WO2012133198A1 - Composition nutritionnelle pour maladies inflammatoires - Google Patents

Composition nutritionnelle pour maladies inflammatoires Download PDF

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WO2012133198A1
WO2012133198A1 PCT/JP2012/057538 JP2012057538W WO2012133198A1 WO 2012133198 A1 WO2012133198 A1 WO 2012133198A1 JP 2012057538 W JP2012057538 W JP 2012057538W WO 2012133198 A1 WO2012133198 A1 WO 2012133198A1
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composition
amino acid
weight
inflammatory diseases
nutritional composition
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PCT/JP2012/057538
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Japanese (ja)
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博之 葛岡
めぐみ 定方
栄二 鹿住
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イーエヌ大塚製薬株式会社
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Publication of WO2012133198A1 publication Critical patent/WO2012133198A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to an amino acid composition for inflammatory diseases and a nutritional composition for inflammatory diseases containing the same. More specifically, the present invention relates to an amino acid composition for inflammatory diseases composed of essential human amino acids and containing no human non-essential amino acids other than arginine, and a nutritional composition containing the same.
  • IBD Inflammatory bowel disease
  • Ultas syndrome which has Crohn's disease and ulcerative colitis as two major diseases, is a chronic intractable disease and is designated as a specific disease.
  • the number of patients in Japan exceeds 100,000 and is still increasing.
  • the etiology of this disease has not yet been identified, but is thought to be involved in the immune mechanism. That is, a mechanism has been pointed out that specific intestinal bacteria and dietary antigens enter the tissue from the intestinal epithelium, which is the site of inflammation, and cause an excessive inflammatory reaction.
  • the immune system is perturbed and attacks itself around the intestinal epithelium, causing inflammation in the intestinal tract.
  • Inflammatory bowel disease usually repeats acute exacerbation / relapse of inflammation (aggravation of inflammation) and remission (reduction of inflammation).
  • acute exacerbations and relapses of inflammatory symptoms patients generally have inadequate dietary intake, digestive absorption disorders, protein leakage from inflammatory sites, and fever due to inflammation. Often fall into undernutrition. Therefore, as a treatment policy, the main focus is on improving the patient's QOL by promptly relieving inflammatory symptoms (inducing remission) and preventing relapse (maintaining remission).
  • Treatment methods for this disease include drug therapy, nutrition therapy, and surgery.
  • drug therapy immunosuppressants, corticosteroids, molecular biological preparations (antibody drugs), aminosalicylic acid preparations, etc. are mainly used.
  • these existing medicines have reported serious side effects and have safety problems.
  • these existing medicines cannot be administered orally and cannot be administered at home.
  • surgery involves excision of the lesion, stenosis, and the like, but there are problems such as a high recurrence rate.
  • Non-Patent Documents 1 to 3 As nutritional therapy, component nutrition that provides a protein as a mixture of its constituent molecules is performed. Protein is blended as an amino acid mixture, and the blending amount is adjusted based on the amino acid composition of ovalbumin having a high nutritional value (see Non-Patent Documents 1 to 3). On the other hand, use of the whole amino acid composition of whey protein hydrolyzate in nutritional therapy for patients with liver failure, which is an inflammatory disease, has been studied (Patent Document 1). Whey protein has an excellent content balance of essential amino acids and non-essential amino acids, and is evaluated to have higher nutritional value than ovalbumin (Non-patent Document 4).
  • amino acid compositions described in these documents are compositions and peptide mixtures consisting of all amino acids including both essential amino acids and non-essential amino acids, and these nutritional therapies are safer than drug therapy. Although it is high and can improve the nutritional status of patients, its anti-inflammatory effect was insufficient.
  • the present invention is effective for the treatment and prevention of inflammatory diseases such as inflammatory bowel disease or induction / maintenance of remission, while improving the nutritional status of patients, compared to existing drugs such as corticosteroids, It is an object of the present invention to provide an amino acid composition for inflammatory diseases which is free from worry about side effects, hardly causes drug resistance, can be administered orally, and is inexpensive. Furthermore, the present invention contains the amino acid composition for inflammatory diseases, is excellent in anti-inflammatory action and amelioration effect of inflammatory diseases such as inflammatory bowel disease, can maintain body protein of patients, nutrition It is an object of the present invention to provide a nutritional composition for inflammatory diseases useful for improving the condition.
  • the present inventors have found that, among amino acid compositions, human essential amino acid compositions have a very excellent anti-inflammatory action, and the present invention has been completed. I let you. Further, the inventors have found that the above-mentioned human essential amino acid composition added with arginine has a further excellent anti-inflammatory action, and have completed the present invention. In addition, the present inventors have found that a nutritional composition having an excellent inflammatory disease condition improving effect can be obtained by blending the amino acid composition into a nutritional composition, and have completed the present invention. Furthermore, the present inventors have found that a nutritional composition having an even better inflammatory disease effect can be obtained by blending fructooligosaccharides into the nutritional composition and blending vitamins C, D and E at high values. Completed.
  • the present invention provides the following therapeutic agent for inflammatory bowel disease and nutrition composition for inflammatory disease.
