JP7401863B2 - Vasospasm inhibitor, vasospasm preventive agent, oral composition for preventing vasospasm, and oral composition for suppressing vasospasm - Google Patents
Vasospasm inhibitor, vasospasm preventive agent, oral composition for preventing vasospasm, and oral composition for suppressing vasospasm Download PDFInfo
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- JP7401863B2 JP7401863B2 JP2020170315A JP2020170315A JP7401863B2 JP 7401863 B2 JP7401863 B2 JP 7401863B2 JP 2020170315 A JP2020170315 A JP 2020170315A JP 2020170315 A JP2020170315 A JP 2020170315A JP 7401863 B2 JP7401863 B2 JP 7401863B2
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- vasospasm
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- oral composition
- fisetin
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Description
本発明は、血管攣縮抑制剤、血管攣縮予防剤、血管攣縮予防用経口組成物及び血管攣縮抑制用経口組成物に関する。 The present invention relates to a vasospasm inhibitor, a vasospasm preventive agent, an oral composition for preventing vasospasm, and an oral composition for suppressing vasospasm.
血管は血圧及び血流を一定に保つために、細胞質Ca2+濃度に依存的な収縮及び弛緩運動を繰り返している。細胞質Ca2+濃度に依存しない血管の異常収縮が、偏頭痛及び血流停滞等の他、重篤な狭心症又はくも膜下出血に伴う血管攣縮等を引き起こす。異常収縮は、最悪の場合、死に至るため突然死の主原因として恐れられているが、特効薬がないのが現状である。 In order to keep blood pressure and blood flow constant, blood vessels repeatedly contract and relax depending on the cytosolic Ca 2+ concentration. Abnormal contraction of blood vessels that does not depend on cytoplasmic Ca 2+ concentration causes migraine headaches, blood flow stagnation, etc., as well as vasospasm associated with severe angina pectoris or subarachnoid hemorrhage. Abnormal contractions are feared as the main cause of sudden death because, in the worst case, they can lead to death, but there is currently no specific cure.
血管平滑筋の異常収縮は、Rhoキナーゼによる血管平滑筋のCa2+感作(sensitization)によって引き起こされる。Rhoキナーゼを活性化することで血管平滑筋のCa2+感作を引き起こす分子としてスフィンゴシルホスホリルコリン(SPC)が知られている。非特許文献1には、SPCによって引き起こされる血管攣縮をエイコサペンタエン酸(EPA)が抑制することが報告されている。 Abnormal contraction of vascular smooth muscle is caused by Ca 2+ sensitization of vascular smooth muscle by Rho kinase. Sphingosylphosphorylcholine (SPC) is known as a molecule that causes Ca 2+ sensitization of vascular smooth muscle by activating Rho kinase. Non-Patent Document 1 reports that eicosapentaenoic acid (EPA) suppresses vasospasm caused by SPC.
EPAは多価不飽和脂肪酸であるため、酸化しやすく不安定である点が不都合である。また、EPAは化学合成の極めて困難な化合物であり、主としてイワシ魚油から抽出及び精製される。イワシの漁獲量が不安定なことに加え、イワシの乱獲による資源枯渇が危惧されている。安定な供給が確実ではないEPA以外で、血管の異常収縮を抑制することができる新規の物質が求められている。 Since EPA is a polyunsaturated fatty acid, it is disadvantageous in that it is easily oxidized and unstable. Furthermore, EPA is a compound that is extremely difficult to chemically synthesize, and is mainly extracted and purified from sardine fish oil. In addition to unstable sardine catches, there are concerns that overfishing will lead to depletion of sardine resources. In addition to EPA, for which stable supply is not guaranteed, there is a need for new substances that can suppress abnormal contraction of blood vessels.
本発明は上述の事情に鑑みてなされたものであり、血管の異常収縮を抑制することができる血管攣縮抑制剤、血管攣縮予防剤、血管攣縮予防用経口組成物及び血管攣縮抑制用経口組成物を提供することを目的とする。 The present invention has been made in view of the above circumstances, and provides a vasospasm inhibitor, a vasospasm preventive agent, an oral composition for preventing vasospasm, and an oral composition for suppressing vasospasm that can suppress abnormal contraction of blood vessels. The purpose is to provide
本発明の第1の観点に係る血管攣縮抑制剤は、
式(1)
前記式(1)におけるR1及びR2は、それぞれ独立して水素原子又は水酸基である。
The vasospasm inhibitor according to the first aspect of the present invention includes:
Formula (1)
R 1 and R 2 in the formula (1) are each independently a hydrogen atom or a hydroxyl group.
この場合、前記式(1)におけるR1は、水酸基である、
こととしてもよい。
In this case, R 1 in the formula (1) is a hydroxyl group,
It may also be a thing.
また、前記化合物は、
フィセチンである、
こととしてもよい。
Further, the compound is
is fisetin,
It may also be a thing.
また、上記本発明の第1の観点に係る血管攣縮抑制剤は、
前記化合物をクワ科クワ属に属する植物の抽出物として含有する、
こととしてもよい。
In addition, the vasospasm inhibitor according to the first aspect of the present invention includes:
Containing the compound as an extract of a plant belonging to the family Moraceae, genus Morus,
It may also be a thing.
本発明の第2の観点に係る血管攣縮予防剤は、
式(1)
前記式(1)におけるR1及びR2は、それぞれ独立して水素原子又は水酸基である。
The vasospasm preventive agent according to the second aspect of the present invention includes:
Formula (1)
R 1 and R 2 in the formula (1) are each independently a hydrogen atom or a hydroxyl group.
本発明の第3の観点に係る血管攣縮予防用経口組成物又は血管攣縮抑制用経口組成物は、
式(1)
前記式(1)におけるR1及びR2は、それぞれ独立して水素原子又は水酸基である。
The oral composition for preventing vasospasm or the oral composition for suppressing vasospasm according to the third aspect of the present invention,
Formula (1)
R 1 and R 2 in the formula (1) are each independently a hydrogen atom or a hydroxyl group .
本発明によれば、血管の異常収縮を抑制することができる。 According to the present invention, abnormal contraction of blood vessels can be suppressed.
本発明に係る実施の形態について図面を参照して説明する。なお、本発明は下記の実施の形態及び図面によって限定されるものではない。なお、下記の実施の形態において、“有する”、“含む”又は“含有する”といった表現は、“からなる”又は“から構成される”という意味も包含する。 Embodiments according to the present invention will be described with reference to the drawings. Note that the present invention is not limited to the following embodiments and drawings. Note that in the embodiments below, expressions such as "have," "include," or "contain" also include the meanings of "consisting of" or "consisting of."
(実施の形態)
本実施の形態に係る血管攣縮抑制剤は、次の式(1)に示される構造を有する化合物又はその塩(以下、単に“化合物X”とする)を有効成分として含有する。式(1)におけるR1及びR2は、それぞれ独立して水素原子又は水酸基である。
(Embodiment)
The vasospasm inhibitor according to the present embodiment contains as an active ingredient a compound having a structure represented by the following formula (1) or a salt thereof (hereinafter simply referred to as "compound X"). R 1 and R 2 in formula (1) are each independently a hydrogen atom or a hydroxyl group.
例えば、式(1)におけるR1が水素原子であって、R2が水酸基である化合物Xはルテオリン(luteolin)である。好ましくは、式(1)におけるR1は水酸基である。R1が水酸基であって、R2が水素原子である化合物Xはフィセチン(fisetin)である。R1及びR2がいずれも水酸基である化合物Xは、ケルセチン(quercetin)である。好適には、血管攣縮抑制剤に有効成分として含有される化合物Xはフィセチンである。 For example, the compound X in which R 1 is a hydrogen atom and R 2 is a hydroxyl group in formula (1) is luteolin. Preferably, R 1 in formula (1) is a hydroxyl group. Compound X in which R 1 is a hydroxyl group and R 2 is a hydrogen atom is fisetin. Compound X in which R 1 and R 2 are both hydroxyl groups is quercetin. Compound X contained as an active ingredient in the vasospasm inhibitor is preferably fisetin.
