Composition for improving sleep quality

Abstract

The present disclosure provides a composition for improving the quality of sleep, the composition containing a fish roe lipid preparation and a diacyl glyceryl ether.

Description

Technical Field

[0001] This patent application claims priority from Japanese Patent Application No. 2021-060752, the entire content of which is incorporated herein by reference. The present disclosure relates to a composition for improving sleep quality.

Background Art

[0002] Sleep functions to rest the brain, organize memories, and recover the body. It has been reported that long-term sleep disorders are closely related to the onset of lifestyle-related diseases such as diabetes, hypertension and ischemic heart disease, as well as the onset of depression. Improving sleep quality is an important issue for maintaining health and quality of life. Factors affecting sleep quality include demographic factors such as age and gender; sociological factors such as late-night lifestyle and employment status; medical factors such as the presence of diseases accompanied by pain or dyspnea and the use of therapeutic drugs having side effects of hypnosis or arousal; temperamental factors, the presence of mental stressors, cognitive perception, and psychological factors such as anxiety; lifestyle habits and circadian rhythms such as meal time, bathing time, moderate exercise, and intake of caffeine and alcohol; and sleep environment such as light, sound and bedding.

[0003] Sleep is divided into REM sleep and non-REM sleep. During REM sleep, rapid eye movements (REMs) occur, which is the origin of the name. Non-REM sleep does not involve rapid eye movements, and is therefore called NREM (Non-Rapid Eye Movement). Non-REM sleep is further divided into stages 1, 2, and 3. Stage 1 non-REM sleep is a light sleep where you can easily wake up if you are called. Stage 2 is a state of sleep where you can receive information through your ears. Stage 3 is called slow-wave sleep or deep sleep, and is a state where both the body and brain are at rest. You will not wake up from minor noises and will only wake up if you are called out to loudly or shaken. Regular repetition of Stage 3 (deep sleep) non-REM sleep and REM sleep is important for sleep quality.

[0004] Non-REM sleep is a type of sleep that allows the brain to rest. During non-REM sleep, the cerebral cortex, which controls perception, voluntary movement, thinking, reasoning, and memory, as well as the sympathetic nervous system, which is active when the body is actively moving, are at rest. Muscle tension is reduced. Also, core body temperature decreases, heat is released from the body to cool the brain, and night sweats are characteristic of this stage. In particular, during stage 3 (deep sleep) of non-REM sleep, the brain consolidates memories as knowledge and stress is relieved.

[0005] REM sleep is a state of sleep characterized by vivid dreams, a blockage of external sensations, and a brain state similar to light sleep. During this time, the brain organizes memories. About an hour after falling asleep, brain waves show a pattern similar to Stage 1 non-REM sleep (light sleep close to wakefulness), with muscle activity decreasing first, followed by the onset of REM sleep. REM sleep is a "primitive sleep" that has developed since the time of cold-blooded animals, maintaining a state of wakefulness in the brain so that we can instinctively respond to external threats even while asleep. During the REM sleep state that occurs after non-REM sleep, the brain may appear to be in a light sleep state, but at the same time, the function of blocking external stimuli is also at work. You are not easily woken up by external stimuli such as noises. As the time to wake up approaches, the duration of REM sleep becomes longer than that of non-REM sleep, and core body temperature rises, preparing the body for wakefulness. Setting an alarm or being woken up during the non-REM sleep phase, which is close to wakefulness, allows for a smoother awakening.

[0006] Treatment options for sleep disorders (insomnia) include drug therapy with sleep-improving medications such as benzodiazepines and antihistamines. These conventional medications are effective in improving sleep disorders by suppressing all brain activity, but they have side effects such as psychiatric symptoms and muscle relaxants. Furthermore, conventional hypnotics such as benzodiazepines enhance γ-aminobutyric acid-A receptors, reducing all brain activity and thus increasing stage 2 sleep while decreasing deep sleep and REM sleep. These changes in sleep structure induce daytime sleepiness and impaired daytime cognitive function.

[0007] It is known that consuming 1000 mg of salmon roe extract oil daily can improve sleep quality (Patent Document 1, Non-Patent Document 1). [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Japanese Patent Publication No. 2010-53054 [Non-patent literature]

[0009] [Non-Patent Document 1] Takeshi Okubo et al.: PC-DHA (DHA-bound phosphatidylcholine) affects REM sleep duration - The influence of dietary environment on sleep -, Journal of the Japanese Society for Sleep Environment, 8, 9-14 (2011) [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] The purpose of this disclosure is to provide a new means of improving sleep quality. [Means for solving the problem]

[0011] This disclosure provides a composition for improving sleep quality, comprising a fish roe lipid preparation and diacylglyceryl ether (DAGE). [Effects of the Invention]

[0012] This disclosure provides new means for improving sleep quality. [Brief explanation of the drawing]

[0013] [Figure 1] The process from the allocation of test foods to the analysis is shown as a test flowchart. [Figure 2] a) shows the proportion of sleep stages in each group before and after consuming the test food. b) shows an example of sleep stages before and after consuming the test food. [Modes for carrying out the invention]

[0014] In this disclosure, when a number is accompanied by the term "approximately," it is intended to include a range of ±10% of that value. For example, "approximately 20" includes "18 to 22." A range of numbers includes all numbers between the two endpoints and the numbers at both endpoints. The "approximately" in relation to a range applies to both endpoints of that range. Therefore, for example, "approximately 20 to 30" includes "18 to 33."

[0015] Unless otherwise specified, terms used in this disclosure have the meanings generally understood by those skilled in the art in the fields of organic chemistry, medicine, pharmacy, molecular biology, microbiology, etc. Some definitions of terms used in this disclosure are given below, but these definitions take precedence over general understandings in this disclosure. In this disclosure, when the proportion of a component is expressed in percentage, it is based on weight unless otherwise specified.

[0016] (Method for producing fish roe lipid preparations) Fish roe lipid preparations are prepared, for example, from the roe of salmonid fish. Salmonids include the genera *Salmonella*, *Salmonella*, *Salmonella*, and *Salmonella*, with *Salmonella* or *Salmonella* being more preferred. Examples of fish belonging to the genus Oncorhynchus include chum salmon (Oncorhynchus keta), coho salmon (Oncorhynchus kisutch), pink salmon (Oncorhynchus gorbuscha), cherry salmon (Oncorhynchus masou masou), masu salmon (Oncorhynchus masou masou), Taiwanese salmon (Oncorhynchus masou formosanus), Satsuki salmon (Oncorhynchus masou ishikawae), amago salmon (Oncorhynchus masou ishikawae), Biwa salmon (Oncorhynchus masou rhodurus), rainbow trout (Oncorhynchus mykiss), Chinook salmon (Oncorhynchus tshawytscha), sockeye salmon (Oncorhynchus nerka), kokanee salmon (Oncorhynchus nerka), and kunimasu salmon (Oncorhynchus kawamurae). Examples of fish belonging to the genus Salmo include Atlantic salmon (Salmo salar) and brown trout (Salmo trutta). In one embodiment, the fish roe lipid preparation is prepared from the roe of pink salmon (Oncorhynchus gorbuscha).

