Composition for improving sleep containing ergothioneine or salt thereof

Abstract

To provide a composition for improving sleep containing a highly safe substance as an active ingredient, and to provide a method for improving sleep.SOLUTION: The present invention provides a composition for improving sleep and the like containing L-ergothioneine or a salt thereof as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for improving sleep. The present invention also relates to a method for improving sleep. [Background technology]

[0002] Sleep is an important physiological activity that accounts for approximately one-third of our lives. In recent years, an increasing number of people are dissatisfied with the quality of their sleep due to factors such as disrupted daily rhythms, stress, and an aging population. Symptoms of poor sleep quality include extended sleep onset latency (difficulty falling asleep), early morning awakening (waking up early in the morning), waking up mid-night (waking up multiple times during the night), and insufficient deep sleep (feeling like you haven't slept well or that your sleep was shallow).

[0003] To improve the quality of sleep, treatment with sleeping pills is also performed. However, since sleeping pills have problems such as side effects and anxiety about taking them, development of food-derived substances that can improve the quality of sleep is being carried out. For example, Patent Document 1 describes an oral sleep-improving agent containing at least one active ingredient selected from the group consisting of menthol and its glycosides.

[0004] Ergothioneine is an amino acid found in mushrooms and the like, and naturally exists in the L-form. Patent Document 2 describes an agent that promotes the production and / or secretion of antimicrobial substances in Paneth cells, containing ergothioneine extracted from mushrooms as an active ingredient. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 2019-6717 [Patent Document 2] Japanese Patent Application Laid-Open No. 2012-180329 Summary of the Invention [Problem to be solved by the invention]

[0006] Patent Documents 1 and 2 do not state that L-ergothioneine or a salt thereof is effective in improving sleep.

[0007] An object of the present invention is to provide a composition for improving sleep that contains a highly safe substance as an active ingredient. Another object of the present invention is to provide a method for improving sleep. [Means for solving the problem]

[0008] As a result of extensive research aimed at solving the above problems, the present inventors have found that L-ergothioneine has a sleep-improving effect.

[0009] That is, the present invention relates to the following sleep-improving compositions, etc. [1] A sleep-improving composition containing L-ergothioneine or a salt thereof as an active ingredient. [2] The sleep improvement composition described in [1] above, wherein the sleep improvement is one or more of the following selected from the group consisting of shortening sleep onset latency, reducing the time and number of awakenings during sleep, and increasing the proportion of non-REM sleep time to total sleep time. [3] A sleep-improving composition according to [1] or [2] above, which is an oral composition. [4] The sleep-improving composition according to any one of [1] to [3] above, which is a food or drink. [5] A method for improving sleep by administering L-ergothioneine or a salt thereof. [6] Use of L-ergothioneine or a salt thereof to improve sleep. [Effects of the Invention]

[0010] According to the present invention, a sleep-improving composition containing a highly safe substance as an active ingredient is provided, and according to the present invention, a sleep-improving method can be provided. [Brief explanation of the drawings]

[0011] [Figure 1]Figure 1 is a graph showing the duration of each sleep stage (non-REM sleep or REM sleep) and total sleep time during the light phase in the control group (stress (-)), non-administration group (stress (+), ergothioneine administration (-)), and ergothioneine administration group (stress (+), ergothioneine administration (+)). [Figure 2] FIG. 2 is a graph showing the results of evaluating the effect of L-ergothioneine on the number of fragmented episodes in each sleep stage during the light phase and the total number of fragmented episodes during sleep. [Figure 3] Figure 3 is a graph showing the results of evaluating the latency to the first appearance of non-REM sleep after the start of the light phase in the control group (stress (-)), non-administration group (stress (+), ergothioneine administration (-)), and ergothioneine administration group (stress (+), ergothioneine administration (+)). [Figure 4] FIG. 4 is a graph showing the proportion of non-REM sleep stage 1 (N1) to total sleep time in the control food group and the test food group. [Figure 5] FIG. 5 is a graph showing the proportion of non-REM sleep stage 2 (N2) to total sleep time in the control food group and the test food group. [Figure 6] FIG. 6 is a graph showing the proportion of non-REM sleep stage 3 (N3) to total sleep time in the control food group and the test food group. [Figure 7] FIG. 7 is a graph showing the change in the proportion of non-REM sleep stages relative to total sleep time in the control food group and the test food group. [Figure 8] FIG. 8 is a graph showing the number of times people woke up during the night in the control food group and the test food group. [Figure 9] FIG. 9 is a graph showing the change in the number of awakenings during the night in the control food group and the test food group. [Figure 10] FIG. 10 is a graph showing the number of awakenings during the two hours before waking up in the control food group and the test food group. [Figure 11] FIG. 11 is a graph showing the change in the number of awakenings during the two hours before waking up in the control food group and the test food group. [Figure 12] FIG. 12 is a graph showing non-REM sleep latency in the control food group and the test food group. [Figure 13] FIG. 13 is a graph showing the change in non-REM sleep latency in the control food group and the test food group. [Figure 14] FIG. 14 is a graph showing the delta power of the first sleep cycle in the control food group and the test food group. [Figure 15] FIG. 15 is a graph showing the amount of change in delta power in the first sleep cycle in the control food group and the test food group. [Figure 16] FIG. 16 is a graph showing sleep efficiency in the control food group and the test food group. [Figure 17] FIG. 17 is a graph showing the change in sleep efficiency in the control food group and the test food group. [Figure 18] FIG. 18 is a graph showing sleep time in the control food group and the test food group. [Figure 19] FIG. 19 is a graph showing the change in sleep time in the control food group and the test food group. [Figure 20] FIG. 20 is a graph showing plasma L-ergothioneine concentrations in the control food group and the test food group. DETAILED DESCRIPTION OF THE INVENTION