化合物Xが式(1)に示される構造を有する化合物の塩である場合、塩は、薬理学上許容され、かつ血管攣縮抑制活性を示す塩であれば特に限定されない。当該化合物の塩としては、例えば、アルカリ金属塩及びアルカリ土類金属塩等が挙げられる。アルカリ金属塩としては、例えばリチウム塩、ナトリウム塩及びカリウム塩等が挙げられ、アルカリ土類金属塩としては、マグネシウム塩及びカルシウム塩等が挙げられる。 When compound X is a salt of a compound having the structure represented by formula (1), the salt is not particularly limited as long as it is pharmacologically acceptable and exhibits vasospasm suppressing activity. Examples of the salts of the compounds include alkali metal salts and alkaline earth metal salts. Examples of the alkali metal salts include lithium salts, sodium salts, and potassium salts, and examples of the alkaline earth metal salts include magnesium salts and calcium salts.
化合物Xは公知の方法で合成できる。化合物Xとして市販のものを用いてもよい。化合物Xは、植物、例えばクワ科(Moraceae)クワ属(Morus)に属する植物に含まれる。 Compound X can be synthesized by a known method. A commercially available compound may be used as compound X. Compound X is contained in plants, for example, plants belonging to the family Moraceae and the genus Morus.
クワ科クワ属に属する植物としては、ヤマグワ(Morus australis)、ログワ(ロソウ)(Morus latifolia)、ナガミグワ(Morus laevigata)、ケグワ(Morus tiliaefolia)、オガサワラグワ(Morus boninensis)、テンジクグワ(Morus serrata)、アカミグワ(Morus rubra)、カラヤマグワ(Morus alba)、クロミグワ(Morus nigra)及びブラックマルベリー(Morus mesozygia)等が挙げられる。 Plants belonging to the genus Morus in the family Moraceae include Morus australis, Morus latifolia, Morus laevigata, Morus tiliaefolia, and Morus boninens. is), Morus serrata, Examples include red mulberry (Morus rubra), yellow mulberry (Morus alba), black mulberry (Morus nigra), and black mulberry (Morus mesozygia).
好適には、化合物Xはクワ科クワ属に属する植物の葉(桑葉)から抽出される。抽出物は、例えば、桑葉をそのまま、あるいは桑葉の加工物を溶媒で抽出して得られる抽出物、その希釈液及び濃縮液、並びにそれらの乾燥物及び粉末が挙げられ、化合物Xが含有されていれば特に限定されない。 Preferably, compound X is extracted from leaves (mulberry leaves) of plants belonging to the family Moraceae, genus Morus. Extracts include, for example, extracts obtained by extracting mulberry leaves as they are or processed mulberry leaves with a solvent, diluted and concentrated solutions thereof, and dried products and powders thereof, and which contain compound X. There is no particular limitation as long as it is.
抽出溶媒は、特に限定されないが、例えば、エタノール、イソプロピルアルコール、1,3-ブチレングリコール、アセトン、ブタノール及び酢酸等である。抽出溶媒は混合溶媒であってもよい。抽出溶媒は、好ましくはエタノールである。抽出時間は、抽出溶媒の種類及び桑葉と抽出溶媒との割合を考慮し適宜選択される。また、得られた抽出物はそのまま利用してもよいが、常法に従って希釈、濃縮、乾燥及び精製等の処理を施してもよい。また、必要に応じて化合物Xの割合を高めるため、減圧濃縮や凍結乾燥により溶媒を除去してもよい。例えば、桑葉を溶媒に浸漬し、一定時間経過後、溶媒を濃縮乾固した乾固物を抽出物としてもよい。 Extraction solvents include, but are not particularly limited to, ethanol, isopropyl alcohol, 1,3-butylene glycol, acetone, butanol, acetic acid, and the like. The extraction solvent may be a mixed solvent. The extraction solvent is preferably ethanol. The extraction time is appropriately selected in consideration of the type of extraction solvent and the ratio of mulberry leaves to extraction solvent. Further, the obtained extract may be used as it is, or may be subjected to treatments such as dilution, concentration, drying, and purification according to conventional methods. Moreover, in order to increase the proportion of compound X, if necessary, the solvent may be removed by vacuum concentration or freeze-drying. For example, a dried product obtained by soaking mulberry leaves in a solvent and concentrating the solvent to dryness after a certain period of time may be used as an extract.
血管攣縮抑制剤は、化合物Xをクワ科クワ属に属する植物の抽出物として含有してもよい。すなわち、血管攣縮抑制剤は、植物の抽出物から分離された化合物Xではなく、化合物Xを含む植物の抽出物を含有する。 The vasospasm inhibitor may contain compound X as an extract of a plant belonging to the family Moraceae and the genus Morus. That is, the vasospasm inhibitor contains a plant extract containing Compound X, rather than Compound X isolated from a plant extract.
化合物Xは、植物の抽出物からクロマトグラフィーで単離及び精製できる。好ましくは、クロマトグラフィーは液体クロマトグラフィー、特に好ましくはHPLCである。 Compound X can be chromatographically isolated and purified from plant extracts. Preferably, the chromatography is liquid chromatography, particularly preferably HPLC.
化合物Xが抽出される植物は、クワ科クワ属に属する植物に限らず、ヒノキ、ヌルデ属、イチゴ、セロリ、ブロッコリー及びピーマン等であってもよい。 The plants from which compound X is extracted are not limited to plants belonging to the genus Morus of the family Moraceae, but may also include cypress, genus Nurdu, strawberries, celery, broccoli, green peppers, and the like.
本実施の形態に係る血管攣縮抑制剤は、既知の方法で製造され、有効成分として0.000001~99.9重量%、0.00001~99.8重量%、0.0001~99.7重量%、0.001~99.6重量%、0.01~99.5重量%、0.1~99重量%、0.5~60重量%、1~50重量%又は1~20重量%の化合物Xを含む。血管攣縮抑制剤は、固形製剤であっても、液状製剤であってもよい。 The vasospasm inhibitor according to the present embodiment is manufactured by a known method, and contains active ingredients of 0.000001 to 99.9% by weight, 0.00001 to 99.8% by weight, and 0.0001 to 99.7% by weight. %, 0.001-99.6% by weight, 0.01-99.5% by weight, 0.1-99% by weight, 0.5-60% by weight, 1-50% by weight or 1-20% by weight Contains compound X. The vasospasm inhibitor may be a solid preparation or a liquid preparation.
血管攣縮抑制剤は化合物Xに加え、薬理学上許容される任意の成分を含んでもよい。任意の成分は、例えば、賦形剤、滑沢剤、結合剤、崩壊剤、溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤及び無痛化剤等である。また、必要に応じて、防腐剤、抗酸化剤、着色剤及び甘味剤等の添加物が血管攣縮抑制剤に配合されてもよい。 In addition to compound X, the vasospasm inhibitor may contain any pharmacologically acceptable component. Optional ingredients include, for example, excipients, lubricants, binders, disintegrants, solvents, solubilizing agents, suspending agents, tonicity agents, buffers, and soothing agents. Additionally, additives such as preservatives, antioxidants, colorants, and sweeteners may be added to the vasospasm inhibitor, if necessary.
賦形剤としては、乳糖、白糖、D-マンニトール、D-ソルビトール、デンプン、α化デンプン、デキストリン、結晶セルロース、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム、アラビアゴム、プルラン、軟質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、キシリトール、ソルビトール及びエリスリトール等が挙げられる。 Excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, pullulan, soft silicic anhydride, Examples include synthetic aluminum silicate, magnesium aluminate metasilicate, xylitol, sorbitol, and erythritol.
滑沢剤は、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ及びポリエチレングリコール等である。 Lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, and polyethylene glycol.
