WO2011102310A1 - Agent de réduction du niveau d'acide urique dans le sang - Google Patents

Agent de réduction du niveau d'acide urique dans le sang Download PDF

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WO2011102310A1
WO2011102310A1 PCT/JP2011/053004 JP2011053004W WO2011102310A1 WO 2011102310 A1 WO2011102310 A1 WO 2011102310A1 JP 2011053004 W JP2011053004 W JP 2011053004W WO 2011102310 A1 WO2011102310 A1 WO 2011102310A1
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Prior art keywords
cheese
protease
degradation product
enzyme
uric acid
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PCT/JP2011/053004
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English (en)
Japanese (ja)
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真 山口
成臣 山田
勝幸 内田
裕之 伊藤
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株式会社明治
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Priority to CN201180009502.5A priority Critical patent/CN102753190B/zh
Priority to IN6608DEN2012 priority patent/IN2012DN06608A/en
Priority to JP2012500581A priority patent/JP5752108B2/ja
Publication of WO2011102310A1 publication Critical patent/WO2011102310A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to a blood uric acid level lowering agent useful for the prevention and treatment of hyperuricemia.
  • Hyperuricemia is a state in which the blood uric acid concentration (blood uric acid level) is high.
  • the blood uric acid concentration abnormally increases, and inflammation that is caused by crystallization of those that could not be dissolved in the blood locally occurs in the body.
  • gout attacks gout arthritis
  • gout nodules when accumulated under the skin
  • renal tubules and renal interstitium causess kidney damage.
  • Non-Patent Document 1 reports that hyperuricemia itself is an independent risk factor for cardiovascular disorders have increased (see Non-Patent Document 1), and gout patients often have arteriosclerotic patients. This is a fact that has been well known since ancient times (for example, see Non-Patent Document 2). It has also been found that there is a very good correlation between the blood uric acid level and risk factors for metabolic syndrome (see Non-Patent Document 3).
  • drugs that lower uric acid levels include drugs that promote excretion of uric acid, such as benzbromarone, and drugs that inhibit uric acid synthesis, such as allopurinol, and are prescribed according to the type of hyperuricemia in patients. Yes. These drugs currently prescribed are extremely excellent as a control agent for uric acid level, and the serum uric acid level can be returned to normal by taking the drug. However, since hyperuricemia itself is a very difficult disease to cure, if you stop taking the medicine, it will return to the state of hyperuricemia again.
  • uric acid excretion enhancer increases the ability to excrete uric acid from the kidney by suppressing the physiological reabsorption of uric acid in the tubules, and lowers the serum uric acid level.
  • side effects include gastrointestinal disorders, headache, and lightheadedness.
  • severe liver damage may occur when administered to idiosyncratic patients (Non-patent Document 4).
  • allopurinol As a uric acid production inhibitor, allopurinol has been introduced and widely used for the treatment of gout. This allopurinol inhibits xanthine oxidase, which acts at the final stage of the purine metabolic pathway, and reduces the amount of uric acid excreted in urine with a decrease in serum uric acid level.
  • xanthine oxidase acts at the final stage of the purine metabolic pathway
  • oxypurinol accumulates in the blood in a large amount and may cause a fatal poisoning syndrome (Non-patent Document 4).
  • a therapeutic agent for hyperuricemia has been desired that can be safely and comfortably taken for a long period of time, for example, a product derived from a natural product that has been ingested daily since ancient times.
  • chitosan Patent Document 1
  • water-soluble dietary fiber Patent Document 2
  • activated carbon Patent Document 3
  • ⁇ -polylysine can be used as substances having the action of regulating the absorption of purines that cause hyperuricemia.
  • cheese enzyme degradation products and peptides found from cheese enzyme degradation products include angiotensin converting enzyme inhibitory action (Patent Documents 5, 6, and 7), anti-inflammatory action (Patent Document 8), and gastrointestinal ulcer treatment effect ( Patent Document 9) is disclosed.
