JP6333339B2 - Sleep enhancer - Google Patents
Sleep enhancer Download PDFInfo
- Publication number
- JP6333339B2 JP6333339B2 JP2016213521A JP2016213521A JP6333339B2 JP 6333339 B2 JP6333339 B2 JP 6333339B2 JP 2016213521 A JP2016213521 A JP 2016213521A JP 2016213521 A JP2016213521 A JP 2016213521A JP 6333339 B2 JP6333339 B2 JP 6333339B2
- Authority
- JP
- Japan
- Prior art keywords
- sleep
- octacosanol
- vehicle
- administration
- time
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、オクタコサノール、その塩、及びそれらの溶媒和物からなる群から選択される少なくとも一種の有効成分を含む、睡眠充実剤に関する。 The present invention relates to a sleep enhancer comprising at least one active ingredient selected from the group consisting of octacosanol, a salt thereof, and a solvate thereof.
オクタコサノール(ポリコサノール)は、麦芽油、米糠油、サトウキビ、ミツロウ等に含まれる長鎖脂肪族アルコールである(非特許文献1)。オクタコサノールは、抗パーキンソン症候群活性に加え、酸化防止活性および強壮活性のような様々な重要な生物活性を有する(非特許文献2)。さらに、オクタコサノールを含む長鎖脂肪族アルコールの混合物は脂肪組織の重量を減少させ(非特許文献3)、コレステロール合成を抑制することが報告されている(非特許文献4)。また、オクタコサノール単独投与によりLDLコレステロールが減りHDLコレステロールが増加することが報告されている(非特許文献5)。オクタコサノールは、脂質代謝に関連する以外にも、血小板凝集能低下作用(非特許文献6)、抗潰瘍作用(非特許文献7)、抗炎症作用(非特許文献8及び9)等の薬理活性を示すことが知られている。 Octacosanol (polycosanol) is a long-chain aliphatic alcohol contained in malt oil, rice bran oil, sugar cane, beeswax and the like (Non-patent Document 1). Octacosanol has various important biological activities such as antioxidant activity and tonic activity in addition to anti-Parkinson syndrome activity (Non-patent Document 2). Furthermore, it has been reported that a mixture of long-chain aliphatic alcohols containing octacosanol reduces the weight of adipose tissue (Non-Patent Document 3) and suppresses cholesterol synthesis (Non-Patent Document 4). Further, it has been reported that LDL cholesterol decreases and HDL cholesterol increases by octacosanol alone (Non-patent Document 5). In addition to being related to lipid metabolism, octacosanol exerts pharmacological activities such as platelet aggregation ability lowering action (Non-patent document 6), anti-ulcer action (Non-patent document 7), anti-inflammatory action (Non-patent documents 8 and 9) and the like. It is known to show.
絶えず変化する環境や仕事での要求は人のストレスの原因となるが、このような中で健康的な生活を維持することは、現代社会において大きな課題である。ストレスは睡眠障害(不眠症)の主な原因の1つである。不眠症は、一般人口の中の10〜15%の人が患っており、また高齢者人口でみると30〜60%の人が患っているといわれている、最も一般的な神経精神障害の1つである(非特許文献10)。不眠症は、身体状態、ホルモン状態および神経化学的な状態の異常に起因して起こる肥満、心疾患、抑うつ、注意欠陥等を含む他の疾病と密接につながる(非特許文献11)。不眠症は、交通事故、仕事量の減少による生産性の低下、及び治療のための医療コストの増加等につながり、社会に大きな経済的損失をもたらす。過去の評価では、不眠症の経済へ影響は、毎年60〜700億ドルといわれている(非特許文献12)。 The ever-changing environment and demands of work cause human stress, but maintaining a healthy life in such a situation is a major challenge in modern society. Stress is one of the main causes of sleep disorders (insomnia). Insomnia is the most common neuropsychiatric disorder that affects 10-15% of the general population and 30-60% of the elderly population. One (Non-Patent Document 10). Insomnia is closely linked to other diseases including obesity, heart disease, depression, attention deficit and the like caused by abnormal physical condition, hormonal condition and neurochemical condition (Non-patent Document 11). Insomnia leads to traffic accidents, a decrease in productivity due to a decrease in work, and an increase in medical costs for treatment, resulting in a great economic loss to society. According to past evaluations, it is said that the effect of insomnia on the economy is 6 to 70 billion dollars every year (Non-patent Document 12).
不眠症を治療する目的でベンゾジアゼピンのような化学合成剤が使用されるが(非特許文献13)、このような薬剤は、脳内でGABA活性を上昇させ、離脱症状等の副作用や依存症等の好ましくない効果を誘導することが知られている。また、このような化学合成剤によって誘導される睡眠は、自然な(生理的な)睡眠とは異なる(非特許文献13)。 A chemical synthetic agent such as benzodiazepine is used for the purpose of treating insomnia (Non-patent Document 13). Such a drug increases GABA activity in the brain and causes side effects such as withdrawal symptoms and dependence. It is known to induce undesired effects. Moreover, sleep induced by such a chemical synthesis agent is different from natural (physiological) sleep (Non-patent Document 13).
本発明の課題は、不眠症を治療するために現在使用される化学合成剤が有する副作用および薬物依存性等を回避した、睡眠充実作用を有する組成物を提供することを課題とする。また、ストレス下で生ずる睡眠時間の減少を回復させる作用を有し、かつ自然界に存在し、食品等にも含まれている化合物を有効成分とする、自然な(生理的な)睡眠を誘導する組成物を提供することを課題とする。 The subject of this invention makes it a subject to provide the composition which has the sleep enhancement effect which avoided the side effect, drug dependence, etc. which the chemical synthesis agent currently used in order to treat insomnia has. In addition, it induces natural (physiological) sleep that has the effect of recovering the decrease in sleep time caused by stress and that is present in nature and contains compounds that are also contained in foods and other active ingredients. It is an object to provide a composition.
本発明者は、鋭意研究を重ねたところ、オクタコサノールにストレス下の睡眠においてノンレム(NREM)睡眠時間を延長する作用、ノンレム睡眠及びレム(REM)睡眠の潜時を短縮する作用があることを見出した。さらにオクタコサノールによって誘導される睡眠が生理的な睡眠であることを見出した。 As a result of extensive research, the present inventor has found that octacosanol has an action of prolonging non-REM (NREM) sleep time in sleep under stress, and an action of shortening latency of non-REM sleep and REM (REM) sleep. It was. Furthermore, we found that sleep induced by octacosanol is physiological sleep.
本発明は、当該知見に基づいて完成されたものであり、以下の態様を含む。
項1.オクタコサノール、その薬学的に許容される塩、及びそれらの薬学的に許容される溶媒和物からなる群から選択される少なくとも一種の有効成分を含む、睡眠充実剤。
項2.有効成分がオクタコサノールである、項1に記載の睡眠充実剤。
項3.オクタコサノールが単離又は合成されたものである、項1又は2に記載の睡眠充実剤。
項4.ストレスを受けた個体に投与されるものである、項1〜3のいずれか一項に記載の睡眠充実剤。
項5.第一夜効果を相殺するものである、項1〜3のいずれか一項に記載の睡眠充実剤。
項6.医薬組成物、医薬部外品、又は飲食品組成物である、項1〜5のいずれか一項に記載の睡眠充実剤。
This invention is completed based on the said knowledge, and contains the following aspects.
Item 1. A sleep enhancer comprising at least one active ingredient selected from the group consisting of octacosanol, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates thereof.
Item 2. Item 2. The sleep enhancing agent according to Item 1, wherein the active ingredient is octacosanol.
