JP2023107887A - Composition for increasing cerebral blood flow - Google Patents
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Abstract
Description
本発明は、脳血流を増加させるための組成物に関する。 The present invention relates to compositions for increasing cerebral blood flow.
加齢、疲労、疾患等に伴い脳血流が低下し、脳循環障害に伴う症状の発生や悪化につながることが知られている。脳血流を改善することは、脳循環の改善につながり、最終的には様々な脳循環障害に伴う症状の予防や緩和に有効であると考えられる。 It is known that cerebral blood flow decreases with aging, fatigue, disease, etc., leading to the occurrence or exacerbation of symptoms associated with cerebral circulation disorders. Improving cerebral blood flow leads to improvement of cerebral circulation, and is ultimately considered to be effective in preventing and alleviating symptoms associated with various cerebral circulation disorders.
これまでに乳酸菌の菌体を用いて迷走神経を活性化させ、それにより脳血流を改善する技術が提案されている（特許文献１）。しかしながら、脳血流を改善可能な、日常生活において手軽に摂取できる食品素材は未だ少ないのが現状である。 A technique has been proposed to improve cerebral blood flow by activating the vagus nerve using lactic acid bacteria (Patent Document 1). However, the current situation is that there are still few food materials that can be easily ingested in daily life that can improve cerebral blood flow.
本発明は脳血流を増加させるための新規素材およびそれを含む組成物を提供することを目的とする。 An object of the present invention is to provide a novel material and a composition containing the same for increasing cerebral blood flow.
本発明者らは今般、ヒト試験において乳タンパク質の酵素分解物に脳血流を増加させる作用があることを見出した。本発明はこの知見に基づくものである。 The present inventors have recently found that an enzymatic hydrolyzate of milk protein has the effect of increasing cerebral blood flow in human tests. The present invention is based on this finding.
本発明によれば以下の発明が提供される。
［１］乳タンパク質酵素分解物を有効成分として含んでなる、脳血流を増加させるための組成物（以下、「本発明の組成物」ということがある）および脳血流増加剤（以下、「本発明の用剤」ということがある）。
［２］乳タンパク質酵素分解物が、ホエイタンパク質酵素分解物である、上記［１］に記載の組成物および用剤。
［３］乳タンパク質酵素分解物が、ＧＴＷＹ（配列番号１）のアミノ酸配列を有するペプチドおよびＷＹのアミノ酸配列を有するペプチドを含む、上記［１］または［２］に記載の組成物および用剤。
［４］脳血流量が低下した対象または脳血流量が低下するリスクがある対象に摂取させるための、上記［１］～［３］のいずれかに記載の組成物および用剤。
［５］学習療法を実施する対象に摂取させるための、上記［１］～［４］のいずれかに記載の組成物および用剤。
［６］ホエイタンパク質酵素分解物を、ヒト１日当たり０．０１～１００ｇ（固形分換算）で摂取させる、上記［１］～［５］のいずれかに記載の組成物および用剤。
［７］食品の形態である、上記［１］～［６］のいずれかに記載の組成物および用剤。
［８］脳血流の増加により治療、予防または改善しうる疾患または症状の治療、予防または改善に用いるための、上記［１］～［７］のいずれかに記載の組成物および用剤。
According to the present invention, the following inventions are provided.
[1] A composition for increasing cerebral blood flow comprising a milk protein enzymatic hydrolyzate as an active ingredient (hereinafter sometimes referred to as "the composition of the present invention") and a cerebral blood flow increasing agent (hereinafter referred to as It may be referred to as "the agent of the present invention").
[2] The composition and preparation according to [1] above, wherein the enzymatic hydrolyzate of whey protein is the enzymatic hydrolyzate of whey protein.
[3] The composition and preparation according to [1] or [2] above, wherein the enzymatic hydrolyzate of milk protein contains a peptide having an amino acid sequence of GTWY (SEQ ID NO: 1) and a peptide having an amino acid sequence of WY.
[4] The composition and preparation according to any one of [1] to [3] above, which are to be ingested by a subject with decreased cerebral blood flow or a subject at risk of decreased cerebral blood flow.
[5] The composition and preparation according to any one of [1] to [4] above, which are to be ingested by a subject undergoing learning therapy.
[6] The composition and preparation according to any one of the above [1] to [5], wherein the whey protein enzymatic hydrolyzate is ingested by humans in an amount of 0.01 to 100 g (solid content conversion) per day.
[7] The composition and agent according to any one of [1] to [6] above, which is in the form of food.
[8] The composition and agent according to any one of [1] to [7] above, which are used for treating, preventing, or ameliorating diseases or symptoms that can be treated, prevented, or ameliorated by increasing cerebral blood flow.
本発明の組成物および用剤が有効成分とするホエイタンパク質酵素分解物は、長年にわたり食経験がある素材である。従って、本発明の組成物および用剤は、脳血流を増加させる機能性食品として利用できるとともに、ヒトを含む哺乳類に安全な機能性食品として利用できる点で有利である。 The whey protein enzymatic hydrolyzate used as an active ingredient in the composition and preparation of the present invention is a material that has been eaten for many years. Therefore, the composition and preparation of the present invention are advantageous in that they can be used as a functional food that increases cerebral blood flow and that they are safe for mammals including humans.
本発明の組成物および用剤の有効成分である乳タンパク質酵素分解物（以下、「本発明の乳タンパク質分解物」ということがある）は、乳タンパク質の酵素分解物である限り特に限定されない。乳タンパク質としては、全乳、粉乳、ミルクプロテインまたはホエイを用いることができ、好ましくはホエイである。ここで、「ホエイ」とは、乳清、乳漿またはホエーともいい、乳から乳脂肪分やカゼインなどを除いた水溶液を意味する。ホエイはβ－ラクトグロブリン、α－ラクトアルブミン、血清アルブミン、免疫グロブリン等から構成される。本発明で使用するホエイの由来動植物は問わないが、牛乳由来ホエイを用いることが好ましい。本発明の乳タンパク質分解物は、好ましくはホエイタンパク質酵素分解物（以下、単に「ホエイ分解物」ということがある）である。 The enzymatic hydrolyzate of milk protein (hereinafter sometimes referred to as "the hydrolyzate of milk protein of the present invention"), which is an active ingredient of the composition and preparation of the present invention, is not particularly limited as long as it is an enzymatic hydrolyzate of milk protein. As milk protein, whole milk, powdered milk, milk protein or whey can be used, preferably whey. Here, "whey" is also referred to as whey, whey, or whey, and means an aqueous solution obtained by removing milk fat, casein, and the like from milk. Whey is composed of β-lactoglobulin, α-lactalbumin, serum albumin, immunoglobulins and the like. The whey used in the present invention may be derived from any animal or plant, but it is preferable to use milk-derived whey. The milk protein hydrolyzate of the present invention is preferably a whey protein enzymatic hydrolyzate (hereinafter sometimes simply referred to as "whey hydrolyzate").
本発明の組成物および用剤は、本発明の乳タンパク質分解物を単独で使用することができ、あるいは、他の成分と混合して使用することもできる。本発明の組成物および用剤における本発明の乳タンパク質分解物の含有量（固形分換算）は、その目的、用途、形態、剤型、症状、年齢などに応じて任意に定めることができ、本発明はこれに限定されないが、例えば、全体量に対して、０．００１～９９質量％（好ましくは０．０１～９５質量％）とすることができる。本発明においては、本発明の用剤を本発明の乳タンパク質分解物からなるものとし、本発明の組成物を本発明の乳タンパク質分解物と他の成分とを含んでなるものとすることができる。 The composition and preparation of the present invention can use the milk protein hydrolyzate of the present invention alone, or can be used by mixing with other ingredients. The content of the milk protein hydrolyzate of the present invention (in terms of solid content) in the composition and preparation of the present invention can be arbitrarily determined according to its purpose, application, form, dosage form, symptoms, age, etc. Although the present invention is not limited to this, for example, it can be 0.001 to 99% by mass (preferably 0.01 to 95% by mass) relative to the total amount. In the present invention, the preparation of the present invention may comprise the milk protein hydrolyzate of the present invention, and the composition of the present invention may comprise the milk protein hydrolyzate of the present invention and other ingredients. can.
