WO2022244727A1 - Composition for improving cognitive function - Google Patents

Abstract

The present disclosure provides a composition for improving cognitive function that comprises a fish roe lipid preparation. In one embodiment, provided is a composition for improving cognitive function that comprises a fish roe lipid preparation prepared so as to provide about 100 mg or more and less than 300 mg per day of DHA, wherein the cognitive function is the linguistic ability of a subject who takes regular exercise.

Description

COMPOSITIONS FOR IMPROVING COGNITIVE FUNCTION

This patent application claims priority from Japanese Patent Application No. 2021-082910, which is incorporated herein in its entirety by reference.
The present disclosure relates to compositions for improving cognitive function.

The percentage of elderly people aged 65 and over in the total population of Japan has continued to rise since 4.9% in 1950, reaching 28.4% in 2019. This percentage will continue to rise, and is expected to reach 35.3% in 2040, when the generation born during the second baby boom period (1971-1974) will reach the age of 65 or older. With the rapid aging of the population in recent years, if the gap between average life expectancy and healthy life expectancy increases, it is conceivable that QOL of life will decline and the period in which nursing care will be required will become longer. Dementia, which is a particular concern among the elderly, is a serious social problem, and as of 2012, the number of people with mild cognitive impairment (MCI) nationwide, which is considered to be a reserve force for dementia, is about 4 million. It is estimated that about one in four elderly people have dementia or MCI. Mental health is also important for maintaining the mental and physical health of the elderly and preventing nursing care. When people become depressed and become passive about health management and daily life, the condition and course of various physical diseases such as ischemic heart disease such as myocardial infarction, cerebrovascular disease such as stroke, diabetes and cancer worsen. It is clear that

Currently, the nootropic drugs on the market have not reached the fundamental treatment, and new drugs are still being developed around the world. Moreover, interest in the prevention of dementia is increasing, and it is considered important to take measures from the age-related forgetfulness stage.

In recent years, n-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have attracted attention. Research results have been reported suggesting that these intakes are effective in improving cognitive function (Non-Patent Document 1), and research is also underway on reducing the risk of developing Alzheimer's disease (Non-Patent Document 2). Conventionally, DHA and EPA derived from fish oil have been widely used. On the other hand, it has been reported that orally ingesting salmon roe oil, which is rich in DHA and EPA, is expected to increase the amount of REM sleep and improve the quality of sleep (Non-Patent Document 3). In addition, lecithin is one of the raw materials of acetylcholine, which is a neurotransmitter, and its intake is expected to improve cognitive function (Non-Patent Document 4). It has also been suggested that DHA and EPA are beneficial for improving mental health in elderly people with MCI (Non-Patent Document 5).

The purpose of this disclosure is to provide new means for improving cognitive function.

The present disclosure provides compositions for improving cognitive function comprising fish egg lipid preparations.

The present disclosure provides new means for improving cognitive function.

The process from allocation of test foods to analysis is shown as a test flow chart.

In the present disclosure, when a numerical value is accompanied by the term "about," it is intended to include a range of ±10% of that value. For example, "about 20" shall include "18-22". Numerical ranges include all numbers between and including the endpoints. "About" in reference to a range applies to both endpoints of that range. Thus, for example, "about 20 to 30" shall include "18 to 33." When percentages of ingredients are expressed in this disclosure, they are by weight unless otherwise stated.

Unless otherwise specified, the terms used in this disclosure have the meanings commonly understood by those skilled in the art in the fields of organic chemistry, medicine, pharmacy, molecular biology, microbiology, and the like. Listed below are definitions for some terms used in this disclosure, which definitions take precedence over general understanding in this disclosure.

(Method for producing fish egg lipid preparation)
Fish egg lipid preparations are prepared, for example, from salmonid fish eggs. Salmonidae includes the genus Atlantic salmon, the genus Atlantic salmon, the genus char, and the genus Ito, and more preferably the genus Atlantic salmon or the genus Atlantic salmon. Examples of Atlantic salmon include chum salmon (Oncorhynchus keta), coho salmon (Oncorhynchus kisutch), pink salmon (Oncorhynchus gorbuscha), cherry salmon (Oncorhynchus masou masou), yamame trout (Oncorhynchus masou masou), Taiwan trout (Oncorhynchus masou formosanus), and salmon trout. (Oncorhynchus masou ishikawae), Amago (Oncorhynchus masou ishikawae), Biwamasu (Oncorhynchus masou rhodurus), Rainbow trout (Oncorhynchus mykiss), Chinook salmon (Oncorhynchus tshawytscha), Sockeye salmon (Oncorhynchus nerka), Kokanee (Oncorhynchus nerka), Kunimasu (Oncorhynchus kawamurae) mentioned. Examples of fish of the genus Atlantic salmon include Atlantic salmon (Salmo salar) and brown trout (Salmo trutta). In one embodiment, the fish egg lipid preparation is prepared from pink salmon (Oncorhynchus gorbuscha) fish eggs.

When referring to fish roe in the present disclosure, the degree of processing does not matter unless otherwise specified. Therefore, in the present disclosure, reference to fish egg lipid preparations also includes lipid preparations made from fish egg extracts, fish egg oils, purified fish egg oils, dried products of any of them, and the like.
In a particularly preferred embodiment, the fish egg lipid preparation is prepared from sardine roe, salmon roe, or any processed product thereof, such as sardine roe extract, salmon roe extract, salmon roe oil, or refined salmon roe oil.

Specifically, the extraction of the fish egg lipid preparation from the raw material, which is fish eggs or processed products thereof, can be carried out by mixing the raw material with a low-polarity organic solvent. Examples of low polar solvents include one or more organic solvents selected from the group consisting of 60 to 99% hydrous ethanol, ethanol, hexane, isopropyl alcohol, ethyl acetate, acetone, ether, chloroform, and methanol. include but are not limited to: The extraction temperature with the organic solvent is 0 to 90°C, preferably 30 to 70°C. It is known that manipulating the water content of hydrous ethanol can increase the content of phospholipids in the resulting extract (see Oleoscience Vol. 2, No. 2, pp. 67-74). Extraction of fish egg lipid preparations from raw materials, which are fish eggs or processed products thereof, can also be carried out by supercritical fluid extraction using carbon dioxide.
For example, the fish egg lipid preparation may be one described in WO2021/132516, especially sarcoplasmic oil PL40.

(Phospholipid)
In some embodiments, the phospholipid content of the fish egg lipid preparation is enhanced. Phospholipids refer to lipids having phosphorus in the form of phosphate esters, and include glycerophospholipids and sphingophospholipids. Representative glycerophospholipids include phosphatidylcholine (PC), α-glycerophosphocholine (α-GPC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), 1-lysophosphatidylcholine (LPC-1), 2- Lysophosphatidylcholine (LPC-2), 2-lysophosphatidylethanolamine (LPE-2), representatives of sphingolipids are sphingomyelin (SM) and dihydrosphingomyelin (DHSM). The phospholipid content of the fish egg lipid preparation is, for example, about 26% or more, may be about 30% or more, preferably about 35% or more, and more preferably about 37.5% or more. , more preferably about 40% or more. The upper limit of the phospholipid content in the fish egg lipid preparation is not particularly limited, but the higher the phospholipid content, the higher the viscosity.

In one embodiment, the fish egg lipid preparation contains at least one selected from the group consisting of α-GPC, SM and DHSM, and in preferred embodiments SM and DHSM. The contents of α-GPC, SM and DHSM are not particularly limited. The content of α-GPC in fish egg lipid preparations is, for example, about 0.050% to 0.60%. The content of SM in fish egg lipid preparations is, for example, about 0.8% to 2.3%. The content of DHSM in fish egg lipid preparations is, for example, about 0.050% to 0.40%.

Phospholipids other than α-GPC, SM and DHSM contained in the fish egg lipid preparation are not particularly limited, and PC, PE, PI, LPC-2 and the like are preferably abundant. The content of PC in the fish egg lipid preparation is, for example, about 24-45%, preferably about 26-43%, more preferably about 28-41%, still more preferably about 30-39%. is. The content of PE in fish egg lipid preparations is, for example, about 0.90-2.3%. The content of PI in fish egg lipid preparations is, for example, about 0.80-1.8%. The content of LPC-2 in fish egg lipid preparations is, for example, about 0.60-3.0%.

