2% aqueous solution of formic acid to a concentration of 1.0 mg / mL, ultrasonically crushed for 10 minutes, and then filtered through a 0.22 μm diameter PVDF filter (manufactured by Millipore). Then, a powder solution is prepared, and LC / MS analysis is carried out under the following measurement conditions. On the other hand, several lysates of the chemical synthesis standard peptide (manufactured by Peptide Institute) of the peptide to be measured are prepared according to the concentration, and LC / MS analysis is carried out under the following measurement conditions to prepare a calibration curve.
Among the peaks in the analysis of the powder solution, those having the same molecular weight and retention time as the standard peptide are identified as the same sequence as the standard peptide. By comparing the peak area of the standard peptide with the peak area of the data powder, the content of the target peptide in the powder solution is determined.
（ｂ）対象ペプチド含有量（ｍｇ／カゼイン加水分解物１ｇ）
対象ペプチド含有量（ｍｇ／カゼイン加水分解物１ｇ）＝〔得られたカゼイン加水分解物中の対象ペプチド測定値（ｍｇ）〕／〔得られたカゼイン加水分解物の質量（ｇ）〕
〔得られたカゼイン加水分解物中の対象ペプチド測定値（ｍｇ）〕は、下記「ＬＣ／ＭＳ」による、試料中の対象ペプチドの測定値である。
(B) Target peptide content (mg / casein hydrolyzate 1 g)
Target peptide content (mg / casein hydrolyzate 1 g) = [measured value of target peptide in the obtained casein hydrolyzate (mg)] / [mass of the obtained casein hydrolyzate (g)]
[Measured value of target peptide (mg) in the obtained casein hydrolyzate] is a measured value of the target peptide in the sample by the following "LC / MS".
（ｃ）ＬＣ／ＭＳ使用機器
質量分析計：ＴＳＱ Ｑｕａｎｔｕｍ Ｄｉｓｃｏｖｅｒｙ ＭＡＸ（サーモフィッシャーサイエンティフィック社製）。
高速液体クロマトグラフ：Ｐｒｏｍｉｎｅｎｃｅ （島津製作所社製）、カラム：ＸＢｒｉｄｇｅ ＢＥＨ３００ Ｃ１８ φ２．１ ｍｍ×２５０ ｍｍ，３．５ μｍ（Ｗａｔｅｒｓ社製）。
(C) Equipment using LC / MS Mass spectrometer: TSQ Quantum Discovery MAX (manufactured by Thermo Fisher Scientific).
High Performance Liquid Chromatograph: Prominence (manufactured by Shimadzu Corporation), Column: XBridge BEH300 C18 φ2.1 mm × 250 mm, 3.5 μm (manufactured by Waters).
（ｄ）ＬＣ／ＭＳ測定条件
移動相Ａ：０．２重量％ ギ酸−水溶液
移動相Ｂ：０．２重量％ ギ酸−アセトニトリル溶液
タイムプログラム：２％Ｂ（０．０分）−２５％Ｂ（５．０分）−６５％Ｂ（５．１分）−６５％Ｂ（１０分）−８５％Ｂ（１０．１分）−８５％Ｂ（１３．０％）−２％Ｂ（１３．１分）−ＳＴＯＰ（３０．０分）。
試料注入量：１０μＬ、カラム温度：４０℃、液体流量：２００μＬ／ｍｉｎ
分析モード：ＳＲＭ測定。
Ｐｒｏｄｕｃｔ Ｍａｓｓ：ｍ／ｚ＝２６０．１０（Ｐａｒｅｎｔ ｍ／ｚ ＝ ３７５．２１）
(D) LC / MS measurement conditions Mobile phase A: 0.2 wt% formic acid-aqueous solution Mobile phase B: 0.2 wt% formic acid-acetonitrile solution Time program: 2% B (0.0 minutes) -25% B ( 5.0 minutes) -65% B (5.1 minutes) -65% B (10 minutes) -85% B (10.1 minutes) -85% B (13.0%) -2% B (13. 1 minute) -STOP (30.0 minutes).
Sample injection volume: 10 μL, column temperature: 40 ° C., liquid flow rate: 200 μL / min
Analysis mode: SRM measurement.
Product Mass: m / z = 260.10 (Partent m / z = 375.21)
得られたタンパク質加水分解物は、未精製のままの状態で使用しても効能を発揮することが可能である。すなわち、タンパク質加水分解物を後述の飲食品や医薬品の態様として、摂取や投与に供してもよい。
また、さらに、得られたタンパク質加水分解物に対して、適宜公知の分離精製を行ってもよい。例えば、得られたタンパク質加水分解物に対して分子量分画を行い、本発明に係るＭＫＰペプチドの分子量に該当する分画を含むタンパク質分解物を得ることができる。
分子量分画として、例えば、限外ろ過、ゲルろ過等の方法が採用でき、これにより不要な分子量のペプチドや遊離アミノ酸の除去率を高めることができる。
限外ろ過の場合には、所望の限外ろ過膜を使用すればよく、ゲルろ過の場合には、所望のサイズ排除クロマトグラフィーに用いるゲルろ過剤を使用すればよい。
さらに、脱塩や不純物を除去したり、純度を高めたりするために、公知の分離精製方法例えば、イオン交換クロマトグラフィー、吸着クロマトグラフィー、逆相クロマトグラフィー、分配クロマトグラフィー等の各種クロマトグラフィー、溶媒沈殿、塩析、２種の液相間での分配等の方法を用いてもよい。
The obtained protein hydrolyzate can exert its efficacy even when used in an unpurified state. That is, the protein hydrolyzate may be used for ingestion and administration in the form of foods and drinks and pharmaceuticals described later.
