JP6063543B2 - Preventive or ameliorating agent for overactive bladder - Google Patents
Preventive or ameliorating agent for overactive bladder Download PDFInfo
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- JP6063543B2 JP6063543B2 JP2015212317A JP2015212317A JP6063543B2 JP 6063543 B2 JP6063543 B2 JP 6063543B2 JP 2015212317 A JP2015212317 A JP 2015212317A JP 2015212317 A JP2015212317 A JP 2015212317A JP 6063543 B2 JP6063543 B2 JP 6063543B2
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- overactive bladder
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- bladder
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Description
本発明は、過活動膀胱の予防、改善剤に関する。 The present invention relates to an agent for preventing or improving overactive bladder.
頻尿（ひんにょう）とは、様々な原因により１日の排尿回数が増えてしまう症状である。頻尿の原因としては、尿崩症、高血圧症、水分、カフェイン、アルコールの過剰摂取などの尿量の増加に因るものと、過活動膀胱、尿路感染、間質性膀胱炎など尿量の増加に因らないものに大別される。さらに、膀胱や前立腺など泌尿器系の臓器に病気が存在して起こる場合や、神経的な緊張も、頻尿の原因の１つと言われている。
一方、過活動膀胱（overactive bladder：OAB）は、尿意切迫感、切迫性尿失禁の排尿障害を呈する疾患である。過活動膀胱の症状は日常生活に支障をきたし生活の質を低下させること、特に高齢者に多く見られ４０歳以上の罹患者は８００万人を超えると推定されていることから、近年の高齢化社会に伴って注目が集まっている。健常人では膀胱内の蓄尿量と尿意は相関関係にあるが、過活動膀胱患者では尿の蓄積によらず膀胱の収縮が起こるため尿意切迫感を引き起こすと考えられている。しかしながら、その発症機構には未だ不明な点が多い。
Frequent urination is a symptom in which the number of urinations per day increases due to various causes. The cause of frequent urination is due to increased urine output such as diabetes insipidus, hypertension, water, caffeine, excessive alcohol consumption, and urine such as overactive bladder, urinary tract infection, interstitial cystitis They are roughly divided into those that do not depend on the increase in quantity. Furthermore, cases of urinary organs such as the urinary bladder and prostate, which are caused by diseases, and nervous tension are said to be one of the causes of frequent urination.
On the other hand, overactive bladder (OAB) is a disease presenting with urinary dysfunction such as urgency and urge incontinence. Symptoms of overactive bladder interfere with daily life and reduce the quality of life, especially in elderly people, and it is estimated that the number of affected people over the age of 40 is over 8 million. Attention has been gathered with the changing society. In healthy people, the amount of urine stored in the bladder and urinary urgency are correlated, but in patients with overactive bladder, it is thought that the urinary urgency is caused because the bladder contracts regardless of urine accumulation. However, there are still many unclear points in the onset mechanism.
近年、過活動膀胱を引き起こす要因の１つとして、膀胱知覚神経系（膀胱求心性神経系）の興奮性の亢進が指摘されている。この知覚神経系の興奮は、蓄尿による膀胱の伸展刺激を受けて膀胱上皮細胞から放出される各種の伝達物質（アデノシン三リン酸（adenosine triphosphate：以下ＡＴＰとも略記する）、アセチルコリン（acetylcholine）等）によって引き起こされると考えられている。ヒトでは加齢により膀胱上皮から放出されるＡＴＰ量が増加すること、及び過活動膀胱患者では膀胱伸展時のＡＴＰ放出量が増大していることが報告されている（例えば、非特許文献１参照）。また、ラットの膀胱にＡＴＰを投与すると排尿筋の過活動が誘発されて排尿間隔が短縮するとの報告もある（例えば、非特許文献２参照）。 In recent years, increased excitability of the bladder sensory nervous system (bladder afferent nervous system) has been pointed out as one of the factors that cause overactive bladder. This sensory nervous system excitement is caused by various mediators released from bladder epithelial cells upon stimulation of bladder expansion by storing urine (adenosine triphosphate (ATP), acetylcholine, etc.) It is thought to be caused by. It has been reported that the amount of ATP released from the bladder epithelium increases with age in humans, and that the amount of ATP released during bladder extension increases in patients with overactive bladder (see, for example, Non-Patent Document 1). ). There is also a report that administration of ATP to the rat bladder induces detrusor overactivity and shortens the urination interval (see, for example, Non-Patent Document 2).
現在のところ、薬物による過活動膀胱の治療には、膀胱収縮を促すアセチルコリンの作用を抑制する抗コリン薬が主に使われている。しかし、抗コリン薬は服用に伴う、口の渇き、便秘、排尿の困難性等の副作用を起こすことが知られている。このような実情から、より効果的な過活動膀胱の予防、治療剤が望まれている。 At present, anticholinergic drugs that suppress the action of acetylcholine, which promotes bladder contraction, are mainly used to treat overactive bladder with drugs. However, it is known that anticholinergic drugs cause side effects such as dry mouth, constipation, difficulty in urination, etc. associated with taking them. From such a situation, more effective preventive and therapeutic agents for overactive bladder are desired.
本発明は、過活動膀胱、又は尿意切迫感、切迫性尿失禁等の排尿障害を予防及び／又は改善する、過活動膀胱の予防又は改善剤を提供することを課題とする。また、本発明は、排尿を制御する神経伝達物質であるＡＴＰの膀胱上皮細胞からの放出を抑制する、ＡＴＰ放出抑制剤を提供することを課題とする。さらに、本発明は、頻尿を予防又は改善する、頻尿予防又は改善剤を提供することを課題とする。 An object of the present invention is to provide an agent for preventing or improving overactive bladder, which prevents and / or improves overactive bladder, or urination disorder such as urinary urgency and urge urinary incontinence. Another object of the present invention is to provide an ATP release inhibitor that suppresses the release of ATP, which is a neurotransmitter that controls urination, from bladder epithelial cells. Furthermore, this invention makes it a subject to provide the frequent urination prevention or improvement agent which prevents or improves frequent urination.
本発明者らは、過活動膀胱の原因とされる種々の要因の中から、特に膀胱求心性神経の興奮性亢進に着目し、この興奮を引き起こしている膀胱上皮からのＡＴＰ放出を抑制する物質が、過活動膀胱の予防又は改善剤として有用であることを明らかにしている（特開２０１１−１３３４４０号公報参照）。
そして、本発明者らは更に研究を進めたところ、アカキャベツ（Brassica oleracea L．var．capitata）抽出物、ユッカフォーム抽出物、ステビア（Stevia rebaudiana）抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ（Thymus vulgaris）抽出物、ベニバナ（Carthamus tinctorius）抽出物、ノートカトン（Nootkatone）、メバスタチン（mevastatin）及びバナナ（Musa paradisiaca）抽出物にＡＴＰ放出を抑制する効果があり、過活動膀胱の予防又は改善、並びに頻尿の予防又は改善に有用であることを見出した。本発明はこれらの知見に基づいて完成するに至ったものである。
The present inventors pay attention to increased excitability of the bladder afferent nerve from various factors that cause overactive bladder, and a substance that suppresses ATP release from the bladder epithelium causing this excitement. However, it has been clarified that it is useful as an agent for preventing or improving overactive bladder (see JP 2011-133440 A).
