JP6991092B2 - Sleep quality improver - Google Patents

Description

The present invention relates to a sleep quality improving agent.

Since 3-hydroxybutyric acid and its salts (hereinafter referred to as 3HB, and when referred to as 3HB, in particular, the monomer thereof) are substances originally present in the human body, they have high biocompatibility and are sugars. It is expected to be an epoch-making energy source to replace quality. It has also been found that 3HB not only plays a role as an energy source, but also acts as a signal transduction substance that affects the expression of various genes and the activity of proteins. 3HB is known to improve cognitive function and long-term persistent memory by inhibiting histone deacetylase, for example, by regulating gene expression, and its effectiveness in preventing Alzheimer's disease has been confirmed. For example, 3HB produced by ingestion of medium-chain fatty acids, which are abundant in coconut oil, and metabolism in the body has the effect of improving the symptoms of patients with Alzheimer's disease and diabetes who cannot make good use of sugar in the brain and body. It has been known. In addition, 3HB is converted into energy more quickly in the body than sugar and has the effect of suppressing the absorption of fat and sugar into cells, so it is applied to the fields of energy substances for athletes, diet and health foods. Can be expected.

On the other hand, sleep is roughly divided into two types: non-REM sleep, in which the activity of the cerebrum is almost stopped, and REM sleep, in which the whole body is weak but part of the brain is actively active and dreaming. These two types of sleep are repeated at regular intervals to form sleep. For good sleep, the time from bedtime to the appearance of non-rem sleep (sleep onset latency) is short, and it is necessary to secure sufficient non-rem sleep time and deep non-rem sleep, especially sufficiently deep non-rem sleep in the early stage of sleep. In addition, it has been reported that the non-rem sleep time is significantly reduced in the elderly as compared with the younger ones, and the quality of sleep is deteriorated due to aging.

Deterioration of sleep quality includes factors such as a long time from bedtime to the appearance of non-rem sleep (sleep onset latency), a short non-rem sleep time, and lack of deep non-rem sleep. For these, pharmaceutical sleeping pills may be used. However, a doctor's diagnosis is required when using sleeping pills. Hypnotics have side effects such as poor awakening, memory loss, and dependence. As described above, it is often difficult to use sleeping pills easily and safely.

Therefore, research and development of sleep-improving agents from natural ingredients and foods and drinks other than pharmaceuticals are being actively carried out, and various sleep-improving agents have been proposed. Examples of the active ingredient of such a sleep improving agent include a component derived from a plant of the genus Withania of the Solanaceae family (Patent Document 1), a fermented product of Akinowasuregusa (Patent Document 2), a tea leaf-derived theamine (Patent Document 3), and Koryo. Ginseng extract (Non-Patent Document 1) and the like have been proposed. However, the effects of these components on sleep onset latency and non-rem sleep time and depth are not clear, and their effects on improving sleep quality are inadequate. It has also been reported that sake yeast is useful for improving sleep quality, but it has not been sufficiently effective in improving REM sleep latency (Non-Patent Document 2).

Under these circumstances, it has also been reported that the oligomer of 3HB is effective as an agent for introducing sleep and the like (Patent Document 4).

3HB can be obtained by causing various microorganisms to produce poly-3hydroxybutyric acid (hereinafter referred to as PHB) and then decomposing the obtained PHB with an enzyme or the like (Patent Document 5). As a form in which 3HB can be administered to humans, it is known that 3HB can be administered intravenously as an oligomer (Patent Document 6).

Japanese Unexamined Patent Publication No. 2006-28051 Japanese Unexamined Patent Publication No. 2006-62298 International Publication No. 2005/097101 Japanese Unexamined Patent Publication No. 2005-65562 Japanese Unexamined Patent Publication No. 2010-168595 Japanese Unexamined Patent Publication No. 06-321778

Young Ho Rhee, et al., Psychopharmacology, 101, p.486-488 (1990) J sleep Res., 25, p.116-123 (2016)

However, in order to improve the quality of sleep, it is not enough to improve the introduction of sleep, and further, the active ingredient of the sleep quality improving agent is being searched for. In addition, in order to improve the quality of sleep, it is required to use a simple form of oral administration.

Therefore, in view of the above circumstances, it is an object of the present invention to provide a sleep quality improving agent that exerts a sleep quality improving effect even by oral administration.

