JP2022141464A - Composition for improving memory updating and shifting functions - Google Patents

Abstract

To provide a composition for improving cognitive functions that is clear to affect which aspect of the cognitive functions.SOLUTION: A composition for improving execution functions contains protein, preferably milk protein, as an active ingredient. The composition can be used for improving any selected from a group consisting of memory updating and shifting functions.SELECTED DRAWING: None

Description

The present invention relates to compositions for improving memory update and switching functions. INDUSTRIAL APPLICABILITY The present invention is useful in fields such as food production, pharmaceutical production, and health promotion.

In recent years, the rate of skipping breakfast has been increasing, especially among young people. According to the results of the 2014 National Health and Nutrition Survey, 14.3% of men and 10.5% of women skipped breakfast. 0% and 23.5% for women. Skipping breakfast has been reported to be associated with poor academic performance and cognitive function. In addition, in the recent declining birthrate and aging society, there is growing interest in how to maintain and improve cognitive function, which declines with aging, and studies on foods and ingredients that are involved in cognitive function are underway. .

For example, Patent Document 1 has a specific amino acid sequence based on the fact that short-term memory was retained when a peptide having a specific sequence obtained from a protein hydrolyzate of whey or casein was administered to mice inducing memory impairment. A composition for enhancing memory learning function and/or cognitive function is proposed, comprising a peptide, or a pharmaceutically acceptable salt or solvate thereof. Patent Document 2 reports that when healthy elderly people ingested a composition containing medium-chain fatty acid triglycerides and the like, an increase in the concentration of blood ketone bodies and an improvement in trail-making test results were observed. Based on such experimental results, powdery powder containing 12.5 to 20 parts by weight of protein, 35 to 45 parts by weight of medium-chain fatty acid triglyceride as lipid, and 7 to 12 parts by weight of carbohydrate per 100 parts by weight wherein the protein is casein, milk protein concentrate (MPC), whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin at least one protein selected from the group consisting of, wherein the carbohydrate is at least one carbohydrate selected from the group consisting of lactose, palatinose, and trehalulose, and is applied at 45 to 55 g per day to improve brain function Suggest a drug. In addition, Patent Document 3 discloses that administration of a sample containing a peptide consisting of Met-Lys-Pro contained in an enzymatic degradation product of casein to a mouse model of brain dysfunction improves the decline in memory ability. An oral composition for improving brain dysfunction caused by amyloid beta protein, containing the peptide as an active ingredient, is proposed. Patent Document 4 considers that whey decomposition products improve attention function and judgment function (executive function) because the results of the word fluency test and the Stroop test were improved in subjects who ingested whey decomposition product-containing tablets. ing. Also proposed is a composition for enhancing, maintaining and/or improving attention function and/or judgment function, which comprises a milk protein enzymatic hydrolyzate as an active ingredient. Furthermore, Non-Patent Document 1 reports the effect of reducing the risk of developing Alzheimer's dementia by ingesting milk and dairy products.

On the other hand, the applicants had healthy male students aged 18 to 24 who did not eat breakfast consume a beverage containing a milk protein concentrate and evaluated it by the score of the Uchida-Kraepelin test. It has been reported that the effect of increasing the

International Publication WO2015/194564 (Patent No. 6022738) International Publication WO2016/013617 (Patent No. 6609555) Japanese Patent Application Laid-Open No. 2018-154640 (Patent No. 6589011) Japanese Unexamined Patent Application Publication No. 2020-11908 JP 2018-184369 A

Ozawa, M., Ohara, T., Ninomiya, M. T., Hata, J., Yoshida, E., Mukai, N., Nagata, M., Uchida, K., Shirota, T., Kitazono, T., and Kiyohara. Y. (2014) Milk and dairy consumption and risk of dementia in an elderly Japanese population: the Hisayama Study. Journal of the American Geriatrics Society 62, 1224-1230. doi:10.1111/jgs.12887 Saito, Y., Murata, N., Noma, T., Itoh, H., Kayano, M., Nakamura, K., and Urashima, T. (2018). Relationship of a Special Acidified Milk Protein Drink with Cognitive Performance : A Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Young Adults. Nutrients, 10(5), 574. doi:10.3390/nu10050574

Cognitive functions include various intellectual functions such as comprehension, judgment, and logic. If it becomes clearer which aspect of cognitive function the active ingredient affects, more appropriate usage will be possible. In addition, if the temporal transition of the effect of ingestion of the active ingredient is clarified, it will be possible to ingest it at a suitable timing, which is desirable.

The present inventors have studied the effect of ingestion of a certain active ingredient on cognitive function, focusing on specific aspects of cognitive function and the temporal transition of the effect, and completed the present invention.

