TW201735942A - Composition for inhibiting migration of endotoxin into blood - Google Patents

Abstract

The purpose of the present invention is to provide a composition for inhibiting the migration of endotoxin into blood. According to the present invention, a composition for inhibiting the migration of endotoxin into blood is provided, which contains a whey protein. The whey protein can be selected from the group consisting of [alpha]-lactalbumin, [beta]-lactoglobulin and lactoferrin. The composition according to the present invention may additionally contain a fermented milk protein.

Description

Composition for migration inhibition in endotoxin [Reference to related applications]

This case is for the benefit of the priority of the Japanese Patent Application 2016-10840 (application date: January 22, 2016) of the previous Japanese application, and the disclosure of the entire system is incorporated by reference into this specification.

The present invention relates to a blood migration inhibiting composition containing endotoxin of whey protein.

Endotoxin is a kind of bacterial toxin which is also called bacterial endotoxin or lipopolysaccharide, and is a cell wall component of Gram-negative bacteria such as Salmonella, Escherichia coli and Pseudomonas aeruginosa. Once these Gram-negative bacteria are destroyed, they will release the lipopolysaccharide (LPS), which is a constituent of their cell walls, and exert toxicity. It is known that the toxicity of endotoxin is weaker than exotoxin, but as soon as it enters the body, it will cause fever, blood pressure, shock, white blood cell count, platelet count, chills, headache, vomiting, muscle pain, heartbeat Systemic symptoms such as speed. These symptoms are also known as endotoxemia or sepsis.

Elderly patients, or patients with reduced resistance after surgery Once you have these symptoms caused by endotoxin, you will often experience a rapid deterioration of your condition. Recently, the causes of various diseases such as cirrhosis, alcoholic hepatitis, non-alcoholic hepatitis (NASH), acute pancreatitis, kidney disease, Alzheimer's disease, diabetes, arteriosclerosis, etc. have recently been clarified (for example, endotoxin is also associated with Non-patent document 1).

[Previous Technical Literature] [Non-patent literature]

[Non-Patent Document 1] Sakaguchi S. et al., Drug Metab. Pharmacokinet 2011; 26 (1): 30-46

The present inventors have found that the ConA-induced hepatitis model mice have ingested a nutrient composition containing a hydrolyzate of whey protein, and it has been found that it is possible to suppress migration of blood to endotoxin and to suppress deterioration of hepatitis. The present invention is based on these findings.

The present invention is directed to providing a composition for inhibiting migration of blood in endotoxin.

According to the present invention, the following invention is provided:

[1] A composition for inhibiting migration of blood in endotoxin, which comprises whey protein.

[2] The composition according to the above [1], wherein the whey protein is in the form of a hydrolyzate.

[3] The composition of the above [1] or [2], wherein whey protein The substance is one or more selected from the group consisting of α-lactalbumin, β-lactoglobulin, and lactoferrin.

[4] The composition according to any one of the above [1] to [3] wherein the whey protein is derived from a protein selected from the group consisting of milk protein concentrate (MPC), whey protein concentrate (WPC), and whey protein. One or two or more kinds of the group (WPI), skimmed milk powder, skim milk concentrate, and raw milk.

[5] The composition according to any one of the above [1] to [4] wherein the composition contains 0.5 to 5.0 g of whey protein per 100 kcal.

[6] The composition according to any one of the above [1] to [5], which further comprises fermented milk protein as a protein.

[7] The composition according to any one of the above [1] to [6], which further comprises a fat or oil containing an n-3 fatty acid as a lipid.

[8] The composition according to any one of the above [1] to [7], which further comprises a saccharide containing isomaltulose as a carbohydrate.

[9] The composition according to any one of the above [1] to [8], which is for use in the treatment of a disease or a symptom which is effective for treating, preventing or ameliorating the treatment, prevention or improvement of blood transfusion for endotoxin improve.

[10] The composition according to the above [9], wherein the diseases and symptoms are selected from the group consisting of liver cirrhosis, alcoholic hepatitis, non-alcoholic hepatitis (NASH), acute pancreatitis, kidney disease, Alzheimer's disease, diabetes, One or more types of arteriosclerosis, fever, blood pressure reduction, white blood cell count, platelet count reduction, chills, headache, vomiting, muscle pain, and tachycardia.

[11] Use of a whey protein for the production of a composition for inhibiting migration of blood in endotoxin.

[12] A whey protein for use in migration inhibition of blood to endotoxin.

[13] A method for inhibiting migration of blood in endotoxin comprising administering an effective amount of whey protein to a subject in need of the method, or administering an effective amount of whey protein thereto.

According to the present invention, a composition for inhibiting migration of blood in endotoxin can be provided. Since the whey protein contained in the composition of the present invention is a milk protein which is used as a raw material of food for a long period of time, the composition of the present invention has less side effects after being taken for a long period of time, and is highly safe in terms of safety. advantageous.

Fig. 1 is a graph showing the activity of aspartate transaminase (AST) in the blood of a nutrient composition group in which a hepatitis mouse is ingested into a nutritional composition (test food) in comparison with a control group (a group in which a control food is ingested). A graph of the activity of alanine transaminase (ALT) in blood. t test, *: p < 0.05 vs control group.

Fig. 2 is a graph showing the concentration of TNF-α in blood and the concentration of IL-6 in blood in a nutrient composition group in which a hepatitis mouse is ingested into a nutritional composition (test food) in comparison with a control group (a group in which a control food is ingested). Figure. t assay, *: p < 0.05 vs control group, #: p < 0.1 vs control group.

Figure 3 shows the presence and absence of endotoxin and initial development by box plot. A graph of the relationship between inflammatory cytokines (TNF-α.IL6) concentrations.