  • An amino acid composition for inflammatory diseases comprising human essential amino acids and containing no human non-essential amino acids other than arginine.
  • the amino acid composition for inflammatory diseases, wherein the human essential amino acid comprises histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, cysteine and tyrosine.
  • Histidine 0.8 to 24.4% by weight (as a free amino acid: the same shall apply hereinafter), isoleucine 1.9 to 50.4% by weight, leucine 3.6 to 75.2% by weight, lysine 1.7 to 68.8 wt%, methionine 0.6-38.0 wt%, cysteine 0.1-42.0 wt%, phenylalanine 0.1-55.6 wt%, tyrosine 0.1-43.6 wt%,
  • the amino acid composition for inflammatory diseases comprising threonine 1.5 to 54.4% by weight, tryptophan 0.4 to 16.4% by weight, and valine 2.3 to 53.6% by weight.
  • Histidine 0.8 to 24.4% by weight (as free amino acid: the same shall apply hereinafter), isoleucine 1.9 to 50.4% by weight, leucine 3.6 to 75.2% by weight, lysine 1.7 to 68.8 wt%, methionine 0.6-38.0 wt%, cysteine 0.1-42.0 wt%, phenylalanine 0.1-55.6 wt%, tyrosine 0.1-43.6 wt%, It contains threonine 1.5 to 54.4% by weight, tryptophan 0.4 to 16.4% by weight, valine 2.3 to 53.6% by weight, and arginine 1.1 to 63.6% by weight.
  • the amino acid composition for inflammatory diseases isoleucine 1.9 to 50.4% by weight, leucine 3.6 to 75.2% by weight, lysine 1.7 to 68.8 wt%, methionine 0.6-38.0 wt%, cysteine 0.1-42.0 wt%, phenylalanine
  • the amino acid composition for inflammatory diseases wherein the inflammatory disease is inflammatory bowel disease.
  • the amino acid composition for inflammatory diseases wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
  • the amino acid composition for inflammatory diseases which can be used for treatment, prevention, induction or maintenance of inflammatory diseases.
  • a nutrition composition for inflammatory diseases comprising the amino acid composition for inflammatory diseases according to any one of the above.
  • the nutrition composition for inflammatory diseases characterized by containing fats and oils, carbohydrates, vitamins and minerals in addition to the amino acid composition.
  • the nutrition composition for inflammatory diseases wherein the fat is a natural fat or a synthetic fat.
  • the inflammatory property wherein the natural fat is selected from the group consisting of soybean oil, corn oil, palm oil, sesame oil, canola oil, safflower oil, sunflower oil, sesame oil, rice oil, olive oil, grape seed oil and fish oil.
  • a nutritional composition for disease 15) The nutrition composition for inflammatory diseases, wherein the synthetic fat is medium chain fatty acid triglyceride. (16) The nutrition composition for inflammatory diseases, wherein the saccharide includes one or more selected from the group consisting of fructooligosaccharides, galactooligosaccharides, dairy oligosaccharides, lactulose and inulin.
  • the mineral is one or more selected from the group consisting of calcium, magnesium, sodium, potassium, phosphorus, chlorine, iron, manganese, copper, iodine, zinc, selenium, chromium and molybdenum.
  • the nutritional composition for inflammatory diseases is one or more selected from the group consisting of vitamin A, vitamin D, vitamin E, vitamin K, vitamin B, and vitamin C.
  • the nutritional composition for inflammatory diseases characterized in that the amino acid composition contains 1.25 to 12.5 g / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • the nutrition composition for inflammatory diseases comprising 23.5 g / 100 kcal nutrition composition.
  • the nutritional composition for inflammatory diseases characterized by the above.
  • Vitamin C (ascorbic acid) 1.10 to 110 mg / 100 kcal nutrition composition, vitamin D 0.10 to 5.6 ⁇ g / 100 kcal nutrition composition, vitamin E ( ⁇ -A nutritional composition for inflammatory diseases, characterized in that it contains 0.10-100 mg / 100 kcal nutritional composition (as tocopherol).
  • the nutrition composition for an inflammatory disease wherein the inflammatory disease is an inflammatory bowel disease.
  • the nutrition composition for inflammatory diseases wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
  • the nutrition composition for inflammatory diseases which can be used for treatment, prevention, induction or maintenance of inflammatory diseases.
  • the amino acid composition for inflammatory diseases of the present invention has excellent pharmacological activity for the treatment and prevention of inflammatory diseases such as inflammatory bowel disease, and induction / maintenance of remission, and is expected to improve nutritional status. Compared to other drugs, there is no worry about side effects, no drug resistance occurs, oral administration is possible, and the cost is low.
  • the nutritional composition for inflammatory diseases of the present invention contains the amino acid composition for inflammatory diseases, has an extremely excellent effect of improving the pathological condition of inflammatory diseases such as inflammatory bowel disease, and maintains body protein. It is useful for improving the nutritional status of patients.
  • the amino acid composition for inflammatory diseases in the present invention is composed of essential human amino acids and does not contain human non-essential amino acids other than arginine.
