JP2006321742A - Sleep-ameliorating medicine - Google Patents
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- JP2006321742A JP2006321742A JP2005145598A JP2005145598A JP2006321742A JP 2006321742 A JP2006321742 A JP 2006321742A JP 2005145598 A JP2005145598 A JP 2005145598A JP 2005145598 A JP2005145598 A JP 2005145598A JP 2006321742 A JP2006321742 A JP 2006321742A
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本発明は、睡眠機構に直接作用して睡眠誘発作用を示すことによる入眠障害、熟眠障害、中途覚醒又は早期覚醒の治療又は予防に有効な睡眠改善薬に関する。 The present invention relates to a sleep-improving drug effective for the treatment or prevention of sleep onset disorder, deep sleep disorder, mid-term awakening or early awakening by directly acting on a sleep mechanism and exhibiting a sleep-inducing action.
睡眠欲求の高い動物の脳内には自然睡眠を誘発する睡眠物質が存在する。本発明者は内因性睡眠物質の生理的作用について研究を行ってきた。内因性睡眠物を研究する過程において外因性の睡眠物質も併せて検証してきた。その中の一つにビタミンB12類がある。ビタミンB12類の睡眠に関する効果としてはすでに睡眠覚醒リズム異常の患者で改善効果が報告されているが、睡眠現象そのものに効果を有するのかについては不明のままである。睡眠覚醒調節には2通りの法則がある。一つは生物時計による1日を周期とした時刻依存性の睡眠覚醒のサーカディアンリズムがあり、これは昼間に眠ろうとしても眠れず夜になると次第に眠くなる現象である。一方、睡眠欲求の高まりとともに脳内に睡眠を促す物質の出現が想定され、この本体が睡眠物質と考えられ、時刻に依存しないで覚醒時間の長さによって睡眠の質と量が決定される睡眠のホメオスタシス現象である。 There is a sleeping substance that induces natural sleep in the brain of animals with a high desire for sleep. The inventor has studied the physiological effects of endogenous sleep substances. In the process of studying endogenous sleep, we have also examined exogenous sleep substances. One of them is vitamin B12. The effect of vitamin B12 on sleep has already been reported in patients with abnormal sleep-wake rhythms, but it remains unclear whether it has an effect on the sleep phenomenon itself. There are two rules for sleep / wake regulation. One is a circadian rhythm of time-dependent sleep-wakefulness with a cycle of one day by a biological clock. This is a phenomenon that even if you try to sleep in the daytime, you can not sleep but at night it becomes sleepy. On the other hand, the emergence of sleep-promoting substances in the brain as sleep desire increases, this body is considered to be a sleep substance, and sleep quality and quantity are determined by the length of awakening time without depending on time It is a homeostasis phenomenon.
本発明者は、すでにメコバラミンを含むビタミンB12類縁体をラット中枢に連続注入することで、その顕著な睡眠促進効果を明らかにし論文発表してある。本研究では、睡眠のホメオスタシス現象を背景とする、つまり、メコバラミンの睡眠覚醒機構への直接的作用について、睡眠剤としての可能性を明らかにするため経口投与法で我々独自に開発した睡眠評価システムを用いて検証した。この睡眠評価方法は、自然な睡眠覚醒リズムを乱すことなく、脳の特定部位、血管内、胃内に必要な量の薬剤を任意の時間に投与できるドラッグ・デリバリー・システムである。本システムを用いることで実験動物を無拘束状態で脳波、筋電図、脳温、行動量、飲水量及び動画の時系列変化の連続測定ができることから、多くの睡眠物質についてもその生理的作用を検証してきた。 The present inventor has already published a paper that clarifies its remarkable sleep promoting effect by continuously injecting a vitamin B12 analog containing mecobalamin into the rat center. In this study, we developed a sleep evaluation system that was originally developed by oral administration in order to clarify the potential of mecobalamin as a sleep agent against the background of sleep homeostasis. It verified using. This sleep evaluation method is a drug delivery system that can administer a necessary amount of drug into a specific part of the brain, blood vessels, and stomach at any time without disturbing the natural sleep-wake rhythm. By using this system, it is possible to continuously measure time-series changes in EEG, electromyogram, brain temperature, action amount, water consumption, and animation in an unrestrained state of experimental animals. Has been verified.
