JP3770659B2 - Novel peptide and method for producing the same - Google Patents
Novel peptide and method for producing the same Download PDFInfo
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- JP3770659B2 JP3770659B2 JP21299096A JP21299096A JP3770659B2 JP 3770659 B2 JP3770659 B2 JP 3770659B2 JP 21299096 A JP21299096 A JP 21299096A JP 21299096 A JP21299096 A JP 21299096A JP 3770659 B2 JP3770659 B2 JP 3770659B2
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Description
【0001】
【発明の属する技術分野】
本発明は、動脈弛緩作用を持ち、血圧降下剤として有用な新規ペプチド及びその製造方法に関する。
【0002】
【従来の技術】
食品中に含まれる蛋白質は栄養効果ばかりでなく種々の生理活性を有することが知られている。例えば血圧を降下する活性を示すものとしていくつかのペプチドがある。かかる作用は主として血管を弛緩させたりアンギオテンシン変換酵素を阻害させることによって生起される。
前者の血管弛緩作用をもつペプチドとしては例えば牛血清アルブミン由来のペプチドが公知である(特開平4−99798号公報)。
【0003】
【発明が解決しようとする課題】
しかしながら、かかる活性をもつペプチドが天然物中に見出されることは極めてまれで、アンギオテンシン変換酵素阻害剤としては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。
【0004】
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(特開昭58−109425号公報、同59−44323号公報、同59−44324号公報、同61−36226号公報、同61−36227号公報)が、新規な阻害物質の開発が望まれているところである。
【0005】
【課題を解決するための手段】
そこで本発明者等が、天然物質で副作用の少ない動脈弛緩作用を示し、血圧降下作用を持つ物質を鋭意探索した結果、蛋白質特に卵白を特定の酵素で加水分解した組成物中にかかる活性を有する物質の存在をつきとめ、該物質が、H−Arg−Ala−Asp−His−Pro−Phe−OHである構造のペプチドであることを見出し本発明を完成した。
【0006】
本発明のH−Arg−Ala−Asp−His−Pro−Phe−OHなるペプチドは文献未載の新規なペプチドであり、卵白アルブミンをキモトリプシンによって加水分解することによって製造され、実用にあたっては組成物をそのまま用いても良く、あるいは必要に応じて精製して使用される。更にはペプチド合成の常套手段を適用して合成することによって製造することもできる。上記でいうArgはアルギニン、Alaはアラニン、Aspはアスパラギン酸、Hisはヒスチジン、Proはプロリン、Pheはフェニルアラニンを意味し、かかるアミノ酸はいずれもL−体である。
【0007】
本発明のペプチドは蛋白質をキモトリプシンで加水分解することによっても、ペプチド合成法でも取得できる。蛋白質をキモトリプシンで加水分解するには、蛋白質の性状により処法が異なるが、難溶性の場合には熱水に蛋白質を混合し強力な撹拌でホモジナイズし、所定量のキモトリプシンを加え温度10〜85℃程度で0.1〜48時間反応を行う。
蛋白質としては、動物由来や微生物由来のもの等が任意に用いられ、特に有用なものは卵白である。
【0008】
単離する場合は加水分解液を遠心分離等の公知の操作で濾過する。その後抽出、濃縮、乾固などを適用した後、あるいはせずしてそのまま、種々の吸着剤に対する吸着親和性の差、種々の溶剤に対する溶解性あるいは溶解度の差、2種の混ざり合わない液相間における分配の差、分子の大きさに基づく溶出速度の差、溶液からの析出性あるいは析出速度の差などを利用する手段を適用して目的物を単離するのが好ましい。これらの方法は必要に応じて単独に用いられ、あるいは任意の順序に組合せ、また反復して適用される。
【0009】
本発明のペプチドはペプチド合成に通常用いられる方法、即ち液相法または固相法でペプチド結合の任意の位置で二分される2種のフラグメントの一方に相当する反応性カルボキシル基を有する原料と、他方のフラグメントに相当する反応性アミノ基を有する原料とをカルボジイミド法、活性エステル法等を用いて縮合させ、生成する縮合物が保護基を有する場合、その保護基を除去させることによっても製造し得る。
【0010】
この反応工程において反応に関与すべきでない官能基は、保護基により保護される。アミノ基の保護基としては、例えばベンジルオキシカルボニル、t−ブチルオキシカルボニル、p−ビフェニルイソプロピロオキシカルボニル、9−フルオレニルメチルオキシカルボニル等が挙げられる。カルボキシル基の保護基としては例えばアルキルエステル、ベンジルエステル等を形成し得る基が挙げられるが固相法の場合は、C末端のカルボキシル基はクロルメチル樹脂、オキシメチル樹脂、P−アルコキシベンジルアルコール樹脂等の担体に結合している。縮合反応は、カルボジイミド等の縮合剤の存在下にあるいはN−保護アミノ酸活性エステルまたはペプチド活性エステルを用いて実施する。
【0011】
縮合反応終了後、保護基は除去されるが、固相法の場合はさらにペプチドのC末端と樹脂との結合を切断する。更に、本発明のペプチドは通常の方法に従い精製される。例えばイオン交換クロマトグラフィー、逆相液体クロマトグラフィー、アフィニティークロマトグラフィー等が挙げられる。
