Compositions comprising diamines and / or polyamines for preventing or improving brain function decline.

Abstract

To provide a composition for preventing deterioration of brain function or improving brain function.SOLUTION: The present invention provides a composition containing diamine and / or polyamine, wherein brain function is at least one selected from the group consisting of comprehensive memory, verbal memory, visual memory, cognitive function speed, motor speed, processing speed, comprehensive attention, cognitive flexibility, response time, and executive function.SELECTED DRAWING: None

Description

Technical Field

[0001] This specification discloses a composition containing diamine and / or polyamine for preventing or improving brain function decline.

Background Art

[0002] Brain function decline mainly occurs with aging, and is accompanied by various symptoms such as learning disorders, memory disorders, language disorders, anxiety disorders, insomnia, and decreased motivation. In modern times when the average life span is extended with the development of medicine, prevention and countermeasures against brain function decline are considered important for extending the healthy life span.

[0003] The diagnosis of brain function disorders is mainly classified into three categories: "healthy people" with no abnormalities, "dementia" in which cognitive function decline causes problems in daily life, and "mild cognitive impairment (MCI)" in which cognitive function decline is observed but there is no problem in daily life. There is no fundamental treatment for dementia, and the main treatments are symptom relief and progression suppression. Therefore, early detection at the MCI stage, and thus prevention at the "pre-disease" stage, are important.

[0004] Diamine is a linear fatty acid hydrocarbon compound having two amines. Polyamine is a linear fatty acid hydrocarbon compound having three or more amines. It is known that diamine and / or polyamine are widely involved in the synthesis of nucleic acids and proteins and the regulation of enzyme activity (Non-Patent Document 1). In addition, Non-Patent Document 2 shows that the serum spermidine content correlates with the score of MMSE representing the brain function level. Therefore, clinical trials on oral administration of spermidine have been conducted in humans, but no positive results regarding improvement of cognitive function have been reported (Non-Patent Document 3). [[ID=二十一]] [[ID=二十二]]

Prior Art Documents

Patent Documents

[0005] [[ID=二十九]] [[ID=三十]] [[ID=三十一]]

Patent Document 1

[0006] [Non-Patent Document 1] Shunsuke Sakai et al., Journal of Urology (1986), 32(3): 343-350. [Non-Patent Document 2] Wien Klin Wonchenschr (2020) 132:42-46 [Non-Patent Document 3] JAMA Network Open. 2022;5(5) [Overview of the project] [Problems that the invention aims to solve]

[0007] The object of the present invention is to provide a composition comprising diamines and / or polyamines for preventing or improving brain function decline. [Means for solving the problem]

[0008] The present invention includes the following embodiments. Section 1. A composition comprising diamines and / or polyamines for preventing or improving brain function decline. Section 2. The composition according to item 1, wherein the brain function is one or more selected from the group consisting of overall memory, verbal memory, visual memory, cognitive function speed, motor speed, processing speed, overall attention, cognitive flexibility, reaction time, and executive function. Section 3. The composition according to item 1 or 2, wherein the recipient of the administration is a person aged 40 years or older. Section 4. The diamine is at least one selected from the group consisting of putrescine, cadaverine, and 1,3-diaminopropane. The polyamine is at least one selected from the group consisting of spermidine, spermine, cardine, homospermidine, aminopropylcadaverine, theremine, thermospermine, canavamin, aminopentylnorspermidine, N,N-bis(aminopropyl)cadaverine, homospermine, cardopentamine, homocardopentamine, cardohexamine, and homocardohexaminespermidine. A composition according to any one of items 1 to 3. Section 5. The composition according to any one of claims 1 to 4, wherein the composition is a food composition or a pharmaceutical oral composition. [Effects of the Invention]

[0009] A composition containing diamines and / or polyamines for preventing or improving brain function can be provided. [Modes for carrying out the invention]

[0010] 1. Composition One embodiment of the present invention relates to a composition comprising diamines and / or polyamines for preventing or improving brain function decline.