The composition of the present invention comprises whey protein as an active ingredient. The term "whey" as used herein refers to an aqueous solution obtained by removing milk fat or casein from milk, and is synonymous with milk and milk. Zhouzhi whey is rich in protein components such as β-lactoglobulin (β-Lg), α-lactalbumin (α-La), lactoferrin, serum albumin, and immunoglobulin. Further, the source of the whey used in the present invention is not particularly limited, and is preferably a milk protein concentrate (MPC, also known as total protein milk (TMP)), whey protein concentrate (WPC), or whey protein isolate ( WPI), skimmed milk powder, skim milk concentrate, raw milk and other whey from cow's milk.

In a preferred embodiment of the invention, the whey protein can be used in the form of a hydrolysate. The hydrolyzate of whey protein can be prepared by, for example, a method comprising the steps of (i) to (v) below.

(i) Dissolving a whey protein isolate (WPI, DAVISCO) having a protein content of about 90% (w/w) in a dried product in distilled water to have a protein concentration of 8% (w/v). An aqueous solution of the protein is obtained.

(ii) The aqueous solution was heat-treated at 85 ° C for 2 minutes to denature the protein. The pH of the aqueous solution after the heat treatment can be adjusted to, for example, about 7.5.

(iii) thereafter, adding Alcalase 2.4L (enzyme, in a ratio of 2.0% (w/w) relative to the concentration of the protein (matrix), Novozymes, this aqueous solution was maintained at 55 ° C for 3 hours for hydrolysis.

(iv) Next, trypsin PTN6.0S (enzyme, Novozymes Japan) was added at a concentration of 3.0% (w/w) relative to the protein (matrix), and the aqueous solution was kept at 55 ° C for 3 hours. The hydrolysis is carried out. That is, the hydrolysis time may be, for example, 6 hours in total. The pH of the aqueous solution at the end of the reaction of such hydrolysis can be adjusted to, for example, about 7.0.

(v) The hydrolyzate of the whey protein was subjected to centrifugation (20,000 × g, 10 minutes), and then treated with an ultrafiltration (UF) membrane (Millipore Ultrafree-MC) having a molecular weight cut off of 10,000.

As a method for preparing a hydrolyzate of milk protein, as a parameter for optimization, there are preheating, ratio of enzyme to substrate (E/S), pH, temperature of hydrolysis, time of hydrolysis, and the like, for example, The following conditions are met. That is, preheating: 65~90°C, E/S: 0.01~0.2, pH: 2~10, hydrolysis temperature: 30~65°C, hydrolysis time: 3~20 hours.

The hydrolyzate of the whey protein of the present invention contains, in addition to the hydrolyzate itself, a retaining solution (retentate) or a permeate (permeate) obtained by treatment with an ultrafiltration membrane, and even contains A hydrolysate of commercially available whey protein of the same activity required in the present invention. For example, in the hydrolyzate of the milk protein of the present invention, any of the cutoff molecular weights of 5000, 6000, 7000, 8000, 9000, and 10000 may be used as the lower limit (~ or higher, or higher than ~), and 15,000. Any one of 20000, 25000, and 30000 is the upper limit (~ below, or low) The ultrafiltration membrane of molecular weight between the two points of ~) is preferably a retention liquid treated with an ultrafiltration membrane having a molecular weight cut off of 10,000.

The blending amount of the whey protein in the composition of the present invention may be based on the blending amount of other components (fermented milk protein, lipid, saccharide, etc.), or the condition, symptom, age, body weight, or the body of the composition of the present invention. Use for appropriate adjustment. Specifically, the blending amount of the whey protein is, for example, 0.5 to 5.0 g, preferably 1.0 to 3.0 g, more preferably 1.5 to 2.5 g per 100 kcal of the composition, but is not limited thereto.

The composition of the present invention may also comprise fermented milk protein as a protein. The fermented milk protein which can be used in the present invention can be used by using milk selected from livestock such as cow, buffalo, goat, sheep, horse, etc., and some of the skim milk, skim milk, reduced whole milk, reduced skim milk, and reduction. One or two or more kinds of liquid milk prepared by using a milk raw material such as a skim milk, a butter, or a cream, and fermented by a fermentation product such as lactic acid bacteria, that is, fermented milk. Examples of the fermented milk protein of the present invention include fresh cheese, natural cheese, yogurt, and whey cheese. The term "cheese" as used herein refers to the removal of whey (whey, whey) from the milk formed by lactic acid bacteria, milk, buttermilk or emulsifiable concentrate, or the addition of enzymes to milk, buttermilk or emulsifiable concentrate. Retained, whether it is cured or mature. As a starter for producing fermented milk, Lactobacillus bulgaricus, Streptococcus thermophilus can be mainly used, but it is not limited thereto, and for example, Streptococcus lactis, Streptococcus cremoris, Streptococcus diacetilactis, Enterococcus faecium, Enterococcus fecalis, Lactobacillus casei, Lactobacillus can also be used. Lavtobacillus or Lactobacillus bifidum of helveticus, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus murinus, Lactobacillus reuteri, Lactobacillus brevis, Lactobacillus gasseri, Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium breve, etc. Further, microorganisms used in the production of fermented milk may be used in combination with Propionibacterium or the like. The composition of the present invention can be prepared by using any type of fermented milk, preferably fresh cheese or yogurt, and more preferably quark or yogurt.

"Fresh cheese" includes huts, quark cheese, string cheese, nachat cheese, sesame cheese, mozzarella cheese, riveta, mascarpone cheese and many more. Among them, quark cheese is a kind of uncooked (fresh) cheese, which is characterized by low fat content, refreshing aroma and sourness.

