WO2022210856A1 - Composition for improving quality of sleep - Google Patents
Composition for improving quality of sleep Download PDFInfo
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- WO2022210856A1 WO2022210856A1 PCT/JP2022/015891 JP2022015891W WO2022210856A1 WO 2022210856 A1 WO2022210856 A1 WO 2022210856A1 JP 2022015891 W JP2022015891 W JP 2022015891W WO 2022210856 A1 WO2022210856 A1 WO 2022210856A1
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- Prior art keywords
- sleep
- composition
- composition according
- fish egg
- dha
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Definitions
- Sleep has the role of resting the brain, organizing memories, and restoring the body. It has been reported that long-term sleep disorders are closely related to the development of lifestyle-related diseases such as diabetes, hypertension, and ischemic heart disease, as well as the development of depression. This is an important issue in maintaining quality. Factors affecting sleep quality include demographic factors such as age and gender, sociological factors such as night owls and work conditions, the presence or absence of diseases associated with pain and dyspnea, and side effects of hypnosis or awakening.
- Medical factors such as taking therapeutic drugs, temperamental factors, presence of mental stressors, cognitive perceptions, psychological factors such as anxiety, meal times, bathing times, moderate exercise, caffeine and alcohol consumption
- lifestyle habits such as intake, life rhythm, and sleep environment such as light, sound, and bedding.
- Non-REM sleep is divided into REM sleep and non-REM sleep.
- REM sleep rapid eye movements
- NREM Non Rapid Eye Movement because there is no rapid eye movement.
- NREM sleep is further divided into stages 1, 2 and 3.
- Stage 1 non-REM sleep is a light sleep that wakes up as soon as it is called out.
- Stage 2 is a state in which a person is asleep enough to receive information through their ears.
- Stage 3 is called slow-wave sleep or deep sleep, and is a state in which both the body and the brain are at rest. It won't wake up with some noise, and it won't wake up unless you call out loud or shake your body. Regular repetition of non-REM sleep and REM sleep in stage 3 (deep sleep stage) is important for sleep quality.
- NREM sleep is a sleep for the brain to rest, and during NREM sleep, the cerebral cortex that controls perception, voluntary movement, thinking, reasoning, memory, etc., and the sympathetic nerves that work when the body is active are rested. There is Body (muscle) tension is reduced. It is also characterized by a drop in core body temperature and the loss of heat from the body to cool the brain, resulting in night sweats. Especially during non-REM sleep in stage 3 (deep sleep), memory as knowledge is fixed in the brain and stress is removed.
- REM sleep is a sleep in which there are clear dreams, external sensations are blocked, and the brain is in a state similar to light sleep. During this time, the brain consolidates memories. About an hour after falling asleep, the brain waves show a shape similar to stage 1 of non-REM sleep (light sleep close to wakefulness), first muscle movement decreases, and then REMs begin. REM sleep is a ⁇ primitive sleep'' that has been developed since the days of poikilotherms. During REM sleep, which occurs after non-REM sleep, the brain appears to be in light sleep, but at the same time, it also functions to block external stimuli. It is not easy to wake up with external stimuli such as noises.
- the time of REM sleep becomes longer than that of non-REM sleep, and the deep body temperature rises to prepare for awakening. If you set the alarm or wake up at the timing of non-REM sleep, which is close to the awakening state, you will wake up smoothly.
- Treatment methods for sleep disorders include pharmacotherapy with sleep-improving medicines such as benzodiazepines and antihistamines. These conventional pharmaceuticals have the effect of suppressing all brain activity and improving sleep disorders, but have side effects such as psychotic symptoms and muscle relaxant effects. Also, conventional hypnotics such as benzodiazepines potentiate gamma-aminobutyric acid-A receptors and decrease all brain activity, thus increasing stage 2 sleep and decreasing deep and REM sleep. Such changes in sleep structure induce daytime sleepiness and decline in daytime cognitive function.
- Patent Document 1 In order to improve the quality of sleep, it is known to take 1000 mg of salmon roe extract oil per day (Patent Document 1, Non-Patent Document 1).
- PC-DHA DHA-bound phosphatidylcholine
- the purpose of the present disclosure is to provide new means for improving sleep quality.
- compositions for improving sleep quality comprising a fish egg lipid preparation and diacylglyceryl ether (DAGE).
- DAGE diacylglyceryl ether
- the present disclosure provides new means for improving sleep quality.
- test flow chart The process from allocation of test foods to analysis is shown as a test flow chart. a) shows the ratio of sleep stages in each group before and after ingestion of the test food. b) shows an example of sleep stages before and after ingestion of the test food.
- 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.
- Atlantic salmon examples 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.
- the fish egg lipid preparation is prepared from pink salmon (Oncorhynchus gorbuscha) fish eggs.
- 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.
- 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.
- the extraction of the fish egg lipid preparation from the raw material can be carried out by mixing the raw material with a low-polarity organic solvent.
- 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.
- 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.
- 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.
- 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), ⁇ -glycerophosphocholine ( ⁇ -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).
- PC phosphatidylcholine
- ⁇ -GPC phosphatidylethanolamine
- PE phosphatidylinositol
- PI 1-lysophosphatidylcholine
- LPC-2 2- Lysophosphatidylcholine
- LPE-2 2-lysophosphatidylethanolamine
- representatives of sphingolipids are sphingomyelin (SM)
- 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.
- the fish egg lipid preparation contains at least one selected from the group consisting of ⁇ -GPC, SM and DHSM, and in preferred embodiments SM and DHSM.
- the contents of ⁇ -GPC, SM and DHSM are not particularly limited.
- the content of ⁇ -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 ⁇ -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 preferred.
- 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%.
- 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.
- 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.
- 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).
- 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.
- 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).
- 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), ⁇ -linolenic acid (C18:3n-3), ⁇ -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.
- 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.
- 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.
- 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.
- PDPC palmito docosahexaenoyl phosphatidylcholine
- 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).
- SDPC stearoyl docosahexaenoyl phosphatidylcholine
- 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.
- 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.
- 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.
- 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.
- DAGE DAGE can be found in deep sea shark liver oil.
- Deep-sea shark liver oil is oil extracted from the livers of sharks that can live in the deep sea, such as the yellow shark, the stingray shark, and the paddlefish shark.
- Liver oil can be extracted by a conventionally known method. For example, shark liver is taken out, finely crushed with a crusher, left to stand for 1 to 4 days, oil and solids are separated, and oil is removed. Cod liver oil can be obtained by taking it out. The cod 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 including DAGE may be extracted from the remaining components.
- the compositions of the present disclosure improve sleep quality.
- "improving sleep quality” means improving the balance between deep sleep and REM sleep, increasing the percentage of deep sleep, increasing the percentage of REM sleep, It means at least one of reducing sleep stage 1, reducing the rate of wakefulness, and improving sleep efficiency.
- Sleep stages during sleep are divided into wakefulness, REM sleep, and non-REM sleep stages 1 to 3, which can be determined by electroencephalogram measurement.
- NREM sleep stages 1 and 2 are light NREM sleep, and NREM sleep stage 3 is deep sleep.
- the time or ratio of wakefulness, REM sleep, and non-REM sleep stages 1 to 3 is the total time or ratio of each sleep stage during sleep (from going to bed to waking up).
- Sleep efficiency refers to the percentage of time spent asleep (total time in REM and non-REM sleep stages 1-3) during sleep.
- the composition of the present disclosure improves sleep quality by regulating sleep rhythms with active ingredients derived from materials that have been eaten, so unlike conventional sleep-improving pharmaceuticals, it improves brain function. Suppressing all of them is thought to cause few side effects.
- the improved sleep quality is at least one selected from improved deep sleep and REM sleep balance, increased deep sleep percentage, increased REM sleep percentage, decreased non-REM sleep stage 1. be. In some embodiments, the improved sleep quality is an improved balance between deep sleep and REM sleep. In some embodiments, the improvement in sleep quality is an increase in the percentage of deep sleep, an increase in the percentage of REM sleep and a decrease in NREM stage 1 sleep. Without being limited by theory, it is believed that these sleep quality improvements are due to the synergistic effect of the fish egg lipid preparation and DAGE.
- the target is typically a human.
- the subject may or may not have a sleep disorder.
- Subjects with sleep disorders include subjects with subjective symptoms of insomnia in daily life and subjects diagnosed with sleep disorders. For example, a subject with a score of 6 or greater on the Pittsburgh Sleep Questionnaire (PSQI, PSQI-j) can be diagnosed as having a sleep disorder.
- PSQI, PSQI-j Pittsburgh Sleep Questionnaire
- compositions of the present disclosure can also be used to reduce anxiety, tension, depressed mood, depression, depression, vigor, energy, general mood state and daytime performance in subjects with reduced energy or energy in daily life. May improve sleepiness.
- a subject with decreased vitality or vitality in daily life is a subject with a VA of less than 50 as assessed by POMS2 (Profile of Mood States 2nd Edition).
- POMS2 Profile of Mood States 2nd Edition
- a composition comprising a fish egg lipid preparation is provided to remedy one.
- anxiety, tension, depressed mood, vigor, energy and daytime sleepiness can be improved in a subject with decreased energy or energy in daily life.
- 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.
- 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.
- the composition of the present disclosure may be a food composition.
- the food composition can be in the form of a typical processed food.
- it can be a solid food, or a liquid food such as a drink, a drink, a powdered drink, or a soup.
- it can be consumed as, for example, juice, confectionery, jelly, tablet, dressing, seasoning, and the like.
- 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 the quality of sleep. 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 fish egg lipid preparation and DAGE may be contained in one composition or may be contained in separate compositions.