[0011] Brain function decline often occurs with age, and can manifest in various symptoms, including learning disabilities, memory impairment, language disorders, anxiety disorders, insomnia, and decreased motivation. While dementia is a representative disease associated with brain function decline, mild cognitive impairment (MCI) is a precursor to it. MCI is an intermediate state between healthy individuals and those with dementia, characterized by cognitive decline but no significant impairment in daily life. The prevalence of MCI is 10-20% of people aged 65 and older, and it has been reported that approximately 70% of those who remain untreated will progress to dementia (Hiroshi Suzuki, Nihon University Medical Journal (2012) 71(6):385-389).

[0012] The diagnostic criteria for MCI are, for example, according to the evaluation criteria of Petersen et al. (Yasushi Yamamoto, Psychiatric Neurology (2011) Vol. 113, No. 6): 1. There is a complaint of memory loss by the patient or family (caregiver). 2. There is a memory impairment that cannot be explained only by the effects of aging. 3. Activities of daily living are independent. 4. General cognitive function is normal. 5. Dementia is not recognized. Treatment of dementia is more likely to be effective when started at an earlier stage, and early detection and treatment at the MCI stage may improve cognitive function and prevent the progression to dementia. From the above, the importance of earlier detection and prevention at the pre-disease stage is further emphasized.

[0013] In the Mini-Mental State Examination (MMSE), a neuropsychological test used as a cognitive function test in clinical settings, according to the US ADNI study, the criteria are as follows: 27 - 30 points: normal (not denying the possibility of MCI), 24 - 26 points: borderline (possible to be normal, MCI, or dementia), 20 - 23 points: suspected early dementia.

[0014] Also, as a simpler dementia questionnaire, a questionnaire method that evaluates six questions by the VAS (visual analog scale) method can be adopted.

[0015] Brain functions improved by the composition according to this embodiment include, for example, cognitive functions such as general memory, verbal memory, visual memory, cognitive function speed, motor speed, processing speed, general attention, cognitive flexibility, reaction time, executive function, and simple attention. These cognitive functions can be examined by the Cognitrax test. The Cognitrax test is a cognitive function test service designed for Japan based on the cognitive function test technology developed by CNS Vital Signs in the United States.

[0016] Preferably, the composition improves one or more of the above 11 cognitive functions. More preferably, it improves two or more, three or more, four or more.

[0017] Hereinafter, each cognitive function based on the Cognitrax test will be described. "Overall memory" indicates the ability to remember and is evaluated as the total score of verbal memory and visual memory. "Verbal memory" indicates the ability to remember words and is evaluated by a verbal memory test. "Visual memory" indicates the ability to remember shapes and is evaluated by a visual memory test. "Cognitive function speed" indicates the ability to quickly process visual information and is evaluated as the total score of the sum of the right - hand average and left - hand average of the finger tapping test and the total number of correct responses in the SDC test. "Motor speed" indicates the ability to quickly repeat delicate movements and is evaluated as the total score of the right - hand average and left - hand average of the finger tapping test. "Processing speed" indicates the ability to quickly process information and is evaluated as the total score obtained by subtracting the number of incorrect responses in the SDC test from the number of correct responses in the SDC test.

[0018] "Overall attention" indicates the ability to maintain attention and respond accurately, and is evaluated as the total score of the number of Stroop incorrect responses in the Stroop test, the number of incorrect responses in the attention shift test, and the total number of missed correct responses and incorrect responses in the sustained attention test.

[0019] "Cognitive flexibility" indicates the ability to process in response to changes in instructions, and is evaluated as the total score obtained by subtracting the number of incorrect responses in the attention shift test and the number of Stroop incorrect responses in the Stroop test from the number of correct responses in the attention shift test. "Reaction time" indicates the ability to quickly react to instructions and is evaluated as the average value of the composite reaction time and the Stroop reaction time in the Stroop test.

[0020] "Executive function" indicates the ability to understand rules and concepts and make decisions, and is evaluated as the total score obtained by subtracting the number of incorrect responses in the attention shift test from the number of correct (response) responses in the attention shift test. "Simple attention" indicates the ability to pay attention for a long time, and is evaluated as the total score obtained by subtracting the number of incorrect responses in the sustained attention test from the number of correct responses in the sustained attention test.