  • the nutritional composition for inflammatory diseases according to the present invention comprises the amino acid composition for inflammatory diseases which is composed of essential human amino acids and does not contain human non-essential amino acids other than arginine. It is. That is, the "amino acid composition for inflammatory diseases" in the present invention is 1) It is composed of “human essential amino acids”; 2) It may be composed of “human essential amino acids” and “arginine”.
  • the amino acid composition of the present invention is characterized in that it contains no human non-essential amino acids other than arginine in both cases 1) and 2).
  • human essential amino acids and human non-essential amino acids may be simply referred to as essential amino acids and non-essential amino acids by omitting “human”.
  • the origin of the composition of the amino acid composition used in the present invention is not particularly limited.
  • the composition ratio (component ratio) of essential human amino acids is extracted from the total amino acid composition constituting milk casein, milk whey, egg yolk, egg white albumin, soybean protein, etc., and each amino acid is blended based on the composition ratio.
  • Essential amino acid compositions can be used.
  • Arginine may or may not be contained, but when arginine is contained, a further excellent effect is obtained.
  • an essential amino acid composition composed of human essential amino acid composition ratios contained in the total amino acid composition constituting milk whey, or a composition obtained by adding arginine to it is particularly preferred.
  • said milk is cow's milk, milk of mammals other than cows, such as goat milk and human breast milk, may be sufficient.
  • “human essential amino acids” are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, cysteine and tyrosine. These amino acids refer to L-form amino acids and may take the form of salts or the like. Examples of the salt include L-histidine hydrochloride, L-lysine hydrochloride, N-acetyl-L-cysteine, L-cystine, N-acetyl-L-tryptophan and the like. Examples of arginine include L-arginine hydrochloride.
  • each essential amino acid in the amino acid composition for inflammatory diseases in the present invention is 0.8 to 24.4% by weight of histidine (as a free amino acid: the same applies hereinafter) in the amino acid composition when arginine is not included. ), Leucine 1.9-50.4%, leucine 3.6-75.2%, lysine 1.7-68.8%, methionine 0.6-38.0%, cysteine 0.1 42.0% by weight, phenylalanine 0.1-55.6% by weight, tyrosine 0.1-43.6% by weight, threonine 1.5-54.4% by weight, tryptophan 0.4-16.4% by weight And 2.3 to 53.6% by weight of valine.
  • “as a free amino acid” means a net amino acid weight, and when a salt or the like is formed, it means that the amount is excluded.
  • a more preferable blending amount of each essential amino acid in the amino acid composition for inflammatory diseases in the present invention is 3.5 to 6.1% by weight of histidine in the amino acid composition (as free amino acid: The same), isoleucine 7.7 to 12.6% by weight, leucine 14.7 to 18.8% by weight, lysine 6.9 to 17.2% by weight, methionine 2.4 to 9.5% by weight, cysteine 0. 6 to 10.5 wt%, phenylalanine 6.1 to 13.9 wt%, tyrosine 5.6 to 10.9 wt%, threonine 6.1 to 13.6 wt%, tryptophan 1.9 to 4.1 wt% % And valine 9.3 to 13.4% by weight.
  • each amino acid in the amino acid composition for inflammatory diseases in the present invention is 0.8 to 24.4% by weight of histidine in the amino acid composition (as free amino acids: the same applies hereinafter).
  • the more preferable amount of each amino acid in the amino acid composition for inflammatory diseases in the present invention is 3.5 to 6.1% by weight of histidine in the amino acid composition (as a free amino acid: the same applies hereinafter).
  • the upper and lower limits of the amount of each amino acid are the composition ratios of essential amino acid requirements (amino acid score pattern) defined in WHO / FAO / UNU2007, milk casein, milk whey, egg yolk, egg white albumin, soy protein It calculated based on the maximum value and the minimum value of the composition ratio excluding the non-essential amino acids other than arginine in the total amino acid composition constituting the.
  • the amino acid composition for inflammatory diseases in the present invention is effective for treatment, prevention, induction / maintenance of remission, etc. of various inflammatory diseases.
  • the inflammatory disease include inflammatory bowel disease, rheumatism, collagen disease, allergic disease, bacteria / viruses and other infectious diseases, liver failure and the like.
  • the amino acid composition for inflammatory diseases of the present invention is particularly effective for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.
  • the amino acid composition for inflammatory diseases in the present invention may be administered to a patient as it is without being formulated, or may be formulated and administered. In the case of formulating, it can be mixed with excipients, adjuvants, additives and the like. When excipients, adjuvants, additives, and the like are used, their types and amounts thereof are not limited as long as they are pharmaceutically acceptable and pharmaceutically acceptable.
  • excipients, adjuvants and additives include, for example, gelling agents, thickeners, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, Stabilizers, buffers, antioxidants, surfactants and the like can be mentioned, and one or more of these can be used as appropriate.
  • the blending amounts of these excipients, adjuvants, additives and the like are, for example, 0.1% to 20.0% by weight, preferably 0.1% to 10% by weight with respect to the amino acid composition. 0.0 wt%, more preferably 0.1 wt% to 5.0 wt%.
  • the dosage form is not particularly limited, and any dosage form such as a dispersion preparation, a granular preparation, a solution preparation, a semi-solid preparation, a molded preparation, etc. You can also Among these, it is preferable to use powders, fine granules, granules, jellies and the like.
