EP1287159A1 - Enzymatic treatment of whey proteins for the production of antihypertensive peptides, the resulting products and treatment of hypertension in mammals - Google Patents
Enzymatic treatment of whey proteins for the production of antihypertensive peptides, the resulting products and treatment of hypertension in mammalsInfo
- Publication number
- EP1287159A1 EP1287159A1 EP01933181A EP01933181A EP1287159A1 EP 1287159 A1 EP1287159 A1 EP 1287159A1 EP 01933181 A EP01933181 A EP 01933181A EP 01933181 A EP01933181 A EP 01933181A EP 1287159 A1 EP1287159 A1 EP 1287159A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hydrolysate
- whey protein
- ace
- treatment
- max
- 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.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
- A23J3/00—Working-up of proteins for foodstuffs
- A23J3/30—Working-up of proteins for foodstuffs by hydrolysis
- A23J3/32—Working-up of proteins for foodstuffs by hydrolysis using chemical agents
- A23J3/34—Working-up of proteins for foodstuffs by hydrolysis using chemical agents using enzymes
- A23J3/341—Working-up of proteins for foodstuffs by hydrolysis using chemical agents using enzymes of animal proteins
- A23J3/343—Working-up of proteins for foodstuffs by hydrolysis using chemical agents using enzymes of animal proteins of dairy proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/556—Angiotensin converting enzyme inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/06—Preparation of peptides or proteins produced by the hydrolysis of a peptide bond, e.g. hydrolysate products
Definitions
- the invention in one aspect relates to a method for suppressing angiotensin- converting enzyme (ACE), a composition effective for this purpose and a method for preparing the composition, specifically by enzymatic conversion of whey proteins.
- ACE angiotensin- converting enzyme
- the invention relates to a method for reducing hypertension in mammals with specific hydrolysates obtained by the enzymatic conversion of whey proteins.
- ACE angiotensin converting enzyme
- the occurrence of pro line might also contribute to the ACE-inhibitory activity of peptides derived from food proteins.
- ACE angiotensin-converting enzyme
- ACE angiotensin-converting enzyme
- the process for preparing the ACE-suppressing composition comprises: preparing an aqueous solution of whey protein isolate and a proteolytic enzyme; holding said solution under conditions effective to partially hydrolyze said whey protein isolate to provide a hydrolysate having increased ACE-suppressing activity in mammals; and recovering said hydrolysate from said solution.
- the proteolytic enzyme is inactivated as necessary, preferably by heating.
- the hydrolysate is preferably dried for use in a regimen which comprises oral administration to a mammal, such as a human or a domestic pet such as a dog or cat, in amounts and at intervals effective to suppress ACE-activity.
- a mammalian treatment regimen entailing orally administration to humans or other mammals effective amounts of a hypertension-reducing composition obtained by: preparing an aqueous solution of whey protein isolate and a proteolytic enzyme; holding said solution under conditions effective to partially hydrolyze said whey protein isolate to provide a hydrolysate having the ability to reduce hypertension in mammals; and recovering said hydrolysate from said solution.
- the proteolytic enzyme is inactivated as necessary, preferably by heating.
- the hydrolysate is preferably dried for use in a regimen which comprises oral administration to a mammal, such as a human or a domestic pet such as a dog or cat, in amounts and at intervals effective to reduce hypertension in mammals.
- Figures 1-4 summarize the results of laboratory testing for antihypersion treatment discussed in detail below.
- Whey protein isolates can be obtained from commercial-scale fractionation of cheese whey by various processes, including ion-exchange processing using cationic and/or anionic resins selected for the intended functionality of the isolate.
- ion-exchange processing such as i?zPROTM (Davisco Foods International, Inc., LeSueur, MN)
- i?zPROTM Daavisco Foods International, Inc., LeSueur, MN
- the protein distribution of a typical WPI shows 55-65% ⁇ -lactoglobulin, 17-25% ⁇ -lactalbumin, 4-7% bovine serum albumin, 1-11% immunoglobulins and less than 1% others.
- 5tPROTM whey protein isolate is the preferred source of whey protein isolate for use in the invention and is available from Davisco Foods International, Inc., with offices at 11000
- the preferred BiPROTM whey protein isolate has a (PDCAAS) Protein Digestibility Corrected Amino Acid Score of 1.14.
- the fat and lactose levels are less than 1 %.
