JP2006199708A - Remedy for liver disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a drug and a food, each of which is used for preventing and/or treating liver diseases, is highly efficacious, and can be easily taken without any fear of side effects. <P>SOLUTION: The drug comprises a peptide which is composed of L-amino acids for constituting natural proteins, has an L-glutamine content of 15-60 mass%, and has an average molecular weight of 200-100,000. The food contains the peptide. By taking the above drug or food, effects of preventing or treating liver diseases can be exhibited. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The number of patients with liver disease, hyperlipidemia and diabetes is a large social problem. Liver disease, hyperlipidemia and diabetes may occur due to unique causes. For example, hepatic diseases caused by infection such as viral hepatitis, primary hyperlipidemia caused by genetic defects, and diabetes due to insufficient insulin secretion. However, liver diseases such as fatty liver and alcoholic hepatitis, dietary hyperlipidemia and dietary diabetes are often closely related to excessive intake of starch, fat, alcoholic beverages, etc., and lifestyle habits. Therefore, liver disease, hyperlipidemia and diabetes often occur together.

  The present invention relates to a preventive and / or therapeutic agent for liver disease, hyperlipidemia and / or diabetes, and a food for preventing and / or treating liver disease, hyperlipidemia and / or diabetes. Specifically, the present invention relates to a preventive and / or therapeutic agent for liver disease, hyperlipidemia and / or diabetes, which contains a peptide rich in L-glutamine, and a food containing the peptide.

Representative examples of liver diseases include fatty liver, viral hepatitis, alcoholic hepatitis, inflammatory hepatitis such as cirrhosis. Glycyrrhizin preparation, polyenephosphatidylcholine, malotilate, diisopropylamine dichloroacetate, thiopronin, protoporphyrin sodium, methylmethionine sulfonium chloride, interferon, ursodeoxycholic acid, Shosaikoto, liver hydrolyzate, glutathione, etc. Is used. However, these drugs have a low effect of promptly improving liver disease and often require a long time for treatment. Even if it is possible to improve liver disease to some extent quickly, the upper limit of the values at which the improved GOT value, GPT value, and γ-GTP value are normal is often reached. Furthermore, even when there is a therapeutic effect on liver disease, there are problems such as side effects.
Thus, it is desired to develop drugs and foods and drinks for prevention or treatment that are easy to ingest on a daily basis, have excellent therapeutic effects, and are highly safe for liver diseases.

  Hyperlipidemia is a disease name given when total cholesterol and / or triglycerides in the blood exceed a certain reference value. Primary hyperlipidemia due to genetic defects and dietary , Sugar, protein, fat and other metabolic abnormalities, secondary hyperlipidemia secondary to the primary disease of liver disease. As a standard for diagnosis of hyperlipidemia, a reference value of 220 mg / dl or more is generally adopted as a reference value for total cholesterol, and a reference value of neutral fat is 150 mg / dl or more.

  Among the causes of hyperlipidemia, the most problematic is secondary hyperlipidemia caused by excessive intake of energy such as high fat diet rich in cholesterol and neutral fat such as meat, high carbohydrate diet, alcohol consumption, etc. It is. Hyperlipidemia can cause arteriosclerosis and causes serious illness such as myocardial infarction and cerebral thrombosis. For this reason, pharmacotherapy for reducing cholesterol and neutral fat in the blood is performed using drugs such as pravastatin sodium, colestimide, simvastatin, nicotinic acid, clofibrate drugs and the like. However, these drugs have problems such as side effects, discomfort during taking, and recurrence after completion of administration.

  In addition, dietary therapy and exercise therapy are performed as a treatment for hyperlipidemia. However, since these therapies take a long time before their effects appear, both of them need to be continued for a long time. For this reason, development of drugs and foods and drinks for the prevention and treatment of hyperlipidemia that are easy to take on a daily basis, have an excellent effect of lowering cholesterol and neutral fat, and are highly safe is desired. It was. It has been reported that a kind of polyphenol contained in tea, red wine, cacao beans, etc. has an action to prevent hypercholesterolemia as an additive that can be added to foods (for example, JP-A-11-308978 and Japan). (See Journal of Nutrition and Food Science, 39 (6), 495-500, 1986).

  Diabetes is a group of diseases characterized by chronic hyperglycemia due to insulin secretion failure, insulin resistance, etc., and genetic and environmental factors are involved in its onset. In diabetes, pancreatic β-cells are destroyed or dysfunctional for some reason, and insulin cannot be secreted and hyperglycemia develops. Type I (insulin-dependent) diabetes, decreased insulin secretion, decreased insulin sensitivity in tissues There are type II (insulin-independent) diabetes due to the above, and gestational diabetes that develops due to a decrease in the action of insulin due to the action of hormones secreted during pregnancy. Insulin-independent type accounts for 90% of these diabetes, and is considered to be caused by excessive intake of energy, unbalanced diet, lack of exercise, stress, etc. in addition to genetic predisposition.

