JP3031693B2 - Method for producing composition containing angiotensin converting enzyme inhibitor - Google Patents
Method for producing composition containing angiotensin converting enzyme inhibitorInfo
- Publication number
- JP3031693B2 JP3031693B2 JP2280139A JP28013990A JP3031693B2 JP 3031693 B2 JP3031693 B2 JP 3031693B2 JP 2280139 A JP2280139 A JP 2280139A JP 28013990 A JP28013990 A JP 28013990A JP 3031693 B2 JP3031693 B2 JP 3031693B2
- Authority
- JP
- Japan
- Prior art keywords
- converting enzyme
- angiotensin converting
- composition containing
- enzyme inhibitor
- albumin
- 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 - Fee Related
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
- Coloring Foods And Improving Nutritive Qualities (AREA)
- 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、降圧に働き、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 lowering, 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れ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 a natural product-derived angiotensin converting enzyme inhibitor is expected to be a low-toxicity and highly safe antihypertensive agent because it is obtained from foods or food raw materials.
[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] しかるに本発明者等は、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、アルブミン、特に卵白アルブミ
ンをペプ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 However, 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, hydrolyzed albumin, particularly ovalbumin, with pepsin. The present inventors have found that peptides having angiotensin converting enzyme inhibitory activity exist in the composition, and have completed the present invention.
ペプシンとは胃に分泌される酸性プロテアーゼの一種
である。本発明の活性をもつ組成物は上記ペプシンを用
いる場合に特に効果的に得られ、公知のプロテアーゼで
あるトリプシン、キモトリプシン等でアルブミンを分解
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。Pepsin is a type of acidic protease secreted by the stomach. The composition having the activity of the present invention can be obtained particularly effectively when the above-mentioned pepsin is used. I can't get it.
更に、アルブミンの分解率は1〜8%の範囲に限られ
ており、1%以下及び8%以上ではアンギオテンシン変
換酵素阻害活性物を得ることができない。Furthermore, the decomposition rate of albumin is limited to the range of 1 to 8%, and if it is 1% or less and 8% or more, an angiotensin converting enzyme inhibitory activity cannot be obtained.
アルブミンとしては、動物や植物の体液及び組織中に
広く分布している可溶性蛋白質例えば、卵白アルブミ
ン、血清アルブミン、乳アルブミン、等が任意に用いら
れるが、特に有用なものは卵白アルブミンである。As albumin, soluble proteins widely distributed in body fluids and tissues of animals and plants, for example, ovalbumin, serum albumin, milk albumin and the like are arbitrarily used, and particularly useful is ovalbumin.
アルブミンをペプシンで加水分解するには、アルブミ
ンの性状により処法は異なるが、難溶性の場合には熱水
にアルブミンを混合し強力な撹拌でホモジナイズした
後、ペプシンをアルブミン溶解液に対して0.1〜10重量
%、好ましくは0.2〜2重量%添加し、温度10〜60℃、
好ましくは20〜40℃、pH0.1〜4.0、好ましくは0.5〜2.
5、反応時間10分〜3日の反応条件下でペプチド結合が
分解率1〜8%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 order to hydrolyze albumin with pepsin, the treatment method varies depending on the properties of albumin, but in the case of poor solubility, mix albumin in hot water and homogenize with vigorous stirring. -10% by weight, preferably 0.2-2% by weight, at a temperature of 10-60 ° C,
Preferably at 20-40 ° C, pH 0.1-4.0, preferably 0.5-2.
5. The reaction is continued under agitation under a reaction condition of 10 minutes to 3 days until the peptide bond is decomposed at a rate of 1 to 8% to obtain a target product.
分解率はJournal of Agricultural and Food Chemist
ry 24 No.6 1090〜1093(1976)に基づいて測定する。Degradation rate is Journal of Agricultural and Food Chemist
It is measured based on ry 24 No. 6 109-1093 (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 an angiotensin converting enzyme inhibitor thus obtained is a mixture of various peptides, and may be used as it is, or may be used 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日当たり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、ブトウ糖、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 1-3 times per day. The peptides of the present invention are usually 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 metasilicate aluminate, 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, macrogol, vegetable oil, wax, 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 a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. 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変換酵素
阻害剤含有組成物が製造できる。[Operation] The present invention can be prepared from a natural product, and in particular, can produce a composition containing an angiotensin converting 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 生卵白を蒸留水で5倍に希釈溶解した後、1N−HC1でp
H1.6に調整した溶解液(20mg/mlの蛋白を含む)にペプ
シン0.2mg/ml(シグマ社製)を添加して37℃、3時間静
置反応を行い100℃、10分間煮沸して反応を停止させ
た。(分解率3.5%)この反応液を10000rpmで5分間遠
心分離を行い、得られ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。結果はまとめて第1表に示
す。Example 1 Raw egg white was diluted and dissolved 5-fold with distilled water and then dissolved in 1N-HC1 to give p.
To the lysate adjusted to H1.6 (containing 20 mg / ml of protein) was added 0.2 mg / ml of pepsin (manufactured by Sigma), and the mixture was allowed to stand at 37 ° C for 3 hours. The reaction was stopped. (Degradation rate: 3.5%) This reaction solution was centrifuged at 10,000 rpm for 5 minutes, and the angiotensin converting enzyme inhibitory activity of the obtained supernatant was measured. The results are summarized in Table 1.