結合剤としては、α化デンプン、ショ糖、ゼラチン、アラビアゴム、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、結晶セルロース、白糖、D-マンニトール、トレハロース、デキストリン、プルラン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース及びポリビニルピロリドン等が例示される。 Binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, white sugar, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinyl. Examples include pyrrolidone.
崩壊剤は、例えば、乳糖、白糖、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロース、軟質無水ケイ酸及び炭酸カルシウム等である。 Examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, soft silicic anhydride, and calcium carbonate.
溶剤としては、注射用水、生理食塩水、リンゲル液、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、ゴマ油、トウモロコシ油、オリーブ油及び綿実油等が挙げられる。溶解補助剤は、例えば、ポリエチレングリコール、プロピレングリコール、D-マンニトール、トレハロース、安息香酸ベンジル、エタノール、トリス(ヒドロキシメチル)アミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム、サリチル酸ナトリウム及び酢酸ナトリウム等である。 Examples of solvents include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil. Examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, tris(hydroxymethyl)aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and acetic acid. Sodium etc.
懸濁化剤としては、例えば、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム及びモノステアリン酸グリセリン等の界面活性剤;ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース及びヒドロキシプロピルセルロース等の親水性高分子;ポリソルベート類、並びにポリオキシエチレン硬化ヒマシ油等が挙げられる。 Suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone, and carboxylic acid. Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
等張化剤は、例えば、塩化ナトリウム、グリセリン、D-マンニトール、D-ソルビトール、ブドウ糖、キシリトール及び果糖等が挙げられる。緩衝剤は、例えば、リン酸塩、酢酸塩、炭酸塩及びクエン酸塩等の緩衝液等である。無痛化剤は、例えば、プロピレングリコール、塩酸リドカイン及びベンジルアルコール等である。 Examples of tonicity agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, xylitol, and fructose. Buffers include, for example, phosphate, acetate, carbonate, and citrate buffers. Examples of soothing agents include propylene glycol, lidocaine hydrochloride, and benzyl alcohol.
防腐剤としては、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸及びソルビン酸等が挙げられる。抗酸化剤としては、亜硫酸塩及びアスコルビン酸塩等が例示される。着色剤としては、水溶性着色タール色素、レーキ色素及び天然色素等が挙げられる。甘味剤は、例えば、サッカリンナトリウム、グリチルリチン酸二カリウム、アスパルテーム及びステビア等である。 Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Examples of antioxidants include sulfites and ascorbates. Examples of the coloring agent include water-soluble colored tar pigments, lake pigments, and natural pigments. Sweeteners include, for example, sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.
血管攣縮抑制剤の投与量は、投与対象の性別、年齢、体重及び症状等によって適宜決定される。血管攣縮抑制剤は、化合物Xが有効量となるように投与される。有効量とは、所望の結果を得るために必要な化合物Xの量であり、治療又は処置する疾患に係る状態の進行の遅延、阻害、予防、逆転又は治癒をもたらすのに必要な量である。血管攣縮抑制剤の投与量は、特には、血管の異常収縮、血管攣縮又は血管痙攣を予防、抑制又は停止するために必要な量である。 The dosage of the vasospasm inhibitor is appropriately determined depending on the gender, age, weight, symptoms, etc. of the subject. The vasospasm inhibitor is administered in such a manner that Compound X is administered in an effective amount. An effective amount is the amount of Compound . The dose of the vasospasm inhibitor is, in particular, the amount necessary to prevent, suppress, or stop abnormal vasoconstriction, vasospasm, or vasospasm.
血管攣縮抑制剤の投与量は、例えば、0.01mg/kg~1000mg/kg、好ましくは0.1mg/kg~200mg/kg、より好ましくは0.2mg/kg~20mg/kgであり、1日に1回、又はそれ以上に分割して投与することができる。血管攣縮抑制剤を分割して投与する場合、血管攣縮抑制剤は、1日に1~4回投与される。また、血管攣縮抑制剤は、毎日、隔日、1週間に1回、隔週及び1ヶ月に1回等の様々な投与頻度で投与してもよい。なお、必要に応じて、上記の範囲外の量を用いることもできる。 The dosage of the vasospasm inhibitor is, for example, 0.01 mg/kg to 1000 mg/kg, preferably 0.1 mg/kg to 200 mg/kg, more preferably 0.2 mg/kg to 20 mg/kg, and is administered per day. It can be administered once or in divided doses. When the vasospasm inhibitor is administered in divided doses, the vasospasm inhibitor is administered 1 to 4 times per day. Additionally, the vasospasm inhibitor may be administered at various administration frequencies, such as daily, every other day, once a week, every other week, and once a month. Note that amounts outside the above range can also be used if necessary.
血管攣縮抑制剤の投与経路は特に限定されない。血管攣縮抑制剤は、例えば非経口又は経口で投与される。非経口投与の場合、静脈注射、皮下注射、腹腔内注射、筋肉内注射、経皮投与、経鼻投与、経肺投与、経腸投与、口腔内投与及び経粘膜投与等であってもよい。血管攣縮抑制剤は、点滴を介して投与されてもよい。 The route of administration of the vasospasm inhibitor is not particularly limited. Vasospasm inhibitors are administered parenterally or orally, for example. In the case of parenteral administration, intravenous injection, subcutaneous injection, intraperitoneal injection, intramuscular injection, transdermal administration, nasal administration, pulmonary administration, enteral administration, oral administration, transmucosal administration, etc. may be used. The anti-vasospasm agent may be administered via an intravenous drip.
血管攣縮抑制剤は、任意の形態の製剤とすることができる。血管攣縮抑制剤は、経口投与の場合、糖衣錠、バッカル錠、コーティング錠及びチュアブル錠等の錠剤、トローチ剤、丸剤、散剤及びソフトカプセル等のカプセル剤、顆粒剤、懸濁剤、乳剤及びドライシロップ等のシロップ剤、並びにエリキシル剤等の液剤であってもよい。非経口投与の場合、血管攣縮抑制剤は、注射剤、経皮吸収テープ、エアゾール剤及び坐剤等であってもよい。 The anti-vasospasm agent can be formulated in any form. For oral administration, vasospasm inhibitors include tablets such as sugar-coated tablets, buccal tablets, coated tablets, and chewable tablets, troches, pills, powders, capsules such as soft capsules, granules, suspensions, emulsions, and dry syrups. Liquid preparations such as syrups and elixirs may also be used. In the case of parenteral administration, the vasospasm inhibitor may be in the form of an injection, a transdermal absorption tape, an aerosol, a suppository, or the like.
血管攣縮抑制剤の投与対象は、脊椎動物が好ましく、哺乳類動物がより好ましい。哺乳類動物としては、例えば、ヒト、チンパンジー及びその他の霊長類、イヌ、ネコ、ウサギ、ウマ、ヒツジ、ヤギ、ウシ、ブタ、ラット、マウス及びモルモット等の家畜動物、愛玩動物及び実験用動物等が挙げられる。特に好ましくは、哺乳類動物はヒトである。 The subject to whom the vasospasm inhibitor is administered is preferably a vertebrate, more preferably a mammal. Examples of mammals include humans, chimpanzees and other primates, domestic animals such as dogs, cats, rabbits, horses, sheep, goats, cows, pigs, rats, mice, and guinea pigs, pet animals, and laboratory animals. Can be mentioned. Particularly preferably the mammal is a human.
本実施の形態に係る血管攣縮抑制剤は、下記実施例において、血管を形成する平滑筋細胞の異常収縮を抑制する化合物Xを有効成分として含有する。このため、血管攣縮抑制剤は、血管攣縮を抑制することができる。 The vasospasm inhibitor according to the present embodiment contains, as an active ingredient, a compound X that suppresses abnormal contraction of smooth muscle cells forming blood vessels in the following examples. Therefore, the vasospasm inhibitor can suppress vasospasm.