Further, the obtained protein hydrolyzate may be subjected to a known separation and purification as appropriate. For example, the obtained protein hydrolyzate can be fractionated by molecular weight to obtain a proteolytic product containing a fraction corresponding to the molecular weight of the MKP peptide according to the present invention.
As the molecular weight fraction, for example, methods such as ultrafiltration and gel filtration can be adopted, whereby the removal rate of peptides and free amino acids having an unnecessary molecular weight can be increased.
In the case of ultrafiltration, a desired ultrafiltration membrane may be used, and in the case of gel filtration, a gel filter agent used for desired size exclusion chromatography may be used.
Further, in order to remove desalting and impurities and increase the purity, known separation and purification methods such as ion exchange chromatography, adsorption chromatography, reverse phase chromatography, partition chromatography and other various chromatographies and solvents are used. Methods such as precipitation, salting out, and distribution between two liquid phases may be used.
分離精製したペプチドの分画物は、ＭＫＰペプチドが含まれているかどうかを確認することを目的として、質量分析法によりペプチドの同定を行うことができる。
このようにして得られたＭＫＰペプチドは、ペプチド溶液のまま使用することもでき、また、必要に応じて、該溶液を公知の方法により、濃縮した濃縮液として使用することもできる。また、該濃縮液を公知の方法により乾燥し、粉末にして使用することもできる。
The separated and purified peptide fraction can be identified by mass spectrometry for the purpose of confirming whether or not the MKP peptide is contained.
The MKP peptide thus obtained can be used as a peptide solution as it is, or if necessary, the solution can be used as a concentrated concentrated solution by a known method. Further, the concentrated solution can be dried by a known method and used as a powder.
（２）化学合成により得る方法
ＭＫＰペプチドは、化学合成又は生合成によっても製造することができる。
ペプチドの化学合成は、オリゴペプチドの合成に通常用いられている液相法または固相法によって行うことができる。合成されたペプチドは必要に応じて脱保護され、未反応試薬や副生物等を除去して、ＭＫＰペプチドを単離することが可能である。このようなペプチドの合成は、市販のペプチド合成装置を用いて行うことができる。
ペプチドの生合成は、宿主生物にペプチド発現ベクターを導入して生成・分泌させるといった常法により行うことができる。
(2) Method obtained by chemical synthesis The MKP peptide can also be produced by chemical synthesis or biosynthesis.
The chemical synthesis of the peptide can be carried out by the liquid phase method or the solid phase method usually used for the synthesis of oligopeptides. The synthesized peptide is deprotected as necessary, and it is possible to isolate the MKP peptide by removing unreacted reagents, by-products and the like. The synthesis of such a peptide can be carried out using a commercially available peptide synthesizer.
Peptide biosynthesis can be carried out by a conventional method such as introducing a peptide expression vector into a host organism to produce and secrete it.
本発明の組成物は、見当識を改善することができる。
ここで、見当識は、時間、場所、人の名前など、現在置かれている状況を正しく認識する能力をいう。より具体的には、年、月、日、曜日、時間、季節、場所、及び人物からなる群から選択される１又は２以上の項目を認識する能力をいう。
見当識が改善したことは、例えば、ＡＤＡＳ−ｃｏｇ（Alzheimer's Disease Assessme
nt Scale-cog）の見当識の項目において、得点が向上することにより確認することができる。
The compositions of the present invention can improve orientation.
Here, orientation refers to the ability to correctly recognize the current situation, such as time, place, and person's name. More specifically, it refers to the ability to recognize one or more items selected from a group consisting of year, month, day, day of the week, time, season, place, and person.
The improvement in orientation is, for example, ADAS-cog (Alzheimer's Disease Assessme).
In the item of orientation of nt Scale-cog), it can be confirmed by improving the score.
見当識が低下すると、アルツハイマー病に進展しやすいとされている（非特許文献４）。このことから、本発明の組成物により見当識が改善されると、アルツハイマー型認知症、血管性認知症、血管障害、脳アミロイドアンギオパチー等の脳機能障害を、予防することが期待される。ここで、脳機能障害の予防とは、脳機能障害を罹患（発症）していない適用対象において、疾患又は症状の発生を防止すること、該発生を遅延させること、及び該発生の危険性を低下させることを含む。 It is said that when orientation is reduced, Alzheimer's disease is likely to develop (Non-Patent Document 4). From this, if orientation is improved by the composition of the present invention, it is expected to prevent brain dysfunction such as Alzheimer-type dementia, vascular dementia, angiopathy, and cerebral amyloid angiopathy. Here, prevention of brain dysfunction means preventing the occurrence of a disease or symptom, delaying the occurrence, and the risk of the occurrence in an application target not suffering (onset) the brain dysfunction. Including lowering.