- the 5/PROTM whey protein isolate is prepared by ion-exchange technology, and contains about 55-65% (w/w) ⁇ -lactoglobulin.
- the whey protein isolate employed according to the invention will contain at least 55% and preferably at least 60% ⁇ -lactoglobulin, with the remaining comprising -lactalbumin, serum albumin and immunoglobulins in the above ranges.
- 5tPRO is essentially undenatured and is fully soluble over the pH range 2.0 to 9.0, and has the following analysis:
- Lactose (%) 1.0 max. ⁇ 0.5 by difference pH 6.7 - 7.5 7.0 ⁇ 0.1 10% Sol. @ 20°C.
- whey protein isolates other than BiPROTM can be employed and where used preferably have similar analyses to that above, varying by from 0 to 25%, e.g., from 5 to 10%, or less, from the above Typical Range values.
- a suitable whey protein isolate can be produced having similar properties through a selective ion exchange process that selects the primary functional proteins - beta-lactoglobulin and alpha-lactalbumin - for concentration and spray drying. Such a process is described in U. S. Patent No. 4,154,675 to Jowett, et al, and U. S. Patent No. 4,218,490 to Phillips, et al.
- whey protein fractions having lower protein contents e.g., as low as 35%
- ⁇ -lg produced by ion exchange separation can also be employed, but is less preferred than the Z?tPROTM whey protein isolate.
- samples were subjected to drying for 24 hours in a dessicator over phosphorus pentoxide and sodium hydroxide.
- the dry samples were hydro lyzed in HCl vapor (6N HCl with 1% phenol and 0.5% sodium sulfite) under Argon atmosphere. After 20 hours of hydrolysis at 110 degrees Celsius, the samples were dissolved in 200 ⁇ l of Beckman Na-S sample buffer. This acid hydrolysis method destroys tryptophan.
- whey protein isolates other than BiPROTM they preferably have similar analyses to that above, varying by from 0 to 25%, e.g., from 5 - 10%, or less, from the above values.
- Enzymatic digests of BiPROTM and of commercial ⁇ -lg-rich product were prepared using animal, bacterial and fungal proteases, in order to determine the potential of these commercial substrates for the preparation of peptide mixtures having antihypertensive activities.
- the objective of the work was to determine the ACE-inhibitory activity of various hydrolysates generated by enzymatic hydrolysis from whey protein isolates obtained by ion- exchange chromatography, in comparison with other commercially-available whey protein hydrolysates.
- Whey protein hydrolysate WPH 917 (84.5% protein w/w) was obtained from New Zealand Milk Product Inc. (Santa Rosa, USA).
- Whey protein hydrolysate LE80GF (80.0% w/w) was obtained from DMV International (New- York, USA).
- Whey protein isolate (BiPROTM) and ⁇ -lactoglobulin-rich product were obtained from Davisco Foods International (Le Sueur, MN, USA).
- Whey proteins (B ⁇ PROTM or ⁇ -lg) were solubilized at 20% W/V, adjusted to pH 8.0 or 8.5 by using a mixture of NaOH and KOH 4N and maintained at temperatures between 40°C and 50°C corresponding to the optimal temperature of the enzymes used.
- Table 1 reports the characteristics of the enzymes used for the preparation of the enzymatic hydrolysates for the study.
- RzPROTM and ⁇ -lg-rich product were utilized for the preparation of 601 and 605, but only BiproTM was used for 603K.
- the protein solutions were incubated with the proteases at an enzyme:substrate ratio of 1 :800 for AS-601, 1 :50 for AS-603K and 1 : 100 for AS-605K.
- the enzymatic hydrolysis was performed under pH-stat conditions until a degree of hydrolysis (DH) of 5.5-6.5% for AS-601 and under a combination of pH-stat and osmometry methods until a DH of 11.0-12.5% for AS-603K, and a DH of 19.5-20.5% for AS-605K.
- the hydrolysis reaction was stopped at the selected DH values by means of heat treatment (75 to 85°C for 15 s) in a plate heat exchanger to inactivate the enzyme and followed by cooling and storage at 5-10 °C until further processing.
- the resulting hydrolysates were further spray dried and handled as powdered ingredient. Fractions can be taken based on molecular weight and tested for relative activity, with the most active fractions selected.
- Chymotrypsin activity 350 U/mg minimum
- the ACE-inhibitory activity was measured in vitro by a spectrophotometric assay according to the method of Cushman and Cheung. (Cushman, D.N., Cheung, H.S. 1971 Spectrophotometric assay and properties of the angiotensin converting enzyme of rabbit lung. Biochemical Pharmacology, 20: 1637-1648.)