化合物Xは、下記実施例に示すように、平滑筋細胞の異常収縮を予防する。このため、上述の血管攣縮抑制剤は、血管攣縮予防剤として使用されてもよい。好ましくは、血管攣縮予防剤は、血管の異常収縮、血管攣縮又は血管痙攣が生じる前に投与される。 Compound X prevents abnormal contraction of smooth muscle cells, as shown in the Examples below. Therefore, the above-mentioned vasospasm inhibitors may be used as vasospasm preventive agents. Preferably, the vasospasm preventive agent is administered before abnormal vasoconstriction, vasospasm, or vasospasm occurs.
別の実施の形態では、化合物Xを有効成分として含む血管攣縮予防用経口組成物又は血管攣縮抑制用経口組成物が提供される。経口組成物としては、具体的には、サプリメント、食品組成物、飲食品、機能性食品及び食品添加剤が挙げられる。 In another embodiment, an oral composition for preventing vasospasm or suppressing vasospasm containing Compound X as an active ingredient is provided. Specific examples of oral compositions include supplements, food compositions, food and drink products, functional foods, and food additives.
サプリメントの形態は、特に制限されず、錠剤、散剤、顆粒剤、カプセル剤、糖衣錠、フイルム剤、トローチ剤、チュアブル剤、溶液、乳濁液、懸濁液等の任意の形態でよい。サプリメントは、化合物X以外に、サプリメントとして通常使用される任意の成分を含んでもよい。当該成分としては、例えば、アミノ酸、ペプチド;ビタミンE、ビタミンC、ビタミンA、ビタミンB及び葉酸等のビタミン類;ミネラル類;糖類;無機塩類;クエン酸又はその塩;茶エキス;油脂;プロポリス、ローヤルゼリー及びタウリン等の滋養強壮成分;ショウガエキス及び高麗人参エキス等の生薬エキス;ハーブ類;並びにコラーゲン等が挙げられる。 The form of the supplement is not particularly limited, and may be any form such as tablets, powders, granules, capsules, sugar-coated tablets, films, troches, chewables, solutions, emulsions, and suspensions. The supplement may contain, in addition to Compound X, any ingredient commonly used as a supplement. The components include, for example, amino acids, peptides; vitamins such as vitamin E, vitamin C, vitamin A, vitamin B, and folic acid; minerals; sugars; inorganic salts; citric acid or its salts; tea extract; oils and fats; propolis; Nutrient and tonic ingredients such as royal jelly and taurine; crude drug extracts such as ginger extract and ginseng extract; herbs; and collagen.
化合物Xを日常的に経口摂取しやすいように各種の食品又は飲料に化合物Xを混合して機能性食品とすることで、化合物Xを長期的に摂取することができる。“機能性食品”とは、健康の維持の目的で摂取する食品又は飲料を意味し、保健機能食品である特定保健用食品、栄養機能食品、健康食品及び栄養補助食品等を含む。この中でも保健機能食品である特定保健用食品又は栄養機能食品が好ましい。なお、機能性食品として製品化する場合には、食品に用いられる様々な添加剤、具体的には、着色料、保存料、増粘安定剤、酸化防止剤漂白剤、防菌防黴剤、酸味料、調味料、乳化剤、強化剤、製造用剤及び香料等を添加してもよい。 Compound X can be ingested over a long period of time by mixing Compound X into various foods or drinks to make functional foods so that Compound X can be easily ingested orally on a daily basis. “Functional food” means food or beverages ingested for the purpose of maintaining health, and includes foods with health claims such as foods for specified health uses, foods with nutritional function claims, health foods, and nutritional supplements. Among these, foods with specified health uses or foods with nutritional functions that are foods with health claims are preferred. In addition, when commercializing the product as a functional food, various additives used in food, specifically coloring agents, preservatives, thickening stabilizers, antioxidants, bleaching agents, antibacterial and antifungal agents, etc. Acidulants, seasonings, emulsifiers, strengthening agents, manufacturing agents, flavorings, etc. may be added.
機能性食品の対象となる、食品及び飲料は特に限定されるものではない。機能性食品の形態は、例えば、栄養ドリンク、清涼飲料水、紅茶及び緑茶等の飲料;キャンデー、クッキー、錠菓、チューインガム及びゼリー等の菓子;麺、パン、米飯及びビスケット等の穀類加工品、ソーセージ、ハム及びかまぼこ等の練り製品;バター及びヨーグルト等の乳製品;ふりかけ;並びに調味料等である。なお、機能性食品には、甘味料、香料及び着色料等の添加物が含まれてもよい。 Foods and beverages that are considered functional foods are not particularly limited. The forms of functional foods include, for example, beverages such as energy drinks, soft drinks, black tea and green tea; confectionery such as candies, cookies, tablets, chewing gum and jelly; processed grain products such as noodles, bread, cooked rice and biscuits; Pasted products such as sausage, ham and kamaboko; dairy products such as butter and yogurt; furikake; and seasonings. Note that the functional food may contain additives such as sweeteners, flavors, and colorants.
経口組成物は、化合物Xを植物の抽出物として含有してもよい。化合物X又は化合物Xを含む植物の抽出物を機能性食品に配合する割合は任意であるが、血管の異常収縮、血管攣縮及び血管痙攣の抑制及び予防の少なくともいずれかに寄与する範囲で割合が選択される。化合物X又は化合物Xを含む植物の抽出物は、食品添加剤として使用することも可能である。 Oral compositions may contain Compound X as a plant extract. The proportion of Compound X or a plant extract containing Compound X added to the functional food is arbitrary, but the proportion may be within a range that contributes to at least one of suppressing and preventing abnormal contraction of blood vessels, vasospasm, and vasospasm. selected. Compound X or an extract of a plant containing compound X can also be used as a food additive.
なお、他の実施の形態では、化合物Xを患者に投与することにより血管攣縮を治療する方法が提供される。また、別の実施の形態は、血管攣縮を治療するための化合物Xの使用である。他の実施の形態では、血管攣縮抑制剤としての使用のための化合物Xが提供される。また、別の実施の形態は、血管攣縮を抑制するための医薬の製造のための化合物Xの使用である。 In yet another embodiment, a method of treating vasospasm by administering Compound X to a patient is provided. Also, another embodiment is the use of Compound X to treat vasospasm. In other embodiments, Compound X is provided for use as an antivasospasm agent. Also, another embodiment is the use of Compound X for the manufacture of a medicament for inhibiting vasospasm.
また、別の実施の形態では、桑葉からフィセチンを抽出するステップを含む、フィセチンの製造方法が提供される。 Further, in another embodiment, a method for producing fisetin is provided, which includes a step of extracting fisetin from mulberry leaves.
以下の実施例により、本発明をさらに具体的に説明するが、本発明は実施例によって限定されるものではない。 The present invention will be explained in more detail with reference to the following examples, but the present invention is not limited by the examples.
(試験例1:桑試料による異常収縮予防効果の評価)
桑葉(ヤマグワ:Morus australis)試料30mgを70%エタノールにより抽出し、濃縮乾固した乾固物をHEPES緩衝液(HK-3320、倉敷紡績社製)で溶解し4mg/mL桑試料抽出液とした。1.0×105細胞/mLの正常ヒト冠状動脈平滑筋細胞の細胞懸濁液100μLと増殖培地(正常ヒト平滑筋細胞用増殖培地KS-2170S、倉敷紡績社製)200μLとを24ウェルプレートの各ウェルに播種し、37℃、CO2濃度5%に設定したCO2インキュベーターで培養した。なお、以下での細胞の培養は37℃、CO2濃度5%に設定したCO2インキュベーターで培養した。
(Test Example 1: Evaluation of abnormal contraction prevention effect using mulberry sample)
30 mg of mulberry leaf (Morus australis) sample was extracted with 70% ethanol, concentrated to dryness, and the dried product was dissolved in HEPES buffer (HK-3320, manufactured by Kurashiki Boseki Co., Ltd.) to form a 4 mg/mL mulberry sample extract. did. 100 μL of a cell suspension of 1.0×10 5 cells/mL of normal human coronary artery smooth muscle cells and 200 μL of growth medium (Normal human smooth muscle cell growth medium KS-2170S, manufactured by Kurashiki Boseki Co., Ltd.) were placed in a 24-well plate. and cultured in a CO 2 incubator set at 37° C. and a CO 2 concentration of 5%. The cells below were cultured in a CO 2 incubator set at 37° C. and a CO 2 concentration of 5%.