本発明の組成物は、食品としての使用実績があり安全性が高い。また、長期間、連続的に投与しても副作用の心配が小さい。さらに、他の薬剤との併用においても安全性が高い。 The composition of the present invention has a track record of use as food and is highly safe. Moreover, even if it is continuously administered for a long period of time, there is little concern about side effects. Furthermore, it is highly safe when used in combination with other drugs.
本発明の組成物を投与する対象（被投与者）及び摂取させる対象（摂取者）は、動物であれば特に限定されないが、通常はヒトである。また、成人、小児、乳児、新生児（低体重児を含む）等のいずれであってもよいが、通常は成人である。また、性別は特に限定されない。
また、本発明の摂取者及び被投与者は、好ましくは認知症ではない状態であり、より好ましくは脳機能障害を有さない状態である。通常、認知症は進行性であり、完治するものではないことから、認知症を発症する前段階にある者が対象となる。なお、軽度認知障害は認知症の前段階であるため、「脳機能障害を有する状態であるが、認知症ではない状態」に該当し、本発明の好ましい摂取者及び被投与者となりえる。
ここで、認知症ではないことは、医師により認知症であると診断されていないこと又は認知症ではないと診断されたことであってもよいし、種々の神経心理検査で認知症の判定基準に該当していないことであってもよい。摂取者（被投与者）がヒトである場合は、好ましくは、長谷川式認知症スケール（ＨＤＳ−Ｒ）やミニメンタルステート検査（ＭＭＳＥ）において、健常（正常）に該当することにより、確認することができる。
The subject to which the composition of the present invention is administered (administrator) and the subject to be ingested (ingestor) are not particularly limited as long as they are animals, but are usually humans. In addition, it may be any of adults, children, infants, newborns (including low-weight babies), etc., but it is usually an adult. The gender is not particularly limited.
In addition, the ingestor and the recipient of the present invention are preferably in a state without dementia, and more preferably in a state without brain dysfunction. Usually, dementia is progressive and does not cure completely, so those who are in the pre-dementia stage are targeted. Since mild cognitive impairment is a pre-stage of dementia, it corresponds to "a condition having brain dysfunction but not dementia", and can be a preferable ingestor and recipient of the present invention.
Here, the fact that the patient does not have dementia may mean that the doctor has not diagnosed the patient as having dementia or that the patient has not been diagnosed as having dementia. It may not correspond to. When the ingestor (administrator) is a human, it is preferably confirmed by the Hasegawa dementia scale (HDS-R) or the Mini-Mental State Examination (MMSE) that it corresponds to healthy (normal). Can be done.
本発明の別の側面は、見当識改善用組成物の製造における、ＭＫＰペプチドの使用である。
本発明の別の側面は、見当識改善における、ＭＫＰペプチドの使用である。
本発明の別の側面は、見当識改善のために用いられる、ＭＫＰペプチドである。
本発明の別の側面は、ＭＫＰペプチドを動物に投与することを含む、見当識を改善する方法である。
Another aspect of the present invention is the use of MKP peptides in the manufacture of orientation-improving compositions.
Another aspect of the invention is the use of MKP peptides in disorientation.
Another aspect of the invention is the MKP peptide used to improve orientation.
Another aspect of the invention is a method of improving orientation, including administering the MKP peptide to an animal.
なお、本明細書において「ペプチドを動物に投与すること」は、「ペプチドを動物に摂取させること」と同義であってよい。摂取は、自発的なもの（自由摂取）であってもよく、強制的なもの（強制摂取）であってもよい。すなわち、投与工程は、具体的には、例えば、ペプチドを飲食品や飼料に配合して対象に供給し、以て対象にペプチドを自由摂取させる工程であってもよい。 In addition, in this specification, "administering a peptide to an animal" may be synonymous with "ingesting a peptide into an animal". Ingestion may be voluntary (free intake) or compulsory (forced intake). That is, specifically, the administration step may be, for example, a step of blending the peptide with food or drink or feed and supplying the peptide to the subject so that the subject can freely ingest the peptide.
本発明の組成物の摂取（投与）時期は、特に限定されず、投与対象の状態に応じて適宜選択することが可能である。 The ingestion (administration) timing of the composition of the present invention is not particularly limited, and can be appropriately selected according to the condition of the administration target.
本発明の組成物の摂取（投与）量は、摂取（投与）対象の年齢、性別、状態、その他の条件等により適宜選択される。
本発明の組成物の摂取（投与）量は、本発明に係るＭＫＰペプチドの摂取量として、例えば、成人において０．１ｍｇ／日〜１ｇ／日の範囲が好ましく、０．１ｍｇ／日〜０．５ｍｇ／日の範囲がさらに好ましい。
なお、摂取（投与）の量や期間にかかわらず、本発明の組成物は１日１回又は複数回に分けて投与することができる。
The ingestion (administration) amount of the composition of the present invention is appropriately selected depending on the age, sex, condition, other conditions, etc. of the ingestion (administration) subject.
The intake (administration) amount of the composition of the present invention is preferably in the range of 0.1 mg / day to 1 g / day, and 0.1 mg / day to 0. A range of 5 mg / day is even more preferred.
The composition of the present invention can be administered once a day or in a plurality of doses regardless of the amount and duration of ingestion (administration).
