JP2008273939A - Sleep improvement agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new sleep improvement agent using vegetable origin extracts with an edible experience. <P>SOLUTION: The sleep improvement agent comprises crocetin represented by formula (1) or a pharmacologically acceptable base as an active ingredient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a sleep improving agent containing crocetin or a pharmacologically acceptable salt thereof as an active ingredient.

  In recent years, an increasing number of people suffer from insomnia reflecting various stresses. Insomnia is a type of sleep disorder in which sleep time is shorter than normal and the body and mind appear to be ill. The symptoms are poor sleep (difficulty falling asleep) and waking up in the middle of the night (midway Awakening), light sleep (difficult to sleep well), and waking up early in the morning (early morning awakening). Currently, benzodiazepines and other sleeping pills are being administered to patients who complain of such symptoms. However, side effects such as sleepiness, lightheadedness, and dizziness, and long-term dependence It is known that there are problems with withdrawal symptoms.

  Therefore, development of a sleep disorder ameliorating agent using an extract derived from a plant with edible experience has been energetically performed, for example, Valeriana plant or its extract, sedation A composition for sleep disorders (see citation 1), a composition for improving sleep (see citation 2), rape ( A sleep disorder ameliorating agent (see citation 3) characterized by containing an extract of a genus Lepidium belonging to the family Cruciferas has been proposed.

  On the other hand, with the progress of research on the functionality of carotenoid pigments in recent years, crocetin has also been shown to act as a singlet oxygen scavenger (see Patent Document 4), etc. It is not clear.

JP 2003-183174 A JP 2005-289948 A JP 2007-31371 A JP-A-5-320036

  An object of this invention is to provide the novel sleep improving agent using the extract derived from the plant with an edible experience.

As a result of intensive studies to solve the above problems, the present inventors have found that crocetin, a kind of carotenoid pigment, has a sleep-improving action, and has completed the present invention based on this finding. .
That is, the present invention comprises a sleep improving agent characterized by containing crocetin represented by the following formula (1) or a pharmacologically acceptable salt thereof as an active ingredient.

By ingesting the sleep-improving agent of the present invention, insomnia symptoms such as “light sleep” can be improved.
By ingesting the sleep-improving agent of the present invention, the number of awakenings during sleep decreases.

  Crocetin used in the present invention is a compound represented by the following formula (2).

このクロセチンは、通常、カロテノイド系の黄色色素であるクロシン（クロセチンのジゲンチオビオースエステル）を加水分解することにより得られる。クロシンは、アカネ科クチナシ（Ｇａｒｄｅｎｉａ ａｕｇｕｓｔａ ＭＥＲＲＩＬ ｖａｒ． ｇｒａｎｄｉｆｌｏｒａ ＨＯＲＴ．，Ｇａｒｄｅｎｉａ ｊａｓｍｉｎｏｉｄｅｓ ＥＬＬＩＳ）の果実、サフランの柱頭の乾燥物などに含まれる。クロシンを得るための工業的原料としてはクチナシの果実が好ましく用いられる。

This crocetin is usually obtained by hydrolyzing crocin (a digentiobiose ester of crocetin), which is a carotenoid yellow pigment. Crocin is included in the fruits of Rubiaceae gardenia (Gardenia augusta MERILIL var. Grandiflora HORT., Gardenia jasminoides ELLIS), dried saffron stigmas, and the like. Gardenia fruit is preferably used as an industrial raw material for obtaining crocin.

  There is no restriction on the method of extracting crocin from the gardenia fruit, for example, a dried gardenia fruit is pulverized and extracted using water, alcohol (for example, methanol, ethanol, etc.) or a mixture thereof. The method is used. For example, when the water / alcohol mixed solution (1: 1) is used, the extraction condition is preferably room temperature (about 0 to 30 ° C.) to 50 ° C. for about 1 to 18 hours, and about 30 to 40 ° C. for about 2 to 4 hours. Is more preferable. In order to further increase the extraction rate of crocin from the pulverized dried fruit, the extraction operation is usually repeated a plurality of times. The extract containing crocin is concentrated by a method known per se, and is usually stored refrigerated as a concentrated solution.

  The hydrolysis of crocin may be performed according to a conventional method, and is usually performed using an acid, an alkali or a suitable hydrolase. Examples of the acid include hydrochloric acid, sulfuric acid, and phosphoric acid. Examples of the alkali include sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Examples of hydrolases include β-glucosidase.

  Industrially, crocin is usually hydrolyzed using alkali. For example, an excess amount of an aqueous sodium hydroxide solution is added to the concentrate containing crocin, and preferably at room temperature (about 0 to 30 ° C.) to 70 ° C. for about 1 to 24 hours, preferably about 40 to under stirring. React at 60 ° C. for about 3-5 hours.