- both compositions may be taken at the same time, or either composition may be taken with a delay as long as the desired effect is achieved. good too.
- 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.
- 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.
- 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, Especially preferred is about 200 mg or less.
- 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.
- 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 intake amount of the composition of the present disclosure can be an amount such that about 100 mg or more of DAGE is ingested per day, preferably about 180 mg or more, and more preferably about 360 mg or more. Also, the intake of the composition of the present disclosure can be an amount that provides about 1800 mg or less of DAGE per day, preferably about 720 mg or less. In some embodiments, the dosage of the composition of the present disclosure is such that about 360 mg (eg, 324 mg to 396 mg) of DAGE is ingested per day.
- 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.
- the daily intake of each component of the composition may be dispersed in 2 to 15, preferably 3 to 10, eg, 6 capsules to be taken daily.
- 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, it is possible to continue ingestion until sleep quality is improved, for example, for one week or more, preferably one month or more, more preferably two months or more, and particularly preferably three months or more. can. There may be periods during which the intake is discontinued.
- the compositions of this disclosure are taken daily for at least 12 weeks.
- 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.
- a composition comprising one or more additional ingredients in addition to the fish egg oil preparation and DAGE may be used.
- ingredients suitable for combined use include astaxanthin.
- the daily intake of astaxanthin can be about 50 ⁇ g or more, preferably about 100 ⁇ g or more, more preferably about 200 ⁇ g or more, and can be about 1000 ⁇ g or less, preferably about 400 ⁇ g or less, for example about 200 ⁇ g. .
- Astaxanthin may be included in the fish egg lipid composition, but astaxanthin from yet another source may be used.
- 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.
- astaxanthin has the effect of protecting and stabilizing DHA and EPA from peroxidation.
- Haematococcus algae specifically, Haematococcus pluvialis, Haematococcus lacustris, Haematococcus capensis, Haematococcus droebakensis, Haematococcus ginseng Babiensis (Haematococcus zimbabwiensis) and the like.
- 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.
- krill-derived astaxanthin examples include Astax-S manufactured by Marine Daio Co., Ltd., and the like.
- a sleep quality improving agent comprising a fish egg lipid preparation and DAGE.
- methods of improving sleep quality comprising ingesting a fish egg lipid preparation and DAGE to a subject in need of improved sleep quality.
- a combination of a fish egg lipid preparation and DAGE for improving sleep quality is provided.
- the use of a fish egg lipid preparation and DAGE to improve sleep quality is provided.
- use of the fish egg lipid preparation and DAGE in the manufacture of a composition for improving sleep quality is provided.
- a composition for improving sleep quality comprising a fish egg lipid preparation and DAGE.
- a composition for improving sleep quality according to item 1 comprising a fish egg lipid preparation containing about 30% or more (preferably about 40% or more) of phospholipids.
- the composition according to item 1 or 2 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.
- composition according to any one of items 2 to 4, wherein the phospholipid contains about 74% or more of PC contains about 74% or more of PC.
- any one of items 1 to 5 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 [7] The composition according to item 1, wherein the DAGE is derived from deep sea shark liver oil.
- a daily intake of about 180 mg to 1800 mg (preferably about 360 mg to 1800 mg, more preferably about 360 mg to 720 mg) of DAGE is prepared to be ingested, according to items 1 to 11.
- Daily intake of about 100 mg to 750 mg (preferably about 150 mg to 750 mg, more preferably about 150 mg to 200 mg) of DHA, 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) and about 180 mg to 1800 mg (preferably about 360 mg to 1800 mg, more preferably about 360 mg to 720 mg) of DAGE are prepared to be ingested. 14.
- composition according to item 14 further comprising about 100 ⁇ g to 1000 ⁇ g (preferably about 200 ⁇ g to 1000 ⁇ g, more preferably about 200 ⁇ g to 400 ⁇ g) of astaxanthin.
- Daily intake of about 160 mg (or 144 mg to 176 mg) of DHA, 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 360 mg (or 324 mg to 396 mg) of DAGE are formulated to be ingested.
- a daily intake of about 160 mg (or 144 mg to 176 mg) of DHA, about 100 mg (or 90 to 110 mg) of EPA, and about 360 mg (or 324 mg to 396 mg) of DAGE is taken. 17.
- the composition of paragraphs 14 or 16, wherein the composition is prepared as [18]
- a daily intake of about 150 mg (or 135 mg to 165 mg) of DHA, about 60 mg (or 54 mg to 66 mg) of EPA, and about 360 mg (or 324 mg to 396 mg) of DAGE is taken. 15.
- composition of paragraph 14 wherein the composition is prepared as [20] The composition according to item 19, which is further prepared so that about 200 ⁇ g (or 180 ⁇ g to 220 ⁇ g) of astaxanthin is ingested. [21] The composition according to any one of items 1 to 20, wherein the fish egg lipid preparation is derived from pink salmon. [22] The composition of any one of paragraphs 1 to 21, which is taken daily for at least 12 weeks. [23] Improved sleep quality includes improved deep and REM sleep balance, increased deep sleep percentage, increased REM sleep percentage, decreased non-REM sleep stage 1, decreased wakefulness percentage, and sleep efficiency. 23.
- composition of any of paragraphs 1-22 comprising one or more (preferably two or more) items selected from improving the [24] improvement in sleep quality is one or more selected from improved deep sleep and REM sleep balance, increased deep sleep percentage, increased REM sleep percentage, and decreased non-REM sleep stage 1 ( 24.
- the composition of any one of items 1 to 24, wherein the improvement in sleep quality is an increase in deep sleep percentage, an increase in REM sleep percentage, and a decrease in non-REM sleep stage 1.
- a composition comprising a fish egg lipid preparation and DAGE for remediation.
- composition according to any one of items 1 to 29, which is a food composition.
- Sleep quality improvers including fish egg lipid preparations and DAGE.
- a method of improving sleep quality comprising ingesting a fish egg lipid preparation and DAGE to a subject in need thereof.
- a combination of fish egg lipid preparation and DAGE used to improve sleep quality.
- Use of a fish egg lipid preparation and DAGE in the manufacture of a composition for improving sleep quality.
- 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. 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.
- DAGE Deep-sea shark liver oil
- AR-SR/AST-DA haematococcus algae pigment
- Table 3 shows the amounts of phospholipid classes contained in the soft capsules.
- DAGE One capsule contained 133.66 mg of deep-sea shark liver oil so that the DAGE content was 360 mg per day (in 6 capsules).
- Astaxanthin 0.67 mg of Haematococcus algae pigment was contained in one capsule so that the content of astaxanthin was 200 ⁇ g per day (in 6 capsules).
- Gelatin is bovine gelatin.
- Selection criteria were (1) healthy men and women aged between 20 and 64 years old, and (2) those with a score of 6 or more on the Pittsburgh Sleep Questionnaire (Japanese version) at the time of the preliminary examination.
- Exclusion criteria are (1) those who are undergoing drug treatment, diet guidance, and exercise therapy, (2) those who are undergoing treatment for sleep, stress, and fatigue, and (3) diabetes, liver disease, kidney disease, and heart disease. (4) Those with a history of mental illness, chronic fatigue syndrome, or insomnia.
- Test food The test food is a soft capsule "ONO-SR/ AST-DA” (Ono Pharmaceutical Co., Ltd.). The placebo added safflower oil in place of the participating ingredients to make them visually indistinguishable from the test food.
- Study method The study was a randomized, double-blind, placebo-controlled, parallel-group study. Table 5 shows the test schedule. A staff member not involved in the study created an allocation table using random numbers, assigned allocation numbers to the test foods, and performed allocation. The randomization table was sealed, sealed and kept unopened until the subjects and data were fixed. One bag (6 grains) of the test food was ingested daily with water or lukewarm water without chewing. The intake period was 12 weeks. During the test period, participants should refrain from changing their lifestyle habits such as drinking, eating, and sleeping as much as possible from before participating in the test, limit excessive exercise that greatly deviates from their daily routine, diet and overeating, and use new health foods. It was decided to prohibit stress relief activities beyond the scope of daily life.
- sleepwell's “Sleepscope” was used to measure electroencephalograms for 5 days on weekdays immediately before the test, and the average data for 3 days was adopted (in principle, 3 days from Tuesday to Thursday were adopted, but at the same time Preferentially selected were nights in which the validity rate of acquired electroencephalogram data was 80% or higher, without fluctuations from normal lifestyle habits in the sleep diaries recorded).
- Body weight and BMI were measured as physical measurements.
- Systolic and diastolic blood pressure and pulse rate were measured as physical examinations.
- Fasting clinical tests include hematological tests (white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count), blood biochemical tests (total protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, ALP, AST, ALT, LD, ⁇ -GT, total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, urea nitrogen, creatinine, uric acid, sodium, potassium, chlorine, blood sugar, HbA1c (preliminary test only)), urinalysis (protein qualitative, Qualitative glucose, occult blood reaction), infectious disease test (HCV (preliminary test only), HBV (preliminary test only)), and catecholamine measurement were performed.
- 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. Of the 243 persons who participated in the preliminary examination, 122 persons who met the selection criteria and did not meet the exclusion criteria were subjected to the pre-ingestion examination, and 80 persons were selected. Subject backgrounds are shown in Table 6. There were no items with significant differences between the groups.
- Subpopulation analysis was performed on the population with pre-ingestion values of Vitality and Vitality (VA) of 50 or more and less than 50 for the POMS2 adult abbreviated version.