In fish egg lipid preparations, PC is contained in a relatively large amount as a content in phospholipids. The PC content in the phospholipid is, for example, about 74% or more, preferably about 80% or more. In fish egg lipid preparations with increased phospholipid content, the content of PC in phospholipids is higher. Therefore, in a preferred embodiment, the phospholipid content in the fish egg lipid preparation is about 35% or more, more preferably about 40% or more, and the PC content in the phospholipids is about 74%. % or more, preferably about 80% or more.

(Fatty acid composition)
The composition ratio of DHA in the constituent fatty acids of the lipid of the fish egg lipid preparation is relatively high. Fish eggs are known to contain DHA in the form of phospholipids or triglycerides (TG). Specifically, the composition ratio of DHA to the constituent fatty acids of the lipid of the fish egg lipid preparation is, for example, about 15% or more, preferably about 18% or more, and more preferably about 22% or more, More preferably, it is about 24% or more. The upper limit of the composition ratio of DHA to the constituent fatty acids of the lipid in the fish egg lipid preparation is not particularly limited, but is, for example, about 46% or less, preferably about 40% or less, and more preferably about 35% or less. , more preferably about 30% or less. In the present disclosure, when the composition ratio of a specific fatty acid to the constituent fatty acids of a lipid is expressed in %, it is based on the area of a chart obtained by analyzing the fatty acid composition by gas chromatography, unless otherwise specified.

The composition ratio of EPA in the constituent fatty acids of the lipid of the fish egg lipid preparation is relatively low, for example, about 25% or less, preferably about 23% or less, more preferably about 21% or less, and still more preferably. is about 19% or less. The lower limit of the composition ratio of EPA to the constituent fatty acids of the lipid in the fish egg lipid preparation is not particularly limited. 0% or more, more preferably about 10% or more, and even more preferably about 11% or more or about 12% or more.

Fish egg lipid preparations contain, as constituent fatty acids, myristic acid (C14:0), palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1, n9c), eicosenoic acid (C20 :1), docosapentaenoic acid (DPA) (C22:5). Other constituent fatty acids include myristoleic acid (C14:1), pentadecenoic acid (C15:1), heptadecenoic acid (C17:1), docosenoic acid (C22:1), tetracosenoic acid (C24:1), linoleic acid ( C18:2n-6), α-linolenic acid (C18:3n-3), γ-linolenic acid (C18:3n-6), eicosadienoic acid (C20:2n-6), eicosatrienoic acid (C20 :3n-6), arachidonic acid (C20:4n-6), docosadienoic acid (C22:2), and the like.

The fish egg lipid preparation contains a large amount of DHA-bound phospholipids. Specifically, the weight of DHA per 100 g of fish egg lipid preparation is, for example, about 10 g or more, preferably about 12 g or more, more preferably about 14 g or more, even more preferably about 15 g or more. Although the upper limit of the weight of DHA per 100 g of the fish egg lipid preparation is not particularly limited, it is, for example, about 30 g or less, preferably about 25 g or less, more preferably about 22 g or less, and still more preferably about 20 g or less. be.

The weight of EPA per 100 g of fish egg lipid preparation is, for example, about 5.0 g or more, more preferably about 6.0 g or more. Although the upper limit of the weight of EPA per 100 g of the fish egg lipid preparation is not particularly limited, it is, for example, about 20 g or less, preferably about 15 g or less.

One of the DHA-bound phospholipids contained in fish egg lipid preparations is palmito docosahexaenoyl phosphatidylcholine (PDPC). PDPC is phosphatidylcholine (38:6) in which one of the acyl groups at C-1 and C-2 is hexadecanoyl (16:0) and the other is docosahexaenoyl (22:6). say something

Another DHA-bound phospholipid contained in fish egg lipid preparations is stearoyl docosahexaenoyl phosphatidylcholine (SDPC). SDPC is a phosphatidylcholine (40:6) in which one of the acyl groups at C-1 and C-2 is stearoyl (18:0) and the other is docosahexaenoyl (22:6). Say.

　One of the phospholipids contained in the fish egg lipid preparation is an ether-type phospholipid. Ether-type phospholipid refers to a phospholipid having a hydrocarbon chain formed by an ether bond, particularly a glycerophospholipid having a hydrocarbon chain formed by a vinyl ether bond at the sn-1 position and a fatty acid at the sn-2 position. are called plasmalogens.

In one embodiment, the fish egg lipid preparation contains any one selected from the group consisting of DHA-bound ether-type phospholipids and EPA-bound ether-type phospholipids.

(Ingredients other than lipids)
Fish egg lipid preparations may contain components other than lipids. Components other than lipids include proteins, sodium, potassium, phosphorus and other inorganic substances. A lipid is a biological substance that is soluble in a nonpolar solvent, and includes simple lipids, complex lipids, and derived lipids (fatty acids, terpenoids, steroids, carotenoids, etc.).
The content of components other than lipids in the fish egg lipid preparation is, for example, 10.0% or less, preferably 8.0% or less, more preferably 7.5% or less, and still more preferably 7.0%. % or less.

The fish egg lipid preparation may contain astaxanthin. The content thereof in 100 g of the fish egg lipid preparation is, for example, about 0.7 mg or more, preferably about 1.0 mg or more, more preferably about 1.2 mg or more, and still more preferably about 1.5 mg or more. is. Although the upper limit of the content of astaxanthin in 100 g of the fish egg lipid preparation is not particularly limited, it is, for example, about 23 mg or less, preferably about 20 mg or less, more preferably about 10 mg or less, and still more preferably about 5.0 mg. It is below.

(Application)
As shown in the examples below, the compositions of the present disclosure improve cognitive function. In the present disclosure, improvement of cognitive function includes maintenance of state, suppression of decline, maintenance of improved state, and suppression of decline from improved state. As used in this disclosure, "cognitive function" includes language ability in subjects with regular exercise habits. Exercise refers to physical activity that is carried out systematically and intentionally for the purpose of maintaining and improving physical strength, and means continuous activity, such as strength training, aerobic exercise, sports, walking and active Hobbies, specifically stretching, gymnastics, yoga, mountain climbing, hiking, dancing, golf, gateball and swimming (including underwater walking) are included in exercise. In certain embodiments, compositions of the present disclosure improve language skills in subjects with regular exercise habits. A regular exercise habit means exercising regularly, for example, every day, 3 times a week or more, 2 times a week or more, 1 time or more a week, 3 times a month or more, or 2 times a month or more, means to do In some embodiments, a regular exercise routine is performing exercise such as stretching, gymnastics, yoga, mountain climbing, hiking, dancing, golf, gateball, or swimming (including underwater walking) at least once a week. Verbal ability means the ability to understand spoken words and written characters, and the ability to communicate using words. In one aspect, it refers to the ability to comprehend, remember, and accurately verbalize the meaning of sentences, which can be assessed, for example, by a Montreal Cognitive Assessment (MoCA) repetition score. MoCA is available in various languages, including the Japanese version of MoCA (MoCA-J).

Compositions containing fish egg lipid preparations also improve mental health or mental aspects of QOL as assessed by the SF-36. In the present disclosure, the improvement of mental health or mental aspects of QOL includes maintenance of the state, suppression of deterioration, maintenance of the improved state, and suppression of deterioration from the improved state. SF-36 is a scale for measuring Health Related Quality of Life (HRQOL). For example, in Japan, SF-36v2, which is an improved version of the original SF-36 (Japanese version is version 1.2), is used. The SF-36 consists of 36 items and consists of eight health concepts (physical function, daily role function (physical), body pain, overall well-being, vitality, social function, daily role function (mental), and mental health). NBS scores (scores by a scoring method based on national norms), and component summary scores can be calculated from them, with higher scores indicating higher QOL.

A high score for "mental health" on the SF-36 indicates that you have been feeling calm, happy, and calm over the past month. In some embodiments, improving mental health is improving at least one of nervousness, depression and depressed mood. In some embodiments, improving mental health is improving calm or joyful mood.

As a component summary score, for example, 3 component summary scores (3MCS; physical aspects, mental aspects, social aspects) of factor coefficients based on the 2002 Japanese survey, 2 components of factor coefficients based on the 1995 US national survey - Summary score (2MCS; physical aspect, mental aspect), 2-component summary score (2MCS (Japanese version); physical aspect, mental aspect) based on the 1995 Japanese national survey. In one embodiment, the mental aspect of QOL is assessed by 3MCS or 2MCS (Japanese version).