Item 3. Item 3. The sleep enhancing agent according to item 1 or 2, wherein octacosanol is isolated or synthesized.
Item 4. Item 4. The sleep enhancing agent according to any one of Items 1 to 3, which is administered to an individual who has received stress.
Item 5. Item 4. The sleep enhancer according to any one of Items 1 to 3, which cancels out the first night effect.
Item 6. Item 6. The sleep enhancer according to any one of Items 1 to 5, which is a pharmaceutical composition, a quasi-drug, or a food or drink composition.
本発明によれば、ストレス下の睡眠において、ノンレム睡眠時間を延長することができ、またノンレム睡眠及びレム睡眠の潜時を短縮することができる。さらに、本発明によれば生理的な睡眠を誘導することができる。 According to the present invention, in sleep under stress, the non-REM sleep time can be extended, and the latency of non-REM sleep and REM sleep can be shortened. Furthermore, according to the present invention, physiological sleep can be induced.
1.用語の説明
初めに、本明細書において使用される用語について説明する。
1. Explanation of Terms First, terms used in this specification will be described.
本発明において、「睡眠充実」とは睡眠を充実させることをいい、好ましくは、(1)ストレス下で減少する睡眠時間を理想的な睡眠時間に近づける又は回復さること;(2)ストレス下でも寝付きをよくすること;(3)自然に覚醒すること;及び(4)睡眠中の脳波の周波数別出力密度分布が生理的な(自然な)睡眠に近似するか同等であること;から選択される少なくとも一種を含む。より好ましくは、(1)ストレス下で減少する睡眠時間を理想的な睡眠時間に近づける又は回復さること;及び(2)ストレス下でも寝付きをよくすることを含み、さらにより好ましくは、(1)ストレス下で減少する睡眠時間を理想的な睡眠時間に近づける又は回復さること;(2)ストレス下でも寝付きをよくすること;及び(3)自然に覚醒することを含み、最も好ましくは(1)ストレス下で減少する睡眠時間を理想的な睡眠時間に近づける又は回復さること;(2)ストレス下でも寝付きをよくすること;(3)自然に覚醒すること;及び(4)睡眠中の脳波の周波数別出力密度分布が生理的な睡眠に近似するか同等であることを含む。より具体的には、ストレス下において、一晩の睡眠における1回あたりのノンレム睡眠時間を延長させ、及び一晩あたりのノンレム睡眠時間の合計時間を増加させること、並びにノンレム睡眠及びレム睡眠の入眠潜時を短縮させることをいう。好ましくは、一晩の睡眠における1回あたりのノンレム睡眠時間を延長させ、及び一晩あたりのノンレム睡眠時間の合計時間を増加させ、並びにノンレム睡眠及びレム睡眠の入眠潜時を短縮させることにより第一夜効果を相殺し、第一夜効果により減少した睡眠時間を回復させ、生理的な睡眠をもたらすことを意味する。なお、好ましくは「睡眠充実」という文言には、眠りを深くすることは含まれない。 In the present invention, “enhanced sleep” refers to enhancing sleep, and preferably (1) bringing sleep time decreased under stress closer to or recovering from ideal sleep time; (2) even under stress Selected from: (3) Awakening naturally; and (4) EEG frequency density distribution during sleep approximates or is equivalent to physiological (natural) sleep. Including at least one kind. More preferably, including (1) approaching or recovering a sleep time that decreases under stress to an ideal sleep time; and (2) improving sleep well under stress, even more preferably (1) Approximate or restore ideal sleep time to a decrease in sleep time under stress; (2) improve sleep under stress; and (3) naturally awake, most preferably (1) Approaching or recovering from sleep time decreased under stress to ideal sleep time; (2) improving sleep even under stress; (3) naturally awakening; and (4) electroencephalogram during sleep. It includes that the output density distribution by frequency approximates or is equivalent to physiological sleep. More specifically, under stress, increasing the non-REM sleep time per time in the night sleep and increasing the total time of the non-REM sleep time per night, and the sleep of the non-REM sleep and the REM sleep. This means shortening the latency. Preferably, by increasing the non-REM sleep time per time in the overnight sleep, increasing the total non-REM sleep time per night, and reducing the sleep latency of the non-REM sleep and the REM sleep. It means that the overnight effect is offset, and the reduced sleep time is recovered by the first night effect, resulting in physiological sleep. Preferably, the phrase “enriched sleep” does not include deepening sleep.
理想的な睡眠は、個体がヒトである場合には、1エピソード(ノンレム睡眠の開始からレム睡眠の終了までの1サイクル)の時間が90〜120分程度(典型的には約90分)、この間のノンレム睡眠の合計時間は第1段階が5〜10%、第2段階が45〜55%、第3段階が15〜25%程度、及び、レム睡眠時間が20〜25%程度である。また、一夜当たりの総睡眠時間が8時間を超え、4〜6回の睡眠エピソードを含み、中途覚醒がない睡眠である。但し、異常な振動や音、外気温の変化等の刺激により、容易に自発的に覚醒できる睡眠である。 Ideal sleep is about 90 to 120 minutes (typically about 90 minutes) for one episode (one cycle from the start of non-REM sleep to the end of REM sleep) when the individual is a human being, The total time of non-REM sleep during this period is 5 to 10% in the first stage, 45 to 55% in the second stage, 15 to 25% in the third stage, and about 20 to 25% in the REM sleep time. In addition, the total sleep time per night exceeds 8 hours, includes 4 to 6 sleep episodes, and sleep without awakening. However, it is sleep that can be awakened easily and spontaneously by stimuli such as abnormal vibrations, sounds, and changes in outside air temperature.
一方、現代の日本人の一夜当たりの総睡眠時間は、10〜60代の男女1206人を対象としたアイシン精機による2014年度の調査によれば、平日では5時間未満が18.5%、5〜6時間が36.2%、6〜7時間が31.5%、7〜8時間が11.8%、8時間以上は2.1%であり、休日は5時間未満が4.2%、5〜6時間が15.8%、6〜7時間が29.9%、7〜8時間が30.0%、8時間以上は20.1%である。従って、平日は慢性的な睡眠不足であり、その不足を休日に補っている状況である。 On the other hand, according to a 2014 survey conducted by Aisin Seiki for 1206 men and women in their 10s and 60s, the total sleep time per night of modern Japanese is less than 5 hours on weekdays, 18.5%, 5 ~ 6 hours 36.2%, 6-7 hours 31.5%, 7-8 hours 11.8%, 8 hours or more 2.1%, holiday less than 5 hours 4.2% 5-6 hours 15.8%, 6-7 hours 29.9%, 7-8 hours 30.0%, 8 hours or more 20.1%. Therefore, weekdays are a chronic lack of sleep, and the lack is compensated for by holidays.
本発明において、「個体」は、特に制限されないが、個体にはヒト及びヒト以外の哺乳動物が含まれる。ヒト以外の哺乳動物としては、例えばウシ、ウマ、ヒツジ、ヤギ、ブタ、イヌ、ネコ、ウサギ、サル等が挙げられる。好ましくは、ヒト、ネコ、イヌ、ウサギ、ブタ、サルである。また、個体の年齢、性別は問わない。 In the present invention, the “individual” is not particularly limited, but the individual includes humans and non-human mammals. Examples of mammals other than humans include cattle, horses, sheep, goats, pigs, dogs, cats, rabbits, monkeys, and the like. Preferred are human, cat, dog, rabbit, pig and monkey. Moreover, the age and sex of an individual are not ask | required.
2.睡眠充実剤
本発明の睡眠充実剤は、オクタコサノール、その薬学的に許容される塩、及びそれらの薬学的に許容される溶媒和物からなる群から選択される少なくとも一種の有効成分を含む。
2. Sleep enhancer The sleep enhancer of the present invention comprises at least one active ingredient selected from the group consisting of octacosanol, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof.
