Composition for improving at least one selected from the group consisting of sleep onset, sleepiness upon awakening, and sleep maintenance

Abstract

The effects of S-propenylcysteine on sleep have not been well studied.SOLUTION: A composition for improving at least one selected from the group consisting of sleep onset, sleepiness upon awakening, and sleep maintenance, comprising S-propenylcysteine as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for improving at least one selected from the group consisting of sleep onset, sleepiness upon waking, and sleep maintenance. [Background technology]

[0002] Garlic has long been used as a nutrient-boosting ingredient in medicines and foods for nutritional tonics, appetite stimulation, and disease prevention or treatment. It is also used worldwide as a spice. Known active ingredients include allicin, alliin, ajoene, and γ-glutamyl-S-allylcysteine. In particular, S-allylcysteine ​​(hereinafter sometimes referred to as "SAC") has been reported to have many functions, but it is only present in trace amounts in raw garlic. For this reason, development efforts have been underway to increase the SAC content. Examples include a method of adding cysteine ​​to crushed garlic to increase the SAC content (Patent Document 1), a method of reacting garlic extract with a Bacillus enzyme to increase the SAC content, followed by powdering with an excipient (Patent Document 2), a method of heating and aging garlic extract to increase the SAC content, followed by concentrating the extract to obtain a paste-like product (liquid) (Patent Document 3), and a method of treating garlic extract with a peptidolytic enzyme and yeast fermentation (Patent Document 4).

[0003] Furthermore, as for the effect of SAC on sleep, it has been reported that an anti-fatigue agent containing heat-aged garlic extract has the effect of "improving the feeling of deep sleep" (Patent Document 3). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2015-140343 [Patent Document 2] Japanese Patent Application Laid-Open No. 2014-23449 [Patent Document 3] Japanese Patent Application Publication No. 2018-70602 [Patent Document 4] Japanese Patent Publication No. 2023-055220 Summary of the Invention [Problem to be solved by the invention]

[0005] The effects of S-propenylcysteine ​​on sleep have not been thoroughly studied. [Means for solving the problem]

[0006] The present inventors have thoroughly investigated the effect of S-propenylcysteine ​​on sleep and have found that it can improve at least one of the following: time to fall asleep, sleepiness upon waking, and sleep maintenance, thereby completing the present invention.

[0007] The present invention includes, for example, the following aspects. Section 1. A composition for improving at least one of the following conditions: sleep onset, sleepiness upon waking, and sleep maintenance, which comprises S-propenylcysteine ​​as an active ingredient. Section 2. Item 1. The composition according to Item 1, wherein the daily intake of S-propenylcysteine ​​is 1 mg or more. Section 3. Item 3. The composition according to item 1 or 2, containing garlic powder containing S-propenylcysteine. Section 4. Item 4. The composition according to any one of Items 1 to 3, wherein the S-propenylcysteine ​​is S-allylcysteine. Section 5. Item 5. The composition according to any one of Items 1 to 4, wherein the composition is a food product, a beverage, a pharmaceutical composition, or a quasi-drug. [Effects of the Invention]

[0008] The present invention can provide a composition that can improve at least one of sleep onset, sleepiness upon waking, and sleep maintenance. [Brief explanation of the drawings]

[0009] [Figure 1]1 is a graph showing the results of Test Example 1 regarding sleep onset. A decrease in score indicates an improvement in sleep onset. [Figure 2] 2 is a graph showing the results of Test Example 2 regarding morning sleepiness. An increase in score indicates an improvement in morning sleepiness. [Figure 3] 3 is a graph showing the results of sleep maintenance in Test Example 3. An increase in score indicates an improvement in sleep maintenance. DETAILED DESCRIPTION OF THE INVENTION

[0010] As used herein, the phrase "comprising" is intended to encompass the phrases "consisting essentially of" and "consisting of."

[0011] In the numerical ranges described in stages in this specification, the upper or lower limit of a numerical range in a certain stage can be arbitrarily combined with the upper or lower limit of a numerical range in the same stage or in another stage. In addition, in the numerical ranges described in this specification, the upper or lower limit of the numerical range may be replaced with a value shown in an example or a value that can be unambiguously derived from an example.

[0012] In this specification, numerical values ​​connected with "to" mean a numerical range that includes the numerical values ​​before and after "to" as the lower and upper limits. For example, "1 to 10% by mass" is equivalent to "1% by mass or more and 10% by mass or less."

