JPH04152892A - Production of composition containing angiotensin converting enzyme inhibitor - Google Patents
Production of composition containing angiotensin converting enzyme inhibitorInfo
- Publication number
- JPH04152892A JPH04152892A JP2280139A JP28013990A JPH04152892A JP H04152892 A JPH04152892 A JP H04152892A JP 2280139 A JP2280139 A JP 2280139A JP 28013990 A JP28013990 A JP 28013990A JP H04152892 A JPH04152892 A JP H04152892A
- Authority
- JP
- Japan
- Prior art keywords
- albumin
- converting enzyme
- pepsin
- angiotensin
- reaction
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 15
- 239000005541 ACE inhibitor Substances 0.000 title claims description 10
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 title claims description 9
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 title claims description 5
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 108010088751 Albumins Proteins 0.000 claims abstract description 17
- 102000009027 Albumins Human genes 0.000 claims abstract description 17
- 102000057297 Pepsin A Human genes 0.000 claims abstract description 12
- 108090000284 Pepsin A Proteins 0.000 claims abstract description 12
- 229940111202 pepsin Drugs 0.000 claims abstract description 12
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 108010000912 Egg Proteins Proteins 0.000 claims abstract description 5
- 102000002322 Egg Proteins Human genes 0.000 claims abstract description 5
- 235000014103 egg white Nutrition 0.000 claims abstract description 5
- 210000000969 egg white Anatomy 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 9
- 238000000354 decomposition reaction Methods 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 235000013305 food Nutrition 0.000 abstract description 8
- 208000001953 Hypotension Diseases 0.000 abstract description 3
- 208000021822 hypotensive Diseases 0.000 abstract description 3
- 230000001077 hypotensive effect Effects 0.000 abstract description 3
- 230000036772 blood pressure Effects 0.000 abstract description 2
- 239000005445 natural material Substances 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
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- 239000004365 Protease Substances 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- 241000416162 Astragalus gummifer Species 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
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- 241000196324 Embryophyta Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
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- 229920000084 Gum arabic Polymers 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
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- 239000005018 casein Substances 0.000 description 1
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- 235000021240 caseins Nutrition 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
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- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
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- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
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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)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野コ
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。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for producing an angiotensin-converting enzyme inhibitor-containing composition that can be prepared from natural products and is particularly useful as a hypotensive agent or food for hypotensives. .
［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−＾ｒｇ −Ｖａｌ −Ｔｙｒ −１１ｅ −Ｈｉｓ
−Ｐｒｏ −Ｐｈｅ −Ｈｉｓ −Ｌｅｕ）に作用し
て、アンギオテンシン■のＣ末端よりノベブチド（Ｈｉ
ｓ”−Ｌｅｕ”）を開裂遊離させ、強力な昇圧作用を有
するアンギオテンンン■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存し、昇圧系に強力に関与してい
る。[Prior art] Angiotensin-converting enzyme exists mainly in the lungs, vascular endothelial cells, and renal proximal tubules, and angiotensin-converting enzyme
p-^rg -Val -Tyr -11e -His
-Pro -Phe -His -Leu)
It is an enzyme that cleaves and liberates s"-Leu") to produce angiotene, which has a strong pressor effect. This enzyme also has the effect of decomposing and inactivating bradykinin, an antihypertensive substance in the 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。It has been conventionally believed that inhibiting the activity of angiotensin converting enzyme lowers blood pressure and is clinically effective in 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, the proline derivative captopril was synthesized and its antihypertensive activity was confirmed, and since then, research has been active in the synthesis of various angiotensin-converting enzyme inhibitors, and efforts are also 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 angiotensin-converting enzyme inhibitors derived from natural products can be obtained from foods or food materials, and are therefore expected to be low-toxic and highly safe antihypertensive agents.
［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ブロタイド（ノナペプチド。[Problems to be Solved by the Invention] However, angiotensin converting enzyme inhibitors found in natural products are extremely rare, and only tebrotide (nonapeptide) obtained from Brazilian and Japanese snake venoms.
５Ｑ２０８８１）等や、ストレプトミセス属に属する放
線菌の代謝産物ｌ５８３ （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ト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５８−１０
９４２５号、同５９−４４３２３号、同５９−４４３２
４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。5Q20881), etc., and the metabolite l583 of actinomycetes belonging to the genus Streptomyces (Japanese Unexamined Patent Publication No. 58-177920
No. 2) is only known. Furthermore, as angiotensin-converting enzyme inhibitors obtained by enzymatically treating natural products, peptides obtained by decomposing milk casein with tryptocin are known (Japanese Unexamined Patent Publication No. 58-10
No. 9425, No. 59-44323, No. 59-4432
No. 4, No. 61-36226, No. 61-36227)
The development of new inhibitors is desired.
