JP2016153387A - Sleep-improving agent - Google Patents
Sleep-improving agent Download PDFInfo
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- JP2016153387A JP2016153387A JP2015178315A JP2015178315A JP2016153387A JP 2016153387 A JP2016153387 A JP 2016153387A JP 2015178315 A JP2015178315 A JP 2015178315A JP 2015178315 A JP2015178315 A JP 2015178315A JP 2016153387 A JP2016153387 A JP 2016153387A
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- alkylresorcinol
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Abstract
Description
本発明は、睡眠の質を改善し、良質な睡眠をもたらし得る睡眠改善剤に関する。 The present invention relates to a sleep-improving agent that can improve the quality of sleep and provide good-quality sleep.
近年、生活リズムの乱れ、ストレス、運動不足などにより睡眠不足、不眠等の睡眠障害を訴える人が増加している。不眠は、一般に、入眠障害（寝つきが悪い）、中途覚醒（夜中に目が覚めてしまう）、熟眠障害（眠りが浅く何度も目が覚める）、早期覚醒（朝早く眼が覚めてしまう）に分類される。 In recent years, an increasing number of people complain of sleep disorders such as lack of sleep and insomnia due to disruption of life rhythm, stress, lack of exercise, and the like. Insomnia generally includes falling asleep (bad sleep), mid-wake awakening (wakes up in the middle of the night), deep sleep disorder (slow sleep and wakes up many times), early awakening (wakes up early in the morning) are categorized.
睡眠には、脳の休息期であり、大脳の活動がほとんど停止しているノンレム睡眠と、体の休息期であり、全身は脱力状態にあるが脳の一部は活発に活動し夢を見ているレム睡眠とがある。睡眠は通常、ノンレム睡眠とレム睡眠とが一定の間隔で繰り返されて形成されている。良質な睡眠は、就寝からノンレム睡眠出現までの時間（入眠潜時）が短く且つノンレム睡眠時間が長い。これに対し、不眠を訴える人の多くは、入眠潜時が長い、ノンレム睡眠時間が短いなどの傾向が見られ、深いノンレム睡眠が得られていない。 Sleep is a rest period of the brain, non-REM sleep where cerebral activity is almost stopped, and rest period of the body, the whole body is weak, but a part of the brain is actively active and dreaming There is a REM sleep. Sleep is usually formed by repeating non-REM sleep and REM sleep at regular intervals. Good quality sleep has a short time from sleep to the appearance of NREM sleep (sleeping latency) and a long NREM sleep time. On the other hand, many people who complain of insomnia tend to have long sleep onset latencies and short non-REM sleep time, and have not obtained deep non-REM sleep.
睡眠障害の治療には、適度のアルコール摂取、生活習慣の改善や寝具の改善などが有効といわれているが、睡眠障害に悩むような人にはこれらはほとんど効果がないのが実状である。また、ベンゾジアゼピン系、抗ヒスタミン系などの医薬品の睡眠改善剤は、精神症状や筋弛緩作用などの副作用が報告されており、それらの使用には改善の余地がある。 It is said that moderate alcohol consumption, improvement of lifestyle habits, and improvement of bedding are effective for the treatment of sleep disorders, but in reality, these are almost ineffective for people who suffer from sleep disorders. Moreover, side effects such as psychiatric symptoms and muscle relaxation have been reported for sleep-improving agents of pharmaceuticals such as benzodiazepines and antihistamines, and there is room for improvement in their use.
これに対し、副作用の少ないものとして、天然成分を用いた睡眠改善剤が提案されている。例えば特許文献１には、植物由来の有機酸類やポリフェノール類から選択される水溶性抗酸化物質と二価金属とを有効成分として含有する睡眠改善剤が記載されている。また特許文献２には、Ｓ−アデノシルメチオニン又はその塩を含有する酵母を有効成分として含有する睡眠改善剤が記載されている。また特許文献３には、冬虫夏草属の微生物の熱水抽出物を有効成分として含有する睡眠改善剤が記載されている。特許文献１〜３記載の睡眠改善剤によれば、ノンレム睡眠時間の増加、入眠潜時の短縮などの効果が得られるとされている。
On the other hand, a sleep improving agent using natural ingredients has been proposed as one having few side effects. For example, Patent Document 1 describes a sleep improving agent containing a water-soluble antioxidant substance selected from plant-derived organic acids and polyphenols and a divalent metal as active ingredients.
睡眠改善剤の効果には個人差があり、従来の睡眠改善剤では、睡眠障害の悩みに十分に対応しきれていないのが実情である。また、睡眠改善剤の中には、ノンレム睡眠時間を減少させるものもあり、使用方法が適切でないと睡眠の質が却って低下する場合もある。また、睡眠改善剤には副作用の問題があり、高い安全性が求められている。こうした課題を解決し得る睡眠改善剤は未だ提供されていない。 There are individual differences in the effects of sleep-improving agents, and it is the actual situation that conventional sleep-improving agents are not able to fully cope with the troubles of sleep disorders. Some sleep-improving agents reduce non-REM sleep time, and if the usage is not appropriate, the quality of sleep may decrease. Moreover, the sleep improving agent has a problem of side effects, and high safety is required. No sleep-improving agent that can solve these problems has been provided.
本発明の課題は、睡眠の質の改善効果に優れ、有害な副作用がなく安全性の高い睡眠改善剤に関する。 The subject of this invention is related with the sleep improvement agent which is excellent in the improvement effect of the quality of sleep, there is no harmful side effect, and is high safety.
本発明は、下記一般式（Ｉ）で表されるアルキルレゾルシノールを有効成分として含有する睡眠改善剤である。
本発明の睡眠改善剤は、ノンレム睡眠の時間を増加させることで睡眠の質を改善することができ、睡眠障害に高い改善効果を示し得る。しかも、本発明の睡眠改善剤は、その有効成分が、食経験が豊富な穀類やナッツ類に含まれている成分であることから、継続的に服用しても有害な副作用がなく安全性が高い。 The sleep-improving agent of the present invention can improve the quality of sleep by increasing the duration of non-REM sleep, and can exhibit a high improvement effect on sleep disorders. Moreover, the sleep-improving agent of the present invention is an ingredient contained in cereals and nuts with abundant dietary experience, so there are no harmful side effects even when taken continuously and safety is ensured. high.
本発明において「睡眠改善剤」とは、睡眠の質を改善する作用を有する薬学的組成物又は飲食用組成物を意味する。睡眠改善剤は、睡眠障害改善剤、睡眠障害の改善作用を有する剤、睡眠障害を改善するために用いられる剤、または睡眠障害の治療剤と言い換えることができ、何れの物質であっても、本発明に記載の睡眠改善剤を意味する。 In the present invention, the “sleep improving agent” means a pharmaceutical composition or a composition for eating and drinking having an action of improving the quality of sleep. The sleep improving agent can be restated as a sleep disorder improving agent, an agent having an action of improving sleep disorder, an agent used to improve sleep disorder, or a therapeutic agent for sleep disorder, The sleep improving agent described in the present invention is meant.
本発明の睡眠改善剤は、前記一般式（Ｉ）で表されるアルキルレゾルシノールを有効成分として含有する。前記一般式（Ｉ）におけるＲ１で表される飽和又は不飽和のアルキル基は、その炭素原子数により制限されるものではないが、炭素原子数１５〜２７であることが好ましく、炭素原子数１５〜２５であることがより好ましい。 The sleep improving agent of the present invention contains an alkylresorcinol represented by the general formula (I) as an active ingredient. The saturated or unsaturated alkyl group represented by R 1 in the general formula (I) is not limited by the number of carbon atoms, but preferably has 15 to 27 carbon atoms, More preferably, it is 15-25.