[0012] The sleep-improving composition of the present invention contains L-ergothioneine or a salt thereof as an active ingredient. In the present invention, improving sleep refers to improving sleep quality and / or increasing sleep duration. The sleep-improving composition of the present invention can improve sleep quality by containing L-ergothioneine or a salt thereof as an active ingredient. In one embodiment, L-ergothioneine or a salt thereof is effective for increasing sleep duration. The sleep-improving composition of the present invention can be used to improve sleep quality and / or increase sleep duration. In one embodiment, the sleep-improving composition of the present invention is preferably used for improving sleep quality. L-ergothioneine or a salt thereof is a compound that is contained in natural products and foods and beverages and has been consumed as a dietary source. Therefore, from the viewpoint of safety, L-ergothioneine or a salt thereof is considered to pose few problems, for example, when taken over a long period of time.

[0013] The salt of L-ergothioneine is not particularly limited as long as it is a pharmacologically acceptable salt or a salt acceptable for use in foods and beverages, and may be either an acidic salt or a basic salt. Examples of acidic salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate; and organic acid salts such as acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate, and propionate. Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt.

[0014] L-ergothioneine or its salts may be chemically synthesized or extracted and purified from natural sources. L-ergothioneine is found in large amounts in the Golden / Yellow Oyster mushroom (scientific name: Pleurotus cornucopiae var. citrinopileatus), a mushroom of the Pleurotus genus in the family Pleurocystis. L-ergothioneine is also found in mushrooms such as white button mushrooms, crimini mushrooms, and portabella mushrooms (Agaricus bisporus), grey oyster mushrooms (Pleurotus ostreatus), shiitake mushrooms (Lentinula edodes), maitake mushrooms (Grifola Frondosa), reishi mushrooms (Ganoderma lucidum), Yamabushitake mushrooms (Hericium erinaceus), willow matsutake mushrooms (Agrocybe aegerita), chanterelles (Cantharellus cibarius), porcini mushrooms (Boletus edulis), and morels (Morchella esculenta). When L-ergothioneine is obtained from a natural product, it is preferably extracted from Pleurotus cornucopiae. L-ergothioneine or a salt thereof can also be produced by microbial fermentation. An extract containing L-ergothioneine or a salt thereof produced by microbial fermentation, or a product purified therefrom, may be used. Extraction and purification from natural products can be carried out by known methods. L-ergothioneine or a salt thereof may be isolated. In the present invention, a mushroom extract containing L-ergothioneine or a salt thereof may be included in the composition of the present invention, as long as the effects of the present invention are achieved.

[0015] Examples of improvements in sleep quality in the present invention include shortening sleep onset latency (the time from waking to falling asleep), reducing the number and duration of awakenings, and increasing the proportion of non-REM sleep (non-rapid eye movement sleep) time relative to total sleep time. Sleep quality in the present invention can be evaluated, for example, using as an index the sleep onset latency, the number and duration of awakenings, or the proportion of non-REM sleep time relative to total sleep time. Sleep quality can also be evaluated using as an index the non-REM sleep latency (the latency until the first onset of non-REM sleep). Non-REM sleep time and sleep onset latency can be evaluated in humans by non-invasive measurement methods such as electroencephalography. The sleep-improving effect of the present invention can be evaluated, for example, by orally ingesting or administering the sleep-improving composition of the present invention to a subject or test animal (e.g., mouse, rat), and then examining the quality of sleep or sleep time after oral ingestion or administration using the methods described above.