細胞の培養開始から約24時間後に上清を100μL/ウェル除去し、最終濃度が2mg/mLとなるよう桑試料抽出液を200μL/ウェル添加後、80~90%コンフルエントになるまで約48時間培養した。培養後、上清を全て除去し、基礎培地(正常ヒト平滑筋細胞用基礎培地KS-2370S、倉敷紡績社製)300μL/ウェルと桑試料抽出液100μL/ウェル(最終濃度:2mg/mL)とを添加し、12時間以上培養した。 Approximately 24 hours after the start of cell culture, remove 100 μL/well of the supernatant, add 200 μL/well of mulberry sample extract to a final concentration of 2 mg/mL, and culture for approximately 48 hours until 80-90% confluence. did. After culturing, remove all the supernatant and add 300 μL/well of basal medium (normal human smooth muscle cell basal medium KS-2370S, manufactured by Kurashiki Boseki Co., Ltd.) and 100 μL/well of mulberry sample extract (final concentration: 2 mg/mL). was added and cultured for 12 hours or more.
プレートをインキュベーターから取り出し、上清を200μL/ウェルずつ除去した後、6μM Fluo3-AMを200μL/ウェル添加(最終濃度:3μM/ウェル)し、1時間培養した。さらに、上清を200μL/ウェル除去し、2mM CaCl2を200μL/ウェル添加後、細胞の培養と同じ条件下で30分間反応させた。培養後、上清を全て除去し、基礎培地100μL/ウェルと桑試料抽出液100μL/ウェル(SPC 200μL/ウェル添加後の最終濃度が2mg/mL)とを添加し異常収縮の形態観察を行った。 After removing the plate from the incubator and removing 200 μL/well of the supernatant, 200 μL/well of 6 μM Fluo3-AM was added (final concentration: 3 μM/well) and cultured for 1 hour. Furthermore, 200 μL/well of the supernatant was removed, and 200 μL/well of 2 mM CaCl 2 was added, followed by a reaction for 30 minutes under the same conditions as for cell culture. After culturing, all the supernatant was removed, and 100 μL/well of basal medium and 100 μL/well of mulberry sample extract (final concentration after addition of SPC 200 μL/well was 2 mg/mL) were added to observe the morphology of abnormal contraction. .
異常収縮の形態観察では、1ウェルずつ蛍光顕微鏡(CKX53、オリンパス社製)にて定点観察し、異常収縮誘発前の画像を取得後、60μM SPCを200μL/ウェル(最終濃度:30μM/ウェル)添加し、1、3、5及び10分後の画像を取得した。細胞は異常収縮すると、縮んでウェルの底から剥がれる。異常収縮誘発前及び誘発後のウェルの底に付着している細胞の表面積を比較することで、異常収縮を評価した。詳細には、得られた画像について、ImageJ(アメリカ国立衛生研究所製)あるいはBZシリーズ解析アプリケーション(キーエンス社製)にて細胞の表面積を算出し、異常収縮誘発前の細胞の表面積を100とした相対値にて異常収縮予防効果を評価した。 To observe the morphology of abnormal contractions, each well was observed at a fixed point using a fluorescence microscope (CKX53, manufactured by Olympus), and after obtaining an image before induction of abnormal contractions, 200 μL/well (final concentration: 30 μM/well) of 60 μM SPC was added. Images were acquired after 1, 3, 5, and 10 minutes. When cells contract abnormally, they shrink and detach from the bottom of the well. Abnormal contraction was evaluated by comparing the surface area of cells attached to the bottom of the well before and after induction of abnormal contraction. In detail, the surface area of the cells was calculated for the obtained images using ImageJ (manufactured by the National Institutes of Health) or BZ series analysis application (manufactured by Keyence Corporation), and the surface area of the cells before abnormal contraction was induced was set as 100. The effect of preventing abnormal contraction was evaluated using relative values.
(結果)
図1は、細胞表面積の相対値の経時変化を示す。桑試料抽出液に暴露しなかった細胞は、異常収縮により細胞表面積が低下したが、桑試料抽出液に暴露した場合、細胞表面積がほとんど低下しなかった。
(result)
FIG. 1 shows the change in relative cell surface area over time. Cells that were not exposed to the mulberry sample extract had a decrease in cell surface area due to abnormal contraction, but when exposed to the mulberry sample extract, the cell surface area hardly decreased.
(試験例2:桑試料による異常収縮抑制効果の評価)
1.0×105細胞/mLの正常ヒト冠状動脈平滑筋細胞の細胞懸濁液100μLと増殖培地200μLとを24ウェルプレートの各ウェルに播種し、培養した。抑制効果の評価では、桑試料抽出液を添加せずに増殖培地での前培養を行った。培養後、上清を全て除去し、基礎培地200μL/ウェルを添加後、12時間以上培養した。プレートをインキュベーターから取り出し、6μM Fluo3-AMを200μL/ウェル添加(最終濃度:3μM/ウェル)後、1時間培養した。さらに、上清を200μL/ウェルずつ除去し、2mM CaCl2を200μL/ウェル添加し、細胞の培養と同じ条件下で30分間反応させた。60μM SPCを200μL/ウェル(最終濃度:30μM/ウェル)添加による異常収縮誘発直後に、4mg/mL桑試料抽出液を100μL/ウェル添加し、37℃、CO2濃度5%に設定したCO2インキュベーターで反応させた。反応後、プレートをインキュベーターから取り出し、異常収縮の形態観察を行った。異常収縮の形態観察では、桑試料抽出液添加後約1分に加え、添加後5分及び10分の画像を取得し、試験例1と同様に評価した。
(Test Example 2: Evaluation of abnormal contraction suppression effect by mulberry sample)
100 μL of a cell suspension of 1.0×10 5 cells/mL of normal human coronary artery smooth muscle cells and 200 μL of growth medium were seeded into each well of a 24-well plate and cultured. For evaluation of the suppressive effect, preculture was performed in a growth medium without adding mulberry sample extract. After culturing, all the supernatant was removed, and 200 μL/well of basal medium was added, followed by culturing for 12 hours or more. The plate was taken out from the incubator, 200 μL/well of 6 μM Fluo3-AM was added (final concentration: 3 μM/well), and cultured for 1 hour. Further, 200 μL/well of the supernatant was removed, 200 μL/well of 2 mM CaCl 2 was added, and the mixture was reacted for 30 minutes under the same conditions as for cell culture. Immediately after inducing abnormal contraction by adding 200 μL/well of 60 μM SPC (final concentration: 30 μM/well), 100 μL/well of 4 mg/mL mulberry sample extract was added and placed in a CO 2 incubator set at 37° C. and a CO 2 concentration of 5%. I reacted with After the reaction, the plate was removed from the incubator and the morphology of abnormal contraction was observed. In observing the morphology of abnormal contraction, images were acquired at about 1 minute after addition of the mulberry sample extract, as well as at 5 minutes and 10 minutes after addition, and evaluated in the same manner as in Test Example 1.
(結果)
図2に示された細胞表面積の相対値の経時変化によれば、異常収縮誘発後に桑試料抽出液に暴露しても、細胞表面積の低下が抑制された。
(result)
According to the change over time in the relative value of cell surface area shown in FIG. 2, even when exposed to the mulberry sample extract after induction of abnormal contraction, the decrease in cell surface area was suppressed.
