JP3073762B2 - Method for producing composition containing angiotensin converting enzyme inhibitor - Google Patents
Method for producing composition containing angiotensin converting enzyme inhibitorInfo
- Publication number
- JP3073762B2 JP3073762B2 JP02267365A JP26736590A JP3073762B2 JP 3073762 B2 JP3073762 B2 JP 3073762B2 JP 02267365 A JP02267365 A JP 02267365A JP 26736590 A JP26736590 A JP 26736590A JP 3073762 B2 JP3073762 B2 JP 3073762B2
- Authority
- JP
- Japan
- Prior art keywords
- converting enzyme
- angiotensin converting
- enzyme inhibitor
- present
- composition containing
- 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
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は、天然物から調製でき、殊に血圧降下剤又は
血圧降下用食品として有用であるアンギオテンシン変換
酵素阻害剤含有組成物の製造法に関する。The present invention relates to a method for producing a composition containing an angiotensin converting enzyme inhibitor which can be prepared from a natural product and is particularly useful as a hypotensive agent or a food for lowering blood pressure. .
［従来の技術］ アンギオテンシン変換酵素は、主として肺や血管内皮
細胞、腎近位尿細管に存在し、アンギオテンシンＩ（As
p−Arg−Val−Tyr−Ile−His−Pro−Phe−His−Leu）に
作用して、アンギオテンシンＩのＣ末端よりジペプチド
（His9−Leu10）を開裂遊離させ、強力な昇圧作用を有
するアンギオテンシンIIを生成させる酵素である。ま
た、この酵素は生体内降圧物質であるブラジキニンを分
解し不活化する作用も併有し、昇圧系に強力に関与して
いる。[Prior art] Angiotensin converting enzyme is mainly present in lung, vascular endothelial cells and renal proximal tubules, and is angiotensin I (As
Acts on p-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) to release the dipeptide (His 9 -Leu 10 ) from the C-terminus of angiotensin I and has a strong pressor action It is an enzyme that produces angiotensin II. In addition, this enzyme has a function of decomposing and inactivating bradykinin, which is a hypotensive substance in a living body, and is strongly involved in the pressor system.
従来より、アンギオテンシン変換酵素の活性を阻害す
れば、昇圧に働き、臨床的には高血圧症の予防、治療に
有効であると考えられている。Hitherto, it has been considered that inhibiting the activity of an angiotensin converting enzyme acts on blood pressure and is clinically effective for preventing and treating hypertension.
最近ではプロリン誘導体であるカプトプリルが合成さ
れ、降圧活性が確認されて以来、種々のアンギオテンシ
ン変換酵素阻害物質の合成研究が盛んであり、又天然物
からの取得も試みられているところである。Recently, since captopril, a proline derivative, has been synthesized and its antihypertensive activity has been confirmed, studies on the synthesis of various angiotensin converting enzyme inhibitors have been actively conducted, and attempts are being made to obtain them from natural products.
天然物由来のアンギオテンシン変換酵素阻害剤は食品
あるいは食品原料から得らるので低毒性で安全性の高い
降圧剤となることが期待されるからである。This is because an angiotensin converting enzyme inhibitor derived from a natural product is obtained from food or a food material, and is therefore expected to be a low toxicity and highly safe antihypertensive agent.
［発明が解決しようとする課題］ しかしながら、天然物中に見出されるアンギオテンシ
ン変換酵素阻害物質は極めてまれで、僅かにブラジル産
や日本産蛇毒より得られたテプロタイド（ノナペプチ
ド,SQ20881）等や、ストレプトミセス属に属する放線菌
の代謝産物IS83（特開昭58−177920号公報）が知られて
いるに過ぎない。また、天然物を酵素処理して得られた
アンギオテンシン変換酵素阻害物質としては、牛乳カゼ
インをトリプシンにより分解して得たペプチド類等が知
られているが（特開昭58−109425号、同59−44323号、
同59−44324号、同61−36226号、同61−36227号）新規
な阻害物質の開発が望まれているところである。[Problems to be Solved by the Invention] However, angiotensin converting enzyme inhibitors found in natural products are extremely rare, such as teprotide (nonapeptide, SQ20881) slightly obtained from Brazilian or Japanese snake venom, and Streptomyces. Only the metabolite IS83 of the genus Actinomycetes belonging to the genus (JP-A-58-177920) is known. Also, as angiotensin converting enzyme inhibitors obtained by enzymatic treatment of natural products, peptides and the like obtained by decomposing milk casein with trypsin are known (JP-A-58-109425, JP-A-58-109425). −44323,
No. 59-44324, No. 61-36226, No. 61-36227) The development of new inhibitors is being demanded.