Further, the present inventors further studied, and as a result, extracted red cabbage ( Brassica oleracea L. var. Capitata ) extract, yucca foam extract, stevia ( Stevia rebaudiana ) extract, β-carotene, Benikouji aureus, tachi Thymus vulgaris extract, safflower ( Carthamus tinctorius ) extract, nootkatone, mevastatin and banana ( Musa paradisiaca ) extract have the effect of suppressing ATP release, preventing or improving overactive bladder As well as the prevention or improvement of frequent urination. The present invention has been completed based on these findings.
本発明は、アカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及びバナナ抽出物からなる群より選ばれる少なくとも１種を有効成分とする、過活動膀胱の予防又は改善剤に関する。
さらに、本発明は、アカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及びバナナ抽出物からなる群より選ばれる少なくとも１種を有効成分とする、ＡＴＰ放出抑制剤に関する。
さらに、本発明は、アカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及びバナナ抽出物からなる群より選ばれる少なくとも１種を有効成分とする、頻尿予防又は改善剤に関する。
The present invention is at least one selected from the group consisting of red cabbage extract, yuccafoam extract, stevia extract, β-carotene, red beetle yellow pigment, periwinkle extract, safflower extract, note katon, mevastatin and banana extract. The present invention relates to a preventive or ameliorating agent for overactive bladder, comprising a seed as an active ingredient.
Further, the present invention is selected from the group consisting of red cabbage extract, yucca foam extract, stevia extract, β-carotene, red beetle yellow primrose, red pepper extract, safflower extract, note katon, mevastatin and banana extract The present invention relates to an ATP release inhibitor containing at least one active ingredient.
Further, the present invention is selected from the group consisting of red cabbage extract, yucca foam extract, stevia extract, β-carotene, red beetle yellow primrose, red pepper extract, safflower extract, note katon, mevastatin and banana extract The present invention relates to an agent for preventing or improving frequent urination containing at least one active ingredient.
本発明の過活動膀胱の予防又は改善剤は、過活動膀胱、又は尿意切迫感、切迫性尿失禁等の排尿障害を予防及び／又は改善することができる。また、本発明のＡＴＰ放出抑制剤は、膀胱上皮細胞からのＡＴＰの放出を抑制することができる。さらに、本発明の頻尿予防又は改善剤は、頻尿を予防又は改善することができる。 The preventive or ameliorating agent for overactive bladder of the present invention can prevent and / or improve overactive bladder, or urination disorder such as urgency and urinary incontinence. Moreover, the ATP release inhibitor of the present invention can suppress the release of ATP from bladder epithelial cells. Furthermore, the frequent urination preventing or improving agent of the present invention can prevent or ameliorate frequent urination.
本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤は、アカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及びバナナ抽出物からなる群より選ばれる少なくとも１種を有効成分とする。 The prophylactic or improving agent for overactive bladder, the ATP release inhibitor and the frequent urinary prophylaxis or ameliorating agent of the present invention are red cabbage extract, yuccafoam extract, stevia extract, β-carotene, red beetle yellow fungus, extract The active ingredient is at least one selected from the group consisting of an extract, safflower extract, note caton, mevastatin and banana extract.
本発明に用いる有効成分のうち、植物抽出物について説明する。
本発明におけるアカキャベツとは、アブラナ（Brassicaceae）科アブラナ（Brassica）属の多年草で、野菜として広く利用されている。
本発明におけるユッカフォームとは、ユッカ・シジゲラ（Yucca schidigera）、ユッカ・アラボレセンス（Yucca arborescens）、ユッカ・モヘーブ（Yucca mohavensis）などの、リュウゼツラン（Agavaceae）科ユッカ（Yucca）属の多年草植物の総称である。
本発明におけるステビアとは、キク（Asteraceae）科ステビア（Stevia）属の多年草植物で、食用、医薬品として利用されている。
本発明におけるタチジャコウソウとは、シソ（Lamiaceae）科イブキジャコウソウ（Thymus）属の多年生植物で、香辛料として用いられている。
本発明におけるベニバナとは、キク（Asteraceae）科ベニバナ（Carthamus）属の一年草で、染料や食用油の原料として広く利用されている。
本発明におけるバナナとは、バショウ（Asteraceae）科バショウ（Musa）属の植物で、食用として広く利用されている。
A plant extract is demonstrated among the active ingredients used for this invention.
The red cabbage in the present invention is a perennial plant belonging to the genus Brassica in the Brassicaaceae family and is widely used as a vegetable.
The Yucca form according to the present invention, Yucca Shijigera (Yucca schidigera), Jukka Araboresensu (Yucca arborescens), such as Yucca Mohebu (Yucca mohavensis), a general term of Agave (Agavaceae) Department of yucca (Yucca) genus of perennial plants is there.
Stevia in the present invention is a perennial plant belonging to the genus Stevia belonging to the family Asteraceae and is used as an edible or pharmaceutical product .
The term “Tachimusou” in the present invention is a perennial plant belonging to the genus Thymus belonging to the family Lamiaceae and is used as a spice.
The safflower in the present invention is an annual plant belonging to the genus Carthamus belonging to the Asteraceae family and is widely used as a raw material for dyes and edible oils.
The banana in the present invention is a plant belonging to the genus Musa in the Asteraceae family and is widely used for food.
本発明における前記植物は、その植物の全ての任意の部分が使用可能である。例えば、上記植物の全木、全草、根、根茎、幹、枝、茎、葉、樹皮、樹液、樹脂、花、果実、種子、果皮、莢、芽、花穂、心材等の任意の部分、及びそれらの組み合わせのいずれか１つ又は２つ以上を使用することができる。
本発明においてアカキャベツ抽出物を得るには、アカキャベツの葉を抽出することが好ましい。あるいは、赤キャベツ色素（アカキャベツの葉を室温時弱酸性水溶液で抽出して得られる）として市販されているものをアカキャベツ抽出物として用いてもよい。
本発明においてユッカフォーム抽出物を得るには、ユッカフォームの全草を抽出することが好ましい。あるいは、ユッカ・アラボレセンス、ユッカ・シジゲラなどの全草より、熱時水で、又は室温時〜微温時でエタノール水溶液又はイソプロピルアルコール水溶液で抽出して得られたものをユッカフォーム抽出物として用いてもよい。
本発明においてステビア抽出物を得るには、ステビアの葉を抽出することが好ましい。あるいは、ステビアの甘味料（ステビアの葉を室温時〜熱時水で抽出し、精製して得られる）として市販されているものをステビア抽出物として用いてもよい。
本発明においてタチジャコウソウ抽出物を得るには、タチジャコウソウの地上部を抽出することが好ましい。あるいは、地上部の水蒸気蒸留品であり、香辛料として市販されているものをタチジャコウソウ抽出物として用いてもよい。
本発明においてベニバナ抽出物を得るには、ベニバナの花を抽出することが好ましい。あるいは、ベニバナ赤色素（ベニバナの花、又はこれを発酵若しくは酵素処理したものから黄色素を除去し、室温時弱アルカリ性水溶液で抽出し、中和して得られる）として市販されているものをベニバナ抽出物として用いてもよい。
本発明においてバナナ抽出物を得るには、バナナの果実を抽出することが好ましい。
Any arbitrary part of the plant can be used as the plant in the present invention. For example, any part of the above-mentioned plant whole tree, whole grass, root, rhizome, stem, branch, stem, leaf, bark, sap, resin, flower, fruit, seed, pericarp, bud, bud, spikelet, heartwood, etc. And any one or more of these combinations can be used.