(ゲルろ過クロマトグラフィーによる分子量ごとの分画の異常収縮予防効果の評価)
ゲルろ過クロマトグラフィーは、Prepacked Disposable PD-10 Column(17085101、グローバルライフサイエンステクノロジーズジャパン社製)に超純水10mL以上を通液し、コンディショニング後、使用した。試料は、桑葉を70%エタノールにより抽出し濃縮乾固した乾固物を乾固物重量が20mg/mLになるように超純水で溶解し、フィルターろ過後、使用した。コンディショニング完了後、20mg/mL桑試料抽出液1mLと超純水2mLを通液し、素通り画分を画分1として回収した。その後、フィルターを枯らさないように超純水を3mL通液し、素通り画分を画分2として回収し、同様の操作を画分8まで繰り返した。得られた素通り画分は、-20℃で凍結し、凍結乾燥後、画分6~8は収量が少なかったため混合し、画分6とした。また画分1は、カラムの特性上、分子量5000以上の物質であることから、経口摂取による機能性が期待されないため除外した。得られた画分2~6の乾固物は、HEPES緩衝液(HK-3320、倉敷紡績社製)にて0.4mg/mLになるように溶解し、0.45μmフィルターろ過後、評価試料とした。評価試料の最終濃度が0.1mg/mLとなるようにHEPES緩衝液で調製し、各画分による異常収縮予防効果を試験例1と同様に確認した。
(Evaluation of the abnormal shrinkage prevention effect of fractionation by molecular weight by gel filtration chromatography)
Gel filtration chromatography was performed after conditioning a Prepacked Disposable PD-10 Column (17085101, manufactured by Global Life Science Technologies Japan) by passing 10 mL or more of ultrapure water through it. The sample was obtained by extracting mulberry leaves with 70% ethanol and concentrating to dryness, dissolving the dried product in ultrapure water so that the weight of the dried product was 20 mg/mL, and using it after filtration. After conditioning was completed, 1 mL of 20 mg/mL mulberry sample extract and 2 mL of ultrapure water were passed through the tube, and the flow-through fraction was collected as fraction 1. Thereafter, 3 mL of ultrapure water was passed through the filter so as not to dry the filter, the flow-through fraction was collected as fraction 2, and the same operation was repeated until fraction 8. The obtained pass-through fraction was frozen at −20° C., and after lyophilization, fractions 6 to 8 were mixed as fraction 6 because the yield was small. Furthermore, Fraction 1 was excluded because it is a substance with a molecular weight of 5000 or more due to the characteristics of the column and is not expected to have functionality when ingested orally. The dried solids of fractions 2 to 6 obtained were dissolved in HEPES buffer (HK-3320, manufactured by Kurashiki Boseki Co., Ltd.) to a concentration of 0.4 mg/mL, and after filtration through a 0.45 μm filter, the evaluation sample was obtained. And so. The evaluation sample was prepared with HEPES buffer so that the final concentration was 0.1 mg/mL, and the abnormal contraction prevention effect of each fraction was confirmed in the same manner as in Test Example 1.
(結果)
図3に示すように、画分6の異常収縮予防効果が最も高かった。画分6から異常収縮を予防又は抑制する物質を以下で同定した。
(result)
As shown in FIG. 3, fraction 6 had the highest effect of preventing abnormal contraction. Substances that prevent or suppress abnormal contractions from fraction 6 were identified below.
(HPLCでの逆相分画(分取))
HPLCでの分取は、LC-2000(日本分光社製)を用い、320nmの吸収スペクトルを検出した。分離カラムは、TSKgel ODS-100Z 5μm(4.6mmI.D.×15.0cm、東ソー社製)を用い、カラムオーブン温度は40℃とし、流速は1mL/分でサンプルは100μL注入した。分離は、0.1vol%トリフルオロ酢酸(202-10733、富士フイルム和光純薬社製)、アセトニトリル(純度99.9%、34888-2.5L、シグマアルドリッチジャパン社製)で、アセトニトリルを(1)0-10分 10%、(2)10-20分 100%まで上昇、(3)20-30分 100%に勾配をかけ分取した。保持時間0-10分、10-20分及び20-30分の画分をそれぞれA、B及びCとした(図4参照)。得られた溶液は、エバポレーターにより減圧濃縮した後、-20℃で凍結し、凍結乾燥し得られた乾固物を評価試料とした。評価試料について、各画分による異常収縮予防効果を試験例1と同様に確認した。
(Reverse phase fractionation (preparation) in HPLC)
For fractionation by HPLC, an absorption spectrum at 320 nm was detected using LC-2000 (manufactured by JASCO Corporation). The separation column used was TSKgel ODS-100Z 5 μm (4.6 mm ID×15.0 cm, manufactured by Tosoh Corporation), the column oven temperature was 40° C., the flow rate was 1 mL/min, and 100 μL of the sample was injected. Separation was performed using 0.1 vol% trifluoroacetic acid (202-10733, manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) and acetonitrile (purity 99.9%, 34888-2.5 L, manufactured by Sigma-Aldrich Japan). ) 0-10 minutes 10%, (2) 10-20 minutes increasing to 100%, (3) 20-30 minutes increasing to 100%. Fractions with retention times of 0-10 minutes, 10-20 minutes, and 20-30 minutes were designated as A, B, and C, respectively (see Figure 4). The obtained solution was concentrated under reduced pressure using an evaporator, then frozen at −20° C., and the dried product obtained by freeze-drying was used as an evaluation sample. Regarding the evaluation samples, the effect of preventing abnormal contraction by each fraction was confirmed in the same manner as in Test Example 1.
(結果)
図5に示すように画分Bの異常収縮予防効果が最も高かった。画分Bに含まれる活性成分を以下のようにLC/MSで同定した。
(result)
As shown in FIG. 5, fraction B had the highest effect of preventing abnormal contraction. The active ingredient contained in fraction B was identified by LC/MS as follows.
(LC/MSによる活性成分の同定)
活性成分の同定は、HPLC Shimadzu system LC20(島津製作所製)を装備したQTRAP LC-MS/MS 3200システム(エービー・サイエックス社製)を用い、ポジティブモードで検出した。以下の条件でAn information dependent acquisition(IDA)によるenhanced mass scan(EMS)でサーベイスキャンを行い、次にenhanced resolution(ER)で質量誤差の補正や、同位体分布を確認した後、enhanced product ion(EPI) scanでプロダクトイオンスキャンを行ってフラグメント情報を取得した。
(Identification of active ingredient by LC/MS)
The active ingredient was identified in positive mode using a QTRAP LC-MS/MS 3200 system (manufactured by AB Sciex) equipped with HPLC Shimadzu system LC20 (manufactured by Shimadzu Corporation). A survey scan was performed using enhanced mass scan (EMS) using an information dependent acquisition (IDA) under the following conditions, and then after correcting the mass error and checking the isotope distribution using enhanced resolution (ER), ed product ( Fragment information was obtained by performing a product ion scan using EPI) scan.
イオン化方式:ESI+、スキャンタイプ:EMS,EPI、Ion Source:Turbo Spray、Curtain Gas:20.0、Collision Gas:High、Ion Spray voltage:5500.0、Temperature:500.0、Ion source gas1:40.0、Ion source gas2:50.0、Declustering Potential:30.0、Entrance Potential:10.0、Collision energy:35.0、Collision Energy Spread:15.0。 Ionization method: ESI+, scan type: EMS, EPI, Ion Source: Turbo Spray, Curtain Gas: 20.0, Collision Gas: High, Ion Spray voltage: 5500.0, Temperature: 500.0, I on source gas1:40. 0, Ion source gas2: 50.0, Declustering Potential: 30.0, Entrance Potential: 10.0, Collision energy: 35.0, Collision Energy Spread: 15 .0.