- VA Vitality and Vitality
- Pittsburgh Sleep Questionnaire Daytime Arousal Difficulty and POMS2 Adult Short Version Depression/Depression (DD), Tension/Anxiety (TA), Vitality/Vitality (VA), Global Mood State (TMD) in the VA ⁇ 50 population was significantly improved in the test food intake group compared with the placebo intake group (Tables 9 and 10).
- the amount of change at week 12 was significantly smaller in group A than in group P in the total time of each sleep stage (non-REM sleep 1) and sleep cycle (second sleep cycle).
- the ratio of each sleep stage (non-REM sleep 3) and the ratio of each sleep stage (REM sleep) were significantly higher in group A than in group P.
- Non-REM sleep consists of alternating REM and non-REM sleep for about 80-100 minutes.
- Non-REM sleep is classified into light sleep (Stage 1, Stage 2) and deep sleep (Stage 3), and the proportion of each sleep stage decreases with aging, and light sleep and mid-waking increases. is known (general 20-year-old sleep stage ratio: 5% middle awakening, 55% light sleep, 20% deep sleep, 25% REM sleep, general 60-year-old sleep stage ratio: 15% middle awakening , light sleep 60%, deep sleep 5%, REM sleep 20%).
- the sleep stage ratio (at the time of allocation) of the subjects in this test was 10.4% of midway awakening, 65.8% of light sleep, 6.0% of deep sleep, and 17.8% of REM sleep, which is close to that of the elderly. there were.
- FIG. 2 shows the ratio of sleep stages in each group before and after ingestion of the test food in this test and an example of sleep stages before and after ingestion of the test food.
- NREM sleep and REM sleep are coordinated and alternately repeated at appropriate intervals (maintaining sleep rhythm), which is an important factor in improving sleep quality. is. From the above, the test food can be expected to have the effect of improving the quality of sleep.
- 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, and DAGE, (2) Those with serious diseases such as diabetes, liver disease, renal disease, and heart disease, and those with (3) Subjects who are at risk of developing an allergy related to the study; (4) Subjects who are undergoing treatment that may affect the study; (5) Those who have a history of drug dependence or alcohol dependence, or those who have a history of current illness, (6) Those who are judged to be unsuitable as subjects based on the clinical test values and measurement values of the preliminary examination, ( 7) Those who participated in other clinical studies within one month after 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) Pregnant or breastfeeding. (9) Subjects who are determined to be unsuitable as subjects based on the results of the lifestyle questionnaire; (10) Other subjects who are considered inappropriate as subjects by the responsible physician who made the decision.
- Test Food was "ONO-SR/AST-DA", which contained 5 g of salmon roe oil (DHA 750 mg, EPA 300 mg), astaxanthin 1,000 ⁇ g, and refined deep-sea shark liver oil (DAGE 1,800 mg) per 30 grains in 5 bags.
- Test method The test was an open study. Five sachets (30 grains) were ingested daily with water or lukewarm water without chewing. 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 test, limit excessive exercise that greatly deviates from your daily range, diet and overeating, and do not start new exercise , and decided not to stop the exercise habits that had been continued until then.
- the subjects were asked to visit the hospital for an interview (confirmation of physical condition), physical measurements, physical examinations, and fasting clinical examinations.
- 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.
- Fasting clinical tests include hematological tests (white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count), blood biochemical tests (total protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, ALP, AST, ALT, LD, ⁇ -GT, total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, urea nitrogen, creatinine, uric acid, sodium, potassium, chlorine, blood sugar, HbA1c (preliminary test only)), urinalysis (protein qualitative, sugar qualitative, occult blood reaction) were performed. Each test was conducted at the time of the pre-inspection, 2 weeks after the intake, 4 weeks after the intake, and 2 weeks after the end of the intake, except for the items for which only the preliminary inspection was performed.
- the evaluation items were adverse events, measured values, and test values.
- Adverse events were defined as subjective symptoms in interviews and diaries, as well as abnormal changes in laboratory values. Subjective symptoms and adverse events as objective findings were determined by the responsible physician.
- test values abnormal changes in test values (adverse events) of individual subjects
- 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.
- JCOG version (CTCAE v5.0-JCOG) and the judgment classification of the Japanese Society of Ningen Dock were used as a reference to determine adverse events by the responsible physician.
- Results 1 Background of Subjects Preliminary examination was performed on 48 subjects who gave written consent to participate in the study. A total of 20 subjects, 10 males and 10 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. In addition, in some subjects, items exceeding the reference range (testing standard values of the laboratory performing the clinical testing) were found in some subjects, but the investigator responsible investigator examined each subject, and there was a problem in participating in the study. was included in the study after it was determined to be absent. All of the 20 subjects started ingesting the test food, all of them completed the ingestion of the test food, and completed the prescribed test schedule and test content. Therefore, all 20 subjects were analyzed for adverse events, measured values, and laboratory values.
- the present disclosure relates to improving sleep quality and can be used in the medical or food fields.
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Abstract
Description
本開示は、睡眠の質を改善するための組成物に関するものである。 This patent application claims priority from Japanese Patent Application No. 2021-060752, which is incorporated herein in its entirety by reference.
The present disclosure relates to compositions for improving sleep quality.
本開示において成分の割合を%で表示するときは、特に記載した場合を除き、重量に基づく。 Unless otherwise specified, terms used in this disclosure have meanings as commonly understood by those of ordinary skill 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.
When percentages of ingredients are expressed in this disclosure, they are by weight unless otherwise stated.
魚卵脂質調製物は、例えば、サケ科の魚卵から調製される。サケ科には、タイヘイヨウサケ属、タイセイヨウサケ属、イワナ属、イトウ属が含まれ、タイヘイヨウサケ属またはタイセイヨウサケ属がより好ましい。タイヘイヨウサケ属の魚の例として、シロザケ(Oncorhynchus keta)、ギンザケ(Oncorhynchus kisutch)、カラフトマス(Oncorhynchus gorbuscha)、サクラマス(Oncorhynchus masou masou)、ヤマメ(Oncorhynchus masou masou)、タイワンマス(Oncorhynchus masou formosanus)、サツキマス(Oncorhynchus masou ishikawae)、アマゴ(Oncorhynchus masou ishikawae)、ビワマス(Oncorhynchus masou rhodurus)、ニジマス(Oncorhynchus mykiss)、マスノスケ(Oncorhynchus tshawytscha)、ベニザケ(Oncorhynchus nerka)、ヒメマス(Oncorhynchus nerka)、クニマス(Oncorhynchus kawamurae)が挙げられる。タイセイヨウサケ属の魚の例として、タイセイヨウサケ(Salmo salar)、ブラウントラウト(Salmo trutta)が挙げられる。ある実施態様では、魚卵脂質調製物は、カラフトマス(Oncorhynchus gorbuscha)の魚卵から調製される。 (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.
特に好ましい実施態様においては、魚卵脂質調製物は、筋子、イクラ、またはそれらのいずれかの加工品、例えば、筋子抽出物、イクラ抽出物、イクラ油、またはイクラ油精製物から調製される。 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.
例えば、魚卵脂質調製物は、WO2021/132516に記載されるもの、特に筋子オイルPL40であり得る。 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.
ある実施態様では、魚卵脂質調製物のリン脂質の含量が高められている。リン脂質とはリン酸エステルの形でリンをもつ脂質をいい、グリセロリン脂質とスフィンゴリン脂質とがある。グリセロリン脂質の代表的なものは、ホスファチジルコリン(PC)、α-グリセロホスホコリン(α-GPC)、ホスファチジルエタノールアミン(PE)、ホスファチジルイノシトール(PI)、1-リゾホスファチジルコリン(LPC-1)、2-リゾホスファチジルコリン(LPC-2)、2-リゾホスファチジルエタノールアミン(LPE-2)であり、スフィンゴリン脂質の代表的なものは、スフィンゴミエリン(SM)およびジヒドロスフィンゴミエリン(DHSM)である。魚卵脂質調製物のリン脂質の含量は、例えば約26%以上であり、約30%以上であってもよく、好ましくは約35%以上であり、より好ましくは約37.5%以上であり、さらに好ましくは約40%以上である。魚卵脂質調製物におけるリン脂質含量の上限は特に限定されないが、リン脂質含量が高くなると粘度が高くなり、粘度が一定以上となると製造上、扱いにくくなるため、例えば約50%以下である。 (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.
魚卵脂質調製物の脂質の構成脂肪酸に占めるDHAの組成比は、比較的高い。魚卵は、リン脂質またはトリグリセリド(TG)の形態で、DHAを含むことが知られている。具体的には、魚卵脂質調製物の脂質の構成脂肪酸に占めるDHAの組成比は、例えば約15%以上であり、好ましくは約18%以上であり、より好ましくは約22%以上であり、さらに好ましくは約24%以上である。魚卵脂質調製物における脂質の構成脂肪酸に占めるDHAの組成比の上限は特に限定されないが、例えば約46%以下であり、好ましくは約40%以下であり、より好ましくは約35%以下であり、さらに好ましくは約30%以下である。なお、本開示において脂質の構成脂肪酸に占める特定の脂肪酸の組成比を%で表示するときは、特に記載した場合を除き、脂肪酸組成をガスクロマトグラフ法で分析したチャートの面積に基づく。 (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.
魚卵脂質調製物は脂質以外の成分を含んでいてもよい。脂質以外の成分としては、たんぱく質、ナトリウム、カリウム、リン等の無機物である。なお脂質とは、非極性溶媒に可溶である、生物由来の物質をいい、これには単純脂質、複合脂質、誘導脂質(脂肪酸、テルペノイド、ステロイド、カロテノイド等)が含まれる。
魚卵脂質調製物における脂質以外の成分の含量は、例えば10.0%以下であり、好ましくは8.0%以下であり、より好ましくは7.5%以下であり、さらに好ましくは7.0%以下である。 (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.
