JP7565173B2 - Autonomic nervous system regulator for use at bedtime - Google Patents

Description

The present invention relates to an agent that regulates autonomic nervous system disorders that occur during sleep.

Women's health is greatly influenced by two female hormones, estrogen (follicular hormone) and progesterone (luteal hormone), which are secreted from the ovaries. Fluctuations in female hormones cause fluctuations in the autonomic nervous system, which can manifest as disorders that impair both the body and mind, such as premenstrual syndrome and menopausal disorders (Non-Patent Document 1). In particular, many women suffer from insomnia caused by an imbalance in the autonomic nervous system while sleeping.

Hormone replacement therapy (HRT) is widely used as a treatment to alleviate symptoms caused by a deficiency of female hormones. However, because HRT is a treatment that artificially supplements large amounts of female hormones, while it is highly effective, it also places a large burden on the body and makes it very difficult to adjust the dosage.

In recent years, plant-derived isoflavones have been attracting attention as components that mimic female hormones. It is believed that this female hormone-like effect is due to the similarity of the chemical structure of isoflavones to that of estrogen. In particular, equol, which is derived from isoflavones contained in soybeans, is known to have estrogenic activity (Non-Patent Documents 2 and 3).

In fact, it has been reported that the improvement in menopausal symptoms in 105 gynecological outpatients who consumed foods containing equol increased over time, from 43% after one month, to 61% after three months, and to 86% after 12 months, and that a similar progress was observed even without the use of hormone replacement therapy (Non-Patent Document 4).

On the other hand, it is important to manage oneself by understanding the state of the autonomic nerves on a daily basis, and sensors and software that can measure the autonomic nerves have been developed. In recent years, in order to make the measurement of the autonomic nerves even easier, a system (COCOLOLO) that can measure the autonomic nerves using a camera of a commercially available smartphone has been developed. The principle of this system is that the amount of hemoglobin in the bloodstream increases or decreases with each breath, which causes a subtle change in the color (brightness) of the skin on the fingertips. The fingertip is placed on the camera part of the smartphone, and the brightness of the skin is continuously acquired to detect the pulse wave waveform from the change in brightness, and the autonomic nerve index is analyzed from the fluctuation of the pulse wave. It has been recognized that there is a high correlation with a heart rate variability analysis system that uses a dedicated fingertip pulse wave sensor, and that reliable data can be obtained (Non-Patent Documents 5, 6, 7).

J. Jp. Soc. Psychosom. Obstet. Gynecol Vol. 12, No. 1・2, pp. 277?287 (2007) Sathyamoorthy, N. and Wang, T. T. , Eur. J. Cancer, 33, 2384-2389 (1997) Schmitt, E. et al. , Toxicol. In Vitro, 15, 433-439 (2001) The Journal of Alternative and Complementary Medicine Vol. 24, No. 7, 701-708 (2018) Health, Vol.8 No.9, 827-845 (2016) Health, Vol.8 No.9, 894-904 (2016) Health, Vol.8 No.10, 959-970 (2016)

Equol is a compound that is expected to serve as an alternative to hormone replacement therapy, but it takes time for its effects to appear, and it is generally believed that it is necessary to take it for at least one month to obtain the effect of regulating the autonomic nervous system. However, insomnia, which is one of the most common menopausal symptoms, also has a negative impact on daytime mental activity and significantly reduces quality of life, so it is desirable to improve the symptoms as soon as possible.

Therefore, the present invention aims to provide an agent that can quickly exert a regulating effect on autonomic nervous system disorders that occur during sleep.

After extensive research, the inventors discovered that by combining equol with herbal medicines and/or herbal extracts, the autonomic nervous system regulation effect during sleep can be achieved more quickly. The present invention was completed based on this finding and through further research.

That is, the present invention provides the following aspects.
Item 1. An autonomic nerve regulator for use at bedtime, comprising equol and a herbal medicine and/or a herbal medicine extract.
Item 2. The autonomic nerve regulator for use at bedtime according to Item 1, wherein the herbal medicine is selected from the group consisting of ginseng, cinnamon bark, licorice, and ginger.

The present invention can quickly regulate autonomic nervous system disorders that occur during sleep, allowing for early relief from painful symptoms such as insomnia.