炭素原子数１５〜２７の飽和アルキル基としては、代表例として、ｎ−ペンタデシル、ｎ−ヘプタデシル、ｎ−ノナデシル、ｎ−ヘンイコシル、ｎ−トリコシル、ｎ−ペンタコシル、ｎ−ヘプタコシル等の直鎖状のものが挙げられ、これらの他に、分岐状又は環状のものでも良い。これらの中でも、炭素原子数１５〜２５の飽和アルキル基が好ましく、炭素原子数１５〜２５の直鎖飽和アルキル基がさらに好ましい。 As typical examples of the saturated alkyl group having 15 to 27 carbon atoms, linear examples such as n-pentadecyl, n-heptadecyl, n-nonadecyl, n-henicosyl, n-tricosyl, n-pentacosyl, n-heptacosyl In addition to these, it may be branched or annular. Among these, a saturated alkyl group having 15 to 25 carbon atoms is preferable, and a linear saturated alkyl group having 15 to 25 carbon atoms is more preferable.
炭素原子数１５〜２７の不飽和アルキル基としては、前記の炭素原子数１５〜２７の飽和アルキル基に対応するものが挙げられる。不飽和アルキル基に含まれる不飽和結合の数及び位置に特に制限はない。 Examples of the unsaturated alkyl group having 15 to 27 carbon atoms include those corresponding to the aforementioned saturated alkyl group having 15 to 27 carbon atoms. There is no restriction | limiting in particular in the number and position of the unsaturated bond contained in an unsaturated alkyl group.
また、前記一般式（Ｉ）におけるＲ２は水素原子であることが好ましく、また、Ｒ１はＲ２に対してパラ位に結合していることが好ましい。 In the general formula (I), R 2 is preferably a hydrogen atom, and R 1 is preferably bonded to R 2 at the para position.
本発明の睡眠改善剤において有効成分として用いられる前記一般式（Ｉ）で表されるアルキルレゾルシノールの具体例としては、以下のものが挙げられる。
１，３−ジヒドロキシ−５−ｎ−ペンタデシルベンゼン（Ｃ１５：０）
１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）
１，３−ジヒドロキシ−５−ｎ−ノナデシルベンゼン（Ｃ１９：０）
１，３−ジヒドロキシ−５−ｎ−ヘンイコシルベンゼン（Ｃ２１：０）
１，３−ジヒドロキシ−５−ｎ−トリコシルベンゼン（Ｃ２３：０）
１，３−ジヒドロキシ−５−ｎ−ペンタコシルベンゼン（Ｃ２５：０）
１，３−ジヒドロキシ−５−ｎ−ヘプタコシルベンゼン（Ｃ２７：０）
The following are mentioned as a specific example of the alkyl resorcinol represented by the said general formula (I) used as an active ingredient in the sleep improving agent of this invention.
1,3-dihydroxy-5-n-pentadecylbenzene (C15: 0)
1,3-dihydroxy-5-n-heptadecylbenzene (C17: 0)
1,3-dihydroxy-5-n-nonadecylbenzene (C19: 0)
1,3-dihydroxy-5-n-henicosylbenzene (C21: 0)
1,3-dihydroxy-5-n-tricosylbenzene (C23: 0)
1,3-dihydroxy-5-n-pentacosylbenzene (C25: 0)
1,3-dihydroxy-5-n-heptacosylbenzene (C27: 0)
前記一般式（Ｉ）で表されるアルキルレゾルシノールとしては、Ｒ１が炭素原子数１５〜２５の飽和アルキル基であり、Ｒ２が水素原子であるものが特に好ましく、とりわけ、下記６種類のアルキルレゾルシノールを含有するものが好ましい。
１）前記一般式（Ｉ）におけるＲ１が炭素原子数１５の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ１５ともいう）。
２）前記一般式（Ｉ）におけるＲ１が炭素原子数１７の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ１７ともいう）。
３）前記一般式（Ｉ）におけるＲ１が炭素原子数１９の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ１９ともいう）。
４）前記一般式（Ｉ）におけるＲ１が炭素原子数２１の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ２１ともいう）。
５）前記一般式（Ｉ）におけるＲ１が炭素原子数２３の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ２３ともいう）。
６）前記一般式（Ｉ）におけるＲ１が炭素原子数２５の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ２５ともいう）。
As the alkylresorcinol represented by the general formula (I), those in which R 1 is a saturated alkyl group having 15 to 25 carbon atoms and R 2 is a hydrogen atom are particularly preferable. Those containing resorcinol are preferred.
1) Alkyl resorcinol (hereinafter, also referred to as AR15) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 15 carbon atoms.
2) Alkyl resorcinol (hereinafter, also referred to as AR17) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 17 carbon atoms.
3) Alkyl resorcinol (hereinafter, also referred to as AR19) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 19 carbon atoms.
4) Alkyl resorcinol (hereinafter, also referred to as AR21) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 21 carbon atoms.
5) Alkyl resorcinol (hereinafter, also referred to as AR23) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 23 carbon atoms.
6) Alkyl resorcinol (hereinafter, also referred to as AR25) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 25 carbon atoms.
ＡＲ１５として特に好ましいものは、Ｒ１が炭素原子数１５の飽和アルキル基、Ｒ２が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ペンタデシルベンゼン（Ｃ１５：０）が挙げられる。
ＡＲ１７として特に好ましいものは、Ｒ１が炭素原子数１７の飽和アルキル基、Ｒ２が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）が挙げられる。
ＡＲ１９として特に好ましいものは、Ｒ１が炭素原子数１９の飽和アルキル基、Ｒ２が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ノナデシルベンゼン（Ｃ１９：０）が挙げられる。
ＡＲ２１として特に好ましいものは、Ｒ１が炭素原子数２１の飽和アルキル基、Ｒ２が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ヘンイコシルベンゼン（Ｃ２１：０）が挙げられる。
ＡＲ２３として特に好ましいものは、Ｒ１が炭素原子数２３の飽和アルキル基、Ｒ２が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−トリコシルベンゼン（Ｃ２３：０）が挙げられる。
ＡＲ２５として特に好ましいものは、Ｒ１が炭素原子数２５飽和アルキル基、Ｒ２が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ペンタコシルベンゼン（Ｃ２５：０）が挙げられる。
Particularly preferred as AR15 is one in which R 1 is a saturated alkyl group having 15 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-pentadecylbenzene (C15 : 0).
Particularly preferred as AR17 is one in which R 1 is a saturated alkyl group having 17 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-heptadecylbenzene (C17 : 0).
Particularly preferred as AR19 is one in which R 1 is a saturated alkyl group having 19 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-nonadecylbenzene (C19 : 0).
Particularly preferred as AR21 is one in which R 1 is a saturated alkyl group having 21 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-henecosylbenzene ( C21: 0).
Particularly preferred as AR23 is one in which R 1 is a saturated alkyl group having 23 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-tricosylbenzene (C23 : 0).
Particularly preferred as AR25 is one in which R 1 is a
本発明の睡眠改善剤において、ＡＲ１５、ＡＲ１７、ＡＲ１９、ＡＲ２１、ＡＲ２３及びＡＲ２５の含有量は、睡眠改善剤による作用効果の一層の向上の観点から、それぞれ、下記範囲内にあることが好ましい。
ＡＲ１５の含有量は、本発明の睡眠改善剤中、好ましくは０．１〜１０．０質量％、更に好ましくは０．１〜５．０質量％、特に好ましくは０．５〜１．５質量％である。
ＡＲ１７の含有量は、本発明の睡眠改善剤中、好ましくは１．０〜２０．０質量％、更に好ましくは５．０〜１５．０質量％、特に好ましくは８．０〜１２．０質量％である。
ＡＲ１９の含有量は、本発明の睡眠改善剤中、好ましくは２５．０〜４０．０質量％、更に好ましくは２７．５〜３７．５質量％、特に好ましくは３０．０〜３５．０質量％である。
ＡＲ２１の含有量は、本発明の睡眠改善剤中、好ましくは４０．０〜５５．０質量％、更に好ましくは４２．５〜５２．５質量％、特に好ましくは４５．０〜５０．０質量％である。
ＡＲ２３の含有量は、本発明の睡眠改善剤中、好ましくは１．０〜１５．０質量％、更に好ましくは２．５〜１２．５質量％、特に好ましくは５．０〜１０．０質量％である。
ＡＲ２５の含有量は、本発明の睡眠改善剤中、好ましくは０〜５．０質量％、更に好ましくは０〜２．０質量％、特に好ましくは０〜１．５質量％である。
In the sleep improving agent of the present invention, the contents of AR15, AR17, AR19, AR21, AR23, and AR25 are each preferably within the following ranges from the viewpoint of further improving the action and effect of the sleep improving agent.