【0012】
本発明で使用するペプチド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で、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と反応しない物質が用いられる。
【0013】
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。
【0014】
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、坐剤、軟膏、クリーム剤、ゲル剤、貼付剤、吸入剤、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。
【0015】
これらの製剤は、本発明のペプチドを0.01重量%以上、好ましくは0.5〜70重量%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。
【0017】
【実施例】
次に実例を挙げて本発明を更に具体的に説明する。
実施例1
〔ペプチドの抽出〕鶏卵白を蒸留水で5倍に希釈した後、1N塩酸あるいはINNaOHでpH7.4に調整した溶解液(20mg/mlの蛋白質を含む)にキモトリプシン0.2mg/ml(シグマ社製)を添加して37℃で3時間加水分解反応を行った。冷却後遠心分離して濃縮し、高速液体クロマトグラフィー(ODS−,Ph−及びCN−カラム)により精製し、ペプチドを得た。
本品を気相プロテインシーケンサー(アプライド バイオシステムズ社製 477 A型)を用いる自動エドマン分解法を適用してアミノ酸配列を分析し、下記の構造を得た。
H−Arg−Ala−Asp−His−Pro−Phe−OH該ペプチドの物性値はつぎのとうりである。
【0018】
【0019】
〔ペプチドの合成〕
市販のBoc(ブトキシカルボニル)−Phe−O−Resin〔ベンジル樹脂(置換率0.55meq/g)〕0.55gをバイオサーチ社のペプチド合成装置SAM TWOの反応槽に分取し、以下のように合成を行った。
45重量%トリフルオロ酢酸、2.5重量%アニソールを含む塩化メチレン中、25分間の反応により、Boc基を除去したのち、塩化メチレンによる洗浄、10重量%ジイソプロピルエチルアミンを含む塩化メチレンによる中和、及び塩化メチレンによる洗浄を行った。
これと5mlの0.4M Boc−Pro−Pheのジメチルホルムアミド溶液、5mlの0.4Mジイソプロピルカルボジイミドの塩化メチレン溶液とを混合した後、反応槽に加え、室温にて2時間撹拌反応させた。
【0020】
得られた樹脂をジメチルホルムアミド、塩化メチレン、10重量%ジイソプロピルエチルアミンを含む塩化メチレン、塩化メチレン更に塩化メチレン及びジメチルホルムアミドとの混合液で洗浄し、Boc−Pro−Phe樹脂を得た。
引き続き同様のBoc基の除去、Bocとアミノ酸のカップリングを繰り返し、Arg(Tos トシル基)−Ala−Asp−His(Tos)−Pro−Phe樹脂を得た。該樹脂を20mlの10重量%アニソールを含むフッ化水素中で0℃、1時間撹拌し、ペプチドを樹脂から遊離させた。
フッ化水素を減圧留去し、残渣を30重量%酢酸で抽出し、凍結乾燥して粗ペプチドを得た。これをODSカラム(Cosmosil 5C18)による逆相クロマトグラフィーにより精製し、H−Arg−Ala−Asp−His−Pro−Phe−OHを得た。
本品を前記と同一のプロテインシーケンサーにより分析した結果、上記の組成であることが判明した。
【0021】
該ペプチドの物性値は上記と同一であった。
(イヌ腸間膜動脈弛緩作用の測定)
イヌより摘出した腸間膜動脈のらせん条片を高木等らの方法(高木等編、薬物学実験、94〜99ページ、南山堂)に従って処理し、標本をマグナス管中で等長性トランスジューサーに接続した。0.5μMのプロスタグランジンF2αによって収縮させた腸間膜動脈に対して本ペプチドは弛緩作用を示した。その際の
ED50(50%弛緩)は100μMであった。
【0022】
(血圧変動の測定)
観血法
15〜20週令の自然発症性高血圧ラットを尾静脈より麻酔した後、大腿部静脈にサンプル注入用カテーテルを挿入し、5mg/kgのサンプルを投与し圧トランスジューサーにより観血的に血圧を測定した。血圧の低下は約20mmHgであった。
【0023】
非観血法(経口投与)
上記のラットに卵黄でエマルジョン化したサンプルを20mg/kgの割合でゾンデ針を使用して強制経口投与した。
そして尾動脈部の血圧をtail−cuff法にて経時的に測定し収縮期血圧における最大降圧値を測定したところ、11mmHgであった。
【0024】
【発明の効果】
本発明のペプチドは、新規なペプチドであり優れた動脈弛緩作用、血圧降下活性を示し、本態性高血圧、腎性高血圧、副腎性高血圧などの高血圧症の予防、治療剤、これらの疾患の診断剤や各種の病態において用いられる血圧降下剤、狭心症や心筋梗塞の治療薬、うっ血性心不全における病態の改善剤として有用である。
また、本発明のペプチドは、卵白等の天然物を加水分解することにより容易に製造することができる。 [0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel peptide having an arterial relaxation action and useful as an antihypertensive agent and a method for producing the same.
[0002]
[Prior art]
