JP7365150B2 - Insomnia treatment before or during menstruation - Google Patents

Description

The present invention relates to a therapeutic agent for insomnia before or during menstruation, which improves insomnia caused by menstrual cycle fluctuations.

A woman's physical condition is strongly influenced by female hormones. Reproductive women have a unique menstrual cycle due to changes in the female hormones estrogen and progesterone. In particular, during the hyperthermia period before menstruation, the amount of progesterone secreted increases, and estrogen is secreted at about 78 to 252 pg/ml, although it is not as high as during the ovulation period (Non-patent Document 1, Non-Patent Document 2). Due to this unique hormonal condition, many women complain of discomfort due to premenstrual syndrome (PMS). One of the main symptoms of PMS is premenstrual insomnia. The cause of premenstrual insomnia is associated with the effect of increasing body temperature due to progesterone (Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5). In addition, it is known that sleep is more likely to occur during phases when rectal temperature is decreasing (Non-Patent Document 6). Since the amplitude becomes small in the late luteal phase (Non-patent Document 5), a sufficient descending phase in which sleep is likely to occur cannot be obtained. For this reason, insomnia symptoms become noticeable before menstruation, especially in the late luteal phase. As a drug therapy for premenstrual insomnia, a small amount of ultra-short-acting sleeping pills are prescribed (Non-Patent Document 3), but premenstrual insomnia is resolved with the onset of menstruation.

On the other hand, when a woman approaches menopause, estrogen and progesterone decrease, and estrogen drops to 39 pg/ml or less after menopause (Non-Patent Document 1, Non-Patent Document 2). During menopause, many women complain of indeterminate complaints due to the unique hormonal condition in which the secretion of female hormones decreases. Insomnia is one of the main symptoms of such indefinite complaints. A decrease in the amount of estrogen is involved in the cause of insomnia during menopause (Non-Patent Document 3, Non-Patent Document 5, Non-Patent Document 7). Medicinal treatments for insomnia during menopause include small amounts of estrogen replacement therapy and taking Chinese herbal medicines such as Tokishakuyakusan, Kamishoyosan, and Keishibukuryogan (Non-Patent Document 3, Non-Patent Document 8). Among these, it has been reported that the specific effect of Kamishoyosan is to slightly increase blood estrogen in ovariectomized rats (Non-Patent Document 9). In other words, the effect of Kamishoyosan on improving sleep disorders during menopause is thought to be due to increasing estrogen.

Obstetrics and Gynecology, 2006, No. 1, 133-140 Clinical Testing Business, Vol. 13-05 C-02, February 2013 Journal of Biomechanism Society, Vol. 29, No. 4, 2005, 205-209 Sleep and Medical Care, Vol. 4, No. 1, 2011, 13-16 Diagnosis and Treatment, Vol. 92, No. 7, 2004(115), 1207-1212 Japanese Pharmacological Journal, 129, 400-403 (2007) Insurance Medical Science, 2015, Vol. 64, No. 1, 33-40 Okinawa Medical Report, Vol. 47, No. 2, 2011, 87-90 Phil Chinese medicine, No. 53, 2015, 12-15

As mentioned above, Kamishoyosan has been used for insomnia during menopause, but it has not been used specifically for insomnia before menstruation. This is because the causes of insomnia during menopause (reduction in estrogen) and the causes of insomnia before menstruation (increase in progesterone) are essentially different, and the additives that have been used for insomnia during menopause Shoyosan has a mechanism of action that relieves insomnia by slightly increasing the amount of estrogen, but because premenstrual estrogen levels are not as low as those during menopause, it may be effective against insomnia during menopause. This is because there was no rational recognition that the applied Kami Shoyosan would be effective against premenstrual insomnia.

Therefore, an object of the present invention is to provide an effective therapeutic agent for insomnia before menstruation, particularly in the late luteal phase when insomnia becomes noticeable.

In addition, before menstruation, the ratio of awake time to sleeping time is particularly high, making it easy to recognize insomnia. On the other hand, it is recognized that during menstruation, insomnia is naturally resolved because progesterone, which is the cause of insomnia, decreases dramatically. However, when the present inventor investigated the quality of sleep due to menstrual cycle fluctuations, it was found that during menstruation, the ratio of deep sleep time to sleep time is short, resulting in a decrease in sleep quality. I found out that it is.

Therefore, another object of the present invention is to provide an effective therapeutic agent for insomnia during menstruation.

The present inventor has found that Kamishoyosan is effective for both premenstrual insomnia and menstrual insomnia. The present invention was completed through further studies based on this knowledge.

