JPWO2015098441A1 - Sleep improving agent, non-REM sleep time increasing agent and sedative - Google Patents

Abstract

A sleep-improving agent, a non-REM sleep time increasing agent, and a sedative agent that provide a feeling of deep sleep. The sleep improving agent, the non-REM sleep time increasing agent and the sedative contain α-lipoic acid as an active ingredient.

Description

  The present invention relates to a sleep improving agent, a non-REM sleep time increasing agent, and a sedative.

  In modern society, the number of people with insomnia is increasing year by year. There are various physiological and psychological factors that can cause insomnia. It is said that insomnia due to psychological factors is responsible for the recent increasing trend. An example of the cause of insomnia is a decrease in the balance recovery ability of the autonomic nerve due to various troubles and worries in a stressed society.

  Therefore, in the current social environment where psychological stress is increasing, there is a demand for a composition having an excellent sleep effect and further having a sedative effect.

  In addition, there are REM sleep and non-REM sleep. The normal sleep composition is a combination of non-REM sleep, the resting state of the brain, and REM sleep, the resting state of the body. Healthy adults repeat this several times a night, It is known to be awakened. In good sleep, non-REM sleep, which is a resting state of the brain, is concentrated immediately after falling asleep, and the time is long. However, many people who complain of insomnia sleep a little, and measuring EEG sleep shows that non-REM sleep times are shorter than those who are satisfied with sleep.

  The effect of natural ingredients is widely known as a technique for improving sleep of people suffering from such insomnia. Cedrol, which is one of the fragrance components contained in conifers such as hinoki and hiba, has been recognized to be effective in extending the total sleep time, shortening the sleep latency, and increasing sleep efficiency (Patent Document 1).

  Alpha lipoic acid is a kind of coenzyme contained in the living body and acting on sugar metabolism and TCA cycle. Alpha lipoic acid is known to have an antioxidant effect (Patent Document 2).

International Publication No. 01/058435 Pamphlet JP 2011-63606 A

However, to date, it is not known that α-lipoic acid increases non-REM sleep time and improves sleep quality.
For sleep improvement, a feeling of deep sleep is required instead of just increasing sleep time. It is considered that a feeling of deep sleep is obtained by increasing the non-REM sleep time, shortening the sleep latency, and sedating during sleep such as suppressing mid-wake. The present condition has not yet obtained the composition which has the effect which increases non-REM sleep time as a sleep improvement effect.

  As described above, development of a sleep-improving agent, a non-REM sleep time increasing agent, and a sedative that can provide a feeling of deep sleep is desired.

  An object of the present invention is to provide a sleep-improving agent, a non-REM sleep time increasing agent, and a sedative that provide a feeling of deep sleep.

That is, the present invention is as follows.
[1] A sleep improving agent containing α-lipoic acid as an active ingredient.
[2] The sleep improving agent according to [1], further containing zinc.
[3] The sleep improving agent according to [2], wherein zinc is incorporated into yeast.
[4] A non-REM sleep time increasing agent containing α-lipoic acid as an active ingredient.
[5] The non-REM sleep time increasing agent according to [4], further containing zinc.
[6] The non-REM sleep time increasing agent according to [5], wherein zinc is incorporated into yeast.
[7] A sedative containing α-lipoic acid as an active ingredient.
[8] The sedative according to [7], further containing zinc.
[9] The sedative according to [8], wherein zinc is incorporated into yeast.

  According to the present invention, it is possible to provide a sleep improving agent, a non-REM sleep time increasing agent, and a sedative that can provide a feeling of deep sleep.

It is the graph which compared the action amount of the mouse | mouth for every hour for 12 hours after sample administration by Example 1, 2 and the comparative example 1. FIG. It is the graph which compared the cumulative action amount of the mouse | mouth over 6 hours after sample administration by Example 1, 2 and the comparative example 1. FIG. It is the graph which compared the non-REM sleep time of the mouse | mouth for every hour over 12 hours after sample administration by Example 3 and Comparative Example 2. FIG. It is the graph which compared the conversion time of the non-REM sleep time of the mouse | mouth over 6 hours after sample administration by Example 3 and Comparative Example 2. FIG.