[0017] In the present disclosure, unless otherwise specifically stated, the term "fish roe" is not limited by the degree of processing. Therefore, in the present disclosure, the term "fish roe lipid preparation" also includes lipid preparations prepared from raw materials such as fish roe extracts, fish roe oil, purified fish roe oil, and dried products of any of the foregoing. In a particularly preferred embodiment, the fish roe lipid preparation is prepared from sujiko, ikura, or processed products of any of the foregoing, for example, sujiko extract, ikura extract, ikura oil, or purified ikura oil.

[0018] Extraction of a fish roe lipid preparation from a raw material that is fish roe or a processed product thereof can be specifically carried out by mixing the raw material with a low-polarity organic solvent. Examples of low-polarity solvents include, but are not limited to, 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. The extraction temperature with the organic solvent is 0 to 90°C, preferably 30 to 70°C. It is known that the phospholipid content in the resulting extract can be increased by adjusting the water content of hydrous ethanol (see Oleoscience, Volume 2, Issue 2, pages 67-74). Extraction of a fish roe lipid preparation from a raw material that is fish roe or a processed product thereof can also be carried out by a supercritical fluid extraction method using carbon dioxide. For example, the fish roe lipid preparation can be that described in WO2021 / 132516, particularly sujiko oil PL40.

[0019] (Phospholipids) In one embodiment, the phospholipid content of the fish egg lipid preparation is increased. Phospholipids refer to lipids containing phosphorus in the form of phosphate esters, and are categorized into glycerophospholipids and sphingophospholipids. Representative glycerophospholipids include phosphatidylcholine (PC), α-glycerophosphocholine (α-GPC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), 1-lysophosphatidylcholine (LPC-1), 2-lysophosphatidylcholine (LPC-2), and 2-lysophosphatidylethanolamine (LPE-2); representative sphingophospholipids include 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, more preferably about 37.5% or more, and still more preferably about 40% or more. The upper limit of the phospholipid content in the fish egg lipid preparation is not particularly limited. However, higher phospholipid content leads to increased viscosity, and when the viscosity exceeds a certain level, it becomes difficult to handle during production, so the content is, for example, about 50% or less.

[0020] In one embodiment, the fish egg lipid preparation comprises at least one selected from the group consisting of α-GPC, SM and DHSM, and in a preferred embodiment, comprises SM and DHSM. The contents of α-GPC, SM and DHSM are not particularly limited. The content of α-GPC in the fish egg lipid preparation is, for example, about 0.050% to 0.60%. The content of SM in the fish egg lipid preparation is, for example, about 0.8% to 2.3%. The content of DHSM in the fish egg lipid preparation is, for example, about 0.050% to 0.40%.

[0021] The phospholipids other than α-GPC, SM, and DHSM contained in the fish roe lipid preparation are not particularly limited, but it is preferable that they contain a large amount of PC, PE, PI, LPC-2, etc. The PC content in the fish roe lipid preparation is, for example, about 24-45%, preferably about 26-43%, more preferably about 28-41%, and even more preferably about 30-39%. The PE content in the fish roe lipid preparation is, for example, about 0.90-2.3%. The PI content in the fish roe lipid preparation is, for example, about 0.80-1.8%. The LPC-2 content in the fish roe lipid preparation is, for example, about 0.60-3.0%.

[0022] In fish roe lipid preparations, PC is present in relatively high amounts as well as in phospholipids. The PC content in phospholipids is, for example, about 74% or more, preferably about 80% or more. In fish roe lipid preparations with a higher phospholipid content, the PC content in phospholipids is even higher. Therefore, in a preferred embodiment, the phospholipid content in the fish roe lipid preparation is about 35% or more, more preferably about 40% or more, and in this case, the PC content in phospholipids is about 74% or more, preferably about 80% or more.

[0023] (Fatty acid composition) The composition ratio of DHA in the constituent fatty acids of the lipids in fish roe lipid preparations is relatively high. Fish roe is known to contain DHA in the form of phospholipids or triglycerides (TG). Specifically, the composition ratio of DHA in the constituent fatty acids of the lipids in fish roe lipid preparations is, for example, about 15% or more, preferably about 18% or more, more preferably about 22% or more, and even more preferably about 24% or more. There is no particular upper limit to the composition ratio of DHA in the constituent fatty acids of the lipids in fish roe lipid preparations, but for example, it is about 46% or less, preferably about 40% or less, more preferably about 35% or less, and even more preferably about 30% or less. In this disclosure, when the composition ratio of a specific fatty acid in the constituent fatty acids of a lipid is expressed in %, unless otherwise specified, it is based on the area of ​​the chart obtained by gas chromatography analysis of the fatty acid composition.

[0024] The composition ratio of EPA to the constituent fatty acids of the lipids in the fish roe lipid preparation is relatively low, for example, about 25% or less, preferably about 23% or less, more preferably about 21% or less, and even more preferably about 19% or less. The lower limit of the composition ratio of EPA to the constituent fatty acids of the lipids in the fish roe lipid preparation is not particularly limited, but for example it may be about 5.0% or more, may be about 6.0% or more, preferably about 8.0% or more, more preferably about 10% or more, and even more preferably about 11% or more or about 12% or more.

[0025] Fish roe lipid preparations contain the following constituent fatty acids: myristic acid (C14:0), palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1, n9c), eicosenoic acid (C20:1), and docosapentaenoic acid (DPA) (C22:5). Other constituent fatty acids may 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), alpha-linolenic acid (C18:3n-3), gamma-linolenic acid (C18:3n-6), eicosadienoic acid (C20:2n-6), eicosatrienoic acid (C20:3n-6), arachidonic acid (C20:4n-6), docosadenoic acid (C22:2), etc.

[0026] Fish roe lipid preparations contain a large amount of phospholipids to which DHA is bound. Specifically, the weight of DHA per 100g of fish roe lipid preparation is, for example, about 10g or more, preferably about 12g or more, more preferably about 14g or more, and even more preferably about 15g or more. There is no particular upper limit to the weight of DHA per 100g of fish roe lipid preparation, but for example, it is about 30g or less, preferably about 25g or less, more preferably about 22g or less, and even more preferably about 20g or less.

[0027] The weight of EPA per 100g of fish roe lipid preparation is, for example, about 5.0g or more, and more preferably about 6.0g or more. There is no particular upper limit to the weight of EPA per 100g of fish roe lipid preparation, but for example it is about 20g or less, and preferably about 15g or less.

[0028] One of the DHA-binding phospholipids contained in fish roe lipid preparations is palmitoyldocosahexaenoylphosphatidylcholine (PDPC). PDPC refers to 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).

[0029] Another DHA-binding phospholipid contained in fish roe lipid preparations is stearoyl docosahexaenoyl phosphatidylcholine (SDPC). SDPC is phosphatidylcholine (40:6) in which one of the C-1 and C-2 acyl groups is stearoyl (18:0) and the other is docosahexaenoyl (22:6).