DAGEは、深海鮫肝油に含まれるものであり得る。深海鮫肝油は、アイザメ、ユメザメ、ヘラツノザメなどの、深海に生息できるサメの肝臓から抽出した油である。肝油は従来から知られている方法により抽出することができ、例えば、サメの肝臓を取り出し、破砕装置で細かく破砕し、1~4日間静置し、油分と固形分とを分離させ、油分を取り出すことにより、肝油を得ることができる。さらに肝油をろ過して細かな固形分を除去し、精製してもよい。あるいは、市販の深海鮫肝油を用いることができる。深海鮫肝油からスクワレンを抽出し、残りの成分からDAGEを含むトリグリセリドを抽出してもよい。 (DAGE)
DAGE can be found in deep sea shark liver oil. Deep-sea shark liver oil is oil extracted from the livers of sharks that can live in the deep sea, such as the yellow shark, the stingray shark, and the paddlefish shark. Liver oil can be extracted by a conventionally known method. For example, shark liver is taken out, finely crushed with a crusher, left to stand for 1 to 4 days, oil and solids are separated, and oil is removed. Cod liver oil can be obtained by taking it out. The cod 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 including DAGE may be extracted from the remaining components.
後述の実施例で示される通り、本開示の組成物は、睡眠の質を改善する。本開示で使用されるとき、「睡眠の質を改善する」とは、深睡眠とレム睡眠のバランスを改善すること、深睡眠の割合を増加させること、レム睡眠の割合を増加させること、ノンレム睡眠ステージ1を減少させること、覚醒の割合を減少させること、および、睡眠効率を改善することの少なくとも1つを意味する。就寝中の睡眠ステージは、覚醒、レム睡眠、ノンレム睡眠ステージ1~3に分けられ、脳波測定により決定できる。ノンレム睡眠ステージ1、2は浅いノンレム睡眠、ノンレム睡眠ステージ3は深睡眠である。覚醒、レム睡眠、ノンレム睡眠ステージ1~3の時間または割合は、就寝中(床についてから起床するまで)の各睡眠ステージを合計した時間または割合である。睡眠効率は、就寝中、睡眠している時間(レム睡眠およびノンレム睡眠ステージ1~3の時間の合計)の割合を意味する。理論により限定されないが、本開示の組成物は、食経験のある素材に由来する有効成分で睡眠リズムを整えることにより睡眠の質を改善するので、従来の睡眠改善医薬品とは異なり、脳機能をすべて抑制することによる副作用は少ないと考えられる。 (Application)
As shown in the examples below, the compositions of the present disclosure improve sleep quality. As used in this disclosure, "improving sleep quality" means improving the balance between deep sleep and REM sleep, increasing the percentage of deep sleep, increasing the percentage of REM sleep, It means at least one of reducing sleep stage 1, reducing the rate of wakefulness, and improving sleep efficiency. Sleep stages during sleep are divided into wakefulness, REM sleep, and non-REM sleep stages 1 to 3, which can be determined by electroencephalogram measurement. NREM sleep stages 1 and 2 are light NREM sleep, and NREM sleep stage 3 is deep sleep. The time or ratio of wakefulness, REM sleep, and non-REM sleep stages 1 to 3 is the total time or ratio of each sleep stage during sleep (from going to bed to waking up). Sleep efficiency refers to the percentage of time spent asleep (total time in REM and non-REM sleep stages 1-3) during sleep. Although not limited by theory, the composition of the present disclosure improves sleep quality by regulating sleep rhythms with active ingredients derived from materials that have been eaten, so unlike conventional sleep-improving pharmaceuticals, it improves brain function. Suppressing all of them is thought to cause few side effects.
ある態様では、睡眠の質の改善を必要としている対象に魚卵脂質調製物およびDAGEを摂取させることを含む、睡眠の質の改善方法が提供される。
ある態様では、睡眠の質を改善するための魚卵脂質調製物とDAGEの組合せが提供される。
ある態様では、睡眠の質を改善するための魚卵脂質調製物およびDAGEの使用が提供される。
ある態様では、睡眠の質を改善するための組成物の製造における、魚卵脂質調製物およびDAGEの使用が提供される。 In one aspect, a sleep quality improving agent is provided comprising a fish egg lipid preparation and DAGE.
In certain aspects, methods of improving sleep quality are provided comprising ingesting a fish egg lipid preparation and DAGE to a subject in need of improved sleep quality.
In one aspect, a combination of a fish egg lipid preparation and DAGE for improving sleep quality is provided.
In one aspect, the use of a fish egg lipid preparation and DAGE to improve sleep quality is provided.
In one aspect, use of the fish egg lipid preparation and DAGE in the manufacture of a composition for improving sleep quality is provided.
[1]魚卵脂質調製物およびDAGEを含む、睡眠の質を改善するための組成物。
[2]リン脂質を約30%以上(好ましくは約40%以上)含む魚卵脂質調製物を含む、第1項に記載の睡眠の質を改善するための組成物。
[3]魚卵脂質調製物がDHA結合リン脂質を含み、脂質の構成脂肪酸に占めるDHAの組成比が約15%以上である、第1項または第2項に記載の組成物。
[4]魚卵脂質調製物が、α-GPC、SMおよびDHSMからなる群(好ましくはSMおよびDHSMからなる群)より選択される少なくとも1つを含む、第1項~第3項のいずれかに記載の組成物。
[5]リン脂質がPCを約74%以上含む、第2項~第4項のいずれかに記載の組成物。
[6]魚卵脂質調製物における脂質の構成脂肪酸に占めるDHA組成比が約15%以上であり、EPAの組成比が約5~25%である、第1項~第5項のいずれかに記載の組成物。
[7]DAGEが深海鮫肝油に由来するものである、第1項に記載の組成物。
[8]アスタキサンチンをさらに含む、第1項~第7項のいずれかに記載の組成物。
[9]アスタキサンチンがヘマトコッカス藻色素に由来するものである、第8項に記載の組成物。
[10]1日摂取量として、約100mg~750mg(好ましくは約150mg~750mg、より好ましくは約150mg~200mg)のDHAが摂取されるように調製されている、第1項~第9項のいずれかに記載の組成物。
[11]1日摂取量として、約160mg(または、144mg~176mg)のDHAが摂取されるように調製されている、第1項~第10項のいずれかに記載の組成物。
[12]1日摂取量として、約180mg~1800mg(好ましくは約360mg~1800mg、より好ましくは約360mg~720mg)のDAGEが摂取されるように調製されている、第1項~第11項のいずれかに記載の組成物。
[13]1日摂取量として、約360mgのDAGE(または、324mg~396mg)が摂取されるように調製されている、第1項~第12項のいずれかに記載の組成物。
[14]1日摂取量として、約100mg~750mg(好ましくは約150mg~750mg、より好ましくは約150mg~200mg)のDHA、約30mg~300mg(好ましくは約60mg~300mg、より好ましくは約60mg~150mg)のエイコサペンタエン酸(EPA)、および、約180mg~1800mg(好ましくは約360mg~1800mg、より好ましくは約360mg~720mg)のDAGEが摂取されるように調製されている、第1項~第13項のいずれかに記載の組成物。
[15]さらに、約100μg~1000μg(好ましくは約200μg~1000μg、より好ましくは約200μg~400μg)のアスタキサンチンを含む第14項に記載の組成物。
[16]1日摂取量として、約160mg(または、144mg~176mg)のDHA、約100~110mg(好ましくは、約100mg(または、90~110mg)、または約110mg(または、99mg~121mg))のEPA、および、約360mg(または、324mg~396mg)のDAGEが摂取されるように調製されている、第14項に記載の組成物。
[17]1日摂取量として、約160mg(または、144mg~176mg)のDHA、約100mg(または、90~110mg)のEPA、および、約360mg(または、324mg~396mg)のDAGEが摂取されるように調製されている、第14項または第16項に記載の組成物。
[18]さらに、約200μg(または、180μg~220μg)のアスタキサンチンが摂取されるように調製されている、第16項または第17項に記載の組成物。
[19]1日摂取量として、約150mg(または、135mg~165mg)のDHA、約60mg(または、54mg~66mg)のEPA、および、約360mg(または、324mg~396mg)のDAGEが摂取されるように調製されている、第14項に記載の組成物。
[20]さらに、約200μg(または、180μg~220μg)のアスタキサンチンが摂取されるように調製されている、第19項に記載の組成物。
[21]魚卵脂質調製物がカラフトマスに由来する、第1項~第20項のいずれかに記載の組成物。
[22]少なくとも12週間にわたって毎日摂取される、第1項~第21項のいずれかに記載の組成物。
[23]睡眠の質の改善が、深睡眠とレム睡眠のバランスの改善、深睡眠の割合の増加、レム睡眠の割合の増加、ノンレム睡眠ステージ1の減少、覚醒の割合の減少、および睡眠効率の改善から選択される1つ以上(好ましくは2つ以上)の項目を含む、第1項~第22項のいずれかに記載の組成物。
[24]睡眠の質の改善が、深睡眠とレム睡眠のバランスの改善、深睡眠の割合の増加、レム睡眠の割合の増加、および、ノンレム睡眠ステージ1の減少から選択される1つ以上(好ましくは2つ以上)の項目を含む、第1項~第23項のいずれかに記載の組成物。
[25]睡眠の質の改善が、深睡眠とレム睡眠のバランスの改善である、第1項~第24項のいずれかに記載の組成物。
[26]睡眠の質の改善が、深睡眠の割合の増加、レム睡眠の割合の増加およびノンレム睡眠ステージ1の減少である、第1項~第24項のいずれかに記載の組成物。
[27]睡眠障害がある対象に使用するための、第1項~第26項のいずれかに記載の組成物。
[28]さらに、日常生活で活気または活力が低下している対象において、不安感、緊張感、ゆううつな気分、抑うつ、落込み、活気、活力、総合的気分状態および日中の眠気の少なくとも1つを改善するための、第1項~第27項のいずれかに記載の組成物。
[29]日常生活で活気または活力が低下している対象において、不安感、緊張感、ゆううつな気分、抑うつ、落込み、活気、活力、総合的気分状態および日中の眠気の少なくとも1つを改善するための、魚卵脂質調製物およびDAGEを含む組成物。
[30]医薬組成物である、第1項~第29項のいずれかに記載の組成物。
[31]食品組成物である、第1項~第29項のいずれかに記載の組成物。
[32]魚卵脂質調製物およびDAGEを含む、睡眠の質の改善剤。
[33]睡眠の質の改善を必要としている対象に魚卵脂質調製物およびDAGEを摂取させることを含む、睡眠の質の改善方法。
[34]睡眠の質を改善するために使用される魚卵脂質調製物とDAGEの組合せ。
[35]睡眠の質を改善するための魚卵脂質調製物およびDAGEの使用。
[36]睡眠の質を改善するための組成物の製造における、魚卵脂質調製物およびDAGEの使用。 For example, the following embodiments are provided.