The present invention provides the following.
[1] Any composition for improvement selected from the group consisting of memory update function and switching function, which contains a protein.
[2] The composition according to 1, wherein the protein is milk protein.
[3] The composition according to 1 or 2, which contains 10 g or more of protein per serving.
[4] The composition according to any one of 1 to 3, which contains 15 g or more of protein per serving.
[5] Consisting of study/learning, examinations, experiments, reading, cooking, exercise, communication, presentation/announcement, document/record creation, calculation/analysis work, computer work, vehicle operation/management, and assembly/maintenance work. 6. The composition of any one of 1 to 5, for ingestion prior to performing any of the groups.
[6] Studying/studying, examinations, experiments, reading, cooking, exercise, communication, presentation/announcement, document/recording, calculation/analysis work, computer work, operation/management of vehicles, assembly/assembly of things, including protein A composition for improving the ability to perform any of the group consisting of maintenance tasks.
[7] A method for producing a pharmaceutical material or food material for improving any one selected from the group consisting of a memory updating function and a switching function, using milk as a raw material.
[8] A composition for improving executive function, comprising a milk protein concentrate.

By ingesting the composition of the present invention, executive function, which is one of cognitive functions, particularly memory update function and switching function within executive function, which is one of cognitive functions, can be improved.

Ingestion of the composition of the present invention may improve the ability to perform any of the following groups: DIY, programming, record keeping, driving, reading, cooking, sports.

According to the present invention, active ingredients may be used for improving executive function, particularly memory updating and switching functions. In addition, the active ingredient can be ingested at a timing suitable for improving the desired function.

Addition and subtraction test results. The vertical axis is the reaction time (seconds). The shorter the reaction time, the better the switching function. At 15 minutes after ingestion, the reaction time was significantly shorter in the milk protein-rich drink intake group than in the placebo drink group, and the reaction time was significantly shorter in the milk protein low drink intake group than in the placebo drink intake group. rice field. There was no significant difference between the low-milk-protein beverage intake group and the high-milk-protein-rich beverage intake group. Furthermore, at 60 minutes after ingestion, the milk protein-rich drink intake group had significantly shorter reaction times than the placebo drink intake group. Percentage of correct answers in memory update tests. The vertical axis is the percentage of correct answers. The higher the correct answer rate, the better the memory update function. No significant difference was observed between groups at 15 minutes after ingestion. However, at 60 minutes after ingestion, the correct answer rate was significantly higher in the milk protein-rich drink intake group than in the placebo drink intake group, and the correct answer rate was significantly higher in the milk protein low drink intake group than in the placebo drink intake group. rice field. There was no significant difference between the low-milk-protein beverage intake group and the high-milk-protein-rich beverage intake group.

The present invention relates to compositions for improving cognitive function.

[Active ingredient]
The composition of the present invention contains protein as an active ingredient. The protein is preferably animal protein, more preferably milk protein.

Milk protein refers to protein derived from milk. Examples of milk proteins for use in the present invention are milk concentrate, total milk protein (TMP), whey protein, whey protein isolate (WPI), whey protein concentrate (WPC), beta-lactoglobulin, alpha-lacto albumin, lactoferrin, casein, and mixtures thereof and hydrolysates of any of them. Preferred examples are milk concentrate, milk protein concentrate (MPC), total milk protein (TMP), whey protein, whey protein isolate (WPI), whey protein concentrate (WPC), β-lactoglobulin, α- Lactalbumin, and lactoferrin, a more preferred example being milk protein concentrate (MPC).

The milk concentrate according to an embodiment of the present invention is raw milk, cow's milk or special milk or skim milk (raw milk, cow's milk or special milk from which milk fat is removed) or partially skimmed milk (from raw milk, cow's milk or special milk) Partially removed milk fat) is concentrated, for example, concentrated milk (raw milk, milk or special milk concentrated with a milk solids content of 25.5% or more and a milk fat content of 7.0% or more) and skimmed concentrated milk (raw milk, milk or special milk from which the milk fat has been removed) with a non-fat milk solid content of 18.5% or more and a bacterial count (per 1 g of the standard plate culture method) of 100,000 or less.) Not only "raw milk, Concentrated milk or special milk with a milk solids content of less than 25.5% (hereinafter referred to as "concentrated milk not specified in ministerial ordinances")", "removal of milk fat from raw milk, cow's milk or special milk" It can be a concentrated product with a non-fat milk solid content of less than 18.5% (hereinafter referred to as "non-ordinance non-fat concentrated skimmed milk"), etc., but milk protein concentrate (Milk Protein Concentrate, MPC). In addition, raw milk, cow's milk, special milk, skim milk and partially skimmed milk may be collectively referred to as "raw milk".

In addition, the milk concentrate contains protein within the range of 9.0% by mass or more and 15.5% by mass or less, and 0.40% by mass or more and 1.55% by mass or less, per 20% by mass of the total solids Ash content, sodium (Na) in the range of 0.01% by mass to 0.10% by mass, potassium (K) in the range of 0.05% by mass to 0.40% by mass, 0.15% by mass or more Calcium (Ca) within the range of 0.40% by mass or less, Magnesium (Mg) within the range of more than 0.00% by mass and 0.03% by mass or less, 0.08% by mass or more and 0.25% by mass or less phosphorus (P) within the range and chlorine (Cl) within the range of more than 0.00% by mass and 0.35% by mass or less.