That is, the present invention provides the inventions of the following aspects.
Item 1. A treatment for insomnia before or during menstruation, containing Kami Shoyosan extract.
Item 2. Item 2. The therapeutic agent for insomnia according to item 1, wherein the Kami Shoyosan extract is an extract of a mixture of Angelica, Peony, Jutsu, Bukryo, Saiko, Botanpi, Sanshishi, Licorice, Gingerbread, and Mentha.
Item 3. Item 3. The insomnia therapeutic agent according to item 1 or 2, which reduces wake time relative to sleep time before or during menstruation.
Item 4. Item 3. The insomnia therapeutic agent according to any one of Items 1 to 3, which increases deep sleep time relative to sleep time during menstruation.

According to the present invention, a therapeutic agent is provided that is effective for both premenstrual insomnia, particularly insomnia in the late luteal phase when insomnia becomes noticeable, and insomnia during menstruation. For example, the ratio of awake time to sleeping time can be reduced not only before menstruation but also during menstruation, and furthermore, the ratio of deep sleep time to sleeping time can be increased during menstruation.

Sleep time, sleep time, ratio of awake time to sleep time, ratio of light sleep time to sleep time, and deep sleep to sleep time during the first cycle of the menstrual cycle (control) when the insomnia treatment agent of the present invention was not taken Shows the percentage of time. Sleep time, ratio of awake time to sleep time, and sleep time in the late luteal phase and menstrual phase for cases where the insomnia treatment agent of the present invention is not taken (control) and cases where the insomnia treatment agent of the present invention is taken, respectively. It shows the ratio of light sleep time to sleep time and the ratio of deep sleep time to sleep time.

Insomnia Treatment Agent The insomnia treatment agent of the present invention is characterized by containing Kamishoyosan extract. The specific composition of the Kamishoyosan extract is not particularly limited as long as it is based on the original text. Specifically, examples of the Kami Shoyosan extract include extracts of mixtures of Angelica, Peony, Jutsu, Bukryō, Saiko, Botanpi, Sanshishi, Licorice, Gingerbread, and Mentha.

Examples of kami-shoyosan extracts include extracts of mixtures of Angelica, Peony, Sojutsu, Bukryō, Saiko, Botanpi, Sanshishi, Licorice, Gingerbread, and Mentha. The weight mixing ratio of these 10 kinds of herbal medicines (Cucumber: Peony: Sojutsu: Bukryo: Saiko: Botanpi: Sanshishi: Licorice: Gingerbread: Mentha) is, for example, 2.0 to 4.0: 2.0 to 4. 0:2.0~4.0:2.0~4.0:2.0~4.0:1.0~3.0:1.0~3.0:0.5~3.0: 0.5-3.0:1.0-2.0, preferably 2.5-3.5:2.5-3.5:2.5-3.5:2.5-3 .5:2.5~3.5:1.5~2.5:1.5~2.5:1.5~2.5:0.5~1.5:1.0~1.5 can be mentioned. In addition, other examples of Kami Shoyosan extracts include combinations of sandalwood instead of the above-mentioned sojutsu (extracts of mixtures of trumpet, peony, sandalwood, bukryō, saiko, botanpi, sardine, licorice, ginger, and mentha). ) are also mentioned, and the weight mixing ratios of these herbal medicines (Cucumber: Peony: Sandalwood: Bukryō: Saiko: Botanpi: Sanshishi: Licorice: Gingerbread: and Mentha) are also the same as above.

Among the above-mentioned Kami Shoyosan extracts, from the viewpoint of obtaining better insomnia-improving effects, the extract must be a mixture of Angelica, Peony, Sojutsu, Bukryo, Saiko, Botanpi, Sanshishi, Licorice, Gingerbread, and Mentha. is preferable, and the weight mixing ratio of these herbal medicines (Cucumber: Peony: Sojutsu: Bukryo: Saiko: Botanpi: Sanshishi: Licorice: Gingerbread: Mentha) is 2.8 to 3.2: 2.8 to 3.2. :2.8~3.2:2.8~3.2:2.8~3.2:1.8~2.2:1.8~2.2:1.8~2.2:0 The ratio is more preferably .8 to 1.2: 1.0 to 1.2, and particularly preferably 3:3:3:3:3:2:2:2:1:1.

Kamishoyosan extract can be obtained by extracting the above-mentioned crude drug mixture using an extraction solvent. Specifically, the extraction solvent used for the extraction process of Kamishoyosan extract includes, for example, water; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as 1,3-butylene glycol and propylene glycol; Examples include polar solvents such as mixed liquids, and water, ethanol, 1,3-butylene glycol, propylene glycol, or mixed solvents thereof, from the viewpoint of obtaining a better insomnia improving effect. From the viewpoint of obtaining better results, water may be mentioned. The size of each herbal medicine in the mixture to be extracted is the size of small pieces specified by the Japanese Pharmacopoeia, and about 5 to 20 times the amount of extraction solvent is added to the mixture, and the mixture is heated to 0.5 An example is a method of extraction by stirring for about 3 hours. After extraction, the extract obtained by subjecting to solid-liquid separation such as centrifugation or filtration to remove solids is concentrated, and may be further dried.