本発明の乳タンパク質分解物（特に、ホエイ分解物）は、好ましくはＧＴＷＹ（配列番号１）のアミノ酸配列を有するペプチドおよびＷＹのアミノ酸配列を有するペプチド（以下、「本発明のペプチド」ということがある）を含有してなるものを使用することができる。ここで、「アミノ酸配列を有するペプチド」とは、該アミノ酸配列により配列が特定されたペプチドを意味する。 The milk protein hydrolyzate (especially whey hydrolyzate) of the present invention is preferably a peptide having an amino acid sequence of GTWY (SEQ ID NO: 1) and a peptide having an amino acid sequence of WY (hereinafter referred to as "the peptide of the present invention"). ) can be used. Here, "a peptide having an amino acid sequence" means a peptide whose sequence is specified by the amino acid sequence.
本発明の乳タンパク質分解物（特に、ホエイ分解物）中のテトラペプチドＧＴＷＹの含有量（固形分換算）は、例えば、０．０１～１質量％（好ましくは０．０５～０．５質量％）であり、ジペプチドＷＹの含有量（固形分換算）は、例えば、０．００５～０．５質量％（好ましくは０．０１～０．１質量％）である。 The content of the tetrapeptide GTWY (in terms of solid content) in the milk protein hydrolyzate (especially, whey hydrolyzate) of the present invention is, for example, 0.01 to 1% by mass (preferably 0.05 to 0.5% by mass). ), and the content of the dipeptide WY (in terms of solid content) is, for example, 0.005 to 0.5% by mass (preferably 0.01 to 0.1% by mass).
本発明の乳タンパク質分解物（特に、本発明のペプチドを含有する乳タンパク質分解物）の製造方法は公知であり、例えば、国際公開公報第２０１７／０８６３０３号の記載に従って製造することができる。あるいは、市販されているホエイ分解物（例えば、ＨＷ－３（雪印メグミルク社製））を本発明の乳タンパク質分解物として用いてもよい。 Methods for producing the hydrolyzate of milk protein of the present invention (particularly, the hydrolyzate of milk protein containing the peptide of the present invention) are known, and can be produced, for example, according to the description of International Publication No. 2017/086303. Alternatively, a commercially available whey hydrolyzate (eg, HW-3 (manufactured by Megmilk Snow Brand)) may be used as the milk protein hydrolyzate of the present invention.
本発明のペプチドを含有する乳タンパク質分解物は、例えば、原料タンパク質にタンパク質分解酵素を含む酵素製剤を作用させることにより製造することができる。 A milk protein hydrolyzate containing the peptide of the present invention can be produced, for example, by reacting a raw material protein with an enzyme preparation containing a protease.
原料としてホエイタンパク質を用いる場合、酵素反応に供されるホエイタンパク質の濃度は、タンパク質が溶解し得る限り限定されないが、タンパク質が溶解し得る限り限定されないが、ゲル化や凝集を抑制し、濃縮の手間を省く観点から、１～３０ｗ／ｖ％とすることが好ましく、より好ましくは１～２０ｗ／ｖ％であり、さらに好ましくは５～１５ｗ／ｖ％である。 When whey protein is used as a raw material, the concentration of whey protein subjected to the enzymatic reaction is not limited as long as the protein can be dissolved, but is not limited as long as the protein can be dissolved. From the viewpoint of saving labor, it is preferably 1 to 30 w/v%, more preferably 1 to 20 w/v%, and still more preferably 5 to 15 w/v%.
原料タンパク質が乳清や乳漿のような水溶液の場合、そのままで、あるいは濃縮または希釈して酵素反応に供すればよく、必要に応じｐＨ調整等をすることができる。原料タンパク質が紛体等の固形物の場合、酵素反応が進行する限りいずれの水系溶媒に溶解させてもかまわないが、食品としての利用を考慮し、水または食品添加物グレードの緩衝液に溶解させることが好ましい。酵素反応で生じたアミノ酸により反応液のｐＨが変化しないようにするため緩衝液を使用することが好ましい。緩衝液の種類は任意であり、その後の利用や風味・味覚・ミネラル量を考慮して決定すればよいが、反応液のｐＨを４～９、好ましくは５～８、より好ましくは７～８に維持できるような組成が好ましい。最も好ましくはリン酸カリウム緩衝液である。緩衝液の濃度は緩衝効果が得られる範囲であれば任意であるが、風味・味覚・ミネラル量を考慮すると、０．０１～０．５Ｍとすることができ、好ましくは０．０５～０．２Ｍであり、より好ましくは約０．１Ｍである。 When the starting protein is an aqueous solution such as whey or whey, it may be subjected to the enzymatic reaction as it is, or after concentration or dilution, and the pH may be adjusted as necessary. If the raw material protein is solid such as powder, it can be dissolved in any aqueous solvent as long as the enzymatic reaction proceeds. is preferred. It is preferable to use a buffer solution in order to prevent the pH of the reaction solution from being changed by the amino acid produced by the enzymatic reaction. The type of buffer solution is arbitrary, and may be determined in consideration of subsequent use, flavor, taste, and mineral content. A composition that can be maintained at Potassium phosphate buffer is most preferred. The concentration of the buffer solution is arbitrary as long as the buffering effect is obtained, but considering the flavor, taste and mineral content, it can be 0.01 to 0.5M, preferably 0.05 to 0.5M. 2M, more preferably about 0.1M.
酵素はタンパク質分解酵素を含む酵素剤であればいずれも使用できるが、中性プロテアーゼを含む酵素製剤であることが好ましく、１種類またはそれ以上を組合せて使用することができる。酵素製剤は、たとえばバチルス・サブティリス、アスペルギルス・オリゼ、アルペルギルス・メレウスなどの微生物を由来としたものを使用することができ、このうちアスペルギルス・オリゼ由来の酵素製剤とアルペルギルス・メレウス由来の酵素製剤が好ましく、より好ましくはアルペルギルス・メレウス由来の酵素製剤である。 Any enzymatic agent containing a proteolytic enzyme can be used as the enzyme, but an enzyme preparation containing a neutral protease is preferable, and one or more of them can be used in combination. Enzyme preparations that can be used are those derived from microorganisms such as Bacillus subtilis, Aspergillus oryzae, and Aspergillus meleus. An enzyme preparation derived from Aspergillus meleus is preferred, and more preferred.
本発明では市販の酵素製剤を使用することができ、例えば、天野エンザイム社、新日本化学工業社、ＤＳＭ社、ダニスコ社、ノボザイム社、ＨＢＩ社などから酵素製剤を入手可能である。酵素製剤の添加量は任意であるが、適度な加水分解反応速度と、コストを考慮すると、例えば、０．０１～５ｗ／ｖ％、好ましくは０．０５～４ｗ／ｖ％、より好ましくは０．１～０．５ｗ／ｖ％とすることができる。 Commercially available enzyme preparations can be used in the present invention, and enzyme preparations are available from, for example, Amano Enzyme, Shin Nihon Chemical Industry, DSM, Danisco, Novozyme, HBI, and the like. The amount of the enzyme preparation added is arbitrary, but considering the appropriate hydrolysis reaction rate and cost, for example, 0.01 to 5 w / v%, preferably 0.05 to 4 w / v%, more preferably 0 .1 to 0.5 w/v%.
酵素反応温度と酵素反応時間は原料タンパク質の加水分解が十分になされ、酵素分解物の品質が保たれるように設定することができる。すなわち、酵素反応温度は、例えば、３０～７０℃とすることができ、好ましくは４０～７０℃であり、より好ましくは４５～６５℃である。また、酵素反応時間は１～１２時間とすることができ、好ましくは２～１０時間であり、より好ましくは４～５時間である。なお、反応温度と反応時間は本発明のペプチドの生成量を確認しながら適宜調整することができる。 The enzymatic reaction temperature and the enzymatic reaction time can be set so that the raw material protein is sufficiently hydrolyzed and the quality of the enzymatic hydrolyzate is maintained. That is, the enzymatic reaction temperature can be, for example, 30 to 70°C, preferably 40 to 70°C, more preferably 45 to 65°C. The enzymatic reaction time can be 1 to 12 hours, preferably 2 to 10 hours, more preferably 4 to 5 hours. The reaction temperature and reaction time can be appropriately adjusted while confirming the production amount of the peptide of the present invention.
