JP2023158866A - Sleepiness alleviation composition or chronic stress alleviation composition - Google Patents

Abstract

To provide a composition which can be safely drunk and eaten and has a sleepiness alleviation effect and a composition which can be safely drunk and eaten and has a chronic stress alleviation effect.SOLUTION: The present invention pertains to a composition containing an Apocynum venetum leaf extract. The composition is used for sleepiness alleviation or chronic stress alleviation. In the composition, a ratio of isoquercetin to 100 pts.mass of hyperoside is preferably 90 pts.mass or more and 120 pts.mass or less. Also, the Apocynum venetum leaf extract preferably contains 3 mass% or more and 10 mass% or less of the sum of the hyperoside and the isoquercetin.SELECTED DRAWING: Figure 2

Description

The present invention relates to a composition for alleviating drowsiness and a composition for alleviating chronic stress.

Problems caused by sleepiness have traditionally occurred frequently. For example, many people want to effectively reduce the phenomenon of drowsiness that occurs while driving a car, working in a meeting, class, studying, watching a play or movie at the theater, or having a conversation. .

In addition, modern people are exposed to a variety of stresses such as PC work, smartphone use, work environment, housework, family circumstances, human relationships, studying, etc. When this state of stress continues for a long time, it causes various problems such as anxiety, depression, depressed mood, difficulty feeling interest or joy, lack of motivation, and poor physical condition.

There is a need for a supplement that can deal with sleepiness and chronic stress as described above.

In recent years, it has been reported that Lafuma leaf extract can be used to improve sleep quality and stress. Apocynum venetum L. belongs to the Apocynaceae family and is a perennial herb that grows naturally in temperate regions from China to Europe and Asia. Lafuma leaves are drunk as a tea in China, and have been proven to lower blood pressure in Japan.

Patent Document 1 describes that a composition containing an extract of Lafuma leaf is effective in reducing stress and improving sleep maintenance. Further, Patent Document 2 describes that a composition containing Lafuma extract and γ-aminobutyric acid (GABA) is effective in reducing stress.

On the other hand, Non-Patent Document 1 describes the anxiolytic effects of benzodiazepine compounds that are GABA receptor agonists. The same document states that while benzodiazepine anxiolytics are fast-acting and effective for anxiety neurosis, they have therapeutic limitations due to dependence on regular doses, drowsiness, effects on driving, etc. . In other words, this literature suggests that drugs that are effective in improving short-term stress are not necessarily effective in improving chronic stress. The same document also indicates that stress improving agents may induce drowsiness and may have the opposite effect to improving drowsiness.

Japanese Patent Application Publication No. 2019-064969 Japanese Patent Application Publication No. 2011-093842

Takeshi Inoue, The forefront of drug treatment for anxiety disorders, Japanese Pharmacological Journal, 2005, 125.5, pp297-300

Thus, although Patent Document 1 describes that a composition containing an extract of Lafuma leaf improves sleep onset and sleep maintenance, the effect of reducing sleepiness is not investigated. Here, in order to have the effect of falling asleep and maintaining sleep, it is necessary to suppress brain activity, whereas in order to have the effect of reducing sleepiness, it is necessary to activate brain activity. have very different mechanisms of action.

Moreover, Patent Document 1 and Patent Document 2 describe that a composition containing an extract of Lafuma leaf significantly suppresses short-term stress, which is an increase in stress after workload. However, the same literature does not examine its effectiveness against chronic stress.

Therefore, an object of the present invention is to provide a composition for alleviating drowsiness that is safe to consume and is effective. Another object of the present invention is to provide a composition for alleviating chronic stress that is safe to consume and is effective.

As a result of conducting research on the above-mentioned issues based on Lafuma leaf extract, the present inventor designed a clinical test to evaluate sleepiness felt in daily life and daily chronic stress, and developed a composition containing Lafuma leaf extract. The present invention was achieved by demonstrating the improvement effect on sleepiness and chronic stress.

That is, the present invention is a composition for alleviating drowsiness that contains Lafuma leaf extract as an active ingredient.

Further, the present invention is a composition for alleviating chronic stress, which contains Lafuma leaf extract as an active ingredient.

According to the present invention, it is possible to provide a composition for reducing drowsiness that is safe to consume and is effective. Further, according to the present invention, it is possible to provide a composition for relieving chronic stress that is safe to consume and is effective.