[0030] One type of phospholipid contained in fish roe lipid preparations is an ether-type phospholipid. An ether-type phospholipid is a phospholipid that has a hydrocarbon chain linked by an ether bond. In particular, a glycerophospholipid that has a hydrocarbon chain linked by a vinyl ether bond at the sn-1 position and a fatty acid bonded at the sn-2 position is called a plasmalogen.

[0031] In one embodiment, the fish roe lipid preparation includes one selected from the group consisting of DHA-bound ether-type phospholipids and EPA-bound ether-type phospholipids.

[0032] (Non-lipid components) Fish roe lipid preparations may contain components other than lipids. These non-lipid components include proteins and inorganic substances such as sodium, potassium, and phosphorus. Lipids are biologically derived substances soluble in nonpolar solvents, and include simple lipids, complex lipids, and derived lipids (fatty acids, terpenoids, steroids, carotenoids, etc.). The content of components other than lipids in the fish roe lipid preparation is, for example, 10.0% or less, preferably 8.0% or less, more preferably 7.5% or less, and even more preferably 7.0% or less.

[0033] The fish roe lipid preparation may contain astaxanthin. The astaxanthin content per 100g of the fish roe lipid preparation is, for example, about 0.7mg or more, preferably about 1.0mg or more, more preferably about 1.2mg or more, and even more preferably about 1.5mg or more. There is no particular upper limit to the astaxanthin content per 100g of the fish roe lipid preparation, but for example, it is about 23mg or less, preferably about 20mg or less, more preferably about 10mg or less, and even more preferably about 5.0mg or less.

[0034] (DAGE) DAGE may be present in deep-sea shark liver oil. Deep-sea shark liver oil is an oil extracted from the livers of sharks that can inhabit the deep sea, such as dogfish, night heron, and horned dogfish. Liver oil can be extracted by conventionally known methods. For example, the shark liver can be removed, finely crushed in a crushing device, left to stand for 1 to 4 days to separate the oil from the solids, and the oil can be extracted to obtain liver oil. The liver oil may be further filtered to remove fine solids and refined. Alternatively, commercially available deep-sea shark liver oil can be used. Squalene may be extracted from deep-sea shark liver oil, and triglycerides containing DAGE may be extracted from the remaining components.

[0035] (Application) As shown in the embodiments described below, the compositions of this disclosure improve sleep quality. As used in this disclosure, “improve sleep quality” means at least one of the following: improving the balance between deep sleep and REM sleep, increasing the proportion of deep sleep, increasing the proportion of REM sleep, decreasing non-REM sleep stage 1, decreasing the proportion of wakefulness, and improving sleep efficiency. Sleep stages during sleep are divided into wakefulness, REM sleep, and non-REM sleep stages 1-3, which can be determined by electroencephalography (EEG). Non-REM sleep stages 1 and 2 are light non-REM sleep, and non-REM sleep stage 3 is deep sleep. The time or proportion of wakefulness, REM sleep, and non-REM sleep stages 1-3 is the total time or proportion of each sleep stage during sleep (from going to bed until waking up). Sleep efficiency means the proportion of time spent sleeping during sleep (the sum of REM sleep and non-REM sleep stages 1-3). Although not limited by theory, the compositions of this disclosure improve sleep quality by regulating sleep rhythms with active ingredients derived from food-safe materials. Therefore, unlike conventional sleep aids, they are thought to have fewer side effects due to the suppression of all brain functions.

[0036] In one embodiment, the improvement in sleep quality is at least one selected from an improved balance between deep sleep and REM sleep, an increase in the proportion of deep sleep, an increase in the proportion of REM sleep, and a decrease in non-REM sleep stage 1. In another embodiment, the improvement in sleep quality is an improved balance between deep sleep and REM sleep. In yet another embodiment, the improvement in sleep quality is an increase in the proportion of deep sleep, an increase in the proportion of REM sleep, and a decrease in non-REM sleep stage 1. While not limited by theory, these improvements in sleep quality are thought to be due to the synergistic effect of the fish roe lipid preparation and DAGE.

[0037] The subjects are typically human. Subjects may or may not have sleep disorders. Subjects with sleep disorders include those who experience insomnia in their daily lives and those who have been diagnosed with a sleep disorder. For example, a subject with a Pittsburgh Sleep Quality Index (PSQI, PSQI-J) score of 6 or higher may be diagnosed with a sleep disorder.

[0038] The compositions of this disclosure may also improve anxiety, tension, depressed mood, depression, low spirits, vitality, overall mood state, and daytime sleepiness in subjects experiencing reduced vitality or energy in their daily lives. In one embodiment, subjects experiencing reduced vitality or energy in their daily lives are those with a VA of less than 50 as assessed by POMS2 (Profile of Mood States 2nd Edition). Accordingly, in one embodiment, a composition comprising a fish roe lipid preparation is provided for improving at least one of anxiety, tension, depressed mood, depression, low spirits, vitality, overall mood state, and daytime sleepiness in subjects experiencing reduced vitality or energy in their daily lives. In one embodiment, anxiety, tension, depressed mood, vitality, energy, and daytime sleepiness may be improved in subjects experiencing reduced vitality or energy in their daily lives.

[0039] The compositions of this disclosure may be pharmaceutical compositions. The method of administration of the pharmaceutical compositions is not particularly limited, but is preferably oral, transdermal, or nasal, and more preferably oral. Dosage forms for oral administration include granules, fine granules, powders, coated tablets, tablets, powders, soft capsules, hard capsules, microcapsules, chewable tablets, liquids, suspensions, and emulsions. Dosage forms for transdermal administration include patches, tapes, sprays, lotions, creams, ointments, liquids, emulsions, and suspensions. Dosage forms for nasal administration include nasal drops and nasal sprays.

[0040] These dosage forms are manufactured by formulation using conventional methods. Furthermore, various pharmaceutically acceptable formulation substances may be added as needed for the formulation. The formulation substances can be appropriately selected depending on the dosage form of the formulation, but examples include buffering agents, surfactants, stabilizers, preservatives, excipients, diluents, additives, disintegrants, binders, coatings, lubricants, flavoring agents, sweeteners, solubilizers, etc.

[0041] Furthermore, the compositions of this disclosure may be food compositions. Such food compositions may be in the form of general processed foods. For example, they may be solid foods, or foods that are consumed as liquids such as beverages, drinks, powdered drinks, soups, etc. Specifically, they may be consumed as juices, confectionery, jellies, tablets, dressings, seasonings, etc.

[0042] Furthermore, such foods may be offered as functional foods or dietary supplements. Functional foods include, for example, foods for specified health uses, foods with nutritional function claims, and foods with functional claims. Functional foods may be labeled as being used for purposes such as improving sleep quality. Labeling may be done directly on the packaging, containers, labels, tags, and accompanying documents of the product, or indirectly through advertising and promotional activities. Dietary supplements include, for example, nutritional supplements and health supplements.