[1] A composition for improving sleep quality comprising a fish egg lipid preparation and DAGE.
[2] A composition for improving sleep quality according to item 1, comprising a fish egg lipid preparation containing about 30% or more (preferably about 40% or more) of phospholipids.
[3] The composition according to item 1 or 2, 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.
[4] Any one of items 1 to 3, 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 .
[5] The composition according to any one of items 2 to 4, wherein the phospholipid contains about 74% or more of PC.
[6] Any one of items 1 to 5, 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.
[7] The composition according to item 1, wherein the DAGE is derived from deep sea shark liver oil.
[8] The composition according to any one of items 1 to 7, further comprising astaxanthin.
[9] The composition according to item 8, wherein the astaxanthin is derived from Haematococcus algal pigment.
[10] A daily intake of about 100 mg to 750 mg (preferably about 150 mg to 750 mg, more preferably about 150 mg to 200 mg) of DHA according to items 1 to 9, which is prepared to be ingested. A composition according to any of the preceding claims.
[11] The composition according to any one of items 1 to 10, which is prepared so that the daily intake is about 160 mg (or 144 mg to 176 mg) of DHA.
[12] A daily intake of about 180 mg to 1800 mg (preferably about 360 mg to 1800 mg, more preferably about 360 mg to 720 mg) of DAGE is prepared to be ingested, according to items 1 to 11. A composition according to any of the preceding claims.
[13] The composition according to any one of items 1 to 12, which is prepared so that the daily intake is about 360 mg of DAGE (or 324 mg to 396 mg).
[14] Daily intake of about 100 mg to 750 mg (preferably about 150 mg to 750 mg, more preferably about 150 mg to 200 mg) of DHA, 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) and about 180 mg to 1800 mg (preferably about 360 mg to 1800 mg, more preferably about 360 mg to 720 mg) of DAGE are prepared to be ingested. 14. A composition according to any of clause 13.
[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] Daily intake of about 160 mg (or 144 mg to 176 mg) of DHA, 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 360 mg (or 324 mg to 396 mg) of DAGE are formulated to be ingested.
[17] A daily intake of about 160 mg (or 144 mg to 176 mg) of DHA, about 100 mg (or 90 to 110 mg) of EPA, and about 360 mg (or 324 mg to 396 mg) of DAGE is taken. 17. The composition of paragraphs 14 or 16, wherein the composition is prepared as
[18] The composition according to item 16 or 17, which is further prepared so that about 200 μg (or 180 μg to 220 μg) of astaxanthin is ingested.
[19] A daily intake of about 150 mg (or 135 mg to 165 mg) of DHA, about 60 mg (or 54 mg to 66 mg) of EPA, and about 360 mg (or 324 mg to 396 mg) of DAGE is taken. 15. The composition of paragraph 14, wherein the composition is prepared as
[20] The composition according to item 19, which is further prepared so that about 200 μg (or 180 μg to 220 μg) of astaxanthin is ingested.
[21] The composition according to any one of items 1 to 20, wherein the fish egg lipid preparation is derived from pink salmon.
[22] The composition of any one of paragraphs 1 to 21, which is taken daily for at least 12 weeks.
[23] Improved sleep quality includes improved deep and REM sleep balance, increased deep sleep percentage, increased REM sleep percentage, decreased non-REM sleep stage 1, decreased wakefulness percentage, and sleep efficiency. 23. The composition of any of paragraphs 1-22, comprising one or more (preferably two or more) items selected from improving the
[24] improvement in sleep quality is one or more selected from improved deep sleep and REM sleep balance, increased deep sleep percentage, increased REM sleep percentage, and decreased non-REM sleep stage 1 ( 24. A composition according to any of paragraphs 1 to 23, comprising preferably two or more items.
[25] The composition according to any one of items 1 to 24, wherein the improvement in sleep quality is an improvement in the balance between deep sleep and REM sleep.
[26] The composition of any one of items 1 to 24, wherein the improvement in sleep quality is an increase in deep sleep percentage, an increase in REM sleep percentage, and a decrease in non-REM sleep stage 1.
[27] A composition according to any one of paragraphs 1 to 26 for use in a subject with a sleep disorder.
[28] In addition, at least one of anxiety, tension, depressed mood, depression, depression, vivacity, vitality, general mood state and daytime sleepiness in a subject with decreased vigor or energy in daily life Clause 28. The composition of any of clauses 1-27 for ameliorating one.
[29] reducing at least one of anxiety, tension, depressed mood, depression, depression, vivacity, vitality, global mood state, and daytime sleepiness in a subject with decreased vigor or energy in daily life; A composition comprising a fish egg lipid preparation and DAGE for remediation.
[30] The composition according to any one of items 1 to 29, which is a pharmaceutical composition.
[31] The composition according to any one of items 1 to 29, which is a food composition.
[32] Sleep quality improvers, including fish egg lipid preparations and DAGE.
[33] A method of improving sleep quality comprising ingesting a fish egg lipid preparation and DAGE to a subject in need thereof.
[34] A combination of fish egg lipid preparation and DAGE used to improve sleep quality.
[35] Use of fish egg lipid preparations and DAGE to improve sleep quality.
[36] Use of a fish egg lipid preparation and DAGE in the manufacture of a composition for improving sleep quality.
以下、実施例にて、本発明をさらに詳細に説明するが、本発明はこの実施例に限定されない。また、上記の説明は、すべて非限定的なものであり、本発明は添付の特許請求の範囲において定義され、その技術的思想を逸脱しない範囲で種々の変更が可能である。 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.
WO2021/132516に記載される方法により魚卵脂質調製物を製造した。具体的には、凍結粉砕したカラフトマス(Oncorhynchus gorbuscha)の生筋子(15kg)に含水エタノール(150L)を加えて抽出し、ろ過により残渣を濾別した。残渣を抽出器に戻し、再度エタノール(75L)を加えて抽出した。得られたろ液を減圧下、溶媒を留去し、赤色油状物質の約40%のリン脂質を含む組成物(40PL)(表1および表2)を製造した。 <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. 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).
*定量値は、総脂質における構成脂肪酸量である。
*The quantitative value is the amount of fatty acids constituting the total lipid.
前記40PLに、深海鮫肝油(DAGE)およびヘマトコッカス藻色素(アスタキサンチン)を追加し、以下の組成のソフトカプセル(ONO-SR/AST-DA)を製造した(表3)。ソフトカプセルに含まれるリン脂質クラスの量を表4に示す。
*DAGE:DAGEの含量が一日量(6カプセル中)360mgとなるように、1カプセル中に深海鮫肝油133.66mg含有させた。
*アスタキサンチン:アスタキサンチンの含量が一日量(6カプセル中)200μgとなるように、1カプセル中にヘマトコッカス藻色素0.67mg含有させた。
*ゼラチンは牛ゼラチンである。 <Production of soft capsules>
Deep-sea shark liver oil (DAGE) and haematococcus algae pigment (astaxanthin) were added to 40PL to produce soft capsules (ONO-SR/AST-DA) having the following composition (Table 3). Table 4 shows the amounts of phospholipid classes contained in the soft capsules.
*DAGE: One capsule contained 133.66 mg of deep-sea shark liver oil so that the DAGE content was 360 mg per day (in 6 capsules).
* Astaxanthin: 0.67 mg of Haematococcus algae pigment was contained in one capsule so that the content of astaxanthin was 200 µg per day (in 6 capsules).
*Gelatin is bovine gelatin.