[0016] As shown in the Examples below, stressed rats showed a decrease in sleep quality, a prolongation of sleep onset latency, an increase in the number and duration of awakenings, and a decrease in non-REM sleep time relative to total sleep time (an increase in REM sleep (rapid eye movement sleep) time). In rats that were orally administered L-ergothioneine, the sleep onset latency, which had been prolonged by stress, was shortened. Furthermore, L-ergothioneine intake reduced the number and duration of awakenings. L-ergothioneine increased the proportion of non-REM sleep time relative to total sleep time. In the examples described below, subjects ingested a food containing L-ergothioneine, and their electroencephalograms during sleep were measured to evaluate sleep quality and sleep duration. As a result, L-ergothioneine intake increased the proportion of non-REM sleep time relative to total sleep time compared to non-intake. Furthermore, L-ergothioneine intake reduced the number and duration of awakenings during sleep. L-ergothioneine shortened non-REM sleep latency and sleep onset latency. Furthermore, L-ergothioneine intake tended to increase the proportion of non-REM sleep stage 3 and the delta power value of the first sleep cycle, thereby increasing the proportion of deep sleep. L-ergothioneine intake also improved sleep efficiency. Furthermore, L-ergothioneine intake increased sleep duration. Therefore, L-ergothioneine or a salt thereof has the effect of improving sleep and can be used as an active ingredient in a composition for improving sleep.

[0017] In one embodiment, the sleep-improving composition of the present invention can be used to improve one or more sleep outcomes selected from the group consisting of shortening sleep onset latency, reducing the duration and number of awakenings, increasing the proportion of non-REM sleep time to total sleep time, and increasing sleep time. In one embodiment, the sleep-improving composition of the present invention can be preferably used to improve one or more sleep outcomes selected from the group consisting of shortening sleep onset latency, reducing the duration and number of awakenings, and increasing the proportion of non-REM sleep time to total sleep time. Furthermore, L-ergothioneine or a salt thereof can be used to improve sleep quality reduced by stress, for example, to improve one or more sleep outcomes selected from the group consisting of shortening sleep onset latency increased by stress, reducing the number and duration of awakenings increased by stress, and increasing non-REM sleep time to total sleep time decreased by stress. Non-REM sleep can be divided into three stages, for example, stages 1 to 3, depending on the depth of sleep. Stage 3 is deep sleep. In the present invention, an increase in the proportion of non-REM sleep time to total sleep time may refer to an increase in the proportion of total non-REM sleep time to total sleep time and / or an increase in the proportion of non-REM sleep stage 3. In one embodiment, the increase in the proportion of non-REM sleep time relative to total sleep time preferably refers to an increase in the proportion of non-REM sleep stage 3 relative to total sleep time. Non-REM sleep stages 1 to 3 can be distinguished from sleep electroencephalograms. In the present invention, non-REM sleep stages 1, 2, and 3 refer to non-REM sleep stages 1, 2, and 3, which are classified according to the depth of sleep in an electroencephalogram measurement using an electroencephalogram (product name) electroencephalogram meter "SleepScope" manufactured by SleepWell Co., Ltd. or an equivalent electroencephalogram measurement method using the electroencephalogram meter. The sleep-improving composition of the present invention is highly effective in resolving sleep-related complaints, such as difficulty falling asleep or shallow sleep (improving sleep onset, improving deep sleep insufficiency (deep sleep disorders), etc.). The sleep-improving composition of the present invention can be used, for example, to prevent or improve conditions or diseases such as sleep disorders. The sleep disorder may be a stress-induced sleep disorder. Sleep disorders include sleep abnormalities such as insomnia. Insomnia refers to the presence of any of the following symptoms: sleep onset disorder (difficulty falling asleep), waking up during the night, waking up early in the morning, and insufficient deep sleep. The insomnia may be stress-induced insomnia. In one aspect, the sleep-improving composition of the present invention can be used to improve one or more insomnia conditions selected from the group consisting of sleep onset disorder, waking up during the night, waking up early in the morning, and insufficient deep sleep. In one aspect, the sleep-improving composition of the present invention can be preferably used to improve waking up during the night, particularly to reduce the duration and frequency of waking up during the night. Preventing a condition or disease includes preventing the onset, delaying the onset, reducing the incidence, reducing the risk of onset, etc. Ameliorating a condition or disease includes recovering a subject from the condition or disease, alleviating the symptoms of the condition or disease, ameliorating the symptoms of the condition or disease, delaying or preventing the progression of the condition or disease, etc.

[0018] The sleep-improving composition of the present invention can be used for either therapeutic (medical) or non-therapeutic (non-medical) purposes. Non-therapeutic uses do not include medical procedures, i.e., surgery, treatment, or diagnosis of humans. The sleep-improving composition of the present invention can be in the form of, for example, a food or drink, a medicine, a quasi-drug, a feed, etc. The sleep-improving composition of the present invention may itself be a food or drink, a medicine, a quasi-drug, a feed, etc. for improving sleep, or may be a material or preparation to be blended into these. The sleep-improving composition of the present invention can be provided in the form of a drug, for example, but is not limited to this form. The drug can be provided as a composition itself, or as a composition containing the drug. In one aspect, the sleep-improving composition of the present invention can also be referred to as a sleep-improving agent. To fully achieve the effects of the present invention, the sleep-improving composition of the present invention is preferably an oral composition, such as a food or drink, an oral drug, a quasi-drug, or a feed, preferably a food or drink or an oral drug, more preferably a food or drink.