［課題を解決するための手段］ 本発明者らは、かかる課題を解決すべく天然物質で副
作用の少ないアンギオテンシン変換酵素阻害物質を鋭意
探索した結果、カツオ節、いわし又は鶏肉をサーモライ
シンにより加水分解した組成物中にアンギオテンシン変
換酵素阻害活性を有するペプチド類が存在することを見
出し本発明を完成するに至った。[Means for Solving the Problems] The present inventors have intensively searched for an angiotensin converting enzyme inhibitor which is a natural substance and has few side effects in order to solve such problems, and as a result, a composition obtained by hydrolyzing bonito node, sardine or chicken with thermolysin The present inventors have found that peptides having angiotensin converting enzyme inhibitory activity are present in the product, and have completed the present invention.
サーモライシンとはバチルス・サーモプロテオリティ
カス（Bacillus thermoproteolyticus）が産生するプロ
テアーゼの一種である。Thermolysin is a type of protease produced by Bacillus thermoproteolyticus.
本発明の活性をもつ組成物は上記のサーモライシンを
用いる場合に特に効果的に得られ、他の公知のプロテア
ーゼであるペプシン、トリプシン、キモトリプシン等で
蛋白を分解しても本発明の如き強力な作用をもつ組成物
は得られない。The composition having the activity of the present invention can be obtained particularly effectively when the above-mentioned thermolysin is used. Even if the protein is degraded by other known proteases such as pepsin, trypsin, chymotrypsin, etc., the strong action as in the present invention can be obtained. Is not obtained.
本発明の方法を実施するに当っては、カツオ節、いわ
し又は鶏肉の性状により処法は異なるが、難溶性の場合
には熱水にカツオ節、いわし又は鶏肉を混合し強力な撹
拌でホモジナイズした後、サーモライシンを該ホモジナ
イズした溶解液に対して0.05〜５重量％添加し、温度10
〜60℃、pH4〜８、反応時間10分〜10時間、好ましくは
１〜６時間の反応条件下で疎水性アミノ酸のペプチド結
合が分解率５％以上になるまで静置又は撹拌下、反応を
続けて目的物を得る。In carrying out the method of the present invention, the treatment method varies depending on the characteristics of bonito, sardine or chicken, but in the case of poorly soluble bonito, sardine or chicken mixed with hot water and homogenized with strong stirring. , Thermolysin was added in an amount of 0.05 to 5% by weight to the homogenized lysate,
Under the reaction conditions of 6060 ° C., pH 4〜8, reaction time of 10 minutes to 10 hours, preferably 1 to 6 hours, the reaction is allowed to proceed under standing or stirring until the peptide bond of the hydrophobic amino acid has a decomposition rate of 5% or more. Continue to get the object.
分解率は全窒素に対するアミノ態窒素の％で表す。但
し、Journal of Agricultural and Food Chemistry 24
No.6 1090〜1093（1976）に基づいて測定する。The decomposition rate is represented by% of amino nitrogen with respect to total nitrogen. However, Journal of Agricultural and Food Chemistry 24
No. 6 Measured based on 1109 to 1093 (1976).
かくして得られたアンギオテンシン変換酵素阻害剤含
有組成物は各種のペプチドの混合物であり、そのまま使
用しても良く、又後処理加工して用いても良い。The composition containing the angiotensin converting enzyme inhibitor thus obtained is a mixture of various peptides, and may be used as it is or after post-processing.