The protein content of the milk concentrate is preferably in the range of 10.0% by mass or more and 15.5% by mass or less, and 10.5% by mass or more and 15.5% by mass or less per 20% by mass of the total solid content. It is more preferably within the range of 0% by mass or less, further preferably within the range of 11.0% by mass or more and 15.0% by mass or less, and 11.5% by mass or more and 14.5% by mass or less. It is more preferably within the range of 12.0% by mass or more and 14.0% by mass or less, and particularly within the range of 12.5% by mass or more and 13.5% by mass or less preferable.

In addition, the ash content of the milk concentrate is preferably in the range of 0.50% by mass or more and 1.55% by mass or less, and 0.55% by mass or more and 1.5% by mass or less per 20% by mass of the total solid content. It is more preferably within the range of 50% by mass or less, further preferably within the range of 0.60% by mass or more and 1.50% by mass or less, and 0.65% by mass or more and 1.45% by mass or less. more preferably within the range of 0.70% by mass or more and 1.45% by mass or less.

In addition, the content of sodium (Na) in the milk concentrate is preferably in the range of 0.01% by mass or more and 0.09% by mass or less per 20% by mass of the total solid content, and 0.01% by mass It is more preferably in the range of 0.08 mass% or less, more preferably in the range of 0.02 mass% or more and 0.08 mass% or less, and 0.02 mass% or more and 0.07 mass% It is particularly preferable to be within the following range.

In addition, the content of potassium (K) in the milk concentrate is in the range of 0.05% by mass or more and 0.38% by mass or less per 20% by mass of the total solids, although it depends on the content of sodium (Na). It is preferably within the range of 0.05% by mass or more and 0.36% by mass or less, more preferably 0.06% by mass or more and 0.34% by mass or less. , 0.06% by mass or more and 0.32% by mass or less. The content of potassium (K) is preferably 3 to 4 times the content of sodium (Na), and 3.2 to 3.9 times the content of sodium (Na). more preferably 3.4 times or more and 3.8 times or less the sodium (Na) content, and 3.6 times or more and 3.7 times or less the sodium (Na) content It is particularly preferred to have

In addition, the content of calcium (Ca) in the milk concentrate is preferably in the range of 0.15% by mass or more and 0.36% by mass or less per 20% by mass of the total solid content, and 0.16% by mass It is more preferably within the range of 0.34% by mass or less, more preferably 0.17% by mass or more and 0.32% by mass or less, and 0.18% by mass or more and 0.30% by mass. It is particularly preferable to be within the following range.

In addition, the content of magnesium (Mg) in the milk concentrate is preferably within the range of more than 0.00% by mass and 0.02% by mass or less per 20% by mass of the total solid content, and 0.00% by mass More preferably, it is in the range of more than 0.01% by mass or less.

In addition, the content of phosphorus (P) in the milk concentrate is preferably in the range of 0.10% by mass or more and 0.24% by mass or less per 20% by mass of the total solid content, and 0.11% by mass It is more preferably within the range of 0.24% by mass or less, more preferably 0.12% by mass or more and 0.23% by mass or less, and 0.13% by mass or more and 0.23% by mass. It is particularly preferable to be within the following range.

In addition, the content of chlorine (Cl) in the milk concentrate is preferably in the range of 0.01% by mass or more and 0.30% by mass or less per 20% by mass of the total solid content, and 0.03% by mass It is more preferably within the range of 0.30% by mass or less, further preferably within the range of 0.05% by mass or more and 0.25% by mass or less, and 0.07% by mass or more and 0.25% by mass. It is particularly preferable to be within the following range.

Furthermore, the total solid content of the milk concentrate is usually in the range of 14% by mass or more and 22% by mass or less, preferably in the range of 16% by mass or more and 22% by mass or less, and 18% by mass % or more and 22 mass % or less, more preferably 20 mass % or more and 22 mass % or less.

In addition, the thermal coagulation time of the milk concentrate at 130 ° C. (time until coagulation occurs in the milk concentrate and time until the viscosity of the milk concentrate increases) is preferably 2 minutes or more. It is more preferably 4 minutes or longer, still more preferably 6 minutes or longer, and particularly preferably 8 minutes or longer.

The milk protein concentrate (MPC) according to the embodiment of the present invention is obtained by concentrating the major proteins of whey by an ultrafiltration (UF) method or the like, followed by drying.

The protein content of the milk protein concentrate is preferably in the range of 40.0% by mass or more and 97.5% by mass or less, regardless of the content of other components, and 50.0% by mass or more and 95% by mass. 0% by mass or less, more preferably 60.0% by mass or more and 92.5% by mass or less, and 70.5% by mass or more and 90.0% by mass or less It is more preferable to be within the range.