  In any case, chronic hyperglycemia not only exacerbates diabetes itself, but also develops complications such as neuropathy, retinopathy and kidney damage, cerebrovascular disorders, ischemic heart disease, diabetic nephropathy It causes serious diseases such as diabetic retinopathy and diabetic neuropathy. Gestational diabetes also causes intrauterine death and neonatal death.

  What is important for the prevention or treatment of diabetes is the control of blood sugar levels, and nutritional guidance, exercise therapy, and drug therapy are performed for that purpose. Nutritional guidance and exercise therapy are effective means for preventing or treating diabetes, but since it takes a long time for the effects to appear, it is necessary to continue strict dietary restrictions and exercise over a long period of time. Exercise therapy may not only cause a hypoglycemic condition, but it may exacerbate complications depending on the patient, and should be used with caution.

  There are two main drug therapies: insulin therapy and oral diabetes drug therapy. Insulin therapy is mainly performed in patients with insulin-dependent diabetes mellitus, but it is necessary not only to inject insulin on a daily basis, but also to control the injection amount of insulin. In addition, as therapeutic drugs for oral diabetes, insulin resistance improvers such as sulfonylurea (SU), biguanide (BG), α-glycosidase inhibitor, pioglitazone hydrochloride and the like are known. In addition to symptoms, there are side effects such as lactic acidosis (bad feeling, vomiting, abdominal pain, coma), liver damage, etc., and caution is also required for concomitant medications. Therefore, it has been desired to develop a drug for preventing or treating diabetes, which is easy to be taken on a daily basis, has an excellent action of lowering blood glucose level, and has high safety, and food and drink.

  On the other hand, a method for obtaining L-glutamine or a peptide containing the same from wheat protein is known (see, for example, Japanese Patent No. 2010439 and Japanese Patent No. 2985193). In addition, it has been reported that L-glutamine or a peptide containing the same is useful for maintaining the structure and function of the intestinal mucosa and improving immune function impairment (for example, JP-A-5-236909 and EP756268-). A2). However, peptides rich in L-glutamine normalize GOT value, GPT value and γ-GTP value, lower blood cholesterol and neutral fat, lower blood sugar level, liver disease, hyperlipidemia Until now, it has not been known to have an action capable of preventing and / or treating diabetes.

  It is an object of the present invention to prevent liver diseases, hyperlipidemia and / or diabetes that are highly effective, have no side effects, can be taken easily, and can be taken for a long time in terms of price and safety. It is to provide a preventive and / or therapeutic agent and a food having an effect of preventing and / or treating liver disease, hyperlipidemia and / or diabetes.

  The present inventors have found that administration of a peptide rich in L-glutamine improves the GOT value, GPT value, and γ-GTP value of a liver disease patient to a normal value or a value close thereto in a short period of time, L-glutamine Administration of a peptide rich in glucose improves total cholesterol, LDL cholesterol, triglycerides, arteriosclerosis index to a normal value or a value close to that in a short period of time, and administration of a peptide rich in L-glutamine reduces blood glucose levels. We found that it improved to a normal value or a value close to it in a short time.

  Therefore, the present invention is characterized by comprising a peptide composed of an L-amino acid constituting a natural protein, having an L-glutamine content of 15 to 60% by mass and an average molecular weight of 200 to 100,000. The present invention relates to a preventive and / or therapeutic agent for liver disease, hyperlipidemia and / or diabetes. The peptide preferably has an L-glutamine content of 20 to 40% by mass and an average molecular weight of 500 to 20,000, and particularly preferably a peptide produced from wheat flour gluten.

In the following description, a peptide having a high glutamine content according to the present invention is referred to as a “glutamine peptide”. Further, in the present specification, the terms “peptide” and “glutamine peptide” mean a peptide composed of L-amino acids constituting a natural protein. Therefore, the term “L-amino acid” or “amino acid” means an L-amino acid that constitutes a natural protein.
Furthermore, the present invention relates to a food containing a peptide having an effect of preventing and / or treating the liver disease, hyperlipidemia and / or diabetes. By containing the glutamine peptide of the present invention in a food or drink, the glutamine peptide can be taken more easily in daily life.

In the present invention, the liver disease is inflammatory hepatitis such as fatty liver, viral hepatitis, alcoholic hepatitis, cirrhosis, etc., but although the disease name is not clear, it is used as an index of liver function such as GOT, GPT, γ-GTP. It also includes symptoms with abnormalities.
GOT (Glutamic Oxaloacetic Transaminase) is an enzyme that is abundant in cells of tissues and organs such as myocardium, liver, skeletal muscle, and kidney, and decomposes proteins to form amino acids. Even in a normal state, cells that make up the human body are simultaneously generated and disrupted, so that a healthy person's blood always contains a predetermined amount of GOT. The GOT content (normal value) in the blood of healthy adults is generally 5 to 40 IU / liter, but when abnormalities occur in the tissues and organs such as the above-mentioned myocardium, liver, skeletal muscle, kidney, A large amount of GOT is released into the blood. For this reason, the GOT value is considered as one of important guidelines for diagnosing the presence or absence of diseases in organs and body tissues.

