JP2021036833A - Constituent act improving composition - Google Patents

Abstract

To provide a technique for improving a constituent act that can be continuously conducted with excellent safety.SOLUTION: A constituent act improving composition contains a peptide composed of Met-Lys-Pro, or a peptide including the amino acid sequence. The composition is taken by or administered to a subject who, preferably, does not have dementia. The composition can be used to improve the ability to memorize and remember routes and/or methods of using articles.SELECTED DRAWING: None

Description

The present invention relates to a composition for improving constituent behavior, which contains a specific peptide.

According to the International Alzheimer's Disease Association, 9.9 million people were newly diagnosed with dementia in 2015, increasing at a rate of 1 in 3 seconds (Non-Patent Document 1). In addition, the number of dementia patients in the world is 46.8 million as of 2015, but it is predicted to reach 131.5 million by 2050. It is known that about 70% of dementia is Alzheimer's disease, and measures against dementia including Alzheimer's disease are urgent issues all over the world. Although there are several drugs that slow the progression of dementia, no curative drug is currently known. Therefore, it has been pointed out that it is important to preventively improve brain function before exhibiting brain dysfunction, that is, before developing dementia (Non-Patent Documents 2 and 3).
Since it is a preventive method for the pre-stage of brain dysfunction, it is considered desirable to have a means that is highly safe and can be continuously tackled.

A component is the ability to form a cohesive object by combining multiple components. Constructional apraxia, which reduces the ability to construct, is known to be one of the characteristic symptoms of Alzheimer's disease (Non-Patent Document 4). Specific symptoms of constructional apraxia include, for example, getting lost and apraxia (not knowing how to use things, using them incorrectly).
Therefore, in people without brain dysfunction, improving the constituent behavior is thought to lead to the prevention of the onset of dementia such as Alzheimer's disease in the future, in addition to living a healthy life now. ..

So far, an Alzheimer-type dementia improving agent for the elderly containing a casein hydrolyzate and a peptide consisting of Met-Lys-Pro contained therein as an active ingredient has been known (Patent Document 1). Further, it has been found that a casein hydrolyzate and a peptide composed of Met-Lys-Pro contained therein have an effect of improving brain dysfunction caused by amyloid beta protein (Patent Document 2). It has also been confirmed that peptides composed of casein hydrolyzate and Met-Lys-Pro have few side effects, are excellent in safety, and do not cause fluctuations in blood pressure.
However, as the action and effect of casein hydrolyzate and the peptide composed of Met-Lys-Pro contained therein, improvement of constituent behavior, particularly improvement of constituent behavior in a person without brain dysfunction, is not known.

Japanese Unexamined Patent Publication No. 2016-69343 JP-A-2018-154640

World Alzheimer report 2015: the global impact of dementia. Analysis of prevalence, incidence, cost and trends. London: Alzheimer's Disease International; (2015). Stop Alzheimer's before it starts. Nature. 2017, 547 (7662): 153-155. Dementia prevention, intervention, and care. Lancet. 2017, 390 (10113): 2673-2734. Dementia Disease Treatment Guidelines 2017 Japan Neurological Society

An object of the present invention is to provide a technique for improving a constituent act, which is excellent in safety and sustainable.

As a result of diligent research to solve the above problems, the present inventors have found that a peptide having Met-Lys-Pro as an amino acid sequence improves the constituent action, and have completed the present invention. ..

That is, the present invention is a composition for improving constituent behavior, which contains a peptide consisting of Met-Lys-Pro or a peptide containing the amino acid sequence.
The compositions of the present invention are preferably ingested or administered to a subject who does not have dementia.
The compositions of the present invention are preferably used to improve the ability to remember and remember directions and / or how to use the article.
The composition of the present invention is preferably a food or drink.
The composition of the present invention is preferably a pharmaceutical product.

According to the present invention, it is possible to improve the constitutional behavior of the ingestor (administrator). In addition, the composition of the present invention has few side effects and is excellent in safety, so that it can be continuously ingested. The composition of the present invention can be preferably applied to a person who does not have dementia, and more preferably to a person who does not have brain dysfunction. In addition, the composition of the present invention is preferably administered to the elderly.

