JP4581064B2 - Insulin secretagogue - Google Patents
Insulin secretagogue Download PDFInfo
- Publication number
- JP4581064B2 JP4581064B2 JP2003378694A JP2003378694A JP4581064B2 JP 4581064 B2 JP4581064 B2 JP 4581064B2 JP 2003378694 A JP2003378694 A JP 2003378694A JP 2003378694 A JP2003378694 A JP 2003378694A JP 4581064 B2 JP4581064 B2 JP 4581064B2
- Authority
- JP
- Japan
- Prior art keywords
- extract
- insulin
- fruit
- cyclic amp
- rosmarinic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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- ZZAFFYPNLYCDEP-HNNXBMFYSA-N Rosmarinsaeure Natural products OC(=O)[C@H](Cc1cccc(O)c1O)OC(=O)C=Cc2ccc(O)c(O)c2 ZZAFFYPNLYCDEP-HNNXBMFYSA-N 0.000 claims description 36
- DOUMFZQKYFQNTF-MRXNPFEDSA-N rosemarinic acid Natural products C([C@H](C(=O)O)OC(=O)C=CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-MRXNPFEDSA-N 0.000 claims description 36
- TVHVQJFBWRLYOD-UHFFFAOYSA-N rosmarinic acid Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=Cc2ccc(O)c(O)c2)C=O TVHVQJFBWRLYOD-UHFFFAOYSA-N 0.000 claims description 36
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Description
本発明は、インスリン分泌促進を必要とする疾患、特に糖尿病および／または糖尿病合併症の治療または予防に利用できるインスリン分泌促進剤に関する。 The present invention relates to an insulin secretagogue that can be used for the treatment or prevention of diseases requiring insulin secretion promotion, particularly diabetes and / or diabetic complications.
インスリンは膵臓ランゲルハンス島B（βとも言う）細胞から分泌されるホルモンで、その主な生理作用は血糖値を下げることにある。インスリンは、筋において、糖、アミノ酸、カリウムの取り込みの促進、グリコーゲン合成、タンパク質合成の促進、脂肪組織では糖の取り込みおよび利用促進、脂肪の合成促進および分解抑制、タンパク質の合成促進、肝では糖新生の抑制、グリコーゲンの合成促進および分解抑制、タンパク質の合成促進等の作用をもち、標的組織の細胞膜上にはインスリン受容体が存在する。食事等により血糖値が上がると、インスリンが膵臓から分泌され、上記の作用により血糖値を正常に保つ。 Insulin is a hormone secreted from pancreatic islets of Langerhans B (also called β) cells, whose main physiological action is to lower blood sugar levels. Insulin promotes sugar, amino acid, and potassium uptake in muscle, glycogen synthesis, promotes protein synthesis, promotes sugar uptake and utilization in adipose tissue, promotes fat synthesis and inhibits degradation, promotes protein synthesis, and sugars in liver Insulin receptors exist on the cell membrane of the target tissue, and have actions such as inhibition of neoplasia, inhibition of glycogen synthesis and degradation, and promotion of protein synthesis. When the blood sugar level rises due to meals or the like, insulin is secreted from the pancreas, and the blood sugar level is kept normal by the above action.
糖尿病は、インスリンの欠乏、または作用の不足によって、ブドウ糖の代謝に異常が起こり、血液中のブドウ糖が増えすぎて尿の中に糖が溢れてきた状態で、慢性的に高血糖状態が続いている病気である。この高血糖状態により、神経障害、白内障、腎障害、網膜症、関節硬化症、アテローム性動脈硬化症、糖尿病性壊疽等の種々の合併症を発症することがある。糖尿病には、I型糖尿病(インスリン依存型)とII型糖尿病(インスリン非依存型)がある。I型糖尿病は、主に15才未満の子供に見られ、「若年型糖尿病」とも呼ばれてきた。これは、膵臓B細胞が、なんらかの原因でインスリンを分泌できなくなり、高血糖として発症するものである。II型糖尿病は、インスリンの分泌量が低下するか（インスリン分泌不全）、インスリンの血糖を下げる作用が弱くなって（インスリン抵抗性）発症するもので、遺伝素因のほかに、エネルギーの過剰摂取や栄養の偏った食生活、運動不足、ストレスが大きく関わっており、日本人の糖尿病の90％を占めている。II型糖尿病の治療でも、血糖値をコントロールするためにインスリン投与が必要になることがある。 Diabetes is a condition in which glucose metabolism is abnormal due to lack of insulin or lack of action, glucose in the blood increases excessively, and sugar is overflowing in the urine. Chronic hyperglycemia continues. I'm sick. This hyperglycemic state may cause various complications such as neuropathy, cataract, nephropathy, retinopathy, arteriosclerosis, atherosclerosis and diabetic gangrene. Diabetes includes type I diabetes (insulin-dependent) and type II diabetes (insulin-independent). Type I diabetes is mainly found in children under 15 years of age and has also been called “young diabetes”. This is because pancreatic B cells cannot secrete insulin for some reason and develop as hyperglycemia. Type II diabetes is caused by a decrease in insulin secretion (insulin secretion failure) or a weakening of blood glucose's action to lower blood sugar (insulin resistance). In addition to genetic predisposition, energy overdose and Nutritionally unbalanced diets, lack of exercise, and stress are greatly involved, accounting for 90% of Japanese diabetes. Even in the treatment of type II diabetes, insulin administration may be required to control blood glucose levels.
ここで、インスリンとは、21個のアミノ酸残基からなるA鎖と30個のアミノ酸残基からなるB鎖から構成されるペプチドであり、A鎖とB鎖は２箇所のジスルフィド結合で結合されている。インスリンは膵臓B細胞の粗面小胞体で前駆体であるプロインスリンとして合成され、インスリンに転換後、B顆粒内に貯蔵され、分泌刺激に応じて血中に放出される。分泌は主としてグルコースにより促進されるが、その他の分泌促進因子として、マンノース等の糖、アミノ酸（アルギニン、リジン等）、ペプチドホルモン（グルカゴン、ガストリック・インビビトリー・ポリペプチド等）、迷走神経刺激剤、交感神経系β受容体刺激剤、交感神経系のα受容体遮断剤、スルホニル尿素剤等がある。 Here, insulin is a peptide composed of an A chain consisting of 21 amino acid residues and a B chain consisting of 30 amino acid residues, and the A chain and the B chain are linked by two disulfide bonds. ing. Insulin is synthesized in the rough endoplasmic reticulum of pancreatic B cells as pro-insulin, which is converted into insulin, stored in B granules, and released into the blood in response to secretory stimulation. Secretion is mainly promoted by glucose, but other secretagogues include sugars such as mannose, amino acids (such as arginine and lysine), peptide hormones (such as glucagon, gastric / invitro / polypeptide), vagus nerve stimulators, Sympathetic nervous system β receptor stimulants, sympathetic nervous system α receptor blockers, sulfonylureas, and the like.
糖尿病の症状を改善するには、インスリンを直接注射する治療法のほかに、前述のスルホニル尿素剤（トルブタミド、クロルブロバミド、アセトヘキサミド、グリクロビラミド、グリベンクラミド、グリクラチド等）のように膵臓B細胞に直接働き、インスリンの分泌を促進する薬剤を服用する方法がある。この場合は、膵臓からインスリンが分泌されていることが必要であるため、この方法はインスリン非依存型のII型糖尿病に用いられる。その他の治療法として、αグルコシダーゼ阻害剤（糖質の消化・吸収を遅らせる効果があり、食後の急激な血糖の上昇を抑制する）を服用する方法もある。 In order to improve the symptoms of diabetes, in addition to the treatment by direct injection of insulin, it works directly on pancreatic B cells like the above sulfonylureas (tolbutamide, chlorbrobamide, acetohexamide, glycloviramide, glibenclamide, gliclatide, etc.) There are ways to take drugs that promote insulin secretion. In this case, since it is necessary for insulin to be secreted from the pancreas, this method is used for insulin-independent type II diabetes. As another treatment method, there is a method of taking an α-glucosidase inhibitor (which has an effect of delaying digestion and absorption of carbohydrates and suppresses a rapid increase in blood glucose after meals).