FIG. 1 is a graph showing changes in mental stress scores after 4 weeks of ingesting the test food. FIG. 2 is a graph showing changes in ESS scores after consuming the test food for 4 weeks.

Embodiments of the present invention will be described in detail below.

The Lafuma leaf extract in the present invention uses Lafuma leaves (scientific name: Apocynum venetum L.). Lafuma is produced in China, such as Qinghai Province and Sichuan Province, and in temperate regions of Europe.

Suitably, the composition comprising an extract of Lafuma leaves comprises hyperoside and isoquercitrin.

Hyperoside and isoquercitrin have structures shown in the following formulas (I) and (II), respectively. Hyperoside is a flavonoid glycoside that has galactose in its structure, and isoquercitrin has glucose in its structure.

The mass ratio of hyperoside and isoquercitrin is preferably 100:10 to 300, more preferably 100:50 to 200, and 100:90 to 120 from the viewpoint of reducing sleepiness and chronic stress. It is particularly preferable.

The amount of hyperoside in the Lafuma leaf extract is preferably 0.1% by mass or more and 20% by weight or less, more preferably 0.5% by weight or more and 15% by weight or less. In the leaf extract, the content of hyperoside is particularly preferably 1% by mass or more and 10% by mass or less, particularly preferably 1% by mass or more and 6% by mass or less.

In the Lafuma leaf extract, the amount of isoquercitrin is preferably 0.1% by mass or more and 20% by mass or less, more preferably 0.5% by mass or more and 15% by mass or less, from the viewpoint of reducing sleepiness and chronic stress. In the Lafuma leaf extract, the content of isoquercitrin is particularly preferably 1% by mass or more and 10% by mass or less, particularly preferably 1% by mass or more and 6% by mass or less.

In order to enjoy the effects of the present invention of reducing sleepiness and reducing chronic stress, the Lafuma leaf extract may contain a total of 0.5% by mass or more and 20% by mass or less of hyperoside and isoquercitrin. The content is preferably 1% by mass or more and 15% by mass or less, and even more preferably 3% by mass or more and 10% by mass or less.

The hyperoside content in the composition is determined as follows. 100 mg of the composition is dissolved in methanol, a portion of this solution is separated by HPLC, and the integral value of the peak derived from hyperoside is calculated. Further, a hyperoside standard product is dissolved in methanol, a part of this solution is separated by HPLC, and the integral value of the peak is calculated. The ratio (former/latter) of the integral values of the peaks derived from hyperoside is calculated. The content of hyperoside is calculated by using the ratio of this integral value and a calibration curve created in advance. HPLC conditions are as follows.
column;
Elution solvent: mixture of water, acetonitrile and 2-propanol (200:38:2)
Elution rate: 1.0mL/min
Retention time (hyperoside): 13.1min
Detection wavelength: 360nm

The content of isoquercitrin in the composition is measured in the same manner as the content of hyperoside, except that the retention time of isoquercitrin is 14.1 min.

As mentioned above, Lahuma leaf extract containing hyperoside and isoquercitrin can be produced as follows.

The Lafuma leaf extract in the present invention includes extract A obtained by extracting and concentrating Lafuma leaves (scientific name: Apocynum venetum L.) with at least one of water, ethanol, aqueous ethanol, and an organic solvent; In addition, the extract A obtained here is adsorbed on a synthetic adsorption resin selected from acrylic synthetic adsorption resin, styrene synthetic adsorption resin, methacrylic synthetic adsorption resin, and aromatic synthetic adsorption resin, and the ethanol concentration is 10 to 95% by volume. Examples include extract B obtained by concentrating the fraction eluted with aqueous ethanol up to 100 ml of water-containing ethanol, and extract C obtained by drying the extract. Extract C includes, for example, the following extracts. Note that the extract C may be mixed with an excipient if necessary.
Extract example: Dried Lafuma leaves are crushed, and aqueous ethanol with an ethanol concentration of 60% by volume is added to the crushed product, and the resulting extract is heated and refluxed. The pH of the resulting extract is adjusted to acidic with an organic carboxylic acid to remove insoluble matter. After removal, the solution is passed through a synthetic adsorption resin selected from acrylic synthetic adsorption resins, styrene-based synthetic adsorption resins, methacrylic synthetic adsorption resins, and aromatic synthetic adsorption resins, and then desorbed with aqueous ethanol with an ethanol concentration of 70% by volume. The fractions were collected, concentrated under reduced pressure, and the extract was dried.