The autonomic nervous system regulator for use at bedtime of the present invention is characterized by containing equol and herbal medicines and/or herbal medicine extracts. The autonomic nervous system regulator for use at bedtime of the present invention is described in detail below.

Equol Equol is a substance produced by the metabolism of daidzein, a type of isoflavone, by intestinal bacteria and digestive enzymes in the body, and specifically refers to 7-hydroxy-3-(4'-hydroxyphenyl)-chroman. Equol is known as a component having female hormone-like activity.

Equol may be synthetic equol obtained by chemical reduction of daidzein (daidzein glycoside, daidzein and/or dihydrodaidzein), or it may be a metabolite of equol-producing bacteria from a raw material containing daidzein (daidzein glycoside, daidzein and/or dihydrodaidzein).

Raw materials containing daidzeins are not particularly limited, and examples thereof include plants (specifically, soybeans, kudzu, kudzu root, red globe, alfalfa, etc.), processed products thereof (specifically, soybean flour, boiled soybeans, tofu, fried tofu, soy milk, soybean hypocotyls, soybean hypocotyl extracts, etc.), and fermented preparations thereof (specifically, natto, soy sauce, miso, tempeh, fermented soy beverages, etc.). In addition, the equol-producing bacteria may be any microorganism that can assimilate daidzeins to produce equol, and examples thereof include microorganisms belonging to the genus Lactococcus, the genus Streptococcus, and the genus Bacteroides.

In the present invention, equol may be blended using a fermentation culture of daidzein-containing raw materials by equol-producing bacteria, or the metabolite equol may be isolated and purified from the fermentation culture. From the viewpoint of further enhancing the effect of early adjustment of the autonomic nerves at bedtime, it is preferable to blend equol using a fermentation culture of daidzein-containing raw materials, preferably soybeans, by equol-producing bacteria.

The amount of equol contained in the autonomic nervous regulator to be used at bedtime according to the present invention may be set depending on the amount of other ingredients contained, the form of the female hormone-like activity enhancer, the amount to be taken per serving, etc., and may be, for example, 0.01 to 30% by weight, preferably 0.05 to 10% by weight, more preferably 0.1 to 3% by weight, and even more preferably 0.1 to 0.5% by weight. In the present invention, when a fermentation culture is used to incorporate equol, the fermentation culture is used so that the equol content therein is the above-mentioned amount.

Herbal medicines and/or herbal extracts In the bedtime autonomic nervous system regulating agent of the present invention, by combining herbal medicines and/or herbal extracts with equol, the onset of the autonomic nervous system regulating effect at bedtime can be accelerated.

The herbal medicines are not particularly limited, and examples thereof include carrot, cinnamon bark, licorice, ginger, safflower, saffron, angelica tree, peony root, and cnidium root. Among these herbal medicines, from the viewpoint of further enhancing the effect of early adjustment of the autonomic nerves at bedtime, carrot, cinnamon bark, licorice, and/or ginger are preferred, and carrot, cinnamon bark, licorice, and ginger are more preferred.

In the present invention, when the herbal medicine is used as it is, it can be blended in the form of herbal powder. When an extract of a herbal medicine is used, the herbal medicine can be blended in the form of an extract liquid obtained by extracting the herbal medicine with water or aqueous ethanol, preferably ethanol, as the extraction solvent, and concentrating the obtained extract liquid as necessary, or in the form of a dried extract powder obtained by drying the extract liquid. The method of drying the extract is not particularly limited, and includes known methods such as the spray drying method and a method of adding an appropriate adsorbent (e.g., silicic anhydride, starch, etc.) to a soft extract with a high concentration of the extract liquid to obtain an adsorbed powder.

In the present invention, the extract of a herbal medicine may be a single extract of a herbal medicine, or a mixed extract of multiple herbal medicines.

In the present invention, from the viewpoint of further enhancing the effect of early adjustment of the autonomic nerves at bedtime, preferred are carrot extract, cinnamon powder, licorice powder, and/or ginger powder, and more preferred are carrot extract, cinnamon powder, licorice powder, and ginger powder.