[0013] In this specification, with regard to numerical ranges, "to" means equal to or greater than the leftmost numerical value and equal to or less than the rightmost numerical value. For example, "0.5 to 10% by mass" and "0.5% to 10% by mass" both mean "0.5% by mass or greater and 10% by mass or less." Furthermore, with regard to numerical ranges, "equal to or greater than" means "the same as or greater than," and "equal to or less than" means "the same as or less than."

[0014] The composition of the present invention may contain S-propenylcysteine ​​(sometimes referred to herein as "SPC") as an active ingredient. The composition of the present invention may be a composition for improving at least one selected from the group consisting of sleep onset, sleepiness upon waking, and sleep maintenance. The composition of the present invention may preferably be a composition for improving at least one selected from the group consisting of sleep onset and sleepiness upon waking. The composition of the present invention may more preferably be a composition for improving sleep onset.

[0015] The improvement in sleep onset can preferably be a reduction in the time it takes to fall asleep. The improvement in sleep onset can be confirmed by a decrease in the score after taking the composition of the present invention compared to before taking the composition, as assessed by a method similar to that in Test Example 1 or using Questions 2 and 5a regarding sleep onset in the Pittsburgh Sleep Quality Index-Japanese version (PSQI-J).

[0016] Improvement in morning sleepiness can be confirmed by a higher score after taking the composition of the present invention compared to before taking the composition in an evaluation using a method similar to that in Test Example 2 or using Question 4 regarding morning sleepiness on the OSA Sleep Questionnaire MA version (OSA-MA).

[0017] Improvement in sleep maintenance can be confirmed by a higher score after taking the composition of the present invention compared to before taking the composition, when evaluated using a method similar to that of Test Example 2 or using Question 16 on sleep maintenance in the OSA Sleep Assessment Questionnaire MA version (OSA-MA).

[0018] Examples of SPCs contained in the composition of the present invention include S-allyl cysteine ​​and S-(1-propenyl) cysteine, which may be contained alone or in combination in the composition of the present invention. S-allyl cysteine ​​and S-(1-propenyl) cysteine ​​have the same structure except for the position of the double bond. A preferred SPC is S-allyl cysteine.

[0019] The content of SPC in the composition of the present invention is not particularly limited as long as it can improve sleep onset, sleepiness upon waking, or sleep maintenance. The SPC content is, for example, 0.0002-3% by mass, 0.0005-3% by mass, 0.001-3% by mass, 0.005-3% by mass, 0.01-3% by mass, 0.05-3% by mass, 0.1-3% by mass, 0.0002-2% by mass, 0.0005-2% by mass, 0.00% by mass, based on the total mass of the composition. It can be 1-2% by mass, 0.005-2% by mass, 0.01-2% by mass, 0.05-2% by mass, 0.1-2% by mass, 0.0002-1% by mass, 0.0005-1% by mass, 0.001-1% by mass, 0.005-1% by mass, 0.01-1% by mass, 0.05-1% by mass, 0.1-1% by mass, etc.

[0020] The composition of the present invention may contain garlic powder containing SPC. Garlic powder produced by the method described in Patent Document 4 has a high SPC content (especially SAC content), making it suitable as the garlic powder containing SPC in the composition of the present invention. The content of the garlic powder containing SPC in the composition of the present invention is not particularly limited, as it can be selected appropriately depending on the form of the composition and the desired amount of SPC to be contained in the composition. For example, a supplement can be made into a tablet consisting only of garlic powder, while if garlic powder is mixed into rice balls, the content of garlic powder in the composition (rice ball) can be very low. The content of garlic powder in the composition of the present invention is, for example, 0.02 to 100 mass%, 0.05 to 100 mass%, 0.1 to 100 mass%, 0.5 to 100 mass%, 1 to 100 mass%, 5 to 100 mass%, 10 to 100 mass%, 20 to 100 mass%, 0.02 to 90 mass%, 0.05 to 90 mass%, 0.1 to 90 mass%, 0.5 to 90 mass%, 1 to 90 mass%, 5 to 90 mass%, 10 to 90 mass%, 20 to 90 mass%, 0.02 to 80 mass%, 0.05 to 80 mass%, 0.1 to 80 mass%, 0.5 to 80 mass%, 1 to 80 mass%, 5 to 80 mass%, Amount%, 10-80 mass%, 20-80 mass%, 0.02-70 mass%, 0.05-70 mass%, 0.1-70 mass%, 0.5-70 mass%, 1-70 mass%, 5-70 mass%, 10-70 mass%, 20-70 mass%, 0.02-60 mass%, 0.05-60 mass%, 0.1-60 mass% %, 0.5-60 mass%, 1-60 mass%, 5-60 mass%, 10-60 mass%, 20-60 mass%, 0.02-50 mass%, 0.05-50 mass%, 0.1-50 mass%, 0.5-50 mass%, 1-50 mass%, 5-50 mass%, 10-50 mass%, 20-50 mass%, etc.