  • Patent Documents 5, 6, and 7 angiotensin converting enzyme inhibitory action
  • Patent Document 8 anti-inflammatory action
  • Patent Document 9 gastrointestinal ulcer treatment effect
  • JP 2001-163788 A Japanese Patent Laid-Open No. 2005-047828 JP 2005-187405 A JP 2006-001898 A WO2004 / 032642 WO2004 / 047543 WO2005 / 061529 WO2007 / 080962 JP 2009-120519 A
  • An object of the present invention is to provide a blood uric acid level-lowering agent that is derived from a natural product and can be taken continuously for a long period of time.
  • a cheese enzyme degradation product is It has been found that it has an excellent blood uric acid level lowering action and active oxygen absorption ability and is useful as a blood uric acid level lowering agent, and thus a prophylactic and therapeutic agent for hyperuricemia.
  • the present invention (1) A blood uric acid level-lowering agent comprising a cheese enzyme degradation product as an active ingredient; (2) The blood uric acid level lowering agent according to (1), wherein the cheese enzyme degradation product is a cheese enzyme degradation product having active oxygen absorption ability; (3) The blood uric acid level-lowering agent according to (2), wherein the content of the enzyme degradation product of cheese is an amount showing an active oxygen absorption capacity of 50 ⁇ M Trolox equivalent or more as a daily dose; (4) The blood uric acid level-lowering agent according to any one of (1) to (3), wherein the cheese enzyme degradation product is a degradation product obtained by treating cheese with lipase and protease; (5) The blood uric acid level-lowering agent according to (4), wherein the protease is at least two kinds selected from endo-type protease, exo-type protease, exo-type peptidase / endo-type protease complex enzyme, and protease / peptidase complex enzyme ; (6)
  • lactis Lactococcus lactis subsp. Cremoris, and Lactococcus lactis subsp. the method according to (37), which is lactis biovar diacylactis; (39) The method according to (29), wherein substantially only a cheese enzyme degradation product is administered as an active ingredient; (40) The method of (39), wherein only the cheese enzyme degradation product and the formulation adjuvant are administered; (41) An active oxygen absorption method comprising administering a cheese enzyme degradation product; (42) The method according to (41), wherein substantially only a cheese enzyme degradation product is administered as an active ingredient, Is to provide. Moreover, this invention provides use of the cheese enzyme degradation product for blood uric acid value lowering agent or active enzyme absorber manufacture.
  • the blood uric acid level-lowering agent of the present invention has an excellent blood uric acid level-lowering action, has a good flavor, and is highly safe. It is possible to control the blood uric acid level for a long period of time, and is useful for the prevention and treatment of hyperuricemia and gout.
  • the active ingredient of the blood uric acid level-lowering agent and active oxygen absorber of the present invention is a cheese enzyme degradation product.
  • the cheese enzyme degradation product is obtained by causing an enzyme selected from lipase and protease to act on cheese and degrading fat and protein in the cheese. More specifically, ripening is promoted by adding lipase, microorganisms such as acidic and neutral protease, and various animal-derived enzymes to green cheese, natural cheese after ripening or during ripening, and processed cheese.
  • the cheese used as the raw material for the enzyme degradation product of cheese includes various cheeses including green cheese, and may be either natural cheese or processed cheese.
  • the raw material of cheese is not particularly limited, and it may be made from human milk as well as milk from various mammals such as sheep and goats as well as cow's milk.
  • the manufacturing method is not limited, and it is a cheese obtained using raw milk or powdered milk as a raw material, and various types such as fermented or ripened by various microorganisms such as lactic acid bacteria and mold as well as unripe cheese Cheese is available. For example, gouda cheese, cheddar cheese, skim cheese or the like can be used, but is not limited to this example.
  • enzymes that decompose fats and proteins in cheese such as lipase and protease are used, but the type is not limited.
  • lipase not only triacylglycerol lipase present in gastric juice but also various lipases isolated from human or mammalian body fluids, tissues thereof, insects, plants, bacteria, and the like are used.
  • protease various proteases isolated from human or mammalian body fluids, tissues, insects, plants, bacteria, etc., such as pepsin, trypsin, and chymotrypsin secreted in the digestive tract are used.
  • proteases There are two types of proteases, endo and exo, due to differences in the cleavage site of the amino acid sequence.
  • the end type cleaves from the middle of the protein
  • the exo type cleaves amino acids one by one from the C-terminal or N-terminal.