  After completion of hydrolysis with an alkali, an appropriate amount of an aqueous solution of an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or an organic acid such as citric acid is added to the reaction solution, and the liquidity is about pH 4.0 or less, preferably about pH 1. Crystals of crocetin are precipitated by adjusting to 0 to 3.0. Alternatively, the reaction solution may be added to an aqueous solution of an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or an organic acid such as citric acid to precipitate crocetin crystals. Thereafter, the liquid mixture containing the crocetin crystals is subjected to solid-liquid separation to obtain a suspension or slurry containing the crocetin crystals.

  When crocin is hydrolyzed using an acid, crocetin crystals are usually precipitated simultaneously with the hydrolysis, so that the reaction solution is obtained as a suspension containing crocetin. After completion of the reaction, the resulting suspension is subjected to solid-liquid separation to obtain a suspension or slurry containing crocetin crystals.

  The suspension or slurry containing crocetin crystals obtained as described above is mixed with crocetin crystals together with acids, neutralized salts and impurities derived from the raw materials. A cleaning process is performed. The treatment may be performed by a known method such as washing the suspension or slurry with a sufficient amount of water, alcohol or a mixture thereof. The washing process is usually repeated several times until the desired purity is obtained. After the washing treatment, the suspension or slurry containing crocetin crystals is dried at a temperature not exceeding about 50 ° C. using, for example, a vacuum dryer to obtain purified crocetin. The purified crocetin is preferably sealed and stored in a container substituted with an inert gas such as nitrogen gas.

  The crocetin used in the present invention is preferably purified crocetin having a purity of about 75% by mass or more. The purity of crocetin is calculated based on the following formula (3) from the color value of the sample containing crocetin.

The color value is a value measured by the following [Color Value Measuring Method].
[Color value measurement method]
1) A sample is accurately weighed so that the absorbance to be measured is in the range of 0.3 to 0.7, and dissolved in dimethyl sulfoxide to make exactly 100 ml.
2) Weigh exactly 5 ml, and add Kolthoff buffer solution (50 mM Na ₂ B ₄ O ₇ .10H ₂ O-50 mM Na ₂ CO ₃ , pH 10.0) to make 50 ml.
3) Weigh exactly 5 ml of the solution, and add Kolthoff buffer (pH 10.0) to make 50 ml.
4) Weigh exactly 5 ml of the solution, add Kolthoff buffer (pH 10.0) to make 50 ml, and use this solution as the test solution.
5) Using the Kolthoff buffer solution (pH 10.0) as a control, measure the absorbance A at the maximum absorption part near 420 nm with a liquid layer length of 1 cm, and obtain the color value by the following formula (4).

  In the present invention, pharmacologically acceptable salts of crocetin include, for example, salts of group 1 elements such as sodium and potassium, salts of group 2 elements such as magnesium and calcium, pyridine, dimethylamine, diethylamine, Examples thereof include pharmaceutically acceptable salts of organic amino compounds such as ethanolamine.

  Since crocetin or a pharmacologically acceptable salt thereof according to the present invention has an effect of improving sleep disorders such as difficulty falling asleep, awakening midway, difficulty sleeping well, or awakening early in the morning, a preparation containing this ingredient as an active ingredient improves sleep. Useful as an agent.

  The sleep-improving agent of the present invention contains the above crocetin or a pharmacologically acceptable salt thereof as it is, or a pharmaceutical additive, a food additive, a food material and the like are appropriately blended, and according to a conventional method, for example, a liquid (for example, a drink) Etc.), powders, granules, tablets, microcapsules, soft capsules, hard capsules, oil / fat compositions, O / W emulsions, W / O emulsions or solubilized liquids.

  Examples of pharmaceutical additives, food additives, and food materials used in the preparation of the above preparations include excipients (lactose, dextrin, corn starch, crystalline cellulose, etc.), lubricants (magnesium stearate, sucrose fatty acid ester, glycerin). Fatty acid esters, etc.), disintegrating agents (carboxymethylcellulose calcium, anhydrous calcium hydrogen phosphate, calcium carbonate, etc.), binders (starch glue solution, hydroxypropylcellulose solution, gum arabic solution, etc.), solubilizers (gum arabic, polysorbate 80) Etc.), sweeteners (sugar, fructose glucose liquid sugar, honey, aspartame, etc.), coloring agents (β-carotene, edible tar pigment, riboflavin, etc.), preservatives (sorbic acid, methyl parahydroxybenzoate, sodium sulfite, etc.), Thickener (alginic acid Thorium, sodium carboxymethylcellulose, sodium polyacrylate, etc.), antioxidants (BHT, BHA, ascorbic acid, tocopherol, etc.), flavors (mint, strawberry flavor, etc.), acidulants (citric acid, lactic acid, DL-malic acid, etc.) ), Seasoning (DL-alanine, sodium 5'-inosinate, sodium L-glutamate, etc.), emulsifier (glycerin fatty acid ester, sucrose fatty acid ester, etc.), pH adjuster (citric acid, trisodium citrate, etc.), Vitamins, minerals, amino acids and the like can be mentioned.