[0021] The composition of the present invention may contain other components that form the composition as needed. The other components may include excipients, proteins, sugars, vitamins, minerals, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegrants, lubricants, colorants, flavorings, stabilizers, preservatives, sustained-release regulators, surfactants, glossing agents, solubilizers, humectants, silicon dioxide, etc., which may be blended singly or in combination in appropriate amounts. Furthermore, the composition of the present invention may be coated with a coating agent (e.g., sucrose, yeast cell wall, zein, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.) or may be coated with two or more layers, as needed.

[0022] Examples of excipients include maltitol, lactose, lactose hydrate, mannitol, glucose, crystalline cellulose, starch, cyclodextrin, calcium carbonate, and the like. Examples of binders include hydroxypropyl cellulose and polyvinylpyrrolidone. The surfactant may be, for example, a sucrose fatty acid ester. Sweeteners include maltitol, trehalose, xylitol, sorbitol, lactitol, and erythritol. Examples of disintegrants include carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium cellulose glycolate, and the like. Examples of lubricants include magnesium stearate, calcium stearate, sucrose fatty acid esters, and talc. Examples of proteins include soy whey, milk whey, and gelatin. Examples of sugars include starch, dextrin, monosaccharides, glucose, fructose, crystalline cellulose, and gums. Examples of vitamins include vitamin A, carotenes, B vitamins, vitamin C, D vitamins, vitamin E, K vitamins, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline, and folic acid. Examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, and selenium.

[0023] The composition of the present invention is preferably in tablet form from the viewpoints of ease of ingestion and ease of control of the amount ingested, but may also be in other forms suitable for oral ingestion, such as liquid, capsule, or granule.

[0024] The composition of the present invention is preferably an oral composition, and may be, for example, a food (including a food additive), a beverage, a pharmaceutical composition, a quasi-drug, etc., with a food being preferred. Foods include not only general foods, but also food additives, health foods, functional foods, nutritional supplements, supplements, health foods, foods for specified health uses, nutritionally functional foods, foods with functional claims, foods for patients, etc. A supplement is preferred as the composition of the present invention.

[0025] The method for producing the composition of the present invention is not particularly limited, and it can be produced by applying any known method for producing oral compositions as is, or by modifying it as appropriate. A preferred production method is one in which garlic powder produced by the method described in Patent Document 4 is used as a raw material and a known method for producing oral compositions is applied to this raw material.

[0026] In the composition of the present invention, the amount of SPC intake can be selected appropriately, and is expected to be 1 mg or more per day. Therefore, the amount of SPC intake per day is 0.3 mg to 20 mg, preferably 1 to 10 mg, and more preferably 1 to 5 mg. The number of times per day to take the composition of the present invention can be selected appropriately, and can be, for example, once, twice, three times, four times, five times, etc. per day. One embodiment of the present invention is a composition for improving at least one selected from the group consisting of sleep onset, morning sleepiness, and sleep maintenance, which contains S-propenylcysteine ​​as an active ingredient, and is a composition in which 0.3 to 20 mg of SPC is orally ingested per day.

[0027] The intake period of the composition of the present invention can be selected appropriately.For example, the intake period can be at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks. In one embodiment, the intake period is from about 2 days to about 16 weeks, preferably from about 7 days to about 16 weeks. One embodiment of the present invention is a composition for improving at least one selected from the group consisting of sleep onset, morning sleepiness, and sleep maintenance, which contains S-propenylcysteine ​​as an active ingredient and is taken for about 2 days to about 16 weeks.

[0028] The timing of ingestion of the composition of the present invention is not particularly limited and may be on an empty stomach, before a meal, within 1 hour after a meal, within 30 minutes after a meal, between meals, etc., but is preferably within 30 minutes after a meal. When the composition is taken once a day, the timing of ingestion is preferably within 30 minutes after breakfast.

[0029] The composition of the present invention is not particularly limited and can be applied to any subject.The subject to which the composition of the present invention is applied includes, for example, mammals such as humans, mice, rats, rabbits, cats, dogs, cows, horses and monkeys.The composition of the present invention is also not particularly limited and can be applied to subjects who wish to improve sleep onset, subjects who wish to improve sleepiness upon waking, subjects who wish to improve sleep maintenance, etc. [Example]

[0030] Hereinafter, one embodiment of the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. All of the following tests were approved by the ethics committee and conducted in accordance with the Declaration of Helsinki (2013 Fortaleza amendment) and the Ethical Guidelines for Life Science and Medical Research Involving Human Subjects (Public Notice No. 1 of the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Ministry of Economy, Trade and Industry of 2023).