酵素反応は温度を上昇させながら行うこともできる。例えば、３０℃から７５℃にまで４～１０時間かけて上昇させながら反応させることができる。好ましくは、３５℃から７５℃まで５～８時間かけて上昇させながら反応させることができ、より好ましくは３５℃から７５℃まで６～８時間かけて反応させることができる。温度上昇スピードは任意であるが、４５℃から５５℃の間での保持時間を長めにし（５～７時間）、その後６０℃まですみやかに上昇させた後に６０℃から７５℃の間で長めに（たとえば１～３時間）保持することが好ましい。最も好ましいのは５０℃で酵素を投入し、５～７時間保持後、任意の速度で昇温させ、６０～６５℃あるいは６５～７５℃の目標温度で１～３時間保持する方法である。 The enzymatic reaction can also be performed while increasing the temperature. For example, the reaction can be carried out while raising the temperature from 30° C. to 75° C. over 4 to 10 hours. Preferably, the reaction can be carried out while raising the temperature from 35°C to 75°C over 5 to 8 hours, more preferably from 35°C to 75°C over 6 to 8 hours. The temperature rise speed is arbitrary, but the holding time between 45°C and 55°C is longer (5-7 hours), followed by a rapid rise to 60°C followed by a longer temperature between 60°C and 75°C. It is preferred to hold (for example 1-3 hours). The most preferable method is to charge the enzyme at 50°C, maintain it for 5-7 hours, raise the temperature at an arbitrary rate, and maintain it at a target temperature of 60-65°C or 65-75°C for 1-3 hours.
反応に際しては反応効率の観点から反応液を撹拌することが好ましい。基質が酵素とよく接するように、液撹拌速度は速い方がよいが、速すぎると反応液が飛び散る恐れがあるため、例えば、１００～５００ｒｐｍとすることができ、好ましくは２００～４００ｒｐｍであり、より好ましくは約２５０ｒｐｍである。 During the reaction, it is preferable to stir the reaction solution from the viewpoint of reaction efficiency. The liquid stirring speed should be fast so that the substrate is in good contact with the enzyme, but if it is too fast, the reaction liquid may scatter. More preferably about 250 rpm.
所望のペプチドが得られたら反応液は酵素反応を停止工程に付すことが好ましい。酵素反応停止工程では、反応液を高温にしたり、キレート剤を添加して酵素の化学構造を変化させたりする方法や、膜処理により酵素を除去する方法を採用することができる。好ましい手法は高温による失活処理である。該方法は８０～９０℃で５～３０分、好ましくは８０～９０℃で２０～３０分間保持することで実施することができる。また、後述の濃縮工程で高温になる場合には、濃縮工程を兼ねて行うことができる。 When the desired peptide is obtained, the reaction solution is preferably subjected to a step of stopping the enzymatic reaction. In the enzymatic reaction termination step, a method of increasing the temperature of the reaction solution, adding a chelating agent to change the chemical structure of the enzyme, or a method of removing the enzyme by membrane treatment can be employed. A preferred technique is high temperature deactivation. The method can be carried out by holding at 80-90°C for 5-30 minutes, preferably at 80-90°C for 20-30 minutes. Moreover, when the temperature becomes high in the later-described concentration step, the concentration step can also be performed.
酵素反応工程および酵素反応停止工程を経た反応液（乳タンパク質分解物）は、さらに殺菌工程に付してもよい。殺菌工程としては、例えば、後述の膜処理工程や高温殺菌工程が挙げられる。加熱殺菌工程は酵素反応停止工程を兼ねることもでき、製造工程の簡略化の点で有利である。 The reaction solution (milk protein hydrolyzate) that has undergone the enzymatic reaction step and the enzymatic reaction termination step may be further subjected to a sterilization step. Examples of the sterilization process include a membrane treatment process and a high-temperature sterilization process, which will be described later. The heat sterilization step can also serve as the enzymatic reaction termination step, which is advantageous in terms of simplification of the manufacturing process.
酵素反応工程および酵素反応停止工程を経た反応液（乳タンパク質分解物）は、さらに精製工程に付してもよい。精製工程としてはたとえば膜処理工程が挙げられ、好ましい膜処理は限外ろ過である。限外ろ過の分画分子量としては３～１００ｋＤａのものが好ましく、５～５０ｋＤａがより好ましい。精製工程を実施すると、実施しなかった場合と比較してペプチド組成物の風味を改善することができる点で有利である。また、精製工程は酵素反応停止工程および殺菌工程を兼ねることもでき、製造工程の簡略化の点でも有利である。 The reaction solution (milk protein hydrolyzate) that has undergone the enzymatic reaction step and the enzymatic reaction termination step may be further subjected to a purification step. The purification step includes, for example, a membrane treatment step, and a preferred membrane treatment is ultrafiltration. The molecular weight cut off in ultrafiltration is preferably 3 to 100 kDa, more preferably 5 to 50 kDa. A purification step is advantageous in that it can improve the flavor of the peptide composition compared to when it is not performed. In addition, the purification step can serve as both the enzymatic reaction termination step and the sterilization step, which is advantageous in terms of simplification of the manufacturing process.
酵素反応工程および酵素反応停止工程を経た反応液（乳タンパク質分解物）は、保管や運搬の観点からさらに濃縮工程に付してもよい。濃縮工程は任意の方法を選択することができるが、減圧濃縮、凍結乾燥および噴霧乾燥（スプレードライ）、膜処理による濃縮（例えば、逆浸透膜を用いる方法）による方法が好ましく、より好ましくは凍結乾燥および噴霧乾燥である。濃縮を大量かつ効率的に実施する観点から噴霧乾燥が特に好ましい。 The reaction solution (milk protein hydrolyzate) that has undergone the enzymatic reaction step and the enzymatic reaction stopping step may be further subjected to a concentration step from the viewpoint of storage and transportation. Any method can be selected for the concentration step, but a method by vacuum concentration, freeze drying and spray drying (spray drying), concentration by membrane treatment (for example, a method using a reverse osmosis membrane) is preferable, and freezing is more preferable. drying and spray drying. Spray drying is particularly preferred from the viewpoint of large-scale and efficient concentration.
本発明のペプチドの含有量の測定は、液体クロマトグラフィータンデム質量分析法（ＬＣ／ＭＳ／ＭＳ）により実施することができる。当業者であればその条件設定は容易に行うことができ、測定の際に標準ペプチドとしてＬＣ／ＭＳ／ＭＳ測定用の純度のものを使用することはいうまでもないが、例えば、ＳＩＧＭＡ ＡＬＤＲＩＣＨ社製ＡＱＵＡペプチドを使用することができる。 The measurement of the peptide content of the present invention can be performed by liquid chromatography tandem mass spectrometry (LC/MS/MS). A person skilled in the art can easily set the conditions, and it is needless to say that a standard peptide of purity for LC/MS/MS measurement is used as a standard peptide for measurement. AQUA peptides manufactured by AQUA can be used.
本発明の組成物および用剤は、脳血流を増加させるためのものである。ここで、「脳血流を増加させる」とは、脳内（特に左脳内）の血流量を増加させることを意味し、脳血流の改善および脳血流の低下抑制を含む意味で用いられる。ここで「脳血流の改善」とは、いったん低下した脳血流量や低下の兆しがある脳血流量を回復させることを意味する。また、本発明において「脳血流の低下抑制」は、脳血流の低下のリスクがある対象において該リスクを低減することを含む意味で用いられる。 Compositions and agents of the present invention are for increasing cerebral blood flow. Here, "increasing cerebral blood flow" means increasing blood flow in the brain (especially in the left brain), and is used in the sense of improving cerebral blood flow and suppressing a decrease in cerebral blood flow. . Here, "improving cerebral blood flow" means recovering cerebral blood flow that has once decreased or is showing signs of decreasing. In addition, in the present invention, "suppression of decrease in cerebral blood flow" is used in a sense including reducing the risk of decrease in cerebral blood flow in a subject at risk.
脳内の血流量の測定は公知の方法に従って行うことができ、いずれの方法を採用することができるが、侵襲が少ない、妥当性が高い、簡便である等の観点から近赤外線分光法（Near-infrared spectroscopy、以下「ＮＩＲＳ法」ということがある）により測定することができる。ＮＩＲＳ法により対象の脳内の血流量を測定した場合には総ヘモグロビン濃度を指標にして単位時間当たりの脳血流量の変化量を測定することができる。 Measurement of blood flow in the brain can be performed according to known methods, and any method can be adopted. -infrared spectroscopy, hereinafter sometimes referred to as "NIRS method"). When the blood flow in the brain of a subject is measured by the NIRS method, the amount of change in the cerebral blood flow per unit time can be measured using the total hemoglobin concentration as an index.