The content of AR15 is preferably 0.1 to 10.0% by mass, more preferably 0.1 to 5.0% by mass, and particularly preferably 0.5 to 1.5% by mass in the sleep improving agent of the present invention. %.
The content of AR17 is preferably 1.0 to 20.0 mass%, more preferably 5.0 to 15.0 mass%, and particularly preferably 8.0 to 12.0 mass% in the sleep improving agent of the present invention. %.
The content of AR19 is preferably 25.0 to 40.0% by mass, more preferably 27.5 to 37.5% by mass, and particularly preferably 30.0 to 35.0% by mass in the sleep improving agent of the present invention. %.
The content of AR21 is preferably 40.0 to 55.0 mass%, more preferably 42.5 to 52.5 mass%, particularly preferably 45.0 to 50.0 mass% in the sleep improving agent of the present invention. %.
The content of AR23 is preferably 1.0 to 15.0 mass%, more preferably 2.5 to 12.5 mass%, particularly preferably 5.0 to 10.0 mass% in the sleep improving agent of the present invention. %.
The content of AR25 is preferably 0 to 5.0% by mass, more preferably 0 to 2.0% by mass, and particularly preferably 0 to 1.5% by mass in the sleep improving agent of the present invention.
前記一般式（Ｉ）で表されるアルキルレゾルシノールは、常法により合成することができ、また市販品として入手することもできる。また、植物から常法により抽出したものを用いることもできる。アルキルレゾルシノールは、天然の非イソテルぺノイド系フェノール性両親媒性化合物であるレゾルシノール脂質として、種々の植物に含まれていることが知られており、アルキルレゾルシノールの給源としては、イネ科植物以外にも、例えば、ウルシ科、イチョウ科、ヤマモガシ科、ヤブコウジ科、サクラソウ科、ニクズク科、アヤメ科、サトイモ科、キク科のヨモギ、マメ科等が知られている。これらの植物の中でも、穀類及びナッツ類、とりわけ穀類は、食経験が豊富で人体に対する安全性が高いことなどから、本発明の睡眠改善剤の有効成分の給源に適している。即ち、本発明の睡眠改善剤は、前記一般式（Ｉ）で表されるアルキルレゾルシノールとして、穀類又はナッツ類から抽出したアルキルレゾルシノール含有抽出物（穀類又はナッツ類由来のアルキルレゾルシノール含有抽出物）を含有することが好ましく、とりわけ、穀類をアルコール抽出して得られる穀類のアルコール抽出物を含有することが好ましい。 The alkylresorcinol represented by the general formula (I) can be synthesized by a conventional method or can be obtained as a commercial product. Moreover, what was extracted from the plant by the conventional method can also be used. Alkylresorcinol is known to be contained in various plants as a resorcinol lipid, which is a natural non-isoterpenoid phenolic amphiphilic compound. In addition, for example, Urushiaceae, Ginkgoaceae, Porcupineaceae, Yabukodiidae, Primulaceae, Stigmaceae, Iridaceae, Araceae, Artemisia, Asteraceae, Legume, and the like are known. Among these plants, cereals and nuts, particularly cereals, are suitable as a source of the active ingredient of the sleep-improving agent of the present invention because of their rich food experience and high safety to the human body. That is, the sleep-improving agent of the present invention is an alkylresorcinol-containing extract extracted from cereals or nuts (alkylresorcinol-containing extract derived from cereals or nuts) as the alkylresorcinol represented by the general formula (I). It is preferable to contain, and it is preferable to contain especially the alcohol extract of the grain obtained by alcohol-extracting a grain.
穀類の中でも、特にイネ科植物は、可食性有効成分としてのアルキルレゾルシノールの研究が進んでいることなどから、前記一般式（Ｉ）で表されるアルキルレゾルシノールの給源として好ましい。イネ科植物としては、例えば、小麦、デュラム小麦、ライ麦、ライ小麦、大麦、オーツ麦、はと麦、トウモロコシ、イネ、ヒエ、アワ、キビ等が挙げられ、これらの１種を単独で又は２種以上を組み合わせて用いることができる。これらのイネ科植物の中でも、アルキルレゾルシノール含量が比較的多く、高い活性が得られる点から、小麦又はライ麦が好ましい。また同様の観点から、ナッツ類としてはカシューナッツが好ましい。 Among cereals, gramineous plants are particularly preferable as a source of alkylresorcinol represented by the general formula (I) because research on alkylresorcinol as an edible active ingredient has been advanced. Examples of gramineous plants include wheat, durum wheat, rye, rye wheat, barley, oats, hard wheat, corn, rice, millet, millet, millet, etc., one of these alone or 2 A combination of more than one species can be used. Among these gramineous plants, wheat or rye is preferred because it has a relatively high alkylresorcinol content and high activity can be obtained. From the same viewpoint, cashew nuts are preferable as nuts.
給源としてイネ科植物を用いる場合は通常、イネ科植物種子が用いられる。イネ科植物種子の形態は特に限定されず、例えば、イネ科植物種子（好ましくは種子外皮；糟糠類）そのもの；当該イネ科植物種子を切断、粉砕若しくは粉末化したもの；当該イネ科植物種子を乾燥したもの；当該イネ科植物種子を乾燥後粉砕若しくは粉末化したもの等を用いることができる。イネ科植物種子外皮を含む好適な例としては、ふすま、末粉、籾殻、ぬか等が挙げられる他、外皮を伴った種子も挙げられる。 When using gramineous plants as a source, gramineous plant seeds are usually used. The form of the grass seed is not particularly limited. For example, the grass seed (preferably seed hull; moss) itself; the grass seed cut, pulverized or powdered; the grass seed A dried product obtained by drying or crushing or pulverizing the grass seed can be used. Preferable examples including grass seed hulls include bran, powder, rice husk, bran and the like, and seeds with hulls.
前記一般式（Ｉ）で表されるアルキルレゾルシノールとして、穀類又はナッツ類から抽出したアルキルレゾルシノール含有抽出物を用いる場合、該アルキルレゾルシノール含有抽出物としては、穀類又はナッツ類のアルコール抽出物が好ましい。アルコールによる抽出方法は特に制限されないが、例えば、前記各種形態のイネ科植物種子をアルコール中に浸漬、攪拌又は還流する方法の他、超臨界流体抽出法等が挙げられる。イネ科植物種子をアルコール中に浸漬、攪拌又は還流する方法の場合、抽出温度（アルコールの液温）は２〜１００℃が好ましく、抽出時間は０．５〜７２時間が好ましく、アルコール使用量は、イネ科植物種子１００質量部に対し５０〜２０００質量部が好ましい。 When an alkylresorcinol-containing extract extracted from cereals or nuts is used as the alkylresorcinol represented by the general formula (I), the alkylresorcinol-containing extract is preferably an alcoholic extract of cereals or nuts. The extraction method with alcohol is not particularly limited, and examples thereof include a supercritical fluid extraction method and the like, in addition to a method of immersing, stirring, or refluxing various kinds of grass seeds in alcohol. In the case of the method of immersing, stirring or refluxing grass seeds in alcohol, the extraction temperature (alcohol liquid temperature) is preferably 2 to 100 ° C., the extraction time is preferably 0.5 to 72 hours, and the amount of alcohol used is 50-2000 mass parts is preferable with respect to 100 mass parts of gramineous plant seeds.