本発明の組成物の摂取（投与）期間は、特に限定されないが、好ましくは１２週間以上、より好ましくは２４週間以上とすると、効果が得られやすい。また、摂取（投与）期間の上限は特に設けられず、継続的な、長期の摂取（投与）が可能である。 The ingestion (administration) period of the composition of the present invention is not particularly limited, but if it is preferably 12 weeks or more, more preferably 24 weeks or more, the effect is likely to be obtained. In addition, there is no particular upper limit on the intake (administration) period, and continuous and long-term intake (administration) is possible.
本発明の組成物の摂取（投与）経路は、経口又は非経口のいずれでもよいが経口が好ましい。また、非経口摂取（投与）としては、経皮、静注、直腸投与、吸入等が挙げられる。 The route of ingestion (administration) of the composition of the present invention may be oral or parenteral, but oral is preferable. In addition, parenteral ingestion (administration) includes transdermal, intravenous injection, rectal administration, inhalation and the like.
本発明の組成物を経口摂取される組成物とする場合は、飲食品の態様とすることが好ましい。 When the composition of the present invention is taken orally, it is preferably in the form of food and drink.
飲食品としては、本発明の効果を損なわず、経口摂取できるものであれば形態や性状は特に制限されず、ＭＫＰペプチドを含有させること以外は、通常飲食品に用いられる原料を用いて通常の方法によって製造することができる。 The form and properties of the food and drink are not particularly limited as long as they do not impair the effects of the present invention and can be ingested orally. It can be manufactured by the method.
飲食品としては、液状、ペースト状、ゲル状固体、粉末等の形態を問わず、例えば、錠菓；流動食（経管摂取用栄養食）；パン、マカロニ、スパゲッティ、めん類、ケーキミックス、から揚げ粉、パン粉等の小麦粉製品；即席めん、カップめん、レトルト・調理食品、調理缶詰め、電子レンジ食品、即席スープ・シチュー、即席みそ汁・吸い物、スープ缶詰め、フリーズ・ドライ食品、その他の即席食品等の即席食品類；農産缶詰め、果実缶詰め、ジャム・マーマレード類、漬物、煮豆類、農産乾物類、シリアル（穀物加工品）等の農産加工品；水産缶詰め、魚肉ハム・ソーセージ、水産練り製品、水産珍味類、つくだ煮類等の水産加工品；畜産缶詰め・ペースト類、畜肉ハム・ソーセージ等の畜産加工品；加工乳、乳飲料、ヨーグルト類、乳酸菌飲料類、チーズ、アイスクリーム類、調製粉乳類、クリーム、その他の乳製品等の乳・乳製品；バター、マーガリン類、植物油等の油脂類；しょうゆ、みそ、ソース類、トマト加工調味料、みりん類、食酢類等の基礎調味料；調理ミックス、カレーの素類、たれ類、ドレッシング類、めんつゆ類、スパイス類、その他の複合調味料等の複合調味料・食品類；素材冷凍食品、半調理冷凍食品、調理済冷凍食品等の冷凍食品；キャラメル、キャンディー、チューインガム、チョコレート、クッキー、ビスケット、ケーキ、パイ、スナック、クラッカー、和菓子、米菓子、豆菓子、デザート菓子、ゼリー、その他の菓子などの菓子類；炭酸飲料、天然果汁、果汁飲料、果汁入り清涼飲料、果肉飲料、果粒入り果実飲料、野菜系飲料、豆乳、豆乳飲料、コーヒー飲料、お茶飲料、粉末飲料、濃縮飲料、スポーツ飲料、栄養飲料、アルコール飲料、その他の嗜好飲料等の嗜好飲料類、ベビーフード、ふりかけ、お茶漬けのり等のその他の市販食品等；育児用調製粉乳；経腸栄養食；機能性食品（特定保健用食品、栄養機能食品）等が挙げられる。 The food and drink may be in the form of liquid, paste, gel-like solid, powder, etc., for example, from tablet confectionery; liquid food (nutrient food for tube intake); bread, macaroni, spaghetti, noodles, cake mix, etc. Wheat flour products such as fried flour and bread flour; instant noodles, cup noodles, retort / cooked foods, canned foods, microwave foods, instant soups / stews, instant miso soups / beverages, canned soups, freeze / dry foods, and other instant foods. Instant foods; canned agricultural products, canned fruits, jams and marmalades, pickles, boiled beans, dried agricultural products, processed agricultural products such as cereals (processed grain products); canned fishery products, fish hams and sausages, fish paste products, fishery delicacies , Processed marine products such as simmered Tsukuda; Canned livestock / pastes, Processed livestock products such as livestock ham / sausage; Processed milk, dairy beverages, yogurts, lactic acid bacteria beverages, cheese, ice cream, prepared powdered milk, cream, Other dairy products such as dairy products; butter, margarines, vegetable oils and other fats and oils; soy sauce, miso, sauces, tomato processed seasonings, mirins, vinegars and other basic seasonings; cooking mixes, curry Complex seasonings / foods such as beverages, sauces, dressings, noodles, spices, and other complex seasonings; frozen foods such as raw materials frozen foods, semi-cooked frozen foods, and cooked frozen foods; caramel, candy , Chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese confectionery, rice confectionery, bean confectionery, dessert confectionery, jelly, and other confectionery; carbonated beverages, natural fruit juices, fruit juice beverages, refreshing with fruit juice Beverages, fruit meat beverages, fruit beverages with fruits, vegetable beverages, soy milk, soy milk beverages, coffee beverages, tea beverages, powdered beverages, concentrated beverages, sports beverages, nutritional beverages, alcoholic beverages, and other favorite beverages. , Baby foods, sprinkles, other commercial foods such as Ochazuke paste; prepared milk powder for childcare; enteral nutritional foods; functional foods (foods for specified health use, nutritional functional foods) and the like.
