JP6175166B2 - Sleep disorder improver - Google Patents

Description

  The present invention relates to an agent for improving sleep disorders. More specifically, the present invention relates to a sleep disorder improving agent containing sesamin or the like as an active ingredient.

  Sleep is an important physiological activity that accounts for about one third of daily life. Particularly in the present age, the number of people who are dissatisfied with sleep increases due to changes in the living environment, such as a 24-hour society, etc., and the increase in the elderly, and this is also regarded as a social problem.

  Sleep disturbances include difficulty in falling asleep (bad sleep), sleep maintenance disorder (getting up often after sleeping), early morning awakening (wakes up early in the morning), insomnia (not feeling well asleep) , It feels like you were a little sleepy). Such sleep time and sleep quality can be evaluated by analyzing behavioral quantities, brain waves, and the like (Non-Patent Document 1).

  For such sleep disorders, treatment with sleeping pills and the like is generally performed, but there are problems such as side effects and anxiety about taking them, so they are not necessarily sufficient solutions for sleep disorders.

  Therefore, a sleep disorder improving agent containing a functional ingredient derived from food as an active ingredient is desired. So far, a composition for promoting sleep containing theanine (Patent Document 1), a deep sleep disorder improving agent containing glycine as an active ingredient (Patent Document 2), and a sleeping or waking up improving agent containing ornithine (Patent Document 3) Etc. have been reported.

  Sesamin is one of the main lignan compounds contained in sesame and is contained in sesame in an amount of about 0.5 to 1%. Sesamin has been reported to have an antioxidant action (Patent Document 4), an anti-fatigue action (Patent Document 5), and an autonomic nerve regulating action (Patent Document 6). However, the effect of sesamin on sleep has not been reported.

WO01 / 074352 JP 2006-333872 A JP 2006-342148 A Japanese Patent Laid-Open No. 05-051388 WO2008 / 126587 WO2004 / 105749

Sleep psychology, Kitaoji Shobo, 2008

  An object of this invention is to provide the sleep disorder improving agent which uses the substance which is excellent in safety | security and shows the effect which improves the quality of sleep effectively as an active ingredient.

  In order to solve the above problems, the present inventors have intensively searched for substances that can improve the sleep state of humans who are dissatisfied with sleep, and as a result, found that sesamins have a sleep disorder improving effect and completed the present invention. It came to do.

That is, the present invention relates to the following [1] to [5].
[1] A sleep disorder improving agent comprising sesamin as an active ingredient.
[2] The sleep disorder improving agent according to [1], wherein the sesamin is sesamin, episesamin, or a mixture thereof.
[3] The sleep disorder improving agent according to [1] or [2], wherein the sleep disorder improvement is an improvement in sleep depth, sleep awakening, or sleep improvement.
[4] The sleep disorder improving agent according to any one of [1] to [3], which is in the form of a food or drink.
[5] The sleep disorder improving agent according to any one of [1] to [3], which is in the form of a pharmaceutical product.

  By including sesamin as an active ingredient, the sleep disorder improving agent of the present invention can eliminate sleep dissatisfaction such as light sleep, poor sleep, and poor sleep, and can improve sleep disorder. .

  In addition, sesamin is a component that has been ingested as a food for a long time and is excellent in safety. Therefore, the sleep disorder improving agent of the present invention can be ingested for a long time.

FIG. 1 shows the transition of the average value of each item from the start of the test in the test food or placebo intake group. FIG. 2 shows the amount of change in the average value of each item from the start of the test in the test food or placebo intake group. FIG. 3 shows the results of stratified analysis by extracting subjects with “slightly sleeping” score of 2 or more before ingestion start (sesamin intake group: 25 people, placebo intake group: 23 people). FIG. 4 shows the results of stratified analysis by extracting subjects with a score of “not awake at night” of 2 or more before ingestion (sesamin intake group: 37 people, placebo intake group: 42 people). FIG. 5 shows the results of stratified analysis by extracting subjects with a score of “not good at sleeping” of 2 or more before ingestion (sesamin intake group: 26 people, placebo intake group: 14 people). FIG. 6 shows the ratio of the awakening time in the light period of 6 hours from the start of measurement in the test of Example 2-1. FIG. 7: shows the ratio of the REM sleep time in the light period 6 hours from the measurement start in the test of Example 2-1. FIG. 8 shows the ratio of non-REM sleep time in the light period of 6 hours from the start of measurement in the test of Example 2-1. FIG. 9 shows the delta wave ratio in the non-REM sleep period in the light period of 6 hours from the start of measurement in the test of Example 2-1. FIG. 10 shows the measurement result of the sleep latency in the test of Example 2-2.

Hereinafter, embodiments of the present invention will be described in detail.
(Sleep disorder improving agent)
In order to improve sleep disorders, it is effective not only to increase sleep time, but also to improve sleep quality, such as shortening sleep onset latency, decreasing the number and duration of awakenings, and increasing deep sleep time . The sleep disorder improving agent of the present invention can improve the quality of sleep by containing sesamin as an active ingredient, and in particular, the sleep dissatisfaction such as light sleep, poor sleep, and poor sleep. Excellent effect in eliminating. Moreover, although the sleep disorder improving agent of this invention exhibits an effect by ingestion for a short time, it shows the effect which eliminates the dissatisfaction regarding sleep notably by continuing ingestion.

The quality of sleep can be analyzed by measuring the electroencephalogram (EEG), for example, in addition to the subjective evaluation by questionnaire. In the rapid eye movement phase (REM (REM) sleep), a low-amplitude electroencephalogram pattern close to arousal is confirmed, but in the non-rapid eye movement sleep phase (non-REM (NREM) sleep), which is deep sleep, delta waves and A brain wave with a large amplitude called frequently appears. It is known that the quality of sleep increases when this delta wave increases (see Psychopharmacology, 130, p.285-291 (1997), J Pharmacol Exp Ther, 299, p.1095-1105 (2001)). ).

(Sesamin)
The sleep disorder improving agent of the present invention contains sesamin as an active ingredient. The sesamin used in the present invention includes sesamin and its analogs. Examples of the sesamin analog include episesamin and dioxabicyclo [3.3.0] octane derivatives described in JP-A-4-9331. Specific examples of sesamin can include sesamin, sesaminol, episesaminol, sesamorin and the like. Among these, sesamin, episesamin or a mixture of sesamin and episesamin is preferable, and in particular, a mixture of sesamin and episesamin is a more preferable component.

  The sesamin used for this invention is not restrict | limited at all by the form, manufacturing method, etc. For example, when sesamin is selected as the sesamin, sesamin extracted from sesame oil by a known method (for example, the method described in JP-A-4-9331) (referred to as sesamin extract or sesamin concentrate) However, commercially available sesame oil (liquid) can be used as it is. However, when sesame oil is used, the sesamin content is low (usually less than 1%), so when trying to formulate the sesamin necessary to obtain the physiological effects of sesamin, per unit dosage of the formulated composition The volume becomes too large, which can cause inconvenience. In particular, when formulated for oral administration, the formulation (tablets, capsules, etc.) becomes too large, resulting in trouble with ingestion. Therefore, it is preferable to use a sesamin extract (or sesamin concentrate) from sesame oil from the viewpoint that the amount of intake may be small. In addition, since the flavor peculiar to sesame oil may be evaluated to be sensory unfavorable, the sesamin extract (or sesamin concentrate) may be made tasteless and odorless by a known means such as activated clay treatment.

  Thus, as sesamin, it is preferable to use a sesamin concentrate obtained by improving the concentration of sesamin by extraction and / or purification from a food-derived material such as sesame oil. The degree of concentration may be appropriately set depending on the type of sesamin used and the form of the composition to be blended. Usually, a sesamin concentrate concentrated so that the total amount of sesamin is 1% by weight or more is used. Is preferred. The total sesamin content in the sesamin concentrate is preferably 20% by weight or more, more preferably 50% by weight or more, still more preferably 70% by weight or more, and is concentrated (purified) to 90% by weight or more. Is optimal.

(Food)
The sleep disorder improving agent of the present invention, for example, is a food or drink containing sesamin as an active ingredient, such as a supplement, and a general food or drink containing sesamin as a component to give the food or drink a sleep disorder improving effect. Functional foods (including health supplements, functional nutritional foods, special-purpose foods, health foods such as foods for specified health use, supplements for animals), animal feeds, etc. The sleep disorder ameliorating agent of the present invention can display the type, use, efficacy effect on sleep disorder improvement, and / or ingestion method of the active ingredient on a package, container or instructions.

  The sleep disorder ameliorating agent of the present invention does not impair the effects of sesamin, i.e., other physiologically active components such as minerals, if necessary, as long as undesirable interaction is not caused by blending with sesamin. Vitamins such as vitamin E, vitamin C, and vitamin A; nutritional ingredients; fragrances; other additives such as pigments can be mixed. Any of these additives commonly used for food and drink can be used.

  The sleep disorder improving agent of the present invention may be prepared by adding and blending sesamin, which is an active ingredient, into a conventional food or drink material, for example, beverages such as juice, milk, coffee beverage, tea beverage, etc. Liquid foods such as soups, pasty foods such as yogurt, semi-solid foods such as jelly and gummi, solid foods such as cookies and gums, and fat and oil-containing foods such as dressing and mayonnaise may be used.

  The sleep disorder improving agent of the present invention contains sesamin as an active ingredient, preferably 0.001 to 10% by weight, more preferably 0.01 to 5% by weight, still more preferably 0.05 to 5% by weight. To do.

(Medicine)
The sleep disorder ameliorating agent of the present invention can be used in the form of a medicinal compound containing a sesamin as it is or a pharmaceutically acceptable additive.

  The sleep disorder improving agent in the form of the pharmaceutical of the present invention can be formulated according to the purpose by a general method together with a pharmacologically acceptable carrier, diluent or excipient. Examples of diluents and carriers include liquid diluents such as water, ethanol, propylene glycol and glycerin, solid diluents and excipients such as glucose, sucrose, dextrin, cyclodextrin and gum arabic. In addition, emulsifiers, tonicity agents (isotonic agents), buffers, solubilizers, preservatives, stabilizers, antioxidants, and the like that are generally used in formulation can be appropriately blended.

  The sleep disorder improving agent in the form of the pharmaceutical of the present invention does not impair the effects of sesamin, i.e., other physiologically active ingredients as necessary, as long as it does not cause an unfavorable interaction when combined with sesamin Other additives such as minerals; vitamins such as vitamin E, vitamin C, vitamin A; nutritional ingredients; fragrances; pigments can be mixed. Any of these additives commonly used in pharmaceuticals can be used.

  The sleep disorder-improving agent of the present invention is not particularly limited in form, for example, solids such as powder, granules, and tablets; liquids such as solutions, emulsions, and dispersions; or pastes It can be prepared in any form such as a semi-solid form. Specific examples of the dosage form include powders, granules, fine granules, tablets, pills, troches, capsules (including soft capsules and hard capsules), chewable agents, and solutions.

  In the sleep disorder improving agent of the present invention, sesamin as an active ingredient is preferably 0.001 to 10% by weight, more preferably 0.01 to 5% by weight, still more preferably 0.05 to 5% by weight. It can be used as a containing form.

What is necessary is just to select suitably the dosage amount and dosage form of the sleep disorder improving agent of this invention according to a subject, a disease state, its progress, and other conditions. For example, when sesamin is selected as the sesamin and is orally administered for the purpose of obtaining a sleep disorder ameliorating effect in humans (adults), generally sesamin is 1 to 200 mg, preferably 3 to 100 mg per day. The dose may be continuously administered at a rate of about 1 to 2 times a day, 5 times or more a week, more preferably about 5 to 50 mg.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Sleep improvement effect of sesamin The sleep improvement effect of sesamin was verified by a placebo-controlled double-blind parallel group comparison test with 95 healthy adult men and women who were unhappy with sleep.
Sesamin-containing capsules were used as test foods. Capsule containing sesamin (content weight per capsule: 203 mg) is 3.71 mg of sesamin bulk (contains 97% or more of sesamin / episesamin (weight ratio) = 1: 1 sesamin / episesamin mixture), containing vitamin E 54.05 mg of oil (containing 18.33 mg of α-tocopherol, 14.7 mg of γ-tocopherol), 1.03 mg of tocotrienol-containing oil (containing 0.66 mg of tocotrienol) and 144.21 mg of wheat germ oil did. As the placebo, a capsule filled with 203 mg of wheat germ oil was used.

  Based on subjective assessments on age, sex, sleep, etc., subjects were assigned to two groups: sesamin intake group (47 people) and placebo intake group (48 people), 3 capsules containing sesamin or placebo capsules per day, They were ingested continuously for a total of 8 weeks. The sleep improvement effect was evaluated by conducting a questionnaire regarding sleep before the start of intake of the test food or placebo (week 0), 2 weeks, 4 weeks, and 8 weeks after the start of intake, and evaluating the subjective sleep state.

  As shown in Table 1, the questionnaire about sleep is a subjective score based on a five-point scale from 0 to 4 for the three items “slow sleep”, “not awake at night”, and “not good at sleeping”. Digitized.

The questionnaire results are shown in FIGS. FIG. 1 shows the transition of the average score of each item of each group subject. FIG. 2 shows the transition (change amount) of the average score of each item of each group subject. Both figures mean that dissatisfaction with sleep improved as the value decreased. There was no consistent improvement trend in the placebo group, and some changes in exacerbations were observed. However, it was found that in the sesamin intake group, the improvement continued stably after the start of intake and the improvement was maintained, and it was confirmed that continuous intake of sesamin was effective in improving sleep. As for vitamin E, as a result of examining the effect on sleep by ingesting 400 IU (≈268 mg) per day for 6 to 12 months in an elderly woman with vitamin E alone or in combination with pravastatin, a sleep improvement effect was observed. There was no report (Carlsson CM et al., Drugs Aging. 2002; 19 (10): 793-805), and 800 IU per day
There is a report (Connolly PS et al., Arch Intern Med. 1994 May 9; 154 (9): 1037-8) that the sleep disorder was not suppressed when ingested ≈573 mg) for 4 weeks. Therefore, the sleep disorder improving effect observed in this study is considered to be due to the effect of sesamins.

Furthermore, for each subjective evaluation item, before the start of ingestion, the score was 2 or more, and people who were dissatisfied were extracted and analyzed by stratification. The results are shown in FIGS. In all three items, as with the overall results, it was observed that the sesamin group in the group continued to improve stably after the start of the intake and the improvement was maintained as compared with the change in the placebo group. Furthermore, since the difference from the placebo intake group was clearly recognized by continuous intake, the effectiveness of the sesamin intake group for these sleep-related sensation items was confirmed.

The sleep improvement effect of sesamin was evaluated using a rat sleep disorder model established by Shinomiya et al. (Folia Pharmacol. Jpn., 131, 33-36, 2008).

Example 2-1 Effect of sesamin on sleep time and sleep quality <Preparation of test substance>
As the test substance, sesamin extracted from sesame (purity of 96% or more) was used. Olive oil was used as a base for administration. For administration to animals, sesamin was dissolved by heating in a base, returned to room temperature, and then administered orally using a sonde.
<Measurement method>
After acclimating a 6-week-old Sprague-Dawley male rat (Japan SLC Co., Ltd.) to a test environment in which the light-dark period was controlled in a 12-hour cycle (from 11:00 to 23:00 light), the rat's head An electrode for recording an electroencephalogram and an electromyogram was embedded in the part. A data measurement cable was connected to the electrodes, and the animals were reared and recovered for an additional week in an environment in which the animals can move freely. Then, administration of the test substance and sleep electroencephalogram measurement were performed.

  The test substance was administered 1 hour before the start of the light period, and stress load and sleep electroencephalogram measurement were started 2 hours after the start of the light period (that is, 3 hours after the test substance was administered). Stress load and sleep electroencephalogram were measured according to the method of Shinomiya et al. Specifically, by placing a wire mesh as a scaffold in the cage and creating a state where the rat is stressed by placing water so that the water surface is 1 cm below this wire mesh, the light period of 6 hours from the start of stress load EEG data and electromyogram data were measured. In addition, about test substance administration and measurement time, it set so that the influence on sleep could be evaluated 4 to 6 hours after administration that the blood concentration of sesamin becomes the maximum.

  As test conditions, the following three conditions A, B, and C were set, and the same individual was measured under all conditions. Specifically, 5 test animals are divided into 2 groups of 3 and 2 animals, 2 groups with A → B → C and 3 groups with A → C → B are set. did. Between each enforcement, it carried out at intervals of 5 days or more.

A: No stress + administration (5ml olive oil / kg))
B: Stressful + administration (5ml olive oil / kg))
C: Stress loading + administration (100mg sesamin / 5ml olive oil / kg)
<Data analysis>
Regarding the determination of wakefulness / sleep stage, based on EEG and electromyogram data, wakefulness, non-REM sleep period (low frequency and high amplitude EEG and low EMG state), REM sleep period (high frequency and low amplitude EEG) And myoelectricity is very low). The brain wave was subjected to fast Fourier transform, and the delta wave, which is a low-frequency, high-amplitude brain wave, was determined as a region of 0.75 to 4.0 Hz, and the theta wave, which is a high-frequency, low-amplitude brain wave, was determined as a region of 6.0 to 10.0 Hz.

For the evaluation of the sleep time, the ratio of the time of the awakening period, the non-REM sleep period, and the REM sleep period occupying 6 hours from the start of measurement was calculated and compared.
Regarding the quality of sleep, it has been reported that the more delta waves appear during the non-REM sleep period, the higher the quality of sleep (Faulhaber et al., Psychopharmacology (Berl). 1997, Apr; 130 (3): 285-91 .). In this example, sleep quality was evaluated by the ratio of delta waves to the sum of delta waves and theta waves, which are the main brain waves during sleep. That is, the appearance ratio of delta waves in the non-REM sleep period during the light period of 6 hours was calculated and compared based on the following formula.

(Delta wave ratio) = (Delta wave intensity) / (Delta wave intensity + Theta wave intensity)
<Result>
The ratios of the awakening period, the non-REM sleep period, and the REM sleep period in the light period of 6 hours from the start of measurement are shown in FIGS. In condition B in which stress was applied as compared to condition A in which no stress was applied, an increase in awakening time, a decrease in non-REM sleep time, and a decrease in REM sleep time were observed, confirming the occurrence of sleep disorders due to stress. In condition C in which sesamin was administered under this sleep disorder, a decrease in awakening time, an increase in non-REM sleep time, and an increase in REM sleep time were observed as compared with condition B in which only the base was administered.

  Moreover, the delta wave ratio of the non-REM sleep period in the light period 6 hours from the measurement start is shown in FIG. In condition B where stress was applied as compared to condition A where there was no stress, a decrease in the delta wave ratio due to sleep disorders was observed. Under condition C in which sesamin was administered under this sleep disorder, an increase in the delta wave ratio, that is, improvement in sleep quality, was observed compared to condition B in which only the base was administered.

Example 2-2 Sesamin's sleep-stimulating action <Test substance preparation and measurement method>
The test was conducted in the same manner as in Example 2-1, except that the test conditions were as follows.

A: No stress load + no administration B: Stress load + administration (5ml olive oil / kg)
C: Stress loading + administration (100mg sesamin / 5ml olive oil / kg)
The test was performed on 6 test animals in the order of A, B, and C, and each test was performed with an interval of 5 days or more.
<Data analysis>
The determination of wakefulness / sleep stage was performed in the same manner as in Example 2-1, and the time from the start of stress load until bedtime was evaluated as the sleep onset latency based on the determination of wakefulness / sleep stage.
<Result>
The results of measuring the sleep latency are shown in FIG. In the condition B where the stress load was applied, extension of the sleep falling latency was confirmed as compared with the condition A where there was no load, and the occurrence of the sleep disorder due to the stress load was confirmed. Under this sleep deprivation disorder, shortening of the sleep sleep latency was observed under the condition C to which sesamin was administered, and the level was improved to almost the same level as the condition A under normal conditions.

  From the above results, it has been clarified that sesamin has not only an increase in sleep amount but also an improvement in sleep quality and a sleep-stimulating action, and was confirmed to be effective in improving sleep disorders.

  ADVANTAGE OF THE INVENTION According to this invention, the sleep disorder improving agent which contains sesamin as an active ingredient can be provided. The sleep disorder ameliorating agent of the present invention exhibits an excellent effect in resolving sleep dissatisfaction, such as light sleep, poor awakening, and poor sleep.

Claims (9)

A composition for improving sleep comprising sesamin,
Sesamin-class compound, sesamin, episesamin, or a mixture der thereof is,
Does not contain melatonin in an amount that improves sleep
Said composition. The composition according to claim 1, wherein the composition is a food or drink. The composition according to claim 2, wherein the food or drink is a health food, a functional food, a health supplement, a nutritional functional food, a special-purpose food, or a food for specified health use. The composition according to any one of claims 1 to 3, wherein the sleep improvement is an improvement in sleep depth, an improvement in waking, or an improvement in sleep. The composition of claim 1, wherein the composition is a pharmaceutical product. The composition according to claim 5, wherein the sleep improvement is an improvement in sleep depth, an improvement in waking, or an improvement in sleep. A method for producing a composition for improving sleep, comprising a step of adding sesamins,
Sesamin-class compound, sesamin, episesamin, or a mixture der thereof is,
The sleep improving composition does not contain melatonin in an amount that exhibits a sleep improving action,
The method, wherein the composition is a food or drink.   The method according to claim 7, wherein the food or drink is a health food, a functional food, a health supplement, a nutritional functional food, a special-purpose food, or a food for specified health use. The method according to claim 7 or 8 , wherein the sleep improvement is an improvement in sleep depth, an improvement in waking, or an improvement in sleep.