抽出に用いられるアルコールとしては、例えば、メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｎ−ブタノール等の１価の低級アルコール（好ましくは炭素原子数１〜４のもの）、及び１，３−ブチレングリコール、プロピレングリコール、グリセリン等の多価アルコール等の室温（２５℃）で液体であるアルコールが挙げられる。これらのアルコールの中でも、操作性や環境性の点から、エタノールが好ましい。尚、抽出に用いられるアルコールとしては、アルコール以外の水性成分（水、純水、蒸留水、水道水、酸性水、アルカリ水、中性水等）が含まれている含水エタノールを用いることもできる。含水アルコール中のアルコール含有量は、通常７０体積％以上、好ましくは８０体積％以上、より好ましくは９０体積％以上である。 Examples of the alcohol used for extraction include monovalent lower alcohols (preferably having 1 to 4 carbon atoms) such as methanol, ethanol, n-propanol, isopropanol, and n-butanol, and 1,3-butylene glycol. , Alcohols that are liquid at room temperature (25 ° C.), such as polyhydric alcohols such as propylene glycol and glycerin. Among these alcohols, ethanol is preferable from the viewpoint of operability and environmental properties. In addition, as alcohol used for extraction, the water-containing ethanol containing aqueous components other than alcohol (water, pure water, distilled water, tap water, acidic water, alkaline water, neutral water, etc.) can also be used. . The alcohol content in the hydrous alcohol is usually 70% by volume or more, preferably 80% by volume or more, more preferably 90% by volume or more.
穀類、ナッツ類等の植物のアルコール抽出物（アルキルレゾルシノール含有抽出物）は、分配クロマトグラフィーによって精製される。分配クロマトグラフィーは、前記一般式（Ｉ）で表されるアルキルレゾルシノールが得られる手法であればその種類は問わないが、移動相として非水系溶媒を用いる順相クロマトグラフィー法が好ましく、オープンカラム法、中圧カラム法、高速液体クロマトグラフィー等の公知の方法を適宜選択することができる。 Alcohol extracts of plants such as cereals and nuts (alkylresorcinol-containing extracts) are purified by partition chromatography. The partition chromatography is not particularly limited as long as the alkylresorcinol represented by the general formula (I) can be obtained, but a normal phase chromatography method using a non-aqueous solvent as a mobile phase is preferable, and an open column method is used. In addition, a known method such as an intermediate pressure column method or high performance liquid chromatography can be appropriately selected.
植物のアルコール抽出物（アルキルレゾルシノール含有抽出物）の分配クロマトグラフィーにおける移動相としては、メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｎ−ブタノール等の１価の低級アルコール（好ましくは炭素原子数１〜４のもの）、及び１，３−ブチレングリコール、プロピレングリコール、グリセリン等の多価アルコール等の室温（２５℃）で液体であるアルコール；ジエチルエーテル、プロピルエーテル等のエーテル；酢酸ブチル、酢酸エチル等のエステル；アセトン、エチルメチルケトン等のケトン；ヘキサン；塩化メチレン；アセトニトリル；並びにクロロホルム等が挙げられ、これら溶媒の１種を単独で又は２種以上を組み合わせて用いることができる。複数の溶媒を組み合わせて移動相とする場合、分配クロマトグラフィーの実施中（植物のアルコール抽出物の精製中）において、複数の溶媒の混合比を一定にするイソクラクティックモードでも良く、あるいは該混合比を変化させるグラジエントモードでも良い。また、分配クロマトグラフィーにおける担体としては、目的とする有効成分を担持−放出できる担体であればいずれも用いることができるが、一般的にはシリカゲル、ポリアクリルアミドゲル、デキストランゲル等を挙げることができる。植物のアルコール抽出物の分配クロマトグラフィーにおける検出波長は、１７０〜３２０ｎｍであれば良く、好ましくは１９０〜２８０ｎｍである。 As a mobile phase in the partition chromatography of a plant alcohol extract (alkylresorcinol-containing extract), monovalent lower alcohols (preferably having 1 to 1 carbon atoms) such as methanol, ethanol, n-propanol, isopropanol, and n-butanol. 4), and alcohols that are liquid at room temperature (25 ° C.) such as polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin; ethers such as diethyl ether and propyl ether; butyl acetate, ethyl acetate, and the like Ester; acetone, ethyl methyl ketone and other ketones; hexane; methylene chloride; acetonitrile; and chloroform, and one of these solvents can be used alone, or two or more thereof can be used in combination. When a plurality of solvents are combined into a mobile phase, an isocratic mode in which the mixing ratio of the plurality of solvents is constant during partition chromatography (purification of the plant alcohol extract) may be used. A gradient mode that changes the ratio may be used. Any carrier can be used as the carrier in the partition chromatography as long as it can carry and release the target active ingredient, and generally includes silica gel, polyacrylamide gel, dextran gel and the like. . The detection wavelength in the partition chromatography of the plant alcohol extract may be 170 to 320 nm, preferably 190 to 280 nm.
植物（好ましくは穀類又はナッツ類）のアルコール抽出物（好ましくはエタノール抽出物）の精製に好適な分配クロマトグラフィーの例として、下記分配クロマトグラフィーＡ及びＢが挙げられる。
・分配クロマトグラフィーＡ：担体としてシリカゲル及び移動相としてヘキサン−酢酸エチル混合溶媒を用いた中圧カラム法（中圧クロマトグラフィー）を用い、且つその分配クロマトグラフィーの実施中に、移動相を「ヘキサン−酢酸エチル混合溶媒においてヘキサンの含有割合が相対的に高いもの」から「ヘキサン−酢酸エチル混合溶媒においてヘキサンの含有割合が相対的に低いもの」へと変化させ（即ち、「ヘキサン大−少」へのグラジエントモードで用い）、且つ検出波長２５４ｎｍでのピーク成分を分取する。
・分配クロマトグラフィーＢ：担体としてシリカゲル及び移動相としてメタノールを用いた高速液体クロマトグラフィー（ＨＰＬＣ）を用い、且つ検出波長２１５ｎｍでのピーク成分を分取する。
Examples of partition chromatography suitable for purification of an alcohol extract (preferably an ethanol extract) of a plant (preferably cereal or nuts) include the following partition chromatography A and B.
Partition chromatography A: using a medium pressure column method (medium pressure chromatography) using silica gel as a carrier and a hexane-ethyl acetate mixed solvent as a mobile phase, and during the execution of the partition chromatography, -Changed from "relatively high hexane content in ethyl acetate mixed solvent" to "relatively low hexane content in hexane-ethyl acetate mixed solvent" And a peak component at a detection wavelength of 254 nm is fractionated.
Partition chromatography B: Using high performance liquid chromatography (HPLC) using silica gel as a carrier and methanol as a mobile phase, a peak component at a detection wavelength of 215 nm is fractionated.
本発明の睡眠改善剤の形態は特に制限されず、例えば、植物のアルコール抽出物（アルキルレゾルシノール含有抽出物）を含む液状物（液体又は半液体）、該液状物中の液媒体（アルコール又は含水アルコール）を蒸発乾固して得られる乾固物又はその粉末、該乾固物又はその粉末をエタノール等のアルコールに溶解してなるアルコール溶液等が挙げられる。 The form of the sleep improving agent of the present invention is not particularly limited. For example, a liquid substance (liquid or semi-liquid) containing a plant alcohol extract (alkylresorcinol-containing extract), a liquid medium (alcohol or water-containing liquid) in the liquid substance Examples thereof include a dried product obtained by evaporating (alcohol) to dryness or a powder thereof, an alcohol solution obtained by dissolving the dried product or the powder thereof in an alcohol such as ethanol.