[0043] The fish roe lipid preparation and DAGE may be contained in one composition or in separate compositions. If the fish roe lipid preparation and DAGE are contained in separate compositions, both compositions may be ingested simultaneously, or one composition may be ingested with a delay, as long as the desired effect is achieved.

[0044] The amount of the composition disclosed herein can be such that approximately 100 mg to 10,000 mg of the fish roe lipid preparation is ingested per day, preferably approximately 300 mg to 5,000 mg, more preferably approximately 500 mg to 2,500 mg, and even more preferably approximately 700 mg to 1,500 mg, for example, approximately 1,000 mg.

[0045] Alternatively, the intake of the composition of this disclosure may be an amount that provides approximately 20 mg or more of DHA per day, preferably approximately 50 mg or more, more preferably approximately 100 mg or more, and even more preferably approximately 150 mg or more. Furthermore, the intake of the composition of this disclosure may be an amount that provides approximately 2000 mg or less of DHA per day, preferably approximately 1000 mg or less, more preferably approximately 750 mg or less, even more preferably approximately 500 mg or less, and particularly preferably approximately 200 mg or less. In one embodiment, the intake of the composition of this disclosure is an amount that provides approximately 150 mg (e.g., 135 mg to 165 mg) or approximately 160 mg (e.g., 144 mg to 176 mg) of DHA per day.

[0046] Furthermore, the intake of the composition of this disclosure can be an amount in which approximately 10 mg or more of EPA is ingested per day, preferably approximately 30 mg or more, more preferably approximately 50 mg or more, and even more preferably approximately 60 mg or more. Alternatively, the intake of the composition of this disclosure can be an amount in which approximately 500 mg or less of EPA is ingested per day, preferably approximately 300 mg or less, and more preferably approximately 150 mg or less. In one embodiment, the intake of the composition of this disclosure is an amount in which approximately 60 mg (e.g., 54 mg to 66 mg), approximately 100 mg (e.g., 90 mg to 110 mg), or approximately 110 mg (e.g., 99 mg to 121 mg) of EPA is ingested per day.

[0047] The intake amount of the composition disclosed herein can be such that approximately 100 mg or more of DAGE is ingested per day, preferably approximately 180 mg or more, and more preferably approximately 360 mg or more. Alternatively, the intake amount of the composition disclosed herein can be such that approximately 1800 mg or less of DAGE is ingested per day, preferably approximately 720 mg or less. In one embodiment, the intake amount of the composition disclosed herein is such that approximately 360 mg of DAGE (for example, 324 mg to 396 mg) is ingested per day.

[0048] Each component in the daily intake may be contained in a single composition, or it may be dispersed among multiple compositions consumed daily. For example, each component in the daily intake of a composition may be dispersed among 2 to 15, preferably 3 to 10, capsules, etc., consumed daily, such as 6 capsules.

[0049] The compositions of this disclosure may be taken in a single or multiple dose. If taken in multiple doses, for example, once to several times a day, for example, once, twice, or three times a day, daily or every few days, for example, every day, every two, every three, or every seven days. The duration of intake is not limited and may be taken continuously for, for example, one week or more, preferably one month or more, more preferably two months or more, and particularly preferably three months or more, until sleep quality improves. There may be periods of interruption in intake. In one embodiment, the compositions of this disclosure are taken daily for at least 12 weeks.

[0050] The compositions of this disclosure can be used alone or in combination with one or more further components. “Combined use” of components means not only the use of a dosage form containing all components and the use of combinations of dosage forms containing each component separately, but also the simultaneous intake of each component or the intake of one component with a delay, as long as they are used for the same purpose. It is also possible to use two or more further components in combination. For example, a composition may be used containing one or more further components in addition to the fish roe oil preparation and DAGE.

[0051] Astaxanthin is a suitable ingredient for concomitant use. The daily intake of astaxanthin may be about 50 μg or more, preferably about 100 μg or more, more preferably about 200 μg or more, and may also be about 1000 μg or less, preferably about 400 μg or less, for example, about 200 μg. Astaxanthin may be contained in fish roe lipid compositions, but astaxanthin from other sources may also be used. For example, astaxanthin extracted from natural products such as krill, salmon, trout, Adonis amurensis, red yeast, and Haematococcus algae, or synthetic products can be used, preferably astaxanthin contained in Haematococcus algae pigment. The extraction solvent for obtaining astaxanthin from natural products may be an aqueous solvent or an organic solvent. Examples of organic solvents include methanol, ethanol, isopropanol, acetone, 1,3-butylene glycol, ethylene glycol, propylene glycol, glycerin, ethyl acetate, ether, and hexane. Furthermore, supercritical carbon dioxide and other solvents can also be used. These solvents may be used individually or in mixtures of two or more. In one embodiment, astaxanthin has the effect of protecting and stabilizing DHA and EPA from peroxidation.

[0052] Examples of Haematococcus algae include Haematococcus pluvialis, Haematococcus lacustris, Haematococcus capensis, Haematococcus droebakensis, and Haematococcus zimbabwiensis. Commercially available Haematococcus algae extracts can also be used, such as ASTOTS-S, ASTOTS-5O, and ASTOTS-10O from Fujifilm Corporation; Astareal Oil 50F and 5F from Fuji Chemical Industries; Astaxanthin-5C and 20C from Oryza Oil & Fat Chemical Corporation; Astaxanthin 5% Oil from Bioactives Japan; and Astabio from Biogenics. (登録商標)Examples include AR1 and AR5. As for krill-derived astaxanthin, examples include Astax-S manufactured by Marine Daioh Co., Ltd.

[0053] In one embodiment, a sleep quality improver is provided, comprising a fish roe lipid preparation and DAGE. In one embodiment, a method for improving sleep quality is provided, which includes administering a fish roe lipid preparation and DAGE to a subject who requires improvement in sleep quality. In one embodiment, a combination of a fish roe lipid preparation and DAGE is provided to improve sleep quality. In one embodiment, the use of fish roe lipid preparations and DAGE to improve sleep quality is provided. In one embodiment, the use of fish roe lipid preparations and DAGE in the manufacture of a composition for improving sleep quality is provided.

[0054] For example, the following embodiments are provided. [1] A composition for improving sleep quality, comprising a fish roe lipid preparation and DAGE. [2] A composition for improving sleep quality as described in paragraph 1, comprising a fish roe lipid preparation containing about 30% or more (preferably about 40% or more) phospholipids. [3] The composition according to paragraph 1 or 2, wherein the fish roe lipid preparation contains DHA-binding phospholipids, and the composition ratio of DHA to the constituent fatty acids of the lipid is approximately 15% or more. [4] The composition according to any one of the first to third paragraphs, wherein the fish roe lipid preparation comprises at least one selected from the group consisting of α-GPC, SM, and DHSM (preferably the group consisting of SM and DHSM). [5] A composition according to any of paragraphs 2 to 4, wherein the phospholipids contain approximately 74% or more PC. [6] The composition according to any one of paragraphs 1 to 5, wherein the DHA composition ratio in the lipid constituent fatty acids of the fish roe lipid preparation is about 15% or more, and the EPA composition ratio is about 5 to 25%. [7] The composition according to paragraph 1, wherein DAGE is derived from deep-sea shark liver oil. [8] The composition according to any one of the items 1 to 7, further comprising astaxanthin. [9] The composition according to paragraph 8, wherein the astaxanthin is derived from Haematococcus algae pigment.