In order to obtain a red cabbage extract in the present invention, it is preferable to extract red cabbage leaves. Alternatively, a commercially available red cabbage pigment (obtained by extracting red cabbage leaves with a weakly acidic aqueous solution at room temperature) may be used as the red cabbage extract.
In order to obtain a yucca foam extract in the present invention, it is preferable to extract the whole yucca foam. Alternatively, it may be used as a yucca foam extract obtained from whole plants such as Yucca alalabense, Yucca shijigera, etc. by extraction with hot water, or with aqueous ethanol or isopropyl alcohol at room temperature to low temperature. Good.
In order to obtain a stevia extract in the present invention, it is preferable to extract stevia leaves. Alternatively, a commercially available stevia sweetener (obtained by extracting and purifying stevia leaves with room temperature to hot water) may be used as the stevia extract.
In the present invention, it is preferable to extract the above-ground part of the head-to-head plant in order to obtain the head-to-head extract. Alternatively, a steam-distilled product of the above-ground part, which is commercially available as a spice, may be used as the extract of the ginger.
In order to obtain a safflower extract in the present invention, it is preferable to extract safflower flowers. Alternatively, safflower red pigments (obtained from safflower flowers, or fermented or enzyme-treated safflower, obtained by neutralizing by extracting with neutral alkaline aqueous solution at room temperature) It may be used as an extract.
In order to obtain a banana extract in the present invention, it is preferable to extract a banana fruit.
本発明において用いる、アカキャベツ、ユッカフォーム、ステビア、タチジャコウソウ、ベニバナ、及びバナナの抽出物の製造方法については特に限定はなく、上記植物を通常の方法で抽出することにより抽出物を得ることができる。具体的には、前記植物を乾燥させた乾燥物又はその粉砕物、その粉砕物等を圧搾抽出することにより得られる搾汁、水蒸気蒸留物、各種抽出溶剤による粗抽出物、粗抽出物を分配又はカラムクロマトなどの各種クロマトグラフィーなどで精製して得られた抽出物画分などを本発明における抽出物として用いることができる。また、このようにして得られた抽出物画分は、必要により公知の方法により脱臭、脱色等の処理を施してから用いてもよい。
上記の植物はそのまま抽出に供することも可能であるが、より抽出効率を高めるために、乾燥、細断、粉砕等の工程を加えることも好ましい。また、本発明においては、前記抽出物、水蒸気蒸留物、圧搾物等のいずれかを単独で、又は２種以上を組み合わせて使用してもよい。なかでも、本発明の植物抽出物としては、上記植物を乾燥させた乾燥物又はその粉砕物から、抽出溶剤を用いて得られた抽出物を用いることがより好ましい。
There is no particular limitation on the method for producing the extract of red cabbage, yucca foam, stevia, red pepper, safflower, and banana used in the present invention, and the extract can be obtained by extracting the above plant by a usual method. it can. Specifically, a dried product obtained by drying the plant or a pulverized product thereof, a squeezed juice obtained by pressing and extracting the pulverized product, a steam distillate, a crude extract using various extraction solvents, and a crude extract are distributed. Alternatively, an extract fraction obtained by purification by various types of chromatography such as column chromatography can be used as the extract in the present invention. Further, the extract fraction obtained in this manner may be used after being subjected to treatments such as deodorization and decolorization by a known method, if necessary.
The above-mentioned plant can be subjected to extraction as it is, but it is also preferable to add steps such as drying, shredding, and pulverization in order to further increase the extraction efficiency. Moreover, in this invention, you may use any of the said extract, steam distillate, a pressing thing, etc. individually or in combination of 2 or more types. Especially, as a plant extract of this invention, it is more preferable to use the extract obtained using the extraction solvent from the dried material which dried the said plant, or its ground material.
抽出溶剤としては、極性溶剤、非極性溶剤のいずれをも使用することができ、これらを混合して用いることもできる。例えば、水；メタノール、エタノール、プロパノール、ブタノール等のアルコール類；エチレングリコール、プロピレングリコール、ブチレングリコール等の多価アルコール類；アセトン、メチルエチルケトン等のケトン類；酢酸メチル、酢酸エチル等のエステル類；テトラヒドロフラン、ジエチルエーテル等の鎖状及び環状エーテル類；ポリエチレングリコール等のポリエーテル類；ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ヘキサン、シクロヘキサン、石油エーテル等の炭化水素類；ベンゼン、トルエン等の芳香族炭化水素類；ピリジン類；超臨界二酸化炭素；油脂、ワックス、その他オイル等が挙げられる。あるいは、上記溶剤の２種以上を組み合わせた混合物を、抽出溶剤として用いることができる。このうち、水；メタノール、エタノール、プロパノール、ブタノール等のアルコール類等を用いるのが好ましく、水、エタノール混液を用いるのがより好ましい。 As the extraction solvent, either a polar solvent or a nonpolar solvent can be used, and these can also be mixed and used. For example, water; alcohols such as methanol, ethanol, propanol and butanol; polyhydric alcohols such as ethylene glycol, propylene glycol and butylene glycol; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; tetrahydrofuran Linear and cyclic ethers such as diethyl ether; polyethers such as polyethylene glycol; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; hydrocarbons such as hexane, cyclohexane and petroleum ether; benzene and toluene Aromatic hydrocarbons such as; pyridines; supercritical carbon dioxide; fats and oils, waxes, and other oils. Or the mixture which combined 2 or more types of the said solvent can be used as an extraction solvent. Among these, it is preferable to use water; alcohols such as methanol, ethanol, propanol, and butanol, and it is more preferable to use a mixed solution of water and ethanol.
本発明で用いられる抽出物を得るための抽出条件については、使用する溶剤によって異なり特に制限はなく、通常の条件を適用できる。例えば、上記植物１質量部に対して１〜１０質量部の溶媒を用い、０〜７０℃、好ましくは１０〜３０℃で数時間〜数週間、好ましくは１２時間〜２日間、浸漬、煎出、浸出、還流抽出、超臨界抽出、超音波抽出及び／又はマイクロ波抽出を行えばよい。また、水蒸気蒸留によっても前記抽出物を得ることが出来る。抽出効率を向上させるため、併せて攪拌を行ったり、溶媒中でホモジナイズ処理を行ってもよい。 The extraction conditions for obtaining the extract used in the present invention are not particularly limited, depending on the solvent used, and normal conditions can be applied. For example, using 1 to 10 parts by mass of a solvent with respect to 1 part by mass of the plant, 0 to 70 ° C., preferably 10 to 30 ° C. for several hours to several weeks, preferably 12 hours to 2 days, soaking and decocting Leaching, reflux extraction, supercritical extraction, ultrasonic extraction, and / or microwave extraction. The extract can also be obtained by steam distillation. In order to improve the extraction efficiency, stirring may be performed together or homogenization treatment may be performed in a solvent.