  The sleep improving agent, non-REM sleep time increasing agent and sedative according to the present invention will be described below.

In general, REM sleep and non-REM sleep are repeated in sleep, and non-REM sleep, which is a state of deep sleep, is concentrated for about 3 hours after sleeping. One of the sleep disorders occurs because this deep non-REM sleep is lost or shortened, resulting in a decrease in sleep quality. Also, insomnia may have long sleep onset (time to go to sleep) and frequent awakening (slow sleep and awaken during sleep). The quality of sleep is reduced.
When the sleep-improving agent, non-REM sleep time increasing agent or sedative according to the present invention is used, non-REM sleep time can be increased, and sleep latency can be shortened, mid-wake arousal can be suppressed, and good arousal can be realized. . Thereby, a feeling of deep sleep can be obtained, and awakening when waking up can be improved, and as a result, the quality of sleep can be improved.

  “Sleep improvement” means that a high sense of deep sleep is obtained, and includes at least one effect of increasing non-REM sleep time and sedation during sleep. “Sedation” refers to sedation during sleep, and includes at least one of the effects of shortening the sleep onset latency, suppressing mid-wake awakening, and good awakening. “A feeling of deep sleep” refers to feeling that a good sleep has been achieved (sleeping deeply).

In this specification, the term “process” is not limited to an independent process, and is included in this term if the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes. .
In addition, in this specification, “to” indicates a range including numerical values described before and after that as a minimum value and a maximum value, respectively.
Furthermore, in this specification, the amount of each component in the composition is the total amount of the plurality of substances present in the composition unless there is a specific indication when there are a plurality of substances corresponding to each component in the composition. means.
The present invention will be described below.

The sleep improving agent of the present invention contains α-lipoic acid as an active ingredient.
Alpha lipoic acid is a compound represented by the chemical formula C ₈ H ₁₄ O ₂ S ₂ (molecular weight 206.3) having the structure shown below.

  Alpha lipoic acid is a compound that exhibits optical activity. The α lipoic acid in the present invention may be any of R, S-(+/−)-α-lipoic acid, R-(+)-α-lipoic acid, and S-(−)-α-lipoic acid. It may be in the form of an acid or a salt.

As α-lipoic acid, generally used synthetic and natural product-derived extracts and commercially available products can be used. The α-lipoic acid may be used as a powder as it is, or may be in the form of being dispersed in an aqueous solution in the presence of an emulsifier.
Moreover, alpha lipoic acid can also be used as an inclusion body of cyclodextrin. Thereby, reaction due to contact with other antioxidants can be prevented, and stability over time can be improved.

  In the sleep improving agent of the present invention, the amount of α-lipoic acid used for mammals including humans may be an amount effective for the sleep improving effect. For example, 1 mg to 1000 mg per day is preferable, more preferably 2 mg to 300 mg, and even more preferably 3 mg to 100 mg.

  The sleep improving agent of the present invention can further contain zinc. Since zinc has the effect of dramatically increasing non-REM sleep time when combined with α-lipoic acid, it is preferable to incorporate zinc into the sleep improving agent.

  Zinc may exist as a simple substance in the sleep improving agent, may exist as a state bound to protein, etc., may be formulated as zinc gluconate and may exist in an ionic state, The form (zinc yeast) taken in may be sufficient.

  “Zinc yeast” refers to yeast that has absorbed zinc into the cells by culturing the yeast in a medium to which zinc is added at a high concentration. Zinc yeast is obtained by culturing yeast in a medium supplemented with zinc, collecting the bacteria, and then performing steps such as concentration, sterilization, and drying. Moreover, what is marketed can be used for yeast. Commercially available yeast such as Saccharomyces, Mycotorula, Torulopsis, baker's yeast, beer yeast, wine yeast, sake yeast, alcohol yeast, miso soy sauce yeast, etc. Can be mentioned.

  Such zinc yeast is preferable because zinc can be ingested without feeling a metallic taste because zinc is taken into the cells of the yeast. Furthermore, because zinc yeast is incorporated into minerals by binding minerals into the yeast cells to form an organic substance, when zinc yeast is applied to mammals including humans, absorption in the body is inorganic. Improved compared to zinc.