  • the optimum pH, temperature, protein resolution, and amino acid cleavage site differ depending on the type of protease. For this reason, when treating with a protease, it is preferable to combine two or more, preferably three or more, proteases having different endo-type, exo-type, protein resolution, optimum pH and optimum temperature.
  • a combination of two or more, particularly three or more selected from endo-type protease, exo-type protease, exo-type peptidase / endo-type protease complex enzyme, and protease / peptidase complex enzyme it is preferable to use a combination of two or more selected from endo-type proteases and protease / peptidase complex enzymes, particularly three or more.
  • endo-type protease examples include trypsin (CAS No. 9002-07-7, EC 3.4.21.4, bovine pancreas-derived, Product No. T8802, SIGMA), pepsin (CAS No. 9001-75-6, EC 3.4.4.1, derived from porcine gastric mucosa, SIGMA), chymotrypsin (Novo, Boehringer), Proleather FG-F (from Bacillus subtilis; Amano Enzyme), biolase (from Bacillus subtilis, Nagase Sangyo), papain W-40 (Amano Enzyme), chymosin (from EC 3.4.23.4, Maxiren, modified yeast Kluyveromyces lactis, GIST-BROCADES NV), Alcala eR (Bacillus licheniformis derived from, Nobosha), Molsin F (Aspergillus saitoi origin, Kikkoman Corporation).
  • trypsin CAS No. 9002-07-7
  • Esperase from Bacillus lentus, Novo
  • Neurase R from Bacillus subtilis, Novo
  • Protamex from bacteria, Novo
  • PTN6.0S pig pancreatic trypsin, Novo
  • protease S "Amano” G from Bacillus stearothermophilus, Amano enzyme
  • exo-type proteases examples include pancreatic carboxypeptidase and small intestinal brush border aminopeptidase.
  • Examples of the endo-type / exo-type protease complex enzyme include neurolase A (derived from Aspergillus niger, Amano Enzyme), and examples of the exo-type peptidase / endo-type protease complex enzyme include flavorzyme (derived from Aspergillus oryzae, Novo). .
  • protease / peptidase complex enzyme for example, protease A “Amano” SD (derived from Aspergillus oryzae, Amano Enzyme), equine enzyme G (peptidases and proteases, derived from Aspergillus oryzae, Amano Enzyme) can be used.
  • protease A “Amano” SD derived from Aspergillus oryzae, Amano Enzyme
  • equine enzyme G peptidases and proteases, derived from Aspergillus oryzae, Amano Enzyme
  • two or more types selected from endo-type proteases and protease / peptidase complex enzymes it is preferable to use two or more types selected from endo-type proteases and protease / peptidase complex enzymes, and more than two types, particularly three or more types, may be used in combination of endo-type proteases and protease / peptidase complex enzymes. Is preferred. More specifically, it is particularly preferable to use a combination of two or more, particularly three or more selected from protease A “Amano” SD, morsin, neurase and equinezyme G.
  • lipases examples include Sumiteam NLS (derived from Aspergillus niger, Shin Nippon Chemical Industry), Lipase A “Amano” 6 (derived from Aspergillus niger, Amano Enzyme), Lipase R “Amano” (derived from Penicillium roqueforti, Amano Enzyme “Renno Enzyme”) Trick esterases "(derived from cattle, manufactured by Lenco New Zealand) are mentioned, but pregastric esterases derived from cattle are particularly preferred.
  • the enzyme treatment conditions are not particularly limited as long as the enzyme is not deactivated. Optimum conditions for the enzyme to be used are preferable from the viewpoint of promoting decomposition, but depending on the effect of the cheese to be processed, the enzyme to be used, and the target cheese enzyme degradation product, the pH and reaction temperature during the reaction, the enzyme and the substrate (Cheese) concentration and reaction time are adjusted. Moreover, when processing using 2 or more types of enzymes, you may process with all the enzymes at once, and can also process sequentially with each enzyme.
  • the reaction temperature for the enzyme treatment in the present invention is usually 20 to 60 ° C., preferably 30 to 50 ° C.
  • the reaction time for the enzyme treatment in the present invention is usually about 1 to 8 days, preferably about 2 to 4 days.
  • the amount of enzyme added varies depending on the titer of the enzyme used, but is usually 0.01% or more, preferably 0.1 to 10% per substrate (cheese).