対象と方法
1.被験者
被験者候補に事前検査を実施し、選択基準を満たし除外基準に該当しない者に対し、睡眠時脳波測定をはじめとする摂取前検査を実施し、適格な者を被験者とした。選択基準は(1)年齢20歳以上64歳以下の健常男女、(2)事前検査時のピッツバーグ睡眠質問票(日本語版)のスコアが6点以上の者とした。除外基準は(1)薬物治療、食事指導や、運動療法を受けている者、(2)睡眠、ストレス、疲労に関する治療を行っている者、(3)糖尿病、肝疾患、腎疾患、心疾患などの疾患や、副腎皮質ホルモンの分泌に影響を及ぼす疾患、その他代謝性疾患を有している者、あるいは既往症がある者、(4)精神疾患、慢性疲労症候群、不眠症の既往がある者、(5)睡眠時無呼吸症候群と診断されたことがある、または、その疑いがある者、(6)夜間頻尿(2回以上)の者、(7)脳波測定用の電極により皮膚障害が起こる可能性がある者、(8)常時投薬が必要な疾患がある者、投薬治療を必要とした重篤な疾患を有している者、あるいは既往症がある者、(9)疲労、ストレス、睡眠の改善を標榜する、または目的としている医薬品、医薬部外品、機能性表示食品、健康食品を常用している者、(10)関与成分を強化した食品を摂取する習慣がある者、(11)昼夜交代制勤務または重量物運搬等の肉体労働に従事している者、(12)生活習慣アンケートの回答から、被験者として不適当と判断された者、(13)試験期間中に、海外旅行や海外出張を行う予定のある者、あるいは連続1週間以上の長期国内出張や国内旅行に行く予定のある者、(14)臨床検査値や心肺機能に異常がみられたことがあり、試験参加に問題があると判断された者、(15)試験に関連してアレルギー発症のおそれがある者、(16)摂取開始前の身体測定値、理学検査値および臨床検査値に、基準範囲から著しく外れた値がみられる者、(17)過去1ヵ月以内に他の臨床試験に参加した者、(18)試験期間中に妊娠、授乳の予定がある者、(19)その他、実施医師責任者が被験者として不適当と判断した者とした。 <Clinical trial>
Objects and Methods 1. Subject Candidate subjects were subjected to a preliminary examination, and those who met the selection criteria but did not meet the exclusion criteria were subjected to pre-ingestion examinations including electroencephalogram measurement during sleep, and qualified subjects were selected as subjects. Selection criteria were (1) healthy men and women aged between 20 and 64 years old, and (2) those with a score of 6 or more on the Pittsburgh Sleep Questionnaire (Japanese version) at the time of the preliminary examination. Exclusion criteria are (1) those who are undergoing drug treatment, diet guidance, and exercise therapy, (2) those who are undergoing treatment for sleep, stress, and fatigue, and (3) diabetes, liver disease, kidney disease, and heart disease. (4) Those with a history of mental illness, chronic fatigue syndrome, or insomnia. , (5) Those who have been diagnosed with sleep apnea syndrome, or those who are suspected of having it, (6) Those who have nocturia (twice or more), (7) Skin disorders caused by electroencephalogram measurement electrodes (8) Those who have a disease that requires constant medication, those who have a serious illness that requires medication, or those who have a history of illness. (9) Fatigue, stress. , Those who regularly use pharmaceuticals, quasi-drugs, foods with functional claims, and health foods that advocate or aim to improve sleep. (11) Persons engaged in physical labor such as day and night shift work or carrying heavy objects, (12) Persons judged to be unsuitable as subjects from the answers to the lifestyle questionnaire, (13) During the test period, Those who plan to travel abroad or go on business trips abroad, or those who plan to go on long-term domestic business trips or domestic trips for more than one week in a row. (15) Subjects who are suspected of developing allergies in connection with the study; (17) Those who participated in other clinical trials within the past month (18) Those who plan to become pregnant or breast-feed during the study period (19) Others, investigators Those who were judged by the person in charge to be unsuitable as subjects were selected.
被験食品は1日摂取量(1袋、6粒)あたりイクラオイル(40PL)1g(DHA150mg以上、EPA60mg以上)、アスタキサンチン200μg以上および深海鮫肝油由来DAGE360mg以上を含有するソフトカプセル「ONO-SR/AST-DA」(小野薬品工業株式会社)であった。プラセボは関与成分の代わりにサフラワー油を添加し、被験食品と外見上の区別がつかないようにした。 2. Test food The test food is a soft capsule "ONO-SR/ AST-DA” (Ono Pharmaceutical Co., Ltd.). The placebo added safflower oil in place of the participating ingredients to make them visually indistinguishable from the test food.
試験は無作為化二重盲検プラセボ対照並行群間比較試験とした。試験スケジュールを表5に示した。試験に関与しない担当者が乱数を用いて割付表を作成し、被験食品に割付番号を付与し、割付を行った。割付表は解析対象者およびデータが固定されるまで封緘、密封保管され、開封しなかった。被験食品は1日に1袋(6粒)を、水またはぬるま湯とともに噛まずに摂取させた。摂取期間は12週間とした。試験期間中は、試験参加前からの飲酒、食事、睡眠等の生活習慣を極力変えないこと、日常範囲を大きく逸脱する過度な運動、節食や過食を制限すること、新たな健康食品の使用を禁止すること、日常範囲を超えるストレス解消行為を禁止することとした。また、睡眠時脳波測定期間は禁酒とし、医薬品の摂取も極力避けること、夕食後にコーヒーや紅茶、緑茶、ウーロン茶、健康ドリンクなどカフェインを含む飲料を摂取しないこと、就寝時以外の睡眠(昼寝等)を禁止すること、脳波測定を開始した後に他の行動(読書や携帯電話操作等)を行わないこととした。 3. Study method The study was a randomized, double-blind, placebo-controlled, parallel-group study. Table 5 shows the test schedule. A staff member not involved in the study created an allocation table using random numbers, assigned allocation numbers to the test foods, and performed allocation. The randomization table was sealed, sealed and kept unopened until the subjects and data were fixed. One bag (6 grains) of the test food was ingested daily with water or lukewarm water without chewing. The intake period was 12 weeks. During the test period, participants should refrain from changing their lifestyle habits such as drinking, eating, and sleeping as much as possible from before participating in the test, limit excessive exercise that greatly deviates from their daily routine, diet and overeating, and use new health foods. It was decided to prohibit stress relief activities beyond the scope of daily life. Also, during the sleep EEG measurement period, do not drink alcohol, avoid taking medicines as much as possible, do not drink coffee, black tea, green tea, oolong tea, health drinks, etc. containing caffeine after dinner, sleep other than bedtime (nap, etc.) ), and other activities (reading, mobile phone operation, etc.) after starting electroencephalogram measurement.
有効性の評価は睡眠時脳波解析とピッツバーグ睡眠質問票(日本語版)(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、土井由利子、簑輪眞澄、大川匡子、内山真: ピッツバーグ睡眠質問票日本語版の作成. 精神科治療学 1998; 13 (6); 755-769)、POMS2成人用短縮版、アテネ式不眠尺度、s-IgA分泌速度、国際標準化身体活動質問票を用いて行った。 4. Evaluation items Efficacy was evaluated using EEG analysis during sleep and the Pittsburgh Sleep Questionnaire (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, Y. Doi, M. Minowa, K. Ohkawa, M. Uchiyama: Pittsburgh sleep Psychiatric Therapeutics 1998; 13 (6); 755-769). gone.
被験者背景を、性別にはχ2乗検定、その他の項目には2標本t検定を用いて評価した。睡眠時脳波解析、POMS2成人用短縮版、s-IgA分泌速度、国際標準化身体活動質問票の摂取後各時点の摂取前からの変化量について、被験食品摂取群をプラセボ摂取群に対して2標本t検定を用いて評価した。ピッツバーグ睡眠質問票(日本語版)とアテネ式不眠尺度の摂取後各時点の検査値を、Mann-WhitneyのU検定を用いて評価した。 5. Analysis method Subject background was evaluated using the chi-square test for sex and the two-sample t-test for other items. Regarding sleep electroencephalogram analysis, POMS2 adult shortened version, s-IgA secretion rate, change from before intake at each time point after intake of the international standardized physical activity questionnaire, two specimens of the test food intake group and the placebo intake group It was evaluated using the t-test. The values of the Pittsburgh Sleep Questionnaire (Japanese version) and the Athens Insomnia Scale at each time point after ingestion were evaluated using the Mann-Whitney U test.
1.被験者
被験者の選択、被験食品の割付から解析までの経過を図1に試験フローチャートとして示した。事前検査に参加した243名のうち、選択基準に合致し、除外基準に抵触しなかった122名に対し摂取前検査を実施し、80名を選択した。被験者背景を表6に示した。群間に有意な差がある項目は認められなかった。 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. Of the 243 persons who participated in the preliminary examination, 122 persons who met the selection criteria and did not meet the exclusion criteria were subjected to the pre-ingestion examination, and 80 persons were selected. Subject backgrounds are shown in Table 6. There were no items with significant differences between the groups.
80名の被験者のうち、2名が本人の自由意思により脱落した。その結果、所定の試験スケジュールと試験内容を終了した者は78名であった。試験を完遂した78名のうち、有効性の解析対象除外基準に抵触した4名を、割付表を開封する前に実施した解析対象者の検討において、有効性解析対象から除外した。また、12週目睡眠時脳波測定データが欠損となった2名と12週目睡眠時脳波測定時に歯痛が発現した1名は睡眠時脳波解析から除外した。 In some subjects, physical measurements or clinical test values were found to be outside the reference range, but they were included in the study after the investigator-in-charge confirmed that there were no problems with participating in the study.
Of the 80 subjects, 2 dropped out of their own free will. As a result, 78 people completed the prescribed test schedule and test content. Of the 78 subjects who completed the study, 4 subjects who met the exclusion criteria for efficacy analysis were excluded from the efficacy analysis subjects in the analysis subject review conducted before opening the randomization table. In addition, 2 subjects with missing electroencephalogram measurement data during the 12th week and 1 subject with toothache during the electroencephalogram measurement during the 12th week were excluded from the analysis of the electroencephalogram during sleep.