(分解率の測定方法) Journal of Agricultural and Food Chemistry 24 N
o.6 1090〜1093(1976)に準じて以下の方法で求めた。(Measurement method of decomposition rate) Journal of Agricultural and Food Chemistry 24 N
o.6 It was determined by the following method according to 1900 to 1093 (1976).
* ニンヒドリン法で測定 ** ケルダール法で測定 (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。 * Measured by ninhydrin method ** Measured by Kjeldahl method (Measurement of angiotensin converting enzyme inhibitory activity) The measurement of angiotensin converting enzyme inhibitory activity is measured by Cheung
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及び上
記で得た上澄液を所定濃度混合し、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 a predetermined concentration of 100 μl of the enzyme substrate, 12 μl of the enzyme solution and the supernatant obtained above, and the whole is mixed with 250 μl of water.
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。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.
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。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(μg/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)
The activity was indicated at 50 (μg / ml).
比較例1〜3 実施例1においてペプシンの代わりに第1表で示すプ
ロテアーゼを用いて実験を行った。Comparative Examples 1 to 3 Experiments were performed using the proteases shown in Table 1 in place of pepsin in Example 1.
但し、生卵白を希釈溶解する際に50mMのリン酸バッファ
ーを用いpH7.0とする。However, when the raw egg white is diluted and dissolved, the pH is adjusted to 7.0 using a 50 mM phosphate buffer.
結果はまとめて第1表に示す。 The results are summarized in Table 1.
実施例2、比較例4〜5 第2表に示す如き卵白中の蛋白質各々に蒸留水を添加
して25mg/mlとした溶解液に1N−HClを用いてPH1.4に調
節した。ペプシンの0.25mg/ml(シグマ社製)を添加し
て37℃、3時間静置反応を行い100℃、10分間煮沸して
反応を停止させた。(分解率3.1%)以後実施例1に従
いアンギオテンシン変換酵素阻害活性を測定した。結果
を第2表に示す。 Example 2 and Comparative Examples 4 and 5 Distilled water was added to each protein in egg white as shown in Table 2 to adjust the pH to 1.4 using 1N-HCl in a solution of 25 mg / ml. 0.25 mg / ml of pepsin (manufactured by Sigma) was added, the reaction was allowed to stand at 37 ° C for 3 hours, and the reaction was stopped by boiling at 100 ° C for 10 minutes. (Degradation rate: 3.1%) Thereafter, angiotensin converting enzyme inhibitory activity was measured according to Example 1. The results are shown in Table 2.
実施例3 卵白アルブミンに蒸留水を添加して20mg/mlとした溶
解液に1N−HClを用いてpH1.6に調節した。ペプシンの0.
20mg/ml(シグマ社製)を添加して37℃で静置反応を行
い経時的に分解率とアンギオテンシン変換酵素阻害活性
を測定した。結果を第3表に示す。 Example 3 A solution obtained by adding distilled water to ovalbumin to 20 mg / ml was adjusted to pH 1.6 using 1N-HCl. 0 of pepsin.
After adding 20 mg / ml (manufactured by Sigma), the mixture was allowed to stand still at 37 ° C., and the degradation rate and angiotensin converting enzyme inhibitory activity were measured over time. The results are shown in Table 3.
[効 果] 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変換酵
素阻害剤含有組成物が製造できる。 [Effect] The present invention can produce 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 food for lowering blood pressure.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 FI A61K 38/55 A61K 37/18 A61P 9/12 37/64 (56)参考文献 特開 平3−280835(JP,A) (58)調査した分野(Int.Cl.7,DB名) C12P 21/00 - 21/06 C12N 9/99 A23J 3/04 A23L 1/30 A61K 38/00 A61K 38/55 A61P 9/12 BIOSIS(DIALOG) WPI(DIALOG)────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. 7 Identification code FI A61K 38/55 A61K 37/18 A61P 9/12 37/64 (56) References JP-A-3-280835 (JP, A) ( 58) Fields investigated (Int. Cl. 7 , DB name) C12P 21/00-21/06 C12N 9/99 A23J 3/04 A23L 1/30 A61K 38/00 A61K 38/55 A61P 9/12 BIOSIS (DIALOG ) WPI (DIALOG)
Claims (2)
率1〜8%と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 a composition containing an angiotensin converting enzyme inhibitor, wherein albumin is hydrolyzed with pepsin to a decomposition rate of 1 to 8%.
記載の製造方法2. The method of claim 1, wherein albumin is used as albumin.
Manufacturing method described
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2280139A JP3031693B2 (en) | 1990-10-17 | 1990-10-17 | Method for producing composition containing angiotensin converting enzyme inhibitor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2280139A JP3031693B2 (en) | 1990-10-17 | 1990-10-17 | Method for producing composition containing angiotensin converting enzyme inhibitor |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH04152892A JPH04152892A (en) | 1992-05-26 |
JP3031693B2 true JP3031693B2 (en) | 2000-04-10 |
Family
ID=17620883
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2280139A Expired - Fee Related JP3031693B2 (en) | 1990-10-17 | 1990-10-17 | Method for producing composition containing angiotensin converting enzyme inhibitor |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP3031693B2 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100470457B1 (en) * | 2001-07-02 | 2005-02-05 | 대한민국 | Antihypertensive egg white protein hydrolysate and manufacturing method thereof |
EP1685764A1 (en) | 2005-01-27 | 2006-08-02 | Globus Egg Sciences B.V. | Anti-hypertensive functional food products |
-
1990
- 1990-10-17 JP JP2280139A patent/JP3031693B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JPH04152892A (en) | 1992-05-26 |
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