Further, the present composition can take the form of a food, a medicine, or a cosmetic, and in particular, in the case of a food, it can take the form of a food with functional claims or a health food. Furthermore, in the case of food, it can take the form of not only solid products but also beverages.

When the present composition is a food, the composition can be in the form of a dessert such as a drink, candy, jelly, or gummy, and when it is a health food or food with functional claims, the composition can be in the form of a tablet, for example, Forms include hard capsules, soft capsules, granules, and drinks.

When the present composition is a pharmaceutical, the pharmaceutical form may include tablets, capsules, pills, liquids, and emulsions. Although the method of administration is not particularly limited, it is desirable that the drug be in a form that can be administered orally. Furthermore, various carriers can be added within a pharmaceutically acceptable range. Examples of carriers include excipients, colorants, sweeteners, suspending agents, and the like.

In order to successfully obtain the effects of the composition of the present invention, the selection of auxiliary materials and their quantitative ratios were studied. When the composition of the present invention is a tablet, for example, the total amount of maltitol, maltose, and cellulose is preferably 50 parts by mass or more and 500 parts by mass or less, and 100 parts by mass or more and 400 parts by mass, based on 100 parts by mass of Lafuma extract. It is more preferable to contain the following.
When cellulose is used, the amount of cellulose is preferably 10 parts by mass or more and 200 parts by mass or less, and more preferably 30 parts by mass or more and 100 parts by mass or less, based on 100 parts by mass of the Lafuma extract.
For example, the fluidizing agent such as silicon dioxide is preferably contained in an amount of 0.1 part by mass or more and 50 parts by mass or less, more preferably 0.5 part by mass or more and 20 parts by mass or less, per 100 parts by mass of Lafuma extract.
For example, lubricants such as calcium stearate and sucrose fatty acid ester are preferably contained in an amount of 0.1 part by mass or more and 100 parts by mass or less, and preferably 1 part by mass or more and 50 parts by mass or less, per 100 parts by mass of Lafuma extract. is more preferable.

In addition, the content of Rafuma leaf extract in the present composition can be adjusted as appropriate according to the expected intake amount, but for example, the content of Rafuma leaf extract as solid content is 0.007% by mass or more and 70% by mass or less. It can be done. Further, in the solid content of the composition, it is preferable that the composition contains Lafuma leaf extract in an amount of 0.07% by mass or more and 70% by mass or less, and more preferably 0.14% by mass or more and 70% by mass or less. Note that in this specification, the solid content refers to the composition from which moisture has been removed, and the solid content is measured, for example, by a heating drying method.

In addition, in order to obtain the effect of reducing stress and reducing daytime sleepiness by the present composition, the daily intake of Lafuma leaf extract is preferably 1 mg or more and 100 mg or less, more preferably 20 mg or more and 90 mg or less, particularly preferably The amount is 40 mg or more and 80 mg or less.

Further, it is preferable that the Lafuma leaf extract in the present composition contains hyperoside and isoquercitrin, which are flavonoid compounds, as active ingredients. When these components are included, it is preferable that the total content of these components in the composition is 0.0002% by mass or more and 10% by mass or less. Further, in the solid content of the composition, the total content of hyperoside and isoquercitrin is preferably 0.0002% by mass or more and 10% by mass or less, and more preferably 0.002% by mass or more and 5% by mass or less. By containing hyperoside and isoquercitrin within the above-mentioned ranges, the effects of the present composition are preferably exhibited.

According to the present invention, while driving a vehicle such as a car, while working at a meeting, etc., while watching a movie or play at a theater, while reading, in class, studying, watching TV, or as a passenger, It can effectively reduce the daily drowsiness you feel while riding, talking, reading, etc.

Additionally, the composition of the present invention can alleviate chronic stress. Examples of chronic stress include stress that has been felt for more than a month due to PC work, smartphone use, work, housework, human relationships (including marital relationships), studying, etc. Symptoms of chronic stress include anxiety, depression, depressed mood, difficulty feeling interest or joy, lack of motivation, and poor physical condition.

The composition of the present invention is preferably ingested continuously, for example, preferably for two weeks or more, and more preferably for four weeks or more. The term "continuously ingested" as used herein preferably means ingested on four or more days during a week, and more preferably means ingested every day.