また、最近の報告によれば、グルカゴンやイソクレチン（腸管内分泌細胞から分泌される）がそれぞれの受容体に結合することによりアデニル酸シクラーゼが活性化され、サイクリックAMP（サイクリックアデノシン3', 5'- 一リン酸、環状AMP、cAMPとも言う）の産生が促進され、このサイクリックAMPがPKA（プロテインキナーゼＡ）依存性機構と、PKA非依存性機構（cAMP-GEFII）を活性化してインスリン分泌を促進する（非特許文献１）。一方、サイクリックAMPはサイクリックヌクレオチドホスホジエステラーゼによって5'-AMPに分解される。したがって、サイクリックヌクレオチドホスホジエステラーゼはアデニル酸シクラーゼとともに、細胞内のサイクリックAMPの量的水準を調節しており、サイクリックヌクレオチドホスホジエステラーゼの活性を制御し、サイクリックAMPの濃度を調節することにより、インスリン分泌を調節することが可能と考えられる。
According to recent reports, adenylate cyclase is activated by binding of glucagon and isocretin (secreted from intestinal endocrine cells) to each receptor, and cyclic AMP (
近年、血糖値上昇を抑制するための機能性食品、特に副作用が少なく、安全性の高い天然成分由来の機能性食品の研究が盛んに行われており、柑橘類から抽出されるノビレチン類（特許文献１）、ブリケリア属の植物抽出物、該植物から単離されたフラボノイド（ルテオリン、ミリセチン、ジヒドロキシケムフェロール、アピゲニン、ケルセチン）（特許文献２）、オリーブ葉またはその抽出物（ルテオリンを含有する）（特許文献３）、野菜または果物抽出物、該抽出物がヘスペリジン、ヘスペレチン、ナリンジン、ナリンゲニン、ジオスミン、ルチン、ケルセチン等のフラボノイド（特許文献４）、イソフラボン、イソフラボン配糖体（特許文献５）等の血糖値上昇抑制効果が報告されている。 In recent years, research on functional foods for suppressing an increase in blood glucose level, especially functional foods derived from citrus fruits, which have few side effects and high safety from natural ingredients has been actively conducted (Patent Documents) 1), a plant extract of the genus Briqueria, a flavonoid isolated from the plant (luteolin, myricetin, dihydroxychemferrol, apigenin, quercetin) (patent document 2), olive leaf or an extract thereof (containing luteolin) ( Patent Document 3), vegetable or fruit extract, flavonoids such as hesperidin, hesperetin, naringin, naringenin, diosmine, rutin, quercetin, etc. (Patent Document 4), isoflavones, isoflavone glycosides (Patent Document 5), etc. It has been reported to have an effect of suppressing an increase in blood glucose level.
しかしながら、これらはいずれも糖分解酵素の抑制あるいは動物実験での血糖値上昇抑制効果を記載しているだけであり、インスリン分泌促進効果を実験で証明したものはない。 However, all of these only describe the effect of inhibiting glycolytic enzymes or the effect of suppressing the increase in blood glucose level in animal experiments, and there has been no evidence of an effect of promoting insulin secretion.
一方、ロズマリン酸（3,4-Dihydroxycinnamic acid (R)-1-carboxy-2-(3,4-dihydroxyphenyl)ethyl ester）は、青ジソ、レモンバーム等のシソ科植物等に含まれているポリフェノールの一種で、抗酸化作用が強く、ヒアルロニダーゼの働きを抑制する効果が知られており（特許文献６）、化粧品成分としての有用性の他、花粉症に有効とされている。また、クミスクチンにαグルコシダーゼ阻害活性があり、阻害活性成分を同定したところ、ロズマリン酸であったこと、さらにロズマリン酸を含むクミスクチン粗精製画分が自然発症糖尿病マウスを用いた実験で血糖値上昇抑制活性があることが報告されている（非特許文献２）。しかし、ロズマリン酸がインスリンの分泌を促進させる機能を有することについての報告はされていない。 On the other hand, rosmarinic acid (3,4-dihydroxycinnamic acid (R) -1-carboxy-2- (3,4-dihydroxyphenyl) ethyl ester) is a polyphenol contained in Lamiaceae plants such as blue diso and lemon balm. It is a kind and has a strong antioxidative effect and is known to have an effect of suppressing the action of hyaluronidase (Patent Document 6). In addition to its usefulness as a cosmetic ingredient, it is effective for hay fever. In addition, cumistin has α-glucosidase inhibitory activity, and when the inhibitory activity component was identified, it was rosmarinic acid, and the crude purified fraction containing rosmarinic acid suppressed the increase in blood glucose level in experiments using spontaneously diabetic mice. It has been reported that there is activity (Non-Patent Document 2). However, there is no report that rosmarinic acid has a function of promoting insulin secretion.
したがって、安全性が高い天然成分由来のインスリン分泌促進剤がいまだに必要とされている。
本発明の課題は、安全性が高い天然成分由来のインスリン分泌促進剤を提供することである。 The subject of this invention is providing the insulin secretion promoter derived from a natural component with high safety | security.
本発明者らは、天然成分由来のインスリン分泌促進物質を求めて鋭意探索した結果、ロズマリン酸、およびクミスクチン、クダモノトケイソウ、ヘチマまたはドラゴンフルーツ由来の物質が膵臓B細胞に働いてインスリン分泌を促進する効果を有することを見出した。 As a result of earnest search for an insulin secretion-promoting substance derived from a natural component, the present inventors have worked on pancreatic B cells to promote insulin secretion by rosmarinic acid and a substance derived from cumistin, damselfly, loofah or dragonfruit. It was found to have an effect.
本発明者らはまた、ロズマリン酸、およびクミスクチン、クダモノトケイソウ、ヘチマまたはドラゴンフルーツ由来の物質が、サイクリックヌクレオチドホスホジエステラーゼの活性を阻害することを見いだした。 The inventors have also found that rosmarinic acid and substances derived from cumistin, damselfly, loofah or dragon fruit inhibit the activity of cyclic nucleotide phosphodiesterase.
上記課題を解決する本発明は以下の発明を包含する。
（１）ロズマリン酸を有効成分として含有するインスリン分泌促進剤。
（２）クミスクチン、クダモノトケイソウ、ヘチマおよびドラゴンフルーツのうちの少なくとも一つに由来し、インスリン分泌促進活性を示す物質を有効成分として含有するインスリン分泌促進剤。
（３）クミスクチン、クダモノトケイソウ、ヘチマおよびドラゴンフルーツのうち少なくとも一つの抽出物および／またはその処理物を有効成分として含有するインスリン分泌促進剤。
（４）ロズマリン酸を有効成分として含有するサイクリックAMPホスホジエステラーゼ阻害剤。
（５）クミスクチン、クダモノトケイソウ、ヘチマおよびドラゴンフルーツのうちの少なくとも一つに由来し、サイクリックAMPホスホジエステラーゼ阻害活性を示す物質を有効成分として含有するサイクリックAMPホスホジエステラーゼ阻害剤。
The present invention for solving the above problems includes the following inventions.
(1) An insulin secretion promoter containing rosmarinic acid as an active ingredient.
(2) An insulin secretagogue comprising, as an active ingredient, a substance exhibiting insulin secretagogue activity, derived from at least one of cumistin, damselfly, loofah and dragon fruit.
(3) An insulin secretagogue comprising as an active ingredient at least one extract of cumistin, damselfly, loofah and dragon fruit and / or a processed product thereof.
(4) A cyclic AMP phosphodiesterase inhibitor containing rosmarinic acid as an active ingredient.
(5) A cyclic AMP phosphodiesterase inhibitor containing, as an active ingredient, a substance that exhibits cyclic AMP phosphodiesterase inhibitory activity, derived from at least one of cumistin, damselfly, loofah, and dragon fruit.
（６）クミスクチン、クダモノトケイソウ、ヘチマおよびドラゴンフルーツのうち少なくとも一つの抽出物および／またはその処理物を有効成分として含有するサイクリックAMPホスホジエステラーゼ阻害剤。
（７）上記（１）〜（３）のいずれか１に記載のインスリン分泌促進剤および／または上記（４）〜（６）のいずれか１に記載のサイクリックAMPホスホジエステラーゼ阻害剤を含有する糖尿病または糖尿病合併症治療剤。
（８）食品に添加するための上記（１）〜（３）のいずれか１に記載のインスリン分泌促進剤。
（９）食品に添加するための上記（４）〜（６）のいずれか１に記載のサイクリックAMPホスホジエステラーゼ阻害剤。
（１０）クミスクチン、クダモノトケイソウ、ヘチマおよびドラゴンフルーツのうちの少なくとも一つを搾汁または粉砕する工程、該搾汁または該粉砕物を抽出する工程、および必要に応じて該搾汁または該粉砕物またはその抽出物に濃縮処理および／または精製処理を行う工程を含む、上記（２）〜（６）のいずれか１に記載のインスリン分泌促進剤またはサイクリックAMPホスホジエステラーゼ阻害剤の製造方法。
(6) A cyclic AMP phosphodiesterase inhibitor containing as an active ingredient at least one extract of cumistin, damselfly, loofah and dragon fruit and / or a processed product thereof.