  GPT (Glutamic Pyruvic Transaminase) is an enzyme involved in amino acid formation, similar to GOT. It is specifically present in hepatocytes and is present in the kidney in about 1/3 of the liver, in other organs. Abundance is small. The normal GPT value in adult blood is generally 5 to 42 IU / liter, but the GPT content (GPT value) in blood reacts sensitively to liver damage such as degeneration and necrosis of hepatocytes. Since it increases, it is regarded as one of the important indicators when diagnosing liver disease.

  Like GOT and GPT, γ-GTP (γ-Glutamyl Transpeptidase) is an enzyme that is most abundant in the kidney, and is also contained in the pancreas, liver, kidney and small intestine. γ-GTP is abundant in hepatocytes at sites related to secretion and absorption of enzymes such as the capillary bile duct side, bile duct epithelium, and intestinal epithelial cells. The normal value of γ-GTP value in adult blood is generally 50 IU / liter or less (0-50 IU / liter). A large amount of γ-GTP is released into the blood when alcohol or drugs that are toxic to the liver destroy hepatocytes, or when the bile duct is blocked and clogged with stones or cancer. Since γ-GTP reacts particularly sensitively to alcohol and shows abnormal values earlier than other enzymes when there is a disease in the liver or biliary tract, γ-GTP values, together with GOT values and GPT values, are liver diseases. It is generally used widely as an indicator of

  In the present invention, hyperlipidemia means a pathological condition in which both cholesterol and / or neutral fat in the blood exceed a certain reference value, and the hyperlipidemia pathological conditions include hypercholesterolemia and triglycerides. Blood pressure is included. Therefore, the prophylactic or therapeutic agent for hyperlipidemia of the present invention is administered or taken to treat or prevent a disease state in which cholesterol or neutral fat exceeds a certain reference value. Here, as an index of hyperlipidemia, not only total cholesterol level (total of free cholesterol and esterified cholesterol) and neutral fat level (also called triglyceride level), but also LDL cholesterol level (low density lipoprotein) Cholesterol value) and the like are also used.

  In the present invention, diabetes means a disease state in which the blood glucose level exceeds a certain reference value. Therefore, the preventive or therapeutic agent for diabetes of the present invention is administered or taken to treat or prevent a disease state in which the blood glucose level exceeds a certain reference value. In addition to blood glucose levels (for example, fasting blood glucose levels), glycohemoglobin A1c (Hb A1c), 1,5-anhydro-D-glucitol (1,5-AG), and the like are used as indicators of diabetes.

  Hb A1c is obtained by binding glucose to hemoglobin A (Hb A), which includes unstable Hb A1c and stable Hb A1c. Stable Hb A1c has a stable binding to glucose, and can know the movement of blood glucose level in the past 4 months, but is usually used to examine the movement of average blood sugar level in the past 1-2 months . The normal value of Hb A1c is in the range of 4.3 to 5.8%, and in the case of 6.0% or more, some kind of treatment is required.

1,5-Anhydro-D-glucitol (1,5-AG) is a monosaccharide in which a part of glucose is reduced. The normal range of 1,5-AG is 14 μg / mL or more, but it decreases immediately according to urinary glucose excretion due to hyperglycemia, and the blood glucose state improves and slowly recovers. For this reason, it is possible to know a short-term change in blood glucose for the past 5 to 7 days, and since it is not affected by meals, it can be evaluated at any time.
The methods for measuring these blood glucose level, Hb A1c and 1,5-AG indices are widely known in the field of diabetes treatment, and standards are also established. For this reason, measuring instruments and test kits according to this are commercially available, and any of these may be used for measurement.
The present invention is described in detail below.

  The glutamine peptide used in the present invention is not particularly limited as long as it is a peptide having an L-glutamine content of at least 15% by mass and an average molecular weight of 200 to 100,000, and is a partial hydrolyzate of a natural or recombinant protein. , Chemically synthesized or genetically engineered peptides, or combinations thereof.

  When the L-glutamine content in the glutamine peptide is less than 15% by mass, sufficient prevention and / or treatment effect of the disease cannot be expected. The upper limit of the L-glutamine content is not particularly limited, but if it exceeds 60% by mass, preparation from a natural protein becomes difficult, so that it is 60% by mass or less from the viewpoint of ease of acquisition and preparation and economy. Preferably, it is 20 to 40% by mass.

  The L-glutamine content in the glutamine peptide is calculated based on the amide nitrogen-containing L-amino acid content obtained from the amide nitrogen content measured by the amide nitrogen substitution method, or the glutamine peptide is a synthetic product Can be determined from the ratio of L-glutamine used in the synthesis.

Moreover, when the average molecular weight of the glutamine peptide is less than 200, the taste is poor due to the bitter taste. On the other hand, when the average molecular weight of the glutamine peptide exceeds 100,000, a viscous lump is formed when water is added, and the handleability becomes poor. The average molecular weight of the glutamine peptide is not particularly limited as long as it is 200 to 100,000, but is preferably 500 to 20,000, and more preferably 1,000 to 10,000.

The average molecular weight of the glutamine peptide as used herein is an average molecular weight as measured by gel filtration, and details thereof are as described in the Examples section below.
As long as the glutamine peptide used in the present invention has an L-glutamine content of at least 15% by mass, the type of L-amino acid other than L-glutamine and the composition ratio thereof are not particularly limited.

