JP6014731B2 - 褐藻類抽出物を有効成分とするgabaa−ベンゾジアゼピン受容体活性を有する睡眠誘導及び改善用組成物 - Google Patents
褐藻類抽出物を有効成分とするgabaa−ベンゾジアゼピン受容体活性を有する睡眠誘導及び改善用組成物 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/02—Algae
- A61K36/03—Phaeophycota or phaeophyta (brown algae), e.g. Fucus
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/31—Foods, ingredients or supplements having a functional effect on health having an effect on comfort perception and well-being
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2300/00—Processes
- A23V2300/14—Extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
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Description
抗不安、抗痙攣、鎮静作用、及び睡眠誘導及び改善効果を有する海藻類を探索するために、5種の緑藻類、7種の紅藻類及び6種の褐藻類、総18種の海藻類のメタノール抽出物を韓国の済州テクノパークの済州生物資源抽出物銀行で購入して、GABAA−ベンゾジアゼピン受容体結合力を測定した。証拠見本(Voucher specimen)は、済州生物資源抽出物銀行に寄託した。
式(1)
結合の置換(%)=[1−((試料のDPM−NSB DPM)/(TB DPM−NSB DPM))]×100
(DPM:1分当りの崩壊(disintegrations per minute)、TB:全結合(total binding)、NSB:非特異的結合)
抽出物の濃度をそれぞれ0.1mg/mL、1mg/mL及び10mg/mLに異ならせて、緑藻類メタノール抽出物のGABAA−ベンゾジアゼピン受容体結合活性の結果は、[表1]に表わし、紅藻類メタノール抽出物の結果は、[表2]に表わし、褐藻類メタノール抽出物の結果は、[表3]に表わした。
実験例1で、90%以上のGABAA−ベンゾジアゼピン受容体結合活性が最も優れたカジメ(ECK)で抽出溶媒を異ならせた時、活性の差があるかを確認するために、抽出溶媒を異ならせたカジメ抽出物を製造した。
1)実験材料
ペントバルビタール(Pentobarbital)は、翰林製薬会社から購入し、GABAA−ベンゾジアゼピン受容体の拮抗剤であるジアゼパム(DZP)は、よく知られた睡眠剤の1つであって、鎮静及び睡眠誘導効果の陽性対照群として使った。
あらゆる実験は、午後1時から5時の間に進行し、マウスは、実験前24時間前に節食させた。経口投与のために、カジメエタノール抽出物を0.5% カルボキシメチルセルロース(0.5%、CMC−食塩水(saline) 10mL/kg)に希釈させ、陽性対照群であるジアゼパム(DZP)は、やはり0.5% CMC−食塩水に希釈させた。カジメエタノール抽出物及び水抽出物(それぞれ100、250、500、1000mg/kg)とジアゼパム(DZP、2mg/kg)とをペントバルビタール投与45分前に経口投与した。また、陰性対照群(Control group、CON)としては、別途の薬物を投与せず、0.5% CMC−食塩水10mL/kgを投与した。
式(2)
睡眠開始(%)=(睡眠状態数/全体数)×100
カジメエタノール抽出物(ECK−E)及び水抽出物(ECK−W)を100、250、500、1,000mg/kgの濃度で経口投与(p.o.)した後、ペントバルビタール(45mg/kg、i.p.)による睡眠誘導効果に及ぼす影響を、下記の図2a及び図2bに表わした。各グラフは、平均値(means±SEM、n=10)を表わす。
