JP6307329B2 - Sleep improver - Google Patents

Description

  The present invention relates to a sleep improving agent.

  Good quality sleep is the foundation for maintaining mental and physical health. In recent years, the Ministry of Health, Labor and Welfare conducted the “Survey on problems related to sleep in the last month (Summary of the Health and Welfare Trend Survey in 2000)” and “2011 National Health and Nutrition Survey”. "I can't sleep" (difficult to fall asleep), "I don't have a good sleep when I wake up in the morning" (lack of deep sleep), "I wake up early" It has been shown that there are many people with various symptoms such as awakening, and improving the quality of sleep is listed as an important issue for the Japanese people.

On the other hand, chlorogenic acids are found in plants such as coffee beans and potatoes, and so far, an antioxidant action, a blood pressure lowering action and the like have been reported (Patent Document 1).
Regarding sleep, when caffeine, chlorogenic acid or caffeic acid was administered to rats a single time, caffeine, chlorogenic acid and caffeic acid had a dose-dependent time to sleep (sleep latency) It has been reported that chlorogenic acid and caffeic acid did not affect wakefulness time and non-REM sleep time (Non-patent Document 1).
However, the effect of repeated and continuous administration of chlorogenic acids on sleep quality is not known.

JP 2002-53464 A

Eur J Pharmacol, 2004, vol. 504 p. 185-189

  The present invention relates to providing a drug having a sleep-improving action, a quasi-drug, food, feed, or a material that can be blended therein.

  The present inventors have found that chlorogenic acids have an effect of improving sleep quality, and that chlorogenic acids are useful as materials capable of exhibiting a sleep improving action.

  That is, this invention provides the sleep improving agent which uses chlorogenic acid or its salt as an active ingredient.

  According to the sleep improving agent of the present invention, better quality sleep can be obtained by taking before sleep. Therefore, the sleep improving agent of the present invention is useful for maintaining mental and physical health.

It is a figure which shows the change of the sleep efficiency by 300 mg of chlorogenic acids. It is a figure which shows the change of the halfway awakening time by 300 mg of chlorogenic acids. It is a figure which shows the change of the feeling of deep sleep at the time of getting up by 300 mg of chlorogenic acids. It is a figure which shows the change of the deep sleep feeling at the time of getting up by 600 mg of chlorogenic acids.

  The “chlorogenic acids” in the present invention are monocaffeoylquinic acid of 3-caffeoylquinic acid, 4-caffeoylquinic acid and 5-caffeoylquinic acid, 3-feruloylquinic acid and 4-feruloylquina. Acid and 5-feruloylquinic acid monoferuloylquinic acid and 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid dicaffeoylquina It is a general term that includes acids. The content of chlorogenic acids is defined based on the total amount of the above nine types.

  Chlorogenic acids may be in the form of salts. Examples of salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, organic amine salts such as monoethanolamine, diethanolamine and triethanolamine, arginine. , Basic amino acid salts such as lysine, histidine, ornithine and the like.

As the chlorogenic acids or salts thereof, an extract of a plant containing the chlorogenic acids, a concentrate thereof, a purified product thereof, or the like can be used. Examples of such plant extracts include sunflower seeds, apple immature fruits, fresh coffee beans, Simon leaves, pine cones, pine seed shells, potatoes, sweet potatoes, sugar cane, wheat and southern leaves. , Burdock, carrot, cabbage, lettuce, arch chalk, tomato, morroheia, eggplant skin, pear, plum, peach, apricot, cherry, ume fruit, dandelion, grape plant and the like. Among these, raw coffee bean extract is preferable from the viewpoint of chlorogenic acid content and the like. The type of coffee tree may be any of Arabica, Robusta, Revelica and Arabsta.
The raw coffee bean extract preferably has caffeine removed, and the mass ratio of caffeine to chlorogenic acids (caffeine / chlorogenic acids) is preferably 0.05 or less, and 0.03 or less from the viewpoint of flavor. More preferred is 0.02 or less. The lower limit of the ratio of caffeine / chlorogenic acids is not particularly limited, and may be 0.
Methods and conditions for extraction, concentration, and purification of chlorogenic acids or salts thereof are not particularly limited, and known methods and conditions can be employed. Of these, extraction with an ascorbic acid aqueous solution, a citric acid aqueous solution or hot water is preferred.
Commercially available chlorogenic acid-containing preparations may be used as raw materials for chlorogenic acids or salts thereof, such as flavor holder RC (Hasegawa Fragrance Co., Ltd.), fresh coffee bean extract P (manufactured by Oriza Oil Chemical Co., Ltd.), Svetol. (Manufactured by Nulex Inc.), OXCH100 (manufactured by Toyo Fermentation Co., Ltd.) and the like.