- hippuric acid is liberated from hippuryl-L-histidyl-L-leucine (HHL) by the enzymatic reaction of ACE.
- HHL hippuryl-L-histidyl-L-leucine
- Table 2 summarizes the experimental conditions used for the assay. Absorbance of the hippuric acid solution at 228 nm was determined by spectrophotometry.
- Substrate solution 1 200 200 200 200 200
- Deionized water 20 20 20 mixed using vortex and equilibrated to 37°C
- HHL was dissolved in HEPES-HCl Buffer to obtain a final concentration of 0.3% (w/v).
- 2 Samples were diluted at the appropriate concentration with HEPES-HCl Buffer.
- 3 HEPES Sodium Salt (50 mM) with 300 mM NaCl, pH adjusted at 8.3 with 1M HCl 4: 1M HCl.
- Inhibitory activity (%) [(A CO ntrol — A S ample)/(A C ontrol — Nblank)] x 100 [ 1 ]
- A absorbance
- a plot of the inhibitory activity (%) versus log 10 of sample concentration (mg powder mH) was generated using 6 different concentrations of samples for 5/PROTM, AS-601 (_9iPROTM ⁇ -lg), commercial hydrolysates (WPH 917, LE80GF) and of synthetic peptide (fl42-148) from ⁇ -lg. Each concentration was tested in triplicate and the mean value was plotted in the curves.
- the IC50 value (expressed in terms of mg powder ml "1 , defined as the concentration of inhibitor which gives 50% inhibition of ACE activity, was calculated using the linear regression equations of the curves.
- Table 3 presents the linear regression equations (y — m InX + b) of the ACE-inhibitory activity curves obtained with synthetic peptide ⁇ -lg (fl42-148), in comparison with the hydrolysates under study.
- BiPROTM whey protein isolate and others similarly prepared are preferred for a composition with regard to principal protein composition ( ⁇ -lg, ⁇ -la, etc.), and content of minor proteins (lactofe ⁇ n, lactoperoxydase, immunoglobulins) or peptidic fragments (caseinomacropeptides, proteoses peptones, etc.) which may be precursors of the production of peptides with very strong ACE-inhibition activity during enzymatic hydrolysis. Some of these minor proteins may be at a lower concentration in the ⁇ -lg-rich product, as a result of the different fractionation conditions.
- principal protein composition ⁇ -lg, ⁇ -la, etc.
- minor proteins lactoperoxydase, immunoglobulins
- peptidic fragments caseinomacropeptides, proteoses peptones, etc.
- Some of these minor proteins may be at a lower concentration in the ⁇ -lg-rich product, as a result of the different fractionation conditions.
- BiPROTM whey protein isolate may also be originating from its low mineral content, especially with regards to divalent cations such as calcium (15-20 meq/kg) or magnesium ( ⁇ 1 meq/kg). These physicochemical conditions may prevent the occurrence of peptide-peptide interactions and therefore preserve the high ACE-inhibitory potential of the hydrolysate. This hypothesis will be further investigated by comparing the mineral composition of 5/PROTM whey protein isolate with that of ⁇ -lg-rich product which showed a lower ACE-inhibitory potential.
- Enzymatic digests of BiPROTM whey protein isolate were prepared using animal, bacterial and fungal proteases, in order to determine the potential of these commercial substrates for the preparation of peptide mixtures having antihypertensive activities.
- the main objective of the present study was to investigate the antihypertensive effect of some specific whey protein hydrolysates.
- SHR conscious spontaneously hypertensive rats
- the SHR are considered as a genetic model of essential hypertension and are currently used to understand the development and establishment of hypertension and to determine the blood pressure lowering effect of newly synthesized antihypertensive drugs.
- Whey protein isolate (BiPROTM) was obtained from Davisco Foods International (Le
- HEPES Sodium salt, Hippuryl-L-Histidyl-L-Leucine, and Angiotensin Converting Enzyme were purchased from Sigma Chemical Co. (St. Louis, USA). All other products used were analytical grade.
- Whey proteins (BiPROTM) were solubilized at 20% W/V, adjusted to pH 8.0 or 8.5 by using a mixture of NaOH and KOH 4N and maintained at temperatures between 40°C and 50°C corresponding to the optimal temperature of the enzymes used. Table 1 reports the characteristics of the enzymes used for the preparation of the enzymatic hydrolysates for the study.