［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, in order to solve the problems, the present inventors conducted an intensive search for an angiotensin-converting enzyme inhibitor that is a natural substance and has few side effects, and as a result, they found that albumin, especially ovalbumin, was hydrolyzed with pepsin. The present inventors have discovered that peptides having angiotensin converting enzyme inhibitory activity are present 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 acid protease secreted in the stomach. The composition having the activity of the present invention can be obtained particularly effectively when the above-mentioned pepsin is used, and even if albumin is decomposed with known proteases such as trypsin and chymotrypsin, the composition having the strong action of the present invention cannot be obtained. 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ンン変換
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 a range of 1 to 8%, and if it is less than 1% or more than 8%, it is not possible to obtain an angiotene converting enzyme inhibitory substance.
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、筋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。Albumin is a soluble protein that is widely distributed in body fluids and tissues of animals and plants, such as ovalbumin,
Serum albumin, milk albumin, muscle albumin, etc. are optionally used, but ovalbumin is particularly useful.
アルブミンをペプシンで加水分解するには、アルブミン
の性状により処決は異なるが、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１０〜６
０℃、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。To hydrolyze albumin with pepsin, the treatment differs depending on the properties of the albumin, but in the case of poorly soluble albumin, mix the albumin with hot water and homogenize with strong stirring.
Pepsin is added in an amount of 0.1-10% by weight, preferably 0.2-2% by weight, based on the albumin solution, and the temperature is 10-6%.
0°C, preferably 20-40°C, PH0.1-4.0,
Preferably, the reaction is continued under reaction conditions of 0.5 to 2.5 and reaction time of 10 minutes to 3 days, with standing or stirring, until the decomposition rate of the peptide bond reaches 1 to 8%, to obtain the desired product.
分解率はＪｏｕｒｎａｌ ｏｆ Ａｇｒｉｃｕｌｔｕｒ
ａｌ ａｎｄ Ｆｏｏｄ Ｃｈｅｍｉｓｔｒｙ ２４
Ｎｏ、６１０９０”１０９３ （１９７６）に基づいて
測定する。Decomposition rate is Journal of Agriculture
al and Food Chemistry 24
No. 61090"1093 (1976).
かくして得られたアンギオテンシン交換酵素阻害剤含有
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 angiotensin exchange enzyme inhibitor-containing composition thus obtained is a mixture of various peptides, and may be used as is or after post-treatment.
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０．００１−１０００＋ｅ９、好ましく
は０．０１−１０ｍｇ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、ブド
ウ糖、マンニット、デキストリン、ンクロデキストリン
、デンプン、蔗糖、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ンウム、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 for the peptides obtained in the present invention may be oral administration, parenteral administration, or intrarectal administration, but oral administration is preferred. The dosage of the peptides of the present invention varies depending on the type of compound, administration method, patient's symptoms, age, etc., but is usually 0.001-1000+e9, preferably 0.01-10mg, 1 to 3 times a day. times. The peptides of the present invention are usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier. As a 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, nclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose, ion exchange resin, methylcellulose. , gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, light silicic anhydride, magnesium stearate, talc, tragacanth, bentonite, vegum, 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, fluorocarbon, nonionic surfactant, propylene glycol,
Examples include water. Dosage forms include tablets, capsules,
Examples include granules, powders, syrups, suspensions, and injections. These formulations are prepared according to conventional methods. In the case of a liquid preparation, it may be dissolved or suspended in water or other suitable medium before use. Furthermore, tablets and granules may be coated by a well-known method. In the case of injections, they are prepared by dissolving the peptides of the present invention in water;
If necessary, it may be dissolved in physiological saline or glucose solution, and a buffer or preservative may be added.
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 can contain the peptides of the present invention in a proportion of 0.01% or more, preferably 0.5 to 70%. These formulations may also contain other ingredients of therapeutic value.