上記溶媒で抽出して得られた抽出物はそのまま使用してもよいが、さらに適当な分離手段、例えばゲル濾過、クロマトグラフィー、精密蒸留、活性炭処理等により活性の高い画分を分画して用いることもできる。本発明において、植物の抽出物とは、ソックスレー抽出器等の抽出器具を用いて得られる各種溶剤抽出液、その希釈液、その濃縮液、その精製物又はそれらの乾燥末を包含するものである。 The extract obtained by extraction with the above-mentioned solvent may be used as it is. However, a fraction having high activity can be fractionated by an appropriate separation means such as gel filtration, chromatography, precision distillation, activated carbon treatment, etc. It can also be used. In the present invention, the plant extract includes various solvent extracts obtained by using an extractor such as a Soxhlet extractor, a diluted solution thereof, a concentrated solution thereof, a purified product thereof or a dry powder thereof. .
次に、本発明に用いる有効成分のうち、ベニコウジ黄色素について説明する。
本発明におけるベニコウジ黄色素とは、ベニコウジ菌（例えば、Monascus pilosus又はMonascus purpureusなどの糸状菌）の培養生成物から抽出して得られる水溶性の黄色色素であり、その主成分はキサントモナシン類などである。ベニコウジ黄色素の調製方法としては、ベニコウジ菌の培養液を乾燥して粉砕し、微温下で、塩酸やエタノール等で抽出し、中和する方法等があるが、本発明はこれに制限するものではない。本発明において、市販されているベニコウジ黄色素を用いてもよい。
Next, among the active ingredients used in the present invention, Beniculio yellow will be described.
In the present invention, the term “Benicoccus aureus” is a water-soluble yellow pigment obtained by extraction from a culture product of a fungus such as Monascus pilosus or Monascus purpureus , and its main component is xanthomonasins. Etc. Examples of the method for preparing Benikouji yellow dye include a method of drying and pulverizing the culture solution of B. niger, extracting it with hydrochloric acid, ethanol, etc., and neutralizing it at a low temperature, but the present invention is limited thereto. is not. In the present invention, commercially available beech mushroom yellow may be used.
次に、本発明に用いる有効成分のうち、β−カロテン、ノートカトン及びメバスタチンについて説明する。 Next, among the active ingredients used in the present invention, β-carotene, note katon and mevastatin will be described.
本発明で用いるβ−カロテンは下記式で表される化合物である。 Β-carotene used in the present invention is a compound represented by the following formula.
前記β−カロテンの製造方法に特に制限はなく、通常の有機化学的合成、微生物を用いた合成等により製造することができ、天然物由来の材料から抽出や精製等したものであってもよい。例えば、オオヒゲマワリ科デュナリエラ（Dunaliella bardawil、Dunaliella salina）の全藻より、熱時油脂で、又は室温時若しくは熱時で、ヘキサン又は加圧下で二酸化炭素で抽出してβ−カロテンを得ることができる。また、試薬として市販されているものをβ−カロテンとして用いることもできる。 There is no restriction | limiting in particular in the manufacturing method of the said beta-carotene, It can manufacture by normal organic-chemical synthesis | combination, the synthesis | combination using microorganisms, etc., The thing extracted and refine | purified from the material derived from a natural product may be used. . For example, Oohigemawari family Dunaliella (Dunaliella bardawil, Dunaliella salina) than the total algae, in hot oil, or at room temperature during the time or heat, can be obtained extract and β- carotene in carbon dioxide with hexane or under pressure. Moreover, what is marketed as a reagent can also be used as (beta) -carotene.
本発明で用いるノートカトンとは、4,4a,5,6,7,8-ヘキサヒドロ-6-イソプロペニル-4,4a-ジメチル-2(3H)-ナフタレノンなるセスキテルペンケトンをいう。当該ノートカトンには、８種類の光学異性体が存在する。本発明においては、それら異性体を単独又は混合して用いることができるが、(+)-ノートカトンを用いるのが好ましい。 The note katon used in the present invention refers to a sesquiterpene ketone of 4,4a, 5,6,7,8-hexahydro-6-isopropenyl-4,4a-dimethyl-2 (3H) -naphthalenone. There are eight types of optical isomers in the note katon. In the present invention, these isomers can be used alone or as a mixture, but (+)-notecatone is preferably used.
前記ノートカトンの製造方法に特に制限はなく、通常の有機化学的合成、微生物を用いた合成等により製造することができ、例えば、特開２００４−１２３５６１号公報、特開２００３−２５０５９１号公報、特表平１１−５０１０５２号公報に記載の方法により得ることができる。また、本発明で用いるノートカトンは、ノートカトンを含有する天然物から通常の方法により抽出することにより得ることもできる。ここで、抽出は、例えば、水、熱水、エタノール、メタノール、イソプロパノール等のアルコール水、アセトン、酢酸エチル、ジエチルエーテル等の有機溶剤等を用いて行う抽出操作と高速液体クロマトグラフやカラムクロマトグラフ等による精製操作や蒸留操作を適宜組み合わせて行う方法により行うことができる。ノートカトンを含有する天然物としては特に制限はないが、例えばミカン（Rutaceae）科のグレープフルーツ（Citrus paradisi）、ザボン（Citrus maxima）、ナツミカン（Citrus natsudaidai）等が挙げられる。グレープフルーツからノートカトンを抽出する場合、その原料としては例えば、グレープフルーツ果実、グレープフルーツ果皮、グレープフルーツオイル、グレープフルーツ濃縮果汁、グレープフルーツ果汁搾汁後の残渣等を用いることができる。抽出条件は通常の条件を適用でき、例えばグレープフルーツなどの天然物を４０〜１００℃で１分〜３日間浸漬又は加熱還流したり、圧搾すればよい。 There is no particular limitation on the method for producing the notebook katon, and it can be produced by ordinary organic chemical synthesis, synthesis using microorganisms, and the like. For example, JP 2004-123561 A, JP 2003-250591, It can be obtained by the method described in Table No. 11-501052. Moreover, the note katon used by this invention can also be obtained by extracting with a normal method from the natural product containing note katon. Here, the extraction is performed using, for example, water, hot water, alcohol water such as ethanol, methanol, and isopropanol, or an organic solvent such as acetone, ethyl acetate, and diethyl ether, and high performance liquid chromatograph and column chromatograph. It can carry out by the method of performing the refining operation by distillation etc. and distillation operation combining suitably. There are no particular limitations on the natural product containing nootkatone, for example, oranges (Rutaceae) family grapefruit (Citrus paradisi), pomelo (Citrus maxima), natsudaidai (Citrus natsudaidai), and the like. When extracting note katon from grapefruit, as the raw material, for example, grapefruit fruit, grapefruit peel, grapefruit oil, grapefruit concentrated juice, residues after squeezing grapefruit juice, and the like can be used. Extraction conditions can apply normal conditions, for example, natural products, such as grapefruit, may be immersed or heated to reflux at 40 to 100 ° C. for 1 minute to 3 days, or pressed.