データ収集には、Analyst(登録商標) software(version1.5.1)を使用した。データ解析には、Mass Bank及びMETLINを用いた。分離カラムは、TSKgel ODS-100Z 5μm(4.6mmI.D.×15.0cm、東ソー社製)を用い、カラムオーブン温度は室温とし、流速は0.4mL/分でサンプルは10μL注入した。分離は、蒸留水(11307-79、関東化学社製)、アセトニトリル(純度99.9%、01033-79、関東化学社製)で、1:1のイソクラティックで行った。 Analyst (registered trademark) software (version 1.5.1) was used for data collection. Mass Bank and METLIN were used for data analysis. The separation column used was TSKgel ODS-100Z 5 μm (4.6 mm ID×15.0 cm, manufactured by Tosoh Corporation), the column oven temperature was set to room temperature, the flow rate was 0.4 mL/min, and 10 μL of the sample was injected. Separation was performed using distilled water (11307-79, manufactured by Kanto Kagaku Co., Ltd.) and acetonitrile (purity 99.9%, 01033-79, manufactured by Kanto Kagaku Co., Ltd.) in a 1:1 isocratic ratio.
(結果)
図6(A)に示されたUVスペクトルにおける保持時間10.12分のピークを質量分析法(MS)で測定することで得られた分子量関連イオンのピークから分子量286.9を確認した。化合物を検索し、分子式を推定し、さらにMS/MS測定によって検出された図6(B)に示すプロダクトイオンスペクトルから画分Bに含まれる活性成分としてフィセチンを同定した。
(result)
A molecular weight of 286.9 was confirmed from the peak of molecular weight-related ions obtained by measuring the peak of retention time 10.12 minutes in the UV spectrum shown in FIG. 6(A) by mass spectrometry (MS). The compound was searched, the molecular formula was estimated, and fisetin was identified as an active ingredient contained in fraction B from the product ion spectrum shown in FIG. 6(B) detected by MS/MS measurement.
(フィセチンの定量)
フィセチンのHPLCによる定量では、LC-2000(ポンプ:PU-2080、検出器:UV-2070、オートサンプラー:AS-4050、カラムオーブン:CO-4060、日本分光社製)を用い、320nmの吸収スペクトルを検出した。分離カラムは、TSKgel ODS-100Z 5μm(4.6mmI.D.×15.0cm、東ソー社製)を用いた。カラムオーブン温度は40℃とし、流速は1mL/分で、サンプルは10μL注入した。分離は、0.1vol%トリフルオロ酢酸(202-10733、富士フイルム和光純薬社製)、メタノール(純度99.8%、21929-23、ナカライテスク社製)で、1:1のイソクラティックで行った。
(Quantification of fisetin)
For the determination of fisetin by HPLC, an absorption spectrum of 320 nm was used using LC-2000 (pump: PU-2080, detector: UV-2070, autosampler: AS-4050, column oven: CO-4060, manufactured by JASCO Corporation). was detected. As the separation column, TSKgel ODS-100Z 5 μm (4.6 mm ID×15.0 cm, manufactured by Tosoh Corporation) was used. The column oven temperature was 40° C., the flow rate was 1 mL/min, and 10 μL of the sample was injected. Separation was performed using 0.1 vol% trifluoroacetic acid (202-10733, manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) and methanol (purity 99.8%, 21929-23, manufactured by Nacalai Tesque) in a 1:1 isocratic ratio. I went there.
検量線はフィセチン(東京化成工業社製)をメタノール:0.1vol%TFA混合溶液に溶解し、100、50、25、12.5、6.25μMとなるように希釈し測定した。測定試料は、桑葉試料を70%エタノールにより抽出し濃縮乾固した乾固物をメタノール:0.1vol%TFA混合溶液に溶解し、乾固物重量が10mg/mLになるように調製し、0.45μmフィルターでろ過した。また、桑果実を、重量測定後に凍結乾燥機(FDU-1200、東京理科器械社製)で乾燥させ、ミル(OML-1、アズワン社製)で粉砕して得られた乾燥粉末についても測定した。乾燥粉末をメタノール:0.1vol%TFA混合溶液に溶解し、10mg/mLになるように調製して測定試料とした。定量は絶対検量線法にて行った。 The calibration curve was measured by dissolving fisetin (manufactured by Tokyo Kasei Kogyo Co., Ltd.) in a mixed solution of methanol and 0.1 vol% TFA and diluting the solution to 100, 50, 25, 12.5, and 6.25 μM. The measurement sample was prepared by extracting a mulberry leaf sample with 70% ethanol, concentrating it to dryness, dissolving it in a mixed solution of methanol: 0.1 vol% TFA, and adjusting the weight of the dry matter to 10 mg/mL. It was filtered through a 0.45 μm filter. In addition, the dry powder obtained by drying the mulberry fruit with a freeze dryer (FDU-1200, manufactured by Tokyo Rikakikai Co., Ltd.) after measuring the weight, and pulverizing it with a mill (OML-1, manufactured by As One Co., Ltd.) was also measured. . The dry powder was dissolved in a mixed solution of methanol and 0.1 vol% TFA, and the solution was adjusted to 10 mg/mL to prepare a measurement sample. Quantification was performed using the absolute calibration curve method.
(結果)
図7にHPLCの結果を示す。保持時間5分のピークがフィセチンに対応する。なお、本実施例で使用した桑葉(ヤマグワ)では、ルテオリンは検出されなかった。図8に示すように、定量の結果、桑葉中のフィセチンの含有量は0.6mg/g乾燥粉末であった。一方、果実にはフィセチンが含まれていなかった。
(result)
Figure 7 shows the HPLC results. The peak with a retention time of 5 minutes corresponds to fisetin. Note that luteolin was not detected in the mulberry leaves used in this example. As shown in FIG. 8, as a result of quantitative determination, the content of fisetin in the mulberry leaves was 0.6 mg/g dry powder. On the other hand, the fruit did not contain fisetin.
(フィセチンによる異常収縮予防効果の評価)
試験例1における桑試料抽出液を市販のフィセチン(東京化成工業社製)に代えて、フィセチンの異常収縮予防効果をさらに評価した。1、10又は100μMの濃度のフィセチンに細胞を暴露し、10分後の細胞の表面積を算出した。
(Evaluation of the effect of preventing abnormal contractions by fisetin)
The mulberry sample extract in Test Example 1 was replaced with commercially available fisetin (manufactured by Tokyo Kasei Kogyo Co., Ltd.), and the abnormal contraction prevention effect of fisetin was further evaluated. Cells were exposed to fisetin at a concentration of 1, 10, or 100 μM, and the surface area of the cells was calculated after 10 minutes.
(結果)
図9に示すように、フィセチンによって細胞表面積はほとんど低下しなかった。図10は、異常収縮誘発前の細胞の画像及び誘発後10分の細胞の画像を示す。細胞の所定の部分の長さを測定し、細胞の異常収縮の程度として長さの変化率を評価したところ、対照は変化率が29.6%であったのに対し、フィセチンに暴露した細胞では、変化率が2.3%でほとんど変化していなかった。
(result)
As shown in FIG. 9, cell surface area was hardly reduced by fisetin. FIG. 10 shows images of cells before induction of abnormal contraction and images of cells 10 minutes after induction. When the length of a predetermined part of the cell was measured and the rate of change in length was evaluated as the degree of abnormal cell contraction, the rate of change in length was 29.6% in the control, whereas in the cells exposed to fisetin, the rate of change in length was 29.6%. In this case, the rate of change was 2.3%, which was almost unchanged.
(桑葉含有成分の構造活性相関の検討)
桑葉に含まれるフィセチン(東京化成工業社製)、ルテオリン(Cayman Chemical社製)及びケルセチン(Cayman Chemical社製)について試験例1と同様に異常収縮予防効果を評価した。5μMの濃度のフィセチン、ルテオリン及びケルセチンに細胞を暴露し、5分後の細胞表面積を算出した。
(Study of structure-activity relationship of mulberry leaf-containing components)
Fisetin (manufactured by Tokyo Kasei Kogyo Co., Ltd.), luteolin (manufactured by Cayman Chemical Co., Ltd.) and quercetin (manufactured by Cayman Chemical Co., Ltd.) contained in mulberry leaves were evaluated for their abnormal shrinkage prevention effects in the same manner as in Test Example 1. Cells were exposed to fisetin, luteolin, and quercetin at a concentration of 5 μM, and the cell surface area was calculated after 5 minutes.