本発明において、オクタコサノールは、1−オクタコサノールを意味し、好ましくはIUPAC名:オクタコサン−1−オール、又はCAS番号:557−61−9で表される化合物である。 In the present invention, octacosanol means 1-octacosanol, preferably a compound represented by IUPAC name: octacosan-1-ol, or CAS number: 557-61-9.
オクタコサノールの塩は、薬学的に許容される限り制限されない。例えば、アルミニウム塩、カルシウム塩、マグネシウム塩、鉄塩、リン酸塩等を挙げることができる。 The salt of octacosanol is not limited as long as it is pharmaceutically acceptable. For example, aluminum salt, calcium salt, magnesium salt, iron salt, phosphate, etc. can be mentioned.
また、オクタコサノール、又はオクタコサノールの薬学的に許容される塩と溶媒和物を形成する溶媒も、特に制限されない。例えば、例えば、エタノール、アセトン、1−プロパノール、2−プロパノール、酢酸エチル、ジエチルエーテル、又はこれらの混合物等を挙げることができる。好ましくはエタノール、1−プロパノール、2−プロパノール又はこれらの混合物である。 In addition, the solvent that forms solvate with octacosanol or a pharmaceutically acceptable salt of octacosanol is not particularly limited. For example, ethanol, acetone, 1-propanol, 2-propanol, ethyl acetate, diethyl ether, or a mixture thereof can be exemplified. Preferred is ethanol, 1-propanol, 2-propanol or a mixture thereof.
オクタコサノール、その薬学的に許容される塩、及びそれらの溶媒和物は、合成されたもの、単離されたもの、又は精製されたものであることが好ましい。 Octacosanol, pharmaceutically acceptable salts thereof, and solvates thereof are preferably synthesized, isolated, or purified.
また、本発明の睡眠充実剤は、睡眠を充実させるための唯一の有効成分としてオクタコサノール、その薬学的に許容される塩、及びそれらの薬学的に許容される溶媒和物からなる群から選択される少なくとも一種を含むことが好ましく、ユビデカレノン、アスタキサンチン、アスタキサンチンのエステル、黒ショウガ抽出物、魚油及、シールオイル、ポリフェノール、ガジュツ、グリフォニアシンプリシフォリア抽出物、アンドログラホリド等を含まない方がより好ましい。 The sleep enhancing agent of the present invention is selected from the group consisting of octacosanol, its pharmaceutically acceptable salt, and their pharmaceutically acceptable solvates as the only active ingredient for enhancing sleep. It is preferable to contain at least one kind of ubidecarenone, astaxanthin, ester of astaxanthin, black ginger extract, fish oil, seal oil, polyphenol, gadget, glyphonia simplicifolia extract, andrographolide, etc. preferable.
睡眠充実剤の投与量は、マウスの投与量から換算することができる。マウスにおける投与量がオクタコサノールに換算して1回当たり50〜300mg/kg程度であるため、他の動物に関しては、マウスの投与量から公知の方法に従って体重又は体表面積に応じて算出することができる。例えば、ヒトの場合の睡眠充実剤の1回当たりの最大投与量は、オクタコサノールに換算して5,000mg/kg、好ましくは1,000mg/kg、より好ましくは500mg/kg、さらに好ましくは300mg/kgである。睡眠充実剤の1回当たりの最小投与量は、オクタコサノールに換算して50mg/kg、好ましくは100mg/kg、より好ましくは300mg/kgである。 The dose of the sleep enhancing agent can be converted from the dose of the mouse. Since the dose in mice is about 50 to 300 mg / kg in terms of octacosanol, it can be calculated for other animals according to body weight or body surface area from the mouse dose according to a known method. . For example, the maximum dose of sleep enhancer per person for humans is 5,000 mg / kg, preferably 1,000 mg / kg, more preferably 500 mg / kg, still more preferably 300 mg / kg in terms of octacosanol. kg. The minimum dose of sleep enhancer per dose is 50 mg / kg, preferably 100 mg / kg, more preferably 300 mg / kg in terms of octacosanol.
睡眠充実剤の投与は、就寝前30以内、好ましくは10分以内、さらに好ましく就寝直前に行うことができる。投与回数は、1日に1回であるが、必要に応じて就寝後1エピソード終了時、又は2エピソード終了時等、睡眠時間帯の途中の覚醒時に再度投与しても良い。睡眠充実剤の投与は、毎日行ってもよいが、ストレス時又は外泊時等の必要時にのみ投与してもよい。 Administration of the sleep enhancing agent can be performed within 30 minutes before bedtime, preferably within 10 minutes, and more preferably immediately before bedtime. The number of administrations is once a day, but may be administered again at the time of awakening during the sleep period, such as at the end of one episode after bedtime or at the end of two episodes, if necessary. Administration of the sleep enhancing agent may be performed every day, but may be administered only when necessary, such as during stress or at night.
睡眠充実剤は、経口投与、筋肉注射、皮下注射、及び/又は血管内投与等により投与することができる。 The sleep enhancing agent can be administered by oral administration, intramuscular injection, subcutaneous injection, and / or intravascular administration.
睡眠充実剤は、有効成分と適当な製剤用の担体又は添加剤を組み合わせて調製することができる。当該製剤の調製に用いられる担体や添加剤としては、製剤の剤形に応じて通常の薬剤に汎用される各種のもの、例えば賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味剤、矯臭剤、界面活性剤等を例示できる。 The sleep enhancing agent can be prepared by combining an active ingredient and an appropriate pharmaceutical carrier or additive. Carriers and additives used for the preparation of the preparation include various types commonly used for ordinary drugs according to the dosage form of the preparation, such as excipients, binders, disintegrants, lubricants, colorants, Examples include flavoring agents, flavoring agents, and surfactants.
上記配合剤又は製剤が経口投与されるもの(舌下に投与されるものを含む)である場合の剤形は、特に制限されないが、錠剤、散剤、顆粒剤、カプセル剤(硬質カプセル剤及び軟質カプセル剤を含む)、液剤、丸剤、懸濁剤、ゼリー製剤、及び乳剤等を例示できる。また上記配合剤又は製剤が、非経口投与されるものである場合には、注射剤、点滴剤、坐剤、点鼻剤、及び経肺投与剤等を例示できる。 The dosage form in the case where the above combination preparation or preparation is orally administered (including those administered sublingually) is not particularly limited, but tablets, powders, granules, capsules (hard capsules and soft capsules) (Including capsules), liquids, pills, suspensions, jelly preparations, and emulsions. Moreover, when the said compounding agent or formulation is administered parenterally, an injection, an instillation, a suppository, a nasal drop, a transpulmonary administration etc. can be illustrated.
上記配合剤又は製剤が、錠剤、散剤、顆粒剤、丸剤、カプセル剤等の経口用固形製剤である場合の調製に際しては、担体として例えば乳糖、白糖、塩化ナトリウム、ブドウ糖、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸、メチルセルロース、グリセリン、アルギン酸ナトリウム、アラビアゴム等の賦形剤;単シロップ、プドウ糖液、デンプン液、ゼラチン溶液、ポリビニルアルコール、ポリビニルエーテル、ポリビニルピロリドン、カルボキシメチルセルロース、セラック、メチルセルロース、エチルセルロース、水、エタノール、リン酸カリウム等の結合剤;乾燥デンプン、アルギン酸ナトリウム、カンテン末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン、乳糖等の崩壊剤;白糖、ステアリン酸、カカオバター、水素添加油等の崩壊抑制剤;ラウリル硫酸ナトリウム等の吸収促進剤;グリセリン、デンプン等の保湿剤;デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤;精製タルク、ステアリン酸塩、ホウ酸末、ポリエチレングリコール等の滑沢剤等を使用できる。 When the above combination or preparation is an oral solid preparation such as a tablet, powder, granule, pill, capsule, etc., as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, carbonate Excipients such as calcium, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, gum arabic; simple syrup, puddle sugar solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, Binders such as shellac, methylcellulose, ethylcellulose, water, ethanol, potassium phosphate; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester Disintegrators such as sucrose, sodium lauryl sulfate, monoglyceride stearate, starch, lactose; disintegration inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil; absorption promoters such as sodium lauryl sulfate; glycerin, starch, etc. Moisturizers; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid; lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol can be used.