  • Protease treatment can be accompanied by lactic acid bacteria fermentation.
  • Lactococcus lactic acid bacteria can be preferably used.
  • Specific examples of bacterial species belonging to Lactococcus lactic acid bacteria include Lactococcus garvieae, Lactococcus lactis, Lactococcus lactis subspice lactis subsp. Lactococcus lactis subsp. Lactococcus lactis subsp. Lactis biovar diacetylactis, Lactococcus pistium, Lactococcus plantarum and Lactococcus rafinolactol Not. In particular, Lactococcus lactis subsp.
  • Lactic acid fermentation makes it possible to maintain the pH in the enzyme treatment step on the acidic side. Moreover, it may replace with lactic acid fermentation and may adjust pH using the organic acid normally used for a pharmaceutical and foodstuffs, such as a citric acid, gluconic acid, hydrochloric acid, acetic acid, lactic acid, phosphoric acid, and an inorganic acid.
  • the pH should be 3.5 to 6.0, preferably 4.0 to 5.6.
  • the cheese enzyme degradation product used in the present invention is particularly preferably a degradation product treated with lipase, protease and lactic acid bacteria.
  • the reaction temperature for these treatments is usually 20 to 60 ° C., preferably 30 to 50 ° C.
  • the reaction time for these treatments is generally about 1 to 8 days, preferably about 2 to 4 days.
  • the amount of enzyme added varies depending on the titer of the enzyme used, but is usually 0.01% or more, preferably 0.1 to 10% per substrate (cheese).
  • the obtained cheese enzyme degradation product has an excellent blood uric acid level lowering action as shown in the Examples described later, and is useful as a prophylactic / therapeutic agent for hyperuricemia and as a prophylactic / therapeutic agent for gout.
  • the cheese enzyme decomposition product has an excellent active oxygen absorption ability and is useful as an active oxygen absorbent.
  • the excellent blood uric acid level lowering action of the enzyme degradation product of cheese is considered to involve such active oxygen absorption ability, that is, antioxidant ability.
  • the cheese enzyme degradation product can be used alone, but is often provided as various compositions together with a carrier that is substantially non-toxic.
  • substantially non-toxic means that undesirable effects are not exerted even when ingested by humans or animals, and there is little risk of reducing the action of the cheese enzyme degradation product, which is pharmaceutically or hygienically acceptable.
  • Various carriers are used. Examples of such carriers (hereinafter also referred to as formulation adjuvants) include various starches such as corn starch, lactose, crystalline cellulose, dextrose, mannitol, sucrose, sorbitol, gelatin, gum arabic, dicalcium phosphate, tricalcium phosphate.
  • Excipients such as monocalcium phosphate, sodium phosphate, sodium carbonate, lubricants such as stearic acid, zinc stearate, calcium stearate or magnesium stearate, binders such as sucrose, polyethylene glycol, polyvinylpyrrolidone, benzoic PH adjusters such as acids, citric acid, tartaric acid, succinic acid, phosphoric acid, hydrochloric acid, and other suitable organic acids and inorganic acids or alkali metal (for example, sodium or potassium) salts, flavoring agents, flavoring agents, coloring agents, Disintegrant, solubilizer, suspension Agents, coating agents and the like.
  • binders such as sucrose, polyethylene glycol, polyvinylpyrrolidone, benzoic PH adjusters such as acids, citric acid, tartaric acid, succinic acid, phosphoric acid, hydrochloric acid, and other suitable organic acids and inorganic acids or alkali metal (for example, sodium or potassium) salts,
  • the cheese enzyme degradation product should be provided as a pharmaceutical composition to be administered orally, such as powders, granules, fine granules, dry syrups, tablets, capsules, liquids, drinks, etc. according to conventional methods. Can do. Further, other components such as an appropriate amount of vitamins, minerals, sugars, amino acids, peptides may be added. Further, the composition of the present invention is preferably a composition containing substantially only a cheese enzyme degradation product as an active ingredient, and more specifically, a composition containing only a cheese enzyme degradation product and a formulation adjuvant. It may be.
  • the blood uric acid level-lowering agent of the present invention may be administered simultaneously or as a mixture with other active ingredients, for example, a composition having a blood uric acid level-lowering action different from the cheese enzyme degradation product.
