JP6224899B2 - Hypoglycemic agent - Google Patents
Hypoglycemic agent Download PDFInfo
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- JP6224899B2 JP6224899B2 JP2013045659A JP2013045659A JP6224899B2 JP 6224899 B2 JP6224899 B2 JP 6224899B2 JP 2013045659 A JP2013045659 A JP 2013045659A JP 2013045659 A JP2013045659 A JP 2013045659A JP 6224899 B2 JP6224899 B2 JP 6224899B2
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- passion fruit
- fruit seed
- blood glucose
- test
- seed extract
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Description
本発明は、パッションフルーツ種子抽出物を有効成分として含有する血糖降下剤に関する。 The present invention relates to a hypoglycemic agent containing a passion fruit seed extract as an active ingredient.
血糖値の高い状態が慢性的に続くと、血中の糖がタンパク質に結合するなどしてその生体機能を障害し、糖尿病やそれにともなう各種合併症にみられるように、腎症、白内障、網膜症、神経障害、下肢壊疽、皮膚症状、血管障害、動脈硬化、心筋梗塞、脳梗塞などを引き起こす。さらに、免疫力が低下するために感染症にも罹りやすくなる。いったん症状が発症すると治癒が困難になるため、症状のない段階で血糖値をコントロールすることが肝要である。 If the state of high blood glucose level continues chronically, sugar in the blood binds to protein, and the biological function is impaired. As seen in diabetes and various complications accompanying it, nephropathy, cataract, retina Cause neuropathy, lower limb gangrene, skin symptoms, vascular disorders, arteriosclerosis, myocardial infarction, cerebral infarction, etc. In addition, the immune system is reduced, making it more susceptible to infections. Once symptoms develop, it becomes difficult to cure, so it is important to control blood sugar levels at the stage of no symptoms.
一般に、血糖値のコントロールにはインスリンの自己注射が広く行われているが、注射による苦痛や、投与管理の煩わしさも、患者には負担である。また、インシュリンショックや急激な血糖降下などによる弊害もともなう。 In general, self-injection of insulin is widely performed to control blood glucose levels, but pain due to injection and troublesome administration management are also burdensome to the patient. In addition, there are also adverse effects such as insulin shock and rapid blood glucose lowering.
これに対して、天然物の抽出物により血糖値の上昇を抑えるという試みもある。これによれば、インスリンほどの効果は期待しないものの、副作用なく日常的に摂取することにより、食事等により影響を受ける血糖値の状態を、患者に負担なく改善できる可能性がある。また、これをインスリン療法と組み合わせてよりよい効果が得られるという可能性もある。例えば、下記特許文献１には血糖降下作用を有するセンブリ粗エキスの製造法、下記特許文献２にはカラスウリ属植物果実の水性抽出物を含むことを特徴とする血糖降下用内服剤、下記特許文献３にはセンダン科植物、ゴーヤー茶又はこれらの抽出物を含有することを特徴とする血糖値低下剤、下記特許文献４には経口低血糖作用を有するバウヒニア・フォルティフィカタの抽出物、などが開示されている。 On the other hand, there is also an attempt to suppress an increase in blood glucose level with a natural product extract. According to this, although it is not expected to be as effective as insulin, it may be possible to improve the blood sugar level affected by meals and the like without burden on the patient by taking it daily without side effects. There is also a possibility that a better effect can be obtained by combining this with insulin therapy. For example, the following Patent Document 1 discloses a method for producing a crude extract having a hypoglycemic action, and the following Patent Document 2 includes an oral extract for hypoglycemia characterized in that it contains an aqueous extract of the fruit of the genus Prunus genus. No. 3 is a blood glucose level-lowering agent characterized by containing a plant belonging to the family Sendanidae, bitter gourd tea or an extract thereof, and the following Patent Document 4 includes an extract of Bauhinia fortificata having an oral hypoglycemic action, etc. It is disclosed.
一方、本出願人は、パッションフルーツの種子抽出物を有効成分とする、コラーゲン産生促進剤やメラニン生成抑制剤の発明を開示している（下記特許文献５〜７）。しかしながら、血糖降下作用については知られていなかった。 On the other hand, the present applicant has disclosed inventions of collagen production promoters and melanin production inhibitors containing a passion fruit seed extract as an active ingredient (Patent Documents 5 to 7 below). However, the hypoglycemic effect has not been known.
血糖降下剤の新たな有効成分を提供できれば治療や処置の選択の幅が広がる。また、有効成分が天然物からの抽出物であれば、副作用のリスクも少ないと考えられるので、望ましい。 If a new active ingredient of a hypoglycemic agent can be provided, the range of choice of treatment and treatment will be expanded. Moreover, if the active ingredient is an extract from a natural product, it is considered that the risk of side effects is low, which is desirable.
そこで本発明の目的は、天然物からの抽出物を有効成分とし、経口摂取によっても有効な、血糖降下剤を提供することにある。 Accordingly, an object of the present invention is to provide a hypoglycemic agent which contains an extract from a natural product as an active ingredient and is effective even by oral intake.
本発明者らは、上記目的を達成するため鋭意研究し、本発明を完成するに至った。すなわち、本発明は以下のとおりである。 The inventors of the present invention have intensively studied to achieve the above object and have completed the present invention. That is, the present invention is as follows.