[0021] The target population may include individuals not suspected of having impaired brain function, individuals suspected of having impaired brain function, and individuals determined to have impaired brain function. Individuals diagnosed with MCI according to Pertersen et al.'s evaluation criteria may fall under the category of individuals suspected of having impaired brain function. Individuals diagnosed with dementia according to Pertersen et al.'s evaluation criteria may fall under the category of individuals determined to have impaired brain function. Furthermore, individuals determined to be healthy or robust according to Pertersen et al.'s evaluation criteria may fall under the category of individuals not suspected of having impaired brain function.

[0022] Since the risk of cognitive decline is higher in the elderly, it is preferable that the target age of those consuming the composition be 40 years or older, and even more preferable that be 50 years or older, 60 years or older, 70 years or older, or 80 years or older.

[0023] Whether brain function decline is prevented or brain function is improved can be determined by evaluating the effects of diamine and / or polyamine intake, as described later. If there is an effect from the intake of diamine and / or polyamine, it can be determined that brain function decline is prevented or that brain function is improved.

[0024] In this specification, a diamine is a linear fatty acid hydrocarbon compound having two amines. A polyamine is a linear fatty acid hydrocarbon compound having three or more amines. Examples of diamines include putrescine, cadaverine, 1,3-diaminopropane, and mixtures thereof. Examples of polyamines include spermidine, spermine, cardine, homospermidine, aminopropylcadaverine, theremine, thermospermine, canavamin, aminopentylnorspermidine, N,N-bis(aminopropyl)cadaverine, homospermine, cardopentamine, homocardopentamine, cardohexamine, homocardohexaminespermidine, and mixtures thereof.

[0025] Diamines and / or polyamines may be added to the composition as synthesized compounds. Alternatively, diamines and / or polyamines may be added to the composition as extracts, biomolecules, or purified products derived from plants containing these compounds. Plant-derived extracts, biomolecules, and purified products derived from extracts (hereinafter also referred to as "diamine and / or polyamine compositions") may contain natural components other than diamines and / or polyamines, such as sugars such as monosaccharides, oligosaccharides, and polysaccharides, peptides, and proteins. In this invention, diamine and / or polyamine compositions are referred to whether they are in aqueous solution or powder form. "Solid content" refers to the solute content of an aqueous solution of a diamine and / or polyamine composition (solution), excluding water, and includes sugars, peptides, and salts in addition to diamines and / or polyamines. When the diamine and / or polyamine composition is in powder form, "solid content" refers to the entire powdered diamine and / or polyamine composition. In this invention, "plant" refers to a plant body or plant tissue, and "plant processed product" refers to a product obtained by processing them. "And / or" means that both are included, or either one alone is acceptable.

[0026] Various plants and plant products can be used, and are not particularly limited, but examples include cucurbitaceae plants, nightshade plants, grasses, brassicas, legumes, mallows, daisies, amaranthaceae plants, camellias, and their plant extracts, plant extracts, and processed products. Specifically, sweet potato, tomato, cucumber, pumpkin, melon, watermelon, tobacco, Arabidopsis thaliana, bell pepper, eggplant, bean, taro, spinach, carrot, strawberry, potato, rice, corn, alfalfa, wheat, barley, soybean, rapeseed, sorghum, eucalyptus, poplar, kenaf, Eucommia ulmoides, sugarcane, sugar beet, cassava, sago palm, goosefoot, lily, orchid, carnation, rose, chrysanthemum, Examples include petunias, torenias, snapdragons, cyclamen, baby's breath, geraniums, sunflowers, grass, cotton, enoki mushrooms, hon-shimeji mushrooms, matsutake mushrooms, shiitake mushrooms, mushrooms, Korean ginseng, agaricus, turmeric, ginseng, citrus fruits, bananas, kiwis, fruit juice, rice, wheat, barley, soybeans, corn, milo, sunflowers, germ extract, germ extract, green tea, black tea, oolong tea, natto, soy milk, and okara. Preferably, grasses and legumes are used.