ここで錠剤には、内服錠(裸錠、糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠、二重錠、多層錠など)、チュアブル錠(口腔内で咀嚼しながら摂取するものを含む)、口中錠(トローチ等のように口腔内で溶解させたなら摂取するものを含む)、舌下錠、及びバッカル錠が含まれる。 Here, internal tablets (bare tablets, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets, etc.) and chewable tablets (things to be ingested while being chewed in the oral cavity) ), Oral tablets (including those taken if dissolved in the oral cavity such as troches), sublingual tablets, and buccal tablets.
上記配合剤又は製剤が、丸剤の経口用固形製剤である場合の調製に際しては、担体として、例えばブドウ糖、乳糖、デンプン、カカオ脂、硬化植物油、カオリン、タルク等の賦形剤;アラビアゴム末、トラガント末、ゼラチン等の結合剤;ラミナラン、カンテン等の崩壊剤等を使用できる。 In the case where the compounding agent or preparation is an oral solid preparation of pills, as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc; Binders such as tragacanth powder and gelatin; disintegrating agents such as laminaran and agar can be used.
上記配合剤又は製剤が、カプセル剤の経口用固形製剤である場合の調製に際しては、カプセル剤は有効成分を上記で例示した各種の担体と混合し、硬質カプセル、又は軟質カプセル等に充填して調製される。 In the case where the compounding agent or preparation is an oral solid preparation of a capsule, the capsule is mixed with various carriers exemplified above and filled into a hard capsule or a soft capsule. Prepared.
上記配合剤又は製剤が液剤の場合には、液状を有していればよく、水性又は油性の懸濁液、溶液、シロップ、エリキシル剤、ドリンク剤であってもよい。液剤は通常の添加剤を用いて常法に従い、調製される。また液剤を充填する容器は、密閉できるものであれば制限されず、ガラス容器、アルミ製容器、及びプラスチック製容器であってもよい。 When the compounding agent or preparation is a liquid, it may be liquid, and may be an aqueous or oily suspension, solution, syrup, elixir, or drink. The liquid preparation is prepared according to a conventional method using ordinary additives. The container filled with the liquid agent is not limited as long as it can be sealed, and may be a glass container, an aluminum container, and a plastic container.
上記配合剤又は製剤が注射剤の場合の調製に際しては、担体として例えば水、エチルアルコール、マクロゴール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等の希釈剤;クエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウム等のpH調整剤;リン酸二カリウム、リン酸三ナトリウム、リン酸水素ナトリウム、クエン酸ナトリウム等の緩衝剤;ピロ亜硫酸ナトリウム、EDTA、チオグリコール酸、チオ乳酸等の安定化剤;凍結乾燥した際の成形剤として例えばマンニトール、イノシトール、マルトース、シュクロース、ラクトース等の糖類を使用できる。なお、この場合等張性の溶液を調整するに十分な量のブドウ糖或いはグリセリンを医薬製剤中に含有せしめてもよく、また通常の溶解補助剤、無痛化剤、局所麻酔剤等を添加しても良い。これらの担体を添加して、常法により皮下、筋肉内、静脈内用注射剤を製造することができる。 In preparation when the above combination or preparation is an injection, carriers such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. Diluent; pH adjuster such as sodium citrate, sodium acetate, sodium phosphate; buffer such as dipotassium phosphate, trisodium phosphate, sodium hydrogen phosphate, sodium citrate; sodium pyrosulfite, EDTA, thioglycol Stabilizers such as acid and thiolactic acid; saccharides such as mannitol, inositol, maltose, sucrose, and lactose can be used as a molding agent when freeze-dried. In this case, a sufficient amount of glucose or glycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, soothing agent, local anesthetic, etc. may be added. Also good. By adding these carriers, subcutaneous, intramuscular and intravenous injections can be produced by conventional methods.
上記配合剤又は製剤が点滴剤の場合には、投与化合物を生理食塩水、リンゲル液等を基本とした等張電解質輸液製剤に溶解して調製することができる。 When the compounding agent or preparation is an infusion, it can be prepared by dissolving the administration compound in an isotonic electrolyte infusion preparation based on physiological saline, Ringer's solution or the like.
3.医薬組成物、医薬部外品、及び飲食品組成物
本発明の睡眠充実剤は、医薬組成物、又は医薬部外品として使用することができる。各組成物の投与量、投与方法、及び製剤形態は、上記2.の説明に準ずる。
3. Pharmaceutical composition, quasi-drug, and food and beverage composition The sleep enhancer of the present invention can be used as a pharmaceutical composition or a quasi-drug. The dosage, administration method, and formulation of each composition are as described in 2. above. According to the explanation.
また、本発明の睡眠充実剤は、飲食品組成物として使用することができる。 Moreover, the sleep enhancing agent of this invention can be used as a food-drinks composition.
本態様の飲食品組成物には、一般食品、保健機能食品(機能性表示食品、栄養機能食品、特定保健用食品)が含まれる。保健機能食品の定義及び分類は、日本の健康増進法、及び食品衛生法に定めるところによる。 The food / beverage composition of this embodiment includes general foods, health functional foods (functional display foods, nutritional functional foods, foods for specified health use). The definition and classification of functional health foods are as stipulated in the Japanese Health Promotion Law and the Food Sanitation Law.
本態様の飲食品組成物には、ペット(イヌ、ネコ、ウサギ、ブタなど)に対する飲食品(ペットフード)に対する飲食品(飼料組成物)も含まれる。 The food / beverage product composition of this embodiment also includes a food / beverage product (feed composition) for a food / beverage product (pet food) for a pet (dog, cat, rabbit, pig, etc.).
なお、各国の国内法において、飲食品組成物に疾患との関係を表示することが禁じられている場合には、上記用途の表示を国内法に抵触しない表示に変更することができる。例えば、ストレス、緊張、又は考え事で眠れないときに;寝具(特に枕)がかわって眠れないときに、等の表現や睡眠期間の回復を連想させるイラスト等を付して用途を表示することができる。 In addition, when the domestic law of each country prohibits the display of the relationship with the disease in the food and beverage composition, the display of the above use can be changed to a display that does not conflict with the domestic law. For example, when you cannot sleep due to stress, tension, or thinking; when you cannot sleep due to bedding (especially pillows), you can display the usage with an expression that reminds you of the recovery of the sleep period, etc. it can.