Next, the present invention will be described in detail. However, the present invention is not limited to the following embodiments, and can be freely changed within the scope of the present invention.

The composition of the present invention contains a peptide consisting of Met-Lys-Pro or a peptide containing the amino acid sequence (collectively referred to as "MKP peptide").
Here, Met (M) indicates a methionine residue, Lys (K) indicates a lysine residue, and Pro (P) indicates a proline residue. All amino acids are preferably L-type amino acids.

The MKP peptide may be in the form of a salt thereof. Examples of the salt include alkali metals such as potassium and sodium; alkaline earth metals such as calcium and magnesium.

In the present invention, the term "peptide containing" a predetermined amino acid sequence means a peptide having one or more arbitrary amino acids having a peptide residue added to the N-terminal or C-terminal of the predetermined amino acid sequence. Specifically, a peptide having 1 to 10 residues, preferably 1 to 5 residues, and more preferably 1 to 3 residues added, and having a constituent action improving action is desirable.

In the composition of the present invention, other peptides may coexist as long as the effects of the present invention are not impaired.

The MKP peptide can be obtained from, for example, (1) a method obtained by decomposing a protein or peptide containing the amino acid sequence of Met-Lys-Pro with a hydrolyzing enzyme or the like, and separating and purifying the obtained degradation product, (2) the peptide. A method for obtaining a desired MKP peptide by separating and purifying the desired MKP peptide from the obtained synthesis after synthesizing the MKP peptide by a synthetic method, (3) from a plant, animal or microorganism producing a peptide containing the MKP peptide according to the present invention. It can be obtained by a method of extracting and separating and purifying from the obtained extract.
The methods (1) and (2) will be specifically described below.

(1) Method obtained by hydrolysis The MKP peptide is obtained by hydrolyzing a protein or peptide containing the amino acid sequence of Met-Lys-Pro with a protein hydrolyzate, an acid, an alkali, or the like, and the MKP peptide is obtained from the obtained hydrolyzate. Can be obtained by separating and purifying. Examples of those containing proteins and peptides as raw materials include proteins derived from milk, soybeans, eggs, wheat, barley, rice, potatoes, sweet potatoes, peas, corn, livestock meat, fish meat, seafood and the like. Of these, casein, which is a milk protein, is particularly preferable.

Hereinafter, a method for obtaining an MKP peptide by treatment with a hydrolase will be described by taking the casein as a raw material as an example.
The casein protein is a protein containing an MKP peptide in its primary structure, and can produce an MKP peptide when appropriately digested with a hydrolase.
First, before being hydrolyzed by an enzyme, the raw material protein is dispersed in water or warm water and dissolved to prepare an aqueous protein solution. The concentration of the aqueous protein solution is not particularly limited, but it is usually preferable to set the protein concentration in the concentration range of 2% by mass or more, more preferably about 5 to 15% by mass.
Further, the protein aqueous solution is subjected to an ion exchange method using a sodium-type or potassium-type cation exchange resin (preferably a strongly acidic cation exchange resin), an electrodialysis method, a microfiltration membrane method, a loose reverse osmosis membrane method, or the like. It is preferable to desalt and adjust the pH and calcium concentration as appropriate. At the time of desalting, either a column type or a batch type may be adopted. Further, the aqueous protein solution may be appropriately sterilized by heating before desalting.

Next, the aqueous protein solution is hydrolyzed. Examples of the hydrolysis treatment include enzyme treatment, acid treatment, alkali treatment, heat treatment and the like, and two or more of these treatments may be appropriately combined.
Examples of the proteolytic enzyme of the present disclosure include plant-derived, animal-derived, and microbial-derived, and one or a combination of two or more of these can be used. As the proteolytic enzyme, endoprotease is suitable.
Examples of the endoprotease include serine protease, metalloprotease, cysteine protease, and aspartic protease, and one or more of these can be selected and used. Of these, it is preferable to use serine protease and / or metalloprotease.
In addition, proteases are classified into alkaline proteases, neutral proteases and acidic proteases. Of these, it is preferable to use a neutral protease.