The lipid content of the milk protein concentrate is preferably in the range of 0.25% by mass or more and 5.0% by mass or less, regardless of the content of other components, and 0.5% by mass or more 4 0% by mass or less, more preferably 0.75% by mass or more and 3.0% by mass or less, and 1.0% by mass or more and 2.0% by mass or less It is more preferable to be within the range.

The content of carbohydrates (sugars + dietary fiber) in the milk protein concentrate is preferably in the range of 3.5% by mass or more and 9.5% by mass or less, regardless of the content of other ingredients. It is more preferably within the range of 4.0% by mass or more and 9.0% by mass or less, further preferably within the range of 5.5% by mass or more and 8.5% by mass or less, and 6.0% by mass or more It is more preferably within the range of 8.0% by mass or less.

The water content of the milk protein concentrate is preferably in the range of 2.0% by mass or more and 6.1% by mass or less, regardless of the content of other ingredients, and 3.0% by mass or more 5 It is more preferably within the range of 9% by mass or less, further preferably within the range of 4.0% by mass or more and 5.7% by mass or less, and 4.5% by mass or more and 5.5% by mass or less It is more preferable to be within the range.

In addition, the ash content of the milk protein concentrate is preferably in the range of 3.5% by mass or more and 9.5% by mass or less, regardless of the content of other components, and 4.0% by mass. It is more preferably within the range of 9.0% by mass or less, more preferably 5.5% by mass or more and 8.5% by mass or less, and 6.0% by mass or more and 8.0% by mass. More preferably, it falls within the following range.

Milk concentrates and milk protein concentrates are used as useful raw materials for various dairy products such as prepared milk powder, beverages, fermented milk, and ice cream. can be used as

As a method for producing a milk concentrate, for example, JP-A-2010-502182, JP-A-2011-024589, JP-A-2018-38359, JP-A-2018-38360, JP-A-2018-38361 can be referred to.

As a method for producing a milk protein concentrate, for example, JP-A-2018-38359, JP-A-2018-64481, JP-A-2018-64482 can be referred to.

[Use]
(improvement of executive functions)
The composition of the present invention can be used for improving executive function, which is one of cognitive functions. Executive functions include updating (memory updating), shifting, and inhibiting. The compositions of the present invention can be used more particularly for improving any one selected from the group consisting of memory update function and switching function.

(memory update function)
The compositions of the present invention can be used for improving memory renewal function. Memory update function refers to the ability to monitor actions when executing a task to ensure that the task is completed according to the plan, and the ability to update information heard in conversations (Miyake, A., Friedman , NP, Emerson, MJ, Witzki, AH, Howerter, A., Wager, TD (2000). The unity and diversity of executive functions and their contributions to complex "Frontal Lobe" tasks: a latent variable analysis. Cognitive Psychology 41, 49-100. doi:10.1006/cogp.1999.0734), https://www.cognifit.com/science/cognitive-skills/updating).

An example of work that requires the memory update function is DIY work in which materials are properly cut and arranged while being careful not to make mistakes (for example, when creating a bookshelf, being careful not to make mistakes) properly cutting and arranging wood), the work of programmers entering code while being careful not to make mistakes, the work of writing while being careful not to make mistakes when taking notes in lectures and meetings, cars Driving a car in the correct direction while paying attention to it, when reading a relatively long sentence (for example, reading), understanding the next sentence based on the information in the previous sentence, mathematics, etc. attention to writing down the correct numbers and monitoring and detecting errors when studying or taking an exam. In addition to these, the memory update function is required in many scenes of daily activities such as cooking, sports, brushing teeth, and taking off clothes.

A person skilled in the art can evaluate the presence or absence or degree of improvement in the memory update function of a certain component by various methods. For example, a suitable subject is given the ingredient, and a memory update test (a 4- to 10-digit number string is randomly presented, and the last 3 (or 4) digits of the number string are answered) is performed. (Fiore, F., Borella, E., Mammarella, I. C., and De Beni, R. (2012). Age differences in verbal and visuo-spatial working memory updating: Evidence from analysis of serial position curves. Memory 20, 14-27. doi:10.1080/09658211.2011.628320, Morris, N., and Jones, D. M. (1990). The role of the central executive. British Journal of Psychology 81, 111-121. doi:10.1111/j.2044-8295.1990.tb02349.x.).

(switching function)
The compositions of the invention can be used for improved switching function. Switching function refers to the ability to adapt to new situations and unexpected changes, and the ability to respond flexibly (Miyake et al. (2000) above, and https://www.cognifit.com/science/cognitive- skills/shifting).