- BiPROTM whey protein isolate was utilized for the preparation of 601, 603K and 605K. The protein solutions were incubated with the proteases at an enzyme:substrate ratio of 1:800 for 601 , 1 : 50 for 603K and 1 : 100 for 605K.
- the enzymatic hydrolysis was performed under pH-stat conditions until a degree of hydrolysis (DH) of 4.5-6.5%) for 601 and under a combination of pH-stat and osmometry methods until a DH of 7.0-10.0%) for 603K, and a DH of 13.0-17.0%) for 605K.
- the hydrolysis reaction was stopped at the selected DH values by means of heat treatment (75 to 85°C for 15 s) in a plate heat exchanger to inactivate the enzyme and followed by cooling and storage at 5-10 °C until further processing.
- the resulting hydrolysates were further spray dried and handled as powdered ingredient. Fractions can be taken based on molecular weight and tested for relative activity, with the most active fractions selected.
- the above hydrolysates are characterized by a degree of hydrolysis of from 4.5% to 10.0%). This is determined by OPA Methodology.
- Chymotrypsin activity 350 U/mg minimum
- the rats were conscious, unrestrained and were allowed free access to water and food for the duration of the experiment.
- cardiovascular changes elicited by oral administration of i?tPRO whey protein isolate or specific whey protein hydrolysates (601, 603K, 605K) have been evaluated in conscious, unrestrained SHR.
- the rats were used on four consecutive days, during which they received increasing doses of only one specific hydrolysate (601, 603K, 605K) or the
- the lyophilized whey protein hydrolysate powder was dissolved in 0.2 mM PBS (pH 7.2) (the same vehicle, 0.2 mM PBS, was used for control administrations) and was given in a volume of 0.5 ml. All solutions were freshly prepared.
- the rats were given the vehicle (control PBS on day 1) or an isolated dose of a specific hydrolysate (30 mg/kg on day 2, 75 mg/kg on day 3 and 150 mg/kg on day 4) or 5rPRO whey protein isolate (30 mg/kg on day 2, 75 mg/kg on day 3 and 150 mg/kg on day 4).
- control PBS control PBS on day 1
- an isolated dose of a specific hydrolysate (30 mg/kg on day 2, 75 mg/kg on day 3 and 150 mg/kg on day 4) or 5rPRO whey protein isolate (30 mg/kg on day 2, 75 mg/kg on day 3 and 150 mg/kg on day 4).
- the blood pressure and heart rate effects of a single oral administration of PBS, BiPRO whey protein isolate or the whey protein hydrolysate was evaluated over a period of 7 hours.
- n is the number of rats.
- MAP mean arterial blood pressure
- HR heart rate
- bpm beats per minute.
- hypotensive effect (significant at 1-7 h) when compared with the effects of control administration of PBS.
- the maximum decrease in mean arterial blood pressure (-39 ⁇ 6 mm Hg) was achieved 6 h after the administration.
- a similar hypotensive effect was also observed following the intra-gastric administration of 150 mg/kg of the hydrolysate (significant at 1 and 3-7 h).
- the maximum decrease in mean arterial blood pressure (-32 ⁇ 7 mm Hg) was achieved 6 h after the administration.
- PBS hydrolysate 603K
- 605K figure 3
- BiPRO whey protein isolate (figure 4) at doses of 30, 75, or 150 mg/kg.