[0027] The plant body or plant tissue used in the production of diamine and / or polyamine compositions is not particularly limited, but is preferably a seed form or a plant body or tissue in the growth stage. Examples of plant bodies or tissues in the seed form or growth stage include whole trees, flowers, buds, ovaries, fruits, leaves, cotyledons, stems, buds, roots, seeds, dried seeds, embryos, germs, and roots. Preferably, these are fruits, leaves, stems, buds, seeds, dried seeds, germs, and embryos, and particularly preferably, seeds, dried seeds, germs, and embryos. Microorganisms can also be used for the production of diamine and / or polyamine compositions. In particular, yeast contains high concentrations of polyamines, and a method for separating and purifying the polyamine-containing fraction by extracting yeast cells or culture solution with an acid solution is described (Japanese Patent Publication No. 10-52291). According to the patent publication (Japanese Patent Publication No. 10-52291), the polyamine content of yeast is approximately 13 mg per 100 g of dried cell mass for Saccharomyces cerevisiae, approximately 23 mg for Saccharomyces diastaticas, and approximately 103 mg for Candida ulitis.

[0028] In the present invention, rice seeds, rice germ, wheat seeds, wheat germ, wheat embryo, soybean seeds, soybean germ, soybean embryo, and plant processed products such as soy milk, okara, or combinations thereof can be suitably used, and more preferably, wheat seeds, wheat germ, wheat embryo, soybean seeds, soybean germ, or soybean embryo can be used.

[0029] A method for producing diamine and / or polyamine compositions includes, for example, immersing plants and / or plant products in an ethanol solution and allowing them to stand or be stirred. This step extracts polysaccharides, polyphenols, and secondary metabolites into the ethanol. When grains such as wheat are used as raw materials, the extraction of gluten, which causes increased viscosity, reduces the viscosity of the extract in this step, and further suppresses the viscosity of the extract in the subsequent step described below. In addition, by removing components other than diamine and / or polyamine, the diamine and / or polyamine content per unit of solids in the final diamine and / or polyamine composition can be improved. The concentration of the ethanol solution in this step is preferably 20% (v / v) or more and 90% (v / v) or less, and more preferably 30% (v / v) or more and 70% (v / v) or less. At concentrations lower than 20% (v / v), extraction of polysaccharides, polyphenols, secondary metabolites, etc., is insufficient, leading to increased viscosity, and also resulting in an increased amount of extracted diamines and / or polyamines, which is undesirable. On the other hand, at concentrations higher than 90% (v / v), the extraction efficiency decreases and the solid content of the diamine and / or polyamine composition increases, which is also undesirable. The processing time varies depending on the amount extracted, but is preferably 10 minutes or more, more preferably 30 minutes or more, and even more preferably 1 hour or more. If the processing time is shorter than 10 minutes, components other than diamines and / or polyamines in this processing step may not be sufficiently extracted. There is no upper limit, but it is usually carried out for 24 hours or less, preferably 12 hours or less, and even more preferably 6 hours or less.

[0030] Since diamines and / or polyamines are poorly extracted with ethanol, after treating plants and / or plant products with ethanol, diamines and / or polyamines are largely present in the plant residue rather than the liquid fraction. Therefore, in a preferred embodiment of the present invention, the liquid fraction is separated from the plant residue and precipitate by centrifugation and / or filtration, the plant residue and precipitate are recovered, and subjected to the next step.

[0031] The "process of treating plants and / or plant products with water" refers to the process of immersing plants and / or plant products in water to extract compositions containing diamines and / or polyamines from the plants and / or plant products. "Water" refers to water to which no acid or alkaline solution has been added. This process may be carried out by standing or stirring. The processing time varies depending on the amount to be extracted, but is preferably 10 minutes or more, more preferably 30 minutes or more, and even more preferably 1 hour or more. If the processing time is shorter than 10 minutes, a sufficient amount of diamine and / or polyamine composition may not be extracted in this processing process. There is no upper limit, but it is usually carried out for 24 hours or less, preferably 12 hours or less, and particularly preferably 6 hours or less. Even if the processing is carried out for 24 hours or more, the amount of diamine and / or polyamine composition extracted will approach saturation, and it is considered that the amount that can be newly extracted thereafter will be limited.