The target is typically a human. Subjects may or may not be cognitively impaired. Cognitive impairment includes forgetfulness and mild cognitive impairment. Forgetful subjects include those who have subjective symptoms of forgetfulness or those who have been told that a close relative also has forgetful symptoms. Although the age of the subject is not limited, it can be middle-aged or older, specifically 45 years old or older, 50 years old or older, 55 years old or older, 60 years old or older, or 65 years old or older, and 95 years old or younger, 85 years old or younger, 80 years old or less than or equal to 75 years of age.

A composition of the present disclosure may be a pharmaceutical composition. The administration method of the pharmaceutical composition is not particularly limited, and oral administration, transdermal administration or nasal administration is preferred, and oral administration is more preferred. Dosage forms for oral administration include granules, fine granules, powders, coated tablets, tablets, powders, soft capsules, hard capsules, microcapsules, chewables, liquids, suspensions, emulsions, and the like. . Dosage forms for transdermal administration include patches, tapes, sprays, lotions, creams, ointments, liquids, emulsions, suspensions and the like. Dosage forms for nasal administration include nasal drops, nasal sprays, and the like.

These dosage forms are manufactured by formulating in a conventional manner. Furthermore, various pharmaceutically acceptable substances for formulation can be blended according to pharmaceutical needs. The substance for formulation can be appropriately selected depending on the dosage form of the formulation. Coating agents, lubricants, flavoring agents, sweeteners, solubilizers and the like are included.

Also, the composition of the present disclosure may be a food composition. The food composition can be in the form of a typical processed food. For example, it can be a solid food, or a liquid food such as a drink, a drink, a powdered drink, or a soup. Specifically, it can be consumed as, for example, juice, confectionery, jelly, tablet, dressing, seasoning, and the like.

In addition, such foods may be provided as foods with health claims or dietary supplements. Foods with health claims include, for example, foods for specified health uses, foods with nutrient claims, and foods with function claims. Foods with health claims can be labeled as being used for purposes such as improving cognitive function. The labeling may be directly on a package, container, label, tag, insert, etc. associated with the product, or indirectly through advertising activities. Dietary supplements include, for example, dietary supplements and health supplements.

The intake of the composition of the present disclosure can be such that about 100 mg to 10000 mg of the fish egg lipid preparation is ingested per day, preferably about 300 mg to 5000 mg, more preferably about 500 mg to 2500 mg, more preferably about 500 mg to 2500 mg. is about 700 mg to 1500 mg, such as about 1000 mg.

Alternatively, the intake of the composition of the present disclosure can be an amount that provides about 20 mg or more of DHA per day, preferably about 50 mg or more, more preferably about 100 mg or more, and even more preferably about 150 mg or more. be. In addition, the intake of the composition of the present disclosure can be an amount such that about 2000 mg or less of DHA is ingested per day, preferably about 1000 mg or less, more preferably about 750 mg or less, even more preferably about 500 mg or less, Even more preferably 300 mg or less or less than 300 mg, particularly preferably about 200 mg or less. In some embodiments, the intake of the compositions of the present disclosure is an amount that provides about 150 mg (eg, 135 mg-165 mg) or about 160 mg (eg, 144 mg-176 mg) of DHA per day.

In addition, the intake of the composition of the present disclosure can be an amount such that about 10 mg or more of EPA is ingested per day, preferably about 30 mg or more, more preferably about 50 mg or more, and even more preferably about 60 mg or more. be. Also, the intake of the composition of the present disclosure can be an amount that provides about 500 mg or less of EPA per day, preferably about 300 mg or less, more preferably about 150 mg or less. In some embodiments, the intake of the compositions of the present disclosure is about 60 mg (eg, 54 mg to 66 mg), about 100 mg (eg, 90 mg to 110 mg), or about 110 mg (eg, 99 mg to 121 mg) of EPA per day. is the amount

The daily intake of each component may be contained in one composition, or may be dispersed and contained in a plurality of compositions to be ingested per day. For example, the daily intake of each component of the composition may be dispersed in 2 to 15, preferably 3 to 10, eg, 4 capsules to be taken daily.

The compositions of the present disclosure may be taken once or multiple times. When taking multiple times, for example, once to several times a day, for example, once, twice or three times a day, every day or every few days, for example, 1 day, 2 days, 3 days or Can be taken every 7 days. The period of ingestion is not limited, for example, until cognitive function, mental health or mental QOL is improved, for example, 1 week or more, preferably 1 month or more, more preferably 2 months or more, particularly preferably 3 months. It can be taken continuously for months or longer. There may be periods during which the intake is discontinued. In some embodiments, the compositions of this disclosure are taken daily for at least 12 weeks.

The compositions of the present disclosure can be used alone or in combination with one or more additional ingredients. "Combining" the ingredients includes not only the use of dosage forms containing all of the ingredients and the use of combinations of dosage forms containing each ingredient separately, but also the use of each ingredient at the same time so long as they are used for the same purpose. , or delayed ingestion of any component. A combination of two or more additional components is also possible. For example, in addition to the fish egg oil preparation, compositions containing one or more additional ingredients may be used.

Ingredients suitable for combined use include astaxanthin. The daily intake of astaxanthin can be about 50 μg or more, preferably about 100 μg or more, more preferably about 200 μg or more, and can be about 1000 μg or less, preferably about 400 μg or less, for example about 200 μg (e.g., 180 μg to 220 μg). Astaxanthin may be included in the fish egg lipid composition, but astaxanthin from yet another source may be used. For example, astaxanthin extracted from natural products such as krill, salmon, trout, adonis, red yeast, and Haematococcus algae or a synthetic product can be used, and astaxanthin is preferably contained in Haematococcus algae pigment. The extraction solvent for obtaining astaxanthin from natural products may be either an aqueous solvent or an organic solvent. Methanol, ethanol, isopropanol, acetone, 1,3-butylene glycol, ethylene glycol, propylene glycol, glycerin, ethyl acetate, ether, hexane and the like can be used as organic solvents. Carbon dioxide in a supercritical state can also be used. These solvents may be used alone, or two or more of them may be mixed and used. In one embodiment, astaxanthin acts to protect and stabilize DHA and EPA from peroxidation.

Haematococcus algae, specifically, Haematococcus pluvialis, Haematococcus lacustris, Haematococcus capensis, Haematococcus droebakensis, Haematococcus ginseng Babiensis (Haematococcus zimbabwiensis) and the like. In addition, commercially available Haematococcus algae extracts can be used, for example, ASTOTS-S, -5O, -10O, etc. manufactured by Fuji Film Co., Ltd., AstaReal Oil 50F, 5F, etc. manufactured by Fuji Chemical Industry Co., Ltd., Astaxanthin-5C and 20C manufactured by Oryza Petrochemical Co., Ltd., astaxanthin 5% oil manufactured by Bioactives Japan, and Astabio ^{(registered trademark)} AR1 and AR5 manufactured by Biogenic. Examples of krill-derived astaxanthin include Astax-S manufactured by Marine Daio Co., Ltd., and the like.

Ingredients suitable for combined use include lecithin. The daily intake of lecithin can be about 50 mg or more, preferably about 60 mg or more, more preferably about 70 mg or more, and can be about 500 mg or less, preferably about 300 mg or less, more preferably about 150 mg or less. , for example about 100 mg (eg, 90 mg to 110 mg). Lecithin is a generic term for lipid products containing phospholipids and can include phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidic acid. Lecithins include, for example, soybean lecithin, enzymatically decomposed soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin, hydrogenated phospholipids, milk-derived phospholipids, lysolecithin, phosphatidylcholine and phosphatidylserine, preferably plant lecithin, particularly soybean lecithin. be. Soy lecithin can be produced as a by-product of the degumming process when manufacturing soybean oil. Further decolorization and purification may be carried out. Also, commercially available lecithins can be used, and examples thereof include purified soybean lecithin manufactured by Nisshin OilliO, purified egg yolk lecithin manufactured by Asahi Kasei Pharma, and egg yolk lecithin PL-100M manufactured by Kewpie.

When the composition of the present disclosure comprises lecithin, in certain embodiments the content of PC contained in the composition is, for example, about 24-45%, preferably about 26-43%, more preferably It is about 28-41%, more preferably about 30-39%. The content of PE contained in the composition is, for example, about 0.90-3.5%. The content of PI contained in the composition is, for example, about 0.80-2.5%. The content of LPC-2 contained in the composition is, for example, about 0.60-3.0%. The content of SM contained in the composition is, for example, about 0.8% to 2.3%. The content of phosphatidic acid contained in the composition is, for example, about 0.10-1.0%. The content of DHSM contained in the composition is, for example, about 0.050% to 0.40%. The content of phospholipids in the present composition is about 35% or more, more preferably about 40% or more, and the content of PC in the phospholipids is about 74% or more, preferably about 77%. That's it.