後記実施例に示される通り、ホエイタンパク質酵素分解物を摂取させることにより対象の脳血流量を増加させることができる。加齢、疲労、疾患等に伴って脳血流が低下し、様々な症状が引き起こされる可能性があるところ、脳血流を改善することは脳虚血や脳循環障害に伴う症状の予防や緩和に有効であることが知られている（例えば、ケタス（商標名）カプセル１０ｍｇ・医薬品インタビューフォーム（杏林製薬社2016年4月改訂（第13版））、オキリコン（商標名）注２０ｍｇシリンジ等・医薬品インタビューフォーム（武田テバファーマ社2017年10月改訂（第8版））、キサンボン（商標名）注射用２０ｍｇ等・医薬品インタビューフォーム（キッセイ薬品工業社2017年8月（改訂第5版））、ミグシス（商標名）錠５ｍｇ・医薬品インタビューフォーム（ファイザー社2017年9月改訂（第8版））参照）。従って、本発明によれば、乳タンパク質酵素分解物を有効成分として含んでなる、脳血流の増加により治療、予防または改善しうる疾患または症状の治療、予防または改善に用いるための組成物と、乳タンパク質酵素分解物を有効成分として含んでなる、脳血流の増加により治療、予防または改善しうる疾患または症状の治療剤、予防剤および改善剤が提供される。上記組成物および用剤は本発明の組成物および用剤に関する記載に従って実施することができる。 As shown in the examples below, cerebral blood flow in subjects can be increased by ingesting whey protein enzymatic hydrolysates. Cerebral blood flow decreases due to aging, fatigue, disease, etc., and various symptoms may be caused. Known to be effective for mitigation (e.g., Ketas (trade name) capsules 10 mg, pharmaceutical interview form (Kyorin Pharmaceutical Co., Ltd. revised in April 2016 (13th edition)), Okirikon (trade name) injection 20 mg syringe, etc.・ Pharmaceutical interview form (Teva Takeda Pharma Co., Ltd. October 2017 revision (8th edition)), Xambon (trade name) 20 mg for injection, etc. ・ Pharmaceutical interview form (Kissei Pharmaceutical Co., Ltd. August 2017 (revised 5th edition)), Migusis (trade name) tablets 5 mg/Pharmaceutical Interview Form (Refer to Pfizer September 2017 revision (8th edition))). Therefore, according to the present invention, a composition for treatment, prevention or amelioration of a disease or condition that can be treated, prevented or ameliorated by an increase in cerebral blood flow, comprising a milk protein enzymatic hydrolyzate as an active ingredient. , a therapeutic agent, a preventive agent and an ameliorating agent for diseases or symptoms that can be treated, prevented or ameliorated by increasing cerebral blood flow, comprising a milk protein enzymatic hydrolyzate as an active ingredient. The compositions and agents described above can be carried out according to the description of the compositions and agents of the present invention.
脳血流の増加により治療、予防または改善しうる疾患または症状としては、例えば、めまい、脳虚血状態、偏頭痛等の脳循環障害に伴う疾患および症状が挙げられる。 Diseases or symptoms that can be treated, prevented, or ameliorated by increasing cerebral blood flow include, for example, diseases and symptoms associated with impaired cerebral circulation, such as dizziness, cerebral ischemia, and migraine.
本発明の組成物および用剤は、脳血流が低下した対象および脳血流の低下のリスクがある対象（特に、加齢、疲労、疾患等により脳血流が低下した対象および加齢、疲労、疾患等により脳血流の低下のリスクがある対象）に摂取させることができ、脳循環障害に伴う症状の予防や緩和を図ることができる。ここで、「脳血流の低下のリスクがある対象」は、脳血流量が低下していないが、将来において脳血流量の低下の恐れがある対象を意味する。 The compositions and preparations of the present invention can be used in subjects with decreased cerebral blood flow and subjects at risk of decreased cerebral blood flow (in particular, subjects with decreased cerebral blood flow due to aging, fatigue, disease, etc. and aging, Subjects at risk of decreased cerebral blood flow due to fatigue, disease, etc.) can be ingested, and symptoms associated with cerebral circulation disorders can be prevented or alleviated. Here, "a subject at risk of decreased cerebral blood flow" means a subject whose cerebral blood flow is not decreased, but who may experience a decrease in cerebral blood flow in the future.
後記実施例に示される通り、ホエイタンパク質酵素分解物を摂取させることにより負荷課題中の対象の脳血流量を増加させることができる。ここで、認知症（特に遂行機能低下）に対する認知リハビリテーションでは、脳活性化パラダイムによる学習療法が提案されているところ、学習療法中の脳賦活効果は、若年者に比して中高年者は脳機能課題遂行時の脳賦活作用が小さいことが知られている（京都大学大学院医学研究科人間健康科学系専攻紀要健康科学第7巻2011（https://repository.kulib.kyoto-u.ac.jp/dspace/handle/2433/155986））。学習療法中の脳賦活効果が大きくなれば学習療法の効果も高くなると考えられる。学習療法は負荷課題中の状況と近似していることから、本発明の組成物および用剤は、認知リハビリテーションの一つである学習療法において対象の脳血流を増加させるために用いることができる。すなわち、本発明の組成物および用剤は、認知リハビリテーションの一つである学習療法を実施する対象に摂取させるためのものとすることができる。 As shown in the Examples below, ingestion of whey protein enzymatic hydrolysates can increase the cerebral blood flow of a subject during a stress task. Here, in cognitive rehabilitation for dementia (especially executive function decline), learning therapy based on a brain activation paradigm has been proposed. It is known that the brain activation effect during task execution is small (Kyoto University Graduate School of Medicine Human Health Science Department Bulletin Health Science Vol. 7 2011 (https://repository.kulib.kyoto-u.ac.jp) /dspace/handle/2433/155986)). It is thought that the greater the brain activation effect during learning therapy, the greater the effect of learning therapy. Since learning therapy resembles the situation during a load task, the composition and preparation of the present invention can be used to increase cerebral blood flow in a subject in learning therapy, which is one of cognitive rehabilitation. . That is, the composition and agent of the present invention can be ingested by a subject who is undergoing learning therapy, which is one of cognitive rehabilitation.
本発明の組成物および用剤は、医薬品（例えば、医薬組成物）、医薬部外品、食品（例えば、食品組成物）、飼料（ペットフード含む）等の形態で提供することができ、下記の記載に従って実施することができる。 The composition and agent of the present invention can be provided in the form of pharmaceuticals (e.g., pharmaceutical compositions), quasi-drugs, foods (e.g., food compositions), feed (including pet food), and the like. can be carried out according to the description of
本発明の組成物および用剤は、ヒトおよび非ヒト動物に経口投与することができる。経口剤としては、顆粒剤、散剤、錠剤（糖衣錠を含む）、丸剤、カプセル剤、シロップ剤、乳剤、懸濁剤が挙げられる。これらの製剤は、当分野で通常行われている手法により、薬学上許容される担体を用いて製剤化することができる。薬学上許容される担体としては、賦形剤、結合剤、希釈剤、添加剤、香料、緩衝剤、増粘剤、着色剤、安定剤、乳化剤、分散剤、懸濁化剤、防腐剤等が挙げられる。 The compositions and preparations of the present invention can be orally administered to humans and non-human animals. Oral preparations include granules, powders, tablets (including sugar-coated tablets), pills, capsules, syrups, emulsions and suspensions. These formulations can be formulated using a pharmaceutically acceptable carrier by a method commonly practiced in the art. Pharmaceutically acceptable carriers include excipients, binders, diluents, additives, perfumes, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc. is mentioned.
本発明の乳タンパク質分解物を食品として提供する場合には、それをそのまま食品として提供することができ、あるいはそれを食品に含有させて提供することができる。例えば、本発明の乳タンパク質分解物を食品として提供する場合には、ホエイ分解物等の乳タンパク質の酵素分解物等を、そのまま食品として提供することができ、あるいはそれを食品に含有させて提供することができる。このようにして提供された食品は本発明の乳タンパク質分解物を有効量含有した食品である。本明細書において、本発明の乳タンパク質分解物を「有効量含有した」とは、個々の食品において通常喫食される量を摂取した場合に後述するような範囲で本発明の乳タンパク質分解物が摂取されるような含有量をいう。また「食品」とは、健康食品、機能性食品、栄養補助食品、保健機能食品（例えば、特定保健用食品、栄養機能食品、機能性表示食品）、特別用途食品（例えば、幼児用食品、妊産婦用食品、病者用食品）およびサプリメントを含む意味で用いられる。なお、本発明の乳タンパク質分解物をヒト以外の動物に摂取させる場合には、本発明でいう食品が飼料として使用されることはいうまでもない。 When the milk protein hydrolyzate of the present invention is provided as food, it can be provided as it is as food, or it can be provided by making it contained in food. For example, when providing the milk protein hydrolyzate of the present invention as a food, the enzymatic hydrolyzate of milk protein such as whey hydrolyzate can be provided as it is as a food, or it can be provided by including it in the food. can do. The food thus provided is a food containing an effective amount of the hydrolyzate of milk protein of the present invention. In the present specification, the phrase "contains an effective amount" of the hydrolyzate of the present invention means that the hydrolyzate of the present invention is within the range described later when the amount normally eaten in each food is ingested. Refers to the content as ingested. In addition, "food" includes health food, functional food, dietary supplement, food with health claims (e.g., food for specified health use, food with nutrient function claims, food with function claims), food for special dietary use (e.g., food for infants, pregnant women food, food for the sick) and supplements. When the milk protein hydrolyzate of the present invention is to be ingested by animals other than humans, it goes without saying that the food of the present invention is used as feed.
