JP6516259B2 - Sleep improver - Google Patents

Description

  The present invention relates to a sleep improving agent which can improve the quality of sleep and provide good sleep.

  In recent years, people complaining of sleep disorders such as sleep deprivation and sleeplessness are increasing due to disturbances in life rhythm, stress, lack of exercise and the like. In general, sleeplessness disorder is poor sleepiness (poor sleep), halfway awakening (waking up in the middle of the night), deep sleep disorder (sleeping shallowly and wakes up several times), early awakening (waking up in the early morning) are categorized.

  Sleep is in the resting period of the brain, non-REM sleep where cerebral activity is almost stopped, and in the resting period of the body, although the whole body is in a state of weakness, but part of the brain is active and sees a dream There is a sleep with REM. Sleep is usually formed by repeating non-REM sleep and REM sleep at regular intervals. Good quality sleep has a short time from sleep to the appearance of non-REM sleep (duration of sleep onset) and a long non-REM sleep time. On the other hand, many people who complain of insomnia tend to have a long sleep latency and a short non-REM sleep time, and deep non-REM sleep is not obtained.

  It is said that proper alcohol intake, lifestyle improvement and bedding improvements are effective for the treatment of sleep disorders, but those who suffer from sleep disorders are practically ineffective. In addition, sleep improving agents for drugs such as benzodiazepines and antihistamines have been reported to have side effects such as mental symptoms and muscle relaxation, and there is room for improvement in their use.

  On the other hand, sleep improving agents using natural ingredients have been proposed as having less side effects. For example, Patent Document 1 describes a sleep improving agent containing, as an active ingredient, a water-soluble antioxidant selected from plant-derived organic acids and polyphenols and a divalent metal. Patent Document 2 describes a sleep improving agent containing, as an active ingredient, a yeast containing S-adenosylmethionine or a salt thereof. In addition, Patent Document 3 describes a sleep improving agent containing a hot water extract of microorganisms of Cordyceps sinensis as an active ingredient. According to the sleep improving agents described in Patent Documents 1 to 3, effects such as an increase in non-REM sleep time and a reduction in sleep onset latency are considered to be obtained.

JP, 2014-172892, A JP, 2013-82641, A Unexamined-Japanese-Patent No. 2010-53098

  There are individual differences in the effect of the sleep improving agent, and it is a fact that conventional sleep improving agents have not sufficiently coped with the troubles of sleep disorder. In addition, some sleep improving agents reduce non-REM sleep time, and if the method of use is not appropriate, the quality of sleep may be reduced. In addition, there are problems with side effects in sleep improving agents, and high safety is required. Sleep improvement agents that can solve these problems have not yet been provided.

  An object of the present invention relates to a highly safe sleep improving agent which is excellent in the effect of improving sleep quality and has no harmful side effects.

The present invention is a sleep improving agent containing, as an active ingredient, an alkylresorcinol represented by the following general formula (I).

  The sleep improving agent of the present invention can improve the quality of sleep by increasing the time of non-REM sleep, and can exhibit a high improvement effect on sleep disorders. Moreover, the sleep improving agent of the present invention has no adverse side effects even when taken continuously since the active ingredient is a component contained in grains and nuts rich in eating experience. high.

FIG. 1 is a graph showing a change in time (seconds) in awake state during each one hour according to the results of measurement of myoelectric potentials of mice which ingested experimental food or control food for 10 days. FIG. 2 is a graph showing a change in time (seconds) spent in non-REM sleep state for each one hour according to the results of electroencephalograms of mice which ingested the experimental diet or the control diet for 10 days. FIG. 3 is a graph showing the change in the time (seconds) spent in the rem sleep state for each one hour according to the result of the electroencephalogram of the mice which ingested the experimental diet or the control diet for 10 days. FIG. 4 is a graph showing a change in time (seconds) in the awake state during each one hour according to the results of measurement of the myoelectric potential of the mice which ingested the experimental diet or the control diet for 1 day. FIG. 5 is a graph showing the change in time (seconds) spent in non-REM sleep state for each one hour according to the results of electroencephalograms of mice which ingested an experimental diet or a control diet for 1 day. FIG. 6 is a graph showing the change in the time (seconds) spent in the rem sleep state for each one hour according to the result of the electroencephalogram of the mice which ingested the experimental diet or the control diet for 1 day. FIG. 7 is a graph showing the distribution of the duration (seconds) of non-REM sleep in ZT4 to ZT7 of FIG.

  In the present invention, the "sleep improving agent" means a pharmaceutical composition or a food / drink composition having an action to improve the quality of sleep. The sleep improving agent can be reworded as a sleep disorder improving agent, an agent having a sleep disorder improving effect, an agent used to improve the sleep disorder, or a treatment for the sleep disorder, whichever substance The sleep improving agent according to the present invention is meant.

The sleep improving agent of the present invention contains the alkylresorcinol represented by the above general formula (I) as an active ingredient. The saturated or unsaturated alkyl group represented by R ₁ in the general formula (I) is not limited by the number of carbon atoms, but preferably has 15 to 27 carbon atoms, and the number of carbon atoms is It is more preferable that it is 15-25.

  As a saturated alkyl group having 15 to 27 carbon atoms, as a representative example, linear such as n-pentadecyl, n-heptadecyl, n-nonadecyl, n-henycosyl, n-tricosyl, n-pentacosyl, n-heptacosyl etc. In addition to these, it may be branched or cyclic. Among these, a saturated alkyl group having 15 to 25 carbon atoms is preferable, and a linear saturated alkyl group having 15 to 25 carbon atoms is more preferable.

  As a C15-C27 unsaturated alkyl group, the thing corresponding to the said C15-C27 saturated alkyl group is mentioned. There are no particular restrictions on the number and position of unsaturated bonds contained in the unsaturated alkyl group.

Further, R ₂ in the general formula (I) is preferably a hydrogen atom, and R ₁ is preferably bonded to the para position relative to R ₂ .

Specific examples of the alkylresorcinol represented by the above general formula (I) used as an active ingredient in the sleep improving agent of the present invention include the following.
1,3-dihydroxy-5-n-pentadecylbenzene (C15: 0)
1,3-dihydroxy-5-n-heptadecylbenzene (C17: 0)
1,3-dihydroxy-5-n-nonadecylbenzene (C19: 0)
1,3-dihydroxy-5-n-henicosyl benzene (C21: 0)
1,3-dihydroxy-5-n-tricosylbenzene (C23: 0)
1,3-dihydroxy-5-n-pentacosylbenzene (C25: 0)
1,3-dihydroxy-5-n-heptacosylbenzene (C27: 0)

As the alkylresorcinol represented by the above general formula (I), it is particularly preferable that R ₁ is a saturated alkyl group having 15 to 25 carbon atoms and R ₂ is a hydrogen atom, and in particular, the following six types of alkyl Those containing resorcinol are preferred.
1) Alkyl resorcinol (hereinafter, also referred to as AR15) in which R ₁ in the general formula (I) is a saturated or unsaturated alkyl group having 15 carbon atoms.
2) Alkyl resorcinol (hereinafter also referred to as AR 17) in which R ₁ in the general formula (I) is a saturated or unsaturated alkyl group having 17 carbon atoms.
3) Alkyl resorcinol in which R ₁ in the general formula (I) is a saturated or unsaturated alkyl group having 19 carbon atoms (hereinafter also referred to as AR 19).
4) Alkyl resorcinol (hereinafter also referred to as AR21) in which R ₁ in the general formula (I) is a saturated or unsaturated alkyl group having 21 carbon atoms.
5) Alkyl resorcinol in which R ₁ in the general formula (I) is a saturated or unsaturated alkyl group having 23 carbon atoms (hereinafter also referred to as AR 23).
6) Alkyl resorcinol in which R ₁ in the general formula (I) is a saturated or unsaturated alkyl group having 25 carbon atoms (hereinafter also referred to as AR 25).

Particularly preferable one as AR15 is one in which R ₁ is a saturated alkyl group having 15 carbon atoms and R ₂ is a hydrogen atom, and specifically, 1,3-dihydroxy-5-n-pentadecylbenzene (C15) : 0) is mentioned.
Particularly preferable ones as AR 17 are those in which R ₁ is a saturated alkyl group having 17 carbon atoms and R ₂ is a hydrogen atom, and specifically, 1,3-dihydroxy-5-n-heptadecylbenzene (C17 : 0) is mentioned.
Particularly preferable one as AR 19 is that in which R ₁ is a saturated alkyl group having 19 carbon atoms and R ₂ is a hydrogen atom, and specifically, 1,3-dihydroxy-5-n-nonadecylbenzene (C 19 : 0) is mentioned.
Particularly preferable examples of AR 21 are those in which R ₁ is a saturated alkyl group having 21 carbon atoms and R ₂ is a hydrogen atom, and specifically, 1,3-dihydroxy-5-n-henycosylbenzene ( C2: 0).
Particularly preferable one as AR23 is one in which R ₁ is a saturated alkyl group having 23 carbon atoms and R ₂ is a hydrogen atom, and specifically, 1,3-dihydroxy-5-n-tricosylbenzene (C23) : 0) is mentioned.
Particularly preferable examples of AR 25 are those in which R ₁ is a 25-carbon saturated alkyl group and R ₂ is a hydrogen atom, and specifically, 1,3-dihydroxy-5-n-pentacosylbenzene (C25) : 0) is mentioned.

In the sleep improving agent of the present invention, the contents of AR15, AR17, AR19, AR21, AR23 and AR25 are preferably within the following ranges, respectively, from the viewpoint of further improving the effects of the sleep improving agent.
The content of AR 15 is preferably 0.1 to 10.0% by mass, more preferably 0.1 to 5.0% by mass, particularly preferably 0.5 to 1.5% by mass in the sleep improving agent of the present invention %.
The content of AR 17 is preferably 1.0 to 20.0% by mass, more preferably 5.0 to 15.0% by mass, particularly preferably 8.0 to 12.0% by mass, in the sleep improving agent of the present invention %.
The content of AR 19 is preferably 25.0 to 40.0% by mass, more preferably 27.5 to 37.5% by mass, particularly preferably 30.0 to 35.0% by mass, in the sleep improving agent of the present invention %.
The content of AR 21 is preferably 40.0 to 55.0% by mass, more preferably 42.5 to 52.5% by mass, particularly preferably 45.0 to 50.0% by mass in the sleep improving agent of the present invention %.
The content of AR 23 is preferably 1.0 to 15.0% by mass, more preferably 2.5 to 12.5% by mass, particularly preferably 5.0 to 10.0% by mass, in the sleep improving agent of the present invention %.
The content of AR 25 is preferably 0 to 5.0% by mass, more preferably 0 to 2.0% by mass, and particularly preferably 0 to 1.5% by mass in the sleep improving agent of the present invention.

  The alkylresorcinol represented by the above general formula (I) can be synthesized by a conventional method or can be obtained as a commercial product. Moreover, what was extracted from a plant by a conventional method can also be used. Alkyl resorcinol is known to be contained in various plants as resorcinol lipid which is a natural non-isoterpenoid phenolic amphiphilic compound, and as a source of alkyl resorcinol, it is known to be other than gramineous plants. Also known are, for example, Urushi, Ginkgo, Phylogeny, Yabu-koji, Primrose, Prunidaceae, Phylogeny, Araceae, Artemisia, Artemisia, Legume and the like. Among these plants, cereals and nuts, in particular cereals, are suitable sources of the active ingredient of the sleep improving agent of the present invention because they are rich in eating experience and highly safe for the human body. That is, the sleep improving agent of the present invention comprises, as the alkylresorcinol represented by the above general formula (I), an alkylresorcinol-containing extract (alkylresorcinol-containing extract derived from grains or nuts) extracted from grains or nuts It is preferable to contain, and it is preferable to contain especially the alcohol extract of the cereals obtained by carrying out alcohol extraction of cereals.

  Among cereals, grasses are particularly preferable as a source of the alkylresorcinol represented by the above general formula (I) because research on alkylresorcinol as an edible active ingredient is progressing. Examples of gramineous plants include wheat, durum wheat, rye, rye wheat, barley, oats, wheat, oats, corn, rice, barn, millet, millet and the like, and one or two of these may be used alone or in combination. More than species can be used in combination. Among these gramineous plants, wheat or rye is preferable in terms of relatively high alkylresorcinol content and high activity. From the same point of view, cashew nuts are preferable as nuts.

  When a gramineous plant is used as a source, a gramineous plant seed is usually used. The form of the gramineous plant seed is not particularly limited. For example, a gramineaceous plant seed (preferably a seed coat; preferably a moss) itself; a cut, a crushed or a powder of the gramineaceous plant seed; It is possible to use dried ones such as those obtained by drying and grinding or pulverizing the seeds of the gramineous plants. As preferable examples including a gramineous plant seed coat, bran, flour, rice husk, rice bran and the like can be mentioned, as well as seeds with the coat.

  When an alkylresorcinol-containing extract extracted from cereals or nuts is used as the alkylresorcinol represented by the general formula (I), an alcohol extract of cereals or nuts is preferable as the alkylresorcinol-containing extract. The method of extraction with alcohol is not particularly limited, and examples thereof include a method of immersing, stirring, or refluxing the above-mentioned various forms of gramineous plant seeds in alcohol, a supercritical fluid extraction method, and the like. In the case of a method of immersing, stirring or refluxing a gramineous plant seed in alcohol, the extraction temperature (liquid temperature of alcohol) is preferably 2 to 100 ° C., the extraction time is preferably 0.5 to 72 hours, and the amount of alcohol used is And 50 to 2000 parts by mass with respect to 100 parts by mass of the gramineous plant seeds.

  Examples of the alcohol used for extraction include monohydric lower alcohols (preferably having 1 to 4 carbon atoms) such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and 1,3-butylene glycol And alcohols which are liquid at room temperature (25 ° C.) such as polyhydric alcohols such as propylene glycol and glycerin. Among these alcohols, ethanol is preferable from the viewpoint of operability and environment. In addition, as alcohol used for extraction, water-containing ethanol containing water components (water, pure water, distilled water, tap water, acidic water, alkaline water, neutral water etc.) other than alcohol can also be used. . The alcohol content in the water-containing alcohol is usually 70% by volume or more, preferably 80% by volume or more, and more preferably 90% by volume or more.

  Alcoholic extracts of plants such as cereals and nuts (alkyl resorcinol-containing extracts) are purified by partition chromatography. The partition chromatography is not limited as long as it is a method by which the alkylresorcinol represented by the general formula (I) can be obtained, but a normal phase chromatography method using a non-aqueous solvent as a mobile phase is preferable, and an open column method Known methods such as medium pressure column method and high performance liquid chromatography can be appropriately selected.

  The mobile phase in partition chromatography of a plant alcohol extract (an alkylresorcinol-containing extract) includes monohydric lower alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol (preferably having 1 to 10 carbon atoms). 4) and alcohols which are liquid at room temperature (25 ° C.) such as polyhydric alcohols such as 1,3-butylene glycol, propylene glycol and glycerin; ethers such as diethyl ether and propyl ether; butyl acetate, ethyl acetate etc. And esters of acetone, ethyl methyl ketone and the like; hexane; methylene chloride; acetonitrile; and chloroform, etc., and one of these solvents may be used alone or in combination of two or more. When a plurality of solvents are combined to form a mobile phase, it is possible to use an isocratic mode in which the mixing ratio of the plurality of solvents is kept constant during partition chromatography (during purification of the alcohol extract of plants), or It may be a gradient mode in which the ratio is changed. Moreover, as a carrier in partition chromatography, any carrier that can support and release the target active ingredient can be used, but generally, silica gel, polyacrylamide gel, dextran gel and the like can be mentioned. . The detection wavelength in partition chromatography of the alcohol extract of plants may be 170 to 320 nm, preferably 190 to 280 nm.

As an example of partition chromatography suitable for purification of an alcohol extract (preferably ethanol extract) of a plant (preferably cereals or nuts), the following partition chromatography A and B can be mentioned.
Partition chromatography A: Medium pressure column method (medium pressure chromatography) using silica gel as a carrier and hexane-ethyl acetate mixed solvent as a mobile phase, and while performing the partition chromatography, the mobile phase is “hexane -Change from a relatively high content of hexane in an ethyl acetate mixed solvent to a relatively low content of hexane in a hexane-ethyl acetate mixed solvent (ie, "large and small amounts of hexane" And the peak component at a detection wavelength of 254 nm.
Distribution chromatography B: high performance liquid chromatography (HPLC) using silica gel as a carrier and methanol as a mobile phase, and fractionating a peak component at a detection wavelength of 215 nm.

  The form of the sleep improving agent of the present invention is not particularly limited. For example, a liquid (liquid or semi-liquid) containing an alcohol extract of plant (an alkylresorcinol-containing extract), a liquid medium (alcohol or water) in the liquid The dried product or its powder obtained by evaporating the alcohol to dryness, the alcohol solution etc. which melt | dissolve this dried product or its powder in alcohol, such as ethanol, etc. are mentioned.

  The sleep improving agent of the present invention is used to improve the sleep quality of a mammal. Mammals include, for example, dogs, cats, mice, rats, rabbits, cows, horses, monkeys and the like in addition to humans. That is, the sleep improving agent of the present invention is applicable not only to humans but also to pets (cargo animals), livestock, etc., and can be applied to all mammals for medical or non-medical purposes.

  The "improvement of the quality of sleep" in the present invention is a state that can be evaluated by criteria such as improvement in sleep, improvement in insomnia, improvement in sleep state, improvement in mood after awakening, and the like. The improvement of sleep quality can be evaluated by measuring electroencephalograms, electromyograms, electrocardiograms, electrocardiograms, body temperature, blood pressure, locomotion and the like from animals such as mice, and examining the amount of sleep of the animals. Evaluation of sleep quality should be performed according to the standard judgment method (Rechtschaffen A. & Kales A., A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects., Public Health Service: Washington DC, 1968). it can. Specifically, a sleep polygraph is created based on measurement data such as electroencephalograms from animals, and the presence or absence of locomotion (locomotion) and amplitude of electroencephalogram (δ wave) every epoch (for example, 4 to 60 seconds) of the sleep polygraph The state of the animal may be determined as each stage of awakening, non-REM sleep, and REM sleep based on the θ wave component ratio of brain waves [θ / (δ + θ)] and the like. Determination of awakening or sleep based on a sleep polygraph can be automatically performed by a program for sleep analysis research: SleepSign (registered trademark) (Kissei Comtech Inc.) or the like. As a result of the discrimination, a substance having an increased sleep stage has an effect of improving the quality of sleep and can be evaluated as a substance capable of improving sleep disorder.

  The sleep improving agent of the present invention has the effect of prolonging sleep time, particularly non-REM sleep time. In addition, the sleep improving agent of the present invention has an action of shortening the sleeping delay. Sleep latency means the time taken from awake state to sleep and is an indicator of good sleep. The sleep improving agent of the present invention can be used for the treatment of sleep disorders whose main complaint is insomnia. The sleep improving agent of the present invention can be applied to, for example, insomnia, initial insomnia (drowsiness to sleep), premature awakening, early awakening, deep sleep disorder, sleep cycle reversal, etc. It is applicable to the sleep disorder in general.

  The sleep improving agent of the present invention can be used as or for producing a pharmaceutical, quasi-drug or food of mammals. The term "food" as used herein includes general foods, and general foods including so-called health foods, as well as health food such as specified health foods and nutritional function foods defined in the health functional food system of the Ministry of Health, Labor and Welfare, supplements And the like, and further includes livestock feed fed to animals, pet food. The sleep improving agent of the present invention contains the alkylresorcinol represented by the above general formula (I) as an active ingredient, and a pharmaceutical for which a sleep improving effect (increasing effect of non-REM sleep time) is intended and indicated to that effect It can be used as a quasi drug or food.

  When the sleep improving agent of the present invention is used as a medicine or quasi-drug, it may contain the alkylresorcinol represented by the above general formula (I) alone as an active ingredient, or further pharmaceutically The carrier may contain an acceptable carrier, or may further contain other active ingredients or pharmacological ingredients as long as the sleep improving effect of the alkyl resorcinol is not impaired. Such carriers include, for example, excipients, coatings, binders, fillers, disintegrants, surfactants, lubricants, diluents, dispersants, buffers, buffers, pH adjusters, Emulsifiers, preservatives, stabilizers, antioxidants, colorants, UV absorbers, moisturizers, thickeners, activity enhancers, anti-inflammatory agents, bactericidal agents, flavoring agents, flavoring agents and the like can be mentioned.

  When the sleep improving agent of the present invention is used as a medicine or quasi drug, it can be administered in any dosage form. The mode of administration may be oral or parenteral. For example, oral dosage forms include tablets, coated tablets, granules, powders, solid dosage forms such as capsules, and liquid dosage forms such as elixirs, syrups and suspensions, and as parenteral dosage forms Examples include injection, infusion, transdermal, transmucosal, nasal, enteral, inhalation, suppository, bolus, patch and the like. Among these, oral administration is preferred.

  When the sleep improving agent of the present invention is used as a food, the alkylresorcinol represented by the above general formula (I) as an active ingredient may be contained alone, or the sleep improving effect by the alkylresorcinol is impaired. In addition, various additives used in the manufacture of medicines, quasi-drugs, and foods may be included within the scope of the present invention. Such additives include, for example, various oils and fats, herbal medicines, amino acids, polyhydric alcohols, natural polymers, vitamins, dietary fibers, surfactants, purified water, excipients, stabilizers, pH adjusters, antioxidants And sweeteners, taste components, acidulants such as organic acids, stabilizers, flavors, coloring agents, flavors and the like.

  When the sleep improving agent of the present invention is used as a food, the form thereof is not particularly limited. For example, the form of the beverage is, for example, tea beverage, coffee beverage, milk beverage, fruit juice beverage, carbonated beverage, alcoholic beverage, soft drink etc. Can be mentioned. In addition, forms of food other than beverages may be solid, semi-solid or liquid, and include tablet form, pill form, capsule form, liquid form, syrup form, powder form, granule form and the like. Specific food forms include breads, noodles, jelly-like foods and various snacks, baked goods, cakes, chocolate, gum, chewing, tablets, capsules, soups, dairy products, frozen foods, instant foods, Supplements, other processed foods, seasonings and materials thereof can be mentioned.

  The content of the active ingredient (alkylresorcinol represented by the above general formula (I)) in the sleep improving agent of the present invention is not particularly limited, and the condition and age of the dosage form and application target (mammal) Although it can be suitably adjusted depending on the gender etc., when targeting human, usually, the dose of the active ingredient of the sleep improving agent of the present invention may be 0.01 to 10 g per adult per day. preferable.

The present invention includes the following modes <1> and <2>.
<1> A method for improving sleep quality (sleep disorder) by administering the alkylresorcinol represented by the above general formula (I) to a living body.
<2> A method of improving the quality of sleep (sleep disorder) for non-medical purposes such as health maintenance and beauty by administering alkylresorcinol represented by the above general formula (I) to a living body.

  Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited by the examples.

Example 1
By the following <extraction and purification method>, a peak component of distribution chromatography of wheat ethanol extract containing the alkylresorcinol represented by the above general formula (I) was obtained. The composition of the obtained peak component is as follows.
-1.2 mass% of 1, 3- dihydroxy 5- n- pentadecyl benzene (C15: 0).
10.9 mass% of 1,3-dihydroxy-5-n-heptadecylbenzene (C17: 0).
-33.9 mass% of 1,3-dihydroxy-5- n-nonadecyl benzene (C19: 0).
・ 46.4 mass% of 1,3-dihydroxy-5-n-henicosyl benzene (C21: 0).
-1,3-Dihydroxy-5-n-tricosyl benzene (C23: 0) 7.5 mass%.
0.1 mass% of 1,3-dihydroxy-5-n-pentacosyl benzene (C25: 0).

<Extraction and purification method>
The wheat bran was added with 5 times volume by weight of ethanol, and extracted with stirring at 600 rpm and room temperature for 16 hours. The extract was filtered to remove unnecessary substances, and the ethanol extract was recovered, and then ethanol was distilled off to obtain a wheat ethanol extract.
The wheat ethanol extract was then purified by medium pressure chromatography. The medium pressure chromatography conditions are as follows. The peak component appearing 31 to 36 minutes after the elution start was recovered and the solvent was distilled off to obtain the peak component of distribution chromatography of the wheat ethanol extract.
(Conditions of medium pressure chromatography)
Column: Silica gel (Inject column 3 L, high flash column 5 L, 60 Å, 40 μm, manufactured by Yamazen Co., Ltd.)
Mobile phase: hexane / ethyl acetate mixed solvent (volume ratio) 9 minutes for 90 minutes, 15 minutes for 80/20, 16 minutes for 60/40 Detection wavelength: 254 nm

The purification of the wheat ethanol extract in the <extraction and purification method> can be performed by HPLC instead of medium pressure chromatography. In that case, methanol is added to the wheat ethanol extract to prepare a methanol additive solution having a concentration of 200 ug / ml of the ethanol extract, and the methanol additive solution is passed through a filter with a pore diameter of 0.45 μm. As a sample for HPLC. The conditions of HPLC are as follows.
(Conditions of HPLC)
Column: silica gel (ODS-80A, 5 μm, 4.6 × 250 mm, manufactured by GL Science Inc.)
Guard column: ODS-80A, 5 μm, 4.6 × 50 mm,
・ Column temperature: 30 ° C
Mobile phase: 100% methanol
・ Detection wavelength: 215 nm

[Evaluation of sleep quality improvement effect]
In order to confirm the effect of the alkylresorcinol represented by the above general formula (I) on the quality of sleep, the following tests 1 and 2 were performed using a mouse to measure brain waves. That is, an electrode was attached to the head of the mouse, the mouse brain waves under free behavior were recorded in a gauge, and each time of "wake up", "non-REM sleep" and "REM sleep" was measured.

[Test 1: Long-term administration test]
(1) Indwelling of sleep polygraph recording electrode in animal A mouse (C57BL / 6J, Japan SLC) was subjected to indwelling operation of a transmitter for sleep electroencephalogram measurement (DSI, TAlOM2-F20-EET) under anesthesia. Specifically, holes were drilled in two places of the skull of the mouse, and an electrode for electroencephalogram was inserted and fixed with dental cement. The insertion position of the electrode was 1 mm laterally (right), 1 mm forward, and 1 mm laterally (left) from the bregma in the cerebral cortex region, and 3 mm backward. In addition, electrode cords for electromyography were inserted and fixed in the neck muscles of the mouse, and transmitters connected to these cords were indwelled subcutaneously in the back.

After a recovery period of 2 weeks after the indwelling operation, the mice were transferred to individual cages for a polysomnograph and fed the following experimental diet or control diet for 10 days (each group: n = 5).
Experimental diet: 0.4% by mass of the peak component (alkylresorcinol represented by the above general formula (I)) of the partition chromatography of the ethanol extract of wheat of Example 1 on purified feed AIN-93 for breeding mice Additive and mixed feed, control food: Purified feed AIN-93 for breeding mice

(2) Recording and Analysis of Sleep Polygraph After 10 days of feeding the experimental diet or the control diet, the electroencephalogram (EEG) and myoelectric potential (EMG) of the mice were measured for 3 consecutive days. The measurement was performed by placing a cage in which the transmitter and the mouse are housed on a receiving board (DSI, RPC-1). The detection data was acquired by a personal computer using data analysis software (DSI, Dataquest ART), and was automatically analyzed by SleepSign (registered trademark) (Kissei Comtech Inc.), a program for sleep analysis research. In the automatic analysis, if the electromyogram of 10 seconds is more than the threshold, it is determined to be "wake up", and for states other than wake up, brain waves of relatively slow frequency (0.5 to When 4 Hz) was above the threshold, it was judged as “non-REM sleep”, and when below 4 Hz, it was judged as “REM sleep”.

(3) Results of Test 1 FIG. 1 shows wake time per second of the mouse (second), FIG. 2 shows time of non rem sleep per hour of the mouse (second), FIG. 3 shows one hour of the mouse per hour Rem sleep time (seconds) is indicated respectively. FIG. 1 was calculated from data of myoelectric potential, and FIGS. 2 and 3 were calculated from data of electroencephalogram. From the average data for 3 days, the group receiving the experimental diet and the group receiving the control diet and the time (ZT: lit at ZT0, ZT12 for total awake time every hour, total non rem sleep time, total rem sleep time 2), the group receiving the experimental food significantly shortened the total awakening time in ZT13 compared to the group receiving the control food. , Total non-REM sleep time has been prolonged.
From the above, by taking the alkylresorcinol represented by the general formula (I) for several times over a relatively long period (specifically, 10 days), the non-REM sleep time of the mouse is prolonged. It can be seen that the quality of sleep is improved.

[Test 2: short-term administration test]
In the test 1, after passing through a recovery period of 2 weeks after the indwelling operation, the mice are transferred to a separate cage for a sleep polygraph and fasted for 24 hours, and then immediately after the end of the fasting period (ZT0) the experimental diet or The EEG and EMG of mice were respectively measured in the same manner as in (1) and (2) of the above-mentioned test 1 except that the control diet was fed for 24 hours (each group: n = 4), and the result was SleepSign ( It analyzed automatically by registered trademark.

(Result of trial 2)
Figure 4 shows the wake time per second of the mouse (second), Figure 5 shows the time of non rem sleep per second of the mouse (second), Figure 6 shows the time of rem sleep per hour of the mouse (second) ) Are shown respectively. FIG. 4 was calculated from data of myoelectric potential, and FIGS. 5 and 6 were calculated from data of electroencephalogram. The total awakening time every hour, the total non-REM sleep time, and the total REM sleep time, the group receiving the experimental diet and the group receiving the control diet and the time (ZT: lights on ZT0, lights off on ZT12) As a result of analysis of variance, as shown in FIG. 4 and FIG. 5, the group receiving the experimental food had a total in ZT4 and ZT7 (time indicated with * in the figure) compared to the group receiving the control food. Awakening time was shortened significantly, and total non-REM sleep time became longer.
Then, the distribution of the duration (seconds) of non-REM sleep during this time was analyzed focusing on the “time of ZT4 to ZT7”, and the result is shown in FIG. As shown in FIG. 7, in the group receiving the experimental diet, the episodes of non-REM sleep tend to be extended, and the number of episodes of 600 seconds to 720 seconds (time marked with * in the figure) is particularly significant. Increased to
From the above, the alkylresorcinol represented by the above general formula (I) is not only the case of multiple administration over several days (long-term administration) but also the case of single administration for only 1 day (short-term administration) However, it is found that it promotes the prolongation of non-REM sleep time in mice and is effective in improving the sleep quality of mice.

Claims (7)

A sleep improving agent comprising an alkylresorcinol represented by the following general formula (I) as an active ingredient, wherein the sleep improvement is an increase in non-REM sleep time or a decrease in sleep latency.

The sleep improving agent according to claim 1, wherein R ₁ in the general formula (I) is bonded to the para position relative to R ₂ . The sleep improving agent according to claim 1 or 2, wherein R ₁ in the general formula (I) is a saturated or unsaturated alkyl group having 15 to 27 carbon atoms. The general formula R ₁ in (I) is a saturated alkyl group having 15 to 25 carbon atoms, sleep-improving agent according to any one of claims 1 to 3 R ₂ is a hydrogen atom.   The sleep improving agent according to any one of claims 1 to 4, which comprises an alkylresorcinol-containing extract derived from cereals or nuts as the alkylresorcinol.   The sleep improving agent according to claim 5, wherein the alkyl resorcinol-containing extract is an alcohol extract of cereals. The sleep improving agent according to claim 5, wherein the cereals are wheat or wheat bran or rye, and the nuts are cashew nuts.

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