In one aspect, agents for improving cognitive function are provided that comprise a fish egg lipid preparation.
In some embodiments, methods of improving cognitive function are provided comprising ingesting a fish egg lipid preparation to a subject in need of improved cognitive function.
In one aspect, fish egg lipid preparations are provided for improving cognitive function.
In one aspect, the use of fish egg lipid preparations to improve cognitive function is provided.
In one aspect, use of the fish egg lipid preparation in the manufacture of a composition for improving cognitive function is provided.

In one aspect, a mental health or mental QOL improving agent comprising a fish egg lipid preparation is provided.
In certain aspects, maintaining, enhancing and/or improving mental health or mental QOL comprising ingesting a fish egg lipid preparation to a subject in need of improved mental health or mental QOL. A method is provided.
In one aspect, fish egg lipid preparations for improving mental health or psychological aspects of QOL are provided.
In one aspect, the use of fish egg lipid preparations for improving mental health or psychological aspects of QOL is provided.
In one aspect, there is provided use of a fish egg lipid preparation in the manufacture of a composition for improving mental health or a psychological aspect of QOL.

For example, the following embodiments are provided.
[1] A composition for improving cognitive function, comprising a fish egg lipid preparation.
[2] The composition according to item 1, wherein the cognitive function is language ability in a subject with a regular exercise habit.
[3] A fish egg lipid preparation prepared so that the daily intake is about 100 mg or more and less than 300 mg (preferably about 100 mg to 200 mg, more preferably about 150 mg to 200 mg) of DHA. A composition for improving cognitive function, comprising: said cognitive function is language ability in a subject with a regular exercise habit.
[4] The composition according to any one of items 1 to 3, for further improving mental health or mental quality of life.
[5] A composition for improving mental health or mental aspects of QOL, comprising a fish egg lipid preparation.
[6] The composition of paragraph 4 or 5 for improving mental health.
[7] The composition according to any one of items 4 to 6, wherein improving mental health is improving at least one of nervousness, depression and depressed mood.
[8] The composition according to any one of items 4 to 6, wherein improving mental health is improving to calm mood or happy mood.
[9] The composition according to item 4 or 5, for improving mental quality of life as determined by 2MCS (Japanese version) of SF-36.
[10] The composition according to item 4 or 5, for improving mental QOL as determined by 3MCS of SF-36.
[11] The composition according to any one of items 1 to 10, comprising a fish egg lipid preparation containing about 30% or more (preferably about 40% or more) of phospholipids.
[12] The composition according to any one of items 1 to 11, wherein the fish egg lipid preparation contains DHA-bound phospholipids, and the composition ratio of DHA to the constituent fatty acids of the lipid is about 15% or more.
[13] Any one of items 1 to 12, wherein the fish egg lipid preparation contains at least one selected from the group consisting of α-GPC, SM and DHSM (preferably the group consisting of SM and DHSM) The composition according to .
[14] The composition according to any one of items 11 to 13, wherein the phospholipid contains about 74% or more of PC.
[15] Any one of items 1 to 14, wherein the composition ratio of DHA to the constituent fatty acids of the lipid in the fish egg lipid preparation is about 15% or more, and the composition ratio of EPA is about 5 to 25%. The described composition.
[16] The composition according to any one of items 1 to 15, further comprising astaxanthin.
[17] The composition according to item 16, wherein the astaxanthin is derived from Haematococcus algal pigment.
[18] The composition according to any one of items 1 to 17, further comprising lecithin.
[19] The composition according to Item 18, wherein the lecithin is soybean lecithin.
[20] Items 1 to 19, which are prepared so that the daily intake of DHA is about 100 mg or more and less than 300 mg (preferably about 100 mg to 200 mg, more preferably about 150 mg to 200 mg). The composition according to any one of
[21] A daily intake of about 30 mg to 300 mg (preferably about 60 mg to 300 mg, more preferably about 60 mg to 150 mg) of eicosapentaenoic acid (EPA) is prepared, item 1 A composition according to any one of paragraphs 1-20.
[22] The composition according to any one of items 1 to 21, which is prepared so that the daily intake is about 160 mg (or 144 mg to 176 mg) of DHA.
[23] Daily intake of DHA of about 100 mg to less than 300 mg (preferably about 100 mg to 200 mg, more preferably about 150 mg to 200 mg), about 30 mg to 300 mg (preferably about 60 mg to 300 mg, more preferably about 60 mg) ~150 mg) of eicosapentaenoic acid (EPA) and from about 50 mg to 500 mg (preferably from about 60 mg to 300 mg, more preferably from about 70 mg to 150 mg) of soy lecithin are prepared for ingestion. 23. A composition according to any of paragraphs 22-24.
[24] The composition according to item 23, further comprising about 100 μg to 1000 μg (preferably about 200 μg to 1000 μg, more preferably about 200 μg to 400 μg) of astaxanthin.
[25] Daily intake of about 160 mg of DHA (or 144 mg to 176 mg), about 100 to 110 mg (preferably about 100 mg (or 90 to 110 mg), or about 110 mg (or 99 mg to 121 mg)) of EPA and about 100 mg (or 90 mg to 110 mg) of soy lecithin are formulated to be ingested.
[26] A daily intake of about 160 mg DHA (or 144 mg to 176 mg), about 110 mg (or 99 mg to 121 mg) EPA, and about 100 mg (or 90 mg to 110 mg) soy lecithin is taken. 24. The composition of paragraph 23, wherein the composition is prepared as
[27] The composition according to item 25 or 26, which is further adjusted so that about 200 μg (or 180 μg to 220 μg) of astaxanthin is ingested.
[28] About 150 mg (or 135 mg to 165 mg) of DHA, about 60 mg (or 54 mg to 66 mg) of EPA, and about 100 mg (or 90 mg to 110 mg) of soy lecithin are taken as a daily intake. 24. The composition of paragraph 23, wherein the composition is prepared as
[29] The composition according to Item 28, which is further adjusted so that about 200 μg (or 180 μg to 220 μg) of astaxanthin is ingested.
[30] The composition of any one of paragraphs 1 to 29, wherein the fish egg lipid preparation is derived from pink salmon.
[31] The composition of any of paragraphs 1-30, which is taken daily for at least 12 weeks.
[32] The composition according to any one of items 1 to 31, which is ingested by middle-aged and elderly people.
[33] The composition according to Item 32, wherein the subject is 60 to 85 years old.
[34] The composition according to any one of items 1 to 33, which is a pharmaceutical composition.
[35] The composition according to any one of items 1 to 33, which is a food composition.
[36] A cognitive function improving agent comprising a fish egg lipid preparation.
[37] A method of improving cognitive function comprising ingesting a fish egg lipid preparation to a subject in need of cognitive improvement.
[38] Fish egg lipid preparations for improving cognitive function.
[39] Use of fish egg lipid preparations to improve cognitive function.
[40] Use of a fish egg lipid preparation in the manufacture of a composition for improving cognitive function.
[41] A mental health or mental quality of life improving agent comprising a fish egg lipid preparation.
[42] A method for improving mental health or mental QOL, comprising ingesting a fish egg lipid preparation to a subject in need of improved mental health or mental QOL.
[43] Fish egg lipid preparations for improving mental health or mental aspects of QOL.
[44] Use of fish egg lipid preparations to improve mental health or psychological aspects of QOL.
[45] Use of a fish egg lipid preparation in the manufacture of a composition for improving mental health or mental aspects of QOL.

All documents cited herein are hereby incorporated by reference.
EXAMPLES The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to these Examples. Moreover, the above description is all non-limiting, and the present invention is defined in the appended claims, and various modifications are possible without departing from the technical idea thereof.

<Production of fish egg lipid preparation from sardines>
A fish egg lipid preparation was produced according to the method described in WO2021/132516. Specifically, hydrous ethanol (150 L) was added to raw sarcomas (15 kg) of frozen and pulverized pink salmon (Oncorhynchus gorbuscha) for extraction, and the residue was separated by filtration. In addition, the residue was returned to the extractor and extracted again by adding ethanol (75 L). The solvent was distilled off from the obtained filtrate under reduced pressure to produce a composition (40PL) containing about 40% phospholipid in the red oily substance (Tables 1 and 2).

*The quantitative value is the amount of fatty acids constituting the total lipid.