本発明の乳タンパク質分解物は、上記のような脳血流を増加させる効果を有するため、日常摂取する食品に含有させることができ、あるいは、サプリメントとして提供することができる。すなわち、本発明の組成物および用剤は食品の形態で提供することができる。この場合、本発明の組成物および用剤は１食当たりに摂取する量が予め定められた単位包装形態で提供することができる。１食当たりの単位包装形態としては、例えば、パック、包装、缶、ボトル等で一定量を規定する形態が挙げられる。本発明の組成物および用剤の各種作用をよりよく発揮させるためには、後述する、本発明の脳血流を増加させる機能の１日当たりの摂取量に従って１食当たりの摂取量を決定できる。本発明の食品は、摂取量に関する説明事項が包装に表示されるか、あるいは説明事項が記載された文書等と一緒に提供されてもよい。 Since the milk protein hydrolyzate of the present invention has the effect of increasing cerebral blood flow as described above, it can be contained in foods to be ingested on a daily basis, or can be provided as a supplement. That is, the composition and preparation of the present invention can be provided in the form of food. In this case, the composition and preparation of the present invention can be provided in a unit packaging form in which the amount to be ingested per meal is predetermined. The unit packaging form for one meal includes, for example, a form in which a fixed amount is defined by a pack, package, can, bottle, or the like. In order to better exhibit various actions of the composition and preparation of the present invention, the intake per meal can be determined according to the daily intake of the function of increasing cerebral blood flow of the present invention, which will be described later. The food of the present invention may be provided with a package containing instructions on the intake amount, or may be provided with a document or the like describing the instructions.
単位包装形態においてあらかじめ定められた１食当たりの摂取量は、１日当たりの有効摂取量であっても、１日当たりの有効摂取量を２回またはそれ以上（好ましくは２または３回）に分けた摂取量であってもよい。従って、本発明の組成物および用剤の単位包装形態には、後述のヒト１日当たりの摂取量で本発明の乳タンパク質分解物を含有させることができ、あるいは、後述のヒト１日当たりの摂取量の２分の１から３分の１の量で本発明の乳タンパク質分解物を含有させることができる。本発明の組成物および用剤は、摂取の便宜上、１食当たりの摂取量が１日当たりの有効摂取量である、「１食当たりの単位包装形態」で提供することが好ましい。 Even if the predetermined intake per meal in the unit packaging form is the effective intake per day, the effective intake per day is divided into two or more (preferably two or three) times. It may be intake amount. Therefore, the unit packaging form of the composition and preparation of the present invention can contain the milk protein hydrolyzate of the present invention at the daily intake for humans described below, or the daily intake for humans described below The milk protein hydrolyzate of the present invention can be contained in an amount of 1/2 to 1/3 of the amount. For convenience of ingestion, the composition and dosage form of the present invention are preferably provided in a "per-meal unit packaging form" in which the amount per meal is the effective daily intake.
「食品」の形態は特に限定されるものではなく、例えば、飲料の形態であっても、半液体やゲル状の形態であっても、固形体や粉末状の形態であってもよい。また、「サプリメント」としては、本発明の乳タンパク質分解物に賦形剤、結合剤等を加え練り合わせた後に打錠することにより製造された錠剤や、カプセル等に封入されたカプセル剤が挙げられる。 The form of the "food" is not particularly limited, and may be, for example, a beverage form, a semi-liquid form, a gel form, a solid form, or a powder form. In addition, as the "supplement", excipients, binders, etc. are added to the milk protein hydrolyzate of the present invention, and then kneaded and then tablets manufactured by tableting, and capsules enclosed in capsules etc. .
本発明で提供される食品は、本発明の乳タンパク質分解物を含有する限り、特に限定されるものではないが、例えば、清涼飲料水、炭酸飲料、果汁入り飲料、野菜汁入り飲料、果汁および野菜汁入り飲料、牛乳等の畜乳、豆乳、乳飲料、乳酸菌飲料、ドリンクタイプのヨーグルト、ドリンクタイプやスティックタイプのゼリー、コーヒー、ココア、茶飲料、栄養ドリンク、エナジー飲料、スポーツドリンク、ミネラルウォーター、ニア・ウォーター、ノンアルコールのビールテイスト飲料等の非アルコール飲料；飯類、麺類、パン類およびパスタ類等炭水化物含有飲食品；チーズ類、ハードタイプまたはソフトタイプのヨーグルト、畜乳その他の油脂原料による生クリーム、アイスクリーム等の乳製品；クッキー、ケーキ、チョコレート等の洋菓子類、饅頭や羊羹等の和菓子類、ラムネ等のタブレット菓子（清涼菓子）、キャンディー類、ガム類、ゼリーやプリン等の冷菓や氷菓、スナック菓子等の各種菓子類；ウイスキー、バーボン、スピリッツ、リキュール、ワイン、果実酒、日本酒、中国酒、焼酎、ビール、アルコール度数１％以下のノンアルコールビール、発泡酒、その他雑酒、酎ハイ等のアルコール飲料；卵を用いた加工品、魚介類や畜肉（レバー等の臓物を含む）の加工品（珍味を含む）、味噌汁等のスープ類等の加工食品、みそ、しょうゆ、ふりかけ、その他シーズニング調味料等の調味料、濃厚流動食等の流動食等を例示することができる。なお、ミネラルウォーターは、発泡性および非発泡性のミネラルウォーターのいずれもが包含される。また、本発明で提供される食品には、食品製造原料および食品添加物のいずれもが含まれる。 The food provided by the present invention is not particularly limited as long as it contains the milk protein hydrolyzate of the present invention. Beverages containing vegetable juice, livestock milk such as milk, soy milk, milk beverages, lactic acid beverages, drink type yogurt, drink type and stick type jelly, coffee, cocoa, tea beverages, nutritional drinks, energy drinks, sports drinks, mineral water Non-alcoholic beverages such as , near water, non-alcoholic beer-taste beverages; Carbohydrate-containing foods and beverages such as rice, noodles, bread and pasta; Cheeses, hard or soft yogurt, livestock milk and other oil and fat ingredients Dairy products such as fresh cream and ice cream; Western confectionery such as cookies, cakes and chocolates; Japanese confectionery such as steamed buns and sweet bean jelly; Frozen desserts, frozen desserts, various confectionery such as snacks; whiskey, bourbon, spirits, liqueurs, wine, fruit wine, Japanese sake, Chinese liquor, shochu, beer, non-alcoholic beer with an alcohol content of 1% or less, low-malt beer, other miscellaneous liquor, Alcoholic beverages such as chuhai; processed products using eggs, processed products of seafood and meat (including offal such as liver) (including delicacies), processed foods such as soups such as miso soup, miso, soy sauce, furikake , seasonings such as seasoning seasonings, liquid foods such as concentrated liquid foods, and the like. Mineral water includes both sparkling mineral water and non-foaming mineral water. In addition, the food provided by the present invention includes both food manufacturing raw materials and food additives.
茶飲料としては、発酵茶、半発酵茶および不発酵茶のいずれもが包含され、例えば、紅茶、緑茶、麦茶、玄米茶、煎茶、玉露茶、ほうじ茶、ウーロン茶、ウコン茶、プーアル茶、ルイボスティー、ローズ茶、キク茶、イチョウ葉茶、ハーブ茶（例えば、ミント茶、ジャスミン茶）が挙げられる。 Tea beverages include fermented tea, semi-fermented tea, and unfermented tea, such as black tea, green tea, barley tea, brown rice tea, sencha, gyokuro tea, roasted tea, oolong tea, turmeric tea, pu-erh tea, and rooibos tea. , rose tea, chrysanthemum tea, ginkgo biloba tea, herbal tea (eg, mint tea, jasmine tea).