The content of Kami Shoyosan extract in the insomnia therapeutic agent of the present invention can be adjusted as appropriate depending on the insomnia improving effect to be exerted, and is preferably 50 to 80% by weight in terms of dry extract. 60 to 70% by weight.

Other Components The insomnia therapeutic agent of the present invention may further contain additives and bases depending on the formulation form, in addition to the above-mentioned Kamishoyosan extract. Additives and bases are not particularly limited as long as they are pharmaceutically acceptable, but include excipients, binders, disintegrants, lubricants, tonicity agents, plasticizers, dispersants, emulsifiers, Solubility aids, wetting agents, stabilizers, suspending agents, adhesives, coating agents, brightening agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble Polymers, surfactants, metallic soaps, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, ultraviolet inhibitors, preservatives, flavoring agents, fragrances, powders, thickeners, pigments , chelating agents, and the like. These additives may be used alone or in combination of two or more. Further, the contents of these additives and bases are appropriately set depending on the types of additives and bases used, the formulation form of the core body temperature improving agent of the present invention, and the like.

Examples of additives and bases include starch, lactose (for example, lactose hydrate), carmellose calcium, light anhydrous silicic acid, magnesium stearate, synthetic aluminum silicate, magnesium aluminate metasilicate, and silicic acid. Calcium, magnesium silicate, synthetic hydrotalcite, anhydrous calcium hydrogen phosphate, carmellose, croscarmellose sodium, sodium starch glycolate, crospovidone, preferably lactose (preferably lactose hydrate), carmellose Includes calcium, light silicic anhydride, and magnesium stearate. These additives may be used alone or in combination of two or more.

Further, the contents of the above-mentioned additives and base material are appropriately set depending on the types of additives and base material used. Preferably, in the insomnia treatment agent, the lactose content (in terms of lactose hydrate) is 0.1 to 0.5% by weight, the carmellose calcium content is 5 to 10% by weight, and a light anhydrous The content of silicic acid is 20 to 30% by weight, and the content of magnesium stearate is 0.5 to 1% by weight.

Moreover, the insomnia therapeutic agent of the present invention may contain nutritional components and pharmacological components other than the above-mentioned crude drug components, if necessary. Such nutritional and pharmacological ingredients are not particularly limited as long as they are pharmaceutically acceptable, but include, for example, antacids, stomachic agents, digestive agents, intestinal regulation agents, antispasmodics, mucosal repair agents, anti-inflammatory agents, and antiemetics. agents, antitussives, expectorants, anti-inflammatory enzymes, sedative-hypnotics, antihistamines, caffeine, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, other herbal powders and/or other herbal medicines Examples include extracts and vitamins. These nutritional components and pharmacological components may be used alone or in combination of two or more. Further, the contents of these components are appropriately set depending on the types of components used.

Formulation The form of the insomnia treatment of the present invention is not particularly limited as long as it can be administered orally, but examples include powders, fine granules, granules, tablets, troches, chewables, and capsules. Solid preparations such as tablets (soft capsules, hard capsules) and pills; semi-solid preparations such as jellies; and liquid preparations such as solutions, suspensions and syrups. Among these formulations, solid formulations are preferred, and tablets are more preferred, from the viewpoint of stability of the ingredients contained, portability, and the like.

Manufacturing method The method for manufacturing the insomnia therapeutic agent of the present invention is to formulate a formulation using the above-mentioned Kami Shoyosan extract and other ingredients that are added as necessary, according to the usual formulation method adopted in the pharmaceutical field. All you have to do is turn it into

Applications The insomnia therapeutic agent of the present invention is used for the purpose of improving symptoms of insomnia before or during menstruation. Premenstrual period refers to a period called the hyperthermia phase or luteal phase of the menstrual cycle. Although the ratio of waking time to sleeping time is particularly high before menstruation, the insomnia therapeutic agent of the present invention can improve the ratio of waking time to sleeping time before menstruation. In addition, the premenstrual insomnia to be treated by the insomnia therapeutic agent of the present invention is preferably insomnia during the latter half of the luteal phase, when insomnia becomes particularly noticeable. Furthermore, the ratio of awake time to sleeping time is relatively high during menstruation, but the insomnia therapeutic agent of the present invention can also improve the ratio of awake time to sleeping time during menstruation. Furthermore, during menstruation, the ratio of deep sleep time to sleep time is short, but with the insomnia treatment agent of the present invention, the ratio of deep sleep time to sleep time can be increased during menstruation, and the quality of sleep can be improved. .