本発明で用いるメバスタチンは下記式で表される化合物であり、高脂血症の特効薬として広く利用されている。 Mevastatin used in the present invention is a compound represented by the following formula and is widely used as a specific drug for hyperlipidemia.
前記メバスタチンの製造方法に特に制限はなく、通常の有機化学的合成、微生物を用いた合成等により製造することができ、天然物由来の材料から抽出や精製等したものであってもよい。また、試薬として市販されているものをメバスタチンとして用いることもできる。 There is no restriction | limiting in particular in the manufacturing method of the said mevastatin, It can manufacture by normal organic-chemical synthesis | combination, the synthesis | combination using microorganisms, etc., The thing extracted and refine | purified from the material derived from a natural product may be used. Moreover, what is marketed as a reagent can also be used as mevastatin.
本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤には、前記有効成分のうちのいずれか１種を利用しても、２種以上を併用してもよい。 The preventive or ameliorating agent for overactive bladder, the ATP release inhibitor and the frequent pollakiting preventive or ameliorating agent of the present invention may be any one of the above active ingredients or may be used in combination of two or more. Good.
前述のように、ＡＴＰは蓄尿による膀胱の伸展刺激を受けて膀胱上皮細胞から放出される。このＡＴＰ放出には、膀胱上皮の伸展という機械的刺激を感知する受容体（メカノセンサー）が関与する。ヒトの膀胱上皮には、ENaC（Epithelial Na channel）ファミリーやTRP（transient receptor potential）ファミリーに属するメカノセンサーが存在することが知られている。過活動膀胱や尿路閉塞患者の膀胱上皮細胞では、これらのメカノセンサーが健常人に比べて高発現しているとの報告がある（Urologia Internationals，2006年，第76巻，p．289-295；Urology View2，2007，第5巻，p．31-36）。さらには、過活動膀胱は頻尿の原因の１つでもある。
後記実施例でも示すように、アカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及びバナナ抽出物は、ＡＴＰ放出抑制効果を示す。したがって、ヒトを含む動物がアカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及び／又はバナナ抽出物を摂取又は投与することで、過活動膀胱の予防又は改善や頻尿の予防又は改善が可能となる。
As described above, ATP is released from bladder epithelial cells in response to bladder extension stimulation by urine storage. This ATP release involves a receptor (mechanosensor) that senses a mechanical stimulus called extension of the bladder epithelium. It is known that mechanosensors belonging to the ENaC (Epithelial Na channel) family and TRP (transient receptor potential) family exist in human bladder epithelium. It has been reported that these mechanosensors are highly expressed in bladder epithelial cells of patients with overactive bladder and urinary tract obstruction (Urologia Internationals, 2006, Vol. 76, p. 289-295). Urology View 2, 2007, Vol. 5, p. 31-36). Furthermore, overactive bladder is one of the causes of frequent urination.
As shown in the Examples below, red cabbage extract, yucca foam extract, stevia extract, β-carotene, yellow-boiled yellow beetle, periwinkle extract, safflower extract, notekaton, mevastatin and banana extract are ATP released. Inhibiting effect. Therefore, animals including humans ingest or extract red cabbage extract, yuccafoam extract, stevia extract, β-carotene, beech mushroom yellow, ginger extract, safflower extract, note katon, mevastatin and / or banana extract By administration, overactive bladder can be prevented or improved, and frequent urination can be prevented or improved.
本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤は、医薬品、医薬部外品、食品、飲料等の用途に適用することができる。さらに本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤は、液状、固形状、乳液状、ペースト状、ゲル状、パウダー状（粉末状）、顆粒状、ペレット状、スティック状等、ヒトや動物に適用されうる各種剤型をとることができる。 The agent for preventing or improving overactive bladder, the agent for inhibiting ATP release, and the agent for preventing or improving frequent urination according to the present invention can be applied to uses such as pharmaceuticals, quasi drugs, foods and beverages. Furthermore, the prophylactic or improving agent for overactive bladder, the ATP release inhibitor and the frequent urinary prophylaxis or ameliorating agent of the present invention are liquid, solid, emulsion, paste, gel, powder (powder), granule, Various dosage forms applicable to humans and animals such as pellets and sticks can be used.
本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤を医薬品、医薬部外品に適用する場合、必要により各種添加剤を配合し、前記有効成分を適量含有させて、各種剤形の医薬品又は医薬部外品として調製することができる。例えば、錠剤、被覆錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、腸溶剤、トローチ剤、ドリンク剤等の経口医薬として、又は、注射剤、坐剤、経皮吸収剤、外用剤等といった非経口医薬として調製することができる。これらの形態のうち、好ましい形態は経口医薬である。このような種々の剤型の医薬製剤を調製するには、各種添加剤を用いて常法に従って製造すればよい。使用する添加剤には特に制限はなく、通常用いられているものを使用することができる。その例としては、薬学的に許容される賦形剤（ソルビトール、グルコース、乳糖、デキストリン、澱粉等の糖類、炭酸カルシウム等の無機物、結晶セルロース、蒸留水、ゴマ油、とうもろこし油、オリーブ油、菜種油等）、液体担体（蒸留水、生理食塩水、ブドウ糖水溶液、エタノール等のアルコール、プロピレングリコール、ポリエチレングリコール等）、油性担体（各種の動植物油、白色ワセリン、パラフィン、ロウ類等）、安定化剤、湿潤剤、乳化剤、結合剤、等張化剤、崩壊剤、滑沢剤、増量剤、界面活性剤、分散剤、懸濁剤、希釈剤、浸透圧調整剤、ｐＨ調整剤、防腐剤、抗酸化剤、着色剤、紫外線吸収剤、保湿剤、増粘剤、光沢剤、緩衝剤、保存剤、嬌味剤、香料、被膜剤、矯臭剤、細菌抑制剤等が挙げられる。 When applying the preventive or ameliorating agent for overactive bladder, the ATP release inhibitor and the frequent urination preventing or ameliorating agent of the present invention to pharmaceuticals and quasi-drugs, various additives are blended as necessary, and the above-mentioned active ingredients are contained in appropriate amounts And can be prepared as pharmaceuticals or quasi drugs in various dosage forms. For example, as an oral medicine such as tablets, coated tablets, capsules, granules, powders, syrups, enteric solvents, troches, drinks, etc., or non-injectables such as injections, suppositories, transdermal absorption agents, external preparations, etc. It can be prepared as an oral medicine. Of these forms, the preferred form is oral medicine. In order to prepare pharmaceutical preparations of such various dosage forms, they may be produced according to conventional methods using various additives. There is no restriction | limiting in particular in the additive to be used, The normally used thing can be used. Examples include pharmaceutically acceptable excipients (sugars such as sorbitol, glucose, lactose, dextrin, starch, inorganic substances such as calcium carbonate, crystalline cellulose, distilled water, sesame oil, corn oil, olive oil, rapeseed oil, etc.) Liquid carriers (distilled water, physiological saline, aqueous glucose solution, alcohols such as ethanol, propylene glycol, polyethylene glycol, etc.), oily carriers (various animal and vegetable oils, white petrolatum, paraffin, waxes, etc.), stabilizers, wet Agent, emulsifier, binder, isotonic agent, disintegrant, lubricant, extender, surfactant, dispersant, suspending agent, diluent, osmotic pressure adjusting agent, pH adjusting agent, preservative, antioxidant Agents, colorants, ultraviolet absorbers, moisturizers, thickeners, brighteners, buffers, preservatives, flavoring agents, fragrances, coating agents, flavoring agents, bacterial inhibitors and the like.