[10] The composition according to any one of paragraphs 1 to 9, which is prepared so that a daily intake of approximately 100 mg to 750 mg (preferably approximately 150 mg to 750 mg, more preferably approximately 150 mg to 200 mg) of DHA is ingested.

[11] A composition according to any one of paragraphs 1 to 10, which is prepared to provide approximately 160 mg (or 144 mg to 176 mg) of DHA per day.

[12] The composition according to any one of paragraphs 1 to 11, which is prepared so that a daily intake of approximately 180 mg to 1800 mg (preferably approximately 360 mg to 1800 mg, more preferably approximately 360 mg to 720 mg) of DAGE is ingested.

[13] A composition according to any one of paragraphs 1 to 12, which is prepared so that approximately 360 mg of DAGE (or 324 mg to 396 mg) is ingested as a daily intake.

[14] A composition according to any one of paragraphs 1 to 13, which is prepared so that a daily intake of approximately 100 mg to 750 mg (preferably approximately 150 mg to 750 mg, more preferably approximately 150 mg to 200 mg) of DHA, approximately 30 mg to 300 mg (preferably approximately 60 mg to 300 mg, more preferably approximately 60 mg to 150 mg) of eicosapentaenoic acid (EPA), and approximately 180 mg to 1800 mg (preferably approximately 360 mg to 1800 mg, more preferably approximately 360 mg to 720 mg) of DAGE is ingested.

[15] The composition according to item 14 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.

[16] The composition according to paragraph 14, which is prepared so that a daily intake of approximately 160 mg (or 144 mg to 176 mg) of DHA, approximately 100 to 110 mg (preferably approximately 100 mg (or 90 to 110 mg), or approximately 110 mg (or 99 mg to 121 mg)) of EPA, and approximately 360 mg (or 324 mg to 396 mg) of DAGE is ingested.

[17] The composition according to paragraph 14 or 16, which is prepared to provide a daily intake of approximately 160 mg (or 144 mg to 176 mg) of DHA, approximately 100 mg (or 90 to 110 mg) of EPA, and approximately 360 mg (or 324 mg to 396 mg) of DAGE.

[18] The composition according to paragraph 16 or 17, further prepared to provide approximately 200 μg (or 180 μg to 220 μg) of astaxanthin.

[19] The composition according to paragraph 14, which is prepared to provide a daily intake of approximately 150 mg (or 135 mg to 165 mg) of DHA, approximately 60 mg (or 54 mg to 66 mg) of EPA, and approximately 360 mg (or 324 mg to 396 mg) of DAGE.

[20] The composition according to paragraph 19, further prepared to provide approximately 200 μg (or 180 μg to 220 μg) of astaxanthin.

[21] The composition according to any one of the claims 1 to 20, wherein the fish roe lipid preparation is derived from pink salmon.

[22] A composition according to any one of the paragraphs 1 to 21, which is taken on a daily basis for at least 12 weeks.

[23] The composition according to any of paragraphs 1 to 22, wherein the improvement in sleep quality includes one or more (preferably two or more) selected from an improved balance between deep sleep and REM sleep, an increase in the proportion of deep sleep, an increase in the proportion of REM sleep, a decrease in non-REM sleep stage 1, a decrease in the proportion of wakefulness, and an improvement in sleep efficiency.

[24] The composition according to any one of paragraphs 1 to 23, wherein the improvement in sleep quality includes one or more (preferably two or more) selected from an improved balance between deep sleep and REM sleep, an increase in the proportion of deep sleep, an increase in the proportion of REM sleep, and a decrease in non-REM sleep stage 1.

[25] The composition according to any one of paragraphs 1 to 24, wherein the improvement in sleep quality is an improvement in the balance between deep sleep and REM sleep.

[26] The composition according to any one of paragraphs 1 to 24, wherein the improvement in sleep quality is an increase in the proportion of deep sleep, an increase in the proportion of REM sleep, and a decrease in non-REM sleep stage 1.

[27] A composition according to any one of paragraphs 1 to 26, for use in subjects with sleep disorders.

[28] Furthermore, a composition according to any one of paragraphs 1 to 27 for improving at least one of anxiety, tension, depressed mood, depression, low spirits, vitality, energy, overall mood state and daytime sleepiness in a subject who is experiencing reduced vitality or energy in daily life.

[29] A composition comprising a fish roe lipid preparation and DAGE for improving at least one of anxiety, tension, depressed mood, depression, low spirits, vitality, energy, overall mood state and daytime sleepiness in subjects who have reduced vitality or energy in their daily lives.

[30] A pharmaceutical composition, as described in any of paragraphs 1 to 29.

[31] A food composition, as described in any of paragraphs 1 to 29.

[32] A sleep quality improver comprising fish roe lipid preparations and DAGE.

[33] A method for improving sleep quality, comprising administering a fish roe lipid preparation and DAGE to subjects in need of improved sleep quality.

[34] A combination of fish roe lipid preparation and DAGE used to improve sleep quality.

[35] Use of fish roe lipid preparations and DAGE to improve sleep quality.

[36] Use of fish roe lipid preparations and DAGE in the manufacture of compositions for improving sleep quality.

[0055] All references cited herein are included as part of this specification upon proper attribution. The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Furthermore, the above description is non-limiting, and the present invention is defined in the appended claims, and various modifications are possible without departing from the technical spirit thereof. [Examples]

[0056] <Preparation of fish roe lipids from salmon roe> Fish roe lipid preparations were prepared according to the method described in WO2021 / 132516. Specifically, 15 kg of freeze-ground fresh salmon roe (Oncorhynchus gorbuscha) was extracted with aqueous ethanol (150 L), and the residue was filtered off. The residue was returned to the extractor, and ethanol (75 L) was added again for extraction. The resulting filtrate was removed under reduced pressure to obtain a composition (40 PL) containing approximately 40% phospholipids in the red oily substance (Tables 1 and 2).

[0057] [Table 1] *The quantitative value represents the amount of constituent fatty acids in total lipids.

[0058] [Table 2]

[0059] <Soft capsule manufacturing> Deep-sea shark liver oil (DAGE) and Haematococcus algae pigment (astaxanthin) were added to the aforementioned 40PL to produce soft capsules (ONO-SR / AST-DA) with the following composition (Table 3). The amounts of phospholipid classes contained in the soft capsules are shown in Table 4. [Table 3] *DAGE: Each capsule contains 133.66 mg of deep-sea shark liver oil so that the daily dose (6 capsules) contains 360 mg of DAGE. *Astaxanthin: Each capsule contains 0.67 mg of Haematococcus algae pigment so that the daily dose (6 capsules) contains 200 μg of astaxanthin. *The gelatin is bovine gelatin.