[0032] The "process of treating plants and / or plant products under acidic conditions" refers to the process of immersing plants and / or plant products in an acidic solution with a pH of 6 or lower, and extracting an extract containing diamines and / or polyamines by standing and / or stirring. From the viewpoint of reducing the salt concentration of the final composition and preventing corrosion of the stainless steel tank, weakly acidic conditions are preferred. Specifically, it is preferable to carry out the process between pH 3.0 and pH 6.0, and more preferably between pH 4.0 and pH 6.0. The pH in this invention is based on the value measured 10 minutes after standing or stirring following the addition of acid or acid solution.

[0033] Acidic solutions used for treatment under acidic conditions include at least one acidic solution selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, citric acid, lactic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, benzoic acid, sulfosalicylic acid, and formic acid. From the viewpoint of use in cosmetics, food, pharmaceuticals, quasi-drugs, and animal feed, it is preferable to use an acidic solution of hydrochloric acid and / or citric acid, and it is particularly preferable to use an acidic solution of citric acid.

[0034] The process of treating plants and / or plant products under acidic conditions is carried out by adding acid or an acidic solution and allowing it to stand or stir, one or more times. A preferred embodiment of the present invention is a process that includes adding acid or an acidic solution and allowing it to stand or stir multiple times. This is because the amount of acid or acidic solution to be added varies depending on the type and amount of plants or plant products, and in order to add the minimum necessary amount of acid or acidic solution, it is better to add it in multiple steps while measuring the pH. In addition, although some neutralization occurs when the acidic solution reacts with plants or plant products, by adding the acid or acidic solution in small amounts, the corrosiveness of the acidic solution to stainless steel is mitigated by the neutralization reaction, thus reducing the burden on the stainless steel tank.

[0035] The processing time under acidic conditions can be appropriately set based on the amount of diamine and / or polyamine composition extracted, but is generally preferred to be 10 minutes or more, more preferably 30 minutes or more, and even more preferably 1 hour or more. If the processing time is shorter than 10 minutes, a sufficient amount of diamine and / or polyamine composition may not be extracted in this processing step. There is no upper limit, but it is usually 24 hours or less, preferably 12 hours or less, and particularly preferably 6 hours or less. Even if processed for 24 hours or more, the amount of diamine and / or polyamine composition extracted will approach saturation, and it is considered that the amount that can be newly extracted thereafter will be limited.

[0036] The step of treating plants and / or plant products under acidic conditions is preferably performed after the step of treating plants and / or plant products with water. In one embodiment of the present invention, after the step of treating plants and / or plant products with water, an acid or acidic solution is added to the aqueous solution to create acidic conditions, and the step of treating plants and / or plant products under acidic conditions is performed consecutively.

[0037] The present invention includes a step of separating and collecting a liquid fraction. This step involves treating plants and / or plant products with water and acidic conditions, then separating the liquid fraction from plant residue and precipitate by centrifugation and / or filtration, and recovering the liquid fraction. The recovered liquid fraction contains a large amount of diamines and / or polyamines, and becomes a diamine and / or polyamine composition.

[0038] The present invention includes a step of adjusting the pH of an acidic solution to pH 6.5 to pH 7.5 as needed. This step can be performed either before or after the step of separating and collecting the liquid fraction, but it is preferable to perform this step after the step of separating and collecting the liquid fraction. pH adjustment can be performed by adding an alkaline solution, and examples of alkaline solutions include solutions of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, calcium hydroxide, calcium carbonate, barium hydroxide, and ammonia. From the viewpoint of the safety of the salt produced during neutralization to the human body, it is preferable to use sodium hydroxide.

[0039] The diamine and / or polyamine compositions are provided in the form of aqueous solutions or powders. The powders of the diamine and / or polyamine compositions can be obtained by treating plants and / or plant products with water and acidic conditions, recovering the liquid fraction by centrifugation or filtration, and then treating it by spray drying or vacuum freeze-drying.

[0040] The composition may be prepared by combining diamines and / or polyamines with carriers or additives. The composition is preferably a food composition or an orally administered pharmaceutical composition.