A commercially available product can be used as the proteolytic enzyme. Examples of the proteolytic enzyme include bioprase (manufactured by Nagase ChemteX), proleather (manufactured by Amano Enzymes), protease S (manufactured by Amano Enzymes), PTN6.0S (manufactured by Novozymes), and sabinase (manufactured by Novozymes). , GODO B. A. P (manufactured by Joint Shusei Co., Ltd.), Protease N (manufactured by Amano Enzyme), GODO B. N. P (manufactured by Joint Sake Seisha), Neutrase (manufactured by Novozymes), Alcalase (manufactured by Novozymes), Trypsin (manufactured by Novozymes), Chymotrypsin (manufactured by Novozymes), Subtilisin (manufactured by Novozymes), Papain (manufactured by Amano Enzymes) ), Bromelain (manufactured by Amano Enzymes), etc., and one or more enzymes may be selected and used from these.
Of these, one or more neutral proteases selected from subtilisin (eg, bioplase), trypsin (eg, PTN6.0S), and bachillolysin (eg, protease N) are preferred and more preferred. Uses these three types in combination.

The amount of endoprotease used for the protein is not particularly limited and may be appropriately adjusted depending on the substrate concentration, enzyme titer, reaction temperature, reaction time, etc., but in general, 2 per 1 g of protein in the protein. It is preferable to add in a ratio of 1,000 to 11,000 active units.
A desired peptide can be obtained by appropriately adjusting the hydrolysis conditions of the proteolytic enzyme.

Prior to hydrolysis by the proteolytic enzyme, the pH of the raw material protein solution can be adjusted to the optimum pH of the enzyme used by using food-grade salts such as potassium carbonate and sodium hydroxide. The pH of the raw material protein solution is preferably adjusted to 5 to 10, more preferably 7 to 10.

The reaction temperature of the proteolytic enzyme is preferably in the optimum temperature range of the enzyme to be used, preferably 30 to 60 ° C, more preferably 40 to 60 ° C.
The reaction retention time of the proteolytic enzyme may be, for example, 0.5 to 24 hours, preferably 1 to 1, as long as the reaction is continued until a preferable decomposition rate is reached while monitoring the decomposition rate of the enzyme reaction. It is 15 hours, more preferably 3 to 10 hours. In particular, when the casein protein is used as a raw material, the decomposition rate is preferably 20 to 30%.

The method for calculating the decomposition rate of the raw material protein is to measure the total nitrogen content of the sample by the Kjeldahl method (edited by the Japan Food Industry Association, "Food Analysis Method", p. 102, Korin Co., Ltd., 1984) and formol. The amount of formal nitrogen in the sample was measured by the titration method (Mitsuda et al., "Food Engineering Experiment Book", Volume 1, page 547, Yokendo, 1970), and the decomposition rate was calculated from these measured values by the following formula. To do.
Decomposition rate (%) = (formole nitrogen amount / total nitrogen amount) x 100

Hydrolysis by the proteolytic enzyme may be terminated by heating the enzyme to inactivate it. The heating temperature and holding time of the heat deactivation treatment can be appropriately set under conditions that allow sufficient deactivation in consideration of the thermal stability of the enzyme used. For example, it is preferable to inactivate at 100 ° C. or higher (preferably 110 to 130 ° C.) for 1 to 3 seconds, and to inactivate at 60 ° C. or higher below 100 ° C. for 3 to 40 minutes. ..
As the heat treatment method, either a batch method or a continuous method can be used, and as the continuous method, a plate heat exchange method, an infusion method, an injection method, or the like can be used.
The heat deactivation treatment can also be used in combination as a sterilization treatment for the hydrolyzate, and a conventional heat treatment method or the like can be used.
After completion of hydrolysis, the pH of the decomposition solution is preferably 6 to 8, more preferably 7.0 ± 0.5, and even more preferably 7.0 ± 0.3, if necessary.

In the production of the proteolytic product according to the present invention, when the solution whose calcium concentration has not been adjusted is hydrolyzed, the obtained decomposition solution may be desalted as described above to adjust the calcium concentration. Good. Then, it is heated by a conventional method to inactivate the enzyme. The reaction heating temperature and the reaction holding time can be appropriately set under conditions that allow sufficient deactivation in consideration of the thermal stability of the enzyme used. After heat deactivation, it can be cooled by a conventional method and used as it is, and if necessary, it can be concentrated to obtain a concentrated solution, and the concentrated solution can be further dried to obtain a powder product.