本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤を飲食品、飼料・ペットフード等に適用する場合、食用又は飲料用に適した形態、例えば、顆粒状、粒状、錠剤、カプセル、ペーストなどに成形して提供することができる。さらに、前記飲食品は、一般飲食品の他、過活動膀胱の予防若しくは改善、又は頻尿の予防若しくは改善剤をコンセプトとし、必要に応じてその旨を表示した美容食品、病者用食品、栄養機能食品又は特定保健用食品等の機能性飲食品の形態とすることができる。 When the preventive or ameliorating agent for overactive bladder, the ATP release inhibitor and the frequent urination preventing or ameliorating agent of the present invention are applied to food and drink, feed and pet food, etc., a form suitable for food or drink, for example, granular It can be provided in the form of granules, tablets, capsules, pastes and the like. Furthermore, in addition to general food and drink, the food and drink is based on the concept of preventing or improving overactive bladder, or preventing or improving frequent urination, and if necessary, beauty food, food for the sick, It can be set as the form of functional food-drinks, such as a nutritive functional food or the food for specified health.
飲食品の形態としては特に制限はなく、例えば、パン、麺類等に代表される小麦粉加工食品、お粥、炊き込みご飯等の米加工食品、ビスケット、ケーキ、ゼリー、チョコレート、せんべい、アイスクリーム等の菓子類、豆腐、その加工食品等の大豆加工食品、清涼飲料、果汁飲料、乳飲料、炭酸飲料等の飲料類、ヨーグルト、チーズ、バター、牛乳等の乳製品、醤油、ソース、味噌、マヨネーズ、ドレッシング等の調味料、ハム、ベーコン、ソーセージ等の蓄肉、蓄肉加工食品、はんぺん、ちくわ、魚の缶詰等の水産加工食品、調理油ならびにフライ用油等が挙げられる。また、錠剤（タブレット）、カプセル等の錠剤食、濃厚流動食、自然流動食、半消化態栄養食、成分栄養食、ドリンク栄養食等の経口経腸栄養食品、機能性食品等の形態としてもよい。
飼料の形態としては特に制限はなく、ウサギ、ラット、マウス等に用いる小動物用飼料、犬、猫、小鳥、リス等に用いるペットフード等が挙げられる。
これらの飲食品は、例えば、甘味剤、着色剤、抗酸化剤、ビタミン類、香料、ミネラル等の添加剤、タンパク質、脂質、糖質、炭水化物、食物繊維等の食品原料を適宜組み合わせて用い、これと本発明の過活動膀胱の予防若しくは改善剤、ＡＴＰ放出抑制剤又は頻尿予防若しくは改善剤とを含有させ、常法に従って各種飲食品の形態とすることにより調製することができる。
There are no particular restrictions on the form of food and drink, such as processed foods such as bread and noodles, processed rice foods such as rice cakes and cooked rice, biscuits, cakes, jelly, chocolate, rice crackers, ice cream, etc. Processed soy foods such as confectionery, tofu, processed foods thereof, soft drinks, fruit juice drinks, milk drinks, carbonated drinks and other dairy products such as yogurt, cheese, butter and milk, soy sauce, sauce, miso, mayonnaise, Examples include seasonings such as dressings, meat storage such as ham, bacon and sausage, processed meat processed foods, marine processed foods such as hampen, chikuwa and canned fish, cooking oil and frying oil. In addition, tablets, tablets, and other tablet foods, concentrated liquid foods, natural liquid foods, semi-digested nutritional foods, ingredient nutritional foods, drink nutritional foods, etc. Good.
There is no restriction | limiting in particular as a form of feed, The pet food etc. which are used for the feed for small animals used for a rabbit, a rat, a mouse | mouth, a dog, a cat, a small bird, a squirrel, etc. are mentioned.
These foods and drinks use, for example, an appropriate combination of food ingredients such as sweeteners, colorants, antioxidants, vitamins, fragrances, minerals, etc., proteins, lipids, carbohydrates, carbohydrates, dietary fibers, etc. It can be prepared by containing this and the preventive or ameliorating agent for overactive bladder of the present invention, an ATP release inhibitor or a frequent urinary prophylaxis or ameliorating agent, and in the form of various foods and beverages according to conventional methods.
本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤はそのままで医薬品、医薬部外品、食品、飲料等として用いてもよいし、医薬品、医薬部外品、食品、飲料等の添加剤又は配合剤として用いてもよい。 The preventive or ameliorating agent for overactive bladder, the ATP release inhibitor and the frequent urinary prophylaxis or improving agent of the present invention may be used as they are as pharmaceuticals, quasi drugs, foods, beverages, etc., or pharmaceuticals, quasi drugs. It may be used as an additive or a compounding agent for foods and beverages.
本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤における前記有効成分の配合量はその使用形態により異なるが、医薬品、例えば、錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤等の経口用固形製剤、内服液剤、シロップ剤等の経口用液体製剤の場合は、固形分濃度として０．００１〜１００質量％が好ましく、０．０１〜９５質量％がより好ましい。飲食品やペットフード等に配合する場合は、固形分濃度として０．００１〜５０質量％が好ましく、０．０１〜１０質量％がより好ましい。 The compounding amount of the active ingredient in the preventive or ameliorating agent for overactive bladder, the ATP release inhibitor and the frequent urination preventing or ameliorating agent of the present invention varies depending on the usage form, In the case of oral solid preparations such as powders and capsules, oral liquid preparations such as oral liquids and syrups, the solid content concentration is preferably 0.001 to 100% by weight, more preferably 0.01 to 95% by weight. . When mix | blending with food-drinks, pet food, etc., 0.001-50 mass% is preferable as solid content concentration, and 0.01-10 mass% is more preferable.
本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤の投与又は摂取量は、個体の状態、体重、性別、年齢、素材の活性又はその他の要因に従って適宜選択、決定される。例えば、成人（６０ｋｇ）１日の投与又は摂取量としては、一般に０．００１〜２５０ｇが好ましい。また、本発明の過活動膀胱の予防又は改善剤、ＡＴＰ放出抑制剤及び頻尿予防又は改善剤は、１日１回〜数回に分け、又は任意の期間及び間隔で摂取・投与され得る。 Administration or intake of the overactive bladder preventive or ameliorating agent, ATP release inhibitor and frequent urination preventing or ameliorating agent of the present invention is appropriately selected according to the individual's condition, body weight, sex, age, material activity or other factors. ,It is determined. For example, the daily dose or intake for adults (60 kg) is generally preferably 0.001 to 250 g. The agent for preventing or improving overactive bladder, the agent for inhibiting ATP release, and the agent for preventing or improving frequent urination according to the present invention can be taken or administered once a day to several times a day, or at an arbitrary period and interval.