It is known that lactic acid bacteria have a beneficial effect on bacteria. In addition, the whey of the fresh cheese obtained by the fermentation of the lactic acid bacteria is known to have antibacterial effects against Escherichia coli, Vibrio cholerae, Lactobacillus bifidum, Bacteroides, and the like (see Japanese Patent Laid-Open No. Hei 7-155103). Therefore, the probiotic effect or the antibacterial effect can be expected by blending the fermented milk protein fermented by the lactic acid bacteria to the composition of the present invention.

The blending amount of the fermented milk protein may be based on the blending amount of other components (milk protein hydrolysate, lipid, saccharide, etc.) or the condition, symptom, age, body weight, use, etc. of the composition of the present invention. Suitable for adjustment. Specifically, the amount of the fermented milk protein blended can be exemplified by The conversion into protein is 0.5 to 6.0 g per 100 kcal, preferably 1.5 to 5.0 g, more preferably 2.5 to 3.5 g, but is not limited thereto. Here, in order to exert the effect of the fermented milk protein and to easily and continuously ingest it while maintaining a good flavor, it is preferred to adjust the blending amount of the fermented milk protein within the above numerical range.

In the milk used in the preparation of the hydrolyzate of milk protein or fermented milk protein in the present invention, it is preferred to use normal milk other than colostrum, that is, mature milk. The source of the milk may be any animal such as cow, buffalo, goat, sheep, horse, human.

The composition of the present invention may further contain proteins other than whey protein and fermented milk protein, and examples of such a protein include full-fat milk powder, skim milk powder, partially skimmed milk powder, casein, α-casein, and β-case. Animal and plant proteins such as protein, κ-casein, soy protein, egg protein, meat protein, and the like; and tallow, whey (whey) minerals, emulsifiable concentrate, whey, non-protein nitrogen, Various components derived from milk such as sialic acid. In addition to this, a peptide or an amino acid such as casein phosphopeptide, lysine or the like may be contained.

The composition of the present invention may also contain a lipid as a blending component. Examples of the lipid which can be incorporated in the composition of the present invention include phospholipids and edible fats and oils. Examples of the phospholipid which can be used in the composition of the present invention include milk phospholipid, soybean lecithin, and egg yolk lecithin, and these may be used singly or in combination.

The edible fats and oils which can be used for the composition of the present invention include fats and oils containing fatty acids. As a fatty acid, for example, saturation Fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids. Preferred among the fats and oils containing fatty acids include fats and oils containing monounsaturated fatty acids such as oleic acid.

The blending amount of the monounsaturated fatty acid such as oleic acid may be 25% or more, preferably 30% or more, more preferably 30 to 50%, in the fatty acid composition of the composition of the present invention, but is not limited thereto. . Further, an n-3 fatty acid (for example, docosahexaenoic acid, eicosapentaenoic acid, linoleic acid) or an n-6 fatty acid (for example, linoleic acid or arachidonic acid) may be added. A medium chain fatty acid such as a polyunsaturated fatty acid, caprylic acid, citric acid or lauric acid.

The composition of the present invention preferably comprises an n-3 fatty acid as a lipid. Examples of the n-3 fatty acid contained in the composition of the present invention include EPA, DHA, α-linolenic acid, DPA, etc., preferably EPA, DHA, and/or α-linolenic acid, and more. Good for EPA or / and DHA. Examples of the fats and oils containing the n-3 fatty acid include perilla oil, linseed oil, sage oil, fish oil, rapeseed oil, soybean oil, salad oil, and linseed oil. In the present invention, these n-3 fatty acids may be directly contained, and may be contained in the form of fats and oils such as fish oil.

Further, the composition of the present invention preferably comprises a medium chain fatty acid triglyceride (MCT: medium-chain triglyceride) as a lipid. MCT has a feature that it is easily absorbed into the body and becomes energy, and it is difficult to attach fat to the body. Examples of the oil and fat containing MCT include palm oil, palm kernel oil, and fats and oils containing medium chain fatty acids. In the present invention, it may directly contain MCT, and may also be contained in the form of oil such as palm kernel oil. Have.

Further, the composition of the present invention may comprise a fatty acid such as oleic acid, palmitic acid, palmitoleic acid, linoleic acid, stearic acid, linoleic acid, arachidonic acid or the like, preferably oleic acid as a lipid. Examples of the fat or oil containing such fatty acids include high oleic sunflower oil, rapeseed oil, olive oil, high oleic safflower oil, soybean oil, corn oil, palm oil, and the like. You can also use sunflower oil, rapeseed oil, olive oil, and a mixture with olive oil. Linoleic acid, arachidonic acid, γ-linolenic acid, and the like are n-6 fatty acids. Examples of the fats and oils containing the n-6-based fatty acid include safflower seed oil, sunflower oil, soybean oil, linseed oil, corn oil, and peanut oil.

The composition of the present invention may contain edible fats and oils other than the above, and examples of such edible fats and oils include lard oil, fish oil, and animal fats such as separated oils, hydrogenated oils, and transesterified oils; Seed oil, coconut oil, vegetable oils such as separated oils, hydrogenated oils, and transesterified oils.

The blending amount of the edible fat or oil containing the fat or oil containing the fatty acid may be based on the blending amount of other components (milk protein hydrolyzate, fermented milk protein, saccharide, etc.) or the condition, symptom, or the person who takes the composition of the present invention. Age, weight, use, etc. are suitable for adjustment. Specifically, the blending amount of the edible fats and oils is, for example, 0.5 to 5.0 g, preferably 1.0 to 4.0 g, more preferably 2.0 to 3.0 g, per 100 kcal of the composition, but is not limited thereto. Further, the blending amount of the MCT may be 0.3 to 1.0 g per 100 kcal, preferably 0.5 to 0.7 g; and the blending amount of the n-3 fatty acid may be 0.03 to 0.10 g per 100 kcal of the composition. Preferably 0.05 ~0.07g. Here, in order to exert the effect of the lipid component and to easily and continuously ingest it while maintaining a good flavor, it is preferred to adjust the blending amount of the lipid component within the above numerical range. Further, in the present invention, in the case of 1 kcal = 1 mL, "the composition per 100 kcal" may be replaced with "the composition per 100 mL".