The characteristic composition of the sleep quality improving agent of the present invention for achieving the above object is that it is an oral preparation containing a 3HB monomer as an active ingredient.

As a result of diligent research, the present inventors have found that the 3HB monomer exerts a sleep quality improving effect for improving REM sleep latency, and have completed the present invention. According to the present invention, 3HB exerts a sleep quality improving effect by oral administration, so that a sleep quality improving effect can be expected easily and safely. In addition, as for the quality of sleep, since the sleep latency of REM sleep is particularly improved, the sleep rhythm cycle of non-REM sleep and REM sleep is improved, which contributes to a fulfilling sleep.

"Sleep quality" in the present invention means that the body and brain tired from sleep can be rested. Even if you sleep for a long time, you cannot get enough tiredness without the quality of sleep. As an index for measuring the quality of sleep, for example, the time from bedtime to the appearance of non-rem sleep (hereinafter referred to as sleep onset latency), the depth of non-rem sleep at the beginning of sleep (rem sleep latency), and non-rem in the entire sleep time. Percentage of sleep time (non-rem deep sleep), lack of sleepiness when waking up, falling asleep and deep sleep, dreaming, sleep satisfaction and fatigue. Of these, sleep onset latency, depth of non-rem sleep in the early stages of sleep, ratio of non-rem sleep time to total sleep time, lack of drowsiness when waking up, falling asleep and feeling of deep sleep, dreaming and fatigue are preferable. These evaluation indexes can be evaluated by using various known methods.

"Improvement of sleep quality" in the present invention means that the above-mentioned sleep quality is improved or improved. Improved sleep quality includes, for example, shorter sleep onset latency (sleep onset latency), deep non-rem sleep in the early stages of sleep (REM sleep latency), and non-rem sleep time in total sleep time. Increased proportion (non-rem deep sleep), improved sleeplessness when waking up, improved sleep and deep sleep, improved dreaming (eg, frequent) It can be judged from one or more selected from the group consisting of (no more dreaming or nightmare) and increased feeling of recovery from fatigue (reduction of feeling of fatigue). Moreover, you may judge from a plurality of these. It can be confirmed under the conditions of the examples that the sleep quality such as sleep onset latency, REM sleep latency, non-REM deep sleep, and feeling of falling asleep and deep sleep is improved. It cannot be said that the lack of drowsiness when waking up, the improvement of dreams, and the feeling of recovery from fatigue were directly improved by the measurement conditions of the examples, but the improvement of the above sleep index naturally leads to the improvement of other indicators. I can imagine that there is.

According to the sleep quality improving agent of the present invention, the quality of sleep can be effectively improved. Further, since 3HB is a substance originally contained in a living body, the sleep quality improving agent of the present invention containing this as an active ingredient is safe for the living body and can be used by the user with peace of mind.

That is, 3HB does not need to be administered intravenously and can be administered orally, so that it can be easily administered to humans. In addition to improving the induction of sleep onset, it also improves the sleep rhythm cycle, which was difficult to improve in the past. By contributing to, it is expected to be applied to the prevention and treatment of diseases related to poor sleep quality, such as diabetes, heart disease, hypertension, hyperlipidemia, and Alzheimer's disease. Therefore, the sleep quality improving agent of the present invention is useful as a final product such as food and drink, pharmaceutical products, and quasi-drugs.

Therefore, it has been possible to provide an orally administrable sleep quality improving agent which is expected to be used for improving various sleep disorders, and particularly for improving REM sleep latency.

The figure which shows the 3HB intake effect of each sleep index

The sleep quality improving agent of the present invention will be described below. In addition, although suitable examples are described below, each of these examples is described in order to more specifically exemplify the present invention, and various changes can be made without departing from the spirit of the present invention. However, the present invention is not limited to the following description.

[Sleep quality improver]
The sleep quality improving agent according to the embodiment of the present invention contains a 3-hydroxybutyric acid monomer (3HB) as an active ingredient, and can be used for the purpose of improving REM sleep latency by oral administration. ..

3HB is considered to have the same effect if it is a monomer, and is not limited to the 3HB monomer itself, but is provided in the form of a salt of 3HB (for example, sodium 3-hydroxybutyrate). You may.