[0031] Example 1: Preparation of tablets containing garlic powder Garlic powder (manufactured by Bizen Kasei Co., Ltd.; SAC content 1% by mass), maltitol, starch, microcrystalline cellulose, silicon dioxide, and calcium stearate were mixed and compressed into tablets at a pressure of 12 kN using a tablet press. The tablets were round, with a diameter of 8 mm and a mass of 260 mg. The content of each ingredient in one tablet was as follows, and the SAC content was 1 mg. Garlic powder 100mg (SAC 1mg) Maltitol 78mg Starch 39mg Crystalline cellulose 35mg Silicon dioxide 4mg Calcium stearate 4mg

[0032] Manufacturing Example 1: Manufacturing of placebo tablets Except for using maltitol instead of garlic powder, placebo tablets weighing 260 mg each (total amount of maltitol contained: 178 mg / tablet) were prepared in the same manner as in Example 1. Both the tablets obtained in Example 1 and the placebo tablets were colored with dyes (tamarind and gardenia) to make them indistinguishable in appearance.

[0033] Test Example In the following test example, the subjects were 44 healthy men and women aged between 20 and 70. Of these, 22 were in the placebo group, who took placebo tablets, and 22 were in the SAC group. The subjects took two test tablets (the tablets of Example 1 or placebo tablets) with water or lukewarm water within 30 minutes after breakfast every morning for 12 weeks (double-blind, parallel-group design). The SAC intake was 2 mg / day.

[0034] Test Example 1: Effect on sleep onset time The effects of the tablet obtained in Example 1 and a placebo tablet on the time to fall asleep were tested using the sleep onset item in the Pittsburgh Sleep Quality Index Japanese version (PSQI-J). The evaluation of sleep onset time was based on the answers to questions about sleep onset time in the PSQI-J. The subjects answered the prescribed questions twice, before and after taking the tablets of Example 1 or the placebo tablets. The first answer was given approximately 12 weeks to approximately 4 weeks before the start date of taking the tablets of Example 1 or the placebo tablets, and the second answer was given the day after the last day of intake. Hereinafter, in this test example, the first answer may be referred to as the "pre-intake answer" and the second answer may be referred to as the "post-intake answer." The details of the questions and evaluation are as follows:

[0035] Pittsburgh Sleep Quality Index Japanese version (PSQI-J) PSQI-J ("Doi Y, Minowa M, Uchiyama M, Okawa M, Kim K, Shibui K, Kamei Y. Psychometric assessment of subjective sleep quality using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J) in psychiatric disordered and control subjects. Psychiatry Res 2000; 97 (2-3):165-172.", "Doi Y, Minowa M, Okawa M, Uchiyama M: Development of the Japanese version of the Pittsburgh Sleep Quality Index. Psychiatry Treatment 1998; 13 (6); 755-769." (*English citation: Doi Y, Minowa M, Okawa M, Uchiyama M. Development of the Japanese version of the Pittsburgh Sleep Quality Index. Japanese Journal of Psychiatry Treatment 1998; 13 (6): 755-763 (in The "Sleep Onset Scale (SAS)" is a questionnaire consisting of 18 items. In Test Example 1, the items related to falling asleep, namely Question 2 and Question 5a, were asked, and the answers were scored according to the attached scoring sheet. The scores for Question 2 and Question 5a were added together to form a total score, and the test was evaluated based on that total score.

[0036] The questions are: We will ask you about your usual sleep habits over the past month. Please answer all of the following questions as accurately as possible, thinking about most days and nights over the past month. Question 2. In the past month, how long did it take you to fall asleep after getting into bed? Approximately minutes During the past month, how often have you had difficulty sleeping because of the following reasons? Please circle the one that best applies. Question 5a. I couldn't fall asleep within 30 minutes of going to bed. 0. None 1. Less than once a week 2. Once or twice a week 3. More than three times a week

[0037] The answers to the questions were scored according to the following criteria: Answers and marks for question 2 Less than 16 minutes: 0 points 16 minutes or more but less than 31 minutes: 1 point 31 minutes or more but less than 61 minutes: 2 points Over 61 minutes 3 points Answers and marks for question 5a 0 0 points 1 1 point 2 2 points 3 3 points

[0038] The score for the answers to Question 2 and Question 5a was added together (total score) and scored according to the following criteria. Total score and scoring 0 points 0 points 1~2 points 1 point 3~4 points 2 points 5~6 points 3 points

[0039] The mean scores based on the total points of the pre-intake responses were 2.0 for the placebo group and 1.5 for the SAC group, and the mean scores based on the total points of the post-intake responses were 1.5 for the placebo group and 0.7 for the SAC group. There was no significant difference in the mean scores between the placebo and SAC groups in the pre-intake responses, but the mean scores of the SAC group improved compared to the placebo group in the post-intake responses, with a p-value of 0.032 (Figure 1).