The carrot extract can be obtained by extracting the fine roots of carrot (Panax ginseng C.A. Meyer (Panax schinseng Nees) of the Araliaceae family) or a fermented product thereof with an extraction solvent. In the present invention, it is preferable to use an extract obtained by extracting the fine roots of carrot with an extraction solvent as the carrot extract. Examples of the extraction solvent used in the carrot extraction process include water and/or ethanol. From the viewpoint of further enhancing the effect of early adjustment of the autonomic nerves at bedtime, preferably ethanol or aqueous ethanol, more preferably aqueous ethanol, and even more preferably an aqueous solution containing 55 to 80 v/v% (preferably 57 to 70 v/v%, more preferably 59 to 65 v/v%) ethanol.

The content of herbal medicines and/or herbal extracts in the autonomic nerve regulator for use at bedtime of the present invention is not limited to, but may be, for example, 5 to 50% by weight, preferably 15 to 35% by weight, in terms of the total amount of raw herbal medicine equivalent (when powdered herbal medicine is used, this refers to the amount of powdered herbal medicine itself, and when an extract is used, this refers to the amount of raw herbal medicine used to prepare the extract).

The content ratio of equol to herbal medicines and/or herbal extracts in the autonomic nervous system regulator for use while sleeping of the present invention is not particularly limited and is determined according to the above-mentioned respective contents, but from the viewpoint of further enhancing the effect of early adjustment of the autonomic nervous system while sleeping, the total amount of the herbal medicines and/or herbal extracts in terms of raw herbal medicine per 1 part by weight of equol is preferably 20 to 200 parts by weight, and more preferably 100 to 150 parts by weight.

When carrot extract is used as the herbal medicine and/or herbal medicine extract, from the viewpoint of further enhancing the effect of early adjustment of the autonomic nerves at bedtime, the content of carrot extract per 1 part by weight of equol is preferably 15 parts by weight or more, more preferably 20 parts by weight or more, and even more preferably 25 parts by weight or more. There is no particular upper limit to the content of carrot extract per 1 part by weight of equol, but an example of this is 30 parts by weight or less.

When licorice powder, cinnamon powder, or shiso powder is used as the herbal medicine and/or herbal medicine extract, from the viewpoint of further enhancing the effect of early adjustment of the autonomic nerves at bedtime, the content of licorice powder, cinnamon powder, or shiso powder per 1 part by weight of equol is preferably 10 parts by weight or more, preferably 15 parts by weight or more, more preferably 25 parts by weight or more, even more preferably 30 parts by weight or more, even more preferably 35 parts by weight or more, and particularly preferably 38 parts by weight or more. There is no particular limit to the upper limit of the content of licorice powder, cinnamon powder, or shiso powder per 1 part by weight of equol, but an example of this is 50 parts by weight or less.

Other components The autonomic nerve regulator for use at bedtime of the present invention may contain other pharmacological components as necessary, in addition to the above-mentioned components. The types of such pharmacological components are not particularly limited, but examples thereof include antacids, stomachic agents, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives, hypnotics, antihistamines, caffeine, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal powders, herbal extracts, vitamins, and menthols. These pharmacological components may be used alone or in combination of two or more. The content of these pharmacological components may be appropriately set from known ones according to the type of pharmacological component to be used.

The autonomic nerve regulator for use at bedtime according to the present invention may contain pharma- ceutically acceptable bases and additives, etc., as necessary, in order to prepare the desired dosage form. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV protection agents, preservatives, flavorings, fragrances, powders, thickeners, dyes, and chelating agents. These bases and additives may be used alone or in combination of two or more. The content of these bases and additives may be appropriately set from known ones according to the type of additive used and the dosage form.

Dosage form The dosage form of the autonomic nerve regulator for use at bedtime of the present invention is not particularly limited, and may be any of tablets, granules, powders, pills, capsules, films, liquids (drinks), etc. Among these dosage forms, from the viewpoint of ease of administration, etc., preferred are tablets, granules, and films. These dosage forms can be prepared using pharma- ceutically acceptable base materials and additives, and the types and amounts of the base materials and additives are also known in the field of formulation technology.