Further, the sleep quality improving agent may contain various components other than 3HB, for example, excipients, disintegrants, binders, lubricants, coating agents, coloring agents, coloring agents, and flavoring agents. Pharmaceutically acceptable additives such as agents, flavoring agents, antioxidants, preservatives, flavoring agents, acidulants, sweeteners, enhancers, vitamins, swelling agents, thickeners, surfactants Can be mentioned. From these, one or two or more additives should be selected according to the dosage form of the final product without impairing the sleep quality improving effect and various properties required for the formulation (for example, formulation stability). Can be done. In addition, an active ingredient such as a sleep quality improving agent other than 3HB may be contained.

The sleep quality improving agent of the present invention can be used as it is as a final product (for example, food and drink, pharmaceutical products, quasi-drugs, etc.). Further, it can be used as an additive for foods and drinks, an additive for pharmaceuticals, and an additive for quasi-drugs. This makes it possible to impart the effect of improving sleep quality to foods and drinks, pharmaceuticals, and quasi-drugs.

The administration form of the sleep quality improving agent and the sleep quality improving composition of the present invention is not particularly limited. For example, oral administration (for example, oral administration, sublingual administration, etc.), parenteral administration (intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, nasal administration, pulmonary administration, etc.) and the like can be mentioned. Among these, a less invasive administration form is preferable, and oral administration is more preferable.

The dosage form of the sleep quality improving agent and the sleeping quality improving composition of the present invention is not particularly limited. Examples of dosage forms for oral administration are liquid (liquid), syrup (syrup), and solid (solid).
Tablets), capsules (capsules), powders (granule, fine granules), soft capsules (soft capsules), semi-liquid, creams, and pastes. Examples of dosage forms for parenteral administration include liquids (injection, nasal drops), atomized (sprays, inhalants) and the like.

3HB can be produced by various known methods. For example, 3HB can be obtained by performing a fermentation process in which Halomonas bacteria having 3HB productivity are added, separating and removing Halomonas bacteria from the obtained fermentation broth, and purifying the Halomonas bacteria. The fermentation process is a process in which 3HB-productive Halomonas bacteria are added as they are to a raw material solution containing a sugar nutrient source such as fruit juice, and aerobic fermentation and slightly aerobic fermentation are carried out in order (Japanese Patent Laid-Open No. 2013-081403, etc.). See). As a result, sugar is converted to 3HB and produced in the fermented liquor. The produced 3HB is used as pure 3HB after undergoing membrane separation and separation purification by a conventional method.

The dose of the sleep quality improving agent is not particularly limited as long as the effect of the present invention is not impaired, and can be appropriately changed depending on factors such as the age and condition of the administered living body to which the present invention is applied. The preferred dose for obtaining the desired effect is preferably 0.5 to 25 g, more preferably 1 to 5 g, as the daily amount of 3HB.

The sleep quality improving agent of the present invention includes, for example, beverages (soft beverages, carbonated beverages, nutritional beverages, powdered beverages, fruit beverages, dairy beverages, jelly beverages, etc.), confectionery (cookies, cakes, gums, candies, tablets, etc.). Gumi, buns, sheep drinks, puddings, jellies, ice creams, sherbets, etc.), processed marine products (kamaboko, chikuwa, hampen, etc.), processed livestock products (hamburgers, hams, sausages, wieners, cheese, butter, yogurt, fresh cream, etc.) Margarine, fermented milk, etc.), soup (powdered soup, liquid soup, etc.), main foods (rice, noodles (dried noodles, raw noodles), bread, cereals, etc.), seasonings (mayonnaise, shortening, dressing, sauce, sauce) , Soy sauce, etc.) can be used as food and drink. Above all, it is preferable to use it as various beverages. For example, it is assumed that 100 mL of a 5% 3HB salt aqueous solution in which 3HB is neutralized to a pH of about 4 to 5 is ingested once a day before going to bed. The mechanism by which 3HB improves sleep is unclear, but daytime intake can be expected to have a similar effect on improving sleep quality.

The sleep quality improving agent of the present invention includes health foods, functional foods, dietary supplements, specified health foods, medical foods, sick foods, infant foods, nursing foods, and elderly foods. It can be used as food and drink. Above all, it is preferable to use health foods and functional foods.