(7) Diabetes containing the insulin secretion promoter according to any one of (1) to (3) and / or the cyclic AMP phosphodiesterase inhibitor according to any one of (4) to (6) above Or a therapeutic agent for diabetic complications.
(8) The insulin secretion promoter according to any one of (1) to (3) above, which is added to food.
(9) The cyclic AMP phosphodiesterase inhibitor according to any one of (4) to (6) above, which is added to food.
(10) A step of squeezing or pulverizing at least one of cumistin, damselfly, loofah and dragon fruit, a step of extracting the squeezed or pulverized product, and, if necessary, the squeezed or pulverized product Or the manufacturing method of the insulin secretion promoter or cyclic AMP phosphodiesterase inhibitor of any one of said (2)-(6) including the process of performing a concentration process and / or a refinement | purification process to the extract.
本発明により、安全性が高い食品系植物由来のインスリン分泌促進剤およびサイクリックAMPホスホジエステラーゼ阻害剤が提供される。 According to the present invention, an insulin secretion promoter and a cyclic AMP phosphodiesterase inhibitor derived from food-based plants with high safety are provided.
本発明のインスリン分泌促進剤およびサイクリックAMPホスホジエステラーゼ阻害剤は、糖尿病および／または糖尿病合併症の治療に用いることができる。 The insulin secretion promoter and cyclic AMP phosphodiesterase inhibitor of the present invention can be used for the treatment of diabetes and / or diabetic complications.
以下、本発明について詳細に説明するが、本発明の範囲はこれらの説明により限定されるものではない。
（１）ロズマリン酸
本発明は、ロズマリン酸を有効成分として含有するインスリン分泌促進剤またはサイクリックAMPホスホジエステラーゼ阻害剤に関する。
Hereinafter, the present invention will be described in detail, but the scope of the present invention is not limited by these descriptions.
(1) Rosmarinic acid TECHNICAL FIELD This invention relates to the insulin secretion promoter or cyclic AMP phosphodiesterase inhibitor which contains rosmarinic acid as an active ingredient.
ロズマリン酸は、上述のように、青ジソ、レモンバーム等のシソ科植物等に含まれているポリフェノールの一種である。本発明で用いるロズマリン酸は、市販のものを用いてもよいが、植物から得ることもできる。 As described above, rosmarinic acid is a kind of polyphenol contained in Lamiaceae plants such as blue disodium and lemon balm. The rosmarinic acid used in the present invention may be a commercially available one, but can also be obtained from a plant.
植物から得る場合は、ロズマリン酸を含有する任意の植物を用いることができる。ロズマリン酸を含有する植物として、例えばクミスクチン、ローズマリー、レモンバーム、青ジソ、赤ジソ、夏枯草、好ましくはクミスクチンが挙げられる。例えば乾燥クミスクチン葉に含まれるロズマリン酸の量は、乾燥クミスクチン葉全体の重量に対して、0.2重量％である。また、植物は、その全体または茎、葉、花、果実、果皮等の搾汁をそのまま用いることができるが、植物の全体または根、茎、葉、花、果実、果皮等を破砕、粉砕等により粉末化処理したものを用いてもよい。また、該搾汁または該粉砕物の抽出物または該搾汁または該粉砕物またはその抽出物の処理物として用いることもできる。 In the case of obtaining from a plant, any plant containing rosmarinic acid can be used. Examples of plants containing rosmarinic acid include cumistin, rosemary, lemon balm, blue disodium, red disodium, summer hay, and preferably cuminctin. For example, the amount of rosmarinic acid contained in the dried cumistin leaf is 0.2% by weight based on the total weight of the dried cumistin leaf. In addition, the whole plant or the juice of stems, leaves, flowers, fruits, fruit skins, etc. can be used as it is, but the whole plant or roots, stems, leaves, flowers, fruits, skins etc. are crushed, crushed, etc. You may use what was pulverized by this. It can also be used as an extract of the juice or the pulverized product or a processed product of the juice or the pulverized product or an extract thereof.
本明細書において、「果皮」とは、果実の外側の皮の部分を意味するが、果肉の部分が付着していてもよい。また、「果肉」とは、果実の半透明のゼリー状の部分を意味するが、果皮、種子の部分が付着していてもよい。また、「抽出物」とは、植物の全体または根、茎、葉、花、果実、果皮等等の部分に含まれる成分を、水、エタノール等の溶媒に溶解させて抽出し適宜乾燥させた、通常は液体または固体の物質を指し、「処理物」とは、搾汁、粉末または抽出物に対してさらに濃縮処理や精製処理等を行うことにより得られる物質を指すものとする。 In the present specification, the “fruit skin” means a skin portion outside the fruit, but a pulp portion may be attached. “Fruit” means a translucent jelly-like portion of the fruit, but the skin and seed portions may be attached. In addition, the “extract” refers to components extracted from the whole plant or parts such as roots, stems, leaves, flowers, fruits, fruit skins, etc. dissolved in a solvent such as water or ethanol and appropriately dried. In general, it refers to a liquid or solid substance, and the “processed product” refers to a substance obtained by further performing a concentration process, a purification process, or the like on the juice, powder or extract.
植物を抽出物として用いる場合、抽出時間は10分〜１時間程度、特に30分程度が好ましく、また抽出に使用する溶媒量は原料に対して質量比で２倍量〜10倍量、特に５倍量が好ましい。抽出溶媒は任意の溶媒であってよく、例えばメタノール、エタノール、酢酸エチル、その他の有機溶媒、および水のうち１種または２種以上を用いることができる。好ましくは、エタノールと水の混合溶媒を用いる。また、溶媒抽出の過程でケイソウ土を加えてもよい。さらに場合により、抽出後、ろ過または遠心分離により抽出残渣を除き抽出液を得ることができる。 When a plant is used as an extract, the extraction time is preferably about 10 minutes to 1 hour, particularly about 30 minutes, and the amount of solvent used for extraction is 2 to 10 times, especially 5 in weight ratio to the raw material. Double amounts are preferred. The extraction solvent may be any solvent, and for example, one or more of methanol, ethanol, ethyl acetate, other organic solvents, and water can be used. Preferably, a mixed solvent of ethanol and water is used. Further, diatomaceous earth may be added in the process of solvent extraction. Further, in some cases, after extraction, the extraction residue can be removed by filtration or centrifugation to obtain an extract.
また、搾汁、粉末または抽出液を濃縮処理することもできる。さらに、搾汁、粉末または抽出液には糖分や有機酸が非常に多く含まれるため、それらを除く精製工程を行うことも好ましい。精製処理の方法として、順相または逆相クロマトグラフィー、イオン交換クロマトグラフィー、ゲルろ過等が挙げられる。これらの方法を組み合わせて用いることもできる。 Further, the juice, powder or extract can be concentrated. Furthermore, since the juice, powder or extract contains a large amount of sugar and organic acid, it is also preferable to carry out a purification step to remove them. Examples of the purification method include normal phase or reverse phase chromatography, ion exchange chromatography, gel filtration and the like. A combination of these methods can also be used.
さらに、ロズマリン酸を単離精製することもできる。単離精製の方法としては、例えば抽出液をＨＰＬＣ、合成吸着剤クロマトグラフィー、イオン交換クロマトグラフィー、ゲルろ過等により単離する方法があるが、特に逆相系の担体を用いたＨＰＬＣを用いることが好ましい。この場合、抽出条件としては、例えば１０〜５０％アセトニトリル溶液を用いて溶出することが好ましい。 Furthermore, rosmarinic acid can be isolated and purified. Isolation and purification methods include, for example, a method of isolating the extract by HPLC, synthetic adsorbent chromatography, ion exchange chromatography, gel filtration, and the like, but in particular, HPLC using a reverse phase carrier is used. Is preferred. In this case, as extraction conditions, it is preferable to elute, for example using a 10-50% acetonitrile solution.
本発明のロズマリン酸を有効成分として含有するインスリン分泌促進剤またはサイクリックAMPホスホジエステラーゼ阻害剤は、ロズマリン酸の搾汁、抽出物または処理物自体をインスリン分泌促進剤またはサイクリックAMPホスホジエステラーゼ阻害剤としてもよい。
なお、ロズマリン酸を得るために用いる青ジソ、レモンバーム等のシソ科植物等の植物は、現在までに食品や飲料等に供されており、安全性は確立されている。
The insulin secretion promoter or cyclic AMP phosphodiesterase inhibitor containing the rosmarinic acid of the present invention as an active ingredient can be obtained by using the rosmarinic acid juice, extract or treated product itself as an insulin secretion promoter or cyclic AMP phosphodiesterase inhibitor. Good.