  The amount of zinc used for mammals including humans may be an amount effective for sleep improvement. For example, the amount of zinc is preferably 1 mg to 300 mg per day, more preferably 2 mg to 100 mg, and still more preferably 3 mg to 50 mg.

  In addition, when zinc is blended in the form of zinc yeast, the amount used for mammals including humans is, for example, preferably 5 mg to 6000 mg per day, more preferably 20 mg to 2000 mg as the mass of zinc yeast. More preferably, it is 25 mg to 300 mg.

  In the present invention, the mass ratio of α-lipoic acid to zinc is preferably 1:50 to 50: 1, more preferably 1:30 to 30: 1, from the viewpoint of sleep improvement effect. In addition, the mass of zinc in this case means the mass as zinc irrespective of the form.

  The sleep improving agent of the present invention is preferably applied to foods and pharmaceuticals. Examples of foods include beverages, confectionery, processed foods such as rice balls, sandwiches, soups, cup noodles, and miscellaneous foods. Examples of pharmaceuticals include nutritional drinks and nourishing tonics. It is not something.

Arbitrary components that can be added to food or pharmaceuticals can be further added to the sleep-improving agent of the present invention.
Examples of the carrier preferably used in the case of a solution include an aqueous medium such as water. As an additive component preferably used for solidification, excipients such as crystalline cellulose and magnesium stearate; swelling agents such as corn starch and alginic acid can be used.

  Furthermore, a low hygroscopic raw material and a hygroscopic agent can be used as arbitrary components that can be added to foods or pharmaceuticals. Preferably, cellulose, powdered cellulose, microcrystalline cellulose, lactose, oligosaccharide, sugar alcohol, trehalose, calcium stearate, etc. are used as the low hygroscopic raw material. As the hygroscopic agent, silicate, magnesium carbonate, ferrocyanide, polysaccharide and the like are used. More preferably, crystalline cellulose, microcrystalline cellulose, or lactose is used as the low hygroscopic raw material. Examples of the compound necessary for molding into a powder, solid agent or liquid agent include erythritol, maltitol, hydroxypropylcellulose, kaolin, talc and the like.

  The dosage form of the sleep improving agent of the present invention is not particularly limited, and can be administered orally or parenterally. As an oral dosage form, it can be taken in solid dosage forms such as tablets, intraoral rapidly disintegrating tablets, capsule preparations, granules and fine granules, and liquid dosage forms such as syrups and suspensions. The parenteral dosage form can be administered in the form of injections, eye drops, patches, ointments, suppositories. As a dosage form of the sleep-improving agent of the present invention, oral administration is preferable, and a solid dosage form in a capsule preparation is preferable from the viewpoint of easy administration.

  When the sleep-improving agent of the present invention is used as a capsule preparation, forms such as hard capsules, soft capsules, microcapsules and seamless capsules can be mentioned. The capsule film is preferably composed of one or more of pork skin gelatin, pork bone gelatin, fish gelatin, and natural hydrophilic polymer. These capsule films can be prepared by a well-known conventional method. Here, “it is composed of pork skin gelatin, pork bone gelatin, fish gelatin or natural hydrophilic polymer” means pork skin gelatin, pork bone gelatin, fish gelatin or natural hydrophilicity with respect to the total mass of the capsule film. It means that the total amount of the polymer is 30% by mass or more, preferably 40% by mass or more, more preferably 50% by mass or more, and particularly preferably 60% by mass or more. As long as the effect of the present invention is not impaired, other materials such as cowhide gelatin may be included in the capsule film.

A natural hydrophilic polymer is a hydrophilic polymer obtained by purifying or synthesizing a natural animal or plant or the like, or a processed polymer thereof. Folia gum, tragacanth gum, karaya gum, pectin, gum arabic, xanthan gum, gellan gum, starch, konjac mannan, galactomannan, funolan, acetan gum, welan, ramsan, fluselan, succinoglycan, scleronoglycan, schizophyllan, tamarind gum, curdlan , At least one selected from carrageenan, pullulan, or dextran. These may be used in combination of two or more, and may be combined with the above-described pig skin gelatin. These hydrophilic polymers may be processed natural products. Of these, pullulan, carrageenan and dextran are particularly preferable, and carrageenan is particularly preferable.
Pork skin gelatin, pork bone gelatin, and fish gelatin are proteins obtained by warm extraction of protein obtained from pork skin, pork bone, and fish. Pig skin gelatin, pork bone gelatin, and fish gelatin are extracted by, for example, treating pig skin, pork bone, perch, sea bream, sea bream, and deep-sea fish with acid or alkali and then heating them in water. It can be purified through an ion exchange treatment step.