The composition of the present invention may also contain a saccharide as a carbohydrate. Examples of the saccharide which can be incorporated in the composition of the present invention include sugar alcohol (sorbitol, xylitol, maltitol, etc.), honey, fine granulated sugar, glucose, fructose, invert sugar, isomaltulose For example, dextrin or the like, it is preferred to blend at least isomaltulose as a saccharide.

Isomaltulose is a disaccharide (molecular weight 342.297, Cas. No. 13718-94-0) in which glucose and fructose are each bonded by α-1,6. Isomaltulose is a structural isomer of sucrose, also known as 6-O-(α-D-Glucopyranosyl)-D-fructose or isomaltulose, palatinose, used in sweeteners and the like. A small amount of isomaltulose is contained in honey or sugar cane. Further, α-glucosyltransferase derived from Protaminobacter rubrum is allowed to act on sucrose to transfer α-1,2 linkage to α-1,6 linkage, and isomaltulose can also be produced. The sweetness of isomaltulose is similar to sucrose, but the sweetness is about half of that of sucrose. Isomaltulose, which is orally ingested, is decomposed by isomaltase in the digestive tract and is absorbed by glucose and fructose in the same way as sucrose (Hida Minshang et al., Japanese Nutrition. Food Society, Vol.36 (3) ): 169-173, 1983). In addition, isomaltose, panose, isomaltotriose, etc., which are said to be digested by isomaltase, compete with isomaltulose digestion due to isomaltulose Ingestion and digestion are inhibited (Japanese Nutrition. Food Society, 36 (3), pp. 169-173 (1983)). The calorie of isomaltulose is 4kcal/g. In the present invention, the isomaltulose comprises a palatinose syrup, a reduced balaginose or a palatinose syrup. The sucrose syrup is a syrup-like liquid substance containing, as a main component, an oligosaccharide such as a tetrasaccharide, a hexasaccharide or an octasaccharide which is produced by dehydration condensation of isomaltulose.

In addition, we know the crystal osmotic pressure adjusting agent such as isomaltulose and dextrin. The combination of the osmotic pressure adjusting agent such as indigestible dextrin is dissolved in water, and the osmotic pressure is adjusted to an aqueous solution of 200 to 440 mOsm/L to remove the harmful bacteria in the intestine and adjust the proliferative environment of the useful bacteria (International Publication No. 2004/ No. 067037). Therefore, by blending the composition of the present invention with isomaltulose, the effect of improving the intestinal environment of the ingestor is expected.

The blending amount of isomaltulose may be based on the blending amount of other components (milk protein hydrolysate, fermented milk protein, lipid, etc.) or the condition, symptom, age, body weight of the composition of the present invention. Use for appropriate adjustment. Specifically, the blending amount of isomaltulose is 4 to 15 g, preferably 6 to 8 g per 100 kcal of the composition, but is not limited thereto.

The blending amount of isomaltulose may be based on the blending amount of other components (whey protein, fermented milk protein, lipid, etc.) or the condition, symptom, age, body weight, use of the composition of the present invention. Wait for the adjustment. Specifically, the blending amount of isomaltulose is 4 to 15 g, preferably 6 to 8 g per 100 kcal of the composition, but is not limited thereto. Here, in order to exert the effect of isomaltulose, and to make it It is easy to continuously ingest while maintaining a good flavor, and it is preferred to adjust the blending amount of isomaltulose to the above numerical range.

The composition of the present invention may contain a saccharide raw material other than the above, and examples of such a saccharide raw material include processed starch such as soluble starch, British starch, oxidized starch, starch ester, and starch ether.

The composition of the present invention can regulate its heat by increasing the amount of protein, lipid, and saccharide blending. The heat of the composition of the present invention may be 50 to 150 kcal per 100 mL of the liquid composition, preferably 80 to 120 kcal, but is not limited thereto.

Further, the energy ratio of the protein, the lipid, and the saccharide in the composition of the present invention to the entire composition can be determined in a manner substantially in accordance with the sixth revision of the nutritional requirement of the Japanese. Specifically, the protein is 15 to 25%, the lipid is 20 to 30%, and the saccharide is 45 to 65%, but is not limited thereto.

The composition of the present invention may further comprise dietary fiber. Food fiber refers to a substance in a food that is not hydrolyzed by human digestive enzymes, and is classified into water-soluble dietary fiber and insoluble dietary fiber depending on the affinity for water. Examples of the water-soluble dietary fiber include indigestible oligosaccharides such as lactulose, lactitol, and raffinose. Among them, in terms of the physiological function of the indigestible oligosaccharide, it is known that the intestine reaches the large intestine in an undigested state, which contributes to the activation and proliferation of the lactobacillus in the intestine, and has an improvement in the intestinal environment, that is, the whole intestine. effect. As other water-soluble dietary fibers, pectin (original pectin, pectin acetate, pectic acid), guar gum. Enzyme decomposition products, tamarind glue, etc.

The composition of the present invention, in addition to the aforementioned protein, lipid, saccharide, dietary fiber, water, vitamins, minerals, organic acids, organic alkalis, fruit juices, spices, emulsifiers, tackifiers, Stabilizers, etc. Examples of the vitamins include vitamin A, carotenes, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, nicotine, nicotinic acid, pantothenic acid, and biotin. , inositol, choline, folic acid, etc. Examples of the minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, and the like. Examples of the organic acid include malic acid, citric acid, lactic acid, tartaric acid, and isoascorbic acid. In addition, it is also possible to use a material having a deodorizing effect (for example, 0.005% to 0.5% of mushroom extract) and a carotenoid preparation (for example, 0.00001% to 0.0002% of α-carotene and β-carotene are contained. A preparation of lycopene, lutein or the like), an antioxidant (catechin, polyphenol, etc.) is contained in the composition of the present invention. These components may be used in combination of two or more kinds, and a synthetic product and/or a large amount of foods containing these may be used.