ビタミンB12類は、末梢神経障害治療薬として臨床で広く使用されている。一方、ビタミンB12類は、光刺激に対する感受性を増加させる作用や、睡眠リズムを整える作用などがあると報告されているが(非特許文献1)、睡眠導入作用については報告がない。 Vitamin B12 is widely used clinically as a therapeutic agent for peripheral neuropathy. On the other hand, vitamins B12 have been reported to have an effect of increasing sensitivity to light stimulation and an effect of adjusting sleep rhythm (Non-patent Document 1), but there is no report on sleep-inducing action.
このような状況で、本発明の目的は、睡眠機構に直接作用して睡眠改善作用を示し、入眠障害、さらに熟眠障害、中途覚醒又は早期覚醒の治療又は予防に有効な睡眠改善剤を提供することである。 In such a situation, an object of the present invention is to provide a sleep improving agent that directly acts on a sleep mechanism and exhibits a sleep improving action, and is effective in the treatment or prevention of sleep deprivation disorder, further deep sleep disorder, mid-wake or early awakening. That is.
本発明者は前記課題を解決するために鋭意検討した結果、末性神経障害治療薬であるビタミンB12類が睡眠機構に直接作用して睡眠誘発作用を示すことを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above-mentioned problems, the present inventor has found that vitamin B12, which is a therapeutic agent for endemic neuropathy, acts directly on the sleep mechanism and exhibits a sleep-inducing action, thereby completing the present invention. It came.
かかる知見に基づき完成した本発明は、ビタミンB12類を有効成分とすることを特徴とする睡眠改善薬である。
本発明において、ビタミンB12類とは、ビタミンB12のほか活性型として知られるメコバラミン、シアノコバラミン、ヒドロキソコバラミン等である。
The present invention completed based on this finding is a sleep improving drug characterized by containing vitamin B12 as an active ingredient.
In the present invention, vitamins B12 include mecobalamin, cyanocobalamin, hydroxocobalamin, and the like known as active forms in addition to vitamin B12.
本発明の睡眠改善薬は、主として経口的に投与することができる。その投与剤型は錠剤、カプセル剤、顆粒剤、細粒、散剤、粉剤、トローチ剤、内服液剤等であり、いずれも慣用の製剤技術(例えば、第14改正日本薬局方に規定する方法等)によって製造することができる。必要に応じて公知の製剤添加剤、例えば、乳糖、D−マンニトール、結晶セルロース、ヒドロキシプロピルセルロース、精製白糖などの賦形剤、デンプン、ゼラチン、メチルセルロース、結晶セルロースなどの結合剤、タルク、沈降炭酸カルシウム、無水ケイ酸などの滑沢剤、カルナバロウ、ゼラチン、ヒドロキシプロピルメチルセルロースなどのコーティング剤、内服液剤の場合には界面活性剤、溶解補助剤、緩衝剤等を使用することができる。また、その他保存剤、香料、色素、甘味剤、遮光のための着色剤等を使用することができる。 The sleep improving agent of the present invention can be administered mainly orally. The dosage forms include tablets, capsules, granules, fine granules, powders, powders, troches, liquids for internal use, etc., all of which are conventional formulation techniques (for example, methods prescribed in the 14th revised Japanese Pharmacopoeia, etc.) Can be manufactured by. Known formulation additives as necessary, for example, excipients such as lactose, D-mannitol, crystalline cellulose, hydroxypropylcellulose, purified sucrose, binders such as starch, gelatin, methylcellulose, crystalline cellulose, talc, precipitated carbonic acid In the case of a lubricant such as calcium and silicic anhydride, a coating agent such as carnauba wax, gelatin and hydroxypropylmethylcellulose, and an internal solution, a surfactant, a solubilizing agent, a buffering agent and the like can be used. In addition, other preservatives, fragrances, pigments, sweeteners, colorants for shading, and the like can be used.
投与量は、通常成人に対しで、1日当たり、有効成分として0.1〜10mgを、入眠前に1回ないし数回に分けて経口投与することができる。更にメコバラミンであれば、0.1〜5mgが好ましい。この投与量は患者の年齢、体重、症状により適宜増減することができる。 The dose is usually 0.1 to 10 mg as an active ingredient per day for an adult, and can be orally administered in one to several times before falling asleep. Furthermore, 0.1 to 5 mg is preferable for mecobalamin. This dose can be appropriately increased or decreased depending on the patient's age, weight and symptoms.