［１］パッションフルーツ種子抽出物を有効成分として含有することを特徴とする血糖降下剤。
［２］前記パッションフルーツ種子抽出物は、パッションフルーツ種子から極性溶媒で抽出された抽出物である、上記［１］記載の血糖降下剤。
［３］前記パッションフルーツ種子抽出物は、該パッションフルーツ種子由来のピセアタンノールを固形分中０．０００５〜３０質量％含有し、該パッションフルーツ種子由来のスキルプシンＢを固形分中０．０００１〜２０質量％含有するものである、上記［１］又は［２］記載の血糖降下剤。
[1] A hypoglycemic agent comprising a passion fruit seed extract as an active ingredient.
[2] The hypoglycemic agent according to [1] above, wherein the passion fruit seed extract is an extract extracted from passion fruit seeds with a polar solvent.
[3] The passion fruit seed extract contains 0.0005 to 30% by mass of piceatannol derived from the passion fruit seed in a solid content, and skillpsin B derived from the passion fruit seed in a solid content of 0.0001 to The hypoglycemic agent according to the above [1] or [2], which contains 20% by mass.
本発明の血糖降下剤によれば、その有効成分であるパッションフルーツ種子抽出物が血糖降下の作用効果を有する。よって、本発明の血糖降下剤を日常的に摂取することにより、食事等による血糖値の上昇を、患者に負担を与えることなく抑制することができる。 According to the hypoglycemic agent of the present invention, the passion fruit seed extract, which is an active ingredient, has the effect of lowering blood glucose. Therefore, by daily intake of the hypoglycemic agent of the present invention, an increase in blood glucose level due to meals or the like can be suppressed without burdening the patient.
パッションフルーツ種子としては、パッシフローラ（Passiflora）属に属し、その実が食用である、例えばPassiflora edulis、Passiflora alata、Passiflora ligularis、Passiflora mollissima、Passiflora quadrangularis等に由来するものが挙げられる。このうちPassiflora edulisは、別名クダモノトケイソウ(果物時計草)とよばれ、その実は甘酸っぱく果物として実をそのまま食したり、その果汁をジュースにして飲んだり、ゼリー、ケーキ等の飲食品に配合して、風味付けに用いられたりされている。パッションフルーツの種子は硬いが小粒で、ジュースなどにする場合には果実から取り除かれることもあるが、ジャムやピューレなどでは種を含む果肉がそのまま用いられている。このような食経験からも裏付けられるように、パッションフルーツの種子は、安全性には問題がないものである。 Passion fruit seeds belong to the genus Passiflora and the fruits are edible, for example, those derived from Passiflora edulis, Passiflora alata, Passiflora ligularis, Passiflora mollissima, Passiflora quadrangularis and the like. Among them, Passifflora edulis is also known as Kudamono Toiiso (fruit clock grass), its fruit is sweet and sour and eats fruit as it is, drinks its juice as juice, blends in food and drink such as jelly, cake, It is used for flavoring. Passion fruit seeds are hard but small and may be removed from the fruit when made into juices, but in jams and purees, the pulp containing the seeds is used as is. As evidenced by this dietary experience, passion fruit seeds are safe.
パッションフルーツ種子抽出物の調製方法は特に限定されず、例えば、種子をそのまま、あるいは乾燥、細断、破砕、磨砕等の処理を施したうえで、種々の溶媒を用いて抽出する方法が挙げられる。抽出温度は適宜設定することができる。また、上記種子は、抽出効率をよくするため、適宜、酸又はアルカリ分解、酵素分解等の化学的処理を施してから抽出することもできる。 The method for preparing the passion fruit seed extract is not particularly limited, and examples thereof include a method in which the seed is extracted using various solvents as it is or after being subjected to treatment such as drying, shredding, crushing, and grinding. It is done. The extraction temperature can be set as appropriate. In addition, in order to improve the extraction efficiency, the seeds can be extracted after being subjected to chemical treatment such as acid or alkali decomposition or enzymatic decomposition as appropriate.
抽出溶媒としては、極性溶媒が好ましく、例えば水（熱水）、エタノール等の炭素数５以下の低級アルコール、酢酸エチル等の炭素数５以下の低級アルキルエステル、アセトン、メチルエチルケトン、ジエチルケトン、クロロアセトン等のケトン系溶媒、グリセリン等のトリオール化合物、プロピレングリコール、ジプロピレングリコール、１，３−ブチレングリコール等のジオール化合物などが挙げられる。これらの一種又は二種以上の混合溶媒を用いてもよく、これらの溶媒を種子に順次接触させて抽出したものを合わせて種子抽出物としてもよい。これらの中で、含水エタノール、含水アセトン、又は含水１，３−ブチレングリコールは、下記のピセアタンノールやスキルプシンＢを効率よく抽出することができるので好ましい。 The extraction solvent is preferably a polar solvent, for example, water (hot water), lower alcohols having 5 or less carbon atoms such as ethanol, lower alkyl esters having 5 or less carbon atoms such as ethyl acetate, acetone, methyl ethyl ketone, diethyl ketone, chloroacetone. And diol compounds such as propylene glycol, dipropylene glycol, and 1,3-butylene glycol. One kind or two or more kinds of mixed solvents may be used, and a seed extract may be obtained by combining these solvents in contact with seeds and extracting them. Among these, water-containing ethanol, water-containing acetone, or water-containing 1,3-butylene glycol is preferable because the following piceatannol and skillpsin B can be efficiently extracted.