Uses The autonomic nerve regulator for use at bedtime of the present invention is used for the purpose of regulating autonomic nerve disorders at bedtime. If the autonomic nerve is appropriately regulated at bedtime, the parasympathetic nerve will be sufficiently dominant. Therefore, the autonomic nerve regulator for use at bedtime of the present invention can be used for subjects with insufficient parasympathetic nerve dominance at bedtime. The dominance of the parasympathetic nerve can be confirmed by the LH/HF ratio. Here, HF means high frequency, and is a fluctuating wave with a period of about 3 to 4 seconds, the signal source of which is breathing. LF means low frequency, and is a fluctuating wave with a period of about 10 seconds, called Mayer wave, the signal source of which is a blood pressure change. The LH/HF ratio can be measured by commercially available sensors, software, and applications. Specifically, the autonomic nerve regulator for use at bedtime of the present invention can be applied to subjects with an LH/HF ratio at bedtime of, for example, 0.8 or more, preferably 0.9 or more, more preferably 2.5 or more, even more preferably 3 or more, even more preferably 4 or more, and particularly preferably 5 or more.

More specifically, the bedtime autonomic nerve regulator of the present invention can be applied to insomnia symptoms such as sleep onset disorder (time taken to fall asleep after going to bed and difficulty falling asleep), awakening during the night (waking up multiple times after falling asleep before waking up the next morning), early morning awakening (waking up more than two hours earlier than usual wake-up time and unable to fall asleep again), and deep sleep disorder (not feeling like one has slept deeply despite having slept for a sufficient amount of time), preferably sleep onset disorder and/or deep sleep disorder.

The bedtime autonomic nervous regulator of the present invention is particularly preferably applied to women who complain of autonomic nervous disorders at bedtime caused by a decrease in female hormones. Therefore, the female hormone-like activity enhancer of the present invention is applied to women with decreased female hormones, particularly women who are aware of symptoms caused by a decrease in female hormones. Specific target subjects include women aged 40 years or older, menopausal women, women with premature ovarian failure after oophorectomy or chemotherapy, women after hysterectomy, elderly women, etc.

Dosage and Usage The autonomic nervous regulator of the present invention is administered orally at bedtime. The dosage of the autonomic nervous regulator of the present invention at bedtime is appropriately set depending on the degree of female hormone reduction, age, etc., and may be, for example, 0.1 to 100 mg, preferably 0.5 to 40 mg, more preferably 1.0 to 10 mg, even more preferably 1.5 to 5 mg, and particularly preferably 1.8 to 3 mg, in terms of the daily intake of equol.

The timing of taking the autonomic nervous regulator of the present invention at bedtime is not particularly limited, and it may be taken before, after, or between meals, but is preferably taken before or between meals.

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

Test Example : An autonomic nervous system regulator for use at bedtime was prepared by blending 40 mg of fermented soy isoflavones (containing 2 mg of equol) as an equol source, an extract powder obtained by extracting ginseng rootlets with a 60 v/v % aqueous ethanol solution and drying as a carrot extract, cinnamon powder, licorice powder, and ginger powder in the amounts (daily amounts) shown in Table 1.

Twelve women complaining of insomnia (disorders of falling asleep and/or deep sleep) as a menopausal symptom were given the autonomic nervous system regulators of Examples 1 to 3 for 10 days, and the autonomic nervous system balance (LH/HF ratio) at bedtime before and after 10 days of administration was measured using the application COCOLOLO (WIN Frontier Co., Ltd.). The results are shown in Tables 2 to 4.

As shown in Tables 2 to 4, all subjects were able to correct the imbalance of the autonomic nervous system at bedtime by simply taking the bedtime autonomic nervous system regulator of the present invention for just 10 days. In fact, it was confirmed that all subjects experienced an improvement in insomnia symptoms (disorders of falling asleep and/or disorders of deep sleep). In particular, the bedtime autonomic nervous system regulator of Example 2 significantly reduced the LH/HF ratio by more than 90% in all subjects, and was particularly effective in early adjustment of the autonomic nervous system at bedtime.

Claims (2)

Contains equol, carrot extract, cinnamon powder, licorice powder, and ginger powder .
An autonomic nerve regulator for use during bedtime for women, wherein the content of the carrot extract is 25 to 30 parts by weight, the content of the cinnamon powder is 35 to 50 parts by weight, the content of the licorice powder is 35 to 50 parts by weight, and the content of the ginger powder is 35 to 50 parts by weight, relative to 1 part by weight of the equol . The autonomic nervous system regulator used at bedtime according to claim 1, which is used for menopausal sleep onset disorder and/or deep sleep disorder.