<Production of soft capsules>
Haematococcus algae pigment (astaxanthin) and soybean lecithin (plant lecithin) were added to the 40PL to produce a soft capsule "ONO-SR/AST-SOYPC" containing the ingredients in the table below in one capsule (Table 3). . Table 4 shows the amounts of phospholipid classes contained in the soft capsules.

*The raw gelatin is derived from cows.

The specifications of ONO-SR/AST-SOYPC were as shown in the table below.

<Clinical trial>
I SUBJECTS AND METHODS 1 . Subjects The subjects were 100 men and women aged 60 to 85 who had subjective symptoms of forgetfulness or who were pointed out to have forgetfulness symptoms in close relatives (some were diagnosed with MCI). include). Prior to conducting the study, we provided the subjects with written informed consent, fully explained the purpose and content of the study, and obtained written consent from the subjects based on their free will. Subjects who did not meet the following exclusion criteria were selected from the preliminary test results of subjects who were able to obtain consent.

(1) Subjects who regularly use health foods rich in DHA, EPA, astaxanthin, and soybean lecithin.
(2) Drugs, health foods, foods for specified health uses, foods with nutrient function claims, and functional claims that contain ingredients that have cognitive function improvement effects, antioxidant effects, or blood flow improvement effects that may affect research results. Subjects who continuously take food more than once a week.
(3) Subjects who have difficulty in performing cognitive function tests due to poor eyesight, or who have been diagnosed with amblyopia or blindness.
(4) Subjects who have difficulty in conducting cognitive function tests due to their low hearing, or who have been diagnosed with hearing loss or deafness.
(5) Those who have a history or current disease of mental disorder, dementia, cranial nerve disease, cerebrovascular disease.
(6) Those who have an existing disease of menopause.
(7) Taking drugs that may affect the research results (dyslipidemia drugs, antipsychotic drugs, antianxiety drugs, antidepressants/congestive drugs, antiparkinsonian drugs, antiepileptic drugs, anticoagulants, etc.) those who are
(8) Subjects with a history of serious disease requiring medication (malignant tumor, diabetes, liver disease (hepatitis), renal disease, heart disease, etc.).
(9) Subjects with a history of drug dependence or alcohol dependence or a current medical history.
(10) Subjects who are suspected of having dementia based on a cognitive function test as a preliminary test or an interview with a doctor.
(11) Subjects whose daily life becomes irregular several times during the study period due to night work, etc.
(12) Current smokers, or those who started smoking cessation within 12 months before the pre-examination.
(13) Subjects who have taken a cognitive function test (Mini-Mental State Examination (MMSE)) or the Japanese version of the Montreal Cognitive Assessment (MoCA-J) within 12 months before the preliminary test.
(14) Subjects who donated 200 mL or 400 mL of whole blood or received blood transfusion within 3 months before the preliminary examination.
(15) Those who have participated in other clinical research within one month before the preliminary examination, or those who plan to participate during the research period.
(16) Persons who are judged to be unsuitable as subjects based on the clinical test values and measured values of the preliminary examination.
(17) Subjects who may develop allergies related to the research.
(18) Subjects judged to be unsuitable as subjects based on the responses to the lifestyle questionnaire.
(19) In addition, those who are judged to be unsuitable as subjects by the responsible physician.

Prior to conducting the study, the researcher instructed all subjects not to violate the following rules.
Throughout the research period,
(1) Do not change lifestyle habits such as drinking, eating, sleeping, and working as much as possible before participating in the study.
(2) Limit excessive exercise, dieting, and overeating that greatly deviate from the daily range.
(3) Do not start new exercise or stop the exercise habits that you have been doing.
(4) Do not travel abroad or go on overseas business trips.
(5) Do not newly consume health foods, foods for specified health uses, foods with nutrient function claims, and foods with function claims. Health foods, etc. that are taken continuously will be taken continuously during the research period.
(6) Do not take medicines, health foods, foods for specified health use, foods with function claims, and nutritional drinks that contain ingredients that may affect cognitive function, antioxidants, or blood flow improvement.
(7) Do not donate blood.
(8) Take a prescribed amount of research food every day, and keep a diary every day.
At the time of preliminary (blood sampling) inspection,
(9) Do not drink alcohol from the morning of the day before the test until the end of the test on the day.
(10) Do not exercise excessively from the day before the examination to the end of the examination on the day.
(11) On the day of the examination, after waking up, the subject should be fasted (drinking water is permitted) until the examination is completed, and should be fasted for at least 8 hours.
During the preliminary (cognitive) test,
(12) The day before the test, get enough sleep and rest.
(13) Prohibit acts that greatly affect cognitive function immediately before the examination.
(14) Comply with items (9) and (10).
At the 6th week test and the 12th week (cognitive) test,
(15) Comply with items (9), (10), (12), and (13).
(16) Visit the hospital on the day of examination without ingesting research food.
(17) In principle, the cognitive function test should be started at the same time as the preliminary (cognitive) test. The morning or afternoon should be the same, and the start time of the preliminary (cognitive) cognitive function test should be within ±2 hours.
(18) Live in such a way that the working conditions before the pre-test (cognitive) test and before the test on the day of the test do not change significantly.
(19) Living in such a way that the pre-examination (cognitive) examination, the exercise status on the day before and on the day of the examination, and the last meal before the examination do not differ significantly.
At the 12th week (blood sampling) test,
(20) Comply with items (9) to (12) and (16).

2. Research Foods There were two types of research foods, a test food and a placebo. The test food contained 1000 mg of salmon roe oil (containing 150 mg of DHA and 60 mg of EPA) in 4 grains, which is the daily intake. As other ingredients, a soft capsule containing astaxanthin, soybean lecithin, gelatin, glycerin, water, and caramel pigment was used. The placebo was a soft capsule containing safflower oil instead of salmon roe oil. For each research food, the daily intake of 4 grains was packed in one bag so that the test food and placebo could not be distinguished from the exterior.

3. Study Design This study was a randomized, double-blind, placebo-controlled, parallel-group study with a 12-week intake period. An allocation manager who was not directly involved in the study created an allocation table using a random number table, and based on this, assigned an allocation number to the study foods. The randomization list was sealed by the person responsible for randomization and kept sealed until the randomization list was opened. The investigator responsible, subjects, medical facility staff, and all other staff involved in this study were blinded.

For all subjects in both groups, prior to the start of intervention, physical measurements (height, weight, calculation of BMI), physical examinations (blood pressure, pulse rate), various clinical examinations (hematologic examination, blood biochemical test, urinalysis), cognitive function test (MMSE, MoCA-J), MOS 36-Item Short-Form Health Survey (SF-36) (S Fukuhara, et al. Translation, adaptation, and validation of the SF- 36 Health Survey for use in Japan. J Clin Epidemiol 1998; 51: 1037-44; S Fukuhara, et al. Psychometric and clinical tests of validity of the Japanese SF-36 Health Survey. J Clin Epidemiol 1998; ) was performed and the resulting value was used as the baseline.

　Each subject was given one bag of the randomly assigned research food, four tablets per day after meals, without chewing, with water or lukewarm water throughout the 12-week intervention period. During the intervention period, subjects were asked to record in a diary the intake of research foods, changes in their physical condition, and the intake of medicines. Six weeks and 12 weeks after the start of intake, all subjects visited the hospital for physical measurements, physical examinations, and cognitive function tests. After 12 weeks, clinical tests, special tests, and SF-36 were performed in addition to the above.

4. Evaluation of Efficacy To evaluate the effectiveness of the study food, MoCA-J was performed as the primary endpoint, and MMSE and SF-36 were performed as secondary endpoints. Both MoCA-J and MMSE are tests that allow multifaceted assessment of various areas of cognitive function. In addition, since both are used for screening for MCI, they were used for evaluation of cognitive function in this study targeting healthy subjects including the MCI region. Details of each test are described below.