［作 用コ
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。[Function] The present invention can produce an angiotensin-converting enzyme inhibitor-containing composition that can be prepared from natural products and is particularly 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。[Example] Hereinafter, the present invention will be explained 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、ｌＮ−ＨＣｌ
でＰＨ１，６に調整した溶解液（２０ａ９／ ｍＱの蛋
白を含む）にペプシン０ 、２ ｍ９７ｙａ（１（シグ
マ社製）を添加して３７℃、３時間静置反応を行い１０
０℃、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１００００ ｒｐｍ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。Example 1 After diluting and dissolving raw egg white 5 times with distilled water, 1N-HCl
Pepsin 0 and 2 m97ya (1 (manufactured by Sigma)) were added to the solution (containing 20a9/mQ protein) adjusted to pH 1.6, and the reaction was allowed to stand at 37°C for 3 hours.
The reaction was stopped by boiling at 0°C for 10 minutes. (Decomposition rate 3
．． 5%) This reaction solution was centrifuged at 10,000 rpm for 5 minutes, and the angiotensin converting enzyme inhibitory activity of the resulting supernatant was measured.
結果はまとめて第１表に示す。The results are summarized in Table 1.
（分解率の測定方法）
Ｊｏｕｒｎａｌ ｏｆ Ａｇｒｉｃｕｌｔｕｒａｌ ａ
ｎｄ Ｆｏｏｄ Ｃｈｅｍｉｓｔｒｙ ２４ Ｎｏ、６
１０９０〜１０９３ （１９７６）に準じて以下の方法
で求めた。(Method for measuring decomposition rate) Journal of Agricultural a
nd Food Chemistry 24 No. 6
1090-1093 (1976) by the following method.
＊ ニンヒドリン法で測定
＊＊ ケルプール法で測定
（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Ｃ
ｕｓｂｍａｎの方法（Ｂｉｏｃｈｅａｉｃａｌ Ｐｈａ
ｒａａａｃｏｌｏｇｙ ２０ 。* Measured by the ninhydrin method ** Measured by the Kelpool method (Measurement of angiotensin converting enzyme inhibitory activity) The measurement of angiotensin converting enzyme inhibitory activity was carried out by Cheung and C.
usbman method (Biocheaical Pha
raaacology 20.
１６３７（１９７１））に準じて以下の方法で行った。1637 (1971)) by the following method.
酵素基質； Ｂｚ （ベンジル） −Ｇｌｙ−Ｈｉｓ−
Ｌｅｕ（８６ｍｌＦ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）
（！９を５０ｍＭのリン酸緩衝液１０ｍ１中で粉砕した
後、遠心分離した上澄液）
上記の酵素基質を！００μｅ、酵素溶液を１２μＱ及び
上記で得た上澄液を所定濃度混合し、水で全体を２５０
μＣとした後、３７℃で３０分間反応を行った。Enzyme substrate; Bz (benzyl) -Gly-His-
Leu (a solution of 86ml F dissolved in 8ml of water and 8ml of phosphate buffer) Enzyme: Rabbit lung acetone powder (manufactured by Sigma)
(Supernatant obtained by pulverizing !9 in 10ml of 50mM phosphate buffer and centrifuging it) The above enzyme substrate! 00μE, 12μQ of the enzyme solution, and the supernatant obtained above were mixed at a specified concentration, and the whole was diluted with water to 250μQ.
After setting the temperature to μC, the reaction was carried out at 37°C for 30 minutes.
反応はｌＮ−ＨＣｌ ２５０μＱを用いて終了させた
。The reaction was terminated using 250 μQ of IN-HCl.
反応終了液に酢酸エチル１．５ｍｌを入れＶ ｏｒｔｅ
ｘで１５秒撹拌し、それを遠心分離した。Add 1.5 ml of ethyl acetate to the reaction completed solution and
Mix at x for 15 seconds and centrifuge it.
酢酸エチル層から１．Ｏｗｌをとり出して、酢酸エチル
を留去し、それにｆｍｌ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２２８ ｎｎの値（ＯＤ
□８）を測定した。1. from the ethyl acetate layer. The Owl was taken out, ethyl acetate was distilled off, fml of distilled water was added thereto to dissolve the residue, and the ultraviolet absorption value of the extracted hippuric acid was 228 nn (OD
□8) was measured.
阻害率は阻害剤なしで反応したときのＯＤ ｔｔｓを１
００％とし、反応時間０分のときのＯＤ ｖ２ｅ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ＩＣ５゜（μｇ／ ｔａ（１）で活性を表示
した。The inhibition rate is 1 OD tts when reacting without inhibitor.