  • the amino acid composition for inflammatory diseases in the present invention can also be used as an active ingredient of a medicine.
  • the amino acid composition for inflammatory diseases of the present invention may be used by blending in a nutritional composition, and the form in that case can be a jelly agent, a liquid agent, a powder agent, a solid agent and the like.
  • the dose of the amino acid composition for inflammatory diseases in the present invention is not particularly limited as long as it is an amount effective for the treatment, prevention, induction and maintenance of inflammatory diseases.
  • it can be 0.001 to 1.5 g / kg body weight / day, preferably 0.1 to 1.0 g / kg body weight / day for an adult.
  • the dose can be appropriately increased or decreased depending on the age, weight, type of disease, degree of symptoms, sex, etc. of the patient.
  • the administration method is not particularly limited, but oral administration, enteral administration by tube, etc. are preferable.
  • the frequency of administration can be divided from once a day to an appropriate number of times.
  • the amino acid composition of the present invention is very effective for the treatment and prevention of inflammatory diseases or for the induction / maintenance of remission compared to a composition comprising all amino acids.
  • the amino acid composition of the present invention has far fewer side effects and less drug resistance than conventional drugs such as immunosuppressants, corticosteroids, molecular biological preparations (antibody drugs), and aminosalicylic acid preparations.
  • conventional drugs such as immunosuppressants, corticosteroids, molecular biological preparations (antibody drugs), and aminosalicylic acid preparations.
  • the safety is extremely high.
  • the amino acid composition of the present invention can be taken orally and is less expensive than the existing drugs, it can contribute to improved compliance and reduced medical costs.
  • the amino acid composition for inflammatory diseases according to the present invention is composed of essential human amino acids or arginine added thereto, the body protein of the patient can be maintained and the nutritional state can be improved. .
  • the nutritional composition for inflammatory diseases of the present invention comprises the amino acid composition for inflammatory diseases.
  • the nutritional composition for inflammatory diseases of the present invention preferably contains other nutritional components in addition to the amino acid composition. However, components other than the amino acid composition may be omitted as appropriate according to the degree of symptoms and nutritional status of the patient.
  • the content of the amino acid mixture in the nutritional composition of the present invention is not particularly limited, but is 1.25 to 12.5 g / 100 kcal nutritional composition per energy of the whole nutritional composition. Preferably 2.5 to 7.5 g / 100 kcal nutritional composition.
  • the amount of each component contained in the nutritional composition of the present invention may be indicated as the amount contained when the nutritional composition is 100 kcal.
  • Other nutrients include fats, sugars, minerals, vitamins and the like.
  • the fats and oils, carbohydrates, minerals and vitamins may be any as long as they are usually contained in the nutritional composition.
  • the fats and oils are not particularly limited, and the number of carbons in addition to natural fats and oils such as soybean oil, corn oil, palm oil, sesame oil, canola oil, safflower oil, sunflower oil, sesame oil, rice oil, grape seed oil and fish oil.
  • Synthetic fats and oils such as medium chain fatty acid triglycerides (MCT) of about 6 to 12 can be mentioned.
  • MCT medium chain fatty acid triglycerides
  • soybean oil, sesame oil, canola oil, olive oil, grape seed oil and the like are preferable as natural fats and oils.
  • a medium chain fatty acid triglyceride (MCT) is preferable.
  • Fatty acids constituting MCT are medium chain fatty acids having about 6 to 12 carbon atoms such as caproic acid, caprylic acid, capric acid, lauric acid, etc., and are composed of one or more of these.
  • MCT is not specifically limited, For example, caproic acid triglyceride, dicaprylic acid capric acid triglyceride, lauric acid capric acid caprylic acid triglyceride, caprylic acid triglyceride (tricaprylin), etc. are mentioned, Among these, tricaprylin is particularly preferable.
  • These fats and oils can be used alone or in combination of two or more.
  • the content of fats and oils in the nutritional composition of the present invention is not particularly limited, but is preferably 0.1 to 3.6 g / 100 kcal nutritional composition per energy of the whole nutritional composition, 0.5 to 2 More preferably, the nutritional composition is 0.0 g / 100 kcal.
  • the carbohydrate is not particularly limited, and examples thereof include starch, dextrin, maltodextrin, fructooligosaccharide, galactooligosaccharide, dairy oligosaccharide, lactulose, inulin, maltose, sucrose and glucose.
  • dextrin, maltodextrin, fructooligosaccharide, galactooligosaccharide, dairy oligosaccharide, lactulose, inulin and maltose are preferable, and dextrin, maltodextrin, fructooligosaccharide and dairy oligosaccharide are particularly preferable. These can be used alone or in combination of two or more.
  • the content of carbohydrate in the nutritional composition of the present invention is not particularly limited, but is preferably 4.4 to 23.5 g / 100 kcal nutritional composition per energy of the entire nutritional composition. More preferably, it is a 18.9 g / 100 kcal nutritional composition.
  • fructooligosaccharides or dairy oligosaccharides are contained as carbohydrates, it is preferable to contain 0.1 to 5.0 g / 100 kcal per total energy of the nutritional composition, and 1.0 to 2. More preferably, it is 5 g / 100 kcal.