It is known that proteins contained in food have various physiological activities as well as nutritional effects. For example, there are several peptides that show activity to lower blood pressure. Such an action is mainly caused by relaxing blood vessels or inhibiting angiotensin converting enzyme.
As the former peptide having a vasorelaxant action, for example, a peptide derived from bovine serum albumin is known (Japanese Patent Laid-Open No. 4-99798).
[0003]
[Problems to be solved by the invention]
However, it is extremely rare that a peptide having such an activity is found in natural products. As angiotensin converting enzyme inhibitors, teprotide (Nonapeptide, SQ20881) obtained from snake venom from Brazil or Japan, Streptomyces, etc. Only the metabolite IS83 (Japanese Patent Laid-Open No. 58-177920) of actinomycetes belonging to the genus is known.
[0004]
As the angiotensin converting enzyme inhibitors obtained natural products by enzymatic treatment, peptides obtained by decomposing by Toriputoshin milk casein is known (JP 58-109425, JP-same 59 -44323, JP same 59-44324, JP-same 61-36226, JP-same 61-36227 JP) is about to develop novel inhibitors are desired.
[0005]
[Means for Solving the Problems]
Therefore, as a result of eager search for a substance that exhibits natural arterial relaxation and has a blood pressure lowering effect, the present inventors have an activity in a composition obtained by hydrolyzing a protein, particularly egg white, with a specific enzyme. The presence of the substance was identified, and the present invention was completed by finding that the substance was a peptide having a structure of H-Arg-Ala-Asp-His-Pro-Phe-OH.
[0006]
The peptide H-Arg-Ala-Asp-His-Pro-Phe-OH of the present invention is a novel peptide not yet described in the literature, and is produced by hydrolyzing ovalbumin with chymotrypsin. It may be used as it is, or it may be purified as necessary. Furthermore, it can also be produced by synthesis by applying conventional means of peptide synthesis. In the above, Arg is arginine, Ala is alanine, Asp is aspartic acid, His is histidine, Pro is proline, Phe is phenylalanine, and all of these amino acids are L-forms.
[0007]
The peptide of the present invention can be obtained by hydrolyzing a protein with chymotrypsin or by a peptide synthesis method. To hydrolyze proteins with chymotrypsin, the treatment method varies depending on the properties of the protein. However, in the case of poor solubility, the protein is mixed with hot water and homogenized by vigorous stirring. The reaction is performed at about 0.1 ° C. for 0.1 to 48 hours.