As shown in the Examples below, chlorogenic acids have effects of shortening the awakening time, improving sleep efficiency, and improving the feeling of deep sleep when waking up. Accordingly, chlorogenic acids can be sleep improving agents that improve sleep quality, can be used as sleep improving agents, and can be used to produce such agents.
Here, the use may be administration or ingestion to a human or non-human animal, and may be therapeutic use or non-therapeutic use. Note that “non-therapeutic” means a concept that does not include medical practice, that is, a concept that does not include a method for operating, treating, or diagnosing a person, more specifically, a doctor or a person who has received instructions from a doctor It is a concept that does not include a method of performing surgery, treatment or diagnosis.

In the present invention, “sleep improvement” means qualitative improvement of sleep, and preferably 1 of shortening midway awakening time, improving early morning awakening, improving sleep efficiency and improving a feeling of deep sleep when waking up. As mentioned above, it means that two or more phenomena are observed.
“Intermediate awakening” refers to a state in which the user wakes up from falling asleep to waking up, and the accumulated time of the wake-up time is referred to as an intermediate awakening time.
“Early morning awakening” refers to a state in which the user wakes up early in the morning and cannot sleep even though she is still drowsy.
“Sleep efficiency” means substantial sleep during sleep, and the sleep time (total sleep time) excluding mid-wake awakening during sleep was divided by the time from sleep onset to wakeup (total bedtime). Value. Therefore, the sleep efficiency decreases when there is a lot of mid-wakening.
Further, “feeling of deep sleep” refers to the satisfaction of deep sleep, and the lack of deep sleep refers to a state of lack of sleep when waking up, while the sleep time is sufficient but there is no satisfaction of deep sleep.
In the present specification, “improvement” refers to improvement of symptoms or conditions, prevention or delay of deterioration of symptoms or conditions, or reversal, prevention or delay of progression of symptoms.

The sleep-improving agent of the present invention may be a pharmaceutical, quasi-drug, food or feed for improving the quality of sleep itself, or may be blended in the pharmaceutical, quasi-drug, food or feed. It may be the material or formulation used.
The foods include foods, functional foods, foods for the sick, foods for specified health use, and supplements that have the concept of qualitative improvement of sleep and indicate that as necessary. Since these foods are foods whose function is permitted, they can be distinguished from general foods.

Examples of the administration form of the above-mentioned pharmaceuticals (including quasi drugs) include oral administration by tablets, capsules, granules, powders, syrups, etc., or parenteral administration by injections, suppositories, inhalants and the like. It is done. In addition, the preparations of such various dosage forms include the chlorogenic acids of the present invention alone or other pharmaceutically acceptable excipients, binders, extenders, disintegrants, surfactants, lubricants. An agent, a dispersant, a buffering agent, a preservative, a flavoring agent, a fragrance, a film agent, a carrier, a diluent, a medicinal component other than the chlorogenic acids of the present invention, and the like can be appropriately combined.
Of these dosage forms, the preferred form is oral administration.

  As the form of the food, in addition to various foods such as soft drinks, tea beverages, coffee beverages, fruit juice beverages, carbonated beverages, jelly, wafers, biscuits, bread, noodles, sausages and nutritional foods, Includes a nutritional supplement composition in the same form (tablet, capsule, syrup, etc.) as the above-mentioned oral preparation.