上記医薬品、医薬部外品又は食品の摂取又は投与対象として特に限定されないが、過活動膀胱又は尿意切迫感及び切迫性尿失禁等の排尿障害の予防又は改善又は治療を目的とするヒトやヒト以外の哺乳動物が好ましい。なお、摂取又は投与対象には、過活動膀胱の症状が認められるヒトやヒト以外の哺乳動物、及びそのおそれがあるヒトやヒト以外の哺乳動物、その疾患・症状の予防を期待するヒトやヒト以外の哺乳動物も含まれる。 Although it is not particularly limited as a subject of ingestion or administration of the above pharmaceuticals, quasi-drugs or foods, humans or non-humans for the purpose of preventing or improving or treating overactive bladder or urination disorder such as urgency and urge urinary incontinence Mammals are preferred. In addition, the subject of ingestion or administration includes humans and non-human mammals with overactive bladder symptoms, humans and non-human mammals who may be at risk, and humans and humans who are expected to prevent the disease / symptoms. Other mammals are also included.
以下、本発明を実施例に基づきさらに詳細に説明するが、本発明はこれに限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to this.
調製例１ アカキャベツ抽出物の調製
アカキャベツ抽出物（商品名：レッドカラーDC、三菱化学フーズ社より入手）を濃度が１％（ｗ／ｖ）となるように５０体積％エタノールで希釈した。
Preparation Example 1 Preparation of red cabbage extract Red cabbage extract (trade name: Red Color DC, obtained from Mitsubishi Chemical Foods) was diluted with 50% by volume ethanol so that the concentration became 1% (w / v).
調製例２ ユッカフォーム抽出物の調製
ユッカフォーム抽出物（商品名：サラキープALS、丸善製薬社より入手）を濃度が１％（ｗ／ｖ）となるように５０体積％エタノールで希釈した。
Preparation Example 2 Preparation of Yuccafoam extract Yuccafoam extract (trade name: Sarakeep ALS, obtained from Maruzen Pharmaceutical Co., Ltd.) was diluted with 50% by volume ethanol so that the concentration became 1% (w / v).
調製例３ ステビア抽出物の調製
ステビア抽出物（商品名：レバウディオA7-10、守田化学社製）を濃度が１％（ｗ／ｖ）となるように５０体積％エタノールで溶解した。
Preparation Example 3 Preparation of Stevia Extract Stevia extract (trade name: Rebaudio A7-10, manufactured by Morita Chemical Co., Ltd.) was dissolved in 50% by volume ethanol so that the concentration became 1% (w / v).
調製例４ β−カロテンの調製
バイオカロチン30MCT（商品名、協和発酵社より入手）を濃度が１％（ｗ／ｖ）となるように９９．５体積％エタノールで溶解した。
Preparation Example 4 Preparation of β-carotene Biocarotene 30MCT (trade name, obtained from Kyowa Hakko) was dissolved in 99.5 vol% ethanol so that the concentration would be 1% (w / v).
調製例５ ベニコウジ黄色素の調製
ベニコウジ黄色素（商品名：マルカラーYM、丸善製薬社より入手）を濃度が１％（ｗ／ｖ）となるように５０体積％エタノールで希釈した。
Preparation Example 5 Preparation of Benikouji Yellow Dye Benikouji Yellow Dye (trade name: Marcolor YM, obtained from Maruzen Pharmaceutical Co., Ltd.) was diluted with 50% by volume ethanol so that the concentration became 1% (w / v).
調製例６ タチジャコウソウ抽出物の調製
香辛料抽出物製剤（商品名：タイムSP-61515、三栄源エフエフアイ社より入手）を原液のまま、タチジャコウソウ抽出物として使用した。
Preparation Example 6 Preparation of extract of Tachimusou Spice extract formulation (trade name: Thyme SP-61515, obtained from San-Eigen FFI Co., Ltd.) was used as the extract of Tachimusou.
調製例７ ベニバナ抽出物の調製
ベニバナ赤色素（OCI社より入手）を５０体積％エタノールに濃度が１％（ｗ／ｖ）となるように溶解した。
Preparation Example 7 Preparation of safflower extract A safflower red pigment (obtained from OCI) was dissolved in 50% by volume ethanol to a concentration of 1% (w / v).
調製例８ ノートカトンの調製
ノートカトン（和光純薬社より入手）を濃度が１００ｍＭになるように５０体積％エタノールに溶解した。
Preparation Example 8 Preparation of Note Katon Note Katon (obtained from Wako Pure Chemical Industries, Ltd.) was dissolved in 50% by volume ethanol to a concentration of 100 mM.
調製例９ メバスタチンの調製
メバスタチン（和光純薬社より入手）を濃度が１０ｍＭになるように９９．５体積％エタノールに溶解した。
Preparation Example 9 Preparation of mevastatin Mevastatin (obtained from Wako Pure Chemical Industries, Ltd.) was dissolved in 99.5% by volume ethanol so that the concentration was 10 mM.
調製例１０ バナナ抽出物の調製
バナナ透明果汁（バナナの圧搾抽出液、雄山商事より入手）を濃度が１．４０％（ｗ／ｖ）となるように２０体積％エタノールで希釈した。
Preparation Example 10 Preparation of Banana Extract Banana transparent fruit juice (banana pressed extract, obtained from Oyama Corporation) was diluted with 20% by volume ethanol so that the concentration was 1.40% (w / v).
試験例１ ＡＴＰ放出抑制試験
特開２０１１−１３３４４０号公報に記載の方法を参考に、下記に示すようにＡＴＰ放出抑制試験を行った。
膀胱上皮細胞株としてHT-1376（ATCC社より購入、下記表１に細胞情報を示す）を用い、下記に示す組成の培地を用いて３７℃、５％CO2条件下で培養した。
HT-1376用培地：MEM（Minimum Essential Medium）
Earle's（Invitrogen社製）に、10％FCS（ウシ胎仔血清）、ピルビン酸ナトリウム（0.055ｇ／500ｍＬ）、L-グルタミン（0.146ｇ／500ｍＬ）を添加
Test Example 1 ATP Release Inhibition Test An ATP release inhibition test was conducted as described below with reference to the method described in JP2011-133440A.
HT-1376 (purchased from ATCC, cell information is shown in Table 1 below) was used as a bladder epithelial cell line, and cultured under conditions of 37 ° C. and 5% CO 2 using a medium having the composition shown below.
Medium for HT-1376: MEM (Minimum Essential Medium)
Add 10% FCS (fetal calf serum), sodium pyruvate (0.055 g / 500 mL), L-glutamine (0.146 g / 500 mL) to Earle's (Invitrogen)
96wellプレートに、４．１×１０4cells/wellになるようにHT-1376を播種し、上記培養条件にて２４時間培養した。培地を吸引除去して等浸透圧液（組成を表２に示す）で２回洗浄し、前記製造例で調製した各成分を表３に示す濃度で含有する等浸透圧液をそれぞれ７５μＬ／well加えて、３７℃、５％CO2環境下で６０分インキュベートした。さらに、前記製造例で調製した各成分を表３に示す濃度で含有する低浸透圧液（組成を表２に示す）を７５μＬ／well添加し、３７℃、５％CO2環境下で６０分インキュベートし、溶液を回収した。 HT-1376 was seeded on a 96-well plate at 4.1 × 10 4 cells / well, and cultured for 24 hours under the above culture conditions. The medium was removed by suction and washed twice with an isotonic solution (composition is shown in Table 2), and each of the isosmotic solutions containing the components prepared in the above preparation examples at the concentrations shown in Table 3 was 75 μL / well. In addition, it was incubated for 60 minutes in a 37 ° C., 5% CO 2 environment. Further, 75 μL / well of a low osmotic pressure solution (the composition is shown in Table 2) containing each component prepared in the above production example at a concentration shown in Table 3, was added for 60 minutes at 37 ° C. in a 5% CO 2 environment. Incubate and collect solution.