In the present invention, the drowsiness reducing agent includes ``reducing daytime sleepiness,'' ``reducing drowsiness experienced in daily life,'' ``reducing drowsiness in daily life,'' ``improving drowsiness,''``awakening,'' and ``improving drowsiness.'' Includes phrases such as "wake up", "keep away sleepiness", "conquer sleepiness", etc. on packaging, advertising materials, etc.
Chronic stress reducers include ``reducing stress in daily life'', ``reducing mental stress felt in daily life'', ``reducing daily mental stress'', and ``reducing mental stress in daily life''. Includes phrases such as "relief", "relief of mental stress felt in daily life", "relief of daily mental stress", etc. attached to packaging, advertising materials, etc.

The present invention will be described in more detail based on Examples, but the present invention is not limited to the following Examples.

(1) Production of Lafuma leaf extract Dried Lafuma leaves were crushed using a lab mixer, and aqueous ethanol with an ethanol concentration of 60% by volume was added to 1 kg of the crushed product, and after heating and refluxing for 2 hours, it was filtered to obtain an extract. The extraction residue was heated and refluxed again for 2 hours in water-containing ethanol with an ethanol concentration of 60% by volume, and then filtered to obtain an extract. The first extract and the second extract were combined, concentrated under reduced pressure, and suspended in water.The pH was adjusted to acidic with citric acid and stirred overnight. Diatomaceous earth was added and body fed, and the liquid was poured onto a filter paper lined with diatomaceous earth and filtered to remove insoluble materials. The obtained filtrate was passed through a synthetic adsorption resin to adsorb the active ingredient, and then washed with water. Thereafter, it was desorbed with aqueous ethanol with an ethanol concentration of 70% by volume, and fractions containing the active ingredient were collected, concentrated under reduced pressure, an emulsifier was added to the concentrate, and the mixture was thoroughly stirred. The resulting solution was spray dried to obtain a Lahuma leaf extract. The obtained Lafuma leaf extract and an excipient were mixed to obtain a Lafuma leaf extract (475 g) containing an excipient containing a total amount of hyperoside and isoquercitrin of 3% by mass or more.

(2) Clinical trial The clinical trial was conducted with 40 healthy Japanese adult men and women (age: 35-50 years old) as subjects. The method of selecting subjects was to conduct a questionnaire survey of healthy adults and ask them whether they have been suffering from chronic mental stress or physical stress due to PC work, smartphone use, work, housework, human relationships (including marital relationships), or studying. The survey targeted people who reported feeling fatigued.
The above questionnaire was specifically conducted as follows.
We conducted a multiple-choice questionnaire regarding the causes of mental stress and physical fatigue felt in daily life. The options were computer work, smartphone use, work, housework, human relationships (including marital relationships), and study. It was confirmed that subjects who had been diagnosed with chronic fatigue syndrome by a doctor or who had a score of 6 or higher on the GDS-J depression scale were not included.

The test food was prepared by mixing reduced maltose, cellulose, silicon dioxide, and calcium stearate with the solid Lafuma leaf extract containing a total of 3% by mass or more of hyperoside and isoquercitrin obtained by the above method. , compressed into tablets (220 mg per serving). In addition, caramel was used instead of Lafuma leaf extract in the control food provided to the placebo group so that it had the same appearance as the test food. Lafuma-derived hyperoside and Lafuma-derived isoquercitrin contained in the test food were analyzed by HPLC and calculated to be 1 mg each per serving.

A placebo-controlled, randomized, double-blind, crossover comparative study was conducted with 40 subjects. The study period was 10 weeks and consisted of a first period from week 1 to week 4, a second period from week 7 to week 10, and a washout period from week 5 to week 6. Ru. During the first period, 16 subjects ingested one serving of the test food and 13 subjects ingested one serving of the control food each day. During the washout period, none of the subjects consumed the test food. During the second period, each subject ingested one meal each day of the food not selected during the first period.

On the days indicated by "○" in Table 1 above, a questionnaire regarding chronic mental stress and daytime sleepiness experienced in daily life was administered to each subject.
Questionnaires regarding mental stress in daily life were conducted using the VAS method, with a score of ``0'' representing the best feeling of feeling no stress at all, and a score of ``worst feeling of feeling extremely stressed''. 100'' was used.

In addition, a sleepiness questionnaire was conducted using the Epworth Sleepiness Scale (ESS) shown in Table 2.

ESS has four answer options for each of the eight question items. The four answer options are: hardly ever sleeps (score: 0), sometimes sleeps (score: 1), often sleeps (score: 2), and rarely sleeps (score: 3). This was the score for that subject.