また、必要に応じて、ビタミンB群(ビタミンB1、ビタミンB2、ビタミンB3、ビタミンB6等)又はそれらの塩類若しくは誘導体、ビタミンC、ビタミンD、ビタミンE又はそれらの塩類若しくは誘導体、カルシウム、マグネシウム又はそれらの塩類、ならびに還元型グルタチオン又は酸化型グルタチオンを補助薬剤として適宜配合することができる。 In addition, vitamin B group (vitamin B1, vitamin B2, vitamin B3, vitamin B6 etc.) or salts or derivatives thereof, vitamin C, vitamin D, vitamin E or salts or derivatives thereof, calcium, magnesium or Those salts and reduced glutathione or oxidized glutathione can be appropriately blended as auxiliary agents.
ビタミンB12類は、睡眠機構に直接作用して睡眠改善作用を示すことが明らかになった。本発明は、入眠障害、さらに熟眠障害、中途覚醒又は早期覚醒にも有効な睡眠改善薬を提供した。 It became clear that vitamin B12 acts directly on the sleep mechanism and exhibits a sleep improving action. The present invention provides a sleep-improving drug that is effective for sleep deprivation disorder, deep sleep disorder, mid-term awakening or early awakening.
以下、試験例を挙げて本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail with reference to test examples.
試験例
実験動物にはSprague-Dawley 系雄ラット(体重: 300 g,60-70日令)を用いた。
飼育環境は、明期を06:00-18:00、暗期を18:00-06:00、室温を25±1℃、湿度を60±6 %とした。被験動物の大脳皮質表面に金メッキしたEEG記録用ネジ電極を、後部頚筋肉内にEMG記録用の電極を、ネンブタール(50 mg/kg, ip)麻酔下で脳定位固定装置を用いて、それぞれ慢性的に装着した。
手術後1週間の回復期を経た被験動物は、睡眠データ記録用飼育ケージ(幅25cm, 高さ36cm, 奥行き35cm)に移し、7日間馴らしてから試料のメコバラミン(以下メチルB12と略称する)あるいは対照としてVehicle(蒸留水)のみの経口投与を行い、睡眠に対する効果を検証した。
Test Example Sprague-Dawley male rats (weight: 300 g, 60-70 days) were used as experimental animals.
The breeding environment was 06: 00-18: 00 in the light period, 18: 00-06: 00 in the dark period, room temperature 25 ± 1 ° C, and humidity 60 ± 6%. Using the EEG recording screw electrode gold-plated on the cerebral cortex surface of the test animal, the EMG recording electrode in the posterior cervical muscle, and using a stereotaxic device under Nembutal (50 mg / kg, ip) anesthesia Attached.
After the recovery period of 1 week after the operation, the test animals are transferred to a sleeping data recording cage (width 25 cm, height 36 cm, depth 35 cm) and acclimatized for 7 days before the sample mecobalamin (hereinafter abbreviated as methyl B12) or As a control, only vehicle (distilled water) was orally administered and the effect on sleep was verified.
睡眠状態の判定は覚醒(W)、ノンレム睡眠(NREM)及びレム睡眠(REM)の3状態をEEG及びEMGの連続記録から自動判定した後、さらに視察判定で確認した。ラットの自発行動量は、飼育ケージに設置した光センサーで検出し、EEG、EMGと同時系列で増幅器からA/D変換器を介して睡眠解析装置SleepSign(キッセイコムテック社)に取り込んだ。睡眠データは対照のVehicle群とメチルB12群を統計的に比較し,メチルB12の睡眠促進効果について評価した。 The determination of the sleep state was further confirmed by visual inspection after automatically determining three states of wakefulness (W), non-REM sleep (NREM), and REM sleep (REM) from continuous recording of EEG and EMG. The rat's self-issued amount of movement was detected by an optical sensor installed in the breeding cage, and taken into the sleep analyzer SleepSign (Kissei Comtech) via an A / D converter from the amplifier simultaneously with EEG and EMG. The sleep data were statistically compared between the control vehicle group and the methyl B12 group, and the sleep promoting effect of methyl B12 was evaluated.