[0019] The sleep-improving composition of the present invention can contain any additives and any components in addition to L-ergothioneine or a salt thereof, as long as the effects of the present invention are not impaired. These additives and components can be selected depending on the form of the composition, and those that can generally be used in foods and beverages, pharmaceuticals, quasi-drugs, feed, etc. can be used. When the sleep-improving composition is made into a food or beverage, pharmaceutical, quasi-drug, feed, etc., there are no particular limitations on the manufacturing method, and it can be manufactured by a general method.

[0020] For example, when the sleep-improving composition of the present invention is made into a food or beverage, various foods and beverages can be prepared by blending L-ergothioneine or a salt thereof with ingredients that can be used in foods and beverages (e.g., food ingredients, food additives used as needed, etc.). The foods and beverages are not particularly limited, and examples include general foods and beverages, health foods, health drinks, functional foods, foods for specified health uses, health supplements, foods and beverages for patients, etc. The health foods, functional foods, foods for specified health uses, health supplements, etc. can be prepared in various dosage forms, such as fine granules, tablets, granules, powders, capsules, chewable tablets, syrups, liquids, and liquid diets.

[0021] When the sleep-improving composition of the present invention is used as a pharmaceutical or quasi-drug, for example, L-ergothioneine or a salt thereof can be combined with a pharmacologically acceptable carrier and, if necessary, additives to produce a pharmaceutical or quasi-drug in various dosage forms. Such carriers, additives, etc. may be any pharmacologically acceptable carriers that can be used in pharmaceuticals or quasi-drugs, and may include, for example, one or more of excipients, binders, disintegrants, lubricants, antioxidants, colorants, etc. Pharmaceuticals or quasi-drugs may be administered orally or parenterally, with oral administration being preferred to achieve the full benefits of the present invention. When the sleep-improving composition of the present invention is used as a pharmaceutical or quasi-drug, oral administration is preferred. Dosage forms for oral administration include liquids, tablets, powders, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, chewable tablets, etc. Dosage forms for parenteral administration include injections and infusions. The pharmaceutical products and quasi-drugs may be for non-human animals.

[0022] When the sleep-improving composition of the present invention is used as feed, L-ergothioneine or a salt thereof may be blended into the feed. Feed also includes feed additives. Examples of feed include livestock feed for cows, pigs, chickens, sheep, horses, etc.; small animal feed for rabbits, rats, mice, etc.; and pet food for dogs, cats, small birds, etc.

[0023] The content of L-ergothioneine or a salt thereof in the sleep-improving composition of the present invention is not particularly limited and can be set depending on the form, etc. The content of L-ergothioneine or a salt thereof in the sleep-improving composition of the present invention is, for example, preferably 0.0001 wt% or more, more preferably 0.001 wt% or more, and preferably 90 wt% or less, more preferably 50 wt% or less, calculated as L-ergothioneine in the composition. In one aspect, the content of L-ergothioneine or a salt thereof in the sleep-improving composition is preferably 0.0001 to 90 wt% or more, more preferably 0.001 to 50 wt%, calculated as L-ergothioneine. In one aspect, when the sleep-improving composition of the present invention is used in foods and beverages, pharmaceuticals, quasi-drugs, feeds, etc., the content of L-ergothioneine or a salt thereof is preferably within the above-mentioned range.

[0024] The sleep-improving composition of the present invention can be ingested or administered in an appropriate manner depending on its form. From the viewpoint of fully obtaining the effects of the present invention, the sleep-improving composition of the present invention is preferably ingested orally (administered orally). The intake amount (which can also be called the administration amount) of the sleep-improving composition of the present invention is not particularly limited, and may be an amount that provides a sleep-improving effect (in one embodiment, preferably an effect of improving sleep quality), and may be appropriately set depending on the administration form, administration method, subject's body weight, etc.