(結果)
図11は、フィセチン、ルテオリン及びケルセチンの各構造と、フィセチンの異常収縮予防効果を100とした場合のルテオリン及びケルセチンの相対的な異常収縮予防効果を示す。フィセチン、ルテオリン及びケルセチンのいずれにも異常収縮予防効果を確認した。フィセチンとの違いがA環5位に水酸基がある点のみであるケルセチンの異常収縮予防効果が、C環3位に水酸基がなくA環5位に水酸基があるルテオリンよりも高かった。ケルセチン及びルテオリンは桑(Morus alba)に含まれることが知られている。
(result)
FIG. 11 shows the respective structures of fisetin, luteolin, and quercetin, and the relative effects of preventing abnormal contractions of luteolin and quercetin when the abnormal contraction preventing effect of fisetin is set as 100. We confirmed that fisetin, luteolin, and quercetin all have an effect on preventing abnormal contractions. Quercetin, which differs from fisetin only in that it has a hydroxyl group at the 5th position of the A ring, was more effective in preventing abnormal contraction than luteolin, which does not have a hydroxyl group at the 3rd position of the C ring but has a hydroxyl group at the 5th position of the A ring. Quercetin and luteolin are known to be contained in mulberry (Morus alba).
本実施例により、フィセチンが桑葉に含まれていること、SPCによる動脈平滑筋細胞の異常収縮をフィセチン、ルテオリン及びケルセチンが予防及び抑制することが示された。 This example demonstrated that fisetin is contained in mulberry leaves, and that fisetin, luteolin, and quercetin prevent and suppress abnormal contraction of arterial smooth muscle cells caused by SPC.
上述した実施の形態は、本発明を説明するためのものであり、本発明の範囲を限定するものではない。すなわち、本発明の範囲は、実施の形態ではなく、特許請求の範囲によって示される。そして、特許請求の範囲内及びそれと同等の発明の意義の範囲内で施される様々な変形が、本発明の範囲内とみなされる。 The embodiments described above are for explaining the present invention, and do not limit the scope of the present invention. That is, the scope of the present invention is indicated by the claims rather than the embodiments. Various modifications made within the scope of the claims and the meaning of the invention equivalent thereto are considered to be within the scope of the present invention.
本発明は、血管疾患、特には血管痙攣、血管攣縮及び血管異常収縮を予防又は抑制する医薬及び食品に有用である。 The present invention is useful for medicines and foods that prevent or suppress vascular diseases, particularly vasospasm, vasospasm, and abnormal vasoconstriction.
Claims (6)
前記式(1)におけるR1及びR2は、それぞれ独立して水素原子又は水酸基である、
血管攣縮抑制剤。 Formula (1)
R 1 and R 2 in the formula (1) are each independently a hydrogen atom or a hydroxyl group,
Vasospasm inhibitor.
請求項1に記載の血管攣縮抑制剤。 R 1 in the formula (1) is a hydroxyl group,
The vasospasm inhibitor according to claim 1.
フィセチンである、
請求項1又は2に記載の血管攣縮抑制剤。 The compound is
is fisetin,
The vasospasm inhibitor according to claim 1 or 2.
請求項1から3のいずれか一項に記載の血管攣縮抑制剤。 Containing the compound as an extract of a plant belonging to the family Moraceae, genus Morus,
The vasospasm inhibitor according to any one of claims 1 to 3.
前記式(1)におけるR1及びR2は、それぞれ独立して水素原子又は水酸基である、
血管攣縮予防剤。 Formula (1)
R 1 and R 2 in the formula (1) are each independently a hydrogen atom or a hydroxyl group,
Vasospasm preventive agent.
前記式(1)におけるR1及びR2は、それぞれ独立して水素原子又は水酸基である、
血管攣縮予防用経口組成物又は血管攣縮抑制用経口組成物。 Formula (1)
R 1 and R 2 in the formula (1) are each independently a hydrogen atom or a hydroxyl group,
Oral composition for preventing vasospasm or suppressing vasospasm.
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001114686A (en) | 1999-10-15 | 2001-04-24 | Sunstar Inc | Th2 CYTOKININ EXPRESSION SUPPRESSANT |
JP2002524522A (en) | 1998-09-15 | 2002-08-06 | コリア リサーチ インスティチュート オブ バイオサイエンス アンド バイオテクノロジー | Composition containing rutin and quercetin for prevention or treatment of diseases caused by high blood lipid levels |
JP2003527434A (en) | 2000-03-22 | 2003-09-16 | エヌ・ヴイ・ヌートリシア | Compositions suitable for treating injury caused by ischemia / reperfusion or oxidative stress |
JP2010504370A (en) | 2006-09-25 | 2010-02-12 | ベンズ ラブ シーオー エルティーディー | Composition comprising a complex herbal extract exhibiting antiallergic rhinitis activity, antiatopic dermatitis activity and antiasthma activity |
JP2012171951A (en) | 2011-02-24 | 2012-09-10 | Kao Corp | Mineralocorticoid receptor inhibitor |
JP2016079117A (en) | 2014-10-14 | 2016-05-16 | 国立大学法人山口大学 | Vasospasm inhibitor |
WO2016132483A1 (en) | 2015-02-18 | 2016-08-25 | 学校法人福岡大学 | Human chymase inhibitor and drug for preventing and treating disease associated with human chymase activity |
-
2020
- 2020-10-08 JP JP2020170315A patent/JP7401863B2/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002524522A (en) | 1998-09-15 | 2002-08-06 | コリア リサーチ インスティチュート オブ バイオサイエンス アンド バイオテクノロジー | Composition containing rutin and quercetin for prevention or treatment of diseases caused by high blood lipid levels |
JP2001114686A (en) | 1999-10-15 | 2001-04-24 | Sunstar Inc | Th2 CYTOKININ EXPRESSION SUPPRESSANT |
JP2003527434A (en) | 2000-03-22 | 2003-09-16 | エヌ・ヴイ・ヌートリシア | Compositions suitable for treating injury caused by ischemia / reperfusion or oxidative stress |
JP2010504370A (en) | 2006-09-25 | 2010-02-12 | ベンズ ラブ シーオー エルティーディー | Composition comprising a complex herbal extract exhibiting antiallergic rhinitis activity, antiatopic dermatitis activity and antiasthma activity |
JP2012171951A (en) | 2011-02-24 | 2012-09-10 | Kao Corp | Mineralocorticoid receptor inhibitor |
JP2016079117A (en) | 2014-10-14 | 2016-05-16 | 国立大学法人山口大学 | Vasospasm inhibitor |
WO2016132483A1 (en) | 2015-02-18 | 2016-08-25 | 学校法人福岡大学 | Human chymase inhibitor and drug for preventing and treating disease associated with human chymase activity |
Non-Patent Citations (3)
Title |
---|
Chen-hui Zhou et al.,"Fisetin alleviates early brain injury following experimental subarachnoid hemorrhage in rats possibly by suppressing TLR 4/NF-κB signaling pathway",BRAIN RESEARCH,2015年,Vol.1629,p.250-259 |
GUL Sanser et al.,"Neuroprotective effects of quercetin on cerebral vasospasm following experimental subarachnoid haemorrhage in rats",Turkish Journal of Medical Sciences,2020年02月23日,Vol.50,p.1106-1110 |
Yu-shu Dong et al.,"Protective Effect of Quercetin against Oxidative Stress and Brain Edema in an Experimental Rat Model of Subarachnoid Hemorrhage",International Journal of Medical Sciences,2014年,Vol.11,p.282-290 |
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