上記抽出溶媒により調製されるパッションフルーツ種子抽出物には、下記化学式（１）で表されるピセアタンノール（Ｐｉｃｅａｔａｎｎｏｌ）や下記化学式（２）で表されるスキルプシンＢ（Ｓｃｉｒｐｕｓｉｎ Ｂ）が含まれている。パッションフルーツ種子抽出物の品質は、これらピセアタンノールやスキルプシンＢの含有濃度を基準にすることが好ましい。 Passion fruit seed extract prepared by the extraction solvent includes Piceatannol represented by the following chemical formula (1) and Skillpusin B represented by the following chemical formula (2). Yes. The quality of the passion fruit seed extract is preferably based on the content concentration of these piceatannol and skillpsin B.
なお、上記化学式（１）には、２個のフェニル基がトランス型のアルケン基で連結した構造を示すが、上記化学式（１）において、２個のフェニル基がシス型のアルケン基で連結した構造であってもよい。 The chemical formula (1) shows a structure in which two phenyl groups are linked by a trans-type alkene group. In the chemical formula (1), two phenyl groups are linked by a cis-type alkene group. It may be a structure.
また、上記化学式（２）では、ピセアタンノールの２量体の構造を有し、２個のフェニル基がトランス型のアルケン基で連結した構造のピセアタンノール構造を包含する構造を示すが、上記ピセアタンノールと同様に、上記化学式（２）において、２個のフェニル基がシス型のアルケン基で連結した構造のピセアタンノール構造を包含する構造であってもよい。 In addition, the chemical formula (2) shows a structure including a piceatannol structure in which a diether structure of piceatannol is included and two phenyl groups are linked by a trans-type alkene group. Similarly to the piceatannol, in the chemical formula (2), a structure including a piceatannol structure in which two phenyl groups are connected by a cis-type alkene group may be used.
具体的には、上記抽出溶媒で抽出して得られる一次抽出物中には、抽出の条件によっても異なるが、通常固形分中０．５μｇ〜３０ｍｇ／１００ｍｇ、より典型的には３μｇ〜１０ｍｇ／１００ｍｇの含有濃度でピセアタンノールが含まれる。また、通常固形分中０．１μｇ〜２０ｍｇ／１００ｍｇ、より典型的には１μｇ〜７ｍｇ／１００ｍｇの含有濃度でスキルプシンＢが含まれる。 Specifically, in the primary extract obtained by extraction with the extraction solvent, it varies depending on the extraction conditions, but usually 0.5 μg to 30 mg / 100 mg, more typically 3 μg to 10 mg / in solid content. Piceatannol is contained at a concentration of 100 mg. In addition, the skillpsin B is usually contained at a concentration of 0.1 μg to 20 mg / 100 mg, more typically 1 μg to 7 mg / 100 mg in the solid content.
ピセアタンノールは、質量分析装置によるマススペクトル測定によってネガティブイオンモードのシグナルとしてｍ／ｚ２４３を呈する化合物として同定でき、また、例えば下記条件でＨＰＬＣにかけたときの保持時間が１９〜２２分に溶出される化合物である。ＨＰＬＣ溶出ピーク下面積を、予め濃度既知の標準品による検量線にあてはめることなどにより定量できる。 Piceatannol can be identified as a compound exhibiting m / z 243 as a signal in negative ion mode by mass spectrum measurement with a mass spectrometer, and the retention time when subjected to HPLC under the following conditions, for example, is eluted at 19 to 22 minutes. It is a compound. The area under the HPLC elution peak can be quantified by, for example, applying it to a calibration curve using a standard product with a known concentration in advance.
［ＨＰＬＣ条件］
・ カラム：Mightysil RP-18 GP250-10 径10mm、長さ250mm（関東化学株式会社製）
・ カラム温度：40℃
・ 溶出条件：流速3ml/min、0％メタノール→30％メタノール（10min）
・ ＵＶ検出：280nm
[HPLC conditions]
・ Column: Mightysil RP-18 GP250-10 Diameter 10mm, Length 250mm (manufactured by Kanto Chemical Co., Inc.)
・ Column temperature: 40 ℃
・ Elution condition: Flow rate 3ml / min, 0% methanol → 30% methanol (10min)
・ UV detection: 280nm
スキルプシンＢは、質量分析装置によるマススペクトル測定によってネガティブイオンモードのシグナルとしてｍ／ｚ４８５を呈する化合物として同定でき、また、例えば下記条件でＨＰＬＣにかけたときの保持時間が１０〜１５分に溶出される化合物である。ＨＰＬＣ溶出ピーク下面積を、予め濃度既知の標準品による検量線にあてはめることなどにより定量できる。 Skillpsin B can be identified as a compound exhibiting m / z 485 as a negative ion mode signal by mass spectrum measurement with a mass spectrometer, and elution time is 10-15 minutes when subjected to HPLC under the following conditions, for example. A compound. The area under the HPLC elution peak can be quantified by, for example, applying it to a calibration curve using a standard product with a known concentration in advance.