[0025] In one embodiment, when the sleep-improving composition of the present invention is orally ingested or administered to a human (adult) subject, the intake amount of L-ergothioneine or a salt thereof per day per 60 kg body weight is preferably 1 mg or more, more preferably 5 mg or more, even more preferably 10 mg or more, and preferably 500 mg or less, more preferably 200 mg or less, even more preferably 100 mg or less, and particularly preferably 50 mg or less. In another embodiment, when the sleep-improving composition of the present invention is orally ingested or administered to a human (adult) subject, the intake amount of L-ergothioneine or a salt thereof per day per 60 kg body weight can be less than 50 mg or 45 mg or less in terms of L-ergothioneine. In one embodiment, when orally ingested or administered to a human (adult), the intake amount of L-ergothioneine or a salt thereof is preferably 1 to 500 mg, more preferably 5 to 200 mg, even more preferably 10 to 100 mg, and particularly preferably 10 to 50 mg, per 60 kg body weight per day, in terms of L-ergothioneine. The intake amount of L-ergothioneine or a salt thereof may be 10 mg or more but less than 50 mg, or even 10 to 45 mg, per 60 kg body weight per day. The above amount is preferably ingested or administered once or more times a day, for example, once a day or in divided doses (e.g., 2 to 3 times a day). In one embodiment of the present invention, the sleep-improving composition may be an oral composition for ingesting or administering the above amount of L-ergothioneine or a salt thereof per 60 kg body weight per day to a human. In one embodiment, when the sleep-improving composition of the present invention is parenterally administered to a human (adult), the dose of L-ergothioneine or a salt thereof is, for example, preferably 1 to 500 mg, more preferably 5 to 200 mg, even more preferably 10 to 100 mg, and particularly preferably 10 to 50 mg, per day per 60 kg body weight, in terms of L-ergothioneine. When parenterally administered to a human (adult), the dose of L-ergothioneine or a salt thereof may be 10 mg or more but less than 50 mg, or may be 10 to 45 mg, per day per 60 kg body weight, in terms of L-ergothioneine.

[0026] It is expected that continuous ingestion or administration of L-ergothioneine or a salt thereof will produce a more excellent sleep-improving effect. Therefore, in a preferred embodiment, the sleep-improving composition of the present invention is continuously ingested or administered. In one embodiment of the present invention, the sleep-improving composition is preferably ingested or administered continuously for one week or more, more preferably two weeks or more.

[0027] The subject to which the sleep-improving composition of the present invention is ingested or administered (also referred to as the administration subject) is not particularly limited. The subject is preferably a human or a non-human mammal, more preferably a human. Subjects to whom the sleep-improving composition of the present invention is administered or ingested include those who need or desire improved sleep, such as those who need or desire improved sleep quality or those who need or desire increased sleep time. Subjects to whom the composition is administered include, for example, humans whose sleep quality has deteriorated (preferably, humans whose sleep quality has deteriorated due to stress) and healthy individuals who need or desire better quality sleep. In one embodiment, subjects to whom the composition is administered include subjects with sleep disorders (preferably, humans with sleep disorders) and subjects with insomnia (preferably, humans with insomnia). Subjects to whom the composition is administered also include humans with one or more insomnia conditions selected from the group consisting of sleep onset disorder, waking up during the night, waking up early in the morning, and insufficient deep sleep, and humans who need or desire improvement of such conditions.

[0028] The sleep-improving composition of the present invention may be labeled with the functions it exhibits through sleep improvement, such as one or more of the following: "reducing sleepiness upon waking," "improving sleep quality," "improving the ability to fall asleep," "improving the feeling of deep sleep," "feeling satisfied upon waking," and "relieving fatigue." In one aspect of the present invention, the sleep-improving composition of the present invention is preferably a food or drink labeled as described above. The label may also indicate that the composition is used to obtain the above-mentioned function.

[0029] The present invention also encompasses the following methods and uses. A method for improving sleep by ingesting or administering L-ergothioneine or a salt thereof. Use of L-ergothioneine or a salt thereof to improve sleep. The above-mentioned methods and uses may be therapeutic or non-therapeutic. Ingesting or administering L-ergothioneine or a salt thereof to a subject can improve sleep quality. In one embodiment, ingestion or administration of L-ergothioneine or a salt thereof can increase sleep time. Preferably, L-ergothioneine or a salt thereof is orally ingested or administered. The above-mentioned methods may be for one or more of the following purposes: shortening sleep onset latency, reducing the duration and number of awakenings during sleep, and increasing the proportion of non-REM sleep time to total sleep time. The above-mentioned uses may be for one or more of the following purposes: shortening sleep onset latency, reducing the duration and number of awakenings during sleep, and increasing the proportion of non-REM sleep time to total sleep time.

[0030] In the above-mentioned methods and uses, L-ergothioneine or a salt thereof, and preferred embodiments thereof, are the same as those of the sleep-improving composition of the present invention described above. In the above-mentioned methods and uses, it is preferable to have a subject ingest or administer L-ergothioneine or a salt thereof at least once a day, for example, once to several times a day (e.g., two to three times a day). The above-mentioned uses are preferably used in humans or non-human mammals, more preferably in humans. In one embodiment, L-ergothioneine or a salt thereof can be used, for example, to prevent or improve sleep disorders. L-ergothioneine or a salt thereof can be used to prevent or improve insomnia. L-ergothioneine or a salt thereof can be used, for example, to improve one or more insomnia conditions selected from the group consisting of sleep onset disorder, waking up during the night, waking up early in the morning, and insufficient deep sleep. The present invention also encompasses a method for improving one or more insomnia conditions selected from the group consisting of sleep onset disorder, waking up during the night, waking up early in the morning, and insufficient deep sleep, which involves ingesting or administering L-ergothioneine or a salt thereof.