[0041] Examples of carriers and additives used in the preparation of the composition include various types commonly used in conventional pharmaceuticals, depending on the dosage form of the composition, such as excipients, binders, disintegrants, lubricants, colorants, flavoring agents, odorants, and surfactants.

[0042] When preparing a composition that is an oral solid dosage form such as tablets, powders, granules, pills, or capsules, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, and gum arabic may be used as carriers; and excipients such as simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, and potassium phosphate may be used as carriers. The following ingredients may be used in the formulation: combination agents such as dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, and lactose; disintegration inhibitors such as sucrose, stearic acid, cocoa butter, and hydrogenated oil; absorption enhancers such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as refined talc, stearate, boric acid powder, and polyethylene glycol.

[0043] Here, tablets include oral tablets (uncoated tablets, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, multi-layered tablets, etc.), chewable tablets (including those taken while being chewed in the mouth), oral tablets (including those taken after dissolving in the mouth, such as lozenges), sublingual tablets, and buccal tablets.

[0044] When preparing the above-mentioned compound or preparation in the form of a pill or solid oral dosage form, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc may be used as carriers; binders such as acacia powder, tragacanth powder, and gelatin; and disintegrants such as laminaran and agar may be used.

[0045] When preparing the above-mentioned combination drug or formulation as an oral solid dosage form in capsule form, the capsule is prepared by mixing the active ingredient with the various carriers exemplified above and filling them into hard capsules, soft capsules, etc.

[0046] If the above-mentioned compound or preparation is a liquid, it only needs to be liquid in nature and may be an aqueous or oily suspension, solution, syrup, elixir, or drink. The liquid is prepared using ordinary additives according to conventional methods. The container for filling the liquid is not limited as long as it can be sealed, and may be a glass container, aluminum container, or plastic container.

[0047] The intake of the composition can be 0.1 mg / day to 10 mg / day, preferably 0.3 mg / day to 5 mg / day, and more preferably 0.5 mg / day to 3 mg / day, in terms of the amount of diamine and / or polyamine per adult. It is preferable to take the composition in 2 to 3 divided doses per day. The composition can be taken, for example, daily, every 2 days, every 3 days, every 4 days, every 5 days, every week, every 2 weeks, every 3 weeks, or every 4 weeks. Preferably, it is preferable to take the composition daily.

[0048] The intake of the composition can be 0.08 mg / day to 8 mg / day, preferably 0.24 mg / day to 4 mg / day, and more preferably 0.4 mg / day to 2.4 mg / day, in terms of spermidine content per adult. It is preferable to take the composition in 2 to 3 divided doses per day. The composition can be taken, for example, daily, every 2 days, every 3 days, every 4 days, every 5 days, every week, every 2 weeks, every 3 weeks, or every 4 weeks. Preferably, it is preferable to take the composition daily.

[0049] 2. Determination of the effects of ingesting diamines and / or polyamines One embodiment of the present invention relates to a method for determining the effects of diamine and / or polyamine intake in subjects who have ingested diamine and / or polyamine (hereinafter referred to as the "determination method").

[0050] The determination method includes obtaining a score value of a brain function index of the subject at a first time point before or during the ingestion of diamines and / or polyamines, and for the same subject, obtaining a score value of the same index of brain function at a second time point after the first time point, during or after the ingestion of diamines and / or polyamines. In the determination method, if the score value at the second time point is equal to or higher than the score value at the first time point, it is suggested that the ingestion of diamines and / or polyamines was effective. Conversely, if the value at the second time point is lower than the value at the first time point, it is suggested that the ingestion of diamines and / or polyamines was not effective. Brain function indicators can be obtained through cognitive function questionnaires using the MMSE or VAS method, as described in 1. above.

[0051] "The score at the second point in time is equal to or greater than the score at the first point in time" means that the score at the second point in time is equal to or greater than the score at the first point in time. "The score at the second point in time is less than the score at the first point in time" means that the score at the second point in time is less than the score at the first point in time. [Examples]

[0052] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the examples.