本態様の飲食品組成物としては、特に制限されることはないが、例えば飲料(例:乳飲料、乳酸菌飲料、果汁入り清涼飲料、炭酸飲料、果汁飲料、野菜飲料、野菜・果実飲料、アルコール飲料、スポーツ飲料、粉末飲料、茶飲料など)、冷菓(例:ゼリー、ババロア、プリンなど)、氷菓(例:アイスクリーム、アイスミルク、ラクトアイス、シャーベット)、菓子類(例:クッキー、ビスケット、おかき、飴類、チョコレート類、ガム類)、パン類、麺類(例:中華麺、パスタ、うどん、蕎麦、素麺)、スープ類(粉末または固形スープを含む)、調味料(例:ドレッシング、ジュレ、ソース、マヨネーズ様ソース、たれ)などを挙げることができる。 Although it does not restrict | limit especially as the food-drinks composition of this aspect, For example, a drink (Example: Milk drink, lactic acid bacteria drink, soft drink containing fruit juice, carbonated drink, fruit juice drink, vegetable drink, vegetable and fruit drink, alcohol Beverages, sports drinks, powdered drinks, tea drinks, etc.), frozen desserts (eg jelly, bavaroa, pudding etc.), ice confections (eg ice cream, ice milk, lacto ice, sorbet), confectionery (eg cookies, biscuits, rice cakes) , Rice cakes, chocolates, gums), breads, noodles (eg Chinese noodles, pasta, udon, buckwheat noodles, soup noodles), soups (including powder or solid soup), seasonings (eg dressing, jelly, Source, mayonnaise-like sauce, sauce).
また本発明の飲食品組成物は、上記形態を有する飲食品の他に、サプリメント形態の飲食品組成物、及び病者用食品(要介護者用食品、及び嚥下困難者用食品を含む)を含む。このようなサプリメント形態の飲食品組成物や病者用食品として調製する場合、継続的な摂取が容易にできるように、上記2.に記載に記載されている剤形のうち、例えば、液剤(ドリンク剤)、シロップ剤、ドライシロップ剤、ゼリー製剤(用時調製用のものを含む。以下同じ)、顆粒剤、散剤、丸剤、錠剤、カプセル剤(硬カプセル剤、軟カプセル剤)、トローチ剤、チュアブル剤等の製剤形態に調製することが好ましい。好ましくは、液剤(ドリンク剤)、ゼリー製剤、顆粒剤、錠剤、カプセル剤(硬カプセル剤、軟カプセル剤)であり、より好ましくは液剤(ドリンク剤)、ゼリー製剤である。 Moreover, the food / beverage product composition of the present invention includes, in addition to the food / beverage products having the above-mentioned form, a food / beverage product composition in a supplement form, and foods for the sick (including foods for care recipients and foods for persons with difficulty swallowing). Including. When preparing as a supplement-type food / beverage composition or a food for a sick person, the above 2. Among the dosage forms described in the above, for example, liquids (drinks), syrups, dry syrups, jelly preparations (including those prepared at the time of use; the same applies hereinafter), granules, powders, pills, It is preferable to prepare in the form of a tablet, capsule (hard capsule, soft capsule), troche, chewable and the like. Preferred are liquid agents (drinks), jelly preparations, granules, tablets, capsules (hard capsules, soft capsules), and more preferred are liquids (drinks) and jelly preparations.
以下に、実施例を示して本発明をより詳細に説明するが、本発明は実施例に限定して解釈されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not construed as being limited to the examples.
1.材料と方法
(1)動物
実験には、体重24〜30g(11〜13週齢)のオスのC57BL/6マウス(日本エスエルシー株式会社;浜松、日本)を使用した。マウスは、自動的に制御された12時間毎の明期/暗期サイクル(照明の点灯は朝5時、100 lux以上の照明強度)で、50±5%の相対湿度、及び23±0.5℃の周囲温度に維持された、隔絶された通常の遮音録音室で飼育した。食物と水は自由に摂取させた。実験のプロトコルは、(公財)大阪バイオサイエンス研究所動物実験倫理委員会によって承認されたものである。また、不要な疼痛および不快を動物に与えないように努力し、使用する動物の数を最小限とするよう努力した。
1. Materials and Methods (1) Animals For the experiments, male C57BL / 6 mice (Japan SLC, Inc .; Hamamatsu, Japan) weighing 24-30 g (11-13 weeks old) were used. Mice are automatically controlled every 12 hours of light / dark cycle (lights on at 5:00 am, light intensity above 100 lux), 50 ± 5% relative humidity, and 23 ± 0.5 ° C Reared in a normal isolated sound insulation recording room maintained at ambient temperature. Food and water were given ad libitum. The experimental protocol was approved by the Osaka Bioscience Institute Animal Experimentation Ethics Committee. Efforts were also made to keep animals from unnecessary pain and discomfort and to minimize the number of animals used.
(2)自発運動
個々のマウスの自発運動(Locomotor Activity:LMA)は、記録室の床の25 cm上に設置した、パッシブ赤外線方式センサー(バイオテックス日本;京都、日本)を使用して記録した。また、移動のカウントは1分毎にコンピューターに送り、マルチチャンネルカウンターユニット(ACT Monitor BA-2216(バイオテックス日本)で解析した。マウスを、個別にチャンバー内に置き、少なくとも3日間馴化したあと、薬学試験に供した。
(2) Spontaneous movement Spontaneous movement (Locomotor Activity: LMA) of individual mice was recorded using a passive infrared sensor (Biotex Japan; Kyoto, Japan) installed 25 cm above the floor of the recording room. . In addition, movement counts were sent to the computer every minute and analyzed with a multichannel counter unit (ACT Monitor BA-2216 (Biotex Japan). After placing the mice individually in the chamber and acclimatizing for at least 3 days, It was subjected to a pharmaceutical test.
(3)手術
ペントバルビタール(50 mg/kg腹腔内投与)の麻酔の下で、Kaushik et al (Exp Neurol 253: 82-90, 2014)に記載の方法に従って、マウスに睡眠ポリグラフィー検査用の脳波(EEG)電極、及び筋電図(EMG)電極を留置装着した。簡単に説明すると、EEG電極はマウスの頭蓋骨に埋め込んだ2本のステンレススチールねじ(直径1 mm)を使用した。片方のステンレススチールねじを、右前頭皮質(ブレグマの1.0 mm前部、及び1.5 mm外側)の硬膜外に留置し、もう一方を右頭骨頭頂部皮質(ラムダの1.0 mm前部、及び1.5 mm外側)の硬膜外に留置した。EMG電極は、絶縁された2本のステンレススチール製のテフロンコーティングされたワイヤー(直径0.2 mm)であり、僧帽筋の両側に留置した。EEG電極およびEMG電極は双方ともミクロコネクターに接続した。その後、電極を自己硬化性歯科用アクリル樹脂で頭蓋に固定した。抗生物質および鎮痛薬は、手術後5日まで投与した。
(3) Surgery Under anesthesia with pentobarbital (50 mg / kg ip), mice were subjected to electroencephalogram for polysomnography according to the method described in Kaushik et al (Exp Neurol 253: 82-90, 2014). An (EEG) electrode and an electromyogram (EMG) electrode were placed in place. Briefly, the EEG electrode used two stainless steel screws (diameter 1 mm) embedded in the mouse skull. Place one stainless steel screw epidurally in the right frontal cortex (1.0 mm anterior to the bregma and 1.5 mm outside) and the other to the right parietal parietal cortex (1.0 mm anterior to the lambda and 1.5 mm) It was placed outside the outer dura mater. The EMG electrodes were two insulated Teflon-coated wires (diameter 0.2 mm) made of stainless steel and placed on both sides of the trapezius muscle. Both EEG and EMG electrodes were connected to microconnectors. Thereafter, the electrode was fixed to the skull with a self-curing dental acrylic resin. Antibiotics and analgesics were administered up to 5 days after surgery.
(4)EEG及びEMG記録、及び解析
マウスを8〜10日間術後回復させた後、4日間の習慣化/順化のため実験用ケージに移し、平衡錘付き記録リード線(counterbalanced recording leads)と接続した。
(4) EEG and EMG recording and analysis After mice have been recovered for 8-10 days post-operatively, they were transferred to an experimental cage for 4 days of habituation / acclimation and counterbalanced recording leads And connected.