[0031] In the above-mentioned methods and uses, L-ergothioneine or a salt thereof may be used in an amount (which may also be referred to as an effective amount) that provides a sleep-improving effect. The preferred dosage and administration targets of L-ergothioneine or a salt thereof are the same as those of the sleep-improving composition of the present invention described above. L-ergothioneine or a salt thereof may be ingested or administered as is, or as a composition containing it. For example, the sleep-improving composition of the present invention may be ingested or administered. Furthermore, L-ergothioneine or a salt thereof can be used to produce foods and drinks, pharmaceuticals, quasi-drugs, feeds, etc. that are used to improve sleep. In one aspect, the present invention also encompasses the use of L-ergothioneine or a salt thereof to produce a composition for improving sleep. The present invention also encompasses L-ergothioneine or a salt thereof for use in improving sleep; L-ergothioneine or a salt thereof for use in preventing or improving sleep disorders; L-ergothioneine or a salt thereof for use in preventing or improving insomnia; L-ergothioneine or a salt thereof for use in improving one or more insomnia conditions selected from the group consisting of difficulty falling asleep, waking up during the night, waking up early in the morning, and insomnia; a composition containing L-ergothioneine or a salt thereof for use in improving sleep; a composition containing L-ergothioneine or a salt thereof for use in preventing or improving sleep disorders; a composition containing L-ergothioneine or a salt thereof for use in preventing or improving insomnia; and a composition containing L-ergothioneine or a salt thereof for use in improving one or more insomnia conditions selected from the group consisting of difficulty falling asleep, waking up during the night, waking up early in the morning, and insomnia. The composition may be the sleep-improving composition described above, and may be in the form of a food or drink, a pharmaceutical product, a quasi-drug, a feed, or the like. [Example]

[0032] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0033] All animal experiments were conducted in compliance with the Animal Welfare and Management Law and other relevant laws and regulations, based on plans approved by the head of the institution after review by the Animal Experiment Committee established at the affiliated institution.

[0034] Example 1 (Stress-induced sleep disorder model) Rats in the ergothioneine-administered group (N=5) and the non-administered group (N=7) were subjected to stress using the following method. During the test period, they were kept under a 12-hour light / dark cycle. Sprague Dawley (SD) rats (8 weeks old) were introduced into a cage containing larger, more aggressive Brown Norway (BN) rats. The two rats were housed together in a cage for 10 minutes, during which direct contact was confirmed, with the BN rat chasing and covering the SD rat. The SD and BN rats were then housed together in a cage separated by a transparent partition with small holes for 24 hours (indirect contact). The following day, stress was administered in the same manner, except that a different BN rat was used as the stressor. Under these conditions, stress was administered once daily for five consecutive days (Monday through Friday), followed by two weekend days during which only indirect contact was permitted. This cycle was repeated for two cycles. Therefore, stress loading under conditions combining direct and indirect contact was carried out a total of 10 times, and stress was applied for a total of 12 days.

[0035] (Administration of L-ergothioneine) The ergothioneine administration group received oral administration of L-ergothioneine from 7 days before the stress load until the end of the stress load. L-ergothioneine was administered as an aqueous solution (L-ergothioneine concentration 0.25 mg / mL) dissolved in water. The dose of L-ergothioneine was approximately 20 mg per kg of body weight per day. The non-administration group received oral administration of water instead of the L-ergothioneine aqueous solution. The control (stress (-)) group (N=4) was not subjected to the above stress and was orally administered water.

[0036] (Sleep EEG measurement) Rats underwent surgery to implant electrodes for recording EEG, and 24-hour sleep-wake EEG recordings were performed after the stress load was terminated. Non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep, and wakefulness were identified from the EEG data using biosignal analysis software Spike2 (CED). The duration of each phase was calculated. Significance was determined using Tukey's multiple comparisons test (*: P<0.05, **: P<0.005, ****: P<0.0001).