本発明で得られるペプチド類の投与経路としては、経
口投与、非経口投与、直腸内投与のいずれでもよいが、
経口投与が好ましい。本発明のペプチド類の投与量は、
化合物の種類、投与方法、患者の症状・年令等により異
なるが、通常１回0.001〜1000mg、好ましくは0.01〜10m
gを１日１〜３回である。本発明のペプチド類は通常、
製剤用担体と混合して調製した製剤の形で投与される。
製剤用担体としては、製剤分野において常用され、かつ
本発明のペプチド類と反応しない物質が用いられる。具
体的には、例えば乳糖、ブドウ糖、マンニット、デキス
トリン、シクロデキストリン、デンプン、庶糖、メタケ
イ酸アルミン酸マグネシウム、合成ケイ酸アルミニウ
ム、カルボキシメチルセルロースナトリウム、ヒドロキ
シプロピルデンプン、カルボキシメチルセルロースカル
シウム、イオン交換樹脂、メチルセルロース、ゼラチ
ン、アラビアゴム、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、ポリビニルピロリ
ドン、ポリビニルアルコール、軽質無水ケイ酸、ステア
リン酸マグネシウム、タルク、トラガント、ベントナイ
ト、ビーガム、酸化チタン、ソルビタン脂肪酸エステ
ル、ラウリル硫酸ナトリウム、グリセリン、脂肪酸グリ
セリンエステル、精製ラノリン、グリセロゼラチン、ポ
リソルベート、マクロゴール、植物油、ロウ、流動パラ
フィン、白色ワセリン、フルオロカーボン、非イオン界
面活性剤、プロピレングリコール、水等が挙げられる。
剤型としては、錠剤、カプセル剤、顆粒剤、散剤、シロ
ップ剤、懸濁剤、注射剤等が挙げられる。これらの製剤
は常法に従って調製される。尚、液体製剤にあっては、
用時、水又は他の適当な媒体に溶解又は懸濁する形であ
ってもよい。また錠剤、顆粒剤は周知の方法でコーティ
ングしてもよい。注射剤の場合には、本発明のペプチド
類を水に溶解させて調製されるが、必要に応じて生理食
塩水あるいはブドウ糖溶液に溶解させてもよく、また緩
衝剤や保存剤を添加してもよい。The administration route of the peptides obtained in the present invention may be any of oral administration, parenteral administration, and rectal administration,
Oral administration is preferred. The dose of the peptides of the present invention,
Depending on the type of compound, administration method, patient symptoms / age, etc., it is usually 0.001 to 1000 mg once, preferably 0.01 to 10 mg.
g 1 to 3 times a day. The peptides of the present invention generally comprise
It is administered in the form of a preparation prepared by mixing with a preparation carrier.
As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the peptides of the present invention is used. Specifically, for example, lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose , Gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, veegum, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, Fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macro Lumpur, vegetable oils, waxes, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol, water and the like.
Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, injections and the like. These preparations are prepared according to a conventional method. In the case of liquid preparations,
When used, it may be in the form of a solution or suspension in water or other suitable medium. Tablets and granules may be coated by a known method. In the case of an injection, the peptide of the present invention is prepared by dissolving the peptide in water, but may be dissolved in a physiological saline solution or a glucose solution as needed, or by adding a buffer or a preservative. Is also good.
これらの製剤は、本発明のペプチド類を0.01％以上、
好ましくは0.5〜70％の割合で含有することができる。
これらの製剤はまた、治療上価値ある他の成分を含有し
ていてもよい。These preparations contain 0.01% or more of the peptides of the present invention,
Preferably, it can be contained at a ratio of 0.5 to 70%.
These formulations may also contain other therapeutically valuable components.
［作用］ 本発明は天然物から調製でき、殊に血圧降下剤又は血
圧降下食品として有用であるアンギオテンシン交換酵素
阻害剤含有組成物が製造できる。[Action] The present invention can be prepared from a natural product, and in particular, can produce a composition containing an angiotensin exchange enzyme inhibitor, which is useful as a hypotensive agent or a hypotensive food.