  • the mineral is not particularly limited, and examples thereof include calcium, magnesium, sodium, potassium, phosphorus, iron, manganese, copper, iodine, zinc, selenium, chromium, and molybdenum. These may be used alone or in combination of two or more, for example, in the form of a salt.
  • the amount of mineral is not particularly limited, but is preferably 1.5 mg to 30.0 g / 100 kcal nutritional composition per energy of the whole nutritional composition, and 2.3 to 6.0 g / 100 kcal nutritional composition. More preferably.
  • the blending amount of the individual minerals is not particularly limited, however, for example, a preferable blending amount of calcium is 0.65 mg to 480 mg / 100 kcal nutritional composition per energy of the entire nutritional composition, and 6.5 mg to 260 mg / 100 kcal nutritional. More preferred are compositions.
  • a preferable blending amount of magnesium is 0.4 mg to 30 mg / 100 kcal nutritional composition, more preferably 4.0 mg to 15 mg / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • the preferred amount of sodium is 0.3 mg to 3000 mg / 100 kcal nutritional composition, more preferably 3.0 mg to 1000 mg / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • a preferable blending amount of potassium is 0.13 mg to 700 mg / 100 kcal nutritional composition, more preferably 13 mg to 350 mg / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • the preferable amount of phosphorus is 0.4 mg to 700 mg / 100 kcal nutritional composition, more preferably 4.0 mg to 350 mg / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • a preferable blending amount of iron is 0.01 mg to 12.0 mg / 100 kcal nutritional composition, more preferably 0.1 mg to 6.0 mg / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • the preferred compounding amount of manganese is 0.001 mg to 3.0 mg / 100 kcal nutritional composition, more preferably 0.01 mg to 1.5 mg / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • a preferable blending amount of copper is 0.001 mg to 3.0 mg / 100 kcal nutritional composition, more preferably 0.01 mg to 1.5 mg / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • a preferable blending amount of iodine is 0.1 ⁇ g to 500 ⁇ g / 100 kcal nutritional composition, more preferably 1 ⁇ g to 250 ⁇ g / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • a preferable blending amount of zinc is 0.005 mg to 10 mg / 100 kcal nutritional composition, more preferably 0.05 mg to 5 mg / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • a preferable blending amount of selenium is 0.03 ⁇ g to 70 ⁇ g / 100 kcal nutritional composition, more preferably 0.3 ⁇ g to 35 ⁇ g / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • the preferable blending amount of chromium is 0.002 ⁇ g to 240 ⁇ g / 100 kcal nutritional composition, more preferably 0.02 ⁇ g to 120 ⁇ g / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • a preferable blending amount of molybdenum is 0.05 ⁇ g to 140 ⁇ g / 100 kcal nutritional composition, more preferably 0.5 ⁇ g to 70 ⁇ g / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • the vitamin is not particularly limited, and examples thereof include fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, and vitamin K, and water-soluble vitamins such as vitamin B and vitamin C. These can be used alone or in combination of two or more, but vitamin C, vitamin D, and vitamin E are preferably used.
  • vitamin A examples include retinol (vitamin A 1 ), 3-dehydroretinol (vitamin A 2 ), retinal, 3-dehydroretinal, retinoic acid and 3-dehydroretinoic acid, and acetates and palmitates thereof. And the like, and provitamin A such as ⁇ -carotene.
  • vitamin D examples include ergocalciferol (vitamin D 2 ), cholecalciferol (vitamin D 3 ), and derivatives such as sulfates thereof.
  • vitamin E examples include ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, and their acetates, nicotinates, Derivatives such as phosphate esters and salts thereof such as ⁇ -tocopherol disodium.
  • vitamin K examples include phytonadione (vitamin K 1 ), menaquinone (vitamin K 2 ), menadione (biotamine K 3 ), and the like.
  • vitamin B examples include thiamine (vitamin B 1 ), riboflavin (vitamin B 2 ), nicotinic acid, nicotinic acid amide (hereinafter, niacin; vitamin B 3 ), pantothenic acid (vitamin B 5 ), pyridoxine, pyridoxal, pyridoxamine (Above, vitamin B 6 ), biotin (vitamin B 7 ), folic acid (vitamin B 9 ), cyanocobalamin, adenosylcobalamin, methylcobalamin, sulfitocobalamin (above, vitamin B 12 ), and salts thereof Etc.
  • vitamin B 1 examples include thiamine (vitamin B 1 ), riboflavin (vitamin B 2 ), nicotinic acid, nicotinic acid amide (hereinafter, niacin; vitamin B 3 ), pantothenic acid (vitamin B 5 ), pyridoxine, pyridoxal,
  • the blending amount of vitamins is not particularly limited, but is preferably 0.005 mg to 1000 mg / 100 kcal nutritional composition, more preferably 1.0 mg to 500 mg / 100 kcal nutritional composition per energy of the whole nutritional composition. preferable.
  • the blending amount of each vitamin is not particularly limited, however, for example, the blending amount of vitamin A is preferably 1.0 ⁇ g to 500 ⁇ g / 100 kcal nutritional composition as retinol equivalent per energy of the whole nutritional composition of the present invention. More preferably, 0 ⁇ g to 300 ⁇ g / 100 kcal.