[0053] 1. Subjects under consideration

[0054] In this study, subjects who met all of the following conditions were selected, and the effect of continuous intake of polyamine-containing capsules (hereinafter referred to as "the test food") for 12 weeks was evaluated on the improvement of cognitive function. • You have received a full explanation of the purpose and content of this study and have the capacity to give consent. Those who fully understand the requirements, volunteer of their own free will, and agree to participate in writing. • Healthy Japanese individuals aged 40 or older at the time of obtaining consent. • People who are aware of their forgetfulness • MMSE score of 24 or higher at the time of screening

[0055] 2. Examination Method (1) Examination design a. Randomization: Randomized comparison b. Blinding: Double-blind c. Control: Placebo control d. Allocation: Parallel group comparison In this study, 60 subjects were randomly assigned to the following study groups of 30 each. Group I: Participants took 9 tablets of test food A daily for 12 weeks, 3 tablets after breakfast, lunch, and dinner. Group II: Participants took nine tablets of test food B daily for 12 weeks, three tablets after breakfast, lunch, and dinner. (2) Overview of the food products used in this test a. Test food Test foods A and B contain polyamine-containing capsules totaling 2700 mg (9 capsules, with 1 active ingredient). The test consisted of either a 0.1 mg polyamine supplement or a 2700 mg placebo (9 tablets). Each test food was formulated with excipients, placed in a dark-colored capsule, and the contents of the capsule were completely invisible from the outside. b. Ingredients / raw material display • Polyamine-containing capsules: Wheat germ extract 409 mg, starch hydrolysate 372 mg, sodium citrate 149 mg, dextrin 1734 mg, calcium stearate 36 mg Placebo: Sodium citrate 149 mg, dextrin 2515 mg, calcium stearate 36 mg (3) Evaluation items The evaluation criteria were as follows: a.Primary endpoint • Cognitive function test (Cognitrax) b. Secondary endpoints • Short-term mental health assessment (MMSE) • VAS questionnaire regarding cognitive function • Polyamines in urine • Blood polyamines c. Safety evaluation items • Subjective findings (daily life diary) Objective findings (medical history) (4) Allocation method This study was conducted using a randomized controlled trial method to ensure that there were no differences in medical background between the study groups due to the allocation of participants. The allocation supervisor assigned 30 participants to each of the two groups, Group I and Group II, based on their MMSE scores and median age at the time of screening. (5) Test flow and schedule and method of obtaining samples and information a. Sample (information) and how to obtain it Information was collected on each inspection day using the following methods. Consent of test participants: Name of consenting participant, date of consent acquisition Background of test participants: Age (date of birth), gender, etc. Questionnaire at the time of examination (including exercise and meals the day before, physical condition and meals on the day of the examination) Physical examination: Height (only during pre-intake testing), weight, BMI Urine test: amount of polyamines in urine Blood test: Blood polyamine levels Daily life log (including daily intake of test foods and physical condition during the test period) b. Schedule The above tests were conducted according to the following schedule.

[0056] [Table 1]

[0057] The subjects in the study were asked to pay attention to the following points.

[0058] • Do not make significant changes to your current lifestyle, such as your diet or exercise habits. Avoid taking any new medications or health functional foods (foods for specified health uses, foods with functional claims, and nutrient function foods) that may affect cognitive function. During the trial period, take any polyamine-containing supplements other than the test food, or natto (1 pack per day). Avoid consuming the above (and more) and soy milk (more than one pack (about 200 mL) per day). • The day before the test, avoid strenuous exercise and finish eating by 9 PM. Also, avoid overeating, excessive drinking, smoking, and staying up late. Avoid excessive exercise on the day of the examination until it is over. • If you experience an acute illness such as fever, diarrhea, or vomiting on the day of the test, the test will be canceled.

[0059] Regarding this exam, I will not disclose any information I learn to any third party. In particular, I will not share information using social media (Facebook, Twitter, Instagram, LINE, etc.).