A glutamine peptide is composed of an L-amino acid constituting a natural protein, and thus is excellent in terms of safety to humans and animals. However, the peptide of the present invention is obtained by hydrolyzing a protein contained in food. It is preferable to use a glutamine peptide, particularly a glutamine peptide obtained by hydrolyzing wheat gluten, from the viewpoints of safety, availability and preparation, and economy.
The glutamine peptide preferably used in the present invention produces a hydrolyzate of wheat gluten containing 25 to 50% by mass of L-glutamine and having an average molecular weight in the range of 200 to 100,000 by protease, acid, alkali, etc. Can be produced by hydrolysis under such conditions.

Wheat gluten usually contains 25 to 50% by weight of L-glutamine, and therefore hydrolyzes wheat gluten under conditions such that the average molecular weight is in the range of 200 to 100,000. By performing a drawing or the like, a glutamine peptide having an L-glutamine content of 15 to 60% by mass can be obtained relatively easily.
Wheat gluten is insoluble in water and inferior in water dispersibility, but the glutamine peptide obtained by hydrolyzing wheat gluten is excellent in water dispersibility because of its low molecular weight.

  A glutamine peptide derived from wheat gluten can be produced, for example, by a method of hydrolyzing wheat gluten using a protease or using a protease and amylase (see Japanese Patent No. 2010439 and Japanese Patent No. 2985193). As the protease at that time, for example, various proteases such as pepsin, trypsin, chymotrypsin, acid protease derived from Hilotake, acid protease derived from Aspergillus, papain, bromelain and the like can be used. When amylase is used together with the hydrolysis of wheat gluten with protease, impurities such as starch and fiber contained in wheat gluten are decomposed and removed, and a high-purity glutamine peptide can be obtained in high yield. Yes (see Japanese Patent No. 2985193).

  The glutamine peptides of the present invention, for example, glutamine peptides derived from wheat gluten, are already commercially available (for example, “Glutamine Peptide GP-1” manufactured by Nisshin Pharma Inc., “Glutamine Peptide GPA” manufactured by DMV, etc.) . These glutamine peptides may be used as they are or may be subjected to treatments such as hydrolysis and fractionation depending on circumstances.

  The agent for preventing or treating liver disease, hyperlipidemia and / or diabetes and the food of the present invention are usually administered in the range of 1 to 40 g per day as an adult mass of glutamine peptide. A typical daily dose is 6-10 g. However, the peptides used in the present invention are highly safe derived from natural products, and the dosage can be further increased. It is desirable to increase or decrease the dose appropriately while observing the effects. Although the daily dose can be administered or ingested at a time, it is desirable to administer it in several divided doses.

  The preventive and / or therapeutic agent for liver disease, hyperlipidemia and / or diabetes of the present invention may be made into oral preparations such as tablets, granules, powders, capsules, syrups, dry syrups, liquids and the like by a conventional method. it can. In that case, other known additives such as excipients, binders, disintegrants, lubricants, flavoring agents, coloring agents, surfactants, coating agents and the like can be used as necessary.

  Excipients include glucose, sucrose, lactose, mannitol, xylitol, sorbitol, crystalline cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, various starches, sodium carboxymethyl starch, dextrin, cyclodextrin, carboxyvinyl polymer, calcium hydrogen phosphate And light anhydrous silicic acid, titanium oxide, magnesium aluminate metasilicate and the like.

  Examples of the binder include tragacanth, gum arabic, corn starch, gelatin, alpha starch, sodium alginate, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol. Examples of the disintegrant include starch, a surfactant, and sodium bicarbonate that reacts with gastric acid to generate gas. Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, microcrystalline wax, beeswax and the like.

  Examples of the flavoring agent include sour agents such as citric acid, sweetening agents such as saccharin, and flavoring agents such as peppermint. As the colorant, a coloring material that has been approved for food use is used.

  Examples of surfactants include polyoxyethylene hydrogenated castor oil, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polysorbates, sodium lauryl sulfate, and sucrose fatty acid esters. Examples of the coating agent include methyl cellulose, ethyl cellulose, and hydroxypropyl cellulose.

  Ingestion is further facilitated by incorporating the glutamine peptide of the present invention into food. Examples of such foods include carbohydrate foods such as bread, udon noodles, cookies and rice crackers, teas, soups, sprinkles, butters, jams and other spreads, liquid foods, juices, jelly-like beverages, etc. The form is mentioned. As health foods and functional foods, it is desirable that the dosage per day can be controlled. The food of the present invention has an effect of preventing or treating liver disease, hyperlipidemia and / or diabetes.