[0060] [Table 4]

[0061] <Clinical Trials> Subjects and Methods 1. Subjects Pre-examination was conducted on potential subjects, and those who met the selection criteria and did not meet the exclusion criteria underwent pre-intake examinations, including sleep electroencephalography, and qualified individuals were selected as subjects. The selection criteria were (1) healthy men and women aged 20 to 64 years, and (2) a score of 6 or higher on the Pittsburgh Sleep Quality Index (Japanese version) at the time of pre-examination. The exclusion criteria are: (1) individuals receiving drug therapy, dietary guidance, or exercise therapy; (2) individuals receiving treatment for sleep, stress, or fatigue; (3) individuals with or with a history of diseases such as diabetes, liver disease, kidney disease, heart disease, diseases affecting the secretion of adrenocortical hormones, or other metabolic diseases; (4) individuals with a history of mental illness, chronic fatigue syndrome, or insomnia; (5) individuals who have been diagnosed with or are suspected of having sleep apnea syndrome; (6) individuals experiencing nocturia (more than twice a night); (7) individuals who may experience skin damage from electrodes used for electroencephalography; (8) individuals with diseases requiring continuous medication, individuals with serious diseases requiring medication, or individuals with a history of such diseases; (9) individuals who regularly use pharmaceuticals, quasi-drugs, functional foods, or health foods that claim to improve fatigue, stress, or sleep; (10) (1) Individuals who have a habit of consuming foods fortified with the active ingredient; (11) Individuals engaged in day and night shift work or physically demanding work such as carrying heavy objects; (12) Individuals deemed unsuitable as subjects based on their responses to a lifestyle questionnaire; (13) Individuals who have plans to travel abroad or go on business trips abroad during the study period, or who have plans to go on long-term domestic business trips or domestic trips lasting one week or more; (14) Individuals who have had abnormalities in clinical test values ​​or cardiopulmonary function and were deemed unsuitable for participation in the study; (15) Individuals who are at risk of developing an allergic reaction in connection with the study; (16) Individuals whose physical measurements, physical examination values, and clinical test values ​​before the start of intake are significantly outside the normal range; (17) Individuals who have participated in other clinical trials within the past month; (18) Individuals who plan to become pregnant or breastfeed during the study period; (19) Others deemed unsuitable as subjects by the principal investigator.

[0062] 2. Test Foods The test food was a soft capsule "ONO-SR / AST-DA" (Ono Pharmaceutical Co., Ltd.) containing 1g of salmon roe oil (40PL) (150mg or more of DHA, 60mg or more of EPA), 200μg or more of astaxanthin, and 360mg or more of deep-sea shark liver oil-derived DAGE per daily intake (1 bag, 6 capsules). The placebo was prepared by adding safflower oil instead of the active ingredients, making it indistinguishable from the test food in appearance.

[0063] 3. Test Method The study was a randomized, double-blind, placebo-controlled, parallel-group comparative study. The study schedule is shown in Table 5. An individual not involved in the study created the allocation table using random numbers, assigned allocation numbers to the test food, and performed the allocation. The allocation table was sealed and stored in an airtight container until the analysis participants and data were finalized and was not opened. The test food was administered once a day (6 tablets) with water or lukewarm water, without chewing. The intake period was 12 weeks. During the study period, participants were instructed to maintain their lifestyle habits, including alcohol consumption, diet, and sleep, as much as possible from before the study; to limit excessive exercise that deviated significantly from their daily routine; to restrict dieting or overeating; to refrain from using new health foods; and to refrain from stress-relieving activities that exceeded their daily routine. Furthermore, participants were instructed to abstain from alcohol during the sleep electroencephalogram (EEG) measurement period, to avoid taking any medications as much as possible, to refrain from consuming caffeinated beverages such as coffee, black tea, green tea, oolong tea, or health drinks after dinner, to refrain from sleeping outside of bedtime (such as napping), and to refrain from other activities (such as reading or using a mobile phone) after the EEG measurement began.

[0064] [Table 5]

[0065] 4. Evaluation Items The effectiveness was evaluated using sleep electroencephalogram (EEG) analysis and the Pittsburgh Sleep Quality Index (Japanese version) (Doi Y, Minowa M, Uchiyama M, Okawa M, Kim K, Shibui K, Kamei Y. Psychometric assessment of subjective sleep quality using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J) in psychiatric disordered and control subjects. Psychiatry Res 2000; 97 (2-3):165-172, Yuriko Doi, Masumi Minowa, Kyoko Okawa, Makoto Uchiyama: Development of the Japanese version of the Pittsburgh Sleep Quality Index. Psychiatry Therapeutics 1998; 13 (6); 755-769).

[0066] Sleep electroencephalogram (EEG) measurements were taken using Sleepwell's "SleepScope" device, measuring EEGs over five weekdays immediately prior to the examination. The average data for the three days was then used (in principle, the three days from Tuesday to Thursday were selected, but priority was given to nights where the EEG data obtained was consistent with the participant's usual lifestyle as recorded in their sleep diary, and where the validity rate of the acquired EEG data was 80% or higher).

[0067] Adverse events were evaluated for safety. Body measurements included weight and BMI. Physical examinations included systolic and diastolic blood pressure and pulse rate. Fasting clinical tests included hematological tests (white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count), blood biochemistry tests (total protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, ALP, AST, ALT, LD, γ-GT, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, urea nitrogen, creatinine, uric acid, sodium, potassium, chloride, blood glucose, HbA1c (pre-test only)), urinalysis (protein qualitative, glucose qualitative, occult blood test), and infectious disease tests (HCV (pre-test only), HBV (pre-test only)). Catecholamine levels were also measured.

[0068] 5.Analysis method Subject characteristics were assessed using a chi-squared test for sex and a two-sample t-test for other items. Sleep electroencephalogram analysis, POMS2 adult short version, s-IgA secretion rate, and changes from baseline to pre-ingestion levels at each time point after ingestion of the International Physical Activity Questionnaire were evaluated for the test food intake group compared to the placebo intake group using a two-sample t-test. Test values ​​for the Pittsburgh Sleep Quality Index (Japanese version) and the Athens Insomnia Scale at each time point after ingestion were evaluated using the Mann-Whitney U test.

[0069] result 1. Subjects Figure 1 shows a flowchart of the study, illustrating the process from subject selection and allocation of test foods to analysis. Of the 243 participants in the pre-examination, 122 met the selection criteria and did not violate the exclusion criteria. Pre-intake testing was then conducted, and 80 participants were selected. Table 6 shows the subject characteristics. No significant differences were observed between the groups.

[0070] [Table 6]

[0071] In some subjects, physical measurements or clinical test values ​​were outside the normal range. However, after the principal investigator confirmed that there were no issues with their participation in the study, they were included in the study. Of the 80 participants, two dropped out of their own free will. As a result, 78 participants completed the prescribed trial schedule and content. Of the 78 participants who completed the trial, four were excluded from the efficacy analysis in the review of participants conducted before opening the allocation sheets, due to violations of the exclusion criteria for efficacy analysis. In addition, two participants with missing sleep electroencephalogram (EEG) data at week 12 and one participant who experienced toothache at week 12 were excluded from the sleep EEG analysis.