In addition, plants such as Labiatae plants such as blue diso and lemon balm used to obtain rosmarinic acid have been used for foods and beverages so far, and safety has been established.
（２）クミスクチン
本発明はまた、クミスクチン由来であって、インスリン分泌促進活性および／またはサイクリックAMPホスホジエステラーゼ阻害活性を示す物質を有効成分として含有するインスリン分泌促進剤またはサイクリックAMPホスホジエステラーゼ阻害剤に関する。
(2) Cumistin The present invention also relates to an insulin secretion promoter or a cyclic AMP phosphodiesterase inhibitor that contains a substance that is derived from cumistin and exhibits insulin secretion promoting activity and / or cyclic AMP phosphodiesterase inhibitory activity as an active ingredient.
クミスクチン（ネコノヒゲ、Orthosiphon aristatus (Bl.) Miq.）は、シソ科の多年草で、インドから東南アジア、オーストラリア北部に広く分布し、沖縄でも広く栽培されている。本発明で使用するクミスクチンの品種と産地は、特に限定されるものではない。 Kumisumchin (Orthosiphon aristatus (Bl.) Miq.) Is a perennial plant belonging to the family Lamiaceae, widely distributed from India to Southeast Asia and northern Australia, and widely cultivated in Okinawa. The variety and production area of cumistin used in the present invention are not particularly limited.
本発明で使用するクミスクチンは、全体または茎、葉、花、果実、果皮等の搾汁をそのまま用いることができるが、クミスクチン全体または根、茎、葉、花、果実、果皮等を破砕、粉砕等により粉末化処理したものを用いてもよい。また、該搾汁または該粉砕物の抽出物または該搾汁または該粉砕物またはその抽出物の処理物として用いることもできる。クミスクチンを抽出物として用いる場合、葉、茎、根または花の抽出物が好ましく、葉の抽出物が特に好ましい。 The cumistin used in the present invention can be used as it is or the whole juice of stems, leaves, flowers, fruits, fruit peels, etc., but the whole cumistin or roots, stems, leaves, flowers, fruits, peels etc. are crushed and crushed. You may use what was pulverized by the above. It can also be used as an extract of the juice or the pulverized product or a processed product of the juice or the pulverized product or an extract thereof. When cumistin is used as an extract, a leaf, stem, root or flower extract is preferred, and a leaf extract is particularly preferred.
クミスクチンを抽出物として用いる場合の抽出時間等の条件や、処理物として用いる場合の精製処理の条件等は、上述（１）のロズマリン酸の場合に準ずる。
例えば、クミスクチン葉を抽出して用いる場合、上述（１）の方法に準じた条件下で、クミスクチンの葉を乾燥した後、遠心破砕器で破砕し、溶媒抽出を行い、抽出液を減圧下で乾燥することにより粉末として得ることができる。
The conditions such as the extraction time when using cumistin as the extract, the conditions for the purification treatment when using as the processed product, and the like are the same as in the case of rosmarinic acid described in (1) above.
For example, when extracting and using cumistin leaves, after drying the cumistin leaves under the conditions according to the above method (1), crushing with a centrifugal crusher, solvent extraction, and extracting the extract under reduced pressure It can be obtained as a powder by drying.
（３）クダモノトケイソウ
本発明はさらにまた、クダモノトケイソウ由来であって、インスリン分泌促進活性および／またはサイクリックAMPホスホジエステラーゼ阻害活性を示す物質を有効成分として含有するインスリン分泌促進剤およびサイクリックAMPホスホジエステラーゼ阻害剤に関する。
(3) Further, the present invention further relates to an insulin secretagogue and cyclic AMP phosphodiesterase inhibition containing, as an active ingredient, a substance that is derived from the fern butterfly and exhibits insulin secretion promoting activity and / or cyclic AMP phosphodiesterase inhibitory activity. It relates to the agent.
クダモノトケイソウ（別名パッションフルーツ、Passiflora edulis）は、南米原産のつる性多年生熱帯果樹であり、現在では世界中の熱帯、亜熱帯地域に広まっており、オーストラリアや東南アジア、台湾等で産業的に栽培されている。日本では沖縄での生産が一番多いが、奄美諸島、小笠原諸島でも栽培されている。本発明で使用するクダモノトケイソウの品種と産地は、特に限定されるものではない。 Kudamono Passiflora (aka Passiflora edulis) is a vine perennial tropical fruit tree native to South America, and is now widely used in tropical and subtropical regions around the world, and is cultivated industrially in Australia, Southeast Asia, Taiwan, and other countries. Yes. Japan has the most production in Okinawa, but it is also cultivated in Amami Islands and Ogasawara Islands. There are no particular limitations on the variety and production area of the damselfly used in the present invention.
本発明で使用するクダモノトケイソウは、全体または根、茎、葉、花、果実、果皮等の搾汁をそのまま用いることができるが、クダモノトケイソウ全体または根、茎、葉、花、果実、果皮等を破砕、粉砕等により粉末化処理したものを用いてもよい。また、該搾汁または該粉砕物の抽出物または該搾汁または該粉砕物またはその抽出物の処理物として用いることもできる。クダモノトケイソウを抽出物として用いる場合、果皮、果肉、果実、葉、茎または根の抽出物が好ましく、果皮抽出物または果肉抽出物が特に好ましい。 As for the damselfly used in the present invention, the whole or the juice of roots, stems, leaves, flowers, fruits, fruit skins, etc. can be used as it is, but the whole damselfly or roots, stems, leaves, flowers, fruits, fruit skins, etc. You may use what was pulverized by crushing, crushing, etc. It can also be used as an extract of the juice or the pulverized product or a processed product of the juice or the pulverized product or an extract thereof. In the case of using damselfly as an extract, an extract of skin, pulp, fruit, leaf, stem or root is preferable, and a skin extract or pulp extract is particularly preferable.
クダモノトケイソウを抽出物として用いる場合の抽出時間等の条件や、処理物として用いる場合の精製処理の条件等は、上述（１）のロズマリン酸の場合に準ずる。 The conditions such as the extraction time in the case of using damselfly as an extract, the conditions for the purification treatment in the case of using as a treated product, and the like are the same as in the case of rosmarinic acid described in (1) above.
例えば、クダモノトケイソウ果皮を抽出して用いる場合、上述（１）の方法に準じた条件下で、クダモノトケイソウの果皮をミキサー等で細かく破砕した後、抽出溶媒中で攪拌し、遠心分離または濾過により不溶物を除去し、上清または濾液を減圧下で乾燥することにより粉末として得ることができる。また、クダモノトケイソウの果肉を抽出して用いる場合、上述（１）の方法に準じた条件下で、クダモノトケイソウの果肉を水とともに攪拌し、遠心分離または濾過により不溶物を除去し、上清または濾液を分画分子量10,000の限外濾過膜を通過させ、回収した溶液を減圧下で乾燥することにより粉末として得ることができる。 For example, in the case of extracting and using pearl millet fruit peel, after crushing the fruit peel of pearl millet fruit finely with a mixer or the like under the conditions according to the above-mentioned method (1), the mixture is stirred in an extraction solvent and centrifuged or filtered. The insoluble matter is removed, and the supernatant or filtrate can be obtained as a powder by drying under reduced pressure. Further, when extracting and using the fruit pulp of damselfly, the fruit pulp of damselfly is stirred with water under the conditions according to the above-mentioned method (1), insoluble matter is removed by centrifugation or filtration, and the supernatant or The filtrate can be obtained as a powder by passing through an ultrafiltration membrane having a fractional molecular weight of 10,000 and drying the collected solution under reduced pressure.
（４）ヘチマ
本発明はさらにまた、ヘチマ由来であって、インスリン分泌促進活性および／またはサイクリックAMPホスホジエステラーゼ阻害活性を示す物質を有効成分として含有するインスリン分泌促進剤およびサイクリックAMPホスホジエステラーゼ阻害剤に関する。
(4) Loofah The present invention further relates to an insulin secretagogue and a cyclic AMP phosphodiesterase inhibitor that contain a substance that is derived from loofah and exhibits insulin secretion promoting activity and / or cyclic AMP phosphodiesterase inhibitory activity as an active ingredient. .
ヘチマ（沖縄の方言名ナーベーラー、Luffa cylindrica (L.) Roem.）は原産地が熱帯アジアのウリ科の１年生草本で、沖縄では食用として栽培されている。本発明で使用するヘチマの品種と産地は、特に限定されるものではない。 Loofah cylindrica (L.) Roem. Is an annual herb of the cucurbitaceae of tropical Asia and is cultivated for food in Okinawa. The varieties and production areas of loofah used in the present invention are not particularly limited.