また、飲食品の一態様として飼料とすることもできる。飼料としては、ペットフード、家畜飼料、養魚飼料等が挙げられる。
飼料の形態としては特に制限されず、ＭＫＰペプチドの他に例えば、トウモロコシ、小麦、大麦、ライ麦、マイロ等の穀類；大豆油粕、ナタネ油粕、ヤシ油粕、アマニ油粕等の植物性油粕類；フスマ、麦糠、米糠、脱脂米糠等の糠類；コーングルテンミール、コーンジャムミール等の製造粕類；魚粉、脱脂粉乳、ホエイ、イエローグリース、タロー等の動物性飼料類；トルラ酵母、ビール酵母等の酵母類；第三リン酸カルシウム、炭酸カルシウム等の鉱物質飼料；油脂類；単体アミノ酸；糖類等を含有するものであってよい。
It can also be used as feed as one aspect of food and drink. Examples of the feed include pet food, livestock feed, fish feed and the like.
The form of the feed is not particularly limited, and in addition to the MKP peptide, for example, grains such as corn, wheat, barley, rye, and milo; vegetable oil cakes such as soybean oil cake, rapeseed oil cake, palm oil cake, and flaxseed oil cake; Bran such as wheat bran, rice bran and defatted rice bran; production cakes such as corn gluten meal and corn jam meal; animal feeds such as fish flour, defatted milk powder, whey, yellow grease and tallow; Yeasts; mineral feeds such as tertiary calcium phosphate and calcium carbonate; oils and fats; single amino acids; sugars and the like may be contained.
本発明の組成物が飲食品（飼料を含む）の態様である場合、見当識改善に関する用途や
、脳機能低下予防、記憶力低下予防等の用途が表示された飲食品として提供・販売されることが可能である。また、本明細書に係るＭＫＰペプチドは、これら飲食品等の製造のために使用可能である。
When the composition of the present invention is in the form of a food or drink (including feed), it shall be provided and sold as a food or drink labeled for use in improving orientation, prevention of brain dysfunction, prevention of memory deterioration, etc. Is possible. In addition, the MKP peptide according to the present specification can be used for producing these foods and drinks.
かかる「表示」行為には、需要者に対して前記用途を知らしめるための全ての行為が含まれ、前記用途を想起・類推させうるような表現であれば、表示の目的、表示の内容、表示する対象物・媒体等の如何に拘わらず、全て本発明における「表示」行為に該当する。
また、「表示」は、需要者が上記用途を直接的に認識できるような表現により行われることが好ましい。具体的には、飲食品に係る商品又は商品の包装に前記用途を記載したものを譲渡し、引き渡し、譲渡若しくは引き渡しのために展示し、輸入する行為、商品に関する広告、価格表若しくは取引書類に上記用途を記載して展示し、若しくは頒布し、又はこれらを内容とする情報に上記用途を記載して電磁気的（インターネット等）方法により提供する行為等が挙げられる。
Such "display" act includes all acts for informing the consumer of the use, and if it is an expression that can recall or analogize the use, the purpose of the display, the content of the display, etc. Regardless of the object or medium to be displayed, all of them fall under the act of "displaying" in the present invention.
Further, it is preferable that the "display" is performed by an expression that allows the consumer to directly recognize the above-mentioned use. Specifically, the act of transferring a product related to food and drink or the packaging of the product with the above-mentioned use, displaying it for delivery, transfer or delivery, and importing it, advertising on the product, price list or transaction documents Examples include the act of describing the above-mentioned use and displaying or distributing it, or describing the above-mentioned use in the information containing these and providing it by an electromagnetic (Internet, etc.) method.
一方、表示内容としては、行政等によって認可された表示（例えば、行政が定める各種制度に基づいて認可を受け、そのような認可に基づいた態様で行う表示等）であることが好ましい。また、そのような表示内容を、包装、容器、カタログ、パンフレット、ＰＯＰ等の販売現場における宣伝材、その他の書類等へ付することが好ましい。 On the other hand, as the display content, it is preferable that the display is approved by the government or the like (for example, a display obtained based on various systems established by the government and performed in a manner based on such approval). In addition, it is preferable to attach such display contents to packaging, containers, catalogs, pamphlets, promotional materials such as POPs at sales sites, and other documents.