Examples of tasks that require a switching function include the task of thinking about what to do when you are about to eat breakfast and realize that there are no ingredients, the task of thinking about what to do when you cannot use your usual means of commuting due to rain, train delays, etc. This includes thinking about why the person you're talking to interrupted the conversation, and considering other ways to contact you when you ring the doorbell and get no response.

A person skilled in the art can confirm whether or not there is an improvement in the switching function, or the degree thereof, by various methods. For example, an appropriate subject ingests the component, and an addition/subtraction test (a trial of performing only one-digit addition, a trial of performing only one-digit subtraction, and a trial of alternately performing single-digit addition and subtraction) is performed. ), and whether or not the results have changed compared to before ingestion can be evaluated (Spector, A., and Biederman, I. (1976). Mental set and mental shift revisited. Am. J. Psychol. 89, 669-679. doi: 10.2307/1421465, Liang Y, Huo M, Kennison R and Zhou R (2017) The Role of Cognitive Control in Older Adult Cognitive Reappraisal: Detached and Positive Reappraisal. Front. Behav. Neurosci. 11:27. doi: 10.3389/fnbeh.2017.00027).

(Concrete example)
Therefore, the composition of the present invention can be used for study/learning, examinations, experiments, reading, cooking, exercise, communication, presentation/announcement, document/recording, calculation/analysis work, computer work, vehicle operation/management, and assembly of objects. • Can be used to improve the ability to perform maintenance work. Communication refers to the exchange of perceptions, emotions, and thoughts between organisms, including both verbal and nonverbal communication, including direct face-to-face communication and communication (general communication between people at a distance). Computer work includes programming and games. Assembly and maintenance work of things includes carpentry work and DIY. Driving and managing a vehicle includes driving a car. Exercise includes exercise and sports.

The compositions of the invention can be used even when given in conjunction with other therapies for improving cognitive function.

[Composition]
(Food composition, etc.)
The composition of the invention can be a food composition or a pharmaceutical composition. Foods and medicines include those for humans as well as non-human animals, unless otherwise specified. Unless otherwise specified, foods include general foods, functional foods, nutritional compositions, and therapeutic foods (things that serve the purpose of treatment. A doctor gives a diet prescription and a dietitian etc. prepares a menu according to it). foods cooked according to the above), dietary therapy foods, ingredient-adjusted foods, nursing care foods, and therapeutic support foods. Foods include not only solids but also liquids such as beverages, drinks, liquid foods, and soups, unless otherwise specified. Functional foods refer to foods that can impart predetermined functionality to living organisms. Functional foods, special purpose foods, dietary supplements, health supplements, supplements (for example, tablets, coated tablets, sugar-coated tablets, capsules, liquids, etc.), beauty foods (for example, diet foods), etc. It includes general health foods. In the present invention, "functional food" includes health foods to which health claims based on food standards of Codex (FAO/WHO Joint Food Standards Committee) are applied.

(subject)
The compositions of the present invention are suitable for administration to subjects wishing to improve executive function. Such subjects include adults (ages 15 and over), middle-aged and seniors, seniors (ages 65 and over), children, infants, people during and after illness, pregnant women, women in childbirth, men and women. In addition, since the composition of the embodiment containing milk protein as an active ingredient is derived from milk that has been eaten for a long time, it is suitable for repeated intake and long-term intake, and it is important to maintain high executive function on a daily basis. Especially suitable for workers.

(route)
The compositions of the invention are suitable for oral ingestion. Examples of routes other than oral administration include enteral administration, nasal administration, buccal administration, sublingual administration, cutaneous administration, subcutaneous injection, intramuscular injection, intradermal injection, intraperitoneal injection, intravenous injection, and arterial administration. Intradural injection, epidural injection, intratumoral injection, intraarticular injection, rectal administration, vaginal administration, intracoronary administration, intrahepatic artery administration, intraportal vein administration, eye administration, intracerebroventricular administration, intratracheal tract administration, intravesical administration Injection, gingival injection.

(Content and dose of active ingredient)
The content of protein, which is an active ingredient, in the composition of the present invention may be any amount that exhibits the desired effect. The dosage or intake of the composition can be appropriately set in consideration of various factors such as age, body weight and symptoms of the subject. The amount of the active ingredient can be, for example, 1 g or more, preferably 5 g or more, more preferably 10 g or more, even more preferably 15 g or more, further preferably 20 g or more. Regardless of the lower limit, the upper limit of the amount of the active ingredient per single dose may be 50 g or less, may be 40 g or less, may be 30 g or less, or may be 25 g or less. .

The compositions may be administered once daily or multiple times daily, eg, three times at each meal. In addition, since the composition of the embodiment containing milk protein as an active ingredient contains a protein that has been eaten for a long time as an active ingredient, it may be ingested repeatedly or over a long period of time. It can be continuously administered and taken for preferably 4 weeks or more, particularly preferably 1 month or more. Preferably, several minutes to several hours, for example, 5 minutes to 2 hours, 10 minutes to 90 minutes, preferably 15 minutes to 60 minutes, preferably 15 minutes to 60 minutes before the work for which you want to exhibit the desired effect, It is preferable to administer an amount sufficient to exhibit the intended effect.