本発明の睡眠改善剤は、哺乳動物の睡眠の質を改善するために用いられる。哺乳動物としては、ヒトの他に、例えばイヌ、ネコ、マウス、ラット、ウサギ、ウシ、ウマ、サル等が含まれる。即ち、本発明の睡眠改善剤は、ヒトのみならず、ペット（愛玩動物）、家畜等に対しても適用可能であり、哺乳動物全般に対して医療目的又は非医療目的で適用し得る。 The sleep improving agent of the present invention is used to improve the quality of sleep in mammals. Examples of mammals include dogs, cats, mice, rats, rabbits, cows, horses, monkeys and the like in addition to humans. That is, the sleep-improving agent of the present invention can be applied not only to humans but also to pets (companion animals), livestock, etc., and can be applied to all mammals for medical purposes or non-medical purposes.
本発明でいう「睡眠の質の改善」とは、寝つきが良くなる、不眠が改善される、睡眠状態が深くなる、覚醒後の気分が良くなる等の基準により評価され得る状態である。睡眠の質の改善は、マウス等の動物から脳波、筋電図、心電図、体温、血圧、行動（locomotion）などを測定し、当該動物の睡眠量を調べることによって評価することができる。睡眠の質の評価は、標準判定方法（Rechtschaffen A. & Kales A., A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects., Public Health Service: Washington DC, 1968）に従って行うことができる。具体的には、動物からの脳波等の測定データに基づいて睡眠ポリグラフを作成し、睡眠ポリグラフのエポック（例えば４〜６０秒間）毎に、行動（locomotion）の有無、脳波（δ波）の振幅、脳波のθ波成分比〔θ／（δ＋θ）〕などに基づいて、動物の状態を覚醒、ノンレム睡眠、レム睡眠の各ステージとして判別すれば良い。睡眠ポリグラフに基づく覚醒又は睡眠の判別は、睡眠解析研究用プログラム：SleepSign（登録商標）（キッセイコムテック株式会社）等により自動で行うことができる。その判別の結果、睡眠ステージを増加させた物質は、睡眠の質の改善効果を有し、睡眠障害を改善し得る物質として評価することができる。 “Improving sleep quality” as used in the present invention is a state that can be evaluated based on criteria such as improved sleep, improved insomnia, deep sleep state, and improved mood after awakening. The improvement in sleep quality can be evaluated by measuring the electroencephalogram, electromyogram, electrocardiogram, body temperature, blood pressure, locomotion, etc. from an animal such as a mouse and examining the sleep amount of the animal. Evaluation of sleep quality should be performed according to standard judgment methods (Rechtschaffen A. & Kales A., A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects., Public Health Service: Washington DC, 1968). it can. Specifically, a polysomnogram is created based on measurement data such as brain waves from animals, and the presence or absence of locomotion and the amplitude of the electroencephalogram (δ wave) every epoch (eg, 4 to 60 seconds) of the polysomnograph Based on the θ wave component ratio [θ / (δ + θ)] of the electroencephalogram, the animal state may be determined as each stage of awakening, non-REM sleep, and REM sleep. Awakening or sleep discrimination based on a polysomnogram can be automatically performed by a sleep analysis research program: SleepSign (registered trademark) (Kissei Comtech Co., Ltd.) or the like. As a result of the discrimination, a substance that has increased sleep stages has an effect of improving sleep quality and can be evaluated as a substance that can improve sleep disorders.
本発明の睡眠改善剤は、睡眠時間、特にノンレム睡眠時間を長期化させる作用を有する。また、本発明の睡眠改善剤は、入眠潜時を短期化させる作用を有する。入眠潜時は、覚醒状態から眠りに入るまでの所要時間を意味し、寝付きの良さの指標となる。本発明の睡眠改善剤は、不眠を主訴とする睡眠障害の治療に用いることができる。本発明の睡眠改善剤は、例えば、不眠症、初期不眠症（就眠困難）、中途覚醒、早期覚醒、熟眠障害、睡眠周期の逆転等に適用可能であるが、これらに限られず、不眠を主訴とする睡眠障害全般に適用可能である。 The sleep improving agent of the present invention has an action of prolonging sleep time, particularly non-REM sleep time. In addition, the sleep improving agent of the present invention has an action of shortening the sleep latency. The sleep onset latency means the time required to go to sleep from an awake state, and is an index of good sleep. The sleep improving agent of the present invention can be used for the treatment of sleep disorders whose main complaint is insomnia. The sleep-improving agent of the present invention can be applied to, for example, insomnia, early insomnia (sleeping difficulty), mid-wake awakening, early awakening, deep sleep disorder, reversal of sleep cycle, etc. It can be applied to all sleep disorders.
本発明の睡眠改善剤は、哺乳動物の医薬品、医薬部外品又は食品として、あるいはそれらを製造するために使用することができる。ここでいう「食品」は、食品全般を包含し、いわゆる健康食品を含む一般食品の他、厚生労働省の保健機能食品制度に規定される特定保健用食品や栄養機能食品等の保健機能食品、サプリメント等を包含し、さらには動物に給餌される家畜用飼料、ペットフードも包含する。本発明の睡眠改善剤は、前記一般式（Ｉ）で表されるアルキルレゾルシノールを有効成分として含有し、且つ睡眠改善効果（ノンレム睡眠時間の増加効果）を企図して、その旨を表示した医薬品、医薬部外品又は食品として使用することができる。 The sleep-improving agent of the present invention can be used as a pharmaceutical product, quasi-drug or food for mammals, or for producing them. “Food” as used herein includes food in general, including general foods including so-called health foods, health functional foods such as foods for specified health use and functional nutrition foods, etc., as defined in the Health Functional Food System of the Ministry of Health, Labor and Welfare. In addition, livestock feed and pet food fed to animals are also included. The sleep-improving agent of the present invention contains an alkylresorcinol represented by the above general formula (I) as an active ingredient, and is intended to have a sleep-improving effect (an effect of increasing the non-REM sleep time), and displays that effect It can be used as a quasi-drug or food.
本発明の睡眠改善剤を医薬品又は医薬部外品として使用する場合、有効成分である前記一般式（Ｉ）で表されるアルキルレゾルシノールを単独で含有していても良く、又は、さらに薬学的に許容される担体を含有していても良く、又は、アルキルレゾルシノールによる睡眠改善効果が損なわれない範囲でさらに他の有効成分や薬理成分を含有していても良い。斯かる担体としては、例えば、賦形剤、被膜剤、結合剤、増量剤、崩壊剤、界面活性剤、滑沢剤、希釈剤、分散剤、緩衝剤、浸透圧調整剤、ｐＨ調整剤、乳化剤、防腐剤、安定剤、酸化防止剤、着色剤、紫外線吸収剤、保湿剤、増粘剤、活性増強剤、抗炎症剤、殺菌剤、矯味剤、矯臭剤等が挙げられる。 When using the sleep-improving agent of the present invention as a pharmaceutical or quasi-drug, it may contain the alkylresorcinol represented by the general formula (I), which is an active ingredient, alone, or pharmaceutically. It may contain an acceptable carrier, or may contain other active ingredients and pharmacological ingredients as long as the effect of improving sleep by alkylresorcinol is not impaired. Examples of such carriers include excipients, coating agents, binders, extenders, disintegrants, surfactants, lubricants, diluents, dispersants, buffers, osmotic pressure adjusting agents, pH adjusting agents, Examples include emulsifiers, preservatives, stabilizers, antioxidants, colorants, ultraviolet absorbers, humectants, thickeners, activity enhancers, anti-inflammatory agents, bactericides, taste-masking agents, and flavoring agents.