［ＨＰＬＣ条件］
・カラム：ODS-3 径4.6mm、長さ150mm（ジーエルサイエンス株式会社製）
・カラム温度：45℃
・溶出条件：流速0.75ml/min、15％アセトニトリル（0min）→40％アセトニトリル（20min）→45％アセトニトリル（25min）
・ＵＶ検出：280nm
[HPLC conditions]
・ Column: ODS-3 diameter 4.6mm, length 150mm (manufactured by GL Sciences Inc.)
・ Column temperature: 45 ℃
・ Elution conditions: Flow rate 0.75ml / min, 15% acetonitrile (0min) → 40% acetonitrile (20min) → 45% acetonitrile (25min)
・ UV detection: 280nm
パッションフルーツの種子抽出物は、上記パッションフルーツ種子の一次抽出物を、そのまま、濃縮して、又は溶媒の一部除去して、液体のまま用いてもよく、そのまま又はデキストリン等の賦形剤を添加したうえ、凍結乾燥又は噴霧乾燥により粉末化して用いることもできる。抽出物中に含まれる不溶物は、パッションフルーツの種子抽出物中に残存せしめてもよく、適宜、濾過などで除いてもよい。除去した不溶物は、これをさらに粉砕し、微細粒子状などにして、もとの抽出物に戻して、パッションフルーツの種子抽出物としてもよい。 The passion fruit seed extract may be used as it is by concentrating the primary extract of the passion fruit seed as it is or by removing a part of the solvent, or using an excipient such as dextrin as it is. In addition, it can be used after pulverizing by freeze-drying or spray-drying. The insoluble matter contained in the extract may remain in the passion fruit seed extract, and may be removed by filtration or the like as appropriate. The removed insoluble matter may be further pulverized, made into fine particles, and returned to the original extract to obtain a passion fruit seed extract.
パッションフルーツ種子抽出物は、また、上記パッションフルーツ種子の一次抽出物のみならず、これをイオン交換・サイズ排除カラムクロマト、ＨＰＬＣ、ゲルろ過、膜分離等により、ピセアタンノール及び／又はスキルプシンＢを指標にして、分画、精製して用いることもできる。ただし、後述する実施例で示すように、パッションフルーツ種子抽出物中のピセアタンノール以外の成分も血糖降下の作用効果に寄与することが示唆されることから、パッションフルーツ種子抽出物中のピセアタンノール及び／又はスキルプシンＢの含有濃度としては、そのパッションフルーツ種子由来のピセアタンノールを固形分中０．０００５〜３０質量％含有し、そのパッションフルーツ種子由来のスキルプシンＢを固形分中０．０００1〜２０質量％含有することが好ましく、ピセアタンノールを固形分中０．００５〜２５質量％含有し、スキルプシンＢを固形分中０．００１〜１５質量％含有することがより好ましく、ピセアタンノールを固形分中０．０５〜２０質量％含有し、スキルプシンＢを固形分中０．０１〜１０質量％含有することが最も好ましい。 Passion fruit seed extract is not only the primary extract of the above passion fruit seed, but it is also used to obtain piceatannol and / or skimpsin B by ion exchange / size exclusion column chromatography, HPLC, gel filtration, membrane separation, etc. It can also be used after fractionation and purification as an index. However, as shown in the examples described later, it is suggested that components other than piceatannol in the passion fruit seed extract also contribute to the effect of lowering blood glucose, so that piceatane in the passion fruit seed extract As the content concentration of the knurpsin and / or the skillpsin B, 0.0005 to 30% by mass of piceatannol derived from the passion fruit seed is contained in the solid content, and the skillpsin B derived from the passion fruit seed is 0.0001 in the solid content. It is preferable to contain ˜20% by mass, more preferably 0.005 to 25% by mass of piceatannol in the solid content, and more preferably 0.001 to 15% by mass of skimpsin B in the solid content. Is contained in an amount of 0.05 to 20% by mass in the solid content and Skillpsin B is contained in an amount of 0.01 to 10% by mass in the solid content. Most preferably.