［実施例］ 以下、本発明を実施例を挙げて更に詳しく説明する。EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples.
実施例１、比較例１〜４ カツオ節5gに水40mlを加え充分ホモジナイズし、第１
表に示すプロテアーゼを作用させた後、100℃で10分間
煮沸後放置して得た上澄液のアンギオテンシン変換酵素
阻害活性を測定した。Example 1, Comparative Examples 1 to 4 To 5 g of skipjack section, add 40 ml of water and homogenize sufficiently.
After the proteases shown in the table were acted on, the angiotensin converting enzyme inhibitory activity of the supernatant obtained by boiling at 100 ° C. for 10 minutes and standing was measured.
（プロテアーゼの作用条件） サーモライシン、トリプトシン、キシトリプトシンを
作用させる場合は反応液を水酸化ナトリウムでpH7.0と
し、又ペプシンを作用させる場合は塩酸でPH1.6とし
て、反応温度37℃で５時間静置反応を行った。(Protease action conditions) When thermolysin, tryptocin, or xytryptosine is allowed to act, the reaction solution is adjusted to pH 7.0 with sodium hydroxide. When pepsin is actuated, the reaction solution is adjusted to pH 1.6 with hydrochloric acid. The reaction was performed.
酵素量はカツオ節液に対して全て1/100重量部添加し
た。The amount of the enzyme was all added to 1/100 parts by weight based on the skipjack sap.
（アンギオテンシン変換酵素阻害活性の測定） アンギオテンシン変換酵素阻害活性の測定は、Cheung
とCushmanの方法〔Biochemical Pharamacology 20,1637
（1971）〕に準じて以下の方法で行った。(Measurement of angiotensin converting enzyme inhibitory activity)
And Cushman's method (Biochemical Pharamacology 20 , 1637
(1971)] according to the following method.
酵素基質;Bz（ベンジル）−Gly−His−Leu （86mgを水8mlとリン酸緩衝液8mlに溶解した溶液） 酵 素；うさぎの肺のアセトンパウダー（シグマ社
製） （1gを50mMのリン酸緩衝液10ml中で粉砕した後、遠心分
離した上澄液） 上記の酵素基質を100μ、酵素溶液を12μ及び本
発明の所定濃度のペプチドを混合し、水で全体を250μ
とした後、37℃で30分間反応を行った。Enzyme substrate; Bz (benzyl) -Gly-His-Leu (86 mg dissolved in 8 ml of water and 8 ml of phosphate buffer) Enzyme; rabbit lung acetone powder (Sigma) (1 g of 50 mM phosphoric acid) Supernatant obtained by pulverization in 10 ml of buffer solution and centrifugation) The above enzyme substrate is mixed with 100 μm, the enzyme solution is mixed with 12 μm and the peptide of the present invention at a predetermined concentration, and the whole is mixed with water to 250 μm
After that, the reaction was carried out at 37 ° C. for 30 minutes.
反応は1N−HCl250μを用いて終了させた。反応終了
液に酢酸エチル1.5mlを入れVortexで15秒撹拌し、それ
を遠心分離した。 酢酸エチル層から1.0mlをとり出し
て、酢酸エチルを留去し、それに1mlの蒸留水を入れて
残渣を溶解し、抽出された馬尿酸の紫外吸収228nmの値
（OD228）を測定した。The reaction was terminated using 250 μl of 1N HCl. 1.5 ml of ethyl acetate was added to the reaction-terminated liquid, followed by stirring with Vortex for 15 seconds, followed by centrifugation. 1.0 ml was taken out from the ethyl acetate layer, ethyl acetate was distilled off, 1 ml of distilled water was added to dissolve the residue, and the value of the ultraviolet absorption 228 nm (OD 228 ) of the extracted hippuric acid was measured.