本発明の睡眠改善剤を医薬品又は医薬部外品として使用する場合、任意の投与形態で投与され得る。投与形態は、経口投与でも非経口投与でも良い。例えば、経口投与形態としては、錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤のような固形投薬形態、並びにエリキシル、シロップ及び懸濁液のような液体投薬形態が挙げられ、非経口投与形態としては、注射、輸液、経皮、経粘膜、経鼻、経腸、吸入、坐剤、ボーラス、貼布剤等が挙げられる。このうち、経口投与形態が好ましい。 When using the sleep improving agent of this invention as a pharmaceutical or a quasi-drug, it can be administered by arbitrary dosage forms. The dosage form may be oral or parenteral. For example, oral dosage forms include solid dosage forms such as tablets, coated tablets, granules, powders, capsules, and liquid dosage forms such as elixirs, syrups and suspensions. Examples include injection, infusion, transdermal, transmucosal, nasal, enteral, inhalation, suppository, bolus, and patch. Of these, oral dosage forms are preferred.
本発明の睡眠改善剤を食品として使用する場合、有効成分である前記一般式（Ｉ）で表されるアルキルレゾルシノールを単独で含有していても良く、又は、アルキルレゾルシノールによる睡眠改善効果が損なわれない範囲でさらに、医薬品、医薬部外品、食品の製造に用いられる種々の添加剤を含有していても良い。斯かる添加剤としては、例えば、各種油脂、生薬、アミノ酸、多価アルコール、天然高分子、ビタミン、食物繊維、界面活性剤、精製水、賦形剤、安定剤、ｐＨ調製剤、酸化防止剤、甘味料、呈味成分、有機酸などの酸味料、安定剤、フレーバー、着色料、香料等が挙げられる。 When using the sleep-improving agent of the present invention as a food, the alkylresorcinol represented by the general formula (I), which is an active ingredient, may be contained alone, or the sleep-improving effect by the alkylresorcinol is impaired. In addition, various additives used for the production of pharmaceuticals, quasi drugs, and foods may be included. Examples of such additives include various fats and oils, crude drugs, amino acids, polyhydric alcohols, natural polymers, vitamins, dietary fibers, surfactants, purified water, excipients, stabilizers, pH adjusters, antioxidants. , Sweeteners, taste components, acidulants such as organic acids, stabilizers, flavors, colorants, flavors and the like.
本発明の睡眠改善剤を食品として使用する場合、その形態は特に限定されないが、例えば、飲料の形態としては、茶飲料、コーヒー飲料、乳飲料、果汁飲料、炭酸飲料、アルコール飲料、清涼飲料等が挙げられる。また、飲料以外の食品の形態としては、固形、半固形又は液状であり得、錠剤形態、丸剤形態、カプセル形態、液剤形態、シロップ形態、粉末形態、顆粒形態等が挙げられる。具体的な食品の形態としては、パン類、麺類、ゼリー状食品や各種スナック類、焼き菓子、ケーキ類、チョコレート、ガム、飴、タブレット、カプセル、スープ類、乳製品、冷凍食品、インスタント食品、サプリメント、その他加工食品、調味料及びそれらの材料等が挙げられる。 When the sleep-improving agent of the present invention is used as a food, the form is not particularly limited. Examples of the form of the beverage include tea drinks, coffee drinks, milk drinks, fruit drinks, carbonated drinks, alcoholic drinks, and soft drinks. Is mentioned. The form of food other than beverages may be solid, semi-solid or liquid, and examples include tablet form, pill form, capsule form, liquid form, syrup form, powder form, and granular form. Specific food forms include breads, noodles, jelly-like foods and various snacks, baked goods, cakes, chocolate, gum, candy, tablets, capsules, soups, dairy products, frozen foods, instant foods, Examples include supplements, other processed foods, seasonings, and materials thereof.
本発明の睡眠改善剤中における有効成分（前記一般式（Ｉ）で表されるアルキルレゾルシノール）の含有量は、特に制限されるものではなく、剤型、適用対象（哺乳動物）の症状や年齢性別などによって適宜調整可能であるが、ヒトを対象とする場合、通常、本発明の睡眠改善剤の有効成分の投与量が成人１人１日当たり０．０１〜１０ｇとなるように含有させることが好ましい。 The content of the active ingredient (alkylresorcinol represented by the general formula (I)) in the sleep-improving agent of the present invention is not particularly limited, and the dosage form, symptom and age of the application target (mammal) Although it can be adjusted as appropriate according to gender, etc., when targeting humans, it is usually contained so that the dose of the active ingredient of the sleep improving agent of the present invention is 0.01 to 10 g per day per adult. preferable.
本発明には、下記＜１＞及び＜２＞の形態が含まれる。
＜１＞前記一般式（Ｉ）で表されるアルキルレゾルシノールを生体に投与することにより睡眠の質（睡眠障害）を改善する方法。
＜２＞前記一般式（Ｉ）で表されるアルキルレゾルシノールを生体に投与することにより、健康維持、美容等の非医療目的で睡眠の質（睡眠障害）を改善する方法。
The present invention includes the following <1> and <2> modes.
<1> A method for improving sleep quality (sleep disorder) by administering an alkylresorcinol represented by the general formula (I) to a living body.
<2> A method for improving the quality of sleep (sleep disorder) for non-medical purposes such as health maintenance and beauty by administering to the living body the alkylresorcinol represented by the general formula (I).
以下、実施例を挙げて、本発明を更に詳細に説明するが、本発明は実施例により制限されるものではない。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not restrict | limited by an Example.
〔実施例１〕
下記＜抽出精製法＞により、前記一般式（Ｉ）で表されるアルキルレゾルシノールを含有する、小麦エタノール抽出物の分配クロマトグラフィーのピーク成分を得た。得られたピーク成分の組成は次の通り。
・１，３−ジヒドロキシ−５−ｎ−ペンタデシルベンゼン（Ｃ１５：０）１．２質量％。
・１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）１０．９質量％。
・１，３−ジヒドロキシ−５−ｎ−ノナデシルベンゼン（Ｃ１９：０）３３．９質量％。
・１，３−ジヒドロキシ−５−ｎ−ヘンイコシルベンゼン（Ｃ２１：０）４６．４質量％。
・１，３−ジヒドロキシ−５−ｎ−トリコシルベンゼン（Ｃ２３：０）７．５質量％。
・１，３−ジヒドロキシ−５−ｎ−ペンタコシルベンゼン（Ｃ２５：０）０．１質量％。
[Example 1]
By the following <extraction purification method>, the peak component of the partition chromatography of wheat ethanol extract containing the alkylresorcinol represented by the general formula (I) was obtained. The composition of the obtained peak component is as follows.
-1,3-dihydroxy-5-n-pentadecylbenzene (C15: 0) 1.2 mass%.
-1,3-dihydroxy-5-n-heptadecylbenzene (C17: 0) 10.9 mass%.
-1,3-dihydroxy-5-n-nonadecylbenzene (C19: 0) 33.9 mass%.
-1,3-dihydroxy-5-n-henicosylbenzene (C21: 0) 46.4 mass%.
-7.5 mass% of 1, 3- dihydroxy-5-n-tricosyl benzene (C23: 0).
-1,3-dihydroxy-5-n-pentacosylbenzene (C25: 0) 0.1 mass%.