本発明で使用するヘチマは、全体または根、茎、葉、花、果実、果皮等の搾汁をそのまま用いることができるが、ヘチマ全体または根、茎、葉、花、果実、果皮等を破砕、粉砕等により粉末化処理したものを用いてもよい。また、該搾汁または該粉砕物の抽出物または該搾汁または該粉砕物またはその抽出物の処理物として用いることもできる。ヘチマを抽出物として用いる場合、果実、葉、茎または根の抽出物が好ましく、未熟果抽出物が特に好ましい。 The loofah used in the present invention can be used as a whole or the juice of roots, stems, leaves, flowers, fruits, peels, etc., but the whole loofah or roots, stems, leaves, flowers, fruits, peels etc. can be crushed. Alternatively, powdered by pulverization or the like may be used. It can also be used as an extract of the juice or the pulverized product or a processed product of the juice or the pulverized product or an extract thereof. When loofah is used as an extract, a fruit, leaf, stem or root extract is preferred, and an immature fruit extract is particularly preferred.
ヘチマを抽出物として用いる場合の抽出時間等の条件や、処理物として用いる場合の精製処理の条件等は、上述（１）のロズマリン酸の場合に準ずる。 The conditions such as the extraction time when the loofah is used as an extract, the conditions for the purification treatment when used as a processed product, and the like are the same as those in the case of rosmarinic acid described in (1) above.
例えば、ヘチマの未熟果を抽出して用いる場合、上述（１）の方法に準じた条件下で、ヘチマの未熟果を乾燥したのち、遠心破砕器で破砕し、これに水を加えて攪拌し、遠心分離または濾過により不溶物を除去し、上清または濾液を分画分子量10,000の限外濾過膜を通過させ、回収した溶液を減圧下で乾燥することにより粉末として得ることができる。 For example, when extracting and using immature fruits of loofah, the immature fruits of loofah are dried under the conditions according to the above-mentioned method (1), then crushed with a centrifugal crusher, added with water and stirred. The insoluble matter is removed by centrifugation or filtration, the supernatant or the filtrate is passed through an ultrafiltration membrane having a fractional molecular weight of 10,000, and the recovered solution can be obtained as a powder by drying under reduced pressure.
（５）ドラゴンフルーツ
本発明はさらにまた、ドラゴンフルーツ由来であって、インスリン分泌促進活性および／またはサイクリックAMPホスホジエステラーゼ阻害活性を示す物質を有効成分として含有するインスリン分泌促進剤およびサイクリックAMPホスホジエステラーゼ阻害剤に関する。
(5) Dragon fruit In addition, the present invention further includes an insulin secretagogue and a cyclic AMP phosphodiesterase inhibition containing as an active ingredient a substance that is derived from dragon fruit and exhibits insulin secretion promoting activity and / or cyclic AMP phosphodiesterase inhibitory activity. It relates to the agent.
ドラゴンフルーツは中米原産のサボテン科の植物であり、太平洋側の中央アメリカ諸国で栽培されている。本発明に使用するドラゴンフルーツの品種と産地は、特に限定されるものではない。 Dragon fruit is a Cactaceae plant native to Central America and is cultivated in Central American countries on the Pacific side. The variety and production area of the dragon fruit used in the present invention are not particularly limited.
本発明で使用するドラゴンフルーツは、全体または根、茎、葉、花、果実、果皮等の搾汁をそのまま用いることができるが、ドラゴンフルーツ全体または根、茎、葉、花、果実、果皮等を破砕、粉砕等により粉末化処理したものを用いてもよい。また、該搾汁または該粉砕物の抽出物または該搾汁または該粉砕物またはその抽出物の処理物として用いることもできる。ドラゴンフルーツを抽出物として用いる場合、果皮、果肉、果実、葉、茎または根の抽出物が好ましく、果皮抽出物が特に好ましい。 The dragon fruit used in the present invention may be the whole or the juice of roots, stems, leaves, flowers, fruits, fruit peels, etc., but the whole dragon fruit or roots, stems, leaves, flowers, fruits, fruit peels, etc. You may use what was pulverized by crushing, crushing, etc. It can also be used as an extract of the juice or the pulverized product or a processed product of the juice or the pulverized product or an extract thereof. When dragon fruit is used as an extract, an extract of fruit skin, pulp, fruit, leaf, stem or root is preferable, and an extract of fruit skin is particularly preferable.
ドラゴンフルーツを抽出物として用いる場合の抽出時間等の条件や、処理物として用いる場合の精製処理の条件等は、上述（１）のロズマリン酸の場合に準ずる。 Conditions such as extraction time when using dragon fruit as an extract, conditions for purification treatment when using as a processed product, and the like are the same as in the case of rosmarinic acid described in (1) above.
例えば、ドラゴンフルーツ果皮を抽出して用いる場合、上述（１）の方法に準じた条件下で、ドラゴンフルーツ果皮をミキサー等で細かく破砕した後、抽出溶媒中で攪拌し、遠心分離または濾過により不溶物を除去し、上清または濾液を減圧下で乾燥することにより粉末として得ることができる。 For example, when dragon fruit peel is extracted and used, the dragon fruit peel is finely crushed with a mixer or the like under the conditions in accordance with the above method (1), then stirred in an extraction solvent, and insoluble by centrifugation or filtration. The product can be removed and the supernatant or filtrate can be dried as a powder by drying under reduced pressure.
なお、上記（１）〜（５）で説明したインスリン分泌促進剤およびサイクリックAMPホスホジエステラーゼ阻害剤は、単独で用いてもよいし、組み合わせて用いてもよい。 The insulin secretion promoter and cyclic AMP phosphodiesterase inhibitor described in (1) to (5) above may be used alone or in combination.
（６）製剤化
上記（１）〜（５）で説明したインスリン分泌促進剤および／またはサイクリックAMPホスホジエステラーゼ阻害剤を単独で、または組み合わせて、公知の医薬用担体と組み合わせて製剤化することができる。
(6) Formulation The insulin secretion promoter and / or cyclic AMP phosphodiesterase inhibitor described in (1) to (5) above may be formulated alone or in combination with a known pharmaceutical carrier. it can.
投与形態としては、特に制限はなく、必要に応じ適宜選択されるが、一般には錠剤、カプセル剤、顆粒剤、細粒剤、散剤、液剤、シロップ剤、懸濁剤、乳剤、エリキシル剤等の経口剤、または注射剤、点滴剤、坐剤、吸入剤、経皮吸収剤、経粘膜吸収剤、貼付剤、軟膏剤等の非経口剤として使用される。 The dosage form is not particularly limited and is appropriately selected as necessary. In general, tablets, capsules, granules, fine granules, powders, solutions, syrups, suspensions, emulsions, elixirs, etc. It is used as oral preparations or parenteral preparations such as injections, drops, suppositories, inhalants, transdermal absorption agents, transmucosal absorption agents, patches, ointments and the like.
経口剤は、例えばデンプン、乳糖、白糖、マンニット、カルボキシメチルセルロース、コーンスターチ、無機塩類等の賦形剤を用いて常法に従って製造される。 Oral preparations are produced according to a conventional method using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.
この種の製剤には、適宜前記賦形剤の他に、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、矯味剤、着色剤、香料等を使用することができる。 In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be appropriately used in addition to the above-mentioned excipients.
結合剤の具体例としては、結晶セルロース、結晶セルロース・カルメロースナトリウム、メチルセルロース、ヒドロキシプロピルセルロース、低置換度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、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルメロースナトリウム、エチルセルロース、カルボキシメチルエチルセルロース、ヒドロキシエチルセルロース、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、デキストリン、アルファー化デンプン、部分アルファー化デンプン、ヒドロキシプロピルスターチ、プルラン、ポリビニルピロリドン、アミノアルキルメタクリレートコポリマーＥ、アミノアルキルメタクリレートコポリマーＲＳ、メタクリル酸コポリマーＬ、メタクリル酸コポリマー、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール、アラビアゴム、アラビアゴム末、寒天、ゼラチン、白色セラック、トラガント、精製白糖、マクロゴールが挙げられる。 Specific examples of the binder include crystalline cellulose, crystalline cellulose / carmellose sodium, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carmellose sodium , Ethylcellulose, carboxymethylethylcellulose, hydroxyethylcellulose, wheat starch, rice starch, corn starch, potato starch, dextrin, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, pullulan, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer E, aminoalkyl METAKU Rate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer, polyvinyl acetal diethylamino acetate, polyvinyl alcohol, gum arabic, gum arabic powder, agar, gelatin, white shellac, tragacanth, purified sucrose, macrogol.