According to a preferred embodiment of the present invention, there is provided a nutrient composition for inhibiting migration of blood in endotoxin, which comprises whey protein and fermented milk protein, and further comprising edible fat and oil containing n-3 fatty acid as The lipid and the saccharide containing isomaltulose are formed as a carbohydrate. The nutrient composition can be preferably provided in the form of a liquid composition. In this case, the content of the whey protein per 100 kcal can be 0.5 to 5.0 g, and the content of the fermented milk protein per composition can be 0.5 to 6.0 per 100 kcal. g, n-3 fatty acid by composition per 100 kcal It can be taken from 0.03 to 0.10 g, and the composition of isomaltulose can be 4 to 15 g per 100 kcal.

The compositions of the present invention can be made by methods well known in the art. For example, it can be produced by blending a part or all of the above-mentioned constituent components and then homogenizing them as needed. The term "homogeneous" as used herein refers to homogenization by thoroughly mixing the components of the blend, and mechanically refining the fat particles or other coarse particles of the other components to prevent the fat from rising and agglomerating. At the same time, the composition is made into a uniform emulsified state.

Heat treatment or heat sterilization can be carried out in the production of the composition of the present invention. The heat sterilization conditions can be sterilized by a general food, and can be heat-sterilized using a conventional device. For example, sterilization can be used at 62 to 65 ° C × 30 minutes, 72 ° C or more × 15 seconds or more, 72 ° C or more × 15 minutes or more, or 120 to 150 ° C × 1 to 5 seconds, or 121 to 124 ° C × 5 to 20 It is divided into sterilization, distillation (pressure heating) sterilization, high-pressure steam sterilization, and the like at 105 to 140 ° C, but is not limited to these examples. Heat sterilization can preferably be carried out under pressure.

Further, a method in which a liquid composition is previously sterilized by heating and then filled in a container aseptically (for example, a method using a UHT sterilization method and an aseptic packaging method); and a liquid nutrient composition is filled in a container, and A method in which a container is heat-sterilized together (for example, an autoclave method); filled in a can container or used for liquid food, orally. Distillation sterilization (for example, 5 to 10 seconds at 115 to 145 ° C) in various containers for nutrition (so-called soft bags, nutrition feeding bags, etc.); filling in tank contents Or for liquid food, oral. Various containers for nutrition (so-called soft bags, nutrition feeding bags, etc.) are subjected to distillation sterilization, heat-sterilized at about 140 to 145 ° C for about 5 to 8 seconds, then cooled, and then aseptically filled, but not Limited to this. Further, after heat treatment or heat sterilization, the starter (lactic acid bacteria, Lactobacillus bifidum, or Propionibacterium, etc.) derived from the fermented milk of the raw material is killed.

When the composition of the present invention is provided in the form of a liquid, the osmotic pressure can be adjusted to 500 to 1000 mOsm/L, preferably to an osmotic pressure of 550 to 750 mOsm/L.

When the composition of the present invention is provided in a liquid form, its viscosity can be adjusted to 20 to 100 cp (1 cp = 0.001 Pa.s), preferably 25 to 60 cp, more preferably 30 to 30, as measured at room temperature. 50 cp, but is not limited to these ranges.

When the composition of the present invention is provided in a liquid form, the pH thereof can be adjusted to 4.6 or less, preferably from 3.0 to 4.3, more preferably from 3.8 to 4.2, but is not limited thereto.

As shown in the examples below, the composition of the present invention containing whey protein can inhibit the migration of endotoxin in blood. Therefore, the composition of the present invention can be used as a composition for endotoxin blood migration inhibition and an endotoxin blood migration inhibitor, and can be used in an endotoxin blood migration inhibition method.

That is, according to the present invention, there is provided a method for inhibiting migration of blood in endotoxin comprising administering an effective amount of whey protein or a composition of the present invention to a subject in need of the method, or administering an effective amount thereof Whey protein or a composition of the invention. Ingested or administered to a subject Human or non-human animal (eg non-human mammal).

According to the present invention, there is further provided a use of a whey protein or a composition comprising the same, which is used for the production of a composition for inhibiting migration of blood in endotoxin. According to the present invention, there is further provided a use of a whey protein or a composition comprising the same, which is for use in the manufacture of a blood translocation inhibitor of endotoxin. According to the present invention, there is further provided a whey protein or a composition comprising the same for use in migration inhibition of blood to endotoxin.

Here, "endotoxin" refers to a cell wall component of Gram-negative bacteria such as Salmonella, Coliform, and Pseudomonas aeruginosa, and is also called endotoxin or lipopolysaccharide. The presence or absence of "endotoxin-induced blood migration inhibition" can be evaluated by using the endotoxin concentration in serum as an index (see Example 1). Further, migration inhibition in endotoxin blood is used in the sense of migration inhibition in blood containing endotoxin.

The use of the compositions of the present invention can be used for human and non-human animals and samples derived therefrom, and is intended to be either therapeutic or non-therapeutic. As used herein, the term "non-therapeutic" means not including the operation, treatment or diagnosis of a human being (ie, a medical act on a human), and specifically, means not including a physician or a physician. A method of surgery, treatment, or diagnosis.