As shown in Table 1, the questionnaire was conducted before and after each four-week test period, and the amount of change in score was calculated by subtracting the score at the beginning from the score at the end of each period. However, in the questionnaire on chronic mental stress felt in daily life, the average value of the scores for three consecutive days at the beginning and end of the first and second periods is used as the score at that point. Using. Table 3 shows various statistics calculated from the amount of change in each subject's score. Further, graphs of the average values of the changes in scores are shown in FIGS. 1 and 2.

As shown in Table 3 and Figures 1 and 2, in the questionnaire on chronic mental stress in daily life, the amount of decrease in the average score of the group that consumed the test food was the same as the decrease in the average score of the group that consumed the control food. It was bigger than Furthermore, since the P value was 0.032, a significant difference was observed between the two groups at a significance level of 5%. In other words, the test food was found to be effective in reducing chronic mental stress in daily life.
Similarly, in the sleepiness questionnaire, the decrease in the average score was greater in the group that consumed the test food than in the group that consumed the control food, and the P value was 0.027, indicating that both groups A significant difference was observed between them at a significance level of 5%. In other words, the test food was found to be effective in reducing sleepiness. More specifically, when you are sitting while reading or watching TV, when you are sitting in a meeting or theater without actively speaking, when you are a passenger in a car for an hour, and when you are in the afternoon. When you are lying down, when you are sitting and talking to someone, when you are sitting quietly after having lunch without drinking alcohol, and when you are driving a car for a few minutes depending on traffic lights or traffic conditions. It was found to be effective in reducing drowsiness when stopped.

[Production Example 1: Production of granules]
After mixing the raw materials listed in Table 4, fluidized bed granulation was performed using a granulator to produce granules. The total amount of hyperoside and isoquercitrin contained in the Lafuma leaf extract was 3% by mass, and the mass ratio of hyperoside and isoquercitrin was 100:100. The granules described in Production Example 1 may be taken in an amount of 3 g per day, and may be taken after being dissolved in 100 ml of a solvent such as water, or may be taken as is without being dissolved. The granules of Production Example 1 are useful for alleviating sleepiness and chronic stress.

[Production Example 2: Production of tablets]
After mixing the raw materials listed in Table 5, tablets each weighing 150 mg were manufactured using a rotary tablet press. The total amount of hyperoside and isoquercitrin contained in the Lafuma leaf extract was 3% by mass, and the mass ratio of hyperoside and isoquercitrin was 100:110. One tablet of the tablet described in Production Example 3 may be taken per day. The tablet of Production Example 2 is useful for alleviating drowsiness and chronic stress.

[Manufacture example 3: Manufacture of tablets]
After mixing the raw materials listed in Table 6, tablets each weighing 200 mg were manufactured using a rotary tablet press. The total amount of hyperoside and isoquercitrin contained in the Lafuma leaf extract was 3.5% by mass, and the mass ratio of hyperoside and isoquercitrin was 100:90. One tablet of the tablet described in Production Example 3 may be taken per day. The tablet of Production Example 3 is useful for alleviating sleepiness and chronic stress.

[Production Example 4: Production of capsule]
After mixing the raw materials listed in Table 7, the mixture was encapsulated with a film containing gelatin or hydroxypropyl cellulose to produce hard capsules each weighing 250 mg. The total amount of hyperoside and isoquercitrin contained in the Lafuma leaf extract was 3% by mass, and the mass ratio of hyperoside and isoquercitrin was 100:120. One hard capsule described in Production Example 4 may be ingested per day. The tablet of Production Example 4 is useful for alleviating sleepiness and chronic stress.

[Production Example 5: Production of beverage]
After mixing the raw materials listed in Table 8, the mixed liquid was packed into a PET container to produce a PET beverage. Each T drink was produced in a volume of 500 ml. The total amount of hyperoside and isoquercitrin contained in the Lafuma leaf extract was 3% by mass, and the mass ratio of hyperoside and isoquercitrin was 100:100. One bottle of the beverage described in Production Example 5 may be taken per day. The beverage of Production Example 5 is useful for alleviating sleepiness and chronic stress.

Claims (4)

A composition for reducing drowsiness, containing Lafuma leaf extract as an active ingredient. A composition for relieving chronic stress, containing Lafuma leaf extract as an active ingredient. The composition according to claim 1 or 2, wherein the ratio of isoquercitrin to 100 parts by mass of hyperoside is 90 parts by mass or more and 120 parts by mass or less. The composition according to claim 2, wherein the chronic stress is mental stress in daily life.