カジメエタノール及び水抽出物が、サブ−ヒプノティック(ペントバルビタール30mg/kg、腹腔注射)濃度での入眠潜時と睡眠時間とを測定して、睡眠誘導効果に及ぼす影響を、下記の[表4]と[表5]とに表わした。実験の結果、カジメエタノール抽出物は、サブ−ヒプノティック濃度のペントバルビタールで対照グループは睡眠を誘導することができなかったが、ジアゼパム(2mg/kg、経口投与)は、睡眠開始が100%で最も高く測定され、いずれもが睡眠状態に入った。カジメエタノール及び水抽出物では、濃度依存的に睡眠開始の入眠潜時の増加と睡眠時間の増加とが表われ、特に、1000mg/kgの濃度では、睡眠開始がそれぞれ92%と90%とで高く表われた。睡眠時間も、それぞれ38.7±6.3分と39.93±4.7分とで有意な増加(p<0.05)を表わした。
睡眠開始(%)=(睡眠状態数/全体数)×100
睡眠時間は、平均値(mean±SEM、n=12)
*は、対照区と比較して、p<0.05で有意差があり、**は、対照区と比較して、p<0.01で有意差がある(Dunnet’s test)。
CON:対照群(0.5% CMC−食塩水 10mL/kg)を経口投与後、ペントバルビタール投与
DZP:ジアゼパム2mg/kgを経口投与後、ペントバルビタール投与
ECK−E:カジメエタノール抽出物100、250、500、1000mg/kgを経口投与後、ペントバルビタール投与
ECK−W:カジメ水抽出物100、250、500、1000mg/kgを経口投与後、ペントバルビタール投与
1)カジメ抽出物分画の製造
GABAA−ベンゾジアゼピン受容体に結合して、鎮静及び睡眠誘導などの活性を表わす有効成分を確認するために、図3に示すように、n−ヘキサン、酢酸エチル、n−ブタノール及び水分画を製造した。
GABAA−ベンゾジアゼピンリガンド[3H]フルマゼニルの結合置換効果は、実験例1の方法で確認して、それぞれのカジメ抽出物分画の[3H]フルマゼニルの結合置換効果を、図4aに表わし、Hypnotic濃度のペントバルビタールによって誘導されたラットでカジメ抽出物分画の睡眠誘導効果を、実験例3の方法で確認して、図4bに表わした。
カジメ抽出物の酢酸エチル分画には、褐藻類特有のポリフェノールであるフロロタンニンが多数含まれているので、前記酢酸エチル分画のGABAA−ベンゾジアゼピンリガンド[3H]フルマゼニルの結合置換効果及び睡眠誘導効果が、フロロタンニンによることである可能性を確認するために、前記それぞれのカジメ抽出物分画の総フェノール含量を分析し、総フェノール含量とGABAA−ベンゾジアゼピン受容体結合活性及び睡眠誘導効果との相関関係を分析した。
前記各カジメ抽出物分画に存在するフロロタンニン化合物のGABAA−ベンゾジアゼピンリガンド[3H]フルマゼニルの結合置換効果を表わすIC50値と結合親和度(Ki)を計算して、[表8]に表わした。結合親和度(Ki)は、下記の式(3)のように計算した。
式(3)
Ki=(IC50)/(1+([L]/Kd))
([L]:使用された放射性リガント([3H]フルマゼニル)の濃度、Kd:[3H]フルマゼニルの競合リガント(competitor−ligand)解離平衡定数。Kd値は1.6nMである。)
前記[表3]の褐藻類のうちからGABAA−ベンゾジアゼピン受容体結合活性が異なるサナダグサ、ヘラヤハズ(Dictyopteris prolifera Okamura)、カジメを選別し、GABAA−ベンゾジアゼピン受容体結合活性が高かったカジメと同一属のクロメとを追加して、それぞれのメタノール抽出物の総フェノール含量を測定し、総フェノール含量とGABAA−ベンゾジアゼピン受容体結合活性及び睡眠誘導効果との相関関係を確認した。
フロログルシノール(phloroglucinol、PG)及びフロロタンニンのうちからエクストロノール(eckstolonol、ETN)、トリフロレトールA(triphlorethol A、TPE−A)、フコジフロレトールG(fucodiphlorethol G、FDE−G)、エコール(eckol)及び6,6’−ビエコール(6,6’−bieckol)の濃度による睡眠誘導効果及びフルマゼニルが、睡眠誘導に及ぼす影響を確認した。
カジメ抽出物と同様に、同じ属に属するクロメも、GABAA−ベンゾジアゼピン受容体結合活性及び睡眠誘導効果を表わすかを確認した。
カジメエタノール及び水抽出物とジアゼパムとの併用経口投与に対する睡眠誘導シナジー効果を調べるために、ペントバルビタールの睡眠誘導効果に影響を与えないほどの低濃度で、ECK−Eは、100mg/kg、ECK−Wは、100mg/kg、DZPは、0.5mg/kgをペントバルビタール投与(hypnotic dosage 45mg/kg)45分前に経口投与して、入眠潜時と睡眠時間とを測定したその結果を、図16a及び図16bに表わした。各グラフは、平均値(means±SEM、n=10)を表わす。