＜抽出精製法＞
小麦ふすまに質量で５倍量のエタノールを添加して、６００ｒｐｍ、室温の条件で、１６時間撹拌抽出した。抽出物を濾過して不要物を除きエタノール抽出液を回収した後、エタノールを留去し、小麦エタノール抽出物を得た。
次いで、この小麦エタノール抽出物を中圧クロマトグラフィーによって精製した。中圧クロマトグラフィー条件は下記の通りである。溶出開始後３１〜３６分に出現するピーク成分を回収して、溶媒留去し、小麦エタノール抽出物の分配クロマトグラフィーのピーク成分を得た。
（中圧クロマトグラフィーの条件）
・カラム：シリカゲル（インジェクトカラム３Ｌ、ハイフラッシュカラム５Ｌ、６０Å、４０μｍ、山善株式会社製）
・移動相：ヘキサン／酢酸エチル混合溶媒（体積比）＝９０／１０にて９分、８０／２０にて１５分、６０／４０にて１６分
・検出波長：２５４ｎｍ
<Extraction purification method>
Ethanol in an amount of 5 times by mass was added to wheat bran, and the mixture was extracted by stirring for 16 hours under conditions of 600 rpm and room temperature. The extract was filtered to remove unnecessary substances and an ethanol extract was collected, and then ethanol was distilled off to obtain a wheat ethanol extract.
The wheat ethanol extract was then purified by medium pressure chromatography. Medium pressure chromatography conditions are as follows. The peak component appearing 31 to 36 minutes after the start of elution was collected, and the solvent was distilled off to obtain the peak component of partition chromatography of the wheat ethanol extract.
(Medium pressure chromatography conditions)
Column: silica gel (injection column 3 L,
・ Mobile phase: Hexane / ethyl acetate mixed solvent (volume ratio) = 9/10 at 90/10, 15 minutes at 80/20, 16 minutes at 60/40 ・ Detection wavelength: 254 nm
尚、前記＜抽出精製法＞における小麦エタノール抽出物の精製は、中圧クロマトグラフィーに代えて、ＨＰＬＣによって行うこともできる。その場合、小麦エタノール抽出物にメタノールを添加して該エタノール抽出物の濃度が２００ｕｇ／ｍｌのメタノール添加液を調製し、該メタノール添加液を、孔径０．４５μｍのフィルターを通過させ、その通過分を、ＨＰＬＣの試料とする。ＨＰＬＣの条件は下記の通り。
（ＨＰＬＣの条件）
・カラム：シリカゲル（ＯＤＳ−８０Ａ、５μｍ、４．６×２５０ｍｍ、ジーエルサイエンス株式会社製）
・ガードカラム：ＯＤＳ−８０Ａ、５μｍ、４．６×５０ｍｍ、
・カラム温度：３０℃
・移動相：メタノール１００％
・検出波長：２１５ｎｍ
In addition, the purification of the wheat ethanol extract in the above <Extraction and purification method> can be performed by HPLC instead of medium pressure chromatography. In this case, methanol is added to the wheat ethanol extract to prepare a methanol additive solution having a concentration of 200 ug / ml, and the methanol additive solution is passed through a filter having a pore size of 0.45 μm. Are HPLC samples. HPLC conditions are as follows.
(HPLC conditions)
Column: silica gel (ODS-80A, 5 μm, 4.6 × 250 mm, manufactured by GL Sciences Inc.)
Guard column: ODS-80A, 5 μm, 4.6 × 50 mm,
-Column temperature: 30 ° C
-Mobile phase: 100% methanol
・ Detection wavelength: 215 nm
〔睡眠の質改善効果の評価〕
前記一般式（Ｉ）で表されるアルキルレゾルシノールが睡眠の質に与える効果を確認するために、マウスを用いて以下の試験１及び２を行い、脳波を測定した。即ち、マウス頭部に電極を装着し、ゲージ内において自由行動下のマウス脳波を記録し、「覚醒」「ノンレム睡眠」「レム睡眠」の各時間を測定した。
[Evaluation of sleep quality improvement effect]
In order to confirm the effect of the alkylresorcinol represented by the general formula (I) on the quality of sleep, the following
〔試験１：長期投与試験〕
（１）動物への睡眠ポリグラフ記録用電極の留置
マウス（Ｃ５７ＢＬ／６Ｊ、日本ＳＬＣ社）に、麻酔下で睡眠脳波測定用送信器（DSI、TAlOM2-F20-EET）の留置手術を行った。具体的には、マウスの頭蓋骨の２カ所にドリルで穴をあけて脳波用電極を挿入し、歯科用セメントで固定した。電極の挿入位置は、大脳皮質領域のブレグマ（bregma）から横（右）に１ｍｍ、前方に１ｍｍの位置、及び横（左）に１ｍｍ、後方に３ｍｍの位置とした。また、筋電図用の電極コードを、マウスの頸部筋肉に差し込み固定し、それらのコードに接続された送信器を背部皮下に留置した。
[Test 1: Long-term administration test]
(1) Indwelling electrodes for polysomnography recording on animals Mice (C57BL / 6J, Japan SLC) were subjected to indwelling operation with a transmitter for measuring sleep electroencephalogram (DSI, TAlOM2-F20-EET) under anesthesia. Specifically, holes were drilled in two places on the skull of the mouse, an electroencephalogram electrode was inserted, and fixed with dental cement. The electrodes were inserted 1 mm laterally (right), 1 mm forward, 1 mm laterally (left), and 3 mm backward from the bregma in the cerebral cortex region. Electromyogram electrode cords were inserted into and fixed to the neck muscles of mice, and transmitters connected to these cords were placed subcutaneously in the back.
前記留置手術後２週間の回復期間を経た後に、マウスを睡眠ポリグラフ用の個別ケージに移し、下記の実験食又は対照食を１０日間給餌した（各群：ｎ＝５）。
・実験食：マウス飼育用の精製飼料ＡＩＮ−９３に、実施例１の小麦エタノール抽出物の分配クロマトグラフィーのピーク成分（前記一般式（Ｉ）で表されるアルキルレゾルシノール）を０．４質量％添加し混合した飼料
・対照食：マウス飼育用の精製飼料ＡＩＮ−９３
After a recovery period of 2 weeks after the indwelling surgery, the mice were transferred to individual cages for polysomnography and fed with the following experimental diet or control diet for 10 days (each group: n = 5).
Experimental food: 0.4% by mass of the peak component (alkylresorcinol represented by the above general formula (I)) of the wheat ethanol extract of Example 1 in purified feed AIN-93 for breeding mice Added and mixed feed / control food: purified feed AIN-93 for breeding mice
（２）睡眠ポリグラフの記録と解析
前記の実験食又は対照食の１０日間の給餌後、マウスの脳波（ＥＥＧ）及び筋電位（ＥＭＧ）をそれぞれ３日間連続で測定した。測定は、送信器及びマウスが収容されているケージを受信ボード（DSI、RPC-1）上に設置して行った。検出データは、データ解析ソフト（DSI、Dataquest A.R.T.）を用いてパーソナルコンピュータに取得され、睡眠解析研究用プログラムであるSleepSign（登録商標）（キッセイコムテック株式会社）によって自動解析された。その自動解析においては、１０秒間の筋電図が閾値以上の場合は「覚醒」と判定され、覚醒以外の状態については、脳波の周波数解析の結果、比較的遅い周波数の脳波（０．５〜４Ｈｚ）が閾値以上の場合は「ノンレム睡眠」と判定され、閾値未満の場合は「レム睡眠」と判定された。
(2) Recording and analysis of polysomnography After feeding the experimental diet or the control diet for 10 days, the electroencephalogram (EEG) and myoelectric potential (EMG) of the mice were each measured continuously for 3 days. The measurement was performed by placing a cage containing a transmitter and a mouse on a receiving board (DSI, RPC-1). The detection data was acquired by a personal computer using data analysis software (DSI, Dataquest ART) and automatically analyzed by SleepSign (registered trademark) (Kissei Comtech Co., Ltd.), which is a sleep analysis research program. In the automatic analysis, if the electromyogram for 10 seconds is equal to or greater than the threshold value, it is determined as “wakefulness”. For states other than awakening, as a result of the electroencephalogram frequency analysis, 4 Hz) is equal to or greater than the threshold value, it is determined as “non-REM sleep”, and when it is less than the threshold value, it is determined as “REM sleep”.