The present invention will be specifically described by the following examples, but the present invention is not limited to the following examples.
The average molecular weight of the peptide (glutamine peptide) and the glutamine content in the peptide were measured by the following methods.
Average molecular weight of peptides:
The aqueous solution of peptide was filtered through a membrane filter having a pore size of 0.45 μm, and the molecular weight was measured by gel filtration. As a column, “Biosil SEC125-5” manufactured by Nippon Bio-Rad Laboratories was used. The measurement conditions were a measurement wavelength of 280 nm, an eluent of 0.2 mM phosphate buffer (pH 6.0, 0.1% SDS), and a flow rate of 0.2 ml / min. In addition, ovalbumin (molecular weight 44 kDa), myoglobulin (molecular weight 17 kDa) and vitamin B12 (molecular weight 1.35 kDa) were used as molecular weight standards.

Glutamine content in peptides:
There are two amino acids containing amide nitrogen, glutamine and asparagine. In wheat protein, 95% by mass or more of amide nitrogen-containing amino acids contained therein is glutamine. That is, even if the amide nitrogen-containing amino acid content in wheat gluten is directly used as the glutamine content, it does not cause a large error. Therefore, the amount of amide nitrogen-containing amino acid in wheat gluten was directly used as the glutamine content.

  The content of amide nitrogen contained in the glutamine peptide was determined according to the method for quantitative determination of amides in chemical substances by Wilcox [Meth. Enzymol., 11, 36-65 (1967)]. Specifically, glutamine peptide is placed in a Conway flask, 1N hydrochloric acid is added thereto, amide nitrogen in the glutamine peptide is liberated as ammonia, and the generated ammonia is subjected to a hygiene inspection guideline [edited by Japan Pharmaceutical Association, “ Hygiene Test Method / Commentary ”, p. 274-276, Kanehara Publishing (1990)], the amount of amide nitrogen contained in the peptide is determined from the quantified amount of ammonia, and based on this, the amount of amino acid containing amide nitrogen is determined as the glutamine content. The content was calculated.

Production Example 1 Production of Glutamine Peptide (1) 9,700 kg of ion-exchanged water, 38 kg of anhydrous citric acid and 1,500 kg of wheat gluten (active gluten, manufactured by Weston Foods Limited) were charged in a reaction kettle and heated to 45 ° C., followed by protease ( Amano Pharmaceutical Co., Ltd. “Protease M Amano”) 2.2 kg and Amylase (Hankyu BioIndustry Co., Ltd. “Liquefaction Enzyme T”) 1.1 kg were added, followed by hydrolysis at 45 ° C. for 5 hours, and then 25% The pH of the solution was adjusted to 4.4 to 4.5 using an aqueous sodium hydroxide solution and kept for 5 hours for enzyme treatment.
(2) Next, after inactivating the protease by maintaining the solution at 80 ° C. for 20 minutes, the solution was cooled to 65 ° C., and 0.5 kg of amylase (“Liquefied enzyme T” manufactured by Hankyu BioIndustry Co., Ltd.) was added thereto. After the starch and fiber contained in the wheat gluten were hydrolyzed, the liquid was kept at 90 ° C. for 20 minutes to inactivate amylase.
(3) Next, after cooling the liquid to 10 ° C. or lower, the solution was heated again to 55 ° C., 100 kg of activated carbon (“Takecol” manufactured by Takeda Pharmaceutical Co., Ltd.) was added thereto, and the mixture was stirred at 55 ° C. for 30 minutes.
(4) Set the liquid temperature to 45 ° C., add concentrated super assistant (“Radiolite” manufactured by Showa Kagaku Kogyo Co., Ltd.), perform filtration using a pressure filtration device, and filtrate 7,000 liters (7 m 3). Was recovered. (5) The filtrate collected in (4) above is concentrated under reduced pressure until the Brix value is 20-40, then sterilized by heating at 110 ° C. for 20 seconds using a plate heater, and then cooled to 55 ° C. did.
(6) Glutamine peptide, which is a hydrolyzate of wheat gluten, by spray drying the liquid obtained in (5) above using a spray dryer under conditions of an air blowing temperature of 160 ° C. and an exhaust air temperature of 80 ° C. About 1,000 kg of powder was obtained.
(7) The non-glutamine peptide powder obtained in (6) above was classified using a 60 mesh sieve (aperture 0.246 mm), and fine powder (glutamine peptide fine powder) that passed through the 60 mesh sieve was recovered.
(8) When the average molecular weight and glutamine content of the glutamine peptide (fine powder) recovered in the above (7) were measured, the average molecular weight was about 8,000 and the glutamine content was 32% by mass.

Production Examples 2-4. Production of Glutamine Peptide A glutamine peptide having the properties shown in Table 1 below was obtained in the same manner as in Production Example 1.

Example 1. Manufacture of tablets 83.8 g of the glutamine peptide obtained in Production Example 1, 10 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.) and 5 g of polyvinyl pyrrolidone (manufactured by BASF) were mixed, and 30 ml of ethanol was added thereto, followed by a wet method. Grains were produced according to a conventional method. After drying the obtained granules, 1.2 g of magnesium stearate was added to make granules for tableting, and tableting was performed using a tableting machine to produce 100 tablets each having 1 g ( Glutamine peptide content per tablet 0.838 g).

Example 2 Manufacture of syrup Boil 400 g of purified water, add 750 g of sucrose and 100 g of the glutamine peptide obtained in Preparation Example 1 while stirring, dissolve with heat, wipe with heat, add purified water to this to make the total amount A syrup was prepared as 1000 ml (glutamine peptide content 10 g per 100 ml of syrup).