As shown in the examples below, it was confirmed that the composition of the present invention can inhibit the migration of endotoxin in blood. It has heretofore been known that an increase in the concentration of endotoxin in blood is associated with the onset or worsening of diseases such as hepatitis (Michelena J et al., Hepatology 2015; 62(3): 762-772; Verdam FJ et al., J Clin Gastroenterol. ;45(2):149-152;Wig JD et Al., J Clin Gastroenterol. 1998; 26(2): 121-124; Wong J et al., Semin Dial. 2015; 28(1): 59-67; Bester J et al. 2015; 6(34): 35284-35303). Moreover, it is known that the increase in blood concentration of endotoxin is associated with symptoms such as fever, decreased blood pressure, decreased white blood cell count, decreased platelet count, chills, headache, vomiting, muscle pain, and tachycardia (Doorduin J et al ., Shock 2015; 44(4): 316-322). Further, as shown in Examples described later, the blood concentration of AST or ALT which is an indicator of hepatitis was significantly reduced in the hepatitis model mice (Example 1). Thus, in the present invention, the composition of the present invention can be used for the treatment, prevention or improvement of the treatment, prevention or improvement of diseases and symptoms which are effective for the inhibition of migration of endotoxin blood. Further, the composition of the present invention can be used as a therapeutic, preventive, and ameliorating agent for treating, preventing, or ameliorating effective diseases and symptoms, and can be used for migration to endotoxin blood. The treatment, prevention, and improvement of the diseases and symptoms which are effective for treating, preventing or ameliorating the same. The treatment method, the prevention method and the improvement method of the present invention can be obtained by subjecting a subject in need of the method to the composition of the present invention or an effective amount of whey protein, or administering the composition of the present invention or an effective amount of whey thereto. Protein is implemented. The subject to be ingested or administered is a human or non-human animal (eg, a non-human mammal).

As a disease which is effective for the treatment, prevention or improvement of endotoxin migration, it may be cirrhosis, alcoholic hepatitis, non-alcoholic hepatitis (NASH), etc., or acute pancreatitis, kidney disease, Az Diseases such as Haimo, diabetes, and arteriosclerosis. Also, as endotoxin blood The inhibition of the middle migration is effective for treating, preventing or ameliorating the symptoms, such as starting from burning, lowering blood pressure, reducing the number of white blood cells, reducing the number of platelets, chills, headache, vomiting, muscle pain, and tachycardia.

The composition of the present invention, the inhibitor of the present invention, and the therapeutic, prophylactic, and ameliorating agents of the present invention can be provided in the form of a pharmaceutical, a quasi-drug, a food, a feed, or the like, and can be carried out in accordance with the following description. Further, the endotoxin blood migration inhibiting method of the present invention, and the therapeutic method, the preventive method and the improvement method of the present invention can be carried out in accordance with the following description.

The composition of the present invention is orally administered to humans and non-human animals as a pharmaceutical or supplement, or administered orally. Examples of the oral preparation include a tablet (sugar-containing tablet), a pill, a capsule, a granule, a powder, a syrup, and the like. Such formulations may be formulated according to methods generally employed in the art using pharmaceutically acceptable carriers. Examples of the pharmaceutically acceptable carrier include excipients, binders, disintegrators, lubricants, odorants, solubilizers, suspending agents, coating agents, perfumes, buffers, tackifiers, colorants, and Stabilizers, emulsifiers, etc. Further, an appropriate amount of calcium may be added, and an appropriate amount of vitamins, minerals, organic acids, sugars, amino acids, peptides, and the like may be further added.

In the present invention, oral administration of a human or non-human animal by oral administration, nasal administration, drip, suppository, or the like may be carried out according to the form of the composition of the present invention. For example, by using the composition of the present invention as a viscous liquid composition or a semi-solid composition, human and non-human animals that are unable to be orally ingested or orally administered to a chewing or swallowing function are also Can be administered. By making it mouth Ingestion of the composition of the present invention in a manner other than ingestion, or administration of the composition of the present invention, even if the chewing or swallowing function decreases with age, etc., the endotoxin can also be inhibited for such human and non-human animals. The migration in the blood is also expected to treat, prevent and improve the diseases such as hepatitis or the symptoms involved in the disease. Further, the composition of the present invention may have a function as a nutritional supplement or an energy replenishing agent depending on the blending component, and therefore, various nutrients or energy can be supplied to human and non-human animals whose chewing or swallowing function is lowered.

The composition of the present invention uses a daily food material such as whey protein or a hydrolyzate thereof as a raw material, and on the other hand, has endotoxin-induced blood migration inhibiting action, and therefore can be provided as a food for daily intake or as a supplement. A food that is ingested, or even a nutritious food for the purpose of nutritional supplementation. The composition of the present invention can be provided by blending it with various foods.

When the composition of the present invention is provided as a food, the food is a food containing an effective amount of the composition of the present invention. Here, the "inclusion effective amount" of the composition of the present invention means the content of the composition of the present invention taken in a range as described later when ingested in an amount generally consumed in each food. In addition, "food" includes healthy foods, functional foods, health-care foods (such as specific health foods, nutritional functional foods, nutritional supplements, functional foods), and special-purpose foods (such as children's foods, maternity). The meaning of food, food for patients). Since the composition of the present invention is a component which can be used as a food component as a blending component, the endotoxin-induced blood migration inhibition or the effects related thereto can be expected, and can be used as a liquid food or oral. Managed nutrients, beverages, gelatinous foods (especially For so-called functional foods, etc. for oral use. Nutritional management of enteral nutrition patients or elderly people, infants and young children.