また、「表示」には、健康食品、機能性食品、経腸栄養食品、特別用途食品、保健機能食品、特定保健用食品、栄養機能食品、機能性表示食品、医薬用部外品等としての表示も挙げられる。この中でも特に、消費者庁によって認可される表示、例えば、特定保健用食品、栄養機能食品、若しくは機能性表示食品に係る制度、又はこれらに類似する制度にて認可される表示等が挙げられる。具体的には、特定保健用食品としての表示、条件付き特定保健用食品としての表示、身体の構造や機能に影響を与える旨の表示、疾病リスク減少表示、科学的根拠に基づいた機能性の表示等を挙げることができ、より具体的には、健康増進法に規定する特別用途表示の許可等に関する内閣府令（平成二十一年八月三十一年内閣府令第五十七号）に定められた特定保健用食品としての表示（特に保健の用途の表示）及びこれに類する表示が典型的な例である。
かかる表示としては、例えば、「見当識（時間や場所、人を認識し、思い出す力）をサポート」、「見当識（現在の時間、場所、周囲の人、状況を正しく認識する力）をサポート」、「時間や場所、人を認識し、思い出す力をサポート」、「現在の時間、場所、周囲の人、状況を正しく認識する力をサポート」、「見当識（時間や場所、人を認識し、思い出す力）を維持」、「見当識（現在の時間、場所、周囲の人、状況を正しく認識する力）を維持」、「時間や場所、人を認識し、思い出す力を維持」、「現在の時間、場所、周囲の人、状況を正しく認識する力を維持」、「見当識（時間や場所、人を認識し、思い出す力）を改善」、「見当識（現在の時間、場所、周囲の人、状況を正しく認識する力）を改善」、「時間や場所、人を認識し、思い出す力を改善」、「現在の時間、場所、周囲の人、状況を正しく認識する力を改善」、「見当識（現在の時間、場所、周囲の人、状況を正しく記憶し思い出す力）をサポート」、「時間や場所、人を記憶し、思い出す力をサポート」、「現在の時間、場所、周囲の人、状況を正しく記憶し思い出す力をサポート」、「見当識（時間や場所、人を記憶し、思い出す力）を維持」、「見当識（現在の時間、場所、周囲の人、状況を正しく記憶し、思い出す力）を維持」、「時間や場所、人を記憶し、思い出す力を維持」、「現在の時間、場所、周囲の人、状況を正しく記憶し、思い出す力を維持」、「見当識（時間や場所、人を記憶し、思い出す力）を改善」、「見当識（現在の時間、場所、周囲の人、状況を正しく記憶し、思い出す力）を改善」、「時間や場所、人を記憶し、思い出す力を改善」、「現在の時間、場所、周囲の人、状況を正しく記憶し、思い出す力を改善」、「見当識が気になる方へ」、「物忘れが気になる方へ」、「うっかりが気になる方へ」、「見当識の改善のために」、「時間や場所、人、状況を正しく認識する力を、改善・維持するために」、「認知機能の低下予防用」、「認知機能をサポー
ト」、「認知の衰えを防ぎたい方へ」等と表示することが挙げられる。
In addition, "labeling" includes health foods, functional foods, enteral nutrition foods, special purpose foods, health functional foods, specified health foods, nutritional functional foods, functionally labeled foods, non-medicinal products, etc. The display is also mentioned. Among these, in particular, labeling approved by the Consumer Affairs Agency, for example, a system related to foods for specified health use, nutritionally functional foods, or functionally labeled foods, or labeling approved by a system similar to these, and the like can be mentioned. Specifically, labeling as a food for specified health use, labeling as a food for specified health use with conditions, labeling to the effect that it affects the structure and function of the body, labeling for reducing the risk of illness, and functionality based on scientific evidence. Labels, etc. can be mentioned, and more specifically, the Cabinet Office Ordinance on Permits for Special Purpose Labeling, etc. stipulated in the Health Promotion Act (Cabinet Office Ordinance No. 57, August 31, 2001) Labeling as food for specified health use (particularly labeling for health use) and similar labeling specified in the above are typical examples.
Such displays include, for example, "supporting knowledge (ability to recognize and remember time, place, and person)" and "supporting knowledge (ability to correctly recognize current time, place, surrounding people, and situation)". , "Supporting the ability to recognize and remember time, place, and people", "Supporting the ability to correctly recognize the current time, place, people around, and situation", "Students (recognizing time, place, and people) "Maintain the ability to remember and remember", "Maintain the ability to correctly recognize the current time, place, people around, and the situation", "Maintain the ability to recognize and remember the time, place, and people", "Maintain the ability to correctly recognize the current time, place, people and situations", "Improve the ability to recognize and remember the time, place and people", "The ability to recognize and remember the current time and place", "The current time and place" Improve the ability to correctly recognize people and situations around) ”,“ Improve the ability to recognize and remember times, places and people ”,“ Improve the ability to correctly recognize current times, places, people around and situations "Improvement", "Supports insight (ability to correctly remember and remember current time, place, surrounding people, situation)", "Supports ability to remember and remember time, place, person", "Current time, Supporting the ability to correctly remember and remember places, people around, and situations "," Maintaining insight (ability to remember and remember time, place, and people) "," Knowledge (current time, place, people around) , "Maintain the ability to remember and remember the situation correctly", "Maintain the ability to remember and remember the time, place, and people", "The ability to correctly remember and remember the current time, place, people around, and the situation""Maintain","Improve knowledge (ability to remember and remember time, place, person)", "Improve knowledge (ability to correctly remember and remember current time, place, people, situation)", "Improve the ability to remember and remember time, place, and people", "Improve the ability to remember and remember the current time, place, people, and situations correctly", "For those who are worried about their insight", "For those who are worried about forgetfulness", "For those who are worried about carelessness", "For improving insight", "For improving and maintaining the ability to correctly recognize time, place, people, and situations""For those who want to prevent cognitive decline", "For prevention of cognitive decline", "Support for cognitive function", "For those who want to prevent cognitive decline", etc.