  • the amount of vitamin D blended is preferably 0.05 ⁇ g to 12 ⁇ g / 100 kcal nutritional composition, more preferably 0.1 ⁇ g to 5.6 ⁇ g / 100 kcal nutritional composition per energy of the whole nutritional composition of the present invention.
  • the amount of vitamin E is preferably 0.05 mg to 150 mg / 100 kcal nutritional composition, more preferably 0.10 mg to 100 mg / 100 kcal nutritional composition as ⁇ -tocopherol equivalent per energy of the whole nutritional composition of the present invention.
  • the blending amount of vitamin K is preferably 0.1 ⁇ g to 100 ⁇ g / 100 kcal nutritional composition, more preferably 1 ⁇ g to 9 ⁇ g / 100 kcal nutritional composition per energy of the whole nutritional composition of the present invention.
  • the amount of vitamin B 1 represents, per energy of the entire nutritional composition of the present invention is preferably 0.001 mg ⁇ 40 mg / 100 kcal nutritional composition, more preferably 0.01 mg ⁇ 15 mg / 100 kcal nutritional composition.
  • the blending amount of vitamin B 2 is preferably 0.01 mg to 50 mg / 100 kcal nutritional composition, more preferably 0.33 mg to 25 mg / 100 kcal nutritional composition per energy of the whole nutritional composition of the present invention.
  • the blending amount of vitamin B 3 is preferably 0 mg to 200 mg / 100 kcal nutritional composition, more preferably 0.1 mg to 100 mg / 100 kcal nutritional composition as niacin equivalent per energy of the whole nutritional composition of the present invention.
  • the amount of vitamin B 5 are per energy of the entire nutritional composition of the present invention is preferably 0.01 mg ⁇ 240 mg / 100 kcal nutritional composition, 0.1 mg ⁇ 120 mg / 100 kcal nutritional composition further preferred.
  • the blending amount of vitamin B 6 is preferably 0.001 mg to 20 mg / 100 kcal nutritional composition, more preferably 0.005 mg to 10 mg / 100 kcal nutritional composition as pyridoxine per energy of the whole nutritional composition of the present invention.
  • the blending amount of vitamin B 7 is preferably 0.01 ⁇ g to 560 ⁇ g / 100 kcal nutritional composition, more preferably 0.1 ⁇ g to 300 ⁇ g / 100 kcal nutritional composition per energy of the whole nutritional composition of the present invention.
  • the blending amount of vitamin B 9 is preferably 0.2 ⁇ g to 240 ⁇ g / 100 kcal nutritional composition, more preferably 2.0 ⁇ g to 200 ⁇ g / 100 kcal based on the total energy of the nutritional composition of the present invention.
  • the amount of vitamin B 12 is per energy of the entire nutritional composition of the present invention, preferably 0.01 ⁇ g ⁇ 340 ⁇ g / 100kcal nutritional composition as cyanocobalamin substantial amount, 0.1 ⁇ g ⁇ 170 ⁇ g / 100kcal nutritional composition further preferred.
  • the blending amount of vitamin C is preferably 0.01 mg to 220 mg / 100 kcal nutritional composition, more preferably 1.1 mg to 110 mg / 100 kcal nutritional composition per energy of the whole nutritional composition.
  • the blending amount of vitamin C is 0.01 mg to 220 mg / 100 kcal nutritional composition, particularly 1.1 mg to 110 mg / 100 kcal nutritional composition in the energy of the whole nutritional composition
  • the vitamin D content is 0.05 ⁇ g to 12 ⁇ g / 100 kcal nutritional composition, in particular, 0.10 ⁇ g to 5.6 ⁇ g / 100 kcal nutritional composition
  • the amount of vitamin E is 0.05 mg to 150 mg / 100 kcal nutritional composition, in particular, 0.10 mg to 100 mg / 100 kcal nutritional composition, As a result, the disease state improving effect on inflammatory diseases can be further improved.
  • the nutrition composition for inflammatory diseases of the present invention may contain components such as excipients, emulsifiers, stabilizers, pH adjusters, and fragrances. These types are not particularly limited, and those usually used in nutritional compositions can be used as appropriate.
  • the form of the nutritional composition for inflammatory diseases of the present invention is not particularly limited, and any form can be used as long as it is a form of a normal nutritional composition.
  • jelly agents liquid agents, powder agents, solid agents and the like can be used.
  • a jelly shape is preferable.
  • the administration route of the nutritional composition for inflammatory diseases of the present invention is not particularly limited, and may be oral administration or enteral administration using a PEG tube or the like.
  • the number of administrations can be appropriately given by dividing once to several times a day.
  • the nutritional composition for inflammatory diseases of the present invention is effective for improving the pathological condition of inflammatory diseases such as inflammatory bowel disease, that is, treatment, prevention and induction / maintenance of remission.
  • inflammatory diseases such as inflammatory bowel disease, that is, treatment, prevention and induction / maintenance of remission.
  • the inflammatory disease include inflammatory bowel disease, rheumatism, collagen disease, allergic disease, bacteria / viruses and other infectious diseases, liver failure and the like.