  • a composition having a blood uric acid level lowering action having a different action mechanism includes, for example, chitosan, water-soluble dietary fiber, activated carbon that adsorbs nucleic acid ingested as food and inhibits nucleic acid from being absorbed from the intestinal tract , ⁇ -polylysine, Atlantic nettle to increase urine volume and promote excretion of uric acid, celery seed extract, lactic acid bacteria to reduce serum uric acid level by degrading purine taken from diet and reducing absorption into the body Anserine, which increases the amount of purine recycle enzyme and suppresses the production of uric acid too much, can be mentioned.
  • propolis having xanthine oxidase inhibitory activity Iris genus, cinnamon, cedron, Iwabenkei, Benikeiten, Galangal, Nutmeg, Hypericum perforatum, and Quercetin.
  • the blood uric acid level-lowering agent of the present invention can be used not only in pharmaceuticals but also in the form of food and drink.
  • prevention or treatment of hyperuricemia is expected by taking it as a special-purpose food such as a food for specified health use or a nutritional functional food.
  • the form thereof is not limited, such as liquid, paste, solid, powder, and various foods (milk, processed milk, milk drink, soft drink, fermented milk, yogurt, cheese, bread, biscuits , Crackers, pizza crusts, ice creams, candy, formula milk, liquid foods, foods for the sick, foods for infants, foods such as infant formula, nutritional foods, dietary supplements, supplements, frozen foods, processed foods, etc. And may be ingested.
  • the food and drink according to the present invention are mixed with water, protein, carbohydrates, lipids, vitamins, minerals, organic acids and inorganic acids, organic bases and inorganic bases, fruit juices, flavors, thickeners, etc. in cheese enzyme degradation products.
  • the protein include whole milk powder, skim milk powder, partially skimmed milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, ⁇ -casein, ⁇ -casein, ⁇ -casein, ⁇ -lactoglobulin , ⁇ -lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein and other animal and vegetable proteins and their degradation products.
  • saccharide examples include saccharides such as sucrose and maltose, processed starch (in addition to dextrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like.
  • lipids include animal oils such as lard and fish oil, fractionated oils, hydrogenated oil, transesterified oil, palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, Examples include vegetable oils such as hydrogenated oils and transesterified oils.
  • vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline.
  • folic acid examples include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, and whey mineral.
  • the organic acid examples include malic acid, citric acid, lactic acid, tartaric acid, and examples of the inorganic acid include hydrochloric acid and phosphoric acid.
  • the thickener include agar, gelatin, carrageenan, guar gum, xanthan gum and the like.
  • milk-derived components such as butter, whey minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipids and lactose, peptides such as casein phosphopeptides, and amino acids such as arginine and lysine. Also good.
  • these components may be either synthetic products or products derived from natural products, or foods containing a large amount of these may be used as raw materials. These components can be used in combination of two or more.
  • the blood uric acid level-lowering agent of the present invention is administered to a human or animal that exhibits hyperuricemia or a human or animal that is predicted to increase in uric acid level, and contains an effective amount of a cheese enzyme degradation product.
  • the dosage is generally 0.01 mg / kg to 2000 mg / kg, preferably 1 mg / kg to 1000 mg / kg, more preferably 10 mg / kg to 500 mg / kg as a cheese enzyme degradation product per day. This dose is appropriately changed according to the age, weight, symptom and target site of the human or animal to be administered, and the type and amount of food to be ingested.
  • the cheese enzyme degradation product has an active oxygen absorption action, and therefore, the dose can be limited based on the active oxygen absorption capacity (ORAC: Oxygen Radial Absorbance Capacity).
  • Active oxygen absorption capacity is an index of antioxidant power developed by the US Department of Agriculture, National Institute for Aging. When a certain reactive oxygen species is generated in a system in which a fluorescent substance is present, the fluorescence intensity of the fluorescent substance decomposed thereby is measured, and when a fluorescence intensity curve that decreases with time is drawn, this reaction system is antioxidant When the substance coexists, the rate of decrease in the fluorescence intensity of the fluorescent substance is delayed.
  • the difference (net AUC) between the area under the curve (AUC: Area Under the Curve) of the fluorescence intensity in the presence of the specimen (or standard substance) and the AUC in the absence (blank) is calculated.