(other ingredients, additives)
The composition of the present invention may contain other active ingredients and nutritional ingredients that are acceptable as foods or pharmaceuticals. Examples of such ingredients include amino acids (e.g., lysine, arginine, glycine, alanine, glutamic acid, leucine, isoleucine, valine), carbohydrates (glucose, sucrose, fructose, maltose, trehalose, erythritol, maltitol, palatinose). , xylitol, dextrin), electrolytes (e.g. sodium, potassium, calcium, magnesium), vitamins (e.g. vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, biotin, folic acid, pantothenic acid and nicotinic acids), minerals (eg, copper, zinc, iron, cobalt, manganese), antibiotics, dietary fiber, proteins, lipids, and the like.

In addition, the composition may further contain food or pharmaceutical acceptable additives. Examples of such additives include inert carriers (solid and liquid carriers), excipients, surfactants, binders, disintegrants, lubricants, solubilizers, suspending agents, coating agents, coloring agents. agents, preservatives, buffers, pH adjusters, emulsifiers, stabilizers, sweeteners, antioxidants, flavors, acidulants, natural products. More specifically, water, other aqueous solvents, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium alginate, water-soluble dextran, water-soluble dextrin, sodium carboxymethyl starch, Pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petroleum jelly, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, sucralose, stevia, aspartame, acesulfame potassium, Citric acid, lactic acid, malic acid, tartaric acid, phosphoric acid, acetic acid, fruit juice, vegetable juice, and the like.

(dosage form/form)
The pharmaceutical composition of the present invention includes solid preparations such as tablets, granules, powders, pills and capsules, liquid preparations such as liquids, suspensions and syrups, gels, aerosols and the like, which are suitable for oral administration. can be any dosage form.

The food composition of the present invention may be prepared in any form such as solids, liquids, mixtures, suspensions, powders, granules, pastes, jelly, gels, capsules and the like. Moreover, the food composition according to the present invention can be in any form such as dairy products, supplements, confectionery, beverages, drinkable preparations, seasonings, processed foods, side dishes, soups, and the like. More specifically, the composition of the present invention can be used in dairy beverages, soft drinks, lactic acid beverages, fermented milk, yogurt, ice cream, tablets, chocolate, cheese, bread, biscuits, crackers, pizza crust, infant formula, liquid milk. , liquid food, food for the sick, nutritional food, frozen food, processed food, etc., and granules, powder, paste, concentrated liquid, etc. for mixing with beverages and foods can be

From the viewpoint of ease of ingestion, it is preferably in the form of a drink.

The concentration of the active ingredient in the composition can be 2.0% by mass or more, more preferably 3.0% by mass or more, and preferably 3.5% by mass or more. More preferred. An upper limit is 10 mass %, for example.

The composition may contain saccharides at a predetermined concentration or less, and the content is not particularly limited, but is preferably in the range of more than 0% by mass and 9% by mass or less, for example. In addition, when glucose is included as a carbohydrate, the content is preferably in the range of more than 0% by mass and 8% by mass or less. It is also preferred that the composition is lipid-free or contains less than 1% by weight of lipid.

The mass of one unit of the composition is not particularly limited, but it is preferably in the range of 100 g or more and 1,000 g or less, from the viewpoint of being able to obtain sufficient effects and being easy to consume in one time, and 100 g. It is more preferably in the range of 800 g or less, further preferably in the range of 100 g or more and 600 g or less, and most preferably in the range of 100 g or more and 500 g or less. This content is based on the premise that the composition contains 2.0% by mass or more of protein. In addition, the above-mentioned one unit may be not only one package such as a bag, box, or container, but may be a unit package for one time contained therein or a unit package for one day. In addition, it is also possible to package a quantity suitable for intake for a plurality of days, for example, one week, or to include a plurality of individual packages.

(timing of intake)
According to the study by the present inventors, the composition of the present invention can be expected to rapidly produce the intended effect with a single ingestion. More specifically, 15 minutes after ingestion of the active ingredient, the switching function may be improved, and 60 minutes after, the memory update function may be improved. Therefore, it can be used more effectively by ingesting it several minutes to several hours, for example, 5 minutes to 2 hours, or 10 minutes to 90 minutes before the desired effect.

(others)
In the production of the composition of the present invention, the step of blending proteins can be selected as appropriate. There are no particular restrictions on the stage of blending as long as the properties of the protein are not significantly impaired. For example, it can be blended with the raw materials in the initial stage of production. Alternatively, the protein can be added separately and mixed in at the last stage of manufacture.