回収したサンプル中のＡＴＰ濃度を、ATP Bioluminescent Assay Kit（SIGMA製）を用いてルシフェリン・ルシフェラーゼ法により測定した。すなわち、サンプルと、ATP Bioluminescent Assay Kit中のATP Assay Mix solutionとを等量で混合し、撹拌後にホタルルシフェラーゼ活性を１秒間測定してＡＴＰ濃度を決定し、ＡＴＰ放出率を測定した。結果を表３に示す。なお、溶媒対照の低浸透圧液を添加した際のＡＴＰ放出率を１００％としたときの相対値で表した。 The ATP concentration in the collected sample was measured by the luciferin luciferase method using ATP Bioluminescent Assay Kit (manufactured by SIGMA). That is, the sample and the ATP Assay Mix solution in the ATP Bioluminescent Assay Kit were mixed in an equal amount, and after stirring, the ATP concentration was determined by measuring the firefly luciferase activity for 1 second, and the ATP release rate was measured. The results are shown in Table 3. In addition, it represented with the relative value when the ATP release rate at the time of adding the low osmotic pressure liquid of a solvent control was set to 100%.
等浸透圧から低浸透圧へと浸透圧を変化させることで膀胱上皮細胞を刺激し伸展させると、ＡＴＰの放出が亢進する。しかし、表３の結果から明らかなように、浸透圧を変化させても、各有効成分を添加することにより、用量依存的にＡＴＰ放出が抑制された。これより、アカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及びバナナ抽出物にはＡＴＰ放抑制作用を有することが示された。 When bladder epithelial cells are stimulated and expanded by changing the osmotic pressure from isotonic pressure to low osmotic pressure, ATP release is enhanced. However, as is clear from the results in Table 3, even when the osmotic pressure was changed, ATP release was suppressed in a dose-dependent manner by adding each active ingredient. From this, red cabbage extract, yuccafoam extract, stevia extract, β-carotene, beech mushroom yellow, periwinkle extract, safflower extract, note katon, mevastatin and banana extract have ATP release inhibitory action It has been shown.
試験例２ ＡＴＰ放出に対する、前記有効成分のクエンチング効果の評価
試験例１において、ＡＴＰ濃度はルシフェリン・ルシフェラーゼ法により測定しているが、サンプルに各有効成分が含まれている。そのため、本発明の各有効成分にクエンチング効果がある場合には、ＡＴＰ濃度が低く計算されてしまい、ＡＴＰ放出阻害活性が擬陽性となる。そこで、本発明の各有効成分のクエンチング効果を検証する目的で、各有効成分含有サンプルのＡＴＰ添加回収率を評価した。
Test Example 2 Evaluation of quenching effect of active ingredient on ATP release In Test Example 1, the ATP concentration was measured by the luciferin-luciferase method, but each active ingredient was contained in the sample. Therefore, when each active ingredient of the present invention has a quenching effect, the ATP concentration is calculated to be low, and the ATP release inhibitory activity becomes false positive. Then, in order to verify the quenching effect of each active ingredient of the present invention, the ATP addition recovery rate of each active ingredient-containing sample was evaluated.
空の96wellプレートに、表４に示す濃度で各有効成分を含む等浸透圧液を７５μＬ／well添加し、３７℃、５％CO2環境下で６０分インキュベートした。さらに、ＡＴＰ及び表４に示す濃度で各有効成分を含む低浸透圧液（ＡＴＰ終濃度：５×１０-8Ｍ）を７５μＬ／well添加し、３７℃、５％CO2環境下で６０分インキュベートし、溶液を回収した。
回収したサンプル溶液は、試験例１と同様に、ルシフェリン・ルシフェラーゼ法により回収したサンプル中のＡＴＰ濃度を測定した。メバスタチン及びノートカトン以外の各有効成分は終濃度0.01％（ｗ／ｖ）、メバスタチン及びノートカトンは終濃度５０μＭにて評価した。結果を表４に示す。結果は、各有効成分を含まない溶液のＡＴＰ濃度に対する相対値（％）で表した。
To an empty 96-well plate, 75 μL / well of an iso-osmotic solution containing each active ingredient at a concentration shown in Table 4 was added and incubated at 37 ° C. in a 5% CO 2 environment for 60 minutes. Furthermore, 75 μL / well of ATP and a low osmotic pressure solution (ATP final concentration: 5 × 10 −8 M) containing each active ingredient at concentrations shown in Table 4 were added, and the mixture was added at 37 ° C. in a 5% CO 2 environment for 60 minutes. Incubate and collect solution.
The collected sample solution was measured for the ATP concentration in the sample collected by the luciferin-luciferase method in the same manner as in Test Example 1. Each active ingredient other than mevastatin and notecaton was evaluated at a final concentration of 0.01% (w / v), and mevastatin and notecaton were evaluated at a final concentration of 50 μM. The results are shown in Table 4. The result was expressed as a relative value (%) with respect to the ATP concentration of the solution not containing each active ingredient.
その結果、各成分に高いＡＴＰ添加回収性が認められた。これより、アカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及びバナナ抽出物自体はＡＴＰ濃度の測定に影響を及ぼさないことが示された。 As a result, high ATP addition recoverability was recognized for each component. As a result, red cabbage extract, yucca foam extract, stevia extract, β-carotene, beech mushroom yellow, periwinkle extract, safflower extract, note katon, mevastatin and banana extract itself have an effect on the measurement of ATP concentration. It was shown not to reach.
以上のように、アカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及びバナナ抽出物は、膀胱上皮細胞伸展時に亢進するＡＴＰ放出を抑制する効果を有する。したがって、アカキャベツ抽出物、ユッカフォーム抽出物、ステビア抽出物、β−カロテン、ベニコウジ黄色素、タチジャコウソウ抽出物、ベニバナ抽出物、ノートカトン、メバスタチン及びバナナ抽出物は、過活動膀胱の予防又は改善効果や頻尿の予防又は改善効果を有する。 As described above, red cabbage extract, yuccafoam extract, stevia extract, β-carotene, red beetle yellow pigment, red ginger extract, safflower extract, note katon, mevastatin and banana extract are It has the effect of suppressing enhanced ATP release. Therefore, red cabbage extract, yuccafoam extract, stevia extract, β-carotene, red beetle, yellow ginger extract, safflower extract, note katon, mevastatin and banana extract are effective in preventing or improving overactive bladder. And prevention or improvement of frequent urination.
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