Dosage/Usage The insomnia therapeutic agent of the present invention is used by oral administration. The dose of the insomnia therapeutic agent of the present invention is appropriately determined depending on the severity of the symptoms of the subject. 5 to 30 g, preferably 10 to 25 g as crude drug equivalent, and 1000 to 3000 mg, preferably 1400 to 2500 mg, more preferably 1600 to 2300 mg of Kamishoyosan extract (dry weight), 1 to 4 times a day. It may be taken twice, preferably 2 to 3 times. Regarding the timing of administration, for the purpose of relieving insomnia before menstruation, it can be taken during the luteal phase (before menstruation), preferably during the late luteal phase, and for the purpose of resolving insomnia during menstruation, it can be taken during the menstrual period (during menstruation). It can be taken to. Furthermore, since it is easy to become insomnia without realizing it during menstruation, it is preferable to take it before menstruation (preferably in the late luteal phase) and during menstruation. The timing of administration is not particularly limited and may be taken before meals, after meals, or between meals, but preferably before meals or between meals.

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.

[Test example]
(1) Preparation of insomnia treatment agent Add 10 times the amount of water by weight as an extraction solvent to the herbal medicine composition with the ingredients and blending amounts shown in Table 1, and perform extraction with stirring at approximately 100°C for 30 minutes. Ta. Thereafter, the extract was collected by centrifugation, concentrated under reduced pressure, and then dried using a spray dryer to prepare a kami shoyosan extract. Using the obtained Kami Shoyosan extract, a tablet composition was prepared with the composition shown in Table 2, and the tablet composition was compressed to obtain a tablet (360 mg/tablet) of an insomnia treatment agent.

(2) Subjects and medication schedule Five women (20 to 30 years old) who have a menstrual cycle and are aware of premenstrual insomnia were examined using a sleep meter sleep scan (TANITA) to assess their nighttime sleep. Condition was measured daily. Measurement of sleep status begins in the late luteal phase of the first cycle of the menstrual cycle and continues until the second menstrual cycle.The average body temperature for each period is calculated for each person, and then the average value of 5 people is calculated. did. Among these, the control group was a control in which no insomnia treatment was taken from the late luteal phase of the first cycle of the menstrual cycle to the menstrual period, and the insomnia treatment was administered 4 times at a time from the late luteal phase of the second menstrual cycle to the menstrual period. Tablets were taken twice a day for 5 days. In addition, the menstrual cycle is determined by measuring the basal body temperature every day before waking up using a basal thermometer (TERUMO), and the late luteal phase is determined by counting the number of days from the day when the basal body temperature rises until the day before menstruation. It was set as the second half of the period.

(3) Results Sleep time, the ratio of awake time to sleep time, the ratio of light sleep time to sleep time, and the ratio of deep sleep time to sleep time during the first cycle of the menstrual cycle (control) are shown in FIG. As is clear from Figure 1, although sleep time slightly decreases during the menstrual period, it is not significantly different from the late luteal phase, while the proportion of awake time particularly increases during the late luteal phase, and light sleep time decreases during the menstrual period. Deep sleep time especially decreased during the menstrual period. In other words, it was found that a high proportion of awake time during the late luteal phase caused insomnia. It was also found that during the menstrual period, the proportion of deep sleep time was low and the quality of sleep was decreased.

Figure 2 shows the sleep time, the ratio of awake time to sleep time, the ratio of light sleep time to sleep time, and the ratio of deep sleep time to sleep time in the late luteal phase and menstrual phase for the control period and when taking the drug. . As is clear from Figure 2, while sleep time was not different between the control and those taking the drug, the percentage of awake time was dramatically reduced by taking the drug during the luteal phase and menstrual period, and during the menstrual period, the percentage of light sleep was reduced by taking the drug. The quality of sleep could be improved by decreasing the proportion and increasing the proportion of deep sleep time.

Claims (3)

A treatment for insomnia before and during menstruation, which contains Kamishoyosan extract ,
An insomnia treatment used to increase the ratio of deep sleep to sleep during menstruation . 2. The insomnia treatment agent according to claim 1, wherein the Kami Shoyosan extract is an extract of a mixture of Angelica, Peony, Jutsu, Bukryo, Saiko, Botanpi, Sanshishi, Licorice, Gingerbread, and Mentha. The insomnia therapeutic agent according to claim 1 or 2, which is used to reduce the ratio of awake time to sleeping time before or during menstruation.