本発明の血糖降下剤は、上記に説明したパッションフルーツ種子抽出物を、血糖降下のための有効成分として含有する。その有効成分以外の他の成分を配合することに特に制限はなく、必要に応じて、薬学的に許容される基材や担体を添加して、公知の製剤方法によって、例えば錠剤、顆粒剤、散剤、液剤、粉末、顆粒、カプセル剤、ゼリー状剤等の形態にして、これを経口剤として利用することができる。また、軟膏剤、クリーム剤、ジェル、パック、化粧水、化粧料等の形態にして、これを皮膚外用剤として利用することができる。更にまた、乳蛋白、大豆蛋白等の蛋白質、植物性油脂等の脂質、砂糖、デキストリン等の糖質、ビタミン類、ミネラル類、着色剤、保存剤、香料、風味剤、甘味剤などの食用素材を配合してもよい。あるいは、動物飼料用の原料である、大豆粕、ホワイトフィッシュミール等の蛋白源、大豆油等の脂肪源、アルファルファミール等の繊維源、小麦、トウモロコシ、フスマ、胚芽、酵母、脱脂米糠、マイロ等の炭水化物源、ビタミンＡ、Ｄ３、Ｅ、Ｂ１、Ｂ２、Ｂ３、Ｂ１２、パントテン酸カルシウム、ナイアシン、葉酸、塩化コリン等のビタミン類、ＣａＣＯ３、ＮａＣｌ、ＦｅＳＯ４、ＭｎＣＯ３、ＣｏＳＯ４・７Ｈ２Ｏ等のミネラル類などを配合してもよい。 The hypoglycemic agent of the present invention contains the passion fruit seed extract described above as an active ingredient for hypoglycemia. There are no particular restrictions on blending other ingredients other than the active ingredient, and if necessary, a pharmaceutically acceptable base or carrier is added and, for example, tablets, granules, It can be used as an oral preparation in the form of powders, liquids, powders, granules, capsules, jellies and the like. Moreover, it can be used as a skin external preparation in the form of an ointment, cream, gel, pack, lotion, cosmetics, and the like. Furthermore, edible materials such as proteins such as milk protein and soy protein, lipids such as vegetable oils and fats, sugars such as sugar and dextrin, vitamins, minerals, coloring agents, preservatives, fragrances, flavors and sweeteners. May be blended. Or raw materials for animal feed, protein sources such as soybean meal and white fish meal, fat sources such as soybean oil, fiber sources such as alfalfa meal, wheat, corn, bran, germ, yeast, defatted rice bran, milo, etc. Carbohydrate sources, vitamins A, D 3 , E, B 1 , B 2 , B 3 , B 12 , vitamins such as calcium pantothenate, niacin, folic acid, choline chloride, CaCO 3 , NaCl, FeSO 4 , MnCO 3 , CoSO such as 4 · 7H 2 O minerals such as may be blended.
本発明の血糖降下剤においては、その投与形態に特に制限はなく、例えば経口投与、静脈内投与、腹腔内投与、皮下投与、筋肉内投与、経皮投与、経鼻投与、吸引等が挙げられる。なかでも摂取者の負担の軽減や服用のし易さの観点からは、経口投与の形態が好ましい。 The dosage form of the hypoglycemic agent of the present invention is not particularly limited, and examples thereof include oral administration, intravenous administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, transdermal administration, nasal administration, and suction. . Among these, the oral administration form is preferable from the viewpoint of reducing the burden on the intake and ease of taking.
本発明の血糖降下剤において、上記有効成分であるパッションフルーツ種子抽出物の含有量は、各製剤形態とした場合に、その製品が使用される量と有効投与量との関係を勘案して適宜定めればよく、特に制限されるものではないが、通常、固形状の製品の場合には、パッションフルーツ種子抽出物の固形分換算で０．０００７〜１００質量％含有させることが好ましく、０．００７〜１００質量％含有させることがより好ましい。また、液状又はゼリー状の製品の場合には、パッションフルーツ種子抽出物の固形分換算で０．０００１７〜１００質量％含有させることが好ましく、０．００１７〜１００質量％含有させることがより好ましい。 In the hypoglycemic agent of the present invention, the content of the passion fruit seed extract, which is the active ingredient, is appropriately determined in consideration of the relationship between the amount of the product used and the effective dose when each formulation is used. However, in the case of a solid product, it is preferably contained in an amount of 0.0007 to 100% by mass in terms of solid content of the passion fruit seed extract. It is more preferable to contain 007-100 mass%. Moreover, in the case of a liquid or jelly-like product, it is preferable to contain 0.00017-100 mass% in conversion of the solid content of a passion fruit seed extract, and it is more preferable to contain 0.0017-100 mass%.
本発明の血糖降下剤は、例えば食事等により血糖値が上昇すると予想される場合などに、その食前、食中、又は食後に適宜摂取することにより、それによる血糖値の上昇を抑制することができる。また、慢性的に血糖値が高い症状に対しては、好ましくは１週間以上、より好ましくは１ヶ月以上にわたり継続的に摂取して、その改善につなげることができる。なお、本発明の血糖降下剤は、ヒトだけでなくペット等の動物にも適用できる。 The hypoglycemic agent of the present invention can suppress an increase in blood glucose level by taking it appropriately before, during or after a meal, for example, when the blood glucose level is expected to increase due to a meal or the like. it can. In addition, for symptoms with chronically high blood glucose levels, it can be taken continuously for more than 1 week, more preferably for more than 1 month, and this can be improved. The hypoglycemic agent of the present invention can be applied not only to humans but also to animals such as pets.
本発明の血糖降下剤の投与量としては、特に制限はないが、典型的に経口摂取する場合には、パッションフルーツ種子抽出物の固形分換算で成人１日当りおよそ４１６μｇ〜２５ｇである。また、ピセアタンノール換算では、成人１日当りおよそ１２５μｇ〜２５０ｍｇである。また、スキルプシンＢ換算では、成人１日当りおよそ１２５〜２５０ｍｇである。 The dosage of the hypoglycemic agent of the present invention is not particularly limited, but is typically about 416 μg to 25 g per day in terms of solid content of passion fruit seed extract when taken orally. Moreover, in terms of piceatannol, it is about 125 μg to 250 mg per day for an adult. Moreover, in terms of skillpsin B, it is approximately 125 to 250 mg per day for an adult.