Further, when the aqueous protein solution is hydrolyzed by acid treatment or alkaline treatment, the pH of the aqueous protein solution may be adjusted for the treatment. In the case of the treatment by the pH adjustment, the pH of the aqueous protein solution is preferably pH 5 or less or pH 9 or more, and more preferably pH 4 or less or pH 10 or more. The pH-treated aqueous solution can be left or stirred at room temperature for several minutes or longer, preferably 5 minutes to 1 hour to obtain an acid-treated or alkaline-treated hydrolyzate. Here, "room temperature" is about 4 to 40 ° C, but 10 to 30 ° C is preferable.
Further, the aqueous protein solution may be hydrolyzed by heat treatment. The aqueous protein solution may be pH unadjusted, or may be pH adjusted (specifically, acidic (pH 5 or less), neutral (pH 6 to 8), alkaline (pH 8 or more)). The heat treatment may be performed at about 4 to 100 ° C. under the conditions such as the above acid-alkali treatment.

A protein hydrolyzate such as casein can be obtained as described above, but a commercially available casein hydrolyzate may be used. Generally, commercially available casein hydrolysates have been confirmed to contain MKP peptides.

The content of the MKP peptide in the protein hydrolyzate is not particularly limited, but the lower limit thereof is preferably 0.001% by mass or more, and 0.005% by mass, from the viewpoint of better exerting the efficacy of the present invention. % Or more, more preferably 0.01% by mass or more, and the upper limit thereof is preferably 1% by mass or less, more preferably 0.5% by mass, from the viewpoint of the production efficiency of the decomposition product of the present invention. % Or less, more preferably 0.4% by mass or less, and even more preferably 0.3% by mass or less.

In the present invention, the peptide content of the target can be measured by the following method.
(A) The sample powder is diluted and dissolved in a 0.2% aqueous formic acid solution so as to have a concentration of 1.0 mg / mL, ultrasonically crushed for 10 minutes, and then filtered through a 0.22 μm diameter PVDF filter (manufactured by Millipore). Then, a powder solution is prepared, and LC / MS analysis is carried out under the following measurement conditions. On the other hand, several lysates of the chemical synthesis standard peptide (manufactured by Peptide Research Institute) of the peptide to be measured are prepared according to the concentration, and LC / MS analysis is performed under the following measurement conditions to prepare a calibration curve.
Among the peaks in the analysis of the powder solution, those having the same molecular weight and retention time as the standard peptide are identified as the same sequence as the standard peptide. The content of the target peptide in the powder solution is determined by comparing the peak area of the standard peptide with the peak area of the data powder.

(B) Target peptide content (mg / casein hydrolyzate 1 g)
Target peptide content (mg / casein hydrolyzate 1 g) = [measured value of target peptide in the obtained casein hydrolyzate (mg)] / [mass of the obtained casein hydrolyzate (g)]
[Measured value of target peptide (mg) in the obtained casein hydrolyzate] is a measured value of the target peptide in the sample by the following "LC / MS".

(C) Equipment using LC / MS Mass spectrometer: TSQ Quantum Discovery MAX (manufactured by Thermo Fisher Scientific).
High Performance Liquid Chromatograph: Prominence (manufactured by Shimadzu Corporation), Column: XBridge BEH300 C18 φ2.1 mm × 250 mm, 3.5 μm (manufactured by Waters).

(D) LC / MS measurement conditions Mobile phase A: 0.2 wt% formic acid-aqueous solution Mobile phase B: 0.2 wt% formic acid-acetonitrile solution Time program: 2% B (0.0 minutes) -25% B ( 5.0 minutes) -65% B (5.1 minutes) -65% B (10 minutes) -85% B (10.1 minutes) -85% B (13.0%) -2% B (13. 1 minute) -STOP (30.0 minutes).
Sample injection volume: 10 μL, column temperature: 40 ° C., liquid flow rate: 200 μL / min
Analysis mode: SRM measurement.
Product Mass: m / z = 260.10 (Partent m / z = 375.21)