Example 3 Manufacture of granules Glutamine peptide GP-1 (average molecular weight 7,000, L-glutamine content 32% by mass; Nisshin Pharma Co., Ltd.) 76 g, lactose (DMV Co.) 13.3 g, crystalline cellulose (Asahi Kasei Co., Ltd.) 6.7 g) and 4 g of polyvinylpyrrolidone (BASF) were mixed, 30 ml of ethanol was added thereto, granules were produced according to a conventional method by a wet method, dried and then granulated to obtain granules. (Glutamine peptide content 7.6 g per 10 g of granules).

Example 4 Manufacture of liquid food To 750 g of pure water at about 65 ° C., 40 g of sodium caseinate (manufactured by DMV), 160 g of maltodextrin (manufactured by Sanwa Starch) and 25 g of glutamine peptide GP-1 (manufactured by Nisshin Pharma Co., Ltd.) After dissolving, 5 g of vitamin mix and each component mixture of trace amounts of minerals were added. The mixed solution was put into a homomixer (manufactured by Tokushu Kika Kogyo Co., Ltd.) and roughly emulsified at about 8000 rpm for 15 minutes. The obtained emulsified liquid was cooled to about 20 ° C., and after adding a fragrance, the final volume was increased. After filling this liquid with 230 g of this liquid in a pouch, the pouch was sealed while purging with nitrogen, and sterilized at 121 ° C. for 15 minutes to obtain a concentrated liquid food. The glutamine peptide content per 230 g of liquid food was about 5 g.

Embodiment 5 FIG. Manufacture of bread Mix 150g of flour (strong flour) and 2g of dry yeast. In addition, 20 g of glutamine peptide GP-1 (manufactured by Nisshin Pharma Co., Ltd.), 20 g of sugar, 3 g of salt, and 6 g of skim milk powder are dissolved in 70 g of hot water, and 1 egg is added and mixed well. Add this to flour and knead well by hand, then add about 40 g of butter and knead well to make 20 roll bread dough. Next, after fermenting, the egg was coated on the surface and baked in an oven at 180 ° C. for about 15 minutes to produce a roll. This roll had about 1 g of glutamine peptide per piece.

Example 6 Production of meat sauce for pasta A portion of meat sauce for pasta (150 g) was placed in a pan, and 5 g of glutamine peptide GP-1 (manufactured by Nisshin Pharma Co., Ltd.) was added and heated at the same time to prepare a meat sauce for pasta. After filling this pouch with a pouch, the pouch was sealed with nitrogen substitution and sterilized at 121 ° C. for 15 minutes to obtain a meat sauce for pasta containing a glutamine peptide.

Example 7 Manufacture of udon To 300 g of flour (medium flour), 15 g of glutamine peptide GP-1 (manufactured by Nisshin Pharma Co., Ltd.) and 15 g of sodium chloride are dispersed in 150 g of water, mixed well and laid down. Thereafter, the dough was stretched and cut into widths of about 5 mm to produce udon. When this was boiled with boiling water for about 10 minutes, the appearance, taste and texture were good. This udon contained about 5 g of glutamine peptide per serving.
Hereinafter, the treatment of liver disease, hyperlipidemia and / or diabetes with the glutamine peptide of the present invention will be described with reference to test examples.

[Test for liver disease]
Below, the pharmacological test regarding the liver disease of the glutamine peptide of this invention is described.
The measuring method of GOT value, GPT value, and γ-GTP value as an index of the therapeutic effect of liver disease is as follows.
GOT value: Measured according to the UV method ("Clinical Chemistry" 18, pp. 231-249 (1989)), which is a standardization method of the Japanese Society for Clinical Chemistry (JSCC).
GPT value: Measured according to the UV method [“Clinical Chemistry” 18, pp. 250-262 (1989)], which is a standardization method of JSCC.
γ-GTP value: Measured according to the colorimetric method [“Clinical Chemistry” 24, pages 106-121 (1995)], which is a standardization method of JSCC.

[Test Example 1 for fatty liver]
Subject A: Male (58 years old)
Administered drug: Granule of Example 3 Dose: Glutamine peptide 9.9 g / day Test method: Glutamine peptide was taken 3 times daily after administration to fatty liver subjects who had complained of general malaise and anorexia GOT, GPT and γ-GTP were measured before and 1 week after the start of administration and 3 weeks later. The results are shown in Table 2.

[Test Example 2 for fatty liver]
Subject B: Male (60 years old)
Administered drug: syrup preparation of Example 2 Dose: Glutamine peptide about 6 g / day Test method: Glutamine peptide was taken 3 times a day after every meal to subjects with fatality and loss of appetite. Three weeks after the start of administration, GOT, GPT and γ-GTP were measured. The results are shown in Table 3.