  Various forms of foods are the chlorogenic acids or salts thereof of the present invention alone, or other food materials, solvents, softeners, oils, emulsifiers, preservatives, acidulants, sweeteners, bitterings, aromatics, Stabilizers, colorants, antioxidants, humectants, thickeners, active ingredients other than chlorogenic acids, and the like can be prepared in appropriate combinations.

  Examples of the feed include feed for small animals used for rabbits, rats, mice, etc., feed for pet foods used for dogs, cats, and the like, and can be prepared in the same form as the above foods.

  The dose or intake of the sleep-improving agent of the present invention can be determined as appropriate, but it is usually preferably 50 mg or more, more preferably 200 mg or more as the chlorogenic acids of the present invention per day for an adult (60 kg). Moreover, it is preferably 1000 mg or less, more preferably 700 mg or less. In the present invention, such an amount is preferably administered or ingested once.

The above preparation can be administered or ingested according to any plan, but is preferably administered or ingested before bedtime, more preferably administered or ingested within 60 minutes before bedtime, and administered or ingested within 30 minutes before bedtime. More preferably.
The period of administration or ingestion is not particularly limited, but it is preferable to administer or ingest repeatedly, preferably to administer or ingest for 3 days or more, more preferably to administer or ingest for 5 days or more. Further preferred.

  The administration or ingestion target is not particularly limited as long as it is a human or non-human animal that needs or desires sleep improvement, but administration or ingestion in a human who does not require specialized treatment is effective.

Test example 1
(1) Using fresh coffee bean extract as chlorogenic acids, beverages (100 mL / book) shown in Table 1 below were prepared.
After extracting the ground coffee beans with hot water and then spray-drying, the powder prepared is dissolved in an aqueous ethanol solution, and the filtrate obtained by filtration is treated with a column using activated carbon and an ion exchange resin. A raw coffee bean extract was obtained.
Chlorogenic acids (3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-feruloylquinic acid, 4-ferloylquina) in the raw coffee bean extract thus obtained. Acid, 5-feruloylquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid) was 20% by mass. The ratio of caffeine / chlorogenic acids was 0.009.
HPLC (manufactured by Hitachi, Ltd.) was used for quantification of chlorogenic acids and caffeine. In HPLC, 1 g of a sample was precisely weighed, made up to 10 mL with an eluent, filtered through a membrane filter (GL chromatodisc 25A, pore size 0.45 μm, GL Science Co., Ltd.), and subjected to analysis.
The quantification of chlorogenic acids was based on the above nine kinds of chlorogenic acids, using 5-caffeoylquinic acid as a standard substance, and the mass% was determined. Caffeine was quantified in the same manner as chlorogenic acids except that caffeine was used as a standard substance.

(2) A test for comparing and verifying a change in sleep state was performed by a double-blind crossover design using the beverage containing the chlorogenic acids prepared in (1) above and a control beverage.
16 healthy men with Epworth Sleepiness Scale score of 11-15 were divided into 2 groups (8 people in each group), one group with chlorogenic acid drink and the other group with 1 control drink each Ingested daily within 30 minutes before going to bed for 13 days. After a one week rest period, the beverages to be ingested were changed, and each group was similarly ingested one beverage different from the first for 13 days every day within 30 minutes before going to bed. Beverages were taken for 13 days before going to bed on Sunday and before going to bed next Friday.
The Epworth Sleepiness Scale is an 8-item questionnaire for subjective evaluation of excessive daytime sleepiness (Journal of the Japanese Respiratory Society, 2006; 44: 896-898).

(2) Evaluation of sleep state Wear a wristwatch-type body motion meter (Toshiba body motion meter NEM-T1) at the time of going to bed for the first 3 days and the last 3 days of the test. Midway awakening time and sleep efficiency were automatically calculated.