The form of the "food" is not particularly limited, and may be in the form of a liquid such as a drink or a liquid food, and may be in the form of a paste, a semi-liquid or a gel, or may be in the form of a solid or a powder. Further, the composition of the present invention can be added to various foods (milk, refreshing drink, fermented milk, yogurt, cheese, bread, biscuits, crackers, PIZZA CRUST (pizza) regardless of the form of liquid, solid, or powder. Cakes), prepared milk powder, liquid foods, special-purpose foods, foods for patients, nutritious foods, frozen foods, processed foods, and other commercially available foods, etc., are ingested. Further, when the use form of the nutritional composition is a powder, it can be produced by, for example, means such as spray drying or freeze drying.

The daily intake or administration amount of the pharmaceutical composition or the food of the composition of the present invention is based on the condition, age, symptom, body weight, use of the subject, or whether the composition of the present invention is the only nutrient or the like. It is not particularly limited. In the case of ingestion and administration for the purpose of inhibition of migration or endotoxin in blood of endotoxin, for example, it may be ingested or administered to the composition of the present invention, and may be administered daily by an adult. Ingestion of 0.5 to 80 g, preferably 2 to 42 g, more preferably 6 to 25 g of whey protein. Further, the composition of the present invention has another aspect of the nutritional composition, and in the case of an adult, an intake amount and an administration amount of 100 to 1600 kcal, preferably 200 to 1400 kcal, more preferably 400 to 1000 kcal per day can be exemplified. In the case of a healthy adult, for example, the intake amount and the dose amount up to 3000 kcal per day can be tolerated. In addition, the intake can also be taken by the attending physician of the subject To decide.

The composition of the present invention can be provided as a composition which is effective for one day of inhalation such as migration inhibition of endotoxin. At this time, the composition of the present invention can be packaged into an effective intake which can be ingested for one day, and the package form can be one pack or multiple packs as long as it can take an effective intake of one day. When it is provided in a package form, it is preferred to add a record relating to the intake amount to the package or to provide a document with the record together so that an effective intake of 1 day can be taken. Moreover, when the effective intake of one day is provided in a multi-package, if it is easy to take in consideration, it is also possible to provide a package with an effective intake of one day in a kit.

The packaging form for providing the composition of the present invention is not particularly limited as long as it can be regulated in a certain amount, and for example, a packaging paper, a bag, a soft bag, a paper container, a can, a bottle, a capsule, or the like can be accommodated. Containers, etc.

In order to exhibit the effect more satisfactorily, the composition of the present invention is preferably continuously administered or ingested for one week or more, and the administration and ingestion time are more preferably from 1 to 4 weeks, particularly preferably from 1 to 2 weeks. Here, "continuously" means the intention of continuous administration or ingestion on a daily basis. When the composition of the present invention is provided in a package form, it is also possible to provide an effective intake amount in a kit for a certain period of time (for example, one week) in order to continuously ingest.

[Examples]

The present invention will be more specifically described based on the following examples, but the present invention is not limited by the examples.

Example 1: Confirmation of the effect of endotoxin migration inhibition in the nutritional composition of the present invention

In order to confirm the effect of inhibiting the migration of endotoxin into the blood by the nutritional composition of the present invention, a hepatitis model mouse administered with concanavalin A (ConA) was used for the following evaluation.

(1) Test feed

As a test food (the nutritional composition of the present invention), a liquid food "Meiji MEIN" (manufactured by Meiji Co., Ltd.) was used. As a control food, a liquid food "Meibalance HP" (manufactured by Meiji Co., Ltd.) was used. Each liquid food was freeze-dried and pulverized and used as a test feed, respectively. The composition of the test food and the control food (per 100 mL) and the raw material composition (per 100 mL) of the test food related to protein, saccharide, fiber and lipid are shown in Tables 1 and 2 below, respectively.

(2) Test conditions

After pre-feeding 6-week-old Balb/c female mice (purchased from Japan SLC), they were divided into 4 groups in the same way as the average body weight, which were taken as normal control group (n=5), normal nutritional composition. Group (n=5), hepatitis control group (n=15), hepatitis nutritional composition group (n=14).

The normal control group and the hepatitis control group were fed for 14 days using control food. The normal nutrient composition group and the hepatitis nutrient composition group were fed for 14 days using test foods. The hepatitis control group and the hepatitis nutrient composition group (hereinafter collectively referred to as "hepatitis group") will be ConA on the 14th day. (manufactured by Sigma) was administered to the tail vein at a dose of 20 mg/kg, and the normal control group and the normal nutrient composition group (hereinafter collectively referred to as "normal group") were not administered with ConA.

(3) Measurement project

The hepatitis group was subjected to hemoglobin-treated syringe for 0.3 mL of blood from the tail vein 2 hours after administration of ConA, and the heparin-treated syringe was used for blood transfusion from the abdominal large vein under isoflurane anesthesia on the following day (day 15). The normal group was subjected to heparin-treated syringes from the large abdominal vein under the isoflurane anesthesia on the 14th day after the start of feeding. The blood system was aseptically extracted, and the platelet-poor plasma of the supernatant was centrifuged at 3000 rpm for 1 minute, and used for detection of the number of bacteria and endotoxin detection. The blood drawn from the tail vein and the blood remaining in a part of the above-mentioned platelet-removing plasma were centrifuged at 12,000 rpm for 5 minutes, and the plasma was used for measurement by cytokines or biochemical tests.

(i) AST‧ALT activity

The obtained plasma (plasma 24 hours after administration of ConA) was used for the hepatitis group, and the activities of aspartate transaminase (AST) and alanine transaminase (ALT), which are indicators of hepatitis, were measured. For the measurement, FUJI DRY-CHEM NX500i (manufactured by FUJIFILM Co., Ltd.) was used.

(ii) TNF-α ‧ IL-6 concentration in plasma

For the hepatitis group, the resulting plasma was used (2 hours after administration of ConA) The plasma was measured for the concentration of inflammatory cytokines, TNF-α and IL-6, which were caused by ConA in the initial stage of induction. The measurement was carried out using a Mouse inflammation kit (manufactured by Dickinson Co., Ltd., Becton, Japan) and BD FACS Verse (manufactured by BD Biosciences Co., Ltd.).