1) MoCA-J
MoCA-J includes Trail Making, visuospatial cognitive function (cube), visuospatial cognitive function (clock drawing), nomenclature, memory, attention (forward chant, reverse chant, vigilance, calculation), repetition, word recall, and abstract thinking. , delayed recall, and orientation, and is a test developed for the purpose of screening for MCI. MCI is suspected with a score of 25 or less out of a maximum score of 30, and has been reported to have a sensitivity of 80-100% and a specificity of 50-87% (Ziad S Nasreddine, et al. The Montreal Cognitive Assessment MoCA: a brief Screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53: 695-9; Bruce A Fage, et al. Mini-Cog for the diagnosis of Alzheimer's disease dementia and other dementias within a community setting. Cochran Database Syst Rev 2015: CD010860). Note that attention (calculation) and orientation items overlap with MMSE in this study. Cognitive function chronological comparison using J. Physical Therapy Science 2019; 34: 331-5). Examinations were performed on the same day in the order of MMSE and MoCA-J. The attention (calculation) of MoCA-J and the attention and calculation of MMSE are the same calculation task (repeating 7 in order from 100 and subtracting 5 times), but considering the time from memory to delayed recall of MoCA-J , MoCA-J also performed computational tasks, and the results of the MMSE were used for the scores. MoCA-J orientation and MMSE orientation to time and orientation to place are performed only in MMSE as the date (year, month, day, day of the week) and place (city, building) tasks are identical The scores were obtained from the MMSE. In both cases, the higher the score, the higher the cognitive function.

2) MMSE
The MMSE is a test consisting of a total of 11 items: orientation to time, orientation to place, memorization, attention and calculation, reproduction, naming, repetition, comprehension, reading, writing, and drawing. Out of a maximum of 30 points, a score of 23 or less suggests dementia (sensitivity 81%, specificity 89%), and a score of 27 or less suggests MCI (sensitivity 45-60%, specificity 65-90%). (MF Folstein, et al. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189-98.; Kelvin K F Tsoi, et al. Cognitive Tests to Detect Dementia: A Systematic Review and Meta-analysis. JAMA Intern Med 2015; 175: 1450-8; Syed H Tariq, et al. Comparison of the Saint Louis University mental status examination and the mini-mental state examination for detecting dementia and mild neurocognitive disorder: a pilot study. Am J Geriatr Psychiatry 2006; 14: 900-10; Judith Saxton, et al. Computer assessment of mild cognitive impairment. Cognitive screening for dementia and mild cognitive impairment in assisted living: comparison of 3 tests. J Am Med Dir Assoc 2008; 9: 586-93). In both cases, the higher the score, the higher the cognitive function.

3) SF-36
SF-36v2 Japanese version was used to evaluate health-related QOL (Health Related Quality of Life). The SF-36 consists of 36 items and consists of eight health concepts (physical function, daily role function (physical), body pain, overall well-being, vitality, social function, daily role function (mental), and mental health). NBS scores (scores by scoring method based on national standard values) and component summary scores (three component summary scores of factor coefficients based on the 2002 Japanese survey (physical aspects, mental aspects, social 2-component summary score of factor coefficients based on the 1995 U.S. national survey (physical and mental aspects), 2-component summary score of factor coefficients based on the 1995 Japanese national survey (physical and mental aspects) aspect)) can be calculated. In both cases, the higher the score, the higher the QOL.

5. Evaluation of Safety The Principal Investigator should assess all undesired or unintended injuries or signs of illness during the ingestion period based on the results of the interviews and physical examinations, physical examinations, and diary entries at each visit. was treated as an adverse event. In addition, clinical tests were performed on the following items. Hematological test (white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count), blood biochemical test (total protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, ALP, AST (GOT), ALT (GPT), LD, γ-GT, total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, urea nitrogen, creatinine, uric acid, Na, K, CL, blood sugar, HbA1c (preliminary test only)), urinalysis (protein (qualitative ), sugar (qualitative), occult blood reaction (qualitative)). The determination of whether or not the test values of individual subjects are abnormal changes corresponding to adverse events is based on the reference values specified by the implementing medical institution, and the criteria for abnormal changes stipulated by the Japanese Society of Chemotherapy, CTCAE v5.0- Conducted by the responsible physician with reference to the JCOG and the Japanese Society of Ningen Dock judgment categories (revised on April 1, 2018, partially changed on December 14, 2018). In addition, the investigator-in-chief investigated and considered the relationship with the study food, and determined whether each adverse event was a side effect of the study food.

For safety analysis subjects, adverse events were subject to subjects who had ingested the research food at least once. Subjects who completed all prescribed research schedules and research content were used for the measured values and test values.

6. Statistical Analysis Even outlier values were used for evaluation in laboratory and measured values. When the cause was clearly determined to be a measurement error, it was excluded from the analysis at that time. Missing values were not imputed and were not included in the analysis as missing.

The values before intervention (baseline) to compare the characteristics of each subject group, the measured values at each time point after ingestion, and the amount of change from the baseline were each shown as the mean ± standard deviation (sex is the number of subjects ). The chi- ^square test was used for between-group comparisons of sex at baseline. For other items, the two-sample t-test was used to compare the amount of change from the baseline and the baseline at each time point after ingestion between groups. A one-sample t-test was used for intra-group comparison of changes from baseline in measured values at each time point after ingestion. As a reference, the change at week 12 when the baseline was 0 was evaluated using the Wilcoxon signed rank sum test. Similar statistical methods were used for between- and within-group comparisons in subgroup analyses. As statistical analysis software, Microsoft Excel 365 (Microsoft, USA) and IBM SPSS statistics 26 for windows (IBM) were used. The level of statistical significance was set at 5% two-sided.

II Results 1. Subjects The process from selection of subjects and assignment of test foods to analysis is shown as a test flow chart in Fig. 1. A preliminary (blood sampling) test was performed on 264 subjects who gave written consent to participate in the study. Preliminary (cognitive) testing was performed on 187 subjects, excluding 72 subjects who were ineligible for study participation and 5 who declined to participate. From these results, 100 individuals (50 each in the test food and placebo groups) who met the inclusion criteria and did not meet any of the exclusion criteria, except for 1 who withdrew from participation after pre-(cognitive) testing, were eligible. The subjects were included in the study. Subject backgrounds are shown in Table 6. There were no items with significant differences between the groups.

2. Data analysis on primary and secondary endpoints Changes after intervention in both groups were investigated for each item of MoCA-J set as the primary endpoint and MMSE and SF-36 set as secondary endpoints. Items with identical baselines and changes in both groups were not tested.

Table 7 shows the total MoCA-J and the scores for each item during the intervention period. Attention (reversal) at week 6 showed a significant increase (improvement) in the placebo group compared to the test food group (P=0.03). Also, total scores, abstract thinking, delayed recall and orientation increased (improved) significantly in both groups at 6 and 12 weeks compared to baseline.

Regarding the total MMSE during the intervention period and the amount of change in each item before and after the intervention, the total score and question 2 (orientation to place) significantly increased in both groups at 6 and 12 weeks compared to the baseline ( However, no significant difference was observed between the placebo group and the test food group in any test week.

Table 8 shows the NBS scores and component summary scores of SF-36 during the intervention period. Regarding the NBS score of mental health at the 12th week, the mental aspect of the 2002 3-component summary score and the 1995 2-component summary score (Japanese version), the test food group was divided into the placebo group and the mental aspect. showed a significant increase (improvement) in comparison (P=0.03, 0.01, 0.03 respectively). In addition, both groups significantly increased (improved) in the NBS score of daily role functioning (psychiatric) and the mental aspects of the 1995 2-component summary score (US version) compared to the baseline at 12 weeks. NBS scores for daily role functioning (physical), the social dimension of the 2002 3-component summary score and the physical dimension of the 1995 2-component summary score (Japanese version) compared to baseline in the placebo group at 12 weeks significantly increased (improved) in NBS scores for physical function, vitality and mental health, mental aspects of the 2002 3-component summary score and 1995 2-component summary score (Japanese version) were compared to baseline in the test food groups. significantly increased (improved) at 12 weeks of

3. Subgroup analysis Regarding the presence or absence of regular exercise habits, all subjects were divided into the group of subjects who exercised at least once a week during the intake period (group with regular exercise habits) and the group of subjects who exercised less than once a week (regular exercise group). No habit layer), and subgroup analysis was performed for each subject layer. In addition, the test was not performed for the items for which the baseline and the amount of change were the same for all the subjects in both groups.

The number of subjects in the placebo group and the test food group in the regular exercise group was 24 (11 men, 13 women) and 26 (15 men, 11 women), respectively, and the non-regular exercise group. The number of subjects in the placebo group and the test food group was 26 (16 males, 10 females) and 24 (11 males, 13 females), respectively. Among the age, male/female ratio, physical measurements, physical examination values, and MoCA-J total score, there was no significant intergroup disparity in age in the group with regular exercise habits and systolic blood pressure in the group without regular exercise habits. A balance was found (P=0.04 for both) (Table 9).

Table 10 shows the total MoCA-J and the scores for each item during the intervention period in the group with regular exercise habits. The test food group showed a significant increase (improvement) in repetition at week 12 compared to the placebo group (P=0.03).