[0060] (6) Exclusion criteria Subjects who met the following criteria were excluded from the study. 1) Individuals with chronic diseases who are receiving drug treatment, or those with a history of serious illness. 2) Individuals suffering from cancer, familial adenomatous polyposis, or Helicobacter pylori infection. 3) Individuals with allergies to the test food (especially those with wheat allergies, as the test food contains wheat germ extract) 4) Individuals who regularly take large amounts of polyamine-containing supplements. 5) People who consume one or more packs of natto every day 6) Those who consume one pack (approximately 200 mL) or more of soy milk every day. 7) Individuals who regularly use medications, health functional foods (foods for specified health uses, foods with functional claims, and nutrient functional foods) that may affect cognitive function. 8) Anyone who has taken another exam within one month prior to the start of this exam, or who plans to take another exam after consenting to take this exam. 9) Individuals deemed ineligible by the supervising physician and the principal investigator of the study. 10) Those who are breastfeeding, pregnant, or planning or hoping to become pregnant during the study period.

[0061] (7) Methods of statistical analysis

[0062] As a general rule, for continuous data, the Shapiro-Wilk test was used to examine normality. For paired data, if normality was indicated, a paired t-test was performed; otherwise, the Wilcoxon signed-rank test was used. For unpaired data, if normality was indicated, the F-test was used to test for variance, followed by Student's t-test (with equal variances) or Aspin-Welch's t-test (without equal variances). If normality was not indicated, the Mann-Whitney U-test was performed. For ordinal data with many levels, the Wilcoxon signed-rank test was used for paired data, and the Mann-Whitney U-test was used for unpaired data. For ordinal data with few levels or nominal data, the McNemar test was used for paired data, and Fisher's exact test or χ² was used for unpaired data depending on the number of data points. 2 Statistical tests were performed. When multiple comparisons were necessary, methods such as the Bonferroni method, Tukey method, and Dunnett method were used depending on the data format. In addition, analysis of variance, correlation coefficient testing, and subgroup analysis were performed as needed. For safety evaluation items, in principle, only within-group comparisons of values ​​before and after intake and between-group comparisons of values ​​before and after intake were performed, and between-group comparisons of the difference between before and after intake were not performed. In two-tailed tests, a significance level of less than 5% was judged as "statistically significant difference," and 5% to less than 10% was judged as "trend." Statistical analysis was mainly performed using R, but IBM SPSS Statistics (ver. 25) was used as needed.

[0063] 3. Test Results 3-1. Effectiveness Evaluation (Primary Endpoint)

[0064] Of the 60 trial participants, 11 dropped out for personal reasons and 1 deviated from the study protocol, leaving 48 participants for the efficacy analysis. Table 2 shows the background of the participants in the efficacy analysis.

[0065] [Table 2]

[0066] The results of the cognitive function test analysis are shown in Table 3.

[0067] Significant improvements were observed in overall memory, cognitive function speed, and motor speed in the polyamine intake group compared to the placebo intake group. Furthermore, a significant trend of improvement was observed in verbal memory and visual memory in the polyamine intake group compared to the placebo intake group.

[0068] [Table 3]

[0069] 3-2. Effectiveness Evaluation (Secondary Endpoints)

[0070] Similar to the primary endpoint, 11 participants who dropped out for personal reasons and 1 participant who deviated from the study protocol were excluded from the 60 study participants, leaving 48 participants for the efficacy analysis. The results of the VAS questionnaire analysis are shown in Table 4. Regarding questions related to cognitive function speed, the polyamine intake group showed a significant improvement compared to the placebo intake group.

[0071] [Table 4]

[0072] 3-3. Safety Evaluation Items The results of the safety assessment analysis are shown in Table 5. Both the polyamine intake group and the placebo intake group showed a significant decrease in body weight and BMI, but no significant difference was observed between the groups.

[0073] [Table 5]

Claims

1. A composition for preventing or improving brain function, Brain function is one or more selected from the group consisting of cognitive function speed and motor speed. Contains polyamines, contains wheat germ extract, Intake is in amounts of 0.5 mg / day to 3 mg / day in terms of polyamines. composition.

2. The composition according to claim 1, wherein the recipient of the administration is a person aged 40 or older.

3. The composition according to claim 1, wherein the composition is a food composition or a pharmaceutical oral composition.

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