EEG及びEMGの記録を行う全てのマウスは異なった日にビヒクル及び様々な用量の薬剤の投与を受け、いずれか2種の薬剤の投与を行う場合、少なくとも2日間あけて行った。EEG及びEMGの記録、並びに薬剤の投与はそれぞれ暗期の開始時(17時)に行った。皮質のEEG及びEMG信号は増幅処理及びフィルタリング処理(EEG:0.5〜30Hz; EMG:20〜200Hz)を行った後、128Hzのサンプリングレートでデジタル化し、Kohtoh et al(Sleep Biol. Rhythms 6: 163-171, 2008)で報告されたSleepSignソフトウェア(キッセイコムテック株式会社;長野、日本)を使用して記録した。 All mice performing EEG and EMG recordings received vehicle and various doses of drug on different days, with at least 2 days between administration of any two drugs. EEG and EMG recordings and drug administration were performed at the beginning of the dark period (17:00), respectively. Cortical EEG and EMG signals are amplified and filtered (EEG: 0.5-30 Hz; EMG: 20-200 Hz), then digitized at a sampling rate of 128 Hz, and Kohtoh et al (Sleep Biol. Rhythms 6: 163- 171, 2008) and recorded using SleepSign software (Kissei Comtech Co., Ltd .; Nagano, Japan).
睡眠ポリグラフィー検査の記録データは、覚醒、REM睡眠、NREM睡眠について10秒エポックで、Huang et al(Proc Natl Acad Sci U S A 98: 9965-9970, 2001)及びKohtoh et alに記載の標準クライテリアを使用してSleepSignソフトウェアによって、オフラインで、自動分析法でスコアリングした。スコアリングにより規定された睡眠覚醒段階は、必要に応じて目視で観察し、修正した。EEGのスペクトル解析は、高速フーリエ変換(FFT)によって行った。また、各0.5 Hzの範囲毎のEEG出力密度は、総出力(0.5〜35Hz)の合計に対する各範囲のパーセンテージを計算することにより平均化した。 Recorded polysomnography data is a 10-second epoch for wakefulness, REM sleep, and NREM sleep, using standard criteria as described in Huang et al (Proc Natl Acad Sci USA 98: 9965-9970, 2001) and Kohtoh et al. Then, with the SleepSign software, it was scored offline and with automated analysis. The sleep-wake stage defined by scoring was visually observed and corrected as necessary. The spectrum analysis of EEG was performed by fast Fourier transform (FFT). Also, the EEG power density for each 0.5 Hz range was averaged by calculating the percentage of each range relative to the total total power (0.5-35 Hz).
(5)薬剤処理
オクタコサノール(シグマ・アルドリッチ)は100mg/kg又は200mg/kgの濃度でマウスに経口投与した。オクタコサノールは、20% Vit-E TPGS(D-α-トコフェロール ポリエチレングリコール1000コハク酸エステル)に懸濁した。Vit-E TPGS 20gを、75mlの蒸留水に加えオーバーナイトで穏やかに加熱しながらマグネチックスターラーで撹拌して溶解し、溶解後最終体積を100mlに合わせた。20% Vit-E TPGSをビヒクルとした。オクタコサノールは、使用直前にビヒクルに懸濁し、使い捨ての1mlの注射器および強制給餌針(0.9mmの直径)を使って10ml/kgとなるように経口投与した。ビヒクルも同様に投与した。投与と同時に、動物を収容しているケージは、覚醒状態を増加させるために新鮮な床敷きおよび食物がある新しいケージに交換した。
(5) Drug treatment Octacosanol (Sigma-Aldrich) was orally administered to mice at a concentration of 100 mg / kg or 200 mg / kg. Octacosanol was suspended in 20% Vit-E TPGS (D-α-tocopherol polyethylene glycol 1000 succinate). 20 g of Vit-E TPGS was dissolved in 75 ml of distilled water by stirring with a magnetic stirrer while gently heating overnight, and the final volume was adjusted to 100 ml after dissolution. 20% Vit-E TPGS was used as the vehicle. Octacosanol was suspended in the vehicle just before use and was orally administered to 10 ml / kg using a disposable 1 ml syringe and a forced feeding needle (0.9 mm diameter). Vehicle was administered similarly. Concurrently with administration, the cage containing the animals was replaced with a new cage with fresh bedding and food to increase wakefulness.
(6)統計分析
データはすべて平均値±SEで表した。自発運動のタイムコースデータ、睡眠覚醒プロファイル、睡眠覚醒出現(発作)の回数、出現継続時間、段階移行、NREM睡眠段階の持続時間の分布およびEEG出力密度は、対応のあるt検定(paired t-test)、または対応のないt検定(unpaired t-test)によって統計学的な有意差を求めた。自発運動、NREM睡眠、REM睡眠、覚醒の量に対する用量依存的な影響を評価するために、一元配置分散分析により有意差を求め、Scheffeの方法のpost-hoc比較によって検定した。全ての統計解析において、p<0.05を有意差有りと判断した。
(6) Statistical analysis All data were expressed as mean ± SE. Time course data of locomotor activity, sleep-wake profile, number of sleep-wake appearances (seizures), appearance duration, stage transition, NREM sleep stage duration distribution and EEG power density are paired t-tests. test), or unpaired t-test, statistically significant differences were determined. To evaluate dose-dependent effects on locomotor activity, NREM sleep, REM sleep, and wakefulness, significant differences were determined by one-way analysis of variance and tested by Scheffe's method post-hoc comparison. In all statistical analyses, p <0.05 was considered significant.
2.実験例1:正常なマウスにおけるオクタコサノールの睡眠誘導効果
オクタコサノール(200mg/kg)又はビヒクルを、暗期の開始時(17時)にマウスに経口投与し、経口投与から24時間睡眠を観察した。オクタコサノール投与群とビヒクル投与群の間には、NREM睡眠、REM睡眠及び覚醒の時間的経過には変化が認められなかった。この結果は、オクタコサノールが正常状態の睡眠には影響しないことを示唆していると考えられた。
2. Experimental Example 1: Octacosanol sleep-inducing effect in normal mice Octacosanol (200 mg / kg) or vehicle was orally administered to mice at the start of the dark period (17:00), and sleep was observed for 24 hours after oral administration. There was no change in the time course of NREM sleep, REM sleep, and arousal between the octacosanol-administered group and the vehicle-administered group. This result was thought to suggest that octacosanol does not affect normal sleep.
3.実験例2:LMAに対するオクタコサノールの効果
持続的な1時間以上の覚醒を誘導するため、新しいケージにマウスを移すケージ交換実験を行った。非特許文献13に記載のされているように、動物を新しいケージに移すと周囲を警戒するための軽度な興奮状態に起因する穏やかなストレスを引き起し、第一夜効果と呼ばれる睡眠障害(覚醒増加に伴う睡眠減少)が現れる。オクタコサノール(100、又は200mg/kg)、又はビヒクルを投与しケージを交換し、経口投与後2時間の間10分間隔でLMAを記録した。
3. Experimental Example 2: Effect of octacosanol on LMA A cage exchange experiment was carried out in which mice were transferred to a new cage in order to induce sustained arousal over 1 hour. As described in Non-Patent Document 13, when an animal is moved to a new cage, it causes a mild stress caused by a mild excitement state to watch out for the surroundings, and a sleep disorder called a first night effect ( A decrease in sleep with increased awakening) appears. Octacosanol (100 or 200 mg / kg) or vehicle was administered and the cage was changed, and LMA was recorded at 10 minute intervals for 2 hours after oral administration.