　There was no significant difference between the placebo group and the test food group in any test week regarding the change in the total MMSE and the score of each item during the intervention period in the group with regular exercise habits.

There was no significant difference between the placebo group and the test food group in any test week regarding the change in the total MoCA-J and MMSE and the score of each item during the intervention period in the group without regular exercise habits. I couldn't.

4. Safety Evaluation Safety evaluation was performed on 50 subjects for safety analysis in each group (Fig. 1) for both adverse events, measured values, and test values. During the intervention period, 21 subjects in the placebo group (55 cases) and 13 subjects in the test food group (23 cases) had positive urine occult blood tests, diarrhea, arthralgia, nasal discharge, lumbago, and other adverse events. Adverse events other than a positive urinary occult blood test must have an identifiable cause other than the research food, or be mild and transient, and none of them are related to the research food, i.e., not a side effect of the research food. was judged by the responsible investigator. The positive urinary occult blood reaction is thought to be caused by the subject's exercise habits, but cannot be identified, so the relationship with the research food is "probably not", but the investigator-in-charge determined that it was within a clinically acceptable range. was done. Measured values and test values were compared before and after ingestion in each group, and significant changes were observed in some items, but all were minor changes within the standard range or reference range. It was judged not to be a clinical problem.

III Consideration This study targets men and women aged 60 or older who have subjective symptoms of forgetfulness or who have been pointed out that their close relatives also have forgetfulness symptoms. It was ingested for a week and its usefulness for cognitive function and health-related QOL was verified.

For both MoCA-J and MMSE, which were used as cognitive function evaluations, no significant inter-group differences were observed in the amount of change at 12 weeks in each of the test items that make up them and in the total score. In cognitive function evaluation, it has been pointed out that there is a ``practice effect'' in which the scores of subsequent tests are higher due to memory and familiarity with previous tests. The total scores of MoCA-J and MMSE increased in both groups compared to the baseline, suggesting that under the conditions of this study, the effect of practice had an effect on the cognition-improving effect of the test food. Furthermore, most of the subjects scored the highest in some test items, and a ceiling effect was also observed. Therefore, it is considered that the effect of the test food was not observed in the overall analysis.

In the SF-36 "mental health" used for health QOL evaluation, the amount of change at week 12 was 0.11±6.37 points for the placebo group and 2.68±5.0 points for the test food group. 20 points, and the improvement effect of the test food significantly exceeded the placebo. A high score for "Mental Health" indicates that "I have felt calm, happy, and calm in the past month." The average score of "mental health" of the subjects in this study was in the 57-point range, and the average score of "mental health" of general Japanese people aged 60 to 84 (2017 NBS scores by age and gender) It is slightly higher than the 53-54 points of the distribution), but it was found that "mental health" was further improved by ingesting the test food. In addition, regarding the summary score, which is the superordinate concept of the eight subscales, the 2002 3-component summary score "Mental aspect" and the 1995 2-component summary score (Japanese version) "Mental aspect" The test food group showed significant improvement compared to the placebo group. The 3-component summary score, "Mental Aspects," consists of "Body Pain," "Overall Health Perception," "Social Functioning," "Daily Role Functions (Mental)," "Vitality," and "Mental Health." The 2-component summary score "mental aspects" consists of "overall health", "social functioning", "daily role functioning (mental)", "vitality", and "mental health". , both of which are scores indicating the QOL of the mental aspect. From the above, results suggesting that ingestion of the test food leads to a “calm, happy, and calm mood,” which is a state of good mental health, and improves mental QOL. Mental health is an important condition for living a vibrant and authentic life. Specifically, being able to notice and express one's emotions (emotional health), thinking appropriately according to the situation, and solving realistic problems. It also has aspects such as being able to do things (intellectual health), building constructive and good relationships with others and society (social health), and finding the purpose and meaning of life and making proactive choices in life (human health). . Ingestion of the test food is thought to improve mental health in these aspects as well.

A subgroup analysis was conducted on the effects of the test foods on cognitive function, depending on whether or not they had exercise habits. As a result, among subjects who exercised once a week or more (group with regular exercise habits), "repeat" of MoCA-J was significantly improved in the test food group compared to the placebo group. "Repetition" is a test related to auditory short-term memory, and the linguistic ability measured by "repetition" is generally considered to be "the ability to understand, memorize, and accurately express the meaning of things." It is said that this language ability has the following three roles. In other words, creating something, thinking based on theories, expressing emotions and feelings, and communicating one's own creations, thoughts, feelings and feelings to someone (communication), and occupy an important position in cognitive functions. ing. These results suggest that the test food has the effect of improving language ability, which is a part of cognitive function, in elderly people who exercise at least once a week.

Regarding safety, one case of "urinary occult blood test positive" was observed in the test food group, and although there was "probably no relationship" to the research food, the investigator-in-charge judged that it was within the range of no clinical problems. rice field. All other adverse events were judged to be unrelated to the study food, and the test food was considered safe to consume under the conditions of this study.

Conclusion Ingesting a supplement containing DHA and EPA derived from salmon roe oil for 12 consecutive weeks in elderly people aged between 60 and 85 years old makes them feel calm, happy, and calm, improving their mental QOL. In addition, it was suggested that those who exercised once a week or more had the effect of improving language ability among cognitive functions. Regarding safety, it was concluded that supplements containing salmon roe oil-derived DHA/EPA can be taken safely under the conditions of this study.

<Safety evaluation by overdose test>
1. Subjects In this study, the purpose of this study was to confirm the safety of overdose (5 times the amount) of salmon roe oil, astaxanthin and soybean lecithin-containing food "ONO-SR/AST-SOYPC". When considering food safety, it is desirable to conduct and examine a wide range of age groups and genders. In order to confirm the safety of taking 1-fold and 2-fold doses as a reference, the number of subjects was reduced to set 5 subjects each for a 1-fold dose group and a 2-fold dose intake group. In Test 2, only 10 people in the 5-fold intake group were tested.

　Before conducting the study, we provided the subjects with a written informed consent, fully explained the purpose and content of the study, and obtained their written consent based on their free will. Preliminary examinations (lifestyle questionnaires, medical interviews, physical measurements, physical examinations, and fasting clinical examinations) were performed on subjects who were able to obtain consent. Subjects who did not meet the following exclusion criteria were selected based on the results of the preliminary examination.

Exclusion Criteria:
(1) Those who regularly use health foods rich in DHA, EPA, astaxanthin, soybean lecithin,
(2) Persons with serious diseases such as diabetes, liver disease, kidney disease, heart disease, etc., and those with a history of such diseases;
(3) Subjects who are at risk of developing allergies related to the research,
(4) Subjects who have a medical condition affecting the study, or who have a history of chronic disease or serious disease requiring medication,
(5) Those who have a history of drug dependence or alcohol dependence or a current medical history,
(6) Persons who are judged to be unsuitable as subjects based on the clinical test values and measured values of the preliminary examination,
(7) Those who have participated in other clinical studies within one month of obtaining consent to participate in this study, or those who plan to participate in other clinical studies after obtaining consent to participate in this study;
(8) Subjects who are pregnant, breast-feeding, or planning to become pregnant or breast-feeding during the research period;
(9) Those who are judged to be unsuitable as subjects based on the results of the lifestyle questionnaire,
(10) In addition, those who are judged to be inappropriate as subjects by the responsible physician.

2. Test food One bag of the test food "ONO-SR/AST-SOYPC" (Ono Pharmaceutical Co., Ltd.) contains 1 g of salmon roe oil (DHA 150 mg, EPA 60 mg) per 4 tablets, astaxanthin 200 μg, soybean lecithin 100 mg, gelatin, glycerin, A soft capsule containing water and caramel color was used. Raw materials and nutritional components are shown in Table 11.

3. Test method The test was an open study. 1 bag (4 tablets) for the 1-fold intake group, 2 bags (8 tablets) for the 2-fold intake group, 5 bags (20 tablets) for the 5-fold intake group, followed by water after meals. Alternatively, they were given without chewing with lukewarm water. In addition, the intake time was not specified, and it was allowed to divide and drink multiple times in one day. The intake period was 4 weeks. During the test period, do not change your lifestyle such as drinking, eating, and sleeping as much as possible from before participating in the study, limit excessive exercise that greatly deviates from your daily range, diet and overeating, do not start new exercise, In addition, it was decided not to stop the exercise habits that had been continued until then.