00%, and OD v2e when reaction time is 0 minutes is 0%.
The activity was expressed as the concentration IC5° (μg/ta(1)) of the inhibitor (peptide of the present invention) when the inhibition rate was 50%.
比較例Ｉ〜３
実施例１においてペプシンの代わりに第２表で示すプロ
テアーゼを用いて実験を行った。Comparative Examples I to 3 In Example 1, an experiment was conducted using proteases shown in Table 2 instead of pepsin.
但し、生卵白を希釈溶解する際に５０５Ｍのリン酸バッ
ファーを用いＰＨ７，０とする。However, when diluting and dissolving raw egg white, use 505M phosphate buffer to adjust the pH to 7.0.
結果はまとめて第１表に示す。The results are summarized in Table 1.
第
表
実施例２、比較例４〜５
第２表に示す如き卵白中の蛋白質外々に蒸留水を添加し
て２５１ｙ／１ｇとした溶解液にＩＮ−ＭＣＩを用いて
ＰＨ１，４に調節した。ペプシンの０ 、２５ ｍｆ／
ａ（！ （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。Table Example 2, Comparative Examples 4 to 5 Distilled water was added to the protein in egg white as shown in Table 2 to make a solution of 251y/1g, and the pH was adjusted to 1.4 using IN-MCI. . 0,25 mf/pepsin
a(! (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. (Decomposition rate: 3°1%) Thereafter, angiotensin was added according to Example 1. The converting enzyme inhibitory activity was measured.The results are shown in Table 2.
第
表
実施例３
卵白アルブミンに蒸留水を添加して２０ ｍ９／ ｔｎ
（ｌとした溶解液にｌＮ−ＨＣｌを用いてＰＨ１，６に
調節した。Table Example 3 Distilled water was added to ovalbumin to produce 20 m9/tn.
(The pH of the solution was adjusted to 1.6 using 1N-HCl.
ペプシンの０．２５ｍｇ／ｍρ（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。0.25 mg/mρ of pepsin (manufactured by Sigma) was added, a standing reaction was carried out at 37°C, and the decomposition rate and angiotensin converting enzyme inhibitory activity were measured over time. The results are shown in Table 3.
第
表
Ｃ効
果フ
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ンン変換酵
素阻害剤含有組成物が製造できる。Effects of Table C The present invention can produce an angiotene converting enzyme inhibitor-containing composition that can be prepared from natural products and is particularly useful as an antihypertensive agent or antihypertensive food.
Claims (1)
％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 ２、アルブミンとして卵白を使用する請求項１記載の製
造方法[Claims] 1. Albumin is hydrolyzed with pepsin, and the decomposition rate is 1 to 8.
%, a method for producing an angiotensin-converting enzyme inhibitor-containing composition 2, the method according to claim 1, wherein egg white is used as albumin.
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 |
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| Publication Number | Publication Date |
|---|---|
| JPH04152892A true JPH04152892A (en) | 1992-05-26 |
| JP3031693B2 JP3031693B2 (en) | 2000-04-10 |
Family
ID=17620883
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| 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 |
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| Country | Link |
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Cited By (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 |
| WO2006009448A1 (en) * | 2004-07-22 | 2006-01-26 | Globus Egg Sciences B.V. | Anti-hypertensive functional food products |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100513977C (en) * | 2005-12-07 | 2009-07-15 | 松下电器产业株式会社 | Heat exchanger |
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1990
- 1990-10-17 JP JP2280139A patent/JP3031693B2/en not_active Expired - Fee Related
Cited By (6)
| 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 |
| WO2006009448A1 (en) * | 2004-07-22 | 2006-01-26 | Globus Egg Sciences B.V. | Anti-hypertensive functional food products |
| JP2008507270A (en) * | 2004-07-22 | 2008-03-13 | グロバス・エッグ・サイエンスィス・ビー．ブイ． | Antihypertensive functional food |
| AU2005264767B2 (en) * | 2004-07-22 | 2012-01-12 | Globus Egg Sciences B.V. | Anti-hypertensive functional food products |
| US8753698B2 (en) | 2004-07-22 | 2014-06-17 | Globus Egg Sciences B.V. | Anti-hypertensive functional food products |
| EP1685764A1 (en) * | 2005-01-27 | 2006-08-02 | Globus Egg Sciences B.V. | Anti-hypertensive functional food products |
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| JP3031693B2 (en) | 2000-04-10 |
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