以下実施例を挙げて本発明を具体的に説明するが、これらの実施例は本発明の範囲を限定するものではない。 EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but these examples do not limit the scope of the present invention.
＜調製例１＞（パッションフルーツ種子抽出物）
パッションフルーツ種子を焙煎して粉砕し、これに８０％含水エタノール（８０ｖ／ｖ％エタノール＋２０ｖ／ｖ％水）を加えて混合、攪拌した後、８３ｍｅｓｈフィルター（目開き１８０μｍ）で濾過することで固液分離した。得られた抽出液をエバポレータで濃縮して、スプレードライによって粉末化した。表１には、この粉末状のパッションフルーツ種子抽出物の一般成分分析の結果を示す。また、表２には、フォーリン・チオカルト（Ｆｏｌｉｎ−Ｃｉｏｃａｌｔｅｕ）法にてポリフェノール類化合物の含有濃度を求めた結果と、ＨＰＬC分析によりピセアタンノール及びスキルプシンＢの含有濃度を求めた結果を示す。なお、ポリフェノール類化合物の含有濃度は、そのすべてをエピカテキン（ＥＣ）あるいは没食子酸（ＧＡ）に換算した値で表わした。
<Preparation Example 1> (Passion fruit seed extract)
Passion fruit seeds are roasted and pulverized, 80% aqueous ethanol (80 v / v% ethanol + 20 v / v% water) is added to this, mixed, stirred, and then filtered through an 83 mesh filter (aperture 180 μm). Solid-liquid separation. The obtained extract was concentrated with an evaporator and powdered by spray drying. Table 1 shows the results of general component analysis of this powdery passion fruit seed extract. Table 2 shows the results of determining the content concentration of the polyphenol compound by the Folin-Ciocalteu method, and the results of determining the content concentrations of Piceatannol and Skillpsin B by HPLC analysis. In addition, the content density | concentration of the polyphenol compound was represented by the value which converted all into epicatechin (EC) or gallic acid (GA).
＜試験例１＞（経口単回投与による血糖降下試験）
（実験動物）
実験動物として日本チャールス・リバー株式会社から入手した自然発症ＩＩ型糖尿病モデルマウス（オスｄｂ／ｄｂ）を使用した。このマウスは摂食抑制ホルモンであるレプチンの受容体が欠損しており、糖尿病の症状を自然発症するマウスである。マウス週齢は、試験開始時に１１週齢となるように試験スケジュールを調整した。
<Test Example 1> (Blood glucose lowering test by single oral administration)
(Experimental animal)
As an experimental animal, a spontaneous type II diabetes model mouse (male db / db) obtained from Charles River Japan Co., Ltd. was used. This mouse is deficient in the receptor for leptin, an antifeedant hormone, and spontaneously develops symptoms of diabetes. The test schedule was adjusted so that the mouse age was 11 weeks at the start of the test.
（試験スケジュール）
飼育環境にマウスを馴らすため、被検物質の投与開始前に２週間の馴化期間を設けた。この期間中、マウスを、室温２１．９〜２４．５℃で昼夜の明暗管理のもと、飼料として「Ｄ０８１１１５０９」（Ｒｅｓｅａｒｃｈ Ｄｉｅｔｓ，Ｉｎｃ）を自由摂取させて飼育した。馴化期間終了後、マウスを体重、血糖値がほぼ均一になるように群分けし（１群：８匹）、被検物質の経口単回投与による血糖降下試験を行なった。続けてその試験日の５日後には、同様の群分けに従って、後述する試験例２における腹腔内ブドウ糖負荷時の血糖降下試験を行なった。図１には、試験スケジュールの概要を示す。
(Examination schedule)
In order to acclimate the mouse to the breeding environment, a 2-week acclimatization period was provided before the start of administration of the test substance. During this period, the mice were reared at room temperature of 21.9 to 24.5 ° C. under day and night light / dark control with “D08111509” (Research Diets, Inc.) as a feed. After the acclimatization period, the mice were divided into groups so that the body weight and blood glucose level were almost uniform (1 group: 8 animals), and a blood glucose lowering test was conducted by single oral administration of the test substance. Subsequently, on the 5th day after the test day, a blood glucose lowering test during intraperitoneal glucose load in Test Example 2 described later was performed according to the same grouping. FIG. 1 shows an outline of the test schedule.
（被検物質及び試験群）
被検物質の投与は以下の試験群の通りとした。
・第１群：０．５質量％カルボキシキシメチルセルロース（ＣＭＣ）含有水（０．５％ＣＭＣ溶媒）を調製し、それを５ｍＬ／ｋｇ体重の投与量で経口投与した。
・第２群：０．５％ＣＭＣ溶媒中に調製例１のパッションフルーツ種子抽出物を２１．１ｍｇ／ｍＬの濃度で含むものを調製し、それをピセアタンノール換算の投与量で１０ｍｇ／ｋｇ体重となるように経口投与した。
・第３群：０．５％ＣＭＣ溶媒中に調製例１のパッションフルーツ種子抽出物を１０５．４ｍｇ／ｍＬの濃度で含むものを調製し、それをピセアタンノール換算の投与量で５０ｍｇ／ｋｇ体重となるように経口投与した。
・第４群：０．５％ＣＭＣ溶媒中に調製例１のピセアタンノールを１０ｍｇ／ｍＬの濃度で含むものを調製し、それをピセアタンノール換算の投与量で５０ｍｇ／ｋｇ体重となるように経口投与した。
(Test substance and test group)
The test substance was administered according to the following test groups.