  • AUC Area Under the Curve
  • a relative value with respect to the net AUC of a standard substance having a known concentration is determined. Based on the relative value, it is converted into the concentration of Trolox to obtain the antioxidant power of the specimen.
  • the dose of the blood uric acid level-lowering agent of the present invention is an amount that exhibits an active oxygen absorption capacity of 50 ⁇ M Trolox equivalent or more, preferably 100 ⁇ M Trolox equivalent or more, more preferably 1000 ⁇ M Trolox equivalent or more as a daily dose. be able to.
  • Example 1 (Preparation of starter culture) A 20 w skim milk powder was dissolved in 200 ml of distilled water and sterilized to prepare a 10 w / v% skim milk medium. This was inoculated with about 0.1 g of three starter bacteria (Lactococcus lactis subsp. Lactis, Lactococcus lactis subsp. Cremoris, Lactococcus lactis subsp. Lactis biovar diactylactis) at 37 ° C. for 16 hours.
  • three starter bacteria Lactis subsp. Lactis, Lactococcus lactis subsp. Cremoris, Lactococcus lactis subsp. Lactis biovar diactylactis
  • Protease A “Amano” SD Aspergillus oryzae-derived protease, Amano Enzyme
  • lipase pregastric esterase, lotus root
  • the pH was adjusted to 4.1 with citric acid
  • Morsine F acidic protease derived from Aspergillus saitoi, manufactured by Kikkoman
  • Umamizyme G protease derived from Aspergillus orizae, manufactured by Amano Enzyme
  • Decomposition was performed by shaking at 0 ° C. Four days later, the pH was adjusted to 5.0 with sodium hydroxide, and the enzyme was deactivated by heating at 110 ° C. for 15 minutes to obtain a cheese enzyme decomposition product.
  • the compounding amount per 100 g of domestic gouda cheese is as follows. [Composition table] 100g domestic gouda cheese Sterile water 50.5g Starter culture solution 18g Sodium chloride 2.2g Protease A “Amano” SD 0.6g Lipase 0.2g Citric acid 3.5g Morsin F 0.2g Ummamizyme G 0.3g Sodium hydroxide 1.5g
  • Example 2 Preparation of cheese enzyme degradation product 2 After adding starter culture solution and sodium chloride prepared in Example 1 to domestic cheddar cheese added with sterilized water and stirring, protease A “Amano” SD (derived from Aspergillus oryzae, Amano Enzyme), lipase (pregastric) Esterase (manufactured by Lenco New Zealand) was added, and the mixture was shaken at 34 ° C. for decomposition. 48 hours later, the pH was adjusted to 4.1 with citric acid, and Neurase R (from Bacillus subtilis, Novo) and Umamizyme G (Aspergillus oryzae-derived protease, Amano Enzyme) were added, respectively. Decomposition was performed by shaking.
  • protease A “Amano” SD derived from Aspergillus oryzae, Amano Enzyme
  • lipase pregastric Esterase
  • the blending amount per 100 g of domestic cheddar cheese is as follows. [Composition table] Domestic cheddar cheese 100g Sterile water 50.5g Starter culture solution 20g Sodium chloride 0.3g Protease A “Amano” SD 0.6g Lipase 0.2g Citric acid 3.3g Neurase R 0.2g Ummamizyme G 0.3g Sodium hydroxide 1.5g
  • Example 3 Preparation of cheese enzyme degradation product 3) Danish skim cheese (ripening period 6 months) with distilled water added to the starter culture solution and sodium chloride prepared in Example 1, and after stirring, protease S “Amano” G (from Bacillus stearothermophilus, Amano Enzyme) Was added and shaken at 34 ° C. for decomposition. 48 hours later, the pH was adjusted to 4.1 with citric acid, and Neurase A (derived from Aspergillus niger, Amano Enzyme) and Umamizyme G (Aspergillus oryzae derived protease, Amano Enzyme) were added and shaken at 34 ° C. The decomposition was performed.