睡眠時脳波解析の結果を表7および表8に示した。ノンレム睡眠1の合計時間、第2睡眠周期の12週目の変化量は、被験食品摂取群においてプラセボ摂取群と比較して有意に小さかった。ノンレム睡眠3とレム睡眠の12週目の睡眠ステージの割合の変化量は、被験食品摂取群において、プラセボ摂取群と比較して有意に大きかった。また、各ノンレム睡眠1の睡眠ステージの割合は、群間で摂取前の値に不均衡が認められたため、12週目の値に共分散分析を実施したところ、被験食品摂取群の値はプラセボ摂取群と比較して有意に小さかった。その他の有効性評価項目に有意な差は認められなかった。 2. Efficacy Evaluation Tables 7 and 8 show the results of electroencephalogram analysis during sleep. The total time of non-REM sleep 1 and the amount of change in the 12th week of the second sleep cycle were significantly smaller in the test food intake group than in the placebo intake group. The amount of change in the sleep stage ratio of NREM sleep 3 and REM sleep at Week 12 was significantly greater in the test food intake group than in the placebo intake group. In addition, the ratio of sleep stages of each non-REM sleep 1 was found to be imbalanced in the values before intake between groups, so when analysis of covariance was performed on the values at week 12, the values of the test food intake group were the placebo It was significantly smaller than that of the ingested group. No significant differences were observed in other efficacy endpoints.
POMS2成人用短縮版の活気・活力(VA)の摂取前の値が50以上と50未満の集団で部分集団解析を行った。VA50未満の集団において、ピッツバーグ睡眠質問票の日中覚醒困難およびPOMS2成人用短縮版の抑うつ・落込み(DD)、緊張・不安(TA)、活気・活力(VA)、総合的気分状態(TMD)は、被験食品摂取群でプラセボ摂取群と比較して有意に改善した(表9、10)。 3. Subpopulation Analysis Subpopulation analysis was performed on the population with pre-ingestion values of Vitality and Vitality (VA) of 50 or more and less than 50 for the POMS2 adult abbreviated version. Pittsburgh Sleep Questionnaire Daytime Arousal Difficulty and POMS2 Adult Short Version Depression/Depression (DD), Tension/Anxiety (TA), Vitality/Vitality (VA), Global Mood State (TMD) in the VA<50 population ) was significantly improved in the test food intake group compared with the placebo intake group (Tables 9 and 10).
有害事象は、被験食品摂取群に11名14件、プラセボ摂取群に13名18件発現した。すべての有害事象について、被験食品との関連性はないと実施医師責任者は判断した。身体測定値、理学検査値、臨床検査値について、事前と比べて摂取後の各時点に有意な変化が見られた項目が散見されたが、いずれも基準値内の軽微な変化であり、実施医師責任者は臨床的に問題ないと判断した。 4. Safety Evaluation Adverse events occurred in 14 cases in 11 subjects in the test food intake group and 18 cases in 13 subjects in the placebo intake group. All adverse events were judged by the principal investigator to be unrelated to the study food. Regarding physical measurements, physical examination values, and laboratory test values, there were some items that showed significant changes at each time point after ingestion compared to before, but all were minor changes within the reference values. The medical director judged that there was no clinical problem.
本試験ではONO-SR/AST-DAの睡眠の質改善効果を検討することを目的として、日常生活において、睡眠不足・ストレスを自覚している年齢が20歳以上64歳以下の男女を対象に、ONO-SR/AST-DAまたはプラセボを1日に1袋(6粒)を12週間摂取させる無作為化二重盲検プラセボ対照並行群間比較試験を実施した。 Discussion In this study, for the purpose of examining the sleep quality improvement effect of ONO-SR / AST-DA, subjects were men and women aged 20 to 64 who were aware of sleep deprivation and stress in their daily lives. In addition, a randomized, double-blind, placebo-controlled, parallel-group study was conducted with ONO-SR/AST-DA or placebo taking one bag (6 tablets) daily for 12 weeks.
本試験の結果から、被験食品摂取によりノンレム睡眠3とレム睡眠の割合を増加させることによる睡眠の質の改善効果が示された。また、活気・活力が低めの人に対し、被験食品摂取による日中の眠気の改善や抗ストレス作用が示唆された。 Conclusion The results of this study showed that intake of the test food improved sleep quality by increasing the ratio of non-REM sleep 3 and REM sleep. In addition, it was suggested that ingestion of the test food improved daytime sleepiness and had an anti-stress effect for people with low vigor and vitality.
1.被験者
本試験では、イクラオイル、アスタキサンチンおよび精製深海鮫肝油含有食品「ONO-SR/AST-DA」の過剰摂取時(5倍量)の安全性を確認することを目的とした。食品の安全性を検討する際は、幅広い年齢層、性別での実施、検討が望ましいため、20~60代の各世代男女がなるべく均等に組み入れられるよう被験者数を20名とした。試験の実施に先立ち、被験者に対して同意説明文書を交付のうえ、試験の趣旨および内容を十分に説明し、被験者の自由意思に基づく同意を文書で取得した。同意の取得できた被験者に事前検査(生活習慣アンケート、問診、身体測定、理学検査、空腹時臨床検査)を実施した。事前検査の結果から、以下の除外基準に該当しない被験者を選択した。 <Safety evaluation by overdose test>
1. Subjects The purpose of this test was to confirm the safety of overdose (5 times the amount) of salmon roe oil, astaxanthin and purified deep sea shark liver oil-containing food "ONO-SR/AST-DA". When examining food safety, it is desirable to conduct and examine a wide range of age groups and genders, so the number of subjects was set at 20 so that men and women of each generation in their 20s to 60s could be included as evenly as possible. Prior to conducting the study, we provided the subjects with a written informed consent form, fully explained the purpose and content of the study, and obtained their voluntary consent in writing. 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.
被験食品は「ONO-SR/AST-DA」であり、5袋、30粒あたりイクラオイル5g(DHA750mg、EPA300mg)、アスタキサンチン1,000μg、精製深海鮫肝油(DAGE1,800mg)を含有した。 2. Test Food The test food was "ONO-SR/AST-DA", which contained 5 g of salmon roe oil (DHA 750 mg, EPA 300 mg), astaxanthin 1,000 μg, and refined deep-sea shark liver oil (DAGE 1,800 mg) per 30 grains in 5 bags.
試験はオープン試験とした。1日に5袋(30粒)を、水またはぬるま湯とともに噛まずに摂取させた。なお、摂取時間は規定せず、1日の中で複数回に分けて飲むことを許可した。摂取期間は4週間とした。試験期間中は、試験参加前からの飲酒、食事、睡眠等の生活習慣を極力変えないこと、日常範囲を大きく逸脱する過度な運動、節食や過食を制限すること、新たに運動を始めないこと、またそれまで続けていた運動習慣を中止しないこととした。 3. Test method The test was an open study. Five sachets (30 grains) were ingested daily with water or lukewarm water without chewing. 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 test, limit excessive exercise that greatly deviates from your daily range, diet and overeating, and do not start new exercise , and decided not to stop the exercise habits that had been continued until then.
問診により、体調の確認、有害事象の有無の確認を行った。身体測定として、身長(事前検査のみ)、体重、BMIを測定した。理学検査として、収縮期および拡張期血圧、脈拍数を測定した。空腹時臨床検査として、血液学的検査(白血球数、赤血球数、ヘモグロビン、ヘマトクリット、血小板数)、血液生化学検査(総蛋白、アルブミン、総ビリルビン、直接ビリルビン、間接ビリルビン、ALP、AST、ALT、LD、γ-GT、総コレステロール、中性脂肪、HDL-コレステロール、LDL-コレステロール、尿素窒素、クレアチニン、尿酸、ナトリウム、カリウム、クロール、血糖、HbA1c(事前検査のみ))、尿検査(蛋白定性、糖定性、潜血反応)を実施した。事前検査のみとする項目を除き、各検査は事前検査時、摂取2週目、摂取4週目、摂取終了2週目に行った。 4. Inspection items/Evaluation items Physical condition was checked and the presence or absence of adverse events was checked by interview. As physical measurements, height (preliminary examination only), weight, and BMI were measured. Systolic and diastolic blood pressure and pulse rate were measured as physical examinations. Fasting clinical tests include hematological tests (white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count), blood biochemical tests (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, chlorine, blood sugar, HbA1c (preliminary test only)), urinalysis (protein qualitative, sugar qualitative, occult blood reaction) were performed. Each test was conducted at the time of the pre-inspection, 2 weeks after the intake, 4 weeks after the intake, and 2 weeks after the end of the intake, except for the items for which only the preliminary inspection was performed.
事前と摂取後の各時点の測定値を、1標本t検定を用いて比較した。検定の有意水準は両側5%とした。統計解析ソフトウェアはMicrosoft Excel (マイクロソフト社)を用いた。 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.
1.被験者背景
文書にて試験参加に同意を得られた被験者48名に対して事前検査を行った。事前検査の結果に基づき、選択基準に該当し、除外基準に該当しない男性10名、女性10名、合計20名を本試験に適格な被験者として選択した。なお、一部の被験者では、臨床検査値に基準範囲(臨床検査実施機関の検査基準値)を超える項目が見られたが、いずれも実施医師責任者が被験者毎に検討し、試験参加に問題がないと判断した後、本試験に組み入れた。20名全員が被験食品の摂取を開始し、全員が被験食品の摂取を完了、所定の試験スケジュールや試験内容を完遂した。よって、有害事象、測定値および検査値は、20名全員を解析対象者として評価した。 Results 1. Background of Subjects Preliminary examination was performed on 48 subjects who gave written consent to participate in the study. A total of 20 subjects, 10 males and 10 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. In addition, in some subjects, items exceeding the reference range (testing standard values of the laboratory performing the clinical testing) were found in some subjects, but the investigator responsible investigator examined each subject, and there was a problem in participating in the study. was included in the study after it was determined to be absent. All of the 20 subjects started ingesting the test food, all of them completed the ingestion of the test food, and completed the prescribed test schedule and test content. Therefore, all 20 subjects were analyzed for adverse events, measured values, and laboratory values.