  Pork skin gelatin, pork bone gelatin, fish gelatin or natural hydrophilic polymer can be reduced in molecular weight by enzyme treatment and the like, and the average molecular weight can be appropriately selected. The average molecular weight is usually 10,000 to 5,000,000, preferably Is 10,000 to 2.5 million, more preferably 10,000 to 1,000,000, and even more preferably about 10,000 to 500,000.

  The capsule film used in the capsule preparation may contain not only the above-described raw materials derived from the specific animals and plants but also oils, fats, polyhydric alcohols, surfactants, antioxidants, pigments, fragrances and the like. Examples of oils and fats include natural oils such as evening primrose oil, soybean oil, safflower oil, olive oil, germ oil, rapeseed oil, sunflower oil, peanut oil, cottonseed oil, rice bran oil, cocoa butter, hardened oils thereof, and glycerides of fatty acids ( Glycerides, diglycerides, triglycerides, etc.) such as polyhydric alcohols, polyethylene glycol, propylene glycol, glycerin, sorbitol, etc., and surfactants, nonionic surfactants such as sorbitan fatty acid esters and polyglycerin fatty acid esters, etc. Examples thereof include carotenoid pigments, anthocyanin pigments, cacao pigments, anthranone pigments, and caramel pigments. Among these, addition of fats and oils, polyhydric alcohols, surfactants, and natural pigments to the capsule film is preferable because the stabilization of the capsule preparation can be further improved.

  The sleep-improving agent according to the present invention can take the form of a preparation as described above in which an effective amount of each component is blended.

  By taking the sleep improving agent of the present invention, a good feeling of deep sleep can be obtained. The timing of taking is preferably taken before bedtime, more preferably 0.5 to 6 hours before bedtime, and even more preferably 1 to 3 hours before bedtime.

  The sleep-improving agent of the present invention varies depending on the age and weight of the user, the method of administration, etc., but the dose per dose is about 0.001 mg / kg / day to about 10,000 mg / kg / day, preferably 2.5 mg / day. It is about kg / day to 20 mg / kg / day.

  The non-REM sleep time increasing agent of the present invention contains α-lipoic acid as an active ingredient. The non-REM sleep time increasing agent in the present invention can increase the amount of non-REM sleep when taken. The timing of taking is preferably taken before bedtime, more preferably 0.5 to 6 hours before bedtime, and even more preferably 1 to 3 hours before bedtime.

The non-REM sleep time increasing agent of the present invention varies depending on the age and weight of the user, the method of taking, etc., and the dose per dose is about 0.001 mg / kg / day to about 10,000 mg / kg / day, preferably 2. It is about 5 mg / kg / day to 20 mg / kg / day.
About the other matter in the non-REM sleep time increasing agent of this invention, the matter demonstrated in the sleep improving agent concerning this invention is applicable.

  The sedative of the present invention contains α lipoic acid as an active ingredient. With a sedative agent, relaxation effects such as relaxation of tension and reduction of stress can be obtained by sedating the minds of mammals including humans during sleep.

  When the sedative of the present invention is taken before going to bed, the sleep effect is smoothed by the relaxation effect, and the effects such as shortening the sleep latency, lowering the awakening during the sleep, and good awakening when waking up are also obtained. Therefore, it is preferable to take the medicine before going to bed. More preferably, it is 0.5 to 6 hours before bedtime, and more preferably 1 to 3 hours before bedtime.