[0037] (result) The results are shown in Figures 1, 2, and 3. In Figures 1 to 3, "Stress (-)" refers to the control group (a group not subjected to stress), "Stress (+), ergothioneine administration (-)" refers to the non-administration group (a group subjected to stress and not administered with L-ergothioneine), and "Stress (+), ergothioneine administration (+)" refers to the ergothioneine administration group (a group subjected to stress and administered with L-ergothioneine). The results shown in Figures 1 to 3 are the mean values ​​for each group ± standard error. White indicates the control group, black indicates the non-administration group, and shaded indicates the ergothioneine administration group. Figure 1 shows the duration of each sleep stage (non-REM or REM sleep) and total sleep time during the light phase for each group. During the light phase, stress reduced the duration of non-REM sleep (NREM), while conversely, REM sleep (REM) duration increased compared to the control group. Administration of L-ergothioneine improved these phenomena to the level of the non-stressed control group (Figure 1). Administration of L-ergothioneine increased the proportion of non-REM sleep time relative to the total sleep time reduced by stress. "Total sleep duration" refers to the time spent asleep, excluding periods of wakefulness during sleep. "Total sleep time" refers to the total sleep time, including periods of wakefulness during sleep. Total sleep time in rats can be considered the total sleep time in humans. Figure 2 shows the number of fragments in each sleep stage during the light phase (number of fragments in non-REM sleep or REM sleep) and the total number of fragments during sleep. "Total sleep" in Figure 2 represents the total number of fragments during sleep. REM sleep fragmentation was enhanced in the stressed non-administered group compared to the control group, while fragmentation in the ergothioneine-administered group was improved to the same level as the control group (Figure 2). Figure 3 shows the latency (seconds) for the first appearance of non-REM sleep after the onset of the light phase by group. Non-REM sleep latency in rats can be considered as sleep onset latency. Compared to the control group, sleep onset latency was prolonged in the non-administered group, but L-ergothioneine administration shortened the prolongation of sleep onset latency (Figure 3). Administration of L-ergothioneine improved the sleep onset latency, which had been prolonged by stress, to a level comparable to that of the non-stressed control group.

[0038] <Example 2> (Sleep quality evaluation test in humans) To investigate the sleep-improving effects of an ergothioneine supplement, including its effects on sleep quality, a placebo-controlled, randomized, double-blind, parallel-group comparative study was conducted in adult men and women (46 in the test food group, 46 in the control food group, a total of 92 subjects) who experienced daily stress and dissatisfaction with their sleep. Participants were asked to take one capsule containing 20 mg of L-ergothioneine (test food) or one capsule without L-ergothioneine (control food) daily for four weeks. Sleep quality and sleep duration were evaluated by measuring electroencephalograms during sleep using SleepWell Co., Ltd.'s "Sleepscope" electroencephalograph. Significant differences between groups were tested using a two-sample t-test (**: p<0.01, *: p<0.05, †: p<0.1 vs. the control food group).

[0039] (Type of food to be evaluated) Two types of food were used for evaluation, and they were indistinguishable in appearance, flavor, etc. Test food: Capsules containing the test substance (L-ergothioneine 20 mg) Control food: Capsules containing no test substance In addition to the test substance, the ingredients of each evaluation food product included dextrin, hydroxypropyl cellulose, carrageenan, potassium chloride, and titanium oxide. The control food was manufactured using the same ingredients as the test foods, except that it did not contain the test substance (L-ergothioneine).

[0040] EEG measurements during sleep were taken before the subjects began taking the test foods (before the start of the study) and after taking the foods for four weeks. The EEG measurement before the start of the study was the pre-test, and the EEG measurement after taking the test foods for four weeks was the fourth-week test. The subjects' blood L-ergothioneine concentrations (μM) were also measured at the pre-test and fourth-week test.

[0041] When measuring brain waves using SleepWell Co., Ltd.'s electroencephalograph "Sleepscope," non-REM sleep is divided into three stages, stages 1 to 3, depending on the depth of sleep. The following were measured and evaluated as indicators of sleep quality. The percentage of each sleep stage (non-REM sleep stage 1, 2, or 3) relative to the total sleep time, the number of awakenings (times), the number of awakenings (times) in the 2 hours before waking up (times), the non-REM sleep latency (minutes), the delta power of the first sleep cycle (delta power during non-REM sleep in the first cycle) (μV 2 ), sleep efficiency (%)

[0042] (Test results) Figures 4-19 show the primary endpoints of sleep quality measured by EEG (proportion of total time spent in each sleep stage to total sleep time, number of awakenings during sleep, number of awakenings during the 2 hours before waking, non-REM sleep latency, delta power during the first sleep cycle, and sleep efficiency) and sleep time measured at the pre-test and the 4-week test, along with their changes (**: p<0.01, *: p<0.05, †: p<0.1, vs. the control diet group). The change is calculated by subtracting the pre-test value from the 4-week test value ("4-week test value" - "pre-test value"). The results shown in Figures 4-20 are the mean ± standard error for each group. Significant differences between groups were tested using a two-sample t-test (**: p<0.01, *: p<0.05, †: p<0.1, vs. the control diet group). In Figures 4, 5, 6, 8, 10, 12, 14, 16, 18, and 20, "Pre." indicates the pre-test and "Post." indicates the 4-week test. Solid lines indicate the test food group and dashed lines indicate the control food group. In Figures 7, 9, 11, 13, 15, 17, and 19, black indicates the test food group and white indicates the control food group.