（３）試験１の結果
図１にはマウスの１時間当たりの覚醒時間（秒）、図２にはマウスの１時間当たりのノンレム睡眠の時間（秒）、図３にはマウスの１時間当たりのレム睡眠の時間（秒）がそれぞれ示されている。図１は筋電位のデータから算出し、図２及び図３は脳波のデータから算出した。３日間の平均データから、１時間ごとの総覚醒時間、総ノンレム睡眠時間、総レム睡眠時間について、実験食を摂取した群及び対照食を摂取した群と時刻（ＺＴ：ＺＴ０に点灯、ＺＴ１２に消灯）との２要因の分散分析を行ったところ、図２に示すように、実験食を摂取した群は、対照食を摂取した群に比して、ＺＴ１３における総覚醒時間が有意に短縮し、総ノンレム睡眠時間が長くなった。
以上のことから、前記一般式（Ｉ）で表されるアルキルレゾルシノールを比較的長期間（具体的には１０日間）複数回にわたって摂取することで、マウスのノンレム睡眠時間が長期化され、マウスの睡眠の質が改善されることがわかる。
(3) Results of Test 1 FIG. 1 shows the awakening time per second (second) of the mouse, FIG. 2 shows the non-REM sleep time per second of the mouse (second), and FIG. Each REM sleep time (seconds) is shown. FIG. 1 was calculated from myoelectric potential data, and FIGS. 2 and 3 were calculated from brain wave data. From the average data for 3 days, the total awakening time, the total non-REM sleep time, and the total REM sleep time for each hour, the group that took the experimental food and the group that took the control food and the time (ZT: lights on ZT0, ZT12 As shown in FIG. 2, the group that ingested the experimental diet significantly reduced the total awakening time in ZT13 as compared to the group that ingested the control diet, as shown in FIG. , Total non-REM sleep time became longer.
From the above, by ingesting the alkylresorcinol represented by the general formula (I) multiple times over a relatively long period of time (specifically, 10 days), the non-REM sleep time of the mouse is prolonged, It can be seen that the quality of sleep is improved.
〔試験２：短期投与試験〕
前記試験１において、前記留置手術後２週間の回復期間を経た後に、マウスを睡眠ポリグラフ用の個別ケージに移して２４時間絶食させた後、その絶食期間の終了直後（ＺＴ０）から前記実験食又は対照食を２４時間だけ給餌した（各群：ｎ＝４）以外は、前記試験１の（１）及び（２）と同様にして、マウスのＥＥＧ及びＥＭＧをそれぞれ測定し、その結果をSleepSign（登録商標）によって自動解析した。
[Study 2: Short-term administration test]
In the test 1, after passing through a recovery period of 2 weeks after the indwelling operation, the mice were transferred to individual cages for polysomnography and fasted for 24 hours, and then immediately after the fasting period ended (ZT0), the experimental food or Except that the control diet was fed for 24 hours (each group: n = 4), the EEG and EMG of the mice were measured in the same manner as in the test 1 (1) and (2). Automatic analysis by registered trademark).
（試験２の結果）
図４にはマウスの１時間当たりの覚醒時間（秒）、図５にはマウスの１時間当たりのノンレム睡眠の時間（秒）、図６にはマウスの１時間当たりのレム睡眠の時間（秒）がそれぞれ示されている。図４は筋電位のデータから算出し、図５及び図６は脳波のデータから算出した。１時間ごとの総覚醒時間、総ノンレム睡眠時間、総レム睡眠時間について、実験食を摂取した群及び対照食を摂取した群と時刻（ＺＴ：ＺＴ０に点灯、ＺＴ１２に消灯）との２要因の分散分析を行ったところ、図４及び図５に示すように、実験食を摂取した群は、対照食を摂取した群に比して、ＺＴ４及びＺＴ７（図中＊を付した時間）における総覚醒時間が有意に短縮し、総ノンレム睡眠時間が長くなった。
そこで、この「ＺＴ４〜ＺＴ７の時間」に着目して、この間におけるノンレム睡眠の継続時間（秒）の分布を分析したので、その結果を図７に示す。図７に示すように、実験食を摂取した群は概ね、ノンレム睡眠の各エピソードが延長する傾向がみられ、特にエピソードが６００秒〜７２０秒（図中＊を付した時間）の回数が有意に増加した。
以上のことから、前記一般式（Ｉ）で表されるアルキルレゾルシノールは、数日間にわたる複数回投与（長期投与）の場合のみならず、１日間だけの単回投与（短期投与）の場合であっても、マウスのノンレム睡眠時間の長期化を促し、マウスの睡眠の質の改善に有効であることがわかる。
(Result of Test 2)
4 shows the awakening time per second (second) of the mouse, FIG. 5 shows the non-REM sleep time per second (second) of the mouse, and FIG. 6 shows the REM sleep time per second of the mouse (second). ) Are shown respectively. FIG. 4 was calculated from myoelectric potential data, and FIGS. 5 and 6 were calculated from brain wave data. Regarding the total awakening time every hour, total non-REM sleep time and total REM sleep time, there are two factors: the group that took the experimental food and the group that took the control food and time (ZT: ZT0 lights up, ZT12 turns off) As shown in FIGS. 4 and 5, the analysis of variance showed that the group that took the experimental diet had a higher total of ZT4 and ZT7 (time marked with * in the figure) than the group that took the control diet. Awakening time was significantly shortened and total non-REM sleep time was lengthened.
Therefore, paying attention to this “time of ZT4 to ZT7”, the distribution of the duration (seconds) of non-REM sleep during this period was analyzed, and the result is shown in FIG. As shown in FIG. 7, in the group that took the experimental food, each episode of non-REM sleep generally tended to be extended, and the number of episodes was particularly significant between 600 seconds and 720 seconds (the time marked with * in the figure). Increased to.
From the above, the alkylresorcinol represented by the general formula (I) is not only in the case of multiple administrations (long-term administration) over several days but also in the case of single administration (short-term administration) for only one day. However, it can be seen that the non-REM sleep time of the mouse is prolonged and it is effective in improving the sleep quality of the mouse.
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| JP2020186214A (en) * | 2019-05-16 | 2020-11-19 | 株式会社日清製粉グループ本社 | Slow wave activity promoter |
| WO2020235546A1 (en) | 2019-05-22 | 2020-11-26 | 日東富士製粉株式会社 | Composition for improving liver function |
| KR20230025645A (en) * | 2021-08-12 | 2023-02-22 | 주식회사 머스카 | Use of natural products to induce sleep and improve sleep quality |
| WO2024087314A1 (en) * | 2022-10-26 | 2024-05-02 | 江南大学 | Method for extracting alkylresorcinols in wheat bran based on ultrasound-assisted enzymolysis method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020186214A (en) * | 2019-05-16 | 2020-11-19 | 株式会社日清製粉グループ本社 | Slow wave activity promoter |
| JP7260113B2 (en) | 2019-05-16 | 2023-04-18 | 株式会社日清製粉グループ本社 | Slow-wave activity promoter |
| WO2020235546A1 (en) | 2019-05-22 | 2020-11-26 | 日東富士製粉株式会社 | Composition for improving liver function |
| KR20230025645A (en) * | 2021-08-12 | 2023-02-22 | 주식회사 머스카 | Use of natural products to induce sleep and improve sleep quality |
| KR102548951B1 (en) * | 2021-08-12 | 2023-06-29 | 주식회사 머스카 | Use of natural products to induce sleep and improve sleep quality |
| WO2024087314A1 (en) * | 2022-10-26 | 2024-05-02 | 江南大学 | Method for extracting alkylresorcinols in wheat bran based on ultrasound-assisted enzymolysis method |
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