As proteins, those derived from animals or microorganisms are arbitrarily used, and a particularly useful protein is egg white.
[0008]
In the case of isolation, the hydrolyzed solution is filtered by a known operation such as centrifugation. After that, after application of extraction, concentration, drying, etc., without or without, difference in adsorption affinity to various adsorbents, difference in solubility or solubility in various solvents, two kinds of liquid phases that do not mix It is preferable to isolate the target product by applying means utilizing the difference in partitioning, the difference in elution rate based on the size of the molecule, the precipitation from the solution or the difference in the precipitation rate. These methods may be used alone as necessary, or may be combined in an arbitrary order and applied repeatedly.
[0009]
The peptide of the present invention is a method generally used for peptide synthesis, that is, a raw material having a reactive carboxyl group corresponding to one of two kinds of fragments bisected at any position of the peptide bond by a liquid phase method or a solid phase method, It is also produced by condensing a raw material having a reactive amino group corresponding to the other fragment using a carbodiimide method, an active ester method, etc., and when the resulting condensate has a protective group, the protective group is removed. obtain.
[0010]
Functional groups that should not participate in the reaction in this reaction step are protected by protecting groups. Examples of the amino-protecting group include benzyloxycarbonyl, t-butyloxycarbonyl, p-biphenylisopropyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and the like. Examples of the protecting group for the carboxyl group include groups capable of forming an alkyl ester, benzyl ester, etc. In the case of the solid phase method, the C-terminal carboxyl group is a chloromethyl resin, oxymethyl resin, P-alkoxybenzyl alcohol resin, etc. It is bound to the carrier. The condensation reaction is carried out in the presence of a condensing agent such as carbodiimide or using an N-protected amino acid active ester or peptide active ester.
[0011]
After completion of the condensation reaction, the protecting group is removed, but in the solid phase method, the bond between the C-terminal of the peptide and the resin is further cleaved. Furthermore, the peptides of the present invention are purified according to conventional methods. Examples thereof include ion exchange chromatography, reverse phase liquid chromatography, affinity chromatography and the like.
[0012]
The administration route of the peptide used in the present invention may be any of oral administration, parenteral administration and rectal administration, but oral administration is preferred. The dose of the peptide of the present invention varies depending on the type of compound, administration method, patient symptom, age, etc., but is usually 0.001 to 1000 mg at a time , preferably 0.01 to 10 mg 1 to 3 times a day. It is. The peptide of the present invention is 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 peptide of the present invention is used.
[0013]
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, bee gum, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, Fatty acid glycerin ester, refined lanolin, glycero gelatin, polysorbate, macro Lumpur, vegetable oils, waxes, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol, water and the like.
[0014]
Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, injections, and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of injection, it is prepared by dissolving the peptide of the present invention in water, but it may be dissolved in physiological saline or glucose solution as necessary, and a buffer or preservative may be added. Good.
[0015]
These preparations can contain the peptide of the present invention in an amount of 0.01 % by weight or more, preferably 0.5 to 70 % by weight . These formulations may also contain other therapeutically valuable ingredients.
[0017]
【Example】
Next, the present invention will be described more specifically with examples.
Example 1
[Peptide Extraction] Chicken egg white was diluted 5-fold with distilled water, and then dissolved in a solution (containing 20 mg / ml protein) adjusted to pH 7.4 with 1N hydrochloric acid or INNaOH, 0.2 mg / ml (Sigma) And a hydrolysis reaction was carried out at 37 ° C. for 3 hours. After cooling, the mixture was centrifuged and concentrated, and purified by high performance liquid chromatography (ODS-, Ph- and CN-columns) to obtain a peptide.
The product was analyzed for amino acid sequence by applying an automated Edman degradation method using a gas phase protein sequencer (type 477 A manufactured by Applied Biosystems) to obtain the following structure.
H-Arg-Ala-Asp-His-Pro-Phe-OH The physical properties of the peptide are as follows.
[0018]
[0019]
(Peptide synthesis)
0.55 g of commercially available Boc (butoxycarbonyl) -Phe-O-Resin [benzyl resin (substitution rate: 0.55 meq / g)] was dispensed into a reaction vessel of a biosynthetic peptide synthesizer SAM TWO. Was synthesized.