- a suitable regimen for treatment with the noted hydrolysate 601 will comprise oral administration of the above doses of 75 to 150 mg/kg at intervals of from 2 to 24 hours. More broadly, the dosages and intervals could be increased or decreased by from 50 to 500 percent, as might be indicated by treatment over time.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Zoology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Wood Science & Technology (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Food Science & Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nutrition Science (AREA)
- Genetics & Genomics (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Polymers & Plastics (AREA)
- Vascular Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US702068 | 1991-05-17 | ||
US09/567,283 US6630320B1 (en) | 2000-05-08 | 2000-05-08 | Treatment of hypertension in mammals with hydrolyzed whey proteins |
US567283 | 2000-05-08 | ||
US09/702,068 US6998259B1 (en) | 1999-05-20 | 2000-10-30 | Enzymatic treatment of whey proteins for the production of antihypertensive peptides and the resulting products |
PCT/US2001/014797 WO2001085984A1 (en) | 2000-05-08 | 2001-05-08 | Enzymatic treatment of whey proteins for the production of antihypertensive peptides, the resulting products and treatment of hypertension in mammals |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1287159A1 true EP1287159A1 (en) | 2003-03-05 |
EP1287159A4 EP1287159A4 (en) | 2005-02-09 |
Family
ID=27074429
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01933181A Withdrawn EP1287159A4 (en) | 2000-05-08 | 2001-05-08 | Enzymatic treatment of whey proteins for the production of antihypertensive peptides, the resulting products and treatment of hypertension in mammals |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1287159A4 (en) |
JP (1) | JP2004519204A (en) |
AU (1) | AU2001259625A1 (en) |
CA (1) | CA2415688A1 (en) |
MX (1) | MXPA02011018A (en) |
NZ (1) | NZ523036A (en) |
WO (1) | WO2001085984A1 (en) |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69920219T2 (en) | 1998-06-17 | 2005-09-22 | New Zealand Dairy Board | BIOACTIVE WHEY BULB HYDROLYSATES |
ATE349918T1 (en) | 2002-07-01 | 2007-01-15 | Unilever Nv | COMPOSITION THAT CAUSES A FEELING OF SATISFACTION |
EP1466529A1 (en) | 2003-04-07 | 2004-10-13 | Chr. Hansen A/S | Composition with heart rate reducing properties |
US7718171B2 (en) | 2003-04-07 | 2010-05-18 | Chr. Hansen A/S | Reducing heart rate in mammals using milk derived fermentation products produced using Lactobacillus helveticus |
JP2006525260A (en) * | 2003-05-05 | 2006-11-09 | ユニリーバー・ナームローゼ・ベンノートシヤープ | Peptide having ACE inhibitory effect |
ES2253036B1 (en) | 2003-07-31 | 2007-07-16 | Consejo Sup. Investig. Cientificas | BIOACTIVE PEPTIDES DERIVED FROM PROTEINS OF THE EGG CLEAR BY ENZYMATIC HYDROLYSIS. |
RU2006125434A (en) * | 2003-12-15 | 2008-01-27 | Юнилевер Н.В. (Nl) | PEPTIDES WITH ACE-INHIBITING ACTION |
EP1685764A1 (en) | 2005-01-27 | 2006-08-02 | Globus Egg Sciences B.V. | Anti-hypertensive functional food products |
NL1026931C2 (en) * | 2004-08-31 | 2006-03-01 | Friesland Brands Bv | ACE-inhibiting whey hydrolysates. |
DK1796480T3 (en) | 2004-09-03 | 2012-02-13 | Chr Hansen As | Fermented milk proteins comprising receptor ligand and uses thereof |
FR2876389B1 (en) * | 2004-10-13 | 2007-05-25 | Viridis Sa | HYDROLYSATS OF WHITE PROTEINS FROM LUZERNE |
ES2319475B1 (en) | 2005-06-08 | 2010-02-16 | Consejo Superior Investig. Cientificas | BIOACTIVE PEPTIDES IDENTIFIED IN ENZYMATIC HYDROLYZES OF LACTEE CASEINS AND PROCEDURE OF OBTAINING. |
DE102008032828A1 (en) | 2008-07-02 | 2010-01-07 | Technische Universität Dresden | Tryptophan-containing peptides from alpha-lactalbumin with hypotensive and vasoprotective action for biofunctional foods |
EA039803B1 (en) | 2013-04-25 | 2022-03-15 | Янссен Вэксинс Энд Превеншн Б.В. | Stabilized soluble prefusion rsv f polypeptides |
EA035909B1 (en) | 2015-07-07 | 2020-08-31 | Янссен Вэксинс Энд Превеншн Б.В. | Stabilized soluble pre-fusion rsv f polypeptides |