崩壊剤の具体例としては、結晶セルロース、メチルセルロース、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、部分アルファー化デンプン、ヒドロキシプロピルスターチ、カルボキシメチルスターチナトリウム、トラガントが挙げられる。 Specific examples of the disintegrant include crystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, wheat starch, rice starch, corn starch, potato starch, and partially pregelatinized. Starch, hydroxypropyl starch, sodium carboxymethyl starch, tragacanth can be mentioned.
界面活性剤の具体例としては、大豆レシチン、ショ糖脂肪酸エステル、ステアリン酸ポリオキシル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、セスキオレイン酸ソルビタン、トリオレイン酸ソルビタン、モノステアリン酸ソルビタン、モノパルミチン酸ソルビタン、モノラウリン酸ソルビタン、ポリソルベート、モノステアリン酸グリセリン、ラウリル硫酸ナトリウム、ラウロマクロゴールが挙げられる。 Specific examples of surfactants include soybean lecithin, sucrose fatty acid ester, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate Sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, lauromacrogol.
滑沢剤の具体例としては、コムギデンプン、コメデンプン、トウモロコシデンプン、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム、含水二酸化ケイ素、軽質無水ケイ酸、合成ケイ酸アルミニウム、乾燥水酸化アルミニウムゲル、タルク、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム、無水リン酸水素カルシウム、ショ糖脂肪酸エステル、ロウ類、水素添加植物油、ポリエチレングリコールが挙げられる。 Specific examples of lubricants include wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dry aluminum hydroxide gel, talc, Examples thereof include magnesium aluminate metasilicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, waxes, hydrogenated vegetable oil, and polyethylene glycol.
流動性促進剤の具体例としては、含水二酸化ケイ素、軽質無水ケイ酸、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、ケイ酸マグネシウムが挙げられる。 Specific examples of the fluidity promoter include hydrous silicon dioxide, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
また、本発明のインスリン分泌促進剤およびサイクリックAMPホスホジエステラーゼ阻害剤は、液剤、シロップ剤、懸濁剤、乳剤、エリキシル剤として投与する場合には、矯味矯臭剤、着色剤を含有してもよい。 In addition, the insulin secretion promoter and the cyclic AMP phosphodiesterase inhibitor of the present invention may contain a flavoring agent and a coloring agent when administered as a liquid, syrup, suspension, emulsion, or elixir. .
ロズマリン酸、またはクミスクチン、クダモノトケイソウ、ヘチマおよびドラゴンフルーツのうちの少なくとも一つに由来し、インスリン分泌促進活性および／またはサイクリックAMPホスホジエステラーゼ阻害活性を示す物質の添加量は、添加対象物の種類、投与目的、投与経路、剤形等の諸条件によって異なるが、ロズマリン酸を用いる場合は、通常、製剤全重量に対し1.0〜20重量％の範囲が好ましい。クミスクチン、クダモノトケイソウ、ヘチマまたはドラゴンフルーツの抽出物を用いる場合、例えば、クミスクチン抽出物、クダモノトケイソウ果皮抽出物またはクダモノトケイソウ果肉抽出物を用いる場合は、製剤全重量に対して0.1〜90重量％であることが好ましい。また、ヘチマ抽出物またはドラゴンフルーツ抽出物を用いる場合は、製剤全重量に対して0.5〜90重量％であることが好ましい。 The amount of rosmarinic acid or a substance that is derived from at least one of cumistin, damselfly, loofah and dragon fruit and exhibits insulin secretion promoting activity and / or cyclic AMP phosphodiesterase inhibitory activity, Although it varies depending on various conditions such as administration purpose, administration route, and dosage form, when rosmarinic acid is used, the range of 1.0 to 20% by weight with respect to the total weight of the preparation is usually preferable. When using an extract of kumisctin, damselfly, loofah or dragon fruit, for example, when using an extract of kumisctin extract, kumonmono passiflora pericarp or kudamono passiflora flesh extract, 0.1 to 90% by weight relative to the total weight of the preparation Preferably there is. Moreover, when using a loofah extract or a dragon fruit extract, it is preferably 0.5 to 90% by weight based on the total weight of the preparation.
（７）投与方法等
本発明のインスリン分泌促進剤および／またはサイクリックAMPホスホジエステラーゼ阻害活性剤の投与量は、患者の年令、体重、疾患の程度、投与経路により適宜選択することができる。投与回数は、通常、経口投与では１日１回〜３回である。例えば、軽症の糖尿病患者にクミスクチン抽出物、クダモノトケイソウ果皮抽出物、クダモノトケイソウ果肉抽出物、ヘチマ抽出物またはドラゴンフルーツ果皮抽出物を含有するインスリン分泌促進剤を経口投与する場合は、１日当たり１mg/kg体重〜200mg/kg体重のインスリン分泌促進剤を、１日３回に分けて投与することが好ましい。
(7) Administration Method, etc. The dosage of the insulin secretion promoter and / or cyclic AMP phosphodiesterase inhibitory activator of the present invention can be appropriately selected depending on the patient's age, body weight, degree of disease, and administration route. The frequency of administration is usually 1 to 3 times a day for oral administration. For example, when an insulin secretagogue containing orally containing Kumistin extract, Kudamono Passiflora peel extract, Kuda mono Passiflora flesh extract, loofah extract or dragon fruit peel extract is orally administered to mildly diabetic patients, 1 mg / day It is preferable to administer an insulin secretagogue with kg body weight to 200 mg / kg body weight divided into three times a day.
本発明のインスリン分泌促進剤および／またはサイクリックAMPホスホジエステラーゼ阻害剤はさらに、常法に従って、清涼飲料、乳酸飲料等の飲料、スープ、ジャム、菓子類等の食品に添加することができる。また、ペットフードや飼料に添加してペットや家畜の糖尿病および／または糖尿病合併症の改善のために用いることもできる。 The insulin secretion promoter and / or cyclic AMP phosphodiesterase inhibitor of the present invention can be further added to beverages such as soft drinks and lactic acid beverages, foods such as soups, jams, and confectionery according to conventional methods. It can also be added to pet food and feed and used to improve diabetes and / or diabetic complications in pets and livestock.
さらに、本発明のインスリン分泌促進剤および／またはサイクリックAMPホスホジエステラーゼ阻害剤を用いて、いわゆる特定保健用食品（例えば、糖尿病予防食品）または機能性食品を製造することもできる。この場合、本発明のインスリン分泌促進剤および／またはサイクリックAMPホスホジエステラーゼ阻害剤は、目的に応じて適量を添加すればよい。例えば、ロズマリン酸を有効成分として含有するインスリン分泌促進剤および／またはサイクリックAMPホスホジエステラーゼ阻害剤を食品に添加する場合には、ロズマリン酸が食品中に、食品の全重量に対して0.1〜10重量％含有されるように添加することが好ましい。また、例えばクミスクチン抽出物、クダモノトケイソウ果皮抽出物、クダモノトケイソウ果肉抽出物、ヘチマ抽出物またはドラゴンフルーツ果皮抽出物を食品に添加する場合は、それぞれ食品の全重量に対して1.0〜100重量％含有されるように添加することが好ましい。 Furthermore, using the insulin secretion promoter and / or cyclic AMP phosphodiesterase inhibitor of the present invention, so-called foods for specific health (for example, foods for preventing diabetes) or functional foods can be produced. In this case, the insulin secretion promoter and / or cyclic AMP phosphodiesterase inhibitor of the present invention may be added in an appropriate amount depending on the purpose. For example, when an insulin secretion promoter and / or a cyclic AMP phosphodiesterase inhibitor containing rosmarinic acid as an active ingredient is added to a food, rosmarinic acid is contained in the food in an amount of 0.1 to 10% relative to the total weight of the food. It is preferable to add so that it may be contained. In addition, for example, when adding a Kumistin extract, a Kudamono Passiflora peel extract, a Kuda mono Passiflora flesh extract, a loofah extract or a dragon fruit peel extract, 1.0 to 100% by weight based on the total weight of the food, respectively. It is preferable to add as described above.
以下、実施例によって本発明を具体的に説明するが、これらは本発明の範囲を限定するものではない。
実施例１ ロズマリン酸のインスリン分泌促進活性
ラットの膵臓B株細胞RINm5F（ATCC CRL-2058）をDiabetes, Vol. 34, p. 717 (1985)に記載された方法に準じて培養した。具体的には、RPMI1640培地（グルタミン300 mg/lを含む、大日本製薬より購入）に炭酸水素ナトリウム2 g/l、非働化処理したウシ胎児血清10%、ストレプトマイシン100μg/ml、ペニシリン100 units/mlを添加した培地で、24穴（１穴2cm2）のマイクロプレートにて、5％CO2存在下、37℃で３日間の培養を行った。次いで、古い培地を捨て、各穴当たり1 mlの新しい培地を加え更に１日間培養した。
EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.