GABAA−ベンゾジアゼピン拮抗剤であるフルマゼニル(FLU)が、実験例2の方法で製造されたカジメエタノール抽出物(ECK−E)、カジメ水抽出物(ECK−W)及び実験例4の方法で製造された酢酸エチル分画(EtOAc)の睡眠誘導効果に及ぼす影響に対して調べるために、ECK−Eは、1000mg/kg、ECK−Wは、1000mg/kg、EtOAcは、200mg/kg、DZPは、0.5mg/kgをペントバルビタール投与(hypnotic dosage 45mg/kg)45分前に経口投与し、FLUは、8mg/kgをECK−E、ECK−W、EtOAc、DZP経口投与10分前にあらかじめ腹腔注射して、入眠潜時と睡眠時間とを測定した。その結果を、下記の図17a及び図17bに表わした。各グラフは、平均値(means±SEM、n=10)を表わす。
SD ラット(200−250g)を1週間適応させた後、脳波(Electroencephalogram、EEG)及び筋電図(Electromyogram、EMG)の測定のために、電極挿入手術を実施した。Ratをペントバルビタール(50mg/kg、i.p.)で痲酔させ、脳定位器(stereotaxic instrument)に頭部を固定させた。頭部皮下結合組織を切開した後、EEG及びEMG測定のために、ステンレス鋼スクリューと銀電極ラインとを挿入した。引き続き歯科用セメントで固定させて縫合した。手術部位の消毒及び抗生剤投与を3日間実施して、手術による炎症を予防し、7日間回復期間を置いた。測定環境に適応させるために、測定4日前からcontrol実験群に使う0.5% CMC−食塩水溶液を経口投与(p.o.)した後、記憶装置を連結して、本実験過程に順応するように誘導した。
実験例1で、90%以上のGABAA−ベンゾジアゼピン受容体結合活性が最も優れたカジメ(ECK)で酵素を利用した酵素抽出物を得て、その酵素抽出物でフロロタンニン濃縮分画を得て、酵素抽出物(ECEE)及びフロロタンニン濃縮分画(PTRF)の総フェノール含量及び抗痙攣効果を確認した。
1kgの凍結乾燥カジメ粉末と蒸溜水10Lとを混合した後、セルラーゼ(Celluclast、Novo Nordisk,Bagsvaerd,Denmark)10mLを添加し、50℃で24時間反応させ、100℃で10分間酵素を不活性化させた。3000xgで20分間遠心分離して、加水分解されていない残渣を除去して得た濾液を得て、これを濃縮した後、凍結乾燥して酵素抽出物(ECEE)を得た。
実験動物は、実験例3のように準備し、ラットに対照群(CON、0.5%、CMC−食塩水 10mL/kg)、ECEE及びDZPを経口投与し、経口投与45分後、7mg/kgのピクロトキシンを静脈注射して発作を誘導した。ピクロトキシンを投与したラットは、直ちに個別ケージに入れて90分間観察して、痙攣の回数とピクロトキシン投与後から発作の発現までの発作潜在期間とを記録した。90分間発作が発現されない場合、発作潜在期間は、0分と記録した。
[表10]は、酵素抽出物(ECEE)及びフロロタンニン濃縮分画(PTRF)の総フェノール含量を表わしたものであり、残留物は、RTRFを除いたECEE部分を意味する。フロロタンニン濃縮分画には、酵素抽出物に比べて、6倍以上多い総フェノール含量を表わした。
50%抑制濃度(IC50)値は、Prism5.0プログラムを用いてone−site competition binding modelを適用させて算出した。あらゆる実験の結果は、平均と標準誤差(means±SEM)とで表わし、各群と対照区との統計的な比較は、Dunnet’s testによる一元配置分散分析(ANOVA)を通じて評価した。有意レベルの表示は、p<0.05(*)、p<0.01(**)、p<0.001(***)レベルで有意性を見せる結果を別表で表示した。2つのグループ間のデータ比較は、対応のないスチューデントのt検定によって分析し、p<0.05(#)、p<0.01(##)、p<0.001(###)レベルで2つのグループ間に統計的に有意差があることを表示した。統計分析プログラムは、Prism5.0ソフトウェアを使って行った。
実験例1で得たカジメエタノール抽出物粉末 20mg
乳糖 100mg
タルク 10mg
前記の成分を混合し、気密布に充填して散剤を製造する。