  • Danish skim cheese 100g 74g of distilled water Starter culture solution 20g Sodium chloride 0.2g Protease S "Amano" G 0.6g Citric acid 3.2g Newase A 0.3g Ummamizyme G 0.3g Sodium hydroxide 1.4g
  • Example 4 Effect of cheese enzyme degradation product on oxonate-induced hyperuricemia (animal experiment) Rats (Wistar, male, 7 weeks old, SLC Japan) were purchased and fed AIN-93G powder during the habituation period. After the acclimation period, blood was collected in the morning and the uric acid level was measured (day 0). Based on this value, it was divided into a total of 5 groups (6 mice per group): negative group, control group, test 1 group, test 2 group, and test 3 group.
  • As the cheese enzyme degradation product one prepared according to the preparation of the cheese enzyme degradation product described in Example 1 was used.
  • AIN-93G is a standard purified feed composition for nutritional research for mice and rats published in 1993 by the American Institute of Nutrition.
  • Negative group AIN-93G feeding, water for injection (10 mL / kg)
  • Control group Potassium oxonate 2.5% mixed AIN-93G feeding, water for injection (10 mL / kg)
  • Test group 1 Feeding potassium oxonate 2.5% AIN-93G, cheese enzyme degradation product (300 mg / kg, 10 mL / kg)
  • Test group 2 Feeding AIN-93G with potassium oxonate 2.5%, cheese enzyme degradation product (1 g / kg, 10 mL / kg)
  • Test group 3 Feeding with 2.5% potassium oxonate mixed AIN-93G, enzyme degradation product of cheese (3 g / kg, 10 mL / kg)
  • the measurement of drinking water is performed on the 0th day (set value), 2nd day (residual value, set value), 6th day (residual value, set value), 8th day (residual value, set value), 12th day ( Residual value, set value), 15th day (residual value, set value), 19th day (residual value, set value), and 22nd day (residual value).
  • Example 5 Measurement of active oxygen absorption capacity of cheese enzymatic degradation product ORAC (Oxygen Radical Absorbance Capacity) was established in 1992 by the United States Department of Agriculture (USDA) and the National Institute on Aging. It is a new index of antioxidant power developed by researchers and is an excellent method for analyzing antioxidant power in foods. Currently, it has the most extensive database of food materials such as vegetables and fruits and processed foods. It is an analytical method.
  • ORAC Oxygen Radical Absorbance Capacity
  • the cheese enzyme degradation product used as a sample was prepared by adding an 8M urea solution to 30 mg / mL, and then the cheese enzyme degradation product was uniformly dispersed by ultrasonic treatment. A 10-fold dilution with 75 mM potassium phosphate buffer (pH 7.4) was performed twice. A labeling substance (Fluorescein: 3 ′, 6′-dihydroxyspiro [isobenzofuran-1 [3H], 9 ′ [9H] -xanthen] -3-one) is added with 75 mM potassium phosphate buffer (pH 7.4), and 117 nM Fluorescein Was prepared.
  • 75 mM potassium phosphate buffer (pH 7.4) was added to a standard substance (Trolox TM : 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) to prepare 50 ⁇ M Trolox.
  • a radical generator (AAPH: 2,2′-azo-bis (2-amidinopropane) dihydrochloride) was added with 75 mM potassium phosphate buffer (pH 7.4) to prepare 40 mM AAPH.
  • 20 ⁇ l of sample (or 50 ⁇ M Trolox of standard substance) and 120 ⁇ l of 117 nM Fluorescein were added and pre-incubated at 37 ° C. for 15 minutes. Thereafter, 60 ⁇ l of 40 mM AAPH as a radical generator was added, and the fluorescence intensity was measured every minute at an excitation wavelength of 485 nm and a fluorescence wavelength of 520 nm.
  • the active oxygen absorption capacity of the cheese enzymatic degradation product was 189.5 ⁇ 11.0 ⁇ M Trolox equivalent / gram.
  • Example 6 Production of fermented milk (Production Example 1 of fermented milk) Plain yogurt was dissolved in a cheese enzyme digest (Meiji cheese taste concentrate G (Gouda type)), L. bulgaricus JCM1002 T , S. prepared by thermophilus ATCC 19258. First, using a skim milk powder 10% medium, L. bulgaricus JCM1002 T , S. A bulk starter of thermophilus ATCC 19258 was prepared. Next, the cheese enzyme degradation product was mixed with yoghurt mix (non-fat milk solids (SNF): 9.5%, fat (FAT): 3.0%), and heat-treated at 95 ° C for 5 minutes. In the mix after this heat treatment, L.