本発明の組成物は、医薬品の態様とすることもできる。
医薬品の投与経路は、経口又は非経口のいずれでもよいが経口が好ましい。また、非経口摂取（投与）としては、経皮、静注、直腸投与、吸入等が挙げられる。
医薬品の形態としては、投与方法に応じて、適宜所望の剤形に製剤化することができる。例えば、経口投与の場合、散剤、顆粒剤、錠剤、カプセル剤等の固形製剤；溶液剤、シロップ剤、懸濁剤、乳剤等の液剤等に製剤化することができる。また、非経口投与の場合、座剤、軟膏剤、注射剤等に製剤化することができる。
製剤化に際しては、ＭＫＰペプチドの他に、通常製剤化に用いられている賦形剤、ｐＨ調整剤、着色剤、矯味剤等の成分を用いることができる。また、他の薬効成分や、公知の又は将来的に見出される見当識改善作用を有する成分等の他の医薬を併用することも可能である。
加えて、製剤化は剤形に応じて適宜公知の方法により実施できる。製剤化に際しては、適宜、通常製剤化に用いる担体を配合して製剤化してもよい。かかる担体としては、賦形剤、結合剤、崩壊剤、滑沢剤、安定剤、矯味矯臭剤等が挙げられる。
The composition of the present invention can also be in the form of a pharmaceutical product.
The route of administration of the drug may be oral or parenteral, but oral is preferable. In addition, parenteral ingestion (administration) includes transdermal, intravenous injection, rectal administration, inhalation and the like.
As the form of the drug, it can be appropriately formulated into a desired dosage form according to the administration method. For example, in the case of oral administration, it can be formulated into a solid preparation such as a powder, a granule, a tablet or a capsule; a liquid preparation such as a solution, a syrup, a suspension or an emulsion. In the case of parenteral administration, it can be formulated into a suppository, an ointment, an injection or the like.
In the formulation, in addition to the MKP peptide, components such as excipients, pH adjusters, colorants, and flavoring agents that are usually used in the formulation can be used. It is also possible to use other medicines such as other medicinal ingredients and ingredients having a known or future orientation-improving effect.
In addition, the formulation can be carried out by a known method as appropriate depending on the dosage form. At the time of formulation, a carrier usually used for formulation may be blended and formulated as appropriate. Examples of such carriers include excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents and the like.
賦形剤としては、例えば、乳糖、白糖、ブドウ糖、マンニット、ソルビット等の糖誘導体；トウモロコシデンプン、馬鈴薯デンプン、α−デンプン、デキストリン、カルボキシメチルデンプン等のデンプン誘導体；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、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カルシウム等のセルロース誘導体；アラビアゴム；デキストラン；プルラン；軽質無水珪酸、合成珪酸アルミニウム、メタ珪酸アルミン酸マグネシウム等の珪酸塩誘導体；リン酸カルシウム等のリン酸塩誘導体；炭酸カルシウム等の炭酸塩誘導体；硫酸カルシウム等の硫酸塩誘導体等が挙げられる。 Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannit, and sorbit; starch derivatives such as corn starch, horse bell starch, α-starch, dextrin, and carboxymethyl starch; crystalline cellulose, hydroxypropyl cellulose, and the like. Cellulous derivatives such as hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium; gum arabic; dextran; purulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate; phosphate derivatives such as calcium phosphate; carbonic acid Carbonate derivatives such as calcium; sulfate derivatives such as calcium sulfate can be mentioned.
結合剤としては、例えば、上記賦形剤の他、ゼラチン；ポリビニルピロリドン；マクロゴール等が挙げられる。 Examples of the binder include gelatin; polyvinylpyrrolidone; macrogol and the like in addition to the above-mentioned excipients.
崩壊剤としては、例えば、上記賦形剤の他、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、架橋ポリビニルピロリドン等の化学修飾されたデンプン又はセルロース誘導体等が挙げられる。 Examples of the disintegrant include, in addition to the above-mentioned excipients, chemically modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium, and crosslinked polyvinylpyrrolidone.
滑沢剤としては、例えば、タルク；ステアリン酸；ステアリン酸カルシウム、ステアリン酸マグネシウム等のステアリン酸金属塩；コロイドシリカ；ピーガム、ゲイロウ等のワックス類；硼酸；グリコール；フマル酸、アジピン酸等のカルボン酸類；安息香酸ナトリウム等のカルボン酸ナトリウム塩；硫酸ナトリウム等の硫酸塩類；ロイシン；ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウム等のラウリル硫酸塩；無水珪酸、珪酸水和物等の珪酸類；デンプン誘導体等が挙げられる。 Examples of the lubricant include talc; stearic acid; metal stearate salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as pea gum and gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid. Sodium carboxylic acid salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic acid anhydride and silicate hydrate; starch derivatives and the like. Be done.