Example 1 Insulin secretion-promoting activity of rosmarinic acid Rat pancreatic B strain cell RINm5F (ATCC CRL-2058) was cultured according to the method described in Diabetes, Vol. 34, p. 717 (1985). Specifically, RPMI1640 medium (containing 300 mg / l glutamine, purchased from Dainippon Pharmaceutical), sodium bicarbonate 2 g / l, inactivated fetal
次にプレートの各穴の培地を捨て、1 ml のクレブス-リンガー重炭酸(KRB) 緩衝液（NaCl 129 mM、NaHCO3 5 mM、KCl 4.8 mM、KH2PO4 1.2 mM、CaCl21.0 mM、MgSO4 1.2 mM、Glucose 2.8 mM、 Bovine serum albumin 0.1%、HEPES 10 mM、pH 7.4)にて各穴を２回洗浄した。その後、360μl のKRB緩衝液に40μlの試料（125〜1000μMのロズマリン酸、または対照としての蒸留水、1μMのグルカゴン）を加えた溶液400μlを各穴に添加し、5％CO2存在下、37℃で0〜180分間静置した。なお、試料添加時における細胞数は１穴あたり1.2 x 106個である。
Then discard the medium in each well of the plate and add 1 ml of Krebs-Ringer bicarbonate (KRB) buffer (NaCl 129 mM, NaHCO 3 5 mM, KCl 4.8 mM, KH 2 PO 4 1.2 mM, CaCl 2 1.0 mM, Each well was washed twice with MgSO 4 1.2 mM, Glucose 2.8 mM, Bovine serum albumin 0.1%,
上清200μlを回収して、遠心により混入した細胞を除去した。上清中のインスリン濃度は、試料を希釈後、レビス インスリン‐ラットELISAキット（シバヤギ社より購入）を用いた酵素免疫測定法により測定した。その結果を表１および図1に示す。表１は120分後のKRB緩衝液中インスリン濃度をn = 3の平均値で示した。図１は試料添加後の各時間におけるKRB緩衝液中のインスリン濃度をn = 3の平均値で示した。ロズマリン酸にインスリン分泌促進効果が認められた。 200 μl of the supernatant was collected, and the contaminated cells were removed by centrifugation. The insulin concentration in the supernatant was measured by an enzyme immunoassay method using a Levis insulin-rat ELISA kit (purchased from Shibayagi) after diluting the sample. The results are shown in Table 1 and FIG. Table 1 shows the insulin concentration in KRB buffer after 120 minutes as an average value of n = 3. FIG. 1 shows the insulin concentration in the KRB buffer at each time after sample addition as an average value of n = 3. Rosmarinic acid has been shown to promote insulin secretion.
次に、MTT (臭化3-[4,5-ジメチルチアゾール-2-イル]-2,5-ジフェニルテトラゾリウム)キット（Roche）により細胞増殖に対するロズマリン酸の影響を検討したところ、表１および図１の濃度範囲では細胞増殖に対して全く影響のないことが確認できた。 Next, the effect of rosmarinic acid on cell proliferation was examined using the MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide) kit (Roche). It was confirmed that there was no influence on cell proliferation in the concentration range of 1.
実施例２ クミスクチン抽出物、クダモノトケイソウ果皮抽出物、クダモノトケイソウ果肉抽出物、ヘチマ抽出物またはドラゴンフルーツ果皮抽出物からなるインスリン分泌促進剤の製造法
クミスクチンの葉を60℃、12時間乾燥させ、これを遠心粉砕器（MRK-Retschm, ZM-100）を用いて粉砕し、0.5mmのスクリーンを通過したものについて、高速溶媒抽出装置（日本ダイオネクス社製、ASE-200）により溶媒抽出を行った。即ち、乾燥重量で2gの試料を８ｇのケイソウ土とともに抽出セルに装填し、25mlの50%エタノールを加え、抽出温度82℃、抽出時間10分、圧力1500psi、抽出回数２回で抽出し、抽出液約50mlを得、そのうち20mlを遠心式エバポレーターで乾燥させることにより300mgの粉末を得た。
Example 2 Method for Producing Insulin Secretion Promoter Consisting of Cumistin Extract, Kudamono Passiflora Extract, Kuda Mono Passiflora Extract, Loofah Extract or Dragon Fruit Peel Extract The leaves of Kumictin are dried at 60 ° C. for 12 hours. Was pulverized using a centrifugal pulverizer (MRK-Retschm, ZM-100), and the solvent passed through a 0.5 mm screen was subjected to solvent extraction with a high-speed solvent extraction device (Nippon Dionex, ASE-200). That is, 2g sample by dry weight is loaded into an extraction cell with 8g diatomaceous earth, 25ml of 50% ethanol is added, extraction temperature is 82 ℃, extraction time is 10min, pressure is 1500psi, and extraction is performed twice. About 50 ml of the liquid was obtained, and 20 ml of the liquid was dried with a centrifugal evaporator to obtain 300 mg of powder.
クダモノトケイソウの果実３個から剥いた果皮（150g）をミキサーで細かく破砕した後、メタノール200mlを加え、電磁スターラーにより400rpm、60分間攪拌した。次いで、濾紙（アドバンテック東洋製濾紙、NO.2、直径30cm）による濾過を行って不溶物を除去した濾液を回収した。濾液をロータリエバポレーターで濃縮し、さらに真空ポンプによる減圧下で乾燥することにより、紫色の粉末3.6gを得た。 The peel (150 g) peeled from the three fruit of Kudamonodiatomia was finely crushed with a mixer, 200 ml of methanol was added, and the mixture was stirred with an electromagnetic stirrer at 400 rpm for 60 minutes. Subsequently, filtration with a filter paper (Advantech Toyo filter paper, NO.2, diameter 30 cm) was performed to recover the filtrate from which insoluble matter was removed. The filtrate was concentrated with a rotary evaporator and further dried under reduced pressure using a vacuum pump to obtain 3.6 g of a purple powder.
クダモノトケイソウの果実３個からゼリー状の果肉（種子を含む）110mlを採取し、これに同量の蒸留水を加え、電磁スターラーにより400rpm、60分間攪拌した。次いで、15,000rpmで20分間の遠心分離を行い不溶物を沈殿させ、上清を回収した。この溶液は限外濾過膜YM-10（分画分子量１万、Millipore）を通過させ、濾液を遠心式エバポレーターで濃縮し、さらに真空ポンプによる減圧下で乾燥することにより、薄いオレンジ色の粉末16gを得た。 110 ml of jelly-like flesh (including seeds) was collected from three fruit of Kudamonodiatomia, the same amount of distilled water was added thereto, and the mixture was stirred with an electromagnetic stirrer at 400 rpm for 60 minutes. Subsequently, centrifugation was performed at 15,000 rpm for 20 minutes to precipitate insoluble matter, and the supernatant was collected. This solution was passed through an ultrafiltration membrane YM-10 (molecular weight cut off 10,000, Millipore), and the filtrate was concentrated with a centrifugal evaporator and dried under reduced pressure with a vacuum pump to obtain a light orange powder of 16 g. Got.
ヘチマの未熟果200gを乾燥したのち、遠心破砕器（MRK-Retschm, ZM-100)で破砕し、0.5mmのスクリーンを通過したものを回収した。このうち1 gに40 mlの水を加え、電磁スターラーにより400rpm、60分間攪拌した。次いで、15,000rpmで20分間の遠心分離を行い不溶物を沈殿させ、上清を回収した。この溶液は限外濾過膜YM-10（分画分子量１万、Millipore）を通過させ、濾液を遠心式エバポレーターで濃縮し、さらに真空ポンプによる減圧下で乾燥することにより、0.56 gの粉末を得た。 After drying 200 g of unripe fruit of loofah, it was crushed with a centrifugal crusher (MRK-Retschm, ZM-100), and the one that passed through a 0.5 mm screen was collected. Among these, 40 ml of water was added to 1 g, and the mixture was stirred with an electromagnetic stirrer at 400 rpm for 60 minutes. Subsequently, centrifugation was performed at 15,000 rpm for 20 minutes to precipitate insoluble matter, and the supernatant was collected. This solution is passed through an ultrafiltration membrane YM-10 (molecular weight cut off 10,000, Millipore), the filtrate is concentrated with a centrifugal evaporator, and further dried under reduced pressure with a vacuum pump to obtain 0.56 g of powder. It was.