In Test 1, the subjects visited the hospital two weeks after taking the test food, and interviews (confirmation of physical condition), physical measurements, physical examinations, and fasting clinical examinations were performed. In addition, the subjects were instructed to keep a test diary every day during the test period, which describes the intake status of the test food, changes in physical condition, mood in daily life, sleep (falling asleep, sleep quality), drug intake status, etc. The same test was planned to be conducted at the 4th week of intake and the 2nd week after the intake, but due to the declaration of a state of emergency for the new coronavirus infection, to ensure the safety of the subjects, the 4th week of intake and the end of intake. The patient was not admitted to the hospital for the second week. After the ingestion period ended, only the entries in the diary were continued for two weeks.

In Test 2, the subjects visited the hospital in the 2nd and 4th weeks after taking the test food, and interviews (confirmation of physical condition), physical measurements, physical examinations, and fasting clinical examinations were performed. In addition, the subjects were instructed to keep a test diary every day during the test period, which describes the intake status of the test food, changes in physical condition, mood in daily life, sleep (falling asleep, sleep quality), drug intake status, etc. After the end of the ingestion period, only the entries in the diary were continued for two weeks.

4. Examination items/Evaluation items Examination includes confirmation of physical condition as an interview, confirmation of the presence or absence of adverse events, physical measurement (height (preliminary examination only), weight, BMI), physical examination (systolic and diastolic blood pressure, pulse rate), Fasting clinical examination hematologic test (white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count), blood biochemical test (total protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, ALP, AST, ALT, LD , γ-GT, total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, urea nitrogen, creatinine, uric acid, sodium, potassium, chloride, blood sugar, HbA1c (preliminary test only)), urinalysis (protein qualitative, sugar qualitative, occult blood reaction) were performed. In Test 1, each test was performed at the time of the pre-inspection, 2 weeks after ingestion, except for items that were to be tested only in the pre-treatment. In Test 2, each test was performed at the time of the pre-inspection, 2 weeks after the intake, 4 weeks after the intake, and 2 weeks after the completion of the intake, except for items that were inspected only before the intake. In addition, the implementation of the clinical examination was entrusted to LSI Medience Co., Ltd. (Shinagawa-ku, Tokyo).

The evaluation items were adverse events, measured values and test values, and adverse events were subjective symptoms in interviews and diaries, as well as abnormal changes in test values. Subjective symptoms and adverse events as objective findings were determined by the responsible physician. Regarding abnormal changes in test values (adverse events) of individual subjects, the criteria for abnormal changes stipulated by the Japanese Society of Chemotherapy and Adverse Event Common Terminology Criteria v5.0 Japanese translation are based on the reference values stipulated by the medical institution. Adverse events were judged by the responsible physician by referring to the JCOG version (CTCAE v5.0-JCOG) and the judgment categories of the Japanese Society of Ningen Dock.

5. Statistical Analysis Pre- and post-feeding time point measurements were compared using the one-sample t-test. The significance level of the test was 5% on both sides. Microsoft Excel (Microsoft Corporation) was used as statistical analysis software.

Results 1) Test 1
1. Background of Subjects In Study 1, a preliminary examination was performed on 63 subjects who gave written consent to participate in the study. A total of 30 subjects, 15 males and 15 females, who met the inclusion criteria and did not meet the exclusion criteria based on the results of the preliminary examination, were selected as eligible subjects for this study. In some subjects, items exceeding the standard range (testing standard values of the laboratory performing the clinical testing) were found in some subjects. It was included in this study after it was determined that there was no

All 30 subjects completed the ingestion of the test food, but one female did not visit the hospital due to refraining from going out due to the spread of the new coronavirus infection. and Therefore, 29 subjects (1-fold intake group: 5 subjects, 2-fold intake group: 5 subjects, 5-fold intake group: 19 subjects), except for one subject excluded from analysis, were measured and tested, and 30 adverse events were reported. All subjects were evaluated as subjects for analysis.

2. Adverse events There were 2 cases of variation in measured values/laboratory values for each subject in 2 subjects. None of the changes in laboratory values were judged to be abnormal (not adverse events).
Headache, abdominal pain/loose stools, and tenosynovitis were observed as adverse events. 40%) 2 cases, and 5 times the amount was 3 cases out of 20 (15%). All adverse events were 'mild' in severity and no serious adverse events occurred in this study. In addition, the relationship with the test food was judged to be "none."

3. Measured values/laboratory values Regarding physical measurements, physical test values, and laboratory test values (hematological tests, blood biochemical tests), there were some items that showed significant changes after ingestion compared to before. However, it was judged by the responsible physician that the change was at a clinically acceptable level. Several subjects showed positive laboratory test values (urinalysis), but it was considered to be due to the influence of physiology, so the responsible physician judged that there was no clinical problem.

2) Test 2
1. Background of Subjects In Study 2, a preliminary examination was performed on 23 subjects who gave written consent to participate in the study. A total of 10 subjects, 5 males and 5 females, who met the inclusion criteria and did not meet the exclusion criteria, were selected as eligible subjects for this study based on the results of the preliminary examination.

All 10 subjects started taking the test food, but 1 female was found to be ineligible as a subject (has a history of asthma cough) on the 15th day of intake, so the study was discontinued. The remaining 9 people completed the prescribed test schedule and test content. Therefore, 9 subjects who completed the intake were evaluated for measured values and test values, and all 10 subjects for adverse events were evaluated as subjects for analysis.

2. Adverse events There were 2 cases of variation in measured values/laboratory values for each subject in 2 subjects. None of the changes in laboratory values were judged to be abnormal (not adverse events).
As adverse events, one case each of diarrhea and sore throat was observed. All adverse events were 'mild' in severity and no serious adverse events occurred in this study. In addition, the relationship with the test food was judged to be "none."

3. Measured values/laboratory values Regarding physical measurements, physical test values, and laboratory test values (hematological tests, blood biochemical tests), there were some items that showed significant changes after ingestion compared to before. However, it was judged by the responsible physician that the change was at a clinically acceptable level. Several subjects showed positive laboratory test values (urinalysis), but it was considered to be due to transient fluctuations, so the responsible physician judged that there were no clinical problems.

Conclusion Based on the results of the above two tests, an overdose test was conducted in which the food "ONO-SR/AST-SOYPC" containing salmon roe oil, astaxanthin and soy lecithin was ingested in an amount five times the recommended daily intake for four consecutive weeks. In this case, it was shown that there is no problem with safety.

The present disclosure relates to improving cognitive function and can be used in the medical or food fields.

Claims (16)

1. A composition for improving cognitive function, comprising a fish egg lipid preparation prepared to provide a daily intake of about 100 mg or more and less than 300 mg of DHA, wherein the cognitive function is regularly improved. language ability in subjects with good exercise habits.
2. The composition of claim 1, comprising a fish egg lipid preparation containing about 30% or more phospholipids.
3. The composition according to claim 1 or 2, wherein the fish egg lipid preparation contains docosahexaenoic acid (DHA)-bound phospholipid, and the composition ratio of DHA to the constituent fatty acids of the lipid is about 15% or more.
4. The composition according to any one of claims 1 to 3, further comprising soy lecithin.
5. The composition according to any one of claims 1 to 4, which is prepared so that the daily intake is about 160 mg of DHA.
6. Claims 1 to 1, wherein the daily intake is prepared so that about 100 mg or more and less than 300 mg of DHA, about 30 mg to 300 mg of eicosapentaenoic acid (EPA), and about 50 mg to 500 mg of soybean lecithin are ingested. 6. The composition according to any one of 5.
7. The composition according to any one of claims 1 to 6, which is prepared so that about 160 mg of DHA, about 110 mg of EPA, and about 100 mg of soybean lecithin are ingested per day.
8. The composition according to any one of claims 1 to 7, which is taken daily for at least 12 weeks.
9. The composition according to any one of claims 1 to 8, for further improving mental health or mental aspects of QOL.
10. The composition according to any one of claims 1 to 8, for further improving mental health.
11. The composition according to claim 9 or 10, wherein improving mental health is improving at least one of nervousness, depression and depressed mood.
12. The composition according to claim 9 or 10, wherein improving mental health is improving calm or joyful mood.
13. The composition according to claim 9, for improving the QOL of the mental aspect as determined by 2MCS (Japanese version) of SF-36.
14. The composition according to claim 9, for improving the mental aspect QOL as determined by the 3MCS of SF-36.
15. The composition according to any one of claims 1 to 14, which is a pharmaceutical composition.
16. The composition according to any one of claims 1 to 14, which is a food composition.

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