〔Example〕
Hereinafter, the present invention will be described with reference to examples.

[Sleep quality improvement effect]
(experimental method)
Observe the sleep index when 100 mL each of a sleep quality improving agent consisting of a 5% 3HB aqueous solution is ingested before going to bed for 4 days with respect to a human subject.

The measurement was performed using an electroencephalograph (Sleepscope, manufactured by Sleepwell).
As a sleep index,
(1) δ power value of the first sleep cycle (μV ² / min): Depth of non-rem sleep at the beginning of sleep (2) Sleep efficiency (%): Percentage of time spent sleeping during bedtime (general sleep quality) )
(3) Midway awakening (%): Percentage of time spent waking up, turning over, bruxism, etc. (4) Non-rem deep sleep (%): Percentage of deep sleep time (deep sleep)
(5) Rem sleep latency (minutes): Rhythm cycle (rhythm) of non-rem sleep / rem sleep
(6) Sleep onset latency (minutes): Time taken to fall asleep (sleeping)
Was measured and evaluated.

The sleep index was compared with the measured values obtained by averaging the measured values of the human subject for 4 days without taking the sleep quality improving agent and the measured values for 4 days after taking the sleep quality improving agent. As a result, it became as shown in FIG.

In addition, the ratio of these improvement effects (improvement ratio) is
(Improvement rate) = (when ingested) / (when not ingested)
Table 1 shows the improvement ratio according to this example and the improvement ratio described in Non-Patent Document 2 (the electroencephalograph used for the measurement is the same as that of this example).

From FIG. 1 and Table 1, when 3HB was ingested, it was compared with the case where it was not ingested.
(1) The δ power value of the first sleep cycle increases, the depth of non-rem sleep improves, and
(2) Sleep efficiency is improved, overall sleep quality is improved, and
(3) Awakening during sleep is reduced, and awakening and movement during sleep are reduced.
(4) Non-rem deep sleep Non-rem 3 increases, deep sleep time becomes longer,
(5) REM sleep latency is shortened and sleep rhythm is greatly improved.
(6) Sleep onset latency is shortened and sleep is better.
I understand.

Examining FIG. 1 and Table 1, it can be seen that the effects of the sleep quality improving agents on the evaluation items (1) to (6) differ depending on the type of the active ingredient. It was found that 3HB worked effectively for each endpoint as a whole and was effective as a sleep quality improving agent. In addition, since the active ingredient of Non-Patent Document 2 exerts an excellent effect in the evaluation items (1) and (5), which has not been confirmed to be effective, it is used as a sleep quality improving agent for improving REM sleep latency. It can be said that it is particularly effective. In this embodiment, six items that can be measured by an electroencephalograph are taken as evaluation items for sleep quality and comprehensively evaluated. However, any one item may be used, and a plurality of types selected from these items may be used. May be. In this case, it is desirable to include REM sleep latency, which has a large effect of 3HB, as an evaluation item. Furthermore, it is possible to additionally include evaluation items such as feeling of falling asleep, dreaming, feeling of fatigue, etc. by a questionnaire survey for panelists. That is, it can be seen that the 3HB monomer can be used as a sleep quality improving agent for improving these evaluation items as sleep quality.

At present, no correlation has been found as to which evaluation item of sleep quality the various active ingredients effectively act on. For example, regarding the evaluation item (6), the active ingredient expected to be effective for sleep onset disorders is also effective for mid-career awakening, early awakening, and deep sleep disorder (sleep quality) with respect to the evaluation items (1)-(5). Not necessarily. Therefore, the 3HB monomer is new as an active ingredient of the sleep quality improving agent for improving the REM sleep latency of the evaluation item (5), and as an active ingredient of the sleep quality improving agent having a different effect from the conventional one. As an active ingredient that generally improves the evaluation items (1) to (6), it has been clarified that it can be said to be an active ingredient of a sleep quality improving agent having a remarkable effect than before. ..

The sleep quality improving agent of the present invention can be used for improving sleep quality, and in particular, can be used as a sleep quality improving agent for improving REM sleep latency.

Claims (2)

A sleep quality improving agent that is an oral preparation containing a 3-hydroxybutyric acid monomer as an active ingredient. The sleep quality improving agent according to claim 1, which improves REM sleep latency.

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