(iii) Is there any endotoxin detected in plasma?

For the normal group and the hepatitis group, the obtained platelet-rich plasma (plasma 24 hours after administration of ConA) was confirmed for the detection of endotoxin. In order to confirm the presence or absence of the endotoxin, the endotoxin concentration was measured using a Toxinometer ET-6000 (manufactured by Wako Pure Chemical Industries, Ltd.) using Limulus ES-F Single Test wako (manufactured by Wako Pure Chemical Industries, Ltd.). When the endotoxin concentration in the plasma is below the detection limit (0.02 EU/mL), it is determined that endotoxin is not detected; when the endotoxin concentration in the plasma is equal to or higher than the detection limit, it is determined that endotoxin is detected.

The results of (i) to (iii) were expressed as mean ± standard deviation (SE), and statistical analysis was performed by t-test (*: p < 0.05) using the statistical analysis software SPSS of IBM Corporation.

(4) Results

During the feeding period, the weight was smoothly increased in any of the groups, and no significant difference was observed between the groups.

(i) AST‧ALT activity

The measurement results of AST and ALT activities are shown in Fig. 1. As for the hepatitis nutrient composition group, the activities of AST and ALT were significantly lower than those of the hepatitis control group. As a result of the above, it was revealed that the onset and deterioration of hepatitis can be suppressed by the nutritional composition of the present invention.

(ii) TNF-α ‧ IL-6 concentration in plasma

The measurement results of the concentrations of TNF-α and IL-6 in plasma are shown in Fig. 2 . The hepatitis nutrient composition group showed a tendency to have a lower concentration of TNF-α than the hepatitis control group. Further, in the hepatitis nutrient composition group, the concentration of IL-6 was significantly lowered as compared with the hepatitis control group. As a result of the above, it was revealed that the nutrient composition of the present invention can suppress the production of primary inflammatory cytokines, and can suppress the onset and deterioration of hepatitis.

(iii) Is there any endotoxin detected in plasma?

The number of individuals in which endotoxin was detected in plasma is shown in Table 3 for each group. In addition, the number of bacteria in the plasma of the normal group and the hepatitis group was examined by the culture method, but no bacteria were observed (data is omitted).

From the results of Table 3, it was found that in the normal population, no endotoxin was detected in all individuals in the control group and the nutritional composition group. On the other hand, in the hepatitis group, in the control group, 6 out of 15 individuals (40%) detected endotoxin; in the nutritional composition group, 2 out of 14 individuals (14%) detected endotoxin. Further, the endotoxin concentration in the plasma of the individual who was determined to have detected endotoxin was 0.022-0.047 EU/mL (3.14-6.71 pg/mL), which was significantly different from the individual who did not detect endotoxin.

From the above results, it is clarified that the nutritional composition of the present invention can inhibit the migration of endotoxin blood, thereby suppressing the onset or deterioration of hepatitis.

Further, since hepatitis induced by administration of ConA is caused by the production of an initial inflammatory cytokine and the migration of endotoxin blood, according to the present embodiment, it was confirmed that the nutritional composition of the present invention can inhibit not only the migration of endotoxin blood. It also inhibits the production of initial inflammatory cytokines. In order to confirm whether the initial production of inflammatory cytokines is affected by endotoxin, the data of initial inflammatory cytokine concentration and the presence or absence of endotoxin were detected as box plots, indicating the initial production of inflammatory cytokines and endotoxin. There was no correlation between inhibition of migration in the blood (Fig. 3). From the above, it is conceivable that the nutritional composition of the present invention can inhibit the migration of endotoxin in the blood, and can suppress the generation of the initial inflammatory cytokine caused by the different route, thereby suppressing hepatitis.

Claims (13)

A blood migration inhibiting composition for endotoxin, which comprises whey protein. The composition of claim 1, wherein the whey protein is in the form of a hydrolysate. The composition of claim 1 or 2, wherein the whey protein is one or more selected from the group consisting of α-lactalbumin, β-lactoglobulin, and lactoferrin. The composition of any one of claims 1 to 3, wherein the whey protein is derived from the group consisting of milk protein concentrate (MPC), whey protein concentrate (WPC), whey protein isolate (WPI), degreased One or two or more types of milk powder, degreased concentrated milk, and raw milk. The composition according to any one of claims 1 to 4, wherein the composition contains 0.5 to 5.0 g of whey protein per 100 kcal. The composition according to any one of claims 1 to 5, which further comprises fermented milk protein as a protein. The composition according to any one of claims 1 to 6, which further comprises a fat or oil containing an n-3 fatty acid as a lipid. The composition according to any one of claims 1 to 7, which further comprises a saccharide containing isomaltulose as a carbohydrate. The composition according to any one of claims 1 to 8, which is for the treatment, prevention or amelioration of a disease or symptom which is effective for treating, preventing or ameliorating the inhibition of migration of blood to endotoxin. The composition of claim 9, wherein the aforementioned diseases and symptoms are selected Free liver cirrhosis, alcoholic hepatitis, non-alcoholic hepatitis (NASH), acute pancreatitis, kidney disease, Alzheimer's disease, diabetes, arteriosclerosis, fever, decreased blood pressure, decreased white blood cell count, decreased platelet count, chills, One or two or more groups of headaches, vomiting, muscle pain, and tachycardia. A use of whey protein for the manufacture of a composition for migration inhibition of blood in endotoxin. A whey protein for migration inhibition in blood used for endotoxin. A method for inhibiting migration of blood in endotoxin, which comprises subjecting a subject in need of such method to an effective amount of whey protein or administering an effective amount of whey protein thereto.