[0040] Test Example 2: Effects on morning sleepiness and sleep maintenance The effects of the tablet obtained in Example 1 and the placebo tablet on sleepiness upon awakening were examined using the items on sleepiness upon awakening and sleep maintenance in the OSA Sleep Assessment Questionnaire MA version (OSA-MA; "Yamamoto Yukari, Tanaka Hideki, Takase Miki, Yamazaki Katsuo, Azumi Kazuo, Shirakawa Shuichiro: Development and standardization of the OSA Sleep Assessment Questionnaire (MA version) for middle-aged and elderly people. Brain and Psychiatry Medicine 10: 401-409, 1999."). Before and after taking the tablets of Example 1 or the placebo tablets, the subjects answered predetermined questions about their most recent sleep for three consecutive days. The pre-intake responses were conducted for three consecutive days from about 12 weeks before to about 4 weeks before the start date of taking the tablets of Example 1 or the placebo tablets, and the post-intake responses were conducted the day before, the day of, and the day after the final day of intake. Hereinafter, in this test example, the pre-intake responses may be referred to as "pre-intake responses," and the post-intake responses may be referred to as "post-intake responses." The questions and scoring details are as follows:

[0041] OSA Sleep Assessment Questionnaire MA version (OSA-MA) The OSA-MA classifies 16 questions into five factors (factor 1: sleepiness upon waking, factor 2: sleep onset and sleep maintenance, factor 3: dreaminess, factor 4: fatigue recovery, factor 5: sleep duration), and evaluates the score (standard deviation) of each factor. The higher the score, the better the sleep state is judged to be. In this test example, the following questions regarding sleepiness upon waking and sleep maintenance were asked, and scores and evaluations were made based on the answers to these questions. Respondents answered the following questions at home upon waking about their sleep over the three days prior to the answer, including the day of the answer. Answers were multiple-choice with four options. The answers were scored based on the scoring criteria, and evaluation was made using the average of the obtained scores.

[0042] Questions about morning sleepiness conducted in this study (4-choice) Please fill it out as soon as you wake up in the morning. We will ask you about your sleep last night and your current physical and mental state. Question 4. Very open, somewhat open, somewhat stressed, very stressed

[0043] Responses to this question were scored according to the following criteria: Very open feeling 33 points Somewhat open feeling 21 points I feel a little stressed - 11 points Very stressed 0 points

[0044] Questions about sleep maintenance conducted in this study (4-choice) Please fill it out as soon as you wake up in the morning. We will ask you about your sleep last night and your current physical and mental state. Question 16. Very light sleep, somewhat light sleep, somewhat deep sleep, very deep sleep

[0045] Responses to this question were scored according to the following criteria: Very light sleep: 0 points Slightly light sleep: 11 points I slept a little deeply - 21 points Very deep sleep: 32 points

[0046] The mean pre-intake scores for question 4 were 15.0 for the placebo group and 16.1 for the SAC group, while the mean post-intake scores for question 4 were 18.6 for the placebo group and 23.2 for the SAC group. The mean post-intake scores for the SAC group improved compared to the placebo group, with a p-value of 0.027 (Figure 2). The mean pre-intake scores for question 16 were 15.4 for the placebo group and 13.4 for the SAC group, and the mean post-intake scores for question 16 were 18.3 for the placebo group and 20.9 for the SAC group. The mean post-intake scores for the SAC group improved compared to the placebo group, with a p-value of 0.044 (Figure 3). There were no significant differences between the placebo and SAC groups in the pre-intake responses to either Question 4 or Question 16.

Claims

1. A composition for improving at least one of the effects selected from the group consisting of sleep onset, sleepiness upon waking, and sleep maintenance, which comprises S-propenylcysteine ​​as an active ingredient.

2. 2. The composition according to claim 1, wherein the daily intake of S-propenylcysteine ​​is 1 mg or more.

3. 10. The composition of claim 1, comprising garlic powder containing S-propenylcysteine.

4. 2. The composition of claim 1, wherein the S-propenyl cysteine ​​is S-allyl cysteine.

5. The composition according to any one of claims 1 to 4, wherein the composition is a food, a beverage, a pharmaceutical composition, or a quasi-drug.

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