  In the case of the above preparation, the content of crocetin or a pharmacologically acceptable salt thereof is usually about 0.0001 to 50% by mass, preferably about 0.0001 to 50% by mass in terms of 100% by mass of crocetin in 100% by mass of the formulation, preferably About 0.001-20 mass%, More preferably, it is about 0.01-10 mass%.

  Furthermore, the sleep improving agent of the present invention can take the form of food and drink. Examples of the food and drink include soft drinks, drops, candy, chewing gum, chocolate, gummy, yogurt, ice cream, pudding, jelly confectionery, and cookies.

  In the case of the above food and drink, the content of crocetin or a pharmacologically acceptable salt thereof is usually about 0.00003 to 10% by mass in terms of 100% by mass of crocetin in 100% by mass of the food and drink, Preferably it is about 0.01-5 mass%.

  When the above preparation and food and drink are taken orally, the daily dose of crocetin or a pharmacologically acceptable salt thereof is about 0.1 to 500 mg in terms of crocetin with a purity of 100% by mass. is there.

  Hereinafter, the present invention will be described with reference to test examples for the pharmacological effect of the preparation of the present invention. However, this is merely to explain the present invention and does not limit the present invention.

[Test Example 1]
In order to evaluate the improvement effect of crocetin on sleep disorders, two types of capsules (180mg / 1 capsule) filled with the contents shown in Table 1 were prepared by a conventional method. A double-blind crossover comparative study was conducted on healthy adult men (25 to 40 years old) who were aware of mild insomnia symptoms such as

表中数値の単位はｍｇである。
１）精製クロセチン（商品名：クロセチンＰ；理研ビタミン社製，純度７７．７質量％）
２）デキストリン（商品名：パインデックス＃６；松谷化学工業社製）

The unit of numerical values in the table is mg.
1) Purified crocetin (trade name: Crocetin P; manufactured by Riken Vitamin Co., Ltd., purity 77.7% by mass)
2) Dextrin (trade name: Paindex # 6; manufactured by Matsutani Chemical Industry Co., Ltd.)

<Test method>
Fourteen subjects were randomly assigned to group A (n = 7) and group B (n = 7), group A was the test drug administration group, and group B was the control drug administration group. Prior to the test, a questionnaire survey was conducted on each subject, and “sleep depth” was evaluated according to the evaluation criteria shown in Table 2 below. Thereafter, the test drug was administered to Group A, and the control drug was administered to Group B after 1 capsule per day. After 4 weeks, each subject was again subjected to a questionnaire survey to the same effect. After a 6-week washout period, a similar test was conducted with the group A as the control drug administration group and the group B as the test drug administration group.

<result>
For each test drug administration group and control drug (placebo) administration group, scores before intake and scores after intake were totaled, and the average value of the scores of 14 subjects in each group was calculated. The results are shown in Table 3.
As a result of the Willcoxon rank sum test based on the aggregated data of each group, a significant difference was found in the comparison of the following two groups.
Test drug administration group (before ingestion) vs Test drug administration group (after ingestion): Risk rate 5%
This result indicates that the sleep-improving agent of the present invention is effective in improving the “sleep depth”.

[Test Example 2]
In order to evaluate the improvement effect of crocetin on sleep disorder, using Actigraph (Model: Micromini RR type, manufactured by A.M.I., USA) The test was conducted on adult men and women (25 to 40 years old). Actigraph is a method for measuring the amount of activity of a subject per unit time, and is considered to be an effective method for observing a rough tendency of sleep / wake rhythm. The determination of sleep / wakefulness by the actigraph was performed using an algorithm (determination formula) based on the amount of activity measured by the actigraph.

<Test method>
Except for the time of bathing and water work, four test subjects wore actigraphs on wrists that were not dominant arms for two consecutive days and measured the amount of activity per minute. Next, the test drugs listed in Table 1 were given to each subject one capsule per day for one week. The actigraph was put on again during the last two days of the test drug taking period, and the amount of activity per minute was measured in the same manner. After the test was completed, the actigraph data was analyzed using the sleep / wake determination formula of Cole et al. To calculate an objective index related to sleep. At that time, the start of sleep determination for 20 minutes or more is assumed to be asleep, and the start of awakening determination that is continued for 20 minutes or more the next morning is awakened. The number of times. Each sleep index derived from the actigraph was analyzed using a paired t-test, with p <0.05 being statistically significant.

<result>
The results are shown in FIG. 1 and FIG.

  As is clear from FIG. 1, the number of wakefulness determinations during sleep (the number of wakefulness during sleep) was significantly reduced by the intake of crocetin. Further, as is clear from FIG. 2, the number of arousal determinations (wakefulness index) per hour of sleep was also significantly reduced by the intake of crocetin. These results indicate that crocetin has a sleep improving effect.

It is the figure which showed the frequency | count of the awakening before and after taking a test drug. It is the figure which showed the arousal index before taking the test drug and after taking it.

Claims (1)

A sleep improving agent comprising crocetin represented by the following formula (1) or a pharmacologically acceptable salt thereof as an active ingredient.

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