Group 1: Water containing 0.5% by mass of carboxyxymethyl cellulose (CMC) (0.5% CMC solvent) was prepared and orally administered at a dose of 5 mL / kg body weight.
Group 2: Prepare one containing the passion fruit seed extract of Preparation Example 1 in a concentration of 21.1 mg / mL in 0.5% CMC solvent, and 10 mg / kg in a dose equivalent to piceatannol It was orally administered to achieve body weight.
-Third group: A preparation containing the passion fruit seed extract of Preparation Example 1 in a concentration of 105.4 mg / mL in 0.5% CMC solvent was prepared, and the dose was converted to 50 mg / kg in terms of piceatannol. It was orally administered to achieve body weight.
Group 4: Prepare the one containing the piceatannol of Preparation Example 1 at a concentration of 10 mg / mL in 0.5% CMC solvent, and make it 50 mg / kg body weight at a dose equivalent to piceatannol Was orally administered.
（採血及び血糖値測定）
被検物質を強制経口投与し、その後マウスは絶食とした。投与直前と１、２、３、及び４時間後にマウスの尾部位から全血を採取し、その全血中の血糖値を血糖自己測定器（商品名「フリースタイル フリーダム」、ニプロ株式会社）にて測定した。図２には、血糖値推移を、投与直前の値からの差により示す。
(Blood collection and blood glucose level measurement)
The test substance was administered by oral gavage, and then the mice were fasted. Whole blood was collected from the tail region of the mouse immediately before administration, 1, 2, 3, and 4 hours later, and the blood glucose level in the whole blood was collected into a blood glucose self-monitoring device (trade name “Freestyle Freedom”, Nipro Corporation). Measured. In FIG. 2, the blood glucose level transition is shown by the difference from the value just before administration.
（結果）
図２に示されるように、０．５％ＣＭＣ溶媒のみを投与した第１群に比べ、パッションフルーツ種子抽出物を投与した第２群及び第３群において、血糖値の低下傾向が認められた。特に第２群においては、ピセアタンノール自体を投与した第４群と比較して、その投与量が１／５であるにも関わらず、血糖値の低下傾向は同程度であり、また第３群においては、ピセアタンノール自体を投与した第４群と比較して、その投与量が同じであるにも関わらず、血糖値の低下傾向においてより優れていた。よって、パッションフルーツ種子抽出物中のピセアタンノール以外の成分も血糖降下の作用効果に寄与していることが示唆された。
(result)
As shown in FIG. 2, the blood glucose level decreased in the second group and the third group administered with the passion fruit seed extract, compared to the first group administered only with 0.5% CMC solvent. . In particular, in the second group, the blood glucose level has a similar tendency to decrease in spite of the dose of 1/5 compared to the fourth group administered with piceatannol itself. In the group, compared with the 4th group which administered piceatannol itself, although the dosage was the same, it was more excellent in the fall tendency of a blood glucose level. Therefore, it was suggested that components other than piceatannol in the passion fruit seed extract also contributed to the effect of hypoglycemia.
＜試験例２＞（腹腔内ブドウ糖負荷時における経口単回投与による血糖降下試験）
試験例１に供した実験動物について、続けてその試験日の５日後には、同様の被検物質及び投与群に従って、腹腔内ブドウ糖負荷時の血糖降下試験を行なった。
<Test Example 2> (Glucose-lowering test by single oral administration at the time of intraperitoneal glucose load)
The test animals used in Test Example 1 were subsequently subjected to a blood glucose lowering test during intraperitoneal glucose load according to the same test substance and administration group 5 days after the test day.
（採血及び血糖値測定）
試験前日より約１６時間絶食し、被検物質を強制経口投与、その１時間後に２ｇ／ｋｇ体重の投与量でブドウ糖を腹腔内投与し、その後マウスは絶食とした。投与直前と０．５、１、１．５、２、３時間後にマウスの尾部位から採血し、その血漿中の血糖値をグルコース濃度測定用試薬キット（商品名「ラボアッセイ（ＴＭ）グルコース」、和光純薬工業株式会社）にて測定した。結果を図３に示す。
(Blood collection and blood glucose level measurement)
Fasted for about 16 hours from the day before the test, the test substance was administered by oral gavage, and 1 hour later, glucose was administered intraperitoneally at a dose of 2 g / kg body weight, and then the mice were fasted. Blood was collected from the tail region of the mouse immediately before administration and 0.5, 1, 1.5, 2 and 3 hours later, and the blood glucose level in the plasma was determined as a glucose concentration measurement reagent kit (trade name “Lab Assay (TM) Glucose”). , Wako Pure Chemical Industries, Ltd.). The results are shown in FIG.