The sedative of the present invention varies depending on the age and weight of the user, the method of administration, etc., but the dose per dose is about 0.001 mg / kg / day to about 10,000 mg / kg / day, preferably 2.5 mg / kg. / Day to about 20 mg / kg / day.
About the other matter of the sedative of this invention, all the matters demonstrated in the sleep improving agent of this invention are applied.
In the present invention, “active ingredient” means a component having at least one of an effect of increasing non-REM sleep, a sedative effect, and a sleep improving effect, and a low moisture-absorbing raw material, a hygroscopic agent, and a capsule film that are optionally added. It is a component excluding such as.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Examples 1 and 2 and Comparative Example 1]
1. Method (i) Animals used C57BL / 6 mice (male, 8 weeks old, weight 22-26 g) were purchased from Japan SLC.
(Ii) Breeding method In a state where 5 to 6 mice are placed in each of a plurality of acrylic gauges installed in a chamber at a constant temperature (22 ± 2 ° C.) and constant humidity (50 ± 2%), Each mouse was managed (mice were grouped). Mice were allowed to freely receive solid feed for mice (feed name: Labo MR Stock, manufactured by Nippon Nosan Kogyo Co., Ltd.) and water under a light / dark cycle every 12 hours (7:00 am; start time of light period). I let you.

(Iii) Measurement of behavior amount Then, it is installed in a constant temperature (22 ± 2 ° C.) and constant humidity (50 ± 2%) chamber (hereinafter sometimes referred to as a recording chamber), which is different from the above chamber. One mouse after group feeding was transferred to each of the plurality of acrylic gauges, and the solid feed for mice under the above-mentioned breeding conditions (12 hours light-dark cycle (7:00 am; light period start time)) And water were allowed to freely ingest) for 3 days (mouse was kept individually). The behavioral amount of the mouse on the third day in the recording chamber (the behavioral amount for 24 hours before administration of the following sample) was confirmed.
The amount of behavior was recorded using a sensor (manufactured by Biotex Japan) that detects infrared rays emitted from the animal and software Biotex 16CH Act Monitor BAI2216 (manufactured by Biotex Japan). The detection range of this sensor is spread at an irradiation angle of 90 degrees, and the range is divided into 64 sections of 8 × 8, and the number of times the animal has crossed the section is counted as an action amount.

(Iv) Sample Preparation / Administration As Example 1, 550 mg of α-lipoic acid was dissolved in 10 mL of purified water to prepare a sample. This sample was orally administered to individual mice (n = 7) using a sonde needle. The dose was adjusted to 10 g of sample per kg per mouse.
As Example 2, a sample was prepared by dissolving 825 mg of a mixture of beer yeast zinc (containing 10% by mass of zinc) and α-lipoic acid in a ratio of 1: 2 in 10 mL of purified water. This sample was orally administered to mice using a sonde needle. The dosage was the same as in Example 1.
In Comparative Example 1, purified water was used as a sample. This purified water was orally administered to mice at the same dose (10 g / kg) as in Example 1 using a sonde needle.
In each of Examples 1 and 2 and Comparative Example 1, the sample was administered to the mice at 7 pm (19:00: start time of dark period) (n = 7).

(V) Recording of behavior amount In order to apply stress to the mouse after oral administration, the mouse was transferred to another acrylic gauge in the recording chamber, and the above breeding conditions (lightness and darkness every 12 hours) were recorded in the recording chamber. Breeding under a cycle (7am; starting time of light period) under conditions that allow free intake of solid feed for mice and water, and measuring the amount of behavior over 12 hours, the number of counts per hour Was recorded. In addition, the cumulative amount of behavior was calculated by accumulating the amount of behavior from oral administration to 6 hours.
Thereafter, the breeding conditions and the breeding in the recording chamber were continued and observed for 24 hours.

2. Results The number of action amounts per hour (cumulative action amount) over 12 hours after sample administration is shown in FIG. The cumulative amount of behavior from oral administration to 6 hours is shown in FIG. 1 and 2, the amount of behavior represents the average number of counts per mouse.
In Examples 1 and 2, the amount of behavior decreased significantly compared to Comparative Example 1 at a dose of 10 g / kg.

[Example 3, Comparative Example 2]
1. Method (i) Animals Used C57BL / 6 mice (male, 12 weeks old, weight 24-27 g) were purchased from Japan SLC.
(Ii) Breeding method The breeding method was the same as in Example 1 except that the light period start time in the 12-hour light-dark cycle was 4 am and the dark period start time was 4 pm.