[0072] 2. Evaluation of effectiveness The results of the sleep electroencephalogram (EEG) analysis are shown in Tables 7 and 8. The total duration of non-REM sleep 1 and the change in the second sleep cycle at week 12 were significantly smaller in the group ingesting the test food compared to the placebo group. The change in the proportion of non-REM sleep 3 and REM sleep stages at week 12 was significantly larger in the group ingesting the test food compared to the placebo group. Furthermore, since there was an imbalance in the pre-ingestion values ​​for the proportion of each non-REM sleep 1 stage between the groups, an analysis of covariance was performed on the values ​​at week 12, and the values ​​in the group ingesting the test food were significantly smaller compared to the placebo group. No significant differences were observed in other efficacy evaluation items.

[0073] [Table 7]

[0074] [Table 8-1]

[0075] [Table 8-2]

[0076] 3. Subgroup Analysis Subgroup analysis was performed on the POMS2 Adult Short Version, dividing participants into two groups: those with a pre-ingestion vitality / energy (VA) score of 50 or higher and those with a pre-ingestion score of less than 50. In the group with a VA of less than 50, daytime wakefulness difficulty on the Pittsburgh Sleep Quality Index and depression / depression (DD), tension / anxiety (TA), vitality / energy (VA), and overall mood state (TMD) on the POMS2 Adult Short Version were significantly improved in the group that consumed the test food compared to the placebo group (Tables 9 and 10).

[0077] [Table 9]

[0078] [Table 10]

[0079] 4. Safety Evaluation Adverse events occurred in 11 individuals (14 events) in the group that consumed the test food, and in 13 individuals (18 events) in the placebo group. The principal investigator determined that none of the adverse events were related to the test food. Significant changes were observed in some anthropometric measurements, physical examination values, and clinical laboratory values ​​at various time points after intake compared to pre-intake values, but all were minor changes within the normal range, and the principal investigator determined that there were no clinical problems.

[0080] Consideration This study aimed to investigate the effect of ONO-SR / AST-DA on improving sleep quality. A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted in which men and women aged 20 to 64 who reported experiencing sleep deprivation and stress in their daily lives were given either ONO-SR / AST-DA or a placebo (6 tablets) per day for 12 weeks.

[0081] As a result, at week 12, the changes were significantly smaller in Group A compared to Group P in terms of the total time of each sleep stage (non-REM sleep 1) and the sleep cycle (second sleep cycle). In addition, the proportion of each sleep stage (non-REM sleep 3) and the proportion of each sleep stage (REM sleep) were significantly larger in Group A compared to Group P.

[0082] Human sleep consists of alternating cycles of REM sleep and non-REM sleep lasting approximately 80-100 minutes. Non-REM sleep is classified into light sleep (stages 1 and 2) and deep sleep (stage 3). It is known that the proportion of each sleep stage decreases with age, while light sleep and awakenings increase (typical sleep stage proportions for a 20-year-old: awakenings 5%, light sleep 55%, deep sleep 20%, REM sleep 25%; typical sleep stage proportions for a 60-year-old: awakenings 15%, light sleep 60%, deep sleep 5%, REM sleep 20%). The sleep stage proportions of the subjects in this study (at the time of allocation) were 10.4% awakenings, 65.8% light sleep, 6.0% deep sleep, and 17.8% REM sleep, which were close to those of elderly individuals. Ingestion of the test food increased the proportion of non-REM sleep stage 3 and REM sleep, bringing the sleep stage proportions closer to those of younger individuals. Figure 2 shows the proportion of sleep stages in each group before and after consuming the test food in this study, as well as an example of sleep stages before and after consuming the test food. Adjusting the proportion of sleep stages to an appropriate level, along with ensuring that non-REM and REM sleep coordinate and alternate at appropriate intervals (maintaining a sleep rhythm), are important factors in improving sleep quality. From the above, it can be expected that the test food has an effect on improving sleep quality.

[0083] Furthermore, to evaluate the subjective effects of consuming the test food, a subgroup analysis was conducted in which subjects were divided into two groups: those with a POMS2 VA (vitality / energy) score of less than 50 and those with a score of 50 or higher. As a result, in the group with a POMS2 VA score of less than 50, daytime wakefulness on the Pittsburgh Sleep Quality Index (PMS2) was significantly improved in group A compared to group P. In addition, DD (depression / dejection), TA (tension / anxiety), VA (vitality / energy), and TMD (overall mood state) on the POMS2 were significantly improved in group A compared to group P.

[0084] Under the conditions of this study, no adverse events suspected to be causally related to ONO-SR / AST-DA were observed, demonstrating the safety of ONO-SR / AST-DA.

[0085] conclusion The results of this study showed that consuming the test food improved sleep quality by increasing the proportion of non-REM sleep (level 3) and REM sleep. Furthermore, the study suggested that consuming the test food improved daytime sleepiness and had an anti-stress effect in individuals with low energy levels.

[0086] <Safety evaluation based on excessive intake tests> 1. Subjects This study aimed to confirm the safety of excessive intake (5 times the normal dose) of the food product "ONO-SR / AST-DA," which contains salmon roe oil, astaxanthin, and refined deep-sea shark liver oil. Since it is desirable to conduct and examine food safety across a wide range of age groups and genders, the number of subjects was set at 20 to ensure an equal representation of men and women from each age group (20s to 60s). Prior to the study, subjects were provided with an informed consent document, the purpose and content of the study were fully explained, and written consent based on the subjects' free will was obtained. Pre-examinations (lifestyle questionnaire, medical interview, physical measurements, physical examination, fasting clinical examination) were conducted on subjects who had given their consent. Based on the results of the pre-examinations, subjects who did not meet the following exclusion criteria were selected.

[0087] Exclusion Criteria: (1) Individuals who regularly use health foods rich in DHA, EPA, astaxanthin, or DAGE; (2) Individuals with serious illnesses such as diabetes, liver disease, kidney disease, or heart disease, or those with a history of such illnesses; (3) Individuals who are at risk of developing an allergic reaction in relation to the study; (4) Individuals with a disease currently under treatment that may affect the study, or a history of chronic or serious illnesses requiring medication; (5) Individuals with a history of drug dependence or alcohol dependence; (6) Individuals deemed unsuitable as subjects based on clinical test values ​​and measurements from pre-examination; (7) Individuals who have participated in other clinical trials within one month of obtaining consent to participate in this study, or who plan to participate in other clinical research after obtaining consent to participate in this study; (8) Individuals who are pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study period; (9) Individuals deemed unsuitable as subjects based on the results of the lifestyle questionnaire; (10) Other individuals deemed unsuitable as subjects by the principal investigator.

[0088] 2. Test Foods The test food was "ONO-SR / AST-DA," which contained 5g of salmon roe oil (750mg DHA, 300mg EPA), 1,000μg of astaxanthin, and refined deep-sea shark liver oil (1,800mg DAGE) per 5 bags (30 capsules).