24時間の絶食後、暗期の始まる20分前にメチルB12を0.1mg/kgの用量でラットにゾンデを用いて経口投与した。メチルB12を投与するとNREMは306.8±10.5分(n=10)となり、対照となるVehicle投与の252.5±12.8(n=9)分と比較すると21.5%の統計的有意(P<0.01)な増加となった(図1)。 After a 24-hour fast, 20 minutes before the dark period began, methyl B12 was orally administered to the rats using a sonde at a dose of 0.1 mg / kg. When Methyl B12 was administered, NREM was 306.8 ± 10.5 minutes (n = 10), which was a 21.5% statistically significant (P <0.01) increase compared to 252.5 ± 12.8 (n = 9) minutes of control vehicle administration. (Fig. 1).
REMではメチルB12の投与で70.5±6.0(n=10)となり、Vehicleの58.5±6.3(n=9)分と比較すると20.5%の増加であったが有意差とはならなかった(P<0.2, 図2)。 In REM, administration of methyl B12 gave 70.5 ± 6.0 (n = 10), an increase of 20.5% compared to 58.5 ± 6.3 (n = 9) of vehicle, but not significantly different (P <0.2). , Figure 2).
睡眠潜時はメチルB12が1736±110秒,Vehicleでは1787±152秒でほとんど差がなかった。 Sleep latency was 1736 ± 110 seconds for methyl B12 and 1787 ± 152 seconds for vehicle.
メチルB12の睡眠効果は、投与後12時間全体に渡り緩やかな作用を示した(図3,4)。 The sleep effect of methyl B12 showed a gradual action over the entire 12 hours after administration (FIGS. 3 and 4).
メチルB12は急性投与で統計的有意な睡眠効果を示したことから、睡眠覚醒機構に直接作用し睡眠促進効果を発現したと考えられる。したがって、従来よりメチルB12の作用は主に睡眠覚醒の日周リズムに及ぼす効果とされていたが、本研究結果からメチルB12は睡眠機構に直接作用して睡眠誘発作用を発現していると考えられた。 Since methyl B12 showed a statistically significant sleep effect upon acute administration, it is thought that it exerted a sleep promoting effect by directly acting on the sleep-wake mechanism. Therefore, conventionally, the action of methyl B12 was mainly considered to have an effect on the diurnal rhythm of sleep awakening. However, the results of this study indicate that methyl B12 acts directly on the sleep mechanism and expresses the sleep-inducing action. It was.
本発明により、入眠障害改善薬が提供され、更にリズム位相改善効果を合わせもつメコバラミンは熟眠障害、中途覚醒又は早期覚醒の治療又は予防に有効な新たな睡眠改善薬となりうる。
21世紀における医療では遺伝子治療、低侵襲性治療、再生医療など医療技術が一段と高度化している中で、種々の疾患に対する新規の治療薬や治療法の開発、そしてQOLの向上に貢献できるような薬剤や機能性食品の開発が求められている。本発明者が独自に開発した評価システムを利用することで、今後さらに有望な睡眠剤を発掘できる可能性がある。
According to the present invention, a sleep onset disorder improving drug is provided, and mecobalamin having an effect of improving rhythm phase can be a new sleep improving drug effective for the treatment or prevention of deep sleep disorder, mid-wake or early awakening.
As medical technology in the 21st century has become more sophisticated, such as gene therapy, minimally invasive therapy, and regenerative medicine, it can contribute to the development of new therapeutic drugs and treatment methods for various diseases and to improve QOL. Development of drugs and functional foods is required. By using the evaluation system originally developed by the present inventor, there is a possibility that a more promising sleeping agent can be found in the future.
Claims (5)
An agent for improving sleep disturbance characterized by containing mecobalamin as an active ingredient.
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JP2002535277A (en) * | 1999-01-20 | 2002-10-22 | エヌ・ヴイ・ヌートリシア | Pharmaceutical compositions for alleviating discomfort |
WO2003041701A2 (en) * | 2001-11-14 | 2003-05-22 | N.V. Nutricia | Preparation for improving the action of receptors |
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WO2003041701A2 (en) * | 2001-11-14 | 2003-05-22 | N.V. Nutricia | Preparation for improving the action of receptors |
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