実験例8のエコール 10mg
トウモロコシ澱粉 100mg
乳糖 100mg
ステアリン酸マグネシウム 2mg
前記の成分を混合した後、通常の錠剤の製造方法によって、打錠して錠剤を製造する。
実験例8のフロログルシノール 10mg
結晶性セルロース 3mg
ラクトース 14.8mg
ステアリン酸マグネシウム 0.2mg
通常のカプセル剤の製造方法によって、前記の成分を混合し、ゼラチンカプセルに充電してカプセル剤を製造する。
実験例8のエクストロノール 10mg
マンニトール 180mg
注射用滅菌蒸溜水 2974mg
Na2HPO4、12H2O 26mg
通常の注射剤の製造方法によって、1アンプル当たり前記の成分含量で製造する。
実験例1で得たカジメエタノール抽出物粉末 20mg
異性化糖 10g
マンニトール 5g
精製水 適量
通常の液剤の製造方法によって、精製水にそれぞれの成分を加えて溶解させ、レモン香を適量加えた後、前記の成分を混合した後、全体を精製水を加えて、全体100に調節した後、褐色瓶に充填して滅菌させて、液剤を製造する。
実験例1で得たカジメエタノール抽出物粉末 1,000mg
ビタミン混合物 適量
ビタミンAアセテート 70μg
ビタミンE 1.0mg
ビタミンB1 0.13mg
ビタミンB2 0.15mg
ビタミンB6 0.5mg
ビタミンB12 0.2μg
ビタミンC 10mg
ビオチン 10μg
ニコチン酸アミド 1.7mg
葉酸 50μg
パントテン酸カルシウム 0.5mg
無機質混合物 適量
硫酸第一鉄 1.75mg
酸化亜鉛 0.82mg
炭酸マグネシウム 25.3mg
第一燐酸カリウム 15mg
第二燐酸カルシウム 55mg
クエン酸カリウム 90mg
炭酸カルシウム 100mg
塩化マグネシウム 24.8mg
前記のビタミン及びミネラル混合物の組成比は、比較的健康機能食品に適した成分を望ましい実施例で混合組成したが、その配合比を任意に変形実施しても良く、通常の健康機能食品の製造方法によって、前記の成分を混合した後、顆粒を製造し、通常の方法によって、健康機能食品組成物の製造に使うことができる。
実験例1で得たカジメエタノール抽出物粉末 1,000mg
クエン酸 1,000mg
オリゴ糖 100g
梅濃縮液 2g
タウリン 1g
精製水 全体900mL
通常の健康飲料の製造方法によって、前記の成分を混合した後、約1時間85℃で撹拌加熱した後、作られた溶液を濾過して、滅菌された2L容器に取得して密封滅菌した後、冷蔵保管した後、本発明の機能性飲料組成物の製造に使う。
Claims (4)
- 褐藻類抽出物を有効成分とするGABAA−ベンゾジアゼピン受容体活性を有する睡眠誘導及び改善用組成物であって、
前記褐藻類は、カジメ(Ecklonia cava)またはクロメ(Ecklonia kurome)であることを特徴とする睡眠誘導及び改善用組成物。 - 前記褐藻類抽出物は、褐藻類水抽出物、褐藻類エタノール抽出物、褐藻類メタノール抽出物、または水、エタノール及びメタノールのうちから選択される何れか2種以上の溶媒の混合溶媒による褐藻類抽出物であることを特徴とする請求項1に記載の睡眠誘導及び改善用組成物。
- 褐藻類抽出物を有効成分とし、前記褐藻類がカジメ(Ecklonia cava)またはクロメ(Ecklonia kurome)であり、前記褐藻類抽出物が、褐藻類水抽出物、褐藻類エタノール抽出物、褐藻類メタノール抽出物、または水、エタノール及びメタノールのうちから選択される何れか2種以上の溶媒の混合溶媒による褐藻類抽出物である、GABA A −ベンゾジアゼピン受容体活性を有する睡眠誘導及び改善用組成物の製造方法であって、
前記褐藻類水抽出物は、40〜100℃の水で2〜48時間褐藻類を抽出して製造し、褐藻類エタノール抽出物は、褐藻類を35〜75%のエタノールで20〜60℃で2〜36時間抽出して製造し、前記褐藻類メタノール抽出物は、褐藻類を35〜85%のメタノールで20〜60℃で2〜36時間抽出して製造することを特徴とする睡眠誘導及び改善用組成物の製造方法。 - 前記褐藻類水抽出物は、セルラーゼ、ビスコザイム、アルカラーゼ及びペクチンからなる群から選択される1種以上の酵素を添加した水で40〜55℃で2〜24時間褐藻類を抽出して製造することを特徴とする請求項3に記載の睡眠誘導及び改善用組成物の製造方法。
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