[Test Example 1 for Chronic Hepatitis C]
Subject C: Male (49 years old)
Drug administered: syrup preparation of Example 2 Dose: Glutamine peptide about 8 g / day Test method: Glutamine peptide is taken twice a day (morning and evening) by subjects with chronic hepatitis C, before administration, 3 weeks from start of administration Later, GOT, GPT and γ-GTP were measured. The results are shown in Table 4.

[Test Example 2 for Chronic Hepatitis C]
Subject D: Male (51 years old)
Drug administered: Granule of Example 3 Dose: Glutamine peptide about 8 g / day Test method: Glutamine peptide is taken twice a day (morning and evening) to subjects with chronic hepatitis C, before administration, 4 weeks from start of administration Later, GOT, GPT and γ-GTP were measured. The results are shown in Table 5.

  In the above test examples, GOT, GPT and γ-GTP, which are indicators of liver function, decreased in all subjects, and improvement in liver function was observed. These results indicate that the glutamine peptide of the present invention has an excellent pharmacological action for the prevention or treatment of liver diseases.

[Study on hyperlipidemia]
The following describes pharmacological studies on glutamine peptide hyperlipidemia.
A specific amount of glutamine peptide is orally administered to a hyperlipidemic subject according to the symptom, and after a certain period, total cholesterol level, triglyceride level, LDL cholesterol level, arteriosclerosis index, etc. are measured. The improvement effect of was evaluated. In addition, total cholesterol, LDL cholesterol, neutral fat, and arterial effect index in blood were measured by the following methods.
Total cholesterol level: Measured by an enzymatic method [Uji et al., Nippon Clinic, Vol. 53, Special Issue, page 615 (1995)] at SRL Inc. (Tokyo), a clinical laboratory contract organization.
LDL cholesterol level: Measured by enzymatic measurement method [Sugano et al., Medicine and Pharmacology, Vol.3, No.3, p.635 (1997)] at SRL Inc. (Tokyo), a clinical laboratory contract organization.
Neutral fat value: Measured by enzyme method (free glycerol elimination method) [Shibuya et al., Nippon Clinic, Vol. 53, Special Issue, page 606 (1995)] at SRL Inc. (Tokyo), a clinical laboratory contract organization did.
Arteriosclerosis index: SRL (Tokyo), a clinical laboratory contracting organization, selectively inhibits HDL cholesterol levels (direct method) [Nakai et al., Nippon Clinic, Vol. 53, Special Issue, page 617 (1995)] The arteriosclerosis index was calculated from the following formula.
Atherosclerosis index = (total cholesterol value−HDL cholesterol value) ÷ (HDL cholesterol value)

[Test Example 1 for Hyperlipidemia]
Subject E: Male (58 years old)
Administered drug: Granule of Example 3 Dose: Glutamine peptide 10 g / day Test method: Glutamine peptide was administered to the subject three times a day after each meal, before administration, after administration, 1 week, 3 weeks and 3 months later Total cholesterol and neutral fat were measured. The results are shown in Table 6.

[Test Example 2 for Hyperlipidemia]
Subject F: Male (60 years old)
Drug administered: Granules of Example 3 Dose: Glutamine peptide 6 g / day Test method: Glutamine peptide was taken by subject after 3 meals per day, total cholesterol, LDL before administration, 3 weeks after administration and 3 months after administration Cholesterol, neutral fat, and arteriosclerosis index were measured. The results are shown in Table 7.

  In the above test examples, the total cholesterol level, the triglyceride level, the LDL cholesterol level, and the arteriosclerosis index, which are indicators of hyperlipidemia, decreased in all subjects, and improvement in hyperlipidemia was observed. These results indicate that the glutamine peptide of the present invention has an excellent pharmacological action for the prevention or treatment of hyperlipidemia.

[Test for diabetes]
Below, the pharmacological test regarding diabetes of glutamine peptide is described.
A specific amount of glutamine peptide was orally administered to diabetic subjects according to their symptoms, and fasting blood glucose levels, Hb A1c and 1,5-AG were measured after a certain period of time, and the improvement effect of diabetes was evaluated. The blood glucose level, Hb A1c, and 1,5-AG are measured as follows.
Blood glucose level: Enzymatic colorimetry such as glucose oxidase (GOD) method, enzyme electrode method such as glucose dehydrogenase (GDH) method, hexokinase (HX) method, glucose oxidase / peroxidase (GOD / POD) method, etc. The method is common, but in this example, it was measured by the GDH method [Maekawa et al., Nippon Clinic, vol. 53, Special Issue, page 527 (1995)] at SRL Inc. (Tokyo), a clinical laboratory contract organization. did.
Hb A1c: As a standard method of Hb A1c, a high-performance liquid chromatography method (HPLC method), a latex agglutination method (LA method), and an affinity method are known. Tokyo) and LA method [Old Woman, Japanese Clinical, vol. 48, special number, page 315 (1990)].
1,5-AG: SRL, Inc. (Tokyo), which is a clinical laboratory contract organization in this example
And the enzyme method [Kawai, Nihon Clinic, vol. 47, special number, page 439 (1989)].