  • the nutritional composition for inflammatory diseases of the present invention is particularly effective for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.
  • the nutritional composition for inflammatory diseases of the present invention may contain a medicine in addition to the nutritional component.
  • the drug may be a drug for inflammatory diseases or a drug having other pharmacological effects.
  • the dose of the nutritional composition for inflammatory diseases of the present invention is not particularly limited as long as it is an amount effective for improving the disease state.
  • it can be administered to an adult in terms of amino acid composition at 0.001 to 1.5 g / kg body weight / day, preferably 0.1 to 1.0 g / kg body weight / day.
  • the dose can be appropriately increased or decreased depending on the age, weight, type of disease, degree of symptoms, sex, etc. of the patient.
  • the administration method is not particularly limited, but oral administration, enteral administration by tube, etc. are preferable.
  • the frequency of administration can be divided from once a day to an appropriate number of times.
  • the nutritional composition for inflammatory diseases of the present invention is very effective for the treatment and prevention of inflammatory diseases or for the induction / maintenance of remission as compared with conventional nutritional compositions containing all amino acid compositions as nitrogen sources.
  • the nutritional composition for inflammatory diseases of the present invention it is possible to improve the pathological condition of inflammatory diseases without resorting to drug therapy.
  • the nutritional composition for inflammatory diseases containing the amino acid mixture of the present invention has no side effects as compared with existing medicines and the like, and is extremely safe. Since the nutritional composition for inflammatory diseases of the present invention comprises an amino acid composition composed of essential human amino acids or an amino acid composition in which arginine is added to it as an active ingredient, the body protein of the patient can be maintained. Nutritional status can also be improved.
  • Example 1 Nutritional compositions having the compositions shown in Tables 1 to 4 below were prepared.
  • the composition shown in Table 1 is a composition containing 20% by weight (as a free amino acid) of a total amino acid mixture as amino acids (Total AA 20% by weight: nutritional composition A) and a mixture of only essential amino acids as amino acids.
  • Total AA 20% by weight: nutritional composition A a composition containing 15% by weight (as free amino acids)
  • EAA 15% by weight: nutritional composition B The nutritional composition A is referred to as “Comparative Example 1”
  • the nutritional composition B is referred to as “Example 1”.
  • composition shown in Table 2 is a composition containing 20% by weight (as a free amino acid) of the total amino acid mixture (Total AA 20% by weight: nutritional composition A) and a mixture of only essential amino acids as amino acids.
  • a composition containing 20% by weight (as free amino acids) (EAA 20% by weight: nutritional composition C).
  • the nutritional composition C is referred to as “Example 2”.
  • composition shown in Table 3 is a composition containing 20% by weight (as a free amino acid) of the total amino acid mixture (Total AA 20% by weight: nutritional composition A), and the amino acids as essential amino acids and arginine in total. It is a composition containing 15% by weight (as free amino acids) (EAA + Arg 15% by weight: nutritional composition D).
  • the nutritional composition D is referred to as “Example 3”.
  • fructooligosaccharide (FOS) is added to the nutrition composition containing the same amino acid composition as the nutrition composition D shown in Table 3, and vitamin D, vitamin E, and vitamin C are added.
  • the nutritional composition E is referred to as “Example 4”.
  • the nutritional composition A and the nutritional composition B, the nutritional composition A and the nutritional composition C, and the nutritional composition A and the nutritional composition D are different only in amino acid composition.
  • Other types of components oil and fats, sugars, minerals, vitamins, additives
  • the increased amount of amino acids can be reduced by reducing the amount of carbohydrate dextrin It was adjusted.
  • the amino acids of the nutritional composition D and the nutritional composition E are almost the same, but the nutritional composition E is mixed with fructooligosaccharide (FOS) as a carbohydrate, and vitamin D, vitamin E, vitamin C was a composition formulated at a higher value than the nutritional composition D, and the increased amount was adjusted by reducing the amount of the dextrin compounded.
  • FOS fructooligosaccharide
  • Total AA indicates all amino acids including essential amino acids and non-essential amino acids
  • EAA indicates essential amino acids.
  • “%” indicates “% by weight”.
  • each nutritional composition was obtained by the usual method for preparing a nutritional composition (powder).
  • Rats used in this test example were prepared according to the method described in Morris GP et al: Gastroenterology, Vol. 96, P795 (1989).
  • the method described in the document is a method of inducing granulomatous formation similar to Crohn's disease by enforcing rat or mouse with trinitrobenzenesulfonic acid (TNBS) together with ethanol.
  • TNBS trinitrobenzenesulfonic acid
  • a solution of TNBS dissolved in 50% ethanol is generally administered into the colon approximately 4 cm from the anus.
  • TNBS chronic colitis similar to Crohn's disease, in which granuloma formation is observed with significant infiltration of mononuclear cells.
  • TNBS was administered not to the large intestine but to the small intestine (ileum), which is a site of frequent inflammation of Crohn's disease (Ohta N, Tsujikawa T, Nakamura, T et al.