安定剤としては、例えば、メチルパラベン、プロピルパラベン等のパラオキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール、フェニルエチルアルコール等のアルコール類；塩化ベンザルコニウム；無水酢酸；ソルビン酸等が挙げられる。 Examples of the stabilizer include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic acid anhydride; and sorbic acid.
矯味矯臭剤としては、例えば、甘味料、酸味料、香料等が挙げられる。
なお、経口投与用の液剤の場合に使用する担体としては、水等の溶剤等が挙げられる。
Examples of the flavoring agent include sweeteners, acidulants, and flavors.
Examples of the carrier used in the case of a liquid preparation for oral administration include a solvent such as water.
本発明の医薬品を摂取するタイミングは、例えば食前、食後、食間、就寝前など特に限定されない。 The timing of ingesting the drug of the present invention is not particularly limited, for example, before meals, after meals, between meals, and before bedtime.
以下に実施例を用いて本発明をさらに具体的に説明するが、本発明はこれら実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
以下の方法で、ランダム化二重盲検プラセボ対照並行群間比較試験を行った。
（１）被験者
スクリーニングにより参加適格と判断された認知症でない成人男女、合計２６８名に、同意を得た上で、被験者として参加してもらった。被験者背景を表１に示す。また、具体的な選択基準及び除外基準は以下の通りである。
選択基準
・年齢４０歳以上
・長谷川式簡易知能評価（ＨＤＳ−Ｒ）が２１点以上
除外基準
・認知症と診断されている者または認知症の疑いを有する者
・統合失調症、うつ病等の精神障害が疑われる者（高齢者用うつ尺度短縮版（ＧＤＳ−１５−Ｊ）にて判定し、６点以上を除外）
・脳、肝臓、腎臓、心臓、肺、消化器、血液、内分泌代謝系等に重篤な疾患を有する者、またはこれらの重篤な既往歴がある者
・妊婦、授乳婦、半年以内に妊娠の計画がある者
・重篤な薬剤アレルギー、食物アレルギーを有する者、またはこれらの重篤な既往歴がある者
・試験責任医師により被験者として不適格と判断された者
A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted by the following method.
(1) A total of 268 adult men and women without dementia who were judged to be eligible for participation by subject screening were asked to participate as subjects after obtaining their consent. The subject background is shown in Table 1. The specific selection criteria and exclusion criteria are as follows.
Selection criteria-Age 40 years or older-Hasegawa simple intelligence evaluation (HDS-R) 21 points or more Exclusion criteria-People who have been diagnosed with dementia or who are suspected of having dementia-Syntax, depression, etc. Persons suspected of having a mental disorder (determined by the shortened version of the Depression Scale for the Elderly (GDS-15-J), excluding 6 points or more)
・ Persons with serious diseases such as brain, liver, kidney, heart, lungs, digestive organs, blood, endocrine and metabolic system, or those with a serious history of these ・ Pregnant women, lactating women, pregnant within 6 months・ Persons who have serious drug allergies or food allergies, or persons who have a serious history of these diseases ・ Persons who are judged to be ineligible as subjects by the investigator
（２）試験方法
本試験は、認知症ではない中高年男女を対象として、ＭＫＰペプチド１ｇ／日を２４週間毎日摂取した時、プラセボ（デキストリン１ｇ／日）摂取と比較して、ＡＤＡＳ−ｃｏｇのスコアが改善するかを検証した。
ＡＤＡＳ−ｃｏｇは、「単語再生」、「口語言語能力」、「言語の聴覚的理解」、「喚語困難」、「口頭命令に従う」、「手指および物品呼称」、「構成行為」、「観念運動」、「見当識」、「単語再認」、及び「テスト教示の再生能力」の１１項目から構成される。これらの項目について割り当てた７０点満点の検査で、得点が低いほど認知機能が正常であると判断されるものである。統計解析は得られた全てのデータを対象として、摂取前値を共変量とした共分散分析により行った。
(2) Test method In this test, in middle-aged and elderly men and women without dementia, when MKP peptide 1 g / day was ingested daily for 24 weeks, the ADAS-cog score was compared with the placebo (dextrin 1 g / day) intake. Was verified to improve.
ADAS-cog is "word reproduction", "verbal language ability", "auditory comprehension of language", "difficulty in speaking", "following oral commands", "name of fingers and articles", "construction", "ideal movement". , "Orientation,""wordrecognition," and "reproduction ability of test teaching." In the examination of 70 points assigned to these items, the lower the score, the more normal the cognitive function is judged. Statistical analysis was performed on all the obtained data by analysis of covariance with the pre-ingestion value as a covariant.
（３）結果
摂取２４週目においてプラセボ群と比較してＭＫＰペプチド群の見当識が有意に改善した（表２）。
また、試験食品摂取に起因する有害事象は認められず、ＭＫＰペプチドの安全性が確認された。
(3) Results At the 24th week of ingestion, the orientation of the MKP peptide group was significantly improved as compared with the placebo group (Table 2).
In addition, no adverse events caused by ingestion of the test food were observed, confirming the safety of the MKP peptide.
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