阻害率は阻害剤なしで反応したときのOD228を100％と
し、反応時間０分のときのOD228を０％として求め阻害
率50％の時の阻害剤（本発明のペプチド）の濃度IC
50（mg/ml）で活性を表示した。Percent inhibition by the OD 228 of when reacted without inhibitor as 100%, the concentration IC of the inhibitor when the OD 228 of the inhibition rate of 50% determined as 0% when the reaction time of 0 minutes (the peptide of the present invention)
Activity was indicated at 50 (mg / ml).
結果を第１表に示す。 The results are shown in Table 1.
実施例２、比較例５〜８ 実施例１においてカツオ節をいわし4.0gに変えた以外
は同例に準じて実験を行った。 Example 2, Comparative Examples 5 to 8 An experiment was performed in the same manner as in Example 1 except that the skipjack section was changed to 4.0 g.
結果を第２表に示す。 The results are shown in Table 2.
実施例３、比較例９〜12 実施例１においてカツオ節を鶏肉5.0gに変更した以外
は同例に準じて実験を行った。 Example 3 and Comparative Examples 9 to 12 An experiment was performed in the same manner as in Example 1 except that the skipjack section was changed to 5.0 g of chicken.
結果を第５表に示す。 The results are shown in Table 5.
［効果］ 本発明は、カツオ節、いわし又は鶏肉から調製でき、
殊に血圧降下剤又は血圧降下食品として有用であるアン
ギオテンシン変換酵素阻害剤含有組成物が製造できる。 [Effect] The present invention can be prepared from skipjack section, sardine or chicken,
Particularly, an angiotensin converting enzyme inhibitor-containing composition useful as a hypotensive agent or a hypotensive food can be produced.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 平２−36127（ＪＰ，Ａ) 特開 平１−240170（ＪＰ，Ａ) 特開 平２−233695（ＪＰ，Ａ) 特開 平２−154693（ＪＰ，Ａ) 特開 昭62−87058（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) C12P 21/00 - 21/06 ＢＩＯＳＩＳ（ＤＩＡＬＯＧ) ＷＰＩ（ＤＩＡＬＯＧ)──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-36127 (JP, A) JP-A-1-240170 (JP, A) JP-A-2-233695 (JP, A) JP-A-2-2 154693 (JP, A) JP-A-62-87058 (JP, A) (58) Fields investigated (Int. Cl. 7 , DB name) C12P 21/00-21/06 BIOSIS (DIALOG) WPI (DIALOG)
Claims (1)
ーモライシンで加水分解することを特徴とするアンギオ
テンシン変換酵素阻害剤含有組成物の製造方法。1. A method for producing an angiotensin converting enzyme inhibitor-containing composition, comprising hydrolyzing any of skipjack section, sardine or chicken meat with thermolysin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP02267365A JP3073762B2 (en) | 1990-10-03 | 1990-10-03 | Method for producing composition containing angiotensin converting enzyme inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP02267365A JP3073762B2 (en) | 1990-10-03 | 1990-10-03 | Method for producing composition containing angiotensin converting enzyme inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04144696A JPH04144696A (en) | 1992-05-19 |
| JP3073762B2 true JP3073762B2 (en) | 2000-08-07 |
Family
ID=17443819
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP02267365A Expired - Lifetime JP3073762B2 (en) | 1990-10-03 | 1990-10-03 | Method for producing composition containing angiotensin converting enzyme inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3073762B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR200487798Y1 (en) | 2017-04-04 | 2018-11-06 | 임정수 | Structure of fixing handle of exercising crank |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI411441B (en) | 2003-03-18 | 2013-10-11 | Suntory Holdings Ltd | Angiotensin-converting enzyme inhibitory peptides |
| JP4493725B1 (en) | 2009-10-02 | 2010-06-30 | 株式会社 ファイナルフューチャーインターナショナル | Composition having lipolysis promoting action |
| CN115047092B (en) * | 2022-04-07 | 2023-10-20 | 济宁医学院 | Screening method of angiotensin-transferase II inhibitor |
-
1990
- 1990-10-03 JP JP02267365A patent/JP3073762B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR200487798Y1 (en) | 2017-04-04 | 2018-11-06 | 임정수 | Structure of fixing handle of exercising crank |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04144696A (en) | 1992-05-19 |
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