The composition of the present invention can be labeled that it can be used for improving cognitive function, improving executive function, improving memory update function, or improving switching function, In addition, it is possible to display recommendations for ingestion for specific subjects or in specific situations (eg, before programming, before reading, etc.). Labeling can be done directly or indirectly. Examples of direct labeling are descriptions on tangible objects such as the product itself, packages, containers, labels, tags, etc. Examples of indirect labeling are: Websites, storefronts, pamphlets, exhibitions, seminars such as media seminars, business negotiation materials, books, newspapers, magazines, television, radio, mail, e-mail, voice, etc., including advertising and publicity activities by place or means .

The present application presents for the first time an ingredient useful for improving milk-derived executive function, more particularly an ingredient effective for improving any one selected from the group consisting of memory updating function and switching function. Accordingly, the present application provides a method for producing a milk-based pharmaceutical or food material for improving executive function. Milk includes raw milk, cream, concentrated skim milk, cow milk, special milk, raw goat milk, pasteurized goat milk, raw goat milk, modified milk, low-fat milk, non-fat milk, and processed milk. Pharmaceutical materials and food materials may be used by being added to pharmaceuticals or foods, or may be pharmaceuticals or foods themselves. For example, food ingredients include milk protein (examples of which are given above), milk fat, fermented milk, yogurt, cheese, butter, and ice cream. The production method of the present invention can include various steps as long as milk is used as a raw material. For example, there are a sterilization process, a mixing process, a stirring process, a homogenization process, a filtration process, a concentration process, a drying process, a cooling process, a fermentation process, and the like.

[Method]
(research design)
Double-blind, parallel-group study

(subject)
Sixty-six healthy right-handed men and women (age: 20 to 30 years old) whose native language is Japanese were used as subjects. Subjects were those who did not fall under the exclusion items referred to in Non-Patent Document 2 cited above.

(test food)
Three beverages, a low milk protein content drink, a high milk protein content drink, and a placebo drink, were used. All beverages had a volume of 400ml. Beverages were served in PET bottles in a manner that made them indistinguishable from the outside. All three test foods used were not for sale and were prepared for this study. The ingredients and nutritional composition of the three beverages are as follows.

As the milk protein concentrate, a protein content of 80.5% by mass, a lipid content of 1.5% by mass, a carbohydrate content of 6.5% by mass, a water content of 5.0% by mass, and an ash content of 6.5% by mass was used. .

(cognitive function test)
Cognitive function tests were performed to measure cognitive function. Cognitive function tests include the "Raven Matrix Test" and "Japanese Reading Ability Test" that measure general cognitive function, the "Stroop Test" that measures inhibitory ability, which is a subclass of executive function, and the "Addition and Subtraction Test" that measures switching ability. , ``memory update test'' to measure memory update ability, ``numerical chanting'' to measure working memory capacity, and ``sign'' to measure processing speed.
Each test took about a few minutes. However, only the Raven matrix test took about 30 minutes. The Raven matrix test and the Japanese Reading Ability test were performed only once from one week to the day before the test date, and the total time taken was about 40 minutes. Other examinations were repeated three times in total, before, 15 minutes, and 60 minutes after ingestion of the beverage on the examination day, and the total time per examination was about 20 minutes.
These cognitive function tests are standardized and include paper-based tests using a pen and test paper or tests using a PC.
All cognitive tests were supervised by trained psychologists. The reason for implementing the Raven Matrix Test and the Japanese Reading Ability Test, which measure general cognitive function, is that they are related to each cognitive function (executive function, working memory, processing speed), so it is possible to grasp the background of the subject. Because it is necessary.
The timing of each inspection is shown in the table below.

Outline of inspection
General cognitive function (measured only once)
Raven Matrix Test: A test in which related figures are selected while looking at the missing parts of a figure and other figures (Raven, J. (1998). Manual for Raven's progressive matrices and vocabulary scales. Oxford: Oxford Psychologist Press. ).
Japanese Reading Ability Test: A test to answer the reading of kanji (Matsuoka, K., Uno, M., Kasai, K., Koyama, K., and Kim, Y. (2006). Estimation of premorbid IQ in individuals with Alzheimer's disease using Japanese ideographic script (Kanji) compound words: Japanese version of National Adult Reading Test. Psychiatry and Clinical Neurosciences 60, 332-339. doi:10.1111/j.1440-1819.2006.01510.x.).

Execution function (3 times measurement)
Stroop test: A test to answer the meaning of the ink color and the color of the words (green and red) that indicate the name of the color printed in various colors (Hakoda, Y., and Watanabe, M. 2004). Manual for New Stroop test II. Fukuoka, Japan: Toyo Physical).
Addition/subtraction test: Perform a trial of adding only one digit, a trial of subtracting only one digit, and a trial of alternately performing addition and subtraction of one digit (Hakoda, Y., and Watanabe, M. 2004)).
Memory update test: A 4- to 10-digit number string is presented randomly. Answer the last three (or four) digits of the number string (Hakoda, Y., and Watanabe, M. (2004), supra).