果汁入り飲料や果汁および野菜汁入り飲料に用いられる果物としては、例えば、リンゴ、ミカン、ブドウ、バナナ、ナシ、モモ、マンゴー、アサイー、ブルーベリーおよびウメが挙げられる。また、野菜汁入り飲料や果汁および野菜汁入り飲料に用いられる野菜としては、例えば、トマト、ニンジン、セロリ、カボチャ、キュウリおよびスイカが挙げられる。 Examples of fruits used in fruit juice-containing beverages and fruit and vegetable juice-containing beverages include apples, mandarin oranges, grapes, bananas, pears, peaches, mangoes, acai, blueberries and plums. Examples of vegetables used in vegetable juice-containing beverages and fruit and vegetable juice-containing beverages include tomatoes, carrots, celery, pumpkins, cucumbers, and watermelons.
本発明の乳タンパク質分解物はヒトが食品として長年摂取してきた乳タンパク質の分解物等に含まれる成分であることから、毒性も低く、それを必要とする哺乳動物（例えば、ヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル、イルカ、アシカ等）に対し安全に用いることができる。本発明の乳タンパク質分解物および本発明のペプチドの摂取量または投与量は、受容者の性別、年齢および体重、症状、投与時間、剤形、投与経路並びに組み合わせる薬剤等に依存して決定できる。脳血流の増加作用を目的とした本発明の乳タンパク質分解物の成人１日当たりの摂取量および投与量（固形分換算）は、例えば、０．０１～１００ｇ（好ましくは０．１～１０ｇ）である。脳血流の増加作用を目的とした本発明のペプチドの成人１日当たりの摂取量および投与量（固形分換算）は、例えば、０．０１～１００ｍｇ（好ましくは０．１～１０ｍｇ）である。 Since the milk protein hydrolyzate of the present invention is a component contained in the hydrolyzate of milk protein that humans have ingested as food for many years, it has low toxicity and mammals that require it (e.g., humans, mice, rats, etc.) , rabbits, dogs, cats, cows, horses, pigs, monkeys, dolphins, sea lions, etc.). The intake or dosage of the milk protein hydrolyzate of the present invention and the peptide of the present invention can be determined depending on the recipient's sex, age and weight, symptoms, administration time, dosage form, administration route, drugs to be combined, and the like. The daily intake and dosage (solid content conversion) of the milk protein hydrolyzate of the present invention for the purpose of increasing cerebral blood flow for adults is, for example, 0.01 to 100 g (preferably 0.1 to 10 g). is. The daily intake and dose (solid content conversion) of the peptide of the present invention for the purpose of increasing cerebral blood flow for adults is, for example, 0.01 to 100 mg (preferably 0.1 to 10 mg).
本発明の乳タンパク質分解物は、例えば、脳血流の増加作用等を期待する日時よりも前に摂取を開始することが望ましく、その開始時期は上記期待日時の６日前（好ましくは７日前、より好ましくは８日前）とすることができる。本発明の乳タンパク質分解物はまた、脳血流増加作用を期待する期間内は摂取を継続することが好ましい。 For the milk protein hydrolyzate of the present invention, for example, it is desirable to start ingestion before the date and time when the effect of increasing cerebral blood flow, etc. is expected, and the start time is 6 days before the expected date and time (preferably 7 days before, more preferably 8 days before). It is also preferable to continue taking the milk protein hydrolyzate of the present invention during the period when the effect of increasing cerebral blood flow is expected.
本発明の乳タンパク質分解物の摂取期間は、前記した１日量での摂取を少なくとも７日間（好ましくは２週間、より好ましくは６週間）とすることができる。また、本発明の乳タンパク質分解物の摂取間隔は、前記した１日量での摂取を３日に１回、２日に１回または１日１回とすることができる。 The intake period of the milk protein hydrolyzate of the present invention can be at least 7 days (preferably 2 weeks, more preferably 6 weeks) at the above daily dose. Moreover, the ingestion interval of the milk protein hydrolyzate of the present invention can be once every three days, once every two days, or once a day in the above-described daily amount.
本発明の乳タンパク質分解物および本発明のペプチドに関する上記摂取量、摂取タイミング、摂取期間および摂取間隔は、本発明の乳タンパク質分解物および本発明のペプチドを非治療目的および治療目的のいずれで使用する場合にも適用があり、治療目的の場合には摂取は投与に読み替えることができる。 The above intake amount, intake timing, intake period and intake interval for the milk protein hydrolyzate of the present invention and the peptide of the present invention are determined for both non-therapeutic and therapeutic purposes of the milk protein hydrolyzate and the peptide of the present invention. In the case of therapeutic purposes, ingestion can be read as administration.
本発明の組成物および用剤並びに食品には、脳血流を増加させる効果を有する旨の表示が付されてもよい。この場合、消費者に理解しやすい表示とするため本発明の組成物および用剤並びに食品には以下の一部または全部の表示が付されてもよい。なお、本発明において「脳血流を増加させる」ことが以下の表示を含む意味で用いられることはいうまでもない。
・脳の血流が気になる方に
・脳の血の巡りを改善したい方に
・脳を活性化したい方に
・脳をイキイキさせたい方に
・脳虚血の気になる方に
・学習療法の効果を高めたい方に
・脳循環が気になる方に
The composition, preparation, and food of the present invention may be labeled as having an effect of increasing cerebral blood flow. In this case, in order to make the labeling easy for consumers to understand, the composition, preparation and food of the present invention may be labeled partially or wholly as follows. It goes without saying that the term "increase cerebral blood flow" in the present invention is used in a sense including the following indications.
・Those who are concerned about blood flow in the brain ・Those who want to improve blood circulation in the brain ・Those who want to activate the brain ・Those who want to activate the brain For those who want to increase the effect ・For those who are concerned about cerebral circulation
本発明の別の面によれば、有効量の本発明の乳タンパク質酵素分解物あるいはそれを含む組成物を、それを必要としている対象に摂取させるか、あるいは投与することを含んでなる、脳血流を増加させる方法が提供される。本発明によればまた、有効量の本発明の乳タンパク質酵素分解物あるいはそれを含む組成物を、それを必要としている対象に摂取させるか、あるいは投与することを含んでなる、脳血流の増加により治療、予防または改善しうる疾患または症状の治療、予防または改善方法が提供される。本発明の方法は、本発明の組成物および用剤に関する記載に従って実施することができる。 According to another aspect of the present invention, an effective amount of the enzymatic degraded milk protein of the present invention or a composition comprising the same is administered to a subject in need thereof, or is administered to a subject in need thereof. A method of increasing blood flow is provided. According to the present invention, there is also a method for improving cerebral blood flow, comprising ingesting or administering an effective amount of the milk protein enzymatic hydrolyzate of the present invention or a composition containing the same to a subject in need thereof. Methods are provided for treating, preventing or ameliorating diseases or conditions that can be treated, prevented or ameliorated by an increase. The methods of the invention can be practiced according to the descriptions for the compositions and dosage forms of the invention.
本発明のさらに別の面によれば、脳血流増加剤の製造のための、脳血流増加剤としての、あるいは、本発明の脳血流増加方法における、本発明の乳タンパク質酵素分解物の使用が提供される。本発明によればまた、脳血流の増加により治療、予防または改善しうる疾患または症状の治療剤、予防剤または改善剤の製造のための、脳血流の増加により治療、予防または改善しうる疾患または症状の治療剤、予防剤または改善剤としての、あるいは、本発明の治療、予防または改善方法における、本発明の乳タンパク質酵素分解物の使用が提供される。本発明の使用は、本発明の組成物および用剤に関する記載に従って実施することができる。 According to still another aspect of the present invention, the enzymatic hydrolyzate of milk protein of the present invention is used as a cerebral blood flow increasing agent for producing a cerebral blood flow increasing agent, or in the cerebral blood flow increasing method of the present invention. is provided for use. According to the present invention, there is also a method for treating, preventing, or ameliorating by increasing cerebral blood flow for the production of therapeutic, preventive, or ameliorating agents for diseases or symptoms that can be treated, prevented, or ameliorated by increasing cerebral blood flow. Use of the milk protein enzymatic hydrolyzate of the present invention as a therapeutic agent, preventive agent or ameliorating agent for a disease or symptom, or in the method of treatment, prevention or amelioration of the present invention is provided. Uses of the present invention can be carried out according to the description regarding the compositions and dosage forms of the present invention.