その結果、図2に示すようにオクタコサノール100mg/kg(灰色の丸)投与群、及びオクタコサノール200mg/kg(黒丸)は、ビヒクル投与群(白丸)と比較して投与後70分間のLMAが有意に減少した。また、オクタコサノール投与量に依存して、LMAが減少した。LMAは、睡眠の量に反比例するため、オクタコサノールによるLMAの減少により、睡眠量が増加する可能性が示唆された。 As a result, as shown in FIG. 2, the LMA at 70 minutes after administration was significantly higher in the octacosanol 100 mg / kg (grey circle) administration group and the octacosanol 200 mg / kg (black circle) compared to the vehicle administration group (white circle). Diminished. In addition, LMA decreased depending on the dose of octacosanol. Since LMA is inversely proportional to the amount of sleep, it was suggested that the decrease in LMA by octacosanol may increase sleep.
4.実験例3:NREM睡眠時間に対するオクタコサノールの効果
次にケージ交換実験を利用して、NREM睡眠時間、REM睡眠時間、又は覚醒時間に対するオクタコサノールの効果を評価した。マウスにオクタコサノール100mg/kg、オクタコサノール200mg/kg又はビヒクル(白丸)をそれぞれ投与した後、各群の1時間あたりのNREM睡眠時間、REM睡眠時間、又は覚醒時間を1時間毎にプロットした。図3Aに示すように、タイムコースによる評価では、オクタコサノール投与群では、ビヒクル投与群と比較して、投与時から投与後5時間までの間におけるNREM睡眠時間が有意に増加した。一方、図3Bに示すように、各単位時間当たりのREM睡眠のタイムコースによる評価では、オクタコサノール投与群とビヒクル投与群の間で有意な差は認められなかった。そして、NREM睡眠時間の増加に伴い、オクタコサノール投与群では覚醒時間が有意に減少した(図3C)。
4). Experimental Example 3: Effect of octacosanol on NREM sleep time Next, cage exchange experiments were used to evaluate the effect of octacosanol on NREM sleep time, REM sleep time, or awakening time. After mice were given 100 mg / kg of octacosanol, 200 mg / kg of octacosanol or vehicle (white circle), NREM sleep time, REM sleep time, or wake-up time per hour for each group was plotted every hour. As shown in FIG. 3A, in the time course evaluation, the NREM sleep time in the octacosanol administration group was significantly increased from the time of administration to 5 hours after administration, as compared to the vehicle administration group. On the other hand, as shown in FIG. 3B, no significant difference was observed between the octacosanol administration group and the vehicle administration group in the evaluation based on the time course of REM sleep per unit time. As the NREM sleep time increased, the awakening time significantly decreased in the octacosanol administration group (FIG. 3C).
図3Dに示すように、薬剤投与時から5時間以内のNREM睡眠時間の合計が、ビヒクル投与群では21.2±6.7分であったのに対して、オクタコサノール100mg/kg投与群では75.7±14.9分であり、オクタコサノール200mg/kg投与群では82.7±9.3分であり、ビヒクル投与群と比較してオクタコサノール投与群では、NREM睡眠時間の合計が有意に増加した。また、オクタコサノールの投与量が多いほどNREM睡眠時間が長くなることが示された。これに付随して、薬剤投与時から5時間以内の覚醒時間の合計は、ビヒクル投与群が278.4±6.9分であるのに対して、オクタコサノール100mg/kg投与群では219.2±15.8分であり、オクタコサノール200mg/kg投与群では213.0±9.7分となり、オクタコサノール投与群で有意に減少した。このことは、NREM睡眠時間の増加に伴って覚醒時間が減少したことを示していると考えられた。 As shown in FIG. 3D, the total NREM sleep time within 5 hours from the time of drug administration was 21.2 ± 6.7 minutes in the vehicle administration group, compared with 75.7 ± 14.9 minutes in the octacosanol 100 mg / kg administration group. Yes, it was 82.7 ± 9.3 minutes in the octacosanol 200 mg / kg administration group, and the total NREM sleep time was significantly increased in the octacosanol administration group compared to the vehicle administration group. Moreover, it was shown that NREM sleep time becomes longer as the dose of octacosanol increases. Concomitantly, the total awakening time within 5 hours from the time of drug administration is 278.4 ± 6.9 minutes in the vehicle administration group, and 219.2 ± 15.8 minutes in the octacosanol 100 mg / kg administration group. It was 213.0 ± 9.7 minutes in the 200 mg / kg administration group, and decreased significantly in the octacosanol administration group. This was considered to indicate that the awakening time decreased with increasing NREM sleep time.
また、薬剤投与時から5時間以内のREM睡眠時間の合計は、ビヒクル投与群が0.4±0.3分であるのに対して、オクタコサノール100mg/kg投与群では5.0±1.1分となり、オクタコサノール200mg/kg投与群では4.2±0.6分となり、顕著に増加していた。 The total REM sleep time within 5 hours from the time of drug administration is 0.4 ± 0.3 minutes in the vehicle administration group, but 5.0 ± 1.1 minutes in the octacosanol 100 mg / kg administration group, and octacosanol 200 mg / kg administration. In the group, it was 4.2 ± 0.6 minutes, showing a significant increase.
これらの結果は、オクタコサノールにはストレス下で誘導される睡眠障害を改善する効果があることを示していると考えられる。 These results are considered to indicate that octacosanol has an effect of improving sleep disturbance induced under stress.
さらに、オクタコサノールによって誘発される睡眠の質を確認するためにEEGの出力密度を測定した(図3E)。暗期6時間のEEGの出力密度は、オクタコサノール200mg/kg投与群及びビヒクル投与群の間に差は認められなかった。このことから、オクタコサノールによって誘導される睡眠の質は、自然な睡眠、すなわち生理的な睡眠の質と同等であることが示された。 In addition, EEG power density was measured to confirm the sleep quality induced by octacosanol (FIG. 3E). There was no difference in EEG power density during the dark period of 6 hours between the octacosanol 200 mg / kg administration group and the vehicle administration group. This indicates that the sleep quality induced by octacosanol is equivalent to natural sleep, that is, physiological sleep quality.
また、オクタコサノールを400mg/kg投与した群についても検討したが、昏睡等の副作用は現れなかった。 Moreover, although the group which administered octacosanol 400mg / kg was also examined, side effects, such as a coma, did not appear.
5.実験例4:睡眠潜時に対するオクタコサノールの効果
オクタコサノール又はビヒクルの投与後、最初にNREM睡眠が現れた時間から睡眠潜時を算出した。ビヒクル投与群では睡眠潜時が117±38.06分であるのに対して、オクタコサノール100mg/kg投与群では36.10±4.15分であり、オクタコサノール200mg/kg投与群では28.50 ±1.81であり、ビヒクル投与群と比較して顕著に睡眠潜時が減少していた(図4)。また、図4に示すようにREM睡眠出現までの潜時も同様に減少した。
5. Experimental Example 4: Effect of Octacosanol on Sleep Latency After administration of octacosanol or vehicle, sleep latency was calculated from the time when NREM sleep first appeared. The sleep latency in the vehicle-administered group was 117 ± 38.06 minutes, compared to 36.10 ± 4.15 minutes in the octacosanol 100 mg / kg group, and 28.50 ± 1.81 in the octacosanol 200 mg / kg group. In comparison, the sleep latency was significantly reduced (FIG. 4). Moreover, as shown in FIG. 4, the latency until the appearance of REM sleep similarly decreased.