  • SNF non-fat milk solids
  • FAT fat
  • bulgaricus JCM1002T Thermophilus ATCC 19258 starter was inoculated at 1% each and fermented at 43 ° C. for 4 hours to obtain plain yogurt.
  • the plain yogurt was cooled in a refrigerator (5 ° C.), and then the flavor and physical properties were confirmed. At this time, both flavor and physical properties were good.
  • the cheese enzyme degradation product was mixed with yoghurt mix (non-fat milk solids (SNF): 9.5%, fat (FAT): 3.0%), and heat-treated at 95 ° C for 5 minutes.
  • SNF non-fat milk solids
  • FAT fat
  • L. bulgaricus JCM1002 T thermophilus ATCC 19258 starter 1% each
  • L.P. Gasseri OLL2959 starter was inoculated at 5% and fermented at 43 ° C. for 4 hours to obtain plain yogurt.
  • the plain yogurt was cooled in a refrigerator (5 ° C.), and then the flavor and physical properties were confirmed. At this time, both flavor and physical properties were good.
  • Example 8 Production of process cheese (production example of process cheese) New Zealand cheddar cheese was used as a raw material cheese, and an enzyme digestion product having an active oxygen absorption capacity of about 150 ⁇ M Trolox equivalent / g was added to prepare a processed cheese by the following production method.
  • the blending ratio is as follows.

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Abstract

La présente invention a pour objet un agent de réduction du niveau d'acide urique dans le sang, qui est dérivé d'une matière naturelle et qui peut être ingéré en continu pendant une longue période. L'agent de réduction du niveau d'acide urique dans le sang comprend un produit de décomposition enzymatique d'un fromage en tant que principe actif.
PCT/JP2011/053004 2010-02-16 2011-02-14 Agent de réduction du niveau d'acide urique dans le sang WO2011102310A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0641191A (ja) * 1992-03-04 1994-02-15 Calpis Food Ind Co Ltd:The ペプチド及びこれを含む生理活性剤
WO2004047543A1 (fr) * 2002-11-28 2004-06-10 Meiji Dairies Corporation Produits alimentaires fonctionnels et leur procede de preparation
WO2007080962A1 (fr) * 2006-01-13 2007-07-19 Meiji Dairies Corporation Composition anti-inflammatoire et procede de production de celle-ci
JP2009120519A (ja) * 2007-11-13 2009-06-04 Meiji Milk Prod Co Ltd 消化管潰瘍の予防又は治療剤

Family Cites Families (4)

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Publication number Priority date Publication date Assignee Title
JPS59113869A (ja) * 1982-12-21 1984-06-30 Snow Brand Milk Prod Co Ltd 風味の強いチ−ズフレ−バ−の生成方法
JPS61152235A (ja) * 1984-12-27 1986-07-10 Meiji Milk Prod Co Ltd チ−ズ味を有するマ−ガリン及びその製造法
JPH0642814B2 (ja) * 1990-07-31 1994-06-08 不二製油株式会社 チーズ類の製造方法
US8263144B2 (en) * 2005-11-17 2012-09-11 Kraft Foods Global Brands Llc Cheese flavor composition and process for making same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0641191A (ja) * 1992-03-04 1994-02-15 Calpis Food Ind Co Ltd:The ペプチド及びこれを含む生理活性剤
WO2004047543A1 (fr) * 2002-11-28 2004-06-10 Meiji Dairies Corporation Produits alimentaires fonctionnels et leur procede de preparation
WO2007080962A1 (fr) * 2006-01-13 2007-07-19 Meiji Dairies Corporation Composition anti-inflammatoire et procede de production de celle-ci
JP2009120519A (ja) * 2007-11-13 2009-06-04 Meiji Milk Prod Co Ltd 消化管潰瘍の予防又は治療剤

Non-Patent Citations (1)

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Title
MASAHIKO KATO ET AL.: "Ko-Nyosankessho no Yakubutsu Chiryo -Yakubutsu Sentaku to sono Tsukaikata", MEDICAL PRACTICE, vol. 20, no. 11, 2003, pages 1927 - 1933 *

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JP5752108B2 (ja) 2015-07-22

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