（結果）
図３に示されるように、０．５％ＣＭＣ溶媒のみを投与した第１群に比べ、パッションフルーツ種子抽出物を投与した第２群及び第３群において、血糖値の低下傾向が認められた。特に糖負荷による初期の最高血糖値の上昇が有意に抑えられた。
(result)
As shown in FIG. 3, compared to the first group to which only 0.5% CMC solvent was administered, in the second group and the third group to which the passion fruit seed extract was administered, a tendency to decrease the blood glucose level was observed. . In particular, the initial increase in the maximum blood glucose level due to glucose load was significantly suppressed.
＜試験例３＞（ヒト糖負荷試験）
３人のヒト被験者にブドウ糖負荷時における経口単回投与による血糖降下試験を行なった。試験は、被検物質として調製例１のパッションフルーツ種子抽出物をピセアタンノール換算で３０ｍｇ／包となるようにオブラートで包んで水とともに摂取する場合と、あるいは何も摂取しない場合とについて、各試験を同一の被験者において日を改めて行なった。
<Test Example 3> (Human glucose tolerance test)
Three human subjects were subjected to a hypoglycemic test by single oral administration during glucose loading. The test was conducted for each of the cases where the passion fruit seed extract of Preparation Example 1 was ingested with water in a form of 30 mg / pack in terms of piceatannol and taken together with water as a test substance, or when nothing was ingested. The test was repeated on the same subject.
被験者には前日夜９時までに夕食を済ませ当日の朝は絶食とした。また、水分の摂取は可、激しい運動は不可とした。部屋で１５分以上安静にしてから指先から採血し、その全血中の血糖値を血糖自己測定器（商品名「グルコカード」、株式会社アークレイ）にて測定した。血糖値測定は２回の平均値とし、２回の測定値が５ｍｇ／ｄＬ以上離れた場合には５ｍｇ／ｄＬ以内になるまで測定した。その測定後にパッションフルーツ種子抽出物を経口摂取してもらい（被摂取の試験のときにはなにも摂取しない）、更にその５分後にブドウ糖液（日医工株式会社）を５０ｇブドウ糖／３００ｍＬ水に調製したものを経口摂取してもらった。ブドウ糖摂取後、３０、６０、９０、１２０分後に上記と同様に血糖値を測定した。３人の結果を平均し、その結果を図４に示す。 The subjects had dinner at 9:00 the night before and were fasted on the morning of the day. In addition, water intake was possible, but intense exercise was not possible. After resting in the room for 15 minutes or longer, blood was collected from the fingertip, and the blood glucose level in the whole blood was measured with a blood glucose self-monitoring device (trade name “Gluco Card”, Arkray, Inc.). The blood glucose level was measured as an average of two times, and when the two measured values were separated by 5 mg / dL or more, they were measured until they were within 5 mg / dL. After the measurement, the passion fruit seed extract was orally ingested (no intake during the ingestion test), and 5 minutes later, a glucose solution (Nichi Medical Co., Ltd.) was prepared in 50 g glucose / 300 mL water. I was taken orally. After ingesting glucose, blood glucose levels were measured in the same manner as described above at 30, 60, 90, and 120 minutes. The results of three people are averaged, and the results are shown in FIG.
図４に示されるように、パッションフルーツ種子抽出物を摂取した場合において、パッションフルーツ種子抽出物を摂取しない場合に比べ、血糖値の低下傾向が認められた。 As shown in FIG. 4, when the passion fruit seed extract was ingested, a tendency to lower the blood glucose level was recognized as compared to the case where the passion fruit seed extract was not ingested.
＜製造例１＞
［錠剤］
下記配合（１錠当り）にて、調製例１のパッションフルーツ種子抽出物を含有する錠剤を製造した。
<Production Example 1>
[tablet]
Tablets containing the passion fruit seed extract of Preparation Example 1 were produced with the following formulation (per tablet).
（配合）
パッションフルーツ種子抽出物 （調製例１） １５０．０ｍｇ
結晶セルロース ５０．０ｍｇ
澱粉分解物 ３５．６ｍｇ
グァーガム ０．９ｍｇ
ステアリン酸カルシウム ７．５ｍｇ
二酸化ケイ素 ６．０ｍｇ
合計 ２５０．０ｍｇ
(Combination)
Passion fruit seed extract (Preparation Example 1) 150.0mg
Crystalline cellulose 50.0mg
Starch degradation product 35.6mg
Guar gum 0.9mg
Calcium stearate 7.5mg
Silicon dioxide 6.0mg
Total 250.0mg
この錠剤は、経口的に摂取するのに適した錠剤であった。 This tablet was suitable for oral intake.
Claims (1)
Passion fruit seed polar solvent extract, wherein the passion fruit seed polar solvent extract contains 0.05-30 % by mass of piceatannol derived from the passion fruit seed in a solid content, the passion fruit seed A hypoglycemic agent characterized by containing the extract containing 0.001 to 20% by mass of the derived skillpsin B as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2013045659A JP6224899B2 (en) | 2013-03-07 | 2013-03-07 | Hypoglycemic agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2013045659A JP6224899B2 (en) | 2013-03-07 | 2013-03-07 | Hypoglycemic agent |
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