  • TNBS sensitization After habituation, rats were sensitized with TNBS. That is, 0.15 ml of 6 mg / 0.15 ml / rat (4% TNBS in physiological saline) was administered to the rats to perform TNBS sensitization. TNBS sensitization has been reported to be effective in stabilizing the TNBS model (such as reduced mortality) (Ishida T, Azuma T et al. (2010) Inflamm Bowel Dis. 16 (1): 87-95 , Kazuo Moriwaki et al. (2004) Production and maintenance of model animals (Life-science information center). (Fasting) Prior to TNBS administration, the rats were fasted for 2 days from day 4 after TNBS sensitization in order to temporarily eliminate intestinal contents.
  • TNBS administration After fasting, the rats were anesthetized with sodium pentobarbital (intraperitoneal administration, 40 mg / 0.8 ml / kg body weight) and then laparotomized, and the area around the small intestine 10 cm upstream from the ileocecal valve was pulled out of the abdominal cavity.
  • a syringe with a 29G needle in the range of 10 cm upstream from the site 10 cm upstream of the ileocecal valve 120 mg / ml TNBS in 50% ethanol was administered in the small intestine at a volume of 0.3 ml / rat. After standing for 30 minutes, the intestinal tract was returned to the abdominal wall, and the abdominal muscles and skin that were cut open were sutured to close the abdomen.
  • the obtained TNBS modified model rats of Test Example 1 were made 10 per group, and each of the nutritional compositions A to E obtained in Comparative Example 1 and Examples 1 to 4 was orally administered at a dose of 15 g / day.
  • the composition shown in Table 1 is a composition containing 20% by weight (as free amino acids) of a total amino acid mixture as amino acids (Total AA 20% by weight: Composition A), and a mixture of only essential amino acids as amino acids. , 15% by weight (as free amino acids) (EAA 15% by weight: Composition B).
  • the composition shown in Table 2 is a composition containing 20% by weight (as a free amino acid) of the total amino acid mixture (Total AA 20% by weight: Composition A) and a mixture of only essential amino acids as amino acids.
  • a composition containing 20% by weight (as free amino acids) (EAA 20% by weight: Composition C).
  • the composition shown in Table 3 is a composition containing 20% by weight (as a free amino acid) of the total amino acid mixture (Total AA 20% by weight: Composition A), and essential amino acids and arginine as amino acids in total.
  • a composition containing 15% by weight (as free amino acids) ((EAA + Arg) 15% by weight: Composition D) is shown.
  • composition shown in Table 4 is a composition containing 15% by weight (as a free amino acid) of the total amino acid mixture (Total AA 15% by weight: Composition D ), and essential amino acids and arginine as amino acids in total. 15% by weight (as free amino acids) and a composition containing FOS + vitamins C, D and E at high values ((EAA + Arg) 15% by weight + FOS + vitamins C, D and E: composition E).
  • Composition A and Composition B, Composition A and Composition C, Composition A and Composition D differ only in amino acid composition, and other components (oils and fats, The content of each component is basically the same as that of carbohydrates, minerals, vitamins, and additives), but the amount of amino acids increased was adjusted by reducing the amount of carbohydrate dextrin.
  • these compositions were manufactured by the manufacturing method of the normal nutrition composition using the commercially available amino acid (made by Kyowa Hakko Co., Ltd.).
  • Total AA indicates all amino acids including essential amino acids and non-essential amino acids
  • EAA indicates essential amino acids.
  • “%” indicates “% by weight”.
  • Each amino acid composition was administered to rats from 7 days before TNBS small intestine administration to 2 days before administration, and from 1 day after TNBS small intestine administration to 7 days after administration.
  • the visual score (1) was calculated by the method of Vilaseca et al. (Dietary fish oil reduces progression of chronic inflammatory lesions in a rat model of granulomatous colitis.Vilaseca J, Salas A, Guarner M, Malagelada JR.Gut. 1990 May; 31 (5): 539-44.) was determined by an improved scoring method.
  • the naked eye score (2) is as follows: Wallace (Assessment of the role of platelet-activating factor in an animal model of inflammatory bowel disease. Wallace JL, Braquet P, Ibbotson GC, MacNaughton WK, Cirino G Mediat. 1989 Jan-Feb; 1 (1): 13-23.) And the like were determined by a modified scoring method.
  • the visual score (3) is calculated as follows: Caroline (Reactivation of hapten-induced colitis and its prevention by anti-inflammatory drugs. Appleyard Caroline B, Wallace JL. Am J Physiol. 1995 Jul; 269 (1 Pt 1) : G119-25.) Et al.
  • Adhesion 0 None 1: Mild (can be easily peeled off) 2: Severe (significant loop or difficulty peeling) Dilation 0: None 1: Mild 2: Moderate 3: Severe (with stenosis) Ulcer 0: None 1: Mild (congested to relatively small and shallow) 2: Severe (a wide range with significant thickening) Thickness 0: 1.0 mm or less 1: 1.0-2.0 mm 2: 2.0-3.0mm 3: Damage score of 3.0 mm or more: The above judgment values were summed for each animal, and an average value of 10 animals was obtained.
  • Score 0 No obstacle. Score 1: hyperemia. No ulcer. Score 2: hyperemia and thickening of the colon wall. No ulcer. Score 3: One ulcer without thickening of the colon wall Score 4: Two or more ulcers or inflammation. Score 