被験者毎の測定値または検査値の変動は、5名に7件見られた。測定値または検査値の変動は、いずれも異常変動ではない(有害事象ではない)と判断された。有害事象の発現頻度および延べ発現件数は、20名中8名(40%)15件であった。いずれの有害事象も程度は「軽度」であり、本試験で重篤な有害事象は発現しなかった。また、被験食品との関連性は「なし」と判断された。 2. Adverse Events Variations in measured values or laboratory values for each subject were observed in 7 events in 5 subjects. Any variation in measurements or laboratory values was considered non-abnormal (not an adverse event). The frequency and total number of adverse events were 15 events in 8 of 20 patients (40%). 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."
身体測定値、理学検査値、臨床検査値(血液学的検査、血液生化学検査)について、事前と比べて摂取後に有意な変化が見られた項目が散見されたが、実施医師責任者はいずれも臨床的に問題はないレベルの変化と判断した。 3. Measured Values and Test Values Regarding physical measurements, physical test values, and clinical test values (hematological tests, blood biochemical tests), there were some items that showed significant changes after ingestion compared to before, but the implementation The chief physician judged that the changes were at a clinically non-problematic level.
以上の結果から、イクラオイル、アスタキサンチンおよび精製深海鮫肝油含有食品「ONO-SR/AST-DA」を1日摂取目安量の5倍量で4週間連続摂取する過剰摂取試験を実施した場合、安全性に問題ないことが示された。 Conclusion From the above results, when an overdose test was conducted in which salmon roe oil, astaxanthin, and refined deep-sea shark liver oil-containing food "ONO-SR/AST-DA" were continuously ingested at 5 times the recommended daily intake for 4 weeks, It was shown that there is no problem with safety.
Claims (16)
- 魚卵脂質調製物およびジアシルグリセリルエーテル(DAGE)を含む、睡眠の質を改善するための組成物。 A composition for improving sleep quality comprising a fish egg lipid preparation and diacylglyceryl ether (DAGE).
- リン脂質を約30%以上含む魚卵脂質調製物を含む、請求項1に記載の組成物。 The composition of claim 1, comprising a fish egg lipid preparation containing about 30% or more phospholipids.
- 魚卵脂質調製物がドコサヘキサエン酸(DHA)結合リン脂質を含み、脂質の構成脂肪酸に占めるDHAの組成比が約15%以上である、請求項1または2に記載の組成物。 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.
- DAGEが深海鮫肝油に由来するものである、請求項1~3のいずれかに記載の組成物。 The composition according to any one of claims 1 to 3, wherein the DAGE is derived from deep sea shark liver oil.
- 1日摂取量として、約100mg~750mgのDHAが摂取されるように調製されている、請求項1~4のいずれかに記載の組成物。 The composition according to any one of claims 1 to 4, which is prepared so that the daily intake is about 100 mg to 750 mg of DHA.
- 1日摂取量として、約160mgのDHAが摂取されるように調製されている、請求項1~5のいずれかに記載の組成物。 The composition according to any one of claims 1 to 5, which is prepared so that the daily intake is about 160 mg of DHA.
- 1日摂取量として、約100mg~750mgのDHA、約30mg~300mgのエイコサペンタエン酸(EPA)、および、約180mg~1800mgのDAGEが摂取されるように調製されている、請求項1~4のいずれかに記載の組成物。 According to claims 1 to 4, prepared so that the daily intake is about 100 mg to 750 mg of DHA, about 30 mg to 300 mg of eicosapentaenoic acid (EPA), and about 180 mg to 1800 mg of DAGE. A composition according to any of the preceding claims.
- 1日摂取量として、約160mgのDHA、約100mgのEPA、および、約360mgのDAGEが摂取されるように調製されている、請求項7に記載の組成物。 The composition according to claim 7, which is prepared so that the daily intake is about 160 mg of DHA, about 100 mg of EPA, and about 360 mg of DAGE.
- 少なくとも12週間にわたって毎日摂取される、請求項1~8のいずれかに記載の組成物。 The composition according to any one of claims 1 to 8, which is taken daily for at least 12 weeks.
- 睡眠の質の改善が、深睡眠とレム睡眠のバランスの改善、深睡眠の割合の増加、レム睡眠の割合の増加、ノンレム睡眠ステージ1の減少、覚醒の割合の減少、および睡眠効率の改善から選択される1つ以上の項目を含む、請求項1~9のいずれかに記載の組成物。 The improvement in sleep quality was derived from an improvement in the balance of deep sleep and REM sleep, an increase in the percentage of deep sleep, an increase in the percentage of REM sleep, a decrease in NREM stage 1, a decrease in the percentage of wakefulness, and an improvement in sleep efficiency. A composition according to any preceding claim, comprising one or more selected items.
- 睡眠の質の改善が、深睡眠とレム睡眠のバランスの改善、深睡眠の割合の増加、レム睡眠の割合の増加、および、ノンレム睡眠ステージ1の減少から選択される1つ以上の項目を含む、請求項1~10のいずれかに記載の組成物。 Improving sleep quality comprises one or more items selected from improving the balance of deep sleep and REM sleep, increasing the percentage of deep sleep, increasing the percentage of REM sleep, and decreasing non-REM sleep stage 1. , a composition according to any one of claims 1 to 10.
- 睡眠の質の改善が、深睡眠とレム睡眠のバランスの改善である、請求項1~11のいずれかに記載の組成物。 The composition according to any one of claims 1 to 11, wherein the improvement in sleep quality is an improvement in the balance between deep sleep and REM sleep.
- 睡眠の質の改善が、深睡眠の割合の増加、レム睡眠の割合の増加およびノンレム睡眠ステージ1の減少である、請求項1~12のいずれかに記載の組成物。 The composition according to any one of claims 1 to 12, wherein the improvement in sleep quality is an increase in the percentage of deep sleep, an increase in the percentage of REM sleep and a decrease in non-REM sleep stage 1.
- 魚卵脂質調製物およびDAGEを含む、日常生活で活気または活力が低下している対象において、不安感、緊張感、ゆううつな気分、抑うつ、落込み、活気、活力、総合的気分状態および日中の眠気の少なくとも1つを改善するための組成物。 Anxiety, Tension, Depressed Mood, Depression, Depression, Vigor, Vitality, Global Mood State and Daytime in Subjects with Decreased Vigor or Vitality in Daily Life, including fish egg lipid preparations and DAGE A composition for ameliorating at least one of the drowsiness of
- 医薬組成物である、請求項1~14のいずれかに記載の組成物。 The composition according to any one of claims 1 to 14, which is a pharmaceutical composition.
- 食品組成物である、請求項1~14のいずれかに記載の組成物。 The composition according to any one of claims 1 to 14, which is a food composition.
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Citations (3)
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JP2010053054A (en) * | 2008-08-27 | 2010-03-11 | Nof Corp | Method of ameliorating sleep |
JP2012519199A (en) * | 2009-03-04 | 2012-08-23 | ネステク ソシエテ アノニム | Methods for increasing endogenous plasmalogen levels in mammals |
JP2018043948A (en) * | 2016-09-14 | 2018-03-22 | マルハニチロ株式会社 | Sleep quality improving agent containing docosahexaenoic acid |
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2022
- 2022-03-30 CN CN202280023435.0A patent/CN117042784A/en active Pending
- 2022-03-30 TW TW111112095A patent/TW202304484A/en unknown
- 2022-03-30 JP JP2023511471A patent/JPWO2022210856A1/ja active Pending
- 2022-03-30 WO PCT/JP2022/015891 patent/WO2022210856A1/en active Application Filing
- 2022-03-30 KR KR1020237032527A patent/KR20230164033A/en unknown
Patent Citations (3)
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JP2010053054A (en) * | 2008-08-27 | 2010-03-11 | Nof Corp | Method of ameliorating sleep |
JP2012519199A (en) * | 2009-03-04 | 2012-08-23 | ネステク ソシエテ アノニム | Methods for increasing endogenous plasmalogen levels in mammals |
JP2018043948A (en) * | 2016-09-14 | 2018-03-22 | マルハニチロ株式会社 | Sleep quality improving agent containing docosahexaenoic acid |
Non-Patent Citations (2)
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ANONYMOUS: "Deep sea drops (boxed) 2 pieces | Squalane Honpo ~Squalane from Okinawa~", SQUALENE HOMPO CO. LTD., 16 June 2017 (2017-06-16), XP055973239, Retrieved from the Internet <URL:http://squalane-h.com/2199.html> [retrieved on 20221020] * |
NAKAGAWA, HAGUMI ET AL.: "Effect of a supplement product containing salmon roe oil-derived DHA and EPA and deep-sea shark liver oil-derived DAGE on the sleep quality and stress in healthy adults who have difficulties sleeping - A randomized, double-blind, placebo controlled, parallel group study -", JAPANESE PHARMACOLOGY AND THERAPEUTICS, RAIFU SAIENSU SHUPPAN, TOKYO., JP, vol. 49, no. 6, 20 June 2021 (2021-06-20), JP , pages 977 - 990, XP009540119, ISSN: 0386-3603 * |
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TW202304484A (en) | 2023-02-01 |
KR20230164033A (en) | 2023-12-01 |
JPWO2022210856A1 (en) | 2022-10-06 |
CN117042784A (en) | 2023-11-10 |
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