(Iii) Electroencephalogram and myoelectric potential measurement electrode treatment surgery and connection to measurement device The mice after group feeding were subjected to electroencephalogram and myoelectric potential electrode treatment surgery. After that, a plurality of acrylics installed in a constant temperature (22 ± 2 ° C.) and constant humidity (50 ± 2%) chamber (hereinafter sometimes referred to as a recording chamber) separate from the group-housed chamber. One mouse after the treatment operation is transferred to each gauge, and the solid feed and water for the mouse are freely available under the above-mentioned breeding conditions (under the light / dark cycle every 12 hours (4 am; start time of light period)). The condition was recovered after 10 days (conditions allowing ingestion). Subsequently, a measurement cable was connected to the electrode, and the mouse after the treatment operation was adapted in that environment for 4 days. The amount of behavior of the mouse on the fourth day in the recording chamber (the amount of behavior for 24 hours before administration of the following sample) was confirmed.

(Iv) Sample preparation / administration As Example 3, 320 mg of α-lipoic acid was dissolved in 10 mL of purified water to prepare a sample. This sample was orally administered to individual mice (n = 7) using a sonde needle. The dose was adjusted to be 10 g of sample per kg of mouse.
In Comparative Example 2, purified water was used as a sample. This purified water was orally administered to mice at the same dose (10 g / kg) as in Example 3 using a sonde needle.
In Example 3 and Comparative Example 2, the sample was administered to mice at 4 pm (16:00: start time of dark period) (n = 7).

(V) Recording and analysis of electroencephalogram and myoelectric potential The electroencephalogram and myoelectric potential were amplified (brain wave: 0.5 to 30 Hz, myoelectric potential: 20 to 200 Hz), and then digitized and recorded at a sampling rate of 128 Hz.
The analysis was performed on the recorded electroencephalogram and myoelectric potential using electroencephalogram recording software “SleepSign” (manufactured by Kissei Comtech). The data for 10 seconds was set to 1 epoch, and each epoch was automatically determined as “wakefulness”, “non-REM sleep”, or “REM sleep” based on the frequency components and waveforms of the electroencephalogram and myoelectric potential. The electroencephalogram data over 12 hours after sample administration was analyzed, and the time of “wakefulness”, “non-REM sleep” and “REM sleep” every hour was calculated. In addition, awakening time and non-REM sleep time over 6 hours after sample administration were integrated, and these integrated times were calculated.

2. Results The hourly non-REM sleep time over 12 hours after sample administration is shown in FIG. FIG. 4 shows the accumulated time obtained by accumulating the non-REM sleep time over 6 hours after sample administration. Table 1 shows the awakening time and non-REM sleep time and the time until sleep on the 6 hours after sample administration. In addition, in FIG. 3, 4 and Table 1, each time represents the average time per mouse | mouth. In Example 3, the effect of prolonging the non-REM sleep time significantly compared to Comparative Example 2 was seen at a dose of 10 g / kg. In Example 3, the time until falling asleep was shorter than in Comparative Example 2.

  According to the present invention, an excellent sleep improvement effect, in particular, an effect of increasing the non-REM sleep time can be obtained. In addition, the sleep latency can be shortened, the awakening can be reduced, the sedative effect, and the relaxation effect can be obtained, and a satisfactory sleep feeling can be obtained when waking up.

Claims (9)

A sleep improving agent containing α-lipoic acid as an active ingredient.
Furthermore, the sleep improving agent of Claim 1 containing zinc.
The sleep improving agent according to claim 2, wherein the zinc is incorporated into yeast.
A non-REM sleep time increasing agent containing α-lipoic acid as an active ingredient.
Furthermore, the non-REM sleep time increasing agent of Claim 4 containing zinc.
The non-REM sleep time increasing agent according to claim 5, wherein the zinc is incorporated into yeast.
A sedative containing α-lipoic acid as an active ingredient.
The sedative according to claim 7, further comprising zinc.
  The sedative according to claim 8, wherein the zinc is in a form incorporated into yeast.

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