[0043] Figures 4, 5, 6 and 7 show the actual measured values ​​and changes in the proportion of non-REM sleep stages to the total sleep time for each group (Figures 4, 5 and 6: actual measured values, Figure 7: changes). Fig. 4 is a graph showing the proportion of non-REM sleep stage 1 (N1) to the total sleep time. Fig. 5 is a graph showing the proportion of non-REM sleep stage 2 (N2) to the total sleep time. Fig. 6 is a graph showing the proportion of non-REM sleep stage 3 (N3) to the total sleep time. Fig. 7 shows the change in the proportion of non-REM sleep stage 1, 2 or 3 to the total sleep time. In the control food group, the proportion of non-REM sleep stage 1, an indicator of light sleep, increased, while non-REM sleep stages 2 and 3, indicators of deep sleep, decreased. Meanwhile, the increase in the proportion of non-REM sleep stage 1 in the control food group was significantly suppressed by L-ergothioneine intervention. Furthermore, the decrease in the proportion of non-REM sleep stages 2 and 3 in the control food group was improved by L-ergothioneine intervention. Overall, L-ergothioneine intervention increased the proportion of deep sleep. Furthermore, the total time spent in non-REM sleep stages 1 to 3 as a percentage of total sleep time increased in the test food group compared to the control food group. L-ergothioneine increased the proportion of non-REM sleep time as a percentage of total sleep time.

[0044] Figures 8 and 9 show the actual measured values ​​and changes in the number of awakenings during the night for each group (Figure 8: measured values, Figure 9: change). Figures 10 and 11 show the actual measured values ​​and changes in the number of awakenings during the two hours before waking for each group (Figure 10: measured values, Figure 11: change). The number of awakenings during the two hours before waking is considered an indicator of early morning awakening and is known to be linked to the ease of waking up. In the control food group, the number of awakenings during the night and the two hours before waking increased, indicating increased sleep fragmentation, while L-ergothioneine significantly suppressed sleep fragmentation. L-ergothioneine reduced the duration and number of awakenings during the night.

[0045] Figures 12 and 13 show the actual measured values ​​and changes in non-REM (NREM) sleep latency for each group (Figure 12: measured values, Figure 13: changes). The time it took to reach deep sleep was extended in the control food group, but L-ergothioneine intervention shortened the extension of the time it took to reach deep sleep. The test food group that took L-ergothioneine had a shorter sleep onset latency compared to the control food group. L-ergothioneine shortened non-REM (NREM) sleep latency, thereby shortening sleep onset latency.

[0046] Figures 14 and 15 show the actual measured values ​​and changes in delta power during the first sleep cycle for each group (Figure 14: measured values, Figure 15: changes). Delta power during the first sleep cycle is known as an indicator of sleep depth. In the control food group, delta power values ​​during the first sleep cycle showed almost no change, but L-ergothioneine intervention increased delta power values ​​during the first sleep cycle. Taking into account the results of Figures 4, 5, 6, and 7, L-ergothioneine is expected to have the effect of inducing deep sleep.

[0047] Figures 16 and 17 show the actual measured values ​​and changes in sleep efficiency for each group (Figure 16: measured values, Figure 17: changes). Sleep efficiency represents the percentage of time spent asleep while in bed and is known as an indicator of overall sleep quality. Sleep efficiency deteriorated in the control food group, but improved with L-ergothioneine intervention.

[0048] Figures 18 and 19 show the actual measured values ​​and changes in sleep time for each group (Figure 18: measured values, Figure 19: changes). Sleep time decreased in the control food group, but increased with L-ergothioneine intervention. Figure 20 shows plasma L-ergothioneine concentrations in the control food group and the test food group. It was confirmed that L-ergothioneine intervention increased plasma L-ergothioneine concentrations. It can be seen that increased L-ergothioneine blood concentrations improved sleep quality and increased sleep duration.

Claims

1. A sleep-improving composition containing L-ergothioneine or a salt thereof as an active ingredient.

2. The sleep-improving composition according to claim 1, wherein the sleep improvement is one or more selected from the group consisting of shortening sleep onset latency, reducing the time and number of awakenings during sleep, and increasing the proportion of non-REM sleep time to total sleep time.

3. 3. The sleep-improving composition according to claim 1, which is an oral composition.

4. The sleep-improving composition according to any one of claims 1 to 3, which is a food or drink.

5. A method for improving sleep by administering L-ergothioneine or a salt thereof.

6. Use of L-ergothioneine or a salt thereof for improving sleep.

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