Working memory (measured three times)
Number chant: A test in which a number string is presented, and the number string is answered in the order given or in the reverse order (Woods, DL, Kishiyama, MM, Yund, EW, Herron, TJ, Edwards, B., Poliva, O., et al. (2011). Improving digit span assessment of short-term verbal memory. Journal of Clinical and Experimental Neuropsychology 33, 101-111. doi:10.1080/13803395.2010.493149. , Wechsler, DA (1997). Wechsler Adult Intelligence Scale Third edition. San Antonio, TX.: The Psychological Corporation.).

Processing speed (measured 3 times)
Symbol: A test in which the symbol corresponding to the number is entered while looking at the correspondence table in which the symbol in one number corresponds (Cornelis, C., De Picker, LJ, Hulstijn, W., Dumont, G. , Timmers, M., Janssens, L., et al. (2015). Preserved Learning during the Symbol Digit Substitution Test in Patients with Schizophrenia, Age-Matched Controls, and Elderly. Frontiers in Psychiatry 5, 189. doi:10.3389/ fpsyt.2014.00189., Silva, PHR, Spedo, CT, Baldassarini, CR, Benini, CD, Ferreira, DA, Barreira, AA, et al. (2019). Brain functional and effective connectivity underlying the information processing speed assessed by the Symbol Digit Modalities Test. NeuroImage 184, 761-770. doi:10.1016/j.neuroimage.2018.09.080.).

(Statistical analysis)
For all cognitive function test items measured before and after ingestion of the test food, the scores before, 15 minutes after, and 60 minutes after ingestion were calculated, and a generalized linear mixed model ( Statistical tests were performed using GLMM). Food, time, sex, and age were used as fixed effects, and subject as a random effect. Analysis was performed by ITT analysis, and missing values were imputed using the multiple imputation method. The results of the GLMM analysis were corrected by the FDR method, and when an interaction was obtained, multiple comparison tests were performed by the Tukey method.

[result]
Of the 66 study subjects, 62 subjects, excluding 4 dropouts, were included in the analysis. In the addition/subtraction test and the memory update test, the low milk protein content drink intake group and the milk protein high content drink intake group had improved performance compared to the placebo drink intake group (there was a statistically significant difference) (Fig. 1). , 2).

Specifically, for the additive-subtractive test, subtests were performed because the interaction between drink and time (adjusted p<0.05) was significant. As a result, the result of the addition and subtraction test (reaction time) was significantly shorter than the placebo group at 15 minutes after ingestion, and the reaction time was significantly shorter in the milk protein-rich beverage intake group than in the placebo beverage intake group. The reaction time was significantly shorter than the placebo drink intake group. There was no significant difference between the low-milk-protein beverage intake group and the high-milk-protein-rich beverage intake group. Furthermore, at 60 minutes after ingestion, the milk protein-rich beverage intake group had a significantly shorter reaction time than the placebo beverage intake group (Fig. 1). In addition, regarding the memory update test, the interaction between drink and time (adjusted p<0.05) was significant, so a sub-test was performed. As a result, there was no significant difference between the groups in the results (percentage of correct answers) of the memory update test at 15 minutes after ingestion. However, at 60 minutes after ingestion, the milk protein-rich beverage intake group had a higher correct answer rate than the placebo beverage intake group, and the milk protein-low beverage intake group had a significantly higher correct answer rate than the placebo beverage intake group. In addition, there was no significant difference between the low-milk protein-containing beverage intake group and the high-milk protein-containing beverage intake group (Fig. 2).

The addition and subtraction test is a test to examine one of the executive functions in cognitive function (Shifting), and the memory update test is a test to examine one of the executive functions in cognitive function (Updating). It was shown that ingestion can immediately improve executive functions (Shifting, Updating). In the Stroop test, no significant difference was observed between the groups under the experimental conditions here.

Claims (8)

Any composition for improvement selected from the group consisting of memory update function and switching function, comprising a protein. 2. The composition of claim 1, wherein the protein is milk protein. 3. The composition of claim 1 or 2, comprising 10g or more of protein per serving. 4. The composition of any one of claims 1-3, comprising 15g or more of protein per serving. Study/Learning, Examination, Experiment, Reading, Cooking, Exercise, Communication, Presentation/Presentation, Document/Record Making, Calculation/Analysis Work, Computer Work, Operation/Management of Vehicles, Assembling/Maintenance Work 6. A composition according to any one of claims 1 to 5, for ingestion prior to performing any of the above. From study/learning, examinations, experiments, reading, cooking, exercise, communication, presentation/announcement, document/recording, calculation/analysis work, computer work, vehicle operation/management, assembly/maintenance work, including protein A composition for improving the ability to perform any of the following groups. A method for producing a pharmaceutical material or food material for improving any one selected from the group consisting of a memory updating function and a switching function, using milk as a raw material. A composition for improving executive function comprising a milk protein concentrate.

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