ドラゴンフルーツの果実１個から剥いた果皮（84 g）をミキサーで細かく破砕した後、メタノール200mlを加え、電磁スターラーにより400rpm、60分間攪拌した。次いで、濾紙（アドバンテック東洋製濾紙、NO.2、直径30cm）による濾過を行って不溶物を除去した濾液を回収した。濾液をロータリエバポレーターで濃縮し、さらに真空ポンプによる減圧下で乾燥することにより、赤紫色の粉末1.2gを得た。 The peel (84 g) peeled from one dragon fruit was finely crushed with a mixer, 200 ml of methanol was added, and the mixture was stirred with an electromagnetic stirrer at 400 rpm for 60 minutes. Subsequently, filtration with a filter paper (Advantech Toyo filter paper, NO.2, diameter 30 cm) was performed to recover the filtrate from which insoluble matter was removed. The filtrate was concentrated with a rotary evaporator and further dried under reduced pressure using a vacuum pump to obtain 1.2 g of a reddish purple powder.
実施例３ クミスクチン抽出物、クダモノトケイソウ果皮抽出物、クダモノトケイソウ果肉抽出物、ヘチマ抽出物またはドラゴンフルーツ果皮抽出物のインスリン分泌促進活性
実施例１と同様に24穴のマイクロプレートにて培養したラット膵臓B株細胞RINm5Fの各穴をKRB)緩衝液で２回洗浄し、360μl のKRB緩衝液に40μlの試料（0.13〜4 mg/mlのクミスクチン抽出物、0.13〜40 mg/mlのクダモノトケイソウ果皮抽出物、2〜8 mg/mlのクダモノトケイソウ果肉抽出物、10〜40 mg/mlのヘチマ抽出物、10〜40 mg/mlのドラゴンフルーツ果皮抽出物、または対照としての蒸留水、1μMのグルカゴン）を加えた溶液400μlを各穴に添加し、5％CO2存在下、37℃で0〜180分間静置した。試料添加時における細胞数は１穴あたり1.2 x 106個である。上清200μlを回収して、遠心により混入した細胞を除去したのち、上清中のインスリン濃度を実施例１と同じレビス インスリン‐ラットELISAキットにより測定した。その結果を表２〜６および図１に示す。表２〜６は120分後のKRB緩衝液中インスリン濃度をn = 3の平均値で示した。図１はクミスクチン抽出物添加後の各時間におけるKRB緩衝液中のインスリン濃度をn = 3の平均値で示した。クミスクチン抽出物、クダモノトケイソウ果皮抽出物、クダモノトケイソウ果肉抽出物、ヘチマ抽出物またはドラゴンフルーツ果皮抽出物にインスリン分泌促進効果が認められた。
Example 3 Insulin secretion-promoting activity of cumistin extract, kudamono passiflora extract, kudamono passiflora extract, loofah extract or dragon fruit peel extract Rat pancreas cultured in a 24-well microplate as in Example 1. Wash each well of cell line RINm5F twice with KRB) buffer and extract 40 μl of sample (0.13-4 mg / ml cumistin extract, 0.13-40 mg / ml citrus peel of 0.13-40 mg / ml) in 360 μl KRB buffer , 2-8 mg / ml citrus flesh extract, 10-40 mg / ml loofah extract, 10-40 mg / ml dragon fruit peel extract, or distilled water as a control, 1 μM glucagon) 400 μl of the above solution was added to each well and allowed to stand at 37 ° C. for 0 to 180 minutes in the presence of 5% CO 2 . The number of cells at the time of sample addition is 1.2 × 10 6 per well. After collecting 200 μl of the supernatant and removing the contaminated cells by centrifugation, the insulin concentration in the supernatant was measured with the same Levis insulin-rat ELISA kit as in Example 1. The results are shown in Tables 2-6 and FIG. Tables 2 to 6 show the insulin concentration in KRB buffer after 120 minutes as an average value of n = 3. FIG. 1 shows the insulin concentration in the KRB buffer at each time after addition of the cumistin extract as an average value of n = 3. The effect of promoting insulin secretion was observed in the Kumistin extract, Kudamono Passiflora extract, Kuda mono Passiflora extract, Loofah extract or Dragonfruit peel extract.
次に、実施例１と同様にロッシュ社のMTTキットにより細胞増殖に対するクミスクチン抽出物、クダモノトケイソウ果皮抽出物、クダモノトケイソウ果肉抽出物、ヘチマ抽出物またはドラゴンフルーツ果皮抽出物の影響を検討したところ、表２〜６および図１の濃度範囲では細胞増殖に対して全く影響のないことが確認できた。 Next, as in Example 1, when the influence of the cumistin extract, the kudamono passiflora extract, the kudamono passiflora extract, the loofah extract or the dragon fruit peel extract was examined on cell proliferation using the Roche MTT kit, It was confirmed that the concentration range shown in Tables 2 to 6 and FIG.
実施例４ ロズマリン酸、クミスクチン抽出物、クダモノトケイソウ果皮抽出物のサイクリックAMPホスホジエステラーゼ阻害作用
サイクリックAMPホスホジエステラーゼ阻害作用の測定は下記の方法により行った。
シグマ社より購入したウシ脳由来ホスホジエステラーゼアクチベータ（カルモジュリン）を緩衝液（62.5mMトリス塩酸緩衝液、pH7.5、6.3mM塩化マグネシウム、3.8mM β-メルカプトエタノール、0.038mM塩化カルシウム）に溶解し、14.3ユニット/mlのアクチベータ溶液とした。また、シグマ社より購入したブタ脳由来ホスホジエステラーゼを上記緩衝液に0.1ユニット/mlの濃度に溶解し、酵素溶液とし、1mMのサイクリックAMP水溶液を基質溶液とした。
Example 4 Cyclic AMP phosphodiesterase inhibitory action of rosmarinic acid, Kumisctin extract, and Kuda mononaceus peel extract The cyclic AMP phosphodiesterase inhibitory action was measured by the following method.
Bovine brain-derived phosphodiesterase activator (calmodulin) purchased from Sigma is dissolved in a buffer solution (62.5 mM Tris-HCl buffer, pH 7.5, 6.3 mM magnesium chloride, 3.8 mM β-mercaptoethanol, 0.038 mM calcium chloride), 14.3 Unit / ml activator solution. Also, porcine brain-derived phosphodiesterase purchased from Sigma was dissolved in the above buffer solution at a concentration of 0.1 unit / ml to make an enzyme solution, and a 1 mM cyclic AMP aqueous solution was used as a substrate solution.
0.5ml容量のプラスチックチューブに、アクチベータ溶液140μl、酵素溶液20μl、測定試料溶液20μl（0.5〜2 mMのロズマリン酸、0.2〜0.8 mg/mlのクミスクチン抽出物、2.5〜20 mg/mlのクダモノトケイソウ果皮抽出物）を入れ、30℃で5分間保温した後、基質溶液20μlを加えよく混合して、37℃で60分間反応を行った。その後、10％トリフルオロ酢酸60μlを添加することにより反応を停止させた。反応停止後、生成したAMPを下記条件下で高速液体クロマトグラフィーにより定量した。
高速液体クロマトグラフィー測定条件
カラム：μBondasphere 5μC18 300Å（ウォーターズ社3.9 x 150 mm）
溶出液：0.1％トリフルオロ酢酸を含む0〜63％のアセトニトリルの直線濃度勾配（20分）
流速：１ml/min
検出：260nmの紫外部吸収
In a 0.5 ml plastic tube, activator solution 140 μl,
Column for high performance liquid chromatography measurement: μBondasphere 5μC18 300Å (Waters 3.9 x 150 mm)
Eluent: Linear gradient of 0 to 63% acetonitrile containing 0.1% trifluoroacetic acid (20 minutes)
Flow rate: 1 ml / min
Detection: 260nm UV absorption
このような実験を複数回行い、阻害率を次の式より算出した。
式１：
阻害率＝ (A - B) / A X 100 (％)
［式中、Ａ：阻害剤を含まない場合のAMPのピーク面積、Ｂ：阻害剤添加の場合のAMPのピーク面積］
Such an experiment was performed a plurality of times, and the inhibition rate was calculated from the following equation.
Formula 1:
Inhibition rate = (A-B) / AX 100 (%)
[Wherein, A: peak area of AMP when no inhibitor is contained, B: peak area of AMP when inhibitor is added]
また、上記阻害率が50％になる阻害剤濃度をIC50値で表した。
このようにして得られたIC50値を表７に示す。
Further, the inhibitor concentration at which the inhibition rate was 50% was expressed as an IC 50 value.
The IC 50 values thus obtained are shown in Table 7.
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