EEGパターン、及び睡眠構造の観察では異常は認められず、睡眠の反跳又は睡眠不足は、オクタコサノールによるNREM睡眠の増加効果が観察されてから24時間の観察では認められなかった。つまり、従来の睡眠作用を有する化学合成剤に見られる昏睡や過眠等の副作用は認められず、マウスが自然に覚醒していることが示唆された。周囲を警戒するための覚醒は障害されていないと考えられた。 No abnormalities were observed in the observation of the EEG pattern and sleep structure, and sleep recoil or sleep deprivation was not observed in the 24-hour observation after the effect of increasing NREM sleep by octacosanol was observed. That is, side effects such as coma and hypersomnia found in conventional chemical synthetic agents having a sleep action were not observed, suggesting that the mice were naturally awake. Awakening to guard the surroundings was considered unhindered.
6.オクタコサノールが睡眠構造に与える影響
睡眠−覚醒構造、及び質を各段階の出現回数、各段階の出現持続時間、段階移行、NREM睡眠段階の持続時間の分布を計算することによって評価した。
6). Effects of Octacosanol on Sleep Structure Sleep-wake structure and quality were evaluated by calculating the number of appearances of each stage, the duration of each stage, the stage transition, and the distribution of the duration of the NREM sleep stage.
図5Aに示すように、ビヒクル又はオクタコサノールの投与開始から6時間まで観察したところ、ビヒクル投与群において、NREM睡眠の出現回数は16.6±2.38回、REM睡眠の出現回数は2.8±0.37回、覚醒時間は17.2±2.29回であったのに対して、オクタコサノール200mg/kg投与群では、NREM睡眠の出現回数は32.4±4.46回、REM睡眠の出現回数は5.4±1.03回、覚醒時間は32.8±4.59回であり、オクタコサノール投与群では全ての段階の出現回数が、ビヒクル投与群よりも顕著に増加していた。 As shown in FIG. 5A, when observed for 6 hours from the start of vehicle or octacosanol administration, the number of NREM sleep appearances was 16.6 ± 2.38 times, the number of REM sleep appearances was 2.8 ± 0.37 times, and the awakening time in the vehicle administration group. Was 17.2 ± 2.29 times, whereas in the octacosanol 200 mg / kg group, NREM sleep appeared 32.4 ± 4.46 times, REM sleep appeared 5.4 ± 1.03 times, and awakening time was 32.8 ± 4.59 times In the octacosanol administration group, the number of appearances of all the stages was significantly increased as compared to the vehicle administration group.
また図5Bに示すように、覚醒の出現平均持続時間は、ビヒクル投与群で1172.4 ±216.11秒/発現であったのに対して、オクタコサノール200mg/kg投与群では、564.0±125.72秒/発現であり、オクタコサノール投与群の方が持続時間が短縮していた。 As shown in FIG. 5B, the average duration of appearance of arousal was 1172.4 ± 216.11 seconds / onset in the vehicle-administered group, whereas it was 564.0 ± 125.72 seconds / onset in the octacosanol 200 mg / kg group. In the octacosanol administration group, the duration was shorter.
さらに図5Cに示すように、ビヒクル又はオクタコサノールの投与開始から6時間まで観察したところ、ビヒクル投与群では、覚醒段階からNREM睡眠段階への段階移行の回数が16.6±2.38回であり、NREM睡眠段階から覚醒段階への段階移行の回数が13.4±2.25回であったのに対して、オクタコサノール200mg/kg投与群では、覚醒段階からNREM睡眠段階への段階移行の回数が32.0±4.51回であり、NREM睡眠段階から覚醒段階への段階移行の回数が27.0±3.86回となり、オクタコサノール投与群では、段階移行回数が顕著に増加していた。 Furthermore, as shown in FIG. 5C, when the vehicle or octacosanol administration was observed up to 6 hours, the vehicle administration group had 16.6 ± 2.38 transitions from the arousal stage to the NREM sleep stage, and the NREM sleep stage. In the octacosanol 200 mg / kg administration group, the number of stage transitions from the awakening stage to the NREM sleep stage was 32.0 ± 4.51 times, whereas the number of stage transitions from the wakefulness stage to the awakening stage was 13.4 ± 2.25 times, The number of stage transitions from the NREM sleep stage to the wakefulness stage was 27.0 ± 3.86, and the number of stage transitions was significantly increased in the octacosanol administration group.
NREM睡眠段階の持続時間の分布をみると、図5Dに示すように、30秒より長く60秒までの範囲(〜60秒)、及び120秒より長く240秒までの範囲(〜240秒)の範囲においてビヒクル投与群よりもオクタコサノール投与群の方が増加する傾向にあった。 As shown in FIG. 5D, the distribution of the duration of the NREM sleep stage is as follows. The range is longer than 30 seconds up to 60 seconds (up to 60 seconds) and longer than 120 seconds up to 240 seconds (up to 240 seconds). In the range, the octacosanol administration group tended to increase more than the vehicle administration group.
7.実験例6:ストレスに対するオクタコサノールの影響
非特許文献13に記載されているように、ケージ交換は第一夜効果を呼ばれるストレス症状を誘導する。この実験モデルを使って、オクタコサノールがマウスのストレスを減少できるかどうか、血漿中のコルチコステロンをストレスマーカーとして検討した。
7). Experimental Example 6: Effect of octacosanol on stress As described in Non-Patent Document 13, cage exchange induces a stress symptom called first night effect. Using this experimental model, whether corticosterone in plasma was a stress marker was examined whether octacosanol can reduce stress in mice.
オスのマウスにビヒクル又はオクタコサノールを投与し、ケージを新しいものに交換した。ケージを移してから1時間後にマウスをイソフルランでガス麻酔し、0.5%EDTAでプレコーティングした26Gの注射針を使って心臓採血した。血液を1.5 mlチューブに移し、10,000 r.p.m.で15分間遠心し血漿を回収し、測定まで−80℃で保管した。 Male mice received vehicle or octacosanol and the cages were replaced with new ones. One hour after the cage was transferred, the mice were anesthetized with isoflurane and blood was collected using a 26G needle pre-coated with 0.5% EDTA. The blood was transferred to a 1.5 ml tube and centrifuged at 10,000 r.p.m. for 15 minutes to collect plasma and stored at −80 ° C. until measurement.
血漿中のコルチコステロンの濃度(ng/ml)はLC-MS-MSによって測定した。 The concentration of corticosterone in plasma (ng / ml) was measured by LC-MS-MS.
図6に示すように、ビヒクル投与群では175.8±8.5 ng/mlであったのに対して、オクタコサノール200mg/kg投与群では、137.4±8.6 ng/mlであり、オクタコサノールには、コルチコステロンの血中濃度を下げる作用があることが示された。 As shown in FIG. 6, it was 175.8 ± 8.5 ng / ml in the vehicle-administered group, whereas it was 137.4 ± 8.6 ng / ml in the octacosanol 200 mg / kg-administered group, and octacosanol contains corticosterone. It was shown to have an effect of lowering blood concentration.
この結果は、オクタコサノールがマウスのストレスを緩和することにより、上記実験例2〜5に示された結果を引き起こしていることを示唆している。 This result suggests that octacosanol causes the results shown in the above Experimental Examples 2 to 5 by relieving the stress of the mouse.
Claims (4)
(1)ノンレム睡眠時間延長
(2)ノンレム睡眠及びレム睡眠の入眠潜時短縮。 Octacosanol, a pharmaceutically acceptable salt thereof, and looking contains at least one active ingredient selected from the group consisting of pharmaceutically acceptable solvates, in sleep under stress, the following (1) or Sleep enhancer used for (1) and (2) :
(1) Non-REM sleep time extension
(2) Short sleep latencies for non-REM sleep and REM sleep .
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