本発明のさらにまた別の面によれば、脳血流の増加に用いるための、あるいは、本発明の脳血流増加方法に用いるための、乳タンパク質酵素分解物が提供される。本発明によればまた、脳血流の増加により治療、予防または改善しうる疾患または症状の治療、予防または改善に用いるための、あるいは、本発明の治療、予防または改善方法に用いるための、乳タンパク質酵素分解物が提供される。上記の乳タンパク質酵素分解物は、本発明の組成物および用剤に関する記載に従って実施することができる。 According to yet another aspect of the present invention, there is provided an enzymatic hydrolyzate of milk protein for use in increasing cerebral blood flow or for use in the method for increasing cerebral blood flow of the present invention. According to the present invention, for use in the treatment, prevention or amelioration of diseases or symptoms that can be treated, prevented or ameliorated by increasing cerebral blood flow, or for use in the treatment, prevention or amelioration method of the present invention, A milk protein enzymatic hydrolyzate is provided. The above milk protein enzymatic hydrolyzate can be carried out according to the description regarding the composition and preparation of the present invention.
本発明の方法および本発明の使用はヒトを含む哺乳動物における使用であってもよく、治療的使用と非治療的使用のいずれもが意図される。本明細書において、「非治療的」とはヒトを手術、治療または診断する行為（すなわち、ヒトに対する医療行為）を含まないことを意味し、具体的には、医師または医師の指示を受けた者がヒトに対して手術、治療または診断を行う方法を含まないことを意味する。 The methods and uses of the invention may be for use in mammals, including humans, and are intended for both therapeutic and non-therapeutic uses. As used herein, the term "non-therapeutic" means that it does not include an act of surgery, treatment or diagnosis of humans (that is, a medical act on humans), specifically, a doctor or a doctor's instruction means that it does not include methods of performing surgery, therapy or diagnosis on humans.
以下の例に基づき本発明をより具体的に説明するが、本発明はこれらの例に限定されるものではない。 The present invention will be described more specifically based on the following examples, but the present invention is not limited to these examples.
例１：ホエイ分解物含有タブレットの調製並びにテトラペプチドＧＴＷＹおよびジペプチドＷＹの含有量の測定
（１）タブレットの調製
ホエイ分解物（ＨＷ－３、雪印メグミルク社製）と、賦形剤および結合剤を混合して練り合わせた後、打錠することによりホエイ分解物含有タブレット（３００ｍｇ／粒）を製造した。タブレット１粒中のホエイ分解物の含有量は１６８ｍｇであった。上記ホエイ分解物（ＨＷ－３）は、ホエイタンパク質にタンパク質分解酵素を含む酵素製剤を作用させ、次いで膜処理を行って未分解物を除去し、乾燥させて得られた製品であり、後述のようにテトラペプチドＧＴＷＹおよびジペプチドＷＹを含有するものである。
Example 1: Preparation of tablet containing whey decomposition product and measurement of content of tetrapeptide GTWY and dipeptide WY (1) Preparation of tablet Whey decomposition product (HW-3, manufactured by Megmilk Snow Brand), excipients and binders After mixing and kneading, tablets containing whey hydrolyzate (300 mg/tablet) were produced by tableting. The content of whey decomposition products in one tablet was 168 mg. The whey hydrolyzate (HW-3) is a product obtained by allowing an enzyme preparation containing a protease to act on the whey protein, then performing a membrane treatment to remove the undegraded product, and drying it, which will be described later. contains the tetrapeptide GTWY and the dipeptide WY.
（２）分析試料の調製
上記（１）で調製したタブレット１００粒（約３０ｇ）を乳鉢でよくすり潰し、その２０ｍｇを秤量し、滅菌水１ｍＬを加えてよく懸濁させた。懸濁液を遠心分離（１５０００ｒｐｍ、室温、３分）して得られた上清５００μＬを限外ろ過フィルター（１０ｋＤａ）でろ過し、ろ液を１０００倍希釈して測定試料とした。
(2) Preparation of Analysis Sample 100 tablets (approximately 30 g) prepared in (1) above were thoroughly ground in a mortar, 20 mg thereof was weighed, and 1 mL of sterilized water was added to suspend well. The suspension was centrifuged (15,000 rpm, room temperature, 3 minutes), and 500 μL of the supernatant was filtered through an ultrafiltration filter (10 kDa), and the filtrate was diluted 1,000 times to obtain a measurement sample.
（３）分析方法
上記（２）で得られた測定試料中のテトラペプチドＧＴＷＹおよびジペプチドＷＹの濃度をＬＣ／ＭＳ／ＭＳ法により下記の分析条件で定量した。なお、ＡＱＵＡ Ｐｅｐｔｉｄｅ（Ｓｉｇｍａ Ａｌｄｒｉｃｈ社製）を標準試料とする検量線法により測定試料のＧＴＷＹ濃度を算出した。
(3) Analysis method The concentrations of tetrapeptide GTWY and dipeptide WY in the measurement sample obtained in (2) above were quantified by the LC/MS/MS method under the following analysis conditions. The GTWY concentration of the measurement sample was calculated by a calibration curve method using AQUA Peptide (manufactured by Sigma Aldrich) as a standard sample.
＜分析条件＞
質量分析装置：４０００Ｑ ＴＲＡＰ（エービー・サイエックス社製）
ＨＰＬＣ装置：Ａｇｉｌｅｎｔ １２００ Ｓｅｒｉｅｓ（アジレント・テクノロジー社製）
カラム：ＴＳＫ ｇｅｌ ＯＤＳ－１００Ｖ ３μｍ ２．０ｍｍ Ｉ．Ｄ．×１５０ｍｍ（東ソー社製）
カラム温度：７０℃
移動相Ａ：０．１％ギ酸水溶液
移動相Ｂ：０．１％ギ酸アセトニトリル溶液
グラジエント条件：表１に示すグラジエント条件を適用した。
<Analysis conditions>
Mass spectrometer: 4000Q TRAP (manufactured by AB Sciex)
HPLC device: Agilent 1200 Series (manufactured by Agilent Technologies)
Column: TSK gel ODS-100V 3 μm 2.0 mm I.D. D. ×150mm (manufactured by Tosoh Corporation)
Column temperature: 70°C
Mobile phase A: 0.1% formic acid aqueous solution Mobile phase B: 0.1% formic acid acetonitrile solution Gradient conditions: Gradient conditions shown in Table 1 were applied.
流量：０．２ｍＬ／分
試料注入量：２μＬ
イオン化法：ＥＳＩ（正イオン検出モード）
カーテンガス：４０ｐｓｉ
ネブライザーガス：５０ｐｓｉ
乾燥ガス：８０ｐｓｉ
乾燥ガス温度：６００℃
コリジョンガス：窒素
イオン化電圧：５０００Ｖ
Flow rate: 0.2 mL/min Sample injection volume: 2 μL
Ionization method: ESI (positive ion detection mode)
Curtain gas: 40psi
Nebulizer gas: 50 psi
Dry gas: 80 psi
Drying gas temperature: 600°C
Collision gas: Nitrogen ionization Voltage: 5000V
＜テトラペプチドＧＴＷＹの分析条件＞
設定質量数（ｍ／ｚ）／コリジョンエネルギー（ｅＶ）：５２６．４→１５９．２／４７、５２６．４→３６８．３／２３
ＤＰ電圧（Ｖ）：３６
<Analysis conditions for tetrapeptide GTWY>
Set mass number (m/z)/collision energy (eV): 526.4→159.2/47, 526.4→368.3/23
DP voltage (V): 36
＜ジペプチドＷＹの分析条件＞
設定質量数（ｍ／ｚ）／コリジョンエネルギー（ｅＶ）：３６８．２→３５１．１／１９、３６８．２→１５９．２／３３
ＤＰ電圧（Ｖ）：５１
<Analysis conditions for dipeptide WY>
Set mass number (m/z)/collision energy (eV): 368.2→351.1/19, 368.2→159.2/33
DP voltage (V): 51
（４）分析結果
ホエイ分解物含有タブレット１粒（３００ｍｇ）中にテトラペプチドＧＴＷＹは０．２７ｍｇ、ジペプチドＷＹは０．１０ｍｇ、それぞれ含まれていることが確認された。
(4) Analysis Results It was confirmed that 0.27 mg of tetrapeptide GTWY and 0.10 mg of dipeptide WY were contained in one whey decomposition product-containing tablet (300 mg).