PL3319633T3 (en) | 2015-07-07 | 2021-04-19 | Janssen Vaccines & Prevention B.V. | Vaccine against rsv |
EA201892250A1 (en) | 2016-04-05 | 2019-03-29 | Янссен Вэксинс Энд Превеншн Б.В. | VACCINE AGAINST RSV |
JP7088841B2 (en) | 2016-04-05 | 2022-06-21 | ヤンセン ファッシンズ アンド プリベンション ベーフェー | Stabilized soluble pre-fusion RSVF protein |
EP3464331B1 (en) | 2016-05-30 | 2020-10-28 | Janssen Vaccines & Prevention B.V. | Stabilized pre-fusion rsv f proteins |
EP3624844A1 (en) | 2017-05-17 | 2020-03-25 | Janssen Vaccines & Prevention B.V. | Methods and compositions for inducing protective immunity against rsv infection |
WO2018210871A1 (en) | 2017-05-17 | 2018-11-22 | Janssen Vaccines & Prevention B.V. | Methods and compositions for inducing protective immunity against rsv infection |
SG11202001458SA (en) | 2017-09-15 | 2020-03-30 | Janssen Vaccines & Prevention Bv | Method for the safe induction of immunity against rsv |
Citations (2)
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---|---|---|---|---|
EP0671126A1 (en) * | 1992-11-30 | 1995-09-13 | Morinaga Milk Industry Co., Ltd. | Low-phosphorus whey protein, process for producing the same, hydrolyzate of purified low-phosphorus whey protein, and process for producing the same |
EP0821968A2 (en) * | 1996-08-02 | 1998-02-04 | The Calpis Food Industry Co., Ltd. | Antihypertensive agent and method for preparing same |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3149199B2 (en) * | 1991-03-12 | 2001-03-26 | カルピス株式会社 | Angiotensin converting enzyme inhibitory peptide |
JP3091772B2 (en) * | 1991-03-12 | 2000-09-25 | カルピス株式会社 | Angiotensin converting enzyme inhibiting peptide composition |
JPH06345664A (en) * | 1993-06-11 | 1994-12-20 | Takako Tomita | New composition for suppressing elevation of blood pressure |
JPH1033115A (en) * | 1996-07-24 | 1998-02-10 | Nouchikusangiyou Shinko Jigyodan | Whey beverage and its production |
-
2001
- 2001-05-08 CA CA002415688A patent/CA2415688A1/en not_active Abandoned
- 2001-05-08 NZ NZ523036A patent/NZ523036A/en unknown
- 2001-05-08 JP JP2001582572A patent/JP2004519204A/en active Pending
- 2001-05-08 WO PCT/US2001/014797 patent/WO2001085984A1/en not_active Application Discontinuation
- 2001-05-08 EP EP01933181A patent/EP1287159A4/en not_active Withdrawn
- 2001-05-08 AU AU2001259625A patent/AU2001259625A1/en not_active Abandoned
- 2001-05-08 MX MXPA02011018A patent/MXPA02011018A/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0671126A1 (en) * | 1992-11-30 | 1995-09-13 | Morinaga Milk Industry Co., Ltd. | Low-phosphorus whey protein, process for producing the same, hydrolyzate of purified low-phosphorus whey protein, and process for producing the same |
EP0821968A2 (en) * | 1996-08-02 | 1998-02-04 | The Calpis Food Industry Co., Ltd. | Antihypertensive agent and method for preparing same |
Non-Patent Citations (7)
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DATABASE WPI Section Ch, Week 199510 Derwent Publications Ltd., London, GB; Class B04, AN 1995-070230 XP002311025 & JP 06 345664 A (TOMITA T) 20 December 1994 (1994-12-20) * |
DATABASE WPI Section Ch, Week 199816 Derwent Publications Ltd., London, GB; Class B04, AN 1998-172040 XP002311024 & JP 10 033115 A (NOCHIKU SANGYO SHINKO JIGYODAN) 10 February 1998 (1998-02-10) * |
MULLALLY MARGARET M ET AL: "Angiotensin-I-converting enzyme inhibitory activities of gastric and pancreatic proteinase digests of whey proteins" INTERNATIONAL DAIRY JOURNAL, vol. 7, no. 5, May 1997 (1997-05), pages 299-303, XP000853725 ISSN: 0958-6946 * |
PIHLANTO-LEPPALA ANNE ET AL: "Angiotensin I converting enzyme inhibitory peptides derived from bovine milk proteins" INTERNATIONAL DAIRY JOURNAL, vol. 8, no. 4, April 1998 (1998-04), pages 325-331, XP000853723 ISSN: 0958-6946 * |
See also references of WO0185984A1 * |
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CA2415688A1 (en) | 2001-11-15 |
EP1287159A4 (en) | 2005-02-09 |
JP2004519204A (en) | 2004-07-02 |
MXPA02011018A (en) | 2004-08-19 |
NZ523036A (en) | 2004-04-30 |
AU2001259625A1 (en) | 2001-11-20 |
WO2001085984A1 (en) | 2001-11-15 |
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