Removal of the Boc group by reaction for 25 minutes in methylene chloride containing 45 % by weight trifluoroacetic acid, 2.5 % by weight anisole, followed by washing with methylene chloride and neutralization with methylene chloride containing 10 % by weight diisopropylethylamine. And washing with methylene chloride.
This was mixed with 5 ml of a 0.4 M Boc-Pro-Phe dimethylformamide solution and 5 ml of a 0.4 M diisopropylcarbodiimide methylene chloride solution, and the mixture was added to the reaction vessel and stirred at room temperature for 2 hours.
[0020]
The obtained resin was washed with a mixed solution of dimethylformamide, methylene chloride, methylene chloride containing 10 % by weight diisopropylethylamine, methylene chloride and further methylene chloride and dimethylformamide to obtain a Boc-Pro-Phe resin.
Subsequently, similar removal of the Boc group and coupling of Boc and amino acid were repeated to obtain Arg (Tos tosyl group) -Ala-Asp-His (Tos) -Pro-Phe resin. The resin was stirred in hydrogen fluoride containing 20 ml of 10 % by weight anisole at 0 ° C. for 1 hour to release the peptide from the resin.
Hydrogen fluoride was distilled off under reduced pressure, and the residue was extracted with 30 % by weight acetic acid and lyophilized to obtain a crude peptide. This was purified by reverse-phase chromatography on an ODS column (Cosmosil 5C 18), to give the H-Arg-Ala-Asp- His-Pro-Phe-OH.
As a result of analyzing this product using the same protein sequencer as described above, it was found to have the above composition.
[0021]
The physical properties of the peptide were the same as above.
(Measurement of canine mesenteric artery relaxation)
A spiral strip of mesenteric artery isolated from a dog is treated according to the method of Takagi et al. (Takagi et al., Pharmacology experiment, pages 94-99, Nanzan-do), and the specimen is isometric transducer in Magnus tube. Connected to. The peptide exhibited a relaxing action on mesenteric arteries contracted with 0.5 μM prostaglandin F 2 α. The ED 50 (50% relaxation) at that time was 100 μM.
[0022]
(Measurement of blood pressure fluctuation)
Opening method After anesthetizing spontaneously hypertensive rats 15 to 20 weeks old from the tail vein, a sample injection catheter was inserted into the femoral vein, and a 5 mg / kg sample was administered. Blood pressure was measured. The decrease in blood pressure was about 20 mmHg.
[0023]
Non-invasive method (oral administration)
Samples emulsified with egg yolk were orally administered by gavage using a sonde needle at a rate of 20 mg / kg.
The blood pressure in the tail artery was measured over time by the tail-cuff method, and the maximum antihypertensive value in systolic blood pressure was measured, and it was 11 mmHg.
[0024]
【The invention's effect】
The peptide of the present invention is a novel peptide that exhibits excellent arterial relaxing action and blood pressure lowering activity, and prevents or treats hypertension such as essential hypertension, renal hypertension, and adrenal hypertension, and diagnostic agent for these diseases It is useful as an antihypertensive agent, an angina pectoris and a myocardial infarction used in various pathological conditions, and a pathological condition improving agent in congestive heart failure.
Moreover, the peptide of this invention can be easily manufactured by hydrolyzing natural products, such as egg white .
Claims (4)
Priority Applications (1)
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JP21299096A JP3770659B2 (en) | 1996-07-23 | 1996-07-23 | Novel peptide and method for producing the same |
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JP21299096A JP3770659B2 (en) | 1996-07-23 | 1996-07-23 | Novel peptide and method for producing the same |
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JPH1036394A JPH1036394A (en) | 1998-02-10 |
JP3770659B2 true JP3770659B2 (en) | 2006-04-26 |
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JP21299096A Expired - Fee Related JP3770659B2 (en) | 1996-07-23 | 1996-07-23 | Novel peptide and method for producing the same |
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Families Citing this family (2)
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ES2253036B1 (en) * | 2003-07-31 | 2007-07-16 | Consejo Sup. Investig. Cientificas | BIOACTIVE PEPTIDES DERIVED FROM PROTEINS OF THE EGG CLEAR BY ENZYMATIC HYDROLYSIS. |
EP1685764A1 (en) * | 2005-01-27 | 2006-08-02 | Globus Egg Sciences B.V. | Anti-hypertensive functional food products |
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