上記試験例において、被験者は糖尿病の指標である空腹時血糖値、Ｈｂ Ａ1cおよび１,５−ＡＧ値に顕著な改善が認められた。この結果は、本発明のグルタミンペプチドが糖尿病の予防または治療に対する優れた薬理作用を有することを示している。 [Examples of diabetes tests]
Subject G: Male (67 years old)
Administered drug: Granule of Example 3 Dose: Glutamine peptide 10 g / day Test method: Glutamine peptide was taken by subject after 3 meals per day, fasting blood glucose level before administration, 1 month after administration and 3 months after administration , Hb A1c and 1,5-AG were measured. The results are shown in Table 8.

In the above test examples, the subjects showed significant improvements in fasting blood glucose levels, Hb A1c and 1,5-AG levels, which are indicators of diabetes. This result shows that the glutamine peptide of the present invention has an excellent pharmacological action for the prevention or treatment of diabetes.

[Test example 1 for concurrent fatty liver and hyperlipidemia]
Subject H: Male (68 years old)
Administered drug: Granule of Example 3 Dose: Glutamine peptide about 8 g / day Test method: Glutamine peptide for 1 day complaining of malaise and loss of appetite The drug was taken twice (morning and evening), and GOT, GPT, γ-GTP, total cholesterol, LDL cholesterol, neutral fat, and arteriosclerosis index were measured before administration, 4 weeks after the start of administration, and 3 months later. The results are shown in Table 9.

[Test example 2 for concurrent fatty liver and hyperlipidemia]
Subject I: Male (50 years old)
Drug administered: Granules of Example 3 Dose: Glutamine peptide about 8 g / day Test method: Glutamine peptide taken twice a day (morning and evening) to subjects with signs of fatty liver and hyperlipidemia GOT, GPT, γ-GTP, total cholesterol, LDL cholesterol, neutral fat, and arteriosclerosis index were measured before administration and 4 weeks and 3 months after the start of administration. The results are shown in Table 10.

  In the above test examples, in all subjects, GOT, GPT, γ-GTP, which are indicators of liver function, and total cholesterol value, triglyceride value, LDL cholesterol value, arteriosclerosis index, which are indicators of hyperlipidemia, The liver function and hyperlipidemia were improved. These results indicate that the glutamine peptide of the present invention has an excellent effect even when fatty liver and hyperlipidemia occur together.

上記試験例において、高脂血症の指標である総コレステロール値、中性脂肪値、ＬＤＬコレステロール値が低下し、糖尿病の指標である空腹時血糖値、Ｈｂ Ａ1cおよび１,５−ＡＧ値に顕著な改善が認められた。この結果は、本発明のグルタミンペプチドが高脂血症と糖尿病を併発している場合にも優れた効果があることを示している。 [Examples of hyperlipidemia and diabetes mellitus]
Subject J: Female (74 years old)
Administered drug: Granule of Example 3 Dose: Glutamine peptide 6 g / day Test method: Glutamine peptide was administered to the subject three times a day after each meal, before administration, after administration, 2 weeks, 4 weeks and 3 months later Total cholesterol, LDL cholesterol, neutral fat, fasting blood glucose level, Hb A1c and 1,5-AG were measured. The results are shown in Table 11.

In the above test examples, the total cholesterol level, triglyceride level and LDL cholesterol level, which are hyperlipidemia indicators, are decreased, and the fasting blood glucose level, Hb A1c and 1,5-AG levels, which are diabetes indicators, are remarkable. Improvement was observed. This result shows that the glutamine peptide of the present invention has an excellent effect even when hyperlipidemia and diabetes occur together.

According to the present invention, it comprises a peptide composed of an L-amino acid constituting a natural protein, having an L-glutamine content of 15 to 60% by mass and an average molecular weight of 200 to 100,000. A preventive and / or therapeutic agent for liver disease, hyperlipidemia and / or diabetes, and a food containing the peptide are provided.
By administering or ingesting the drug or food of the present invention, liver disease, hyperlipidemia and / or diabetes are remarkably improved in a short period of time. Moreover, the glutamine peptide used in the present invention is excellent in safety and suitable for long-term administration. Therefore, the drug and food of the present invention are extremely useful for the prevention and / or treatment of liver disease, hyperlipidemia and / or diabetes.

Claims (6)

  Prevention and / or prevention of liver disease, comprising a peptide composed of L-amino acids constituting a natural protein, having an L-glutamine content of 15 to 60% by mass and an average molecular weight of 200 to 100,000 Or therapeutic agent.   The preventive and / or therapeutic agent for liver disease according to claim 1, wherein the L-glutamine content is 15 to 60% by mass and the average molecular weight is 7,000 to 100,000.   The preventive and / or therapeutic agent for liver disease according to claim 1, which is a peptide having an L-glutamine content of 20 to 40% by mass and an average molecular weight of 500 to 20,000.   The preventive and / or therapeutic agent for liver disease according to any one of claims 1 to 3, which is a peptide produced using wheat gluten as a raw material.   The preventive and / or therapeutic agent for liver disease according to any one of claims 1 to 4, wherein the liver disease is fatty liver or chronic hepatitis C.   A food or drink comprising the peptide according to any one of claims 1 to 4, and a label indicating that it is for the prevention and / or treatment of liver disease.