[0089] 3. Test Method The study was conducted as an open trial. Participants were instructed to take 5 packets (30 tablets) daily with water or lukewarm water without chewing. There was no set time for taking the tablets, and participants were allowed to take them in multiple doses throughout the day. The duration of the study was 4 weeks. During the study period, participants were instructed to maintain their lifestyle habits, including alcohol consumption, diet, and sleep, as much as possible from before the study; to limit excessive exercise that deviated significantly from their daily routine; to limit dieting or overeating; to refrain from starting new exercises; and to not discontinue their existing exercise habits.

[0090] In the second and fourth weeks of ingesting the test food, subjects visited the clinic for a medical interview (checking their physical condition), physical measurements, physical examinations, and fasting clinical tests. Subjects were also instructed to keep a daily log throughout the study period, recording their intake of the test food, changes in their physical condition, mood in daily life, sleep (falling asleep, quality of sleep), and medication use. After the end of the intake period, subjects continued to keep the log for two weeks, and in the second week after the end of intake, various tests were conducted as a follow-up examination.

[0091] 4. Inspection Items and Evaluation Items Through a medical interview, the patient's physical condition and the presence of adverse events were checked. Physical measurements included height (pre-test only), weight, and BMI. Physical examinations included systolic and diastolic blood pressure and pulse rate. Fasting clinical tests included hematological tests (white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count), blood biochemistry tests (total protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, ALP, AST, ALT, LD, γ-GT, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, urea nitrogen, creatinine, uric acid, sodium, potassium, chloride, blood glucose, HbA1c (pre-test only)), and urinalysis (protein qualitative test, glucose qualitative test, occult blood test). Except for items performed only in the pre-test, each test was performed at the time of the pre-test, in the second week of intake, in the fourth week of intake, and in the second week after the end of intake.

[0092] The evaluation items were adverse events, measured values, and laboratory values. Adverse events were defined as subjective symptoms reported in interviews and diaries, as well as abnormal changes in laboratory values. Subjective symptoms and objective findings of adverse events were judged by the principal investigator. For abnormal changes in individual laboratory values ​​(adverse events), the principal investigator made the judgment of adverse events based on the reference values ​​set by the medical institution, with reference to the criteria for determining abnormal changes set by the Japanese Society of Chemotherapy, the Japanese translation of the Common Terminology Criteria for Adverse Events v5.0 (JCOG version) (CTCAE v5.0-JCOG), and the judgment categories of the Japan Society for Human Dock.

[0093] 5.Statistical analysis Measurement values ​​at pre- and post-intake time points were compared using a one-sample t-test. The significance level for the test was set at a two-sided 5%. Statistical analysis was performed using Microsoft Excel.

[0094] result 1. Subject Background Pre-tests were conducted on 48 subjects who provided written consent to participate in the study. Based on the results of the pre-tests, 20 subjects (10 men and 10 women) who met the inclusion criteria and not the exclusion criteria were selected as eligible subjects for the main study. In some subjects, clinical laboratory values ​​exceeded the reference range (test reference values ​​of the clinical laboratory), but in each case, the principal investigator reviewed the subjects individually and, after determining that there were no problems with their participation in the study, they were included in the main study. All 20 subjects started consuming the test food, all completed consuming the test food, and completed the prescribed study schedule and content. Therefore, adverse events, measured values, and laboratory values ​​were evaluated for all 20 subjects as subjects for analysis.

[0095] 2. Adverse Events Seven instances of variability in measured or test values ​​were observed among five subjects. All of these variability was judged not to be abnormal (not an adverse event). The frequency and total number of adverse events were 15 events in 8 out of 20 subjects (40%). All adverse events were mild, and no serious adverse events occurred in this study. Furthermore, no association with the test food was found.

[0096] 3. Measured values ​​and test results While some physical measurements, physical examination values, and clinical test values ​​(hematological tests, blood biochemistry tests) showed significant changes after ingestion compared to before, the supervising physician determined that all of these changes were at a level that did not pose a clinical problem.

[0097] conclusion Based on these results, it was shown that there were no safety concerns when an overdose study was conducted in which participants consumed five times the recommended daily intake of the food product "ONO-SR / AST-DA," which contains salmon roe oil, astaxanthin, and refined deep-sea shark liver oil, for four consecutive weeks. [Industrial applicability]

[0098] This disclosure relates to improving sleep quality and may be used in the medical or food fields.

Claims

1. A composition for improving sleep quality, comprising a fish roe lipid preparation and diacylglyceryl ether (DAGE), wherein the fish roe lipid preparation contains docosahexaenoic acid (DHA)-bound phospholipids, and the composition ratio of DHA to the constituent fatty acids of the lipid is approximately 15% or more.

2. The composition according to claim 1, comprising a fish roe lipid preparation containing approximately 30% or more phospholipids.

3. The composition according to claim 1 or 2, wherein DAGE is derived from deep-sea shark liver oil.

4. The composition according to any one of claims 1 to 3, which is prepared so that approximately 100 mg to 750 mg of DHA is ingested per day.

5. The composition according to any one of claims 1 to 4, which is prepared so that approximately 160 mg of DHA is ingested as a daily intake.

6. The composition according to any one of claims 1 to 3, which is prepared so that a daily intake of approximately 100 mg to 750 mg of DHA, approximately 30 mg to 300 mg of eicosapentaenoic acid (EPA), and approximately 180 mg to 1800 mg of DAGE is ingested.

7. The composition according to claim 6, which is prepared so that approximately 160 mg of DHA, approximately 100 mg of EPA, and approximately 360 mg of DAGE are ingested as a daily intake.

8. A 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, wherein the improvement in sleep quality includes one or more items selected from an improved balance between deep sleep and REM sleep, an increase in the proportion of deep sleep, an increase in the proportion of REM sleep, a decrease in non-REM sleep stage 1, a decrease in the proportion of wakefulness, and an improvement in sleep efficiency.

10. The composition according to any one of claims 1 to 9, wherein the improvement in sleep quality includes one or more items selected from an improved balance between deep sleep and REM sleep, an increase in the proportion of deep sleep, an increase in the proportion of REM sleep, and a decrease in non-REM sleep stage 1.

11. The composition according to any one of claims 1 to 10, wherein the improvement in sleep quality is an improvement in the balance between deep sleep and REM sleep.

12. The composition according to any one of claims 1 to 11, wherein the improvement in sleep quality is an increase in the proportion of deep sleep, an increase in the proportion of REM sleep, and a decrease in non-REM sleep stage 1.

13. A composition comprising a fish roe lipid preparation and DAGE for improving at least one of anxiety, tension, depressed mood, depression, low spirits, vitality, energy, overall mood state, and daytime sleepiness in a subject experiencing decreased vitality or energy in daily life, wherein the fish roe lipid preparation contains docosahexaenoic acid (DHA) bound phospholipids, and the composition ratio of DHA to the constituent fatty acids of the lipid is about 15% or more.

14. A pharmaceutical composition, as described in any one of claims 1 to 13.

15. A food composition, as described in any one of claims 1 to 13.

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