例２：ホエイ分解物の脳血流改善効果の確認
（１）試験の概要
例２では、ホエイ分解物が脳負荷時の脳血流に及ぼす効果を検証する試験を実施した。本試験は、プラセボを対照とした無作為化二重盲検並行群間比較試験とした。試験期間は６週間とし、試験期間中は試験食品または対照食品を摂取させた。具体的には、物忘れや間違いの多さなどの脳の衰えを自覚している５０歳以上７５歳以下の認知症を有さない健康な男女に試験食品として「ホエイ分解物含有タブレット」を、対照食品として「ホエイ分解物非含有タブレット」をそれぞれ摂取させて、ホエイ分解物の脳血流への効果を確認した。
Example 2 Confirmation of Cerebral Blood Flow Improving Effect of Whey Decomposition Products (1) Outline of Test In Example 2, a test was conducted to verify the effect of whey decomposition products on cerebral blood flow during brain stress. This study was a randomized, double-blind, parallel-group, placebo-controlled study. The test period was 6 weeks, and the test food or control food was ingested during the test period. Specifically, healthy men and women between the ages of 50 and 75 who do not have dementia and who are aware of brain decline such as forgetfulness and frequent mistakes were given "tablets containing whey decomposition products" as test foods. As a control food, "tablets not containing whey hydrolyzate" were given, and the effect of whey hydrolyzate on cerebral blood flow was confirmed.
（２）被験者
事前検査において医師から健常と判断された者を試験食品群（５７名）と対照食品群（５７名）に無作為に割付けた。解析対象者は、試験食品群では５３名（男性２０名、女性３３名）、対照食品群では５１名（男性１７名、女性３４名）であり、解析対象者の年齢（平均値±標準偏差）は試験食品群が６１．２±５．６歳、対照食品群が６０．７±５．７歳であった。被験者には試験期間中は試験期間前と同様の生活を継続させた。
(2) Subjects Subjects judged to be healthy by a doctor in a preliminary examination were randomly assigned to a test food group (57 persons) and a control food group (57 persons). There were 53 subjects (20 men, 33 women) in the test food group and 51 subjects (17 men, 34 women) in the control food group. ) was 61.2±5.6 years old in the test food group and 60.7±5.7 years old in the control food group. The subjects were allowed to continue the same lifestyle as before the test period during the test period.
（３）被験食品
試験期間中（６週間）、試験食品群には６粒の試験食品を、対照食品群には６粒の対照食品を１日１回水またはぬるま湯とともに毎日摂取させた。試験食品としては例１（１）で製造した「ホエイ分解物含有タブレット」（タブレット１粒（３００ｍｇ）中にホエイ分解物を１６８ｍｇ含有する）を用いた。また、対照食品としてはホエイ分解物に代えてマルトデキストリンを１６８ｍｇ配合する以外は例１（１）と同様の方法で製造した、ホエイ分解物非含有タブレットを用いた。
(3) Test food During the test period (6 weeks), the test food group was given 6 tablets of the test food, and the control food group was given 6 tablets of the control food once a day with water or lukewarm water every day. As the test food, the "whey decomposition product-containing tablet" produced in Example 1 (1) (one tablet (300 mg) contains 168 mg of whey decomposition product) was used. As a control food, a whey hydrolyzate-free tablet produced in the same manner as in Example 1 (1) except that 168 mg of maltodextrin was blended instead of the whey hydrolyzate was used.
（４）測定
ア 測定項目
測定項目は、以下の項目とした。
・近赤外線分光法（ＮＩＲＳ法）による脳血流量測定
(4) Measurement a. Measurement items The measurement items were as follows.
・Cerebral blood flow measurement by near-infrared spectroscopy (NIRS method)
イ 測定時期
６週間の摂取終了後の時点で、対象の脳血流測定を実施した。
B. Time of Measurement Cerebral blood flow was measured in the subjects after 6 weeks of ingestion.
ウ 測定方法
（ｉ）脳血流変化量測定
負荷課題実施中の前頭葉の脳血流変化をＮＩＲＳ法により測定した。ＮＩＲＳ法は、近赤外分光法を利用してヘモグロビンの濃度変化を測定することにより脳血流変化量を評価する方法である。本試験では、NeU社製HOT-1000を用い、総ヘモグロビン（total-Hb）濃度を計測することにより脳血流変化量を評価した。プローブは脳波測定の国際１０－２０法におけるFp1, Fp2位に設置した。計測は０．１秒毎に行い、１秒の移動平均処理を行った。被験者には５分間の安静の後、負荷課題を実施させた。各負荷課題の前に１０秒のレスト時間を設け、レスト時間５～１０秒の間のtotal-Hb濃度平均値をベースライン値とした。ベースライン値に対する負荷課題中のtotal-Hb濃度の変化量を算出することにより、負荷課題中の脳血流変化量を評価した。
C. Measurement method (i) Measurement of changes in cerebral blood flow Changes in cerebral blood flow in the frontal lobe during the load task were measured by the NIRS method. The NIRS method is a method for evaluating changes in cerebral blood flow by measuring changes in hemoglobin concentration using near-infrared spectroscopy. In this test, changes in cerebral blood flow were evaluated by measuring total hemoglobin (total-Hb) concentration using HOT-1000 manufactured by NeU. The probes were placed at positions Fp1 and Fp2 according to the international 10-20 method of electroencephalogram measurement. Measurement was performed every 0.1 seconds, and moving average processing was performed for 1 second. After resting for 5 minutes, the subject was asked to perform a load task. A rest period of 10 seconds was provided before each load task, and the average total-Hb concentration during the rest period of 5 to 10 seconds was used as the baseline value. The change in cerebral blood flow during the stress task was evaluated by calculating the amount of change in the total-Hb concentration during the stress task relative to the baseline value.
（ii）負荷課題
2-backテストはもともと、遂行機能の下位概念であるワーキングメモリを測定する試験であり、被験者には提示された数字がその二つ前に提示されたものと同一であったかどうか判断するものである。被験者には該試験を受けさせることで脳負荷を与えた。
(ii) load task
The 2-back test was originally a test to measure working memory, which is a subordinate concept of executive function, and to judge whether the number presented to the subject was the same as the number presented two years before. . Subjects were subjected to a brain challenge by undergoing the test.
（５）評価と解析
解析対象者全員を対象とし、体動による異常値については当該データを解析から除外した。それぞれの負荷課題中における総ヘモグロビン変化量について、左右別々に算出した。ホエイ分解物含有群とプラセボ群の値の比較を、２標本ｔ検定を用いて行った。ｐ＜０．０５で有意差有り、ｐ＜０．１で有意傾向有りとした。課題中脳血流変化量は以下の式で算出した（レスト時のtotal-Hb濃度平均値はベースライン値である。）。
(5) Evaluation and Analysis All subjects were subject to analysis, and abnormal values due to body movements were excluded from the analysis. The change in total hemoglobin during each load task was calculated separately for the left and right. A comparison of the values of the whey digest containing group and the placebo group was performed using a two-sample t-test. P < 0.05 indicates a significant difference, and p < 0.1 indicates a significant trend. The change in mid-cerebral blood flow during the task was calculated using the following formula (the average total-Hb concentration during rest is the baseline value).
（６）結果
それぞれの負荷課題中の脳血流変化量の測定結果は表２に示される通りであった。
課題移行時における脳血流の変化量は、左前頭葉においてプラセボ群に比しホエイペプチド群で大きく、負荷課題１回目において、群間に有意差が認められた（ｐ＝０．０４６）。また、２回の負荷課題実施時の平均でみると左前頭葉において群間差の有意傾向が認められた（ｐ＝０．０９）。 The amount of change in cerebral blood flow during the transition to the task was greater in the whey peptide group than in the placebo group in the left frontal lobe, and a significant difference was observed between the groups in the first load task (p=0.046). In addition, when looking at the average of the two loading tasks, there was a tendency for a significant difference between the groups in the left frontal lobe (p=0.09).
以上の結果から、ホエイ分解物含有タブレットを摂取することにより、物忘れや間違いの多さを自覚している被験者において、ワーキングメモリ課題遂行時の脳血流量が亢進することが示された。 From the above results, it was shown that ingestion of whey hydrolyzate-containing tablets increases cerebral blood flow during working memory tasks in subjects who are aware of frequent forgetfulness and mistakes.
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