The obtained protein hydrolyzate can exert its efficacy even when used in an unpurified state. That is, the protein hydrolyzate may be used for ingestion and administration in the form of foods and drinks and pharmaceuticals described later.
Further, the obtained protein hydrolyzate may be subjected to a known separation and purification as appropriate. For example, the obtained protein hydrolyzate can be fractionated by molecular weight to obtain a proteolytic product containing a fraction corresponding to the molecular weight of the MKP peptide according to the present invention.
As the molecular weight fraction, for example, methods such as ultrafiltration and gel filtration can be adopted, whereby the removal rate of peptides and free amino acids having an unnecessary molecular weight can be increased.
In the case of ultrafiltration, a desired ultrafiltration membrane may be used, and in the case of gel filtration, a gel filter agent used for desired size exclusion chromatography may be used.
Further, in order to remove desalting and impurities and increase the purity, known separation and purification methods such as ion exchange chromatography, adsorption chromatography, reverse phase chromatography, partition chromatography and other various chromatographies and solvents are used. Methods such as precipitation, salting out, and distribution between two liquid phases may be used.

The separated and purified peptide fraction can be identified by mass spectrometry for the purpose of confirming whether or not the MKP peptide is contained.
The MKP peptide thus obtained can be used as a peptide solution as it is, or if necessary, the solution can be used as a concentrated solution by a known method. Further, the concentrated solution can be dried by a known method and used as a powder.

(2) Method obtained by chemical synthesis The MKP peptide can also be produced by chemical synthesis or biosynthesis.
The chemical synthesis of the peptide can be carried out by the liquid phase method or the solid phase method usually used for the synthesis of oligopeptides. The synthesized peptide is deprotected as necessary, and it is possible to isolate the MKP peptide by removing unreacted reagents, by-products and the like. The synthesis of such a peptide can be carried out using a commercially available peptide synthesizer.
Peptide biosynthesis can be carried out by a conventional method such as introducing a peptide expression vector into a host organism to produce and secrete it.

The composition of the present invention can improve the constituent action.
Here, the component act refers to the ability to form one cohesive object by combining a plurality of components.
The improvement of the constituent action can be confirmed, for example, by improving the score in the item of the constituent action of ADAS-cog (Alzheimer's Disease Assessment Scale-cog).
According to the composition of the present invention, the act of constructing is improved, so that the ability to memorize and remember directions and / or how to use the article is improved.

Constructional apraxia, which reduces the ability to construct, is known to be one of the characteristic symptoms of Alzheimer's disease (Non-Patent Document 4). From this, it is expected that when the constituent action is improved by the composition of the present invention, brain dysfunction such as Alzheimer-type dementia, vascular dementia, angiopathy, and cerebral amyloid angiopathy can be prevented. Here, prevention of brain dysfunction means preventing the occurrence of a disease or symptom, delaying the occurrence, and the risk of the occurrence in an application target not suffering (onset) the brain dysfunction. Including lowering.

The composition of the present invention has a track record of use as food and is highly safe. Moreover, even if it is continuously administered for a long period of time, there is little concern about side effects. Furthermore, it is highly safe when used in combination with other drugs.

The subject to which the composition of the present invention is administered (administrator) and the subject to be ingested (ingestor) are not particularly limited as long as they are animals, but are usually humans. Further, it may be any of adults, children, infants, newborns (including low-weight infants), etc., but it is usually an adult, preferably an elderly person. In the present invention, the "elderly person" refers to a person aged 65 or over. When the target is a non-human animal, it may be an elderly animal corresponding to the elderly.
In addition, the sex of the ingestor and the recipient of the composition of the present invention is not particularly limited.
In addition, the ingestor and the recipient of the composition of the present invention are preferably those who do not have dementia, more preferably those who do not have brain dysfunction, and more preferably elderly people who do not have dementia. Yes, especially preferably elderly people without brain dysfunction. Usually, dementia is progressive and does not cure completely, so those who are in the pre-dementia stage are targeted. Since mild cognitive impairment is a pre-stage of dementia, it corresponds to "a condition having brain dysfunction but not dementia", and can be a preferable ingestor and recipient of the present invention.
Here, the fact that the patient does not have dementia may mean that the doctor has not diagnosed the patient as having dementia or that the patient has not been diagnosed as having dementia. It may not correspond to. When the ingestor (administrator) is a human, it is preferably confirmed by the Hasegawa dementia scale (HDS-R) or the Mini-Mental State Examination (MMSE) that it corresponds to healthy (normal). Can be done.

Another aspect of the present invention is the use of MKP peptides in the production of compositions for improving constituent behavior.
Another aspect of the invention is the use of MKP peptides in improving constitutive behavior.
Another aspect of the invention is the MKP peptide used to improve constitutive behavior.
Another aspect of the invention is a method of improving constructive behavior, including administering the MKP peptide to an animal.

In addition, in this specification, "administering a peptide to an animal" may be synonymous with "ingesting a peptide into an animal". Ingestion may be voluntary (free intake) or compulsory (forced intake). That is, specifically, the administration step may be, for example, a step of blending the peptide with food or drink or feed and supplying it to the subject, thereby allowing the subject to freely ingest the peptide.

The ingestion (administration) timing of the composition of the present invention is not particularly limited, and can be appropriately selected according to the condition of the administration target.

The ingestion (administration) amount of the composition of the present invention is appropriately selected depending on the age, sex, condition, other conditions, etc. of the ingestion (administration) subject.
The intake (administration) amount of the composition of the present invention is preferably in the range of 0.1 mg / day to 1 g / day, and 0.1 mg / day to 0. For example, as the intake amount of the MKP peptide according to the present invention. A range of 5 mg is even more preferred.
The composition of the present invention can be administered once a day or in a plurality of doses regardless of the amount and duration of ingestion (administration).

The ingestion (administration) period of the composition of the present invention is not particularly limited, but if it is preferably 12 weeks or more, more preferably 24 weeks or more, the effect is likely to be obtained. In addition, there is no particular upper limit on the intake (administration) period, and continuous and long-term intake (administration) is possible.

The route of ingestion (administration) of the composition of the present invention may be oral or parenteral, but oral is preferable. In addition, parenteral ingestion (administration) includes transdermal, intravenous injection, rectal administration, inhalation and the like.

When the composition of the present invention is taken orally, it is preferably in the form of food and drink.

The form and properties of the food and drink are not particularly limited as long as they do not impair the effects of the present invention and can be ingested orally. It can be manufactured by the method.

Foods and drinks may be in the form of liquid, paste, gel solid, powder, etc., for example, from tablet confectionery; liquid food (nutrient food for tube intake); bread, macaroni, spaghetti, noodles, cake mix, etc. Wheat flour products such as fried flour and bread flour; instant noodles, cup noodles, retort / cooked foods, canned foods, microwave foods, instant soups / stews, instant miso soup / suckers, canned soups, freeze / dry foods, and other instant foods. Instant foods; canned agricultural products, canned fruits, jams and marmalades, pickles, boiled beans, dried agricultural products, processed agricultural products such as cereals (processed grain products); canned fishery products, fish hams and sausages, fish paste products, fishery delicacies , Processed marine products such as boiled Tsukuda; Canned livestock / pastes, Processed livestock products such as livestock ham / sausage; Processed milk, dairy drinks, yogurts, lactic acid bacteria drinks, cheese, ice creams, prepared powdered milk, cream, Other dairy products such as dairy products; butter, margarines, vegetable oils and other fats and oils; soy sauce, miso, sauces, tomato processed seasonings, mirins, vinegars and other basic seasonings; cooking mixes, curry Complex seasonings / foods such as ingredients, sauces, dressings, noodle soups, spices, and other complex seasonings; frozen foods such as raw material frozen foods, semi-cooked frozen foods, and cooked frozen foods; caramel, candy , Chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese confectionery, rice confectionery, bean confectionery, dessert confectionery, jelly, and other confectionery; carbonated beverages, natural fruit juice, fruit juice beverages, refreshing with fruit juice Favorite beverages such as beverages, fruit meat beverages, fruit beverages containing fruits, vegetable beverages, soy milk, soy milk beverages, coffee beverages, tea beverages, powdered beverages, concentrated beverages, sports beverages, nutritional beverages, alcoholic beverages, and other favorite beverages. , Baby foods, sprinkles, other commercial foods such as Ochazuke paste; prepared powdered milk for childcare; enteral nutritional foods; functional foods (foods for specified health use, foods with nutritional function) and the like.

It can also be used as feed as one aspect of food and drink. Examples of the feed include pet food, livestock feed, fish feed and the like.
The form of the feed is not particularly limited, and in addition to the MKP peptide, for example, cereals such as corn, wheat, barley, rye, and mylo; vegetable oil lees such as soybean oil lees, rapeseed oil lees, coconut oil lees, and flaxseed oil lees; Rice bran, rice bran, defatted rice bran, etc.; corn gluten meal, corn jam meal, etc. production cereals; fish flour, defatted milk powder, whey, yellow grease, tallow, etc. It may contain yeasts; mineral feeds such as tertiary calcium phosphate and calcium carbonate; fats and oils; simple amino acids; sugars and the like.

When the composition of the present invention is in the form of a food or drink (including feed), it is provided and sold as a food or drink indicating an application for improving constituent behavior, prevention of deterioration of brain function, prevention of deterioration of memory, etc. Is possible. In addition, the MKP peptide according to the present specification can be used for producing these foods and drinks.

Such "display" act includes all acts for informing the consumer of the use, and if it is an expression that can recall or analogize the use, the purpose of the display, the content of the display, etc. Regardless of the object or medium to be displayed, all of them fall under the act of "displaying" in the present invention.
Further, it is preferable that the "display" is performed by an expression that allows the consumer to directly recognize the above-mentioned use. Specifically, the act of transferring a product related to food and drink or the packaging of the product with the above-mentioned use, displaying it for delivery, transfer or delivery, and importing it, advertising on the product, price list or transaction documents Examples include the act of describing the above-mentioned use and displaying or distributing it, or describing the above-mentioned use in the information containing these and providing it by an electromagnetic (Internet, etc.) method.

On the other hand, as the display content, it is preferable that the display is approved by the government or the like (for example, a display obtained based on various systems established by the government and performed in a manner based on such approval). In addition, it is preferable to attach such display contents to packaging, containers, catalogs, pamphlets, promotional materials such as POPs at sales sites, and other documents.

In addition, "labeling" includes health foods, functional foods, enteric nutritional foods, special purpose foods, health functional foods, specified health foods, nutritional functional foods, functional foods, non-medicinal products, etc. The display is also mentioned. Among these, in particular, labeling approved by the Consumer Affairs Agency, for example, a system related to foods for specified health use, foods with nutritional function, or foods with functional claims, or labeling approved by a system similar to these, and the like can be mentioned. Specifically, labeling as a food for specified health use, labeling as a conditional food for specified health use, labeling to the effect that it affects the structure and function of the body, labeling for reducing the risk of illness, and functionality based on scientific grounds. Indications, etc. can be mentioned, and more specifically, Cabinet Office Ordinance on permission for special use indications stipulated in the Health Promotion Act (Cabinet Office Ordinance No. 57, August 31, 2001) Labeling as a food for specified health use (particularly labeling for health use) and similar labeling specified in the above are typical examples.
Such displays include, for example, "supporting the ability to memorize and remember directions and how to use things", "supporting the ability to memorize and remember how to use directions and things", and "supporting the ability to memorize and remember directions and things". "Maintain the ability to memorize and remember how to use things", "Maintain the ability to remember and remember directions and how to use things", "Improve the compositional actions (the ability to memorize and remember how to use things and directions)", ""Improve the ability to remember and remember directions and how to use things", "For those who are worried about composition", "For those who are worried about forgetting things", "For those who carelessly", "For those who are worried about composition""Forimprovement","To improve and maintain the ability to memorize and remember directions and how to use things", "For prevention of cognitive decline", "Support for cognitive function", "Prevent cognitive decline""To those who want" etc. may be displayed.

The composition of the present invention can also be in the form of a pharmaceutical product.
The route of administration of the drug may be oral or parenteral, but oral is preferable. In addition, parenteral ingestion (administration) includes transdermal, intravenous injection, rectal administration, inhalation and the like.
As the form of the drug, it can be appropriately formulated into a desired dosage form according to the administration method. For example, in the case of oral administration, it can be formulated into solid preparations such as powders, granules, tablets and capsules; liquid preparations such as solutions, syrups, suspensions and emulsions. In the case of parenteral administration, it can be formulated into a suppository, an ointment, an injection or the like.
In the formulation, in addition to the MKP peptide, components such as excipients, pH adjusters, colorants, and flavoring agents usually used in the formulation can be used. It is also possible to use other medicines such as other medicinal ingredients and ingredients having a known or future component action improving action.
In addition, formulation can be carried out by a known method as appropriate depending on the dosage form. At the time of formulation, a carrier usually used for formulation may be blended and formulated as appropriate. Examples of such carriers include excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents and the like.

Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannit, and sorbit; starch derivatives such as corn starch, horse bell starch, α-starch, dextrin, and carboxymethyl starch; crystalline cellulose, hydroxypropyl cellulose, and the like. Cellulous derivatives such as hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium; gum arabic; dextran; purulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate; phosphate derivatives such as calcium phosphate; carbonic acid Carbonate derivatives such as calcium; sulfate derivatives such as calcium sulfate can be mentioned.

Examples of the binder include gelatin; polyvinylpyrrolidone; macrogol and the like in addition to the above-mentioned excipients.

Examples of the disintegrant include, in addition to the above-mentioned excipients, chemically modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium, and crosslinked polyvinylpyrrolidone.

Examples of the lubricant include talc; stearic acid; metal stearate salts such as calcium stearate and magnesium sulfate; colloidal silica; waxes such as pea gum and gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid. Sodium carboxylic acid salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic acid anhydride and silicate hydrate; starch derivatives and the like. Be done.

Examples of the stabilizer include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalconium chloride; acetic anhydride; and sorbic acid.

Examples of the flavoring agent include sweeteners, acidulants, and flavors.
Examples of the carrier used in the case of a liquid preparation for oral administration include a solvent such as water.

The timing of ingesting the drug of the present invention is not particularly limited, for example, before meals, after meals, between meals, and before bedtime.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted by the following method.
(1) A total of 268 adult men and women without dementia who were judged to be eligible for participation by subject screening were asked to participate as subjects after obtaining their consent. The subject background is shown in Table 1. The specific selection criteria and exclusion criteria are as follows.
Selection criteria-Age 40 years or older-Hasegawa simple intelligence evaluation (HDS-R) 21 points or more Exclusion criteria-People who have been diagnosed with dementia or who are suspected of having dementia-Schizophrenia, depression, etc. Persons suspected of having a mental disorder (determined by the shortened version of the depression scale for the elderly (GDS-15-J), excluding 6 points or more)
・ Persons with serious diseases such as brain, liver, kidney, heart, lungs, digestive organs, blood, endocrine and metabolic system, or those with a serious history of these ・ Pregnant women, lactating women, pregnant within 6 months・ Persons with serious drug allergies or food allergies, or persons with a serious history of these ・ Persons who are judged to be ineligible as subjects by the investigator

(2) Test method In this test, the score of ADAS-cog was compared with the placebo (dextrin 1 g / day) intake when MKP peptide 1 g / day was ingested daily for 24 weeks in middle-aged and elderly men and women without dementia. Was verified to improve.
ADAS-cog is "word reproduction", "verbal language ability", "auditory comprehension of language", "difficulty in speaking", "following oral commands", "name of fingers and articles", "construction", "ideal movement". , "Orientation,""wordrecognition," and "reproduction ability of test teaching." In the examination of 70 points assigned to these items, the lower the score, the more normal the cognitive function is judged. Statistical analysis analyzed all the data obtained and analyzed subjects aged 65 years and over. Analysis of covariance was performed using the pre-ingestion value as a covariate.

(3) Results At the 24th week of ingestion of subjects aged 65 years or older, the constituent behavior of the MKP peptide group was significantly improved as compared with the placebo group (Table 2).
In addition, no adverse events caused by ingestion of the test food were observed, confirming the safety of the MKP peptide.

Claims (5)

A composition for improving constituent behavior, which comprises a peptide consisting of Met-Lys-Pro or a peptide containing the amino acid sequence. The composition according to claim 1, which is ingested or administered to a subject who does not have dementia. The composition according to claim 1 or 2, which is used to improve the ability to memorize and remember directions and / or how to use the article. The composition according to any one of claims 1 to 3, which is a food or drink. The composition according to any one of claims 1 to 3, which is a pharmaceutical product.