(4) Evaluation of deep sleep feeling The deep sleep feeling was evaluated by a subjective method using a visual analog scale (VAS). Every day during the test period, on the straight line of 100mm drawn on the paper after getting up, marking the position that seems to be most applicable to the state at the time of entry between 0mm (sleeped well) to 100mm (not sleepable at all) at the left end I let you. The shorter the length measured from the left end of the straight line at the position marked on the straight line, the better the feeling of deep sleep, and the longer the length, the worse the feeling of deep sleep.

The results of 15 final analysis subjects are shown in FIGS. For statistics, paired t-test was used, and significance levels were set to * P <0.05 and #P <0.1.
The sleep efficiency in the second half of the test relative to the first half of the test was significantly reduced in the control drink group (FIG. 1), whereas the decrease in the chlorogenic acid drink group was suppressed. In addition, the mid-wake time of the second half of the test relative to the first half of the test was significantly increased in the control drink group, whereas the increase was suppressed in the chlorogenic acid drink group (FIG. 2).

From the change in the feeling of deep sleep during the test period by VAS, there was no significant difference between the chlorogenic acid drink group and the control drink group between the chlorogenic acid drink group and the control drink group until the first week after drinking started. (Figure 3). However, the deterioration of the feeling of deep sleep in the chlorogenic acid drink group was significantly suppressed in the chlorogenic acid drink group over the weekend of the second week from the start of drink intake (Tuesday and Thursday: p <0.1), 2 A statistically significant difference (p <0.05) was observed on the Wednesday and Friday of the week (FIG. 3).

Test example 2
(1) Using the same green coffee bean extract as in Test Example 1 as chlorogenic acids, beverages (100 mL / book) shown in Table 2 below were prepared.

(2) The test which verifies the change of a sleep state by the gradual increase design using the drink which mix | blended the chlorogenic acids prepared by said (1), and a control | contrast drink was done.
Ten healthy men with an Epworth sleepiness scale score of 8-18 were given a control drink for the first 7 days, one daily within 30 minutes before going to bed, and a chlorogenic acid drink for the next 7 days. Ingested similarly. Drinks were taken for 7 days from bedtime on Saturday to bedtime on Friday the next week.

In the same manner as in Test Example 1, the feeling of deep sleep was evaluated.
The results are shown in FIG. For statistics, paired t-test was used, and the significance level was ** P <0.01.
In the chlorogenic acid drink group, the deterioration of the feeling of deep sleep when waking up 5 to 7 days after the start of drink intake (Wednesday to Friday) was significantly suppressed compared to the control drink group (FIG. 4).
From these results, it was confirmed that the quality of sleep was improved by ingestion of chlorogenic acids before going to bed.

Claims (6)

Chlorogenic acids or a sleep-improving agent of a salt thereof as an active ingredient, shortening of sleep improvement arousal during time, Ri 1 or more symptoms der selected from improvement of deep sleep feeling during improving sleep efficiency and getting up, chlorogenic Acids are 3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-feruloylquinic acid, 4-feruloylquinic acid, 5-feruloylquinic acid, 3,4-dicaffee Oirukina acid, Oh Ru sleep-improving agent in the 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid.   The sleep-improving agent according to claim 1, which is orally administered or ingested as chlorogenic acids per day for adults at 50 mg to 1000 mg.   The sleep improving agent according to claim 1 or 2, which is orally administered or ingested within 60 minutes before going to bed. Chlorogenic acids or a sleep-improving food to a salt thereof as an active ingredient, shortening of sleep improvement arousal during time, Ri 1 or more symptoms der selected from improvement of deep sleep feeling during improving sleep efficiency and getting up, Chlorogenic acids are 3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-feruloylquinic acid, 4-feruloylquinic acid, 5-feruloylquinic acid, 3,4-di caffeoylquinic acid, 3,5-dicaffeoylquinic acid and 4,5-cafe Oh Ru sleep for improving food oil quinic acid.   The food for improving sleep according to claim 4, which is orally ingested as chlorogenic acids by 50 mg to 1000 mg per day for an adult.   The food for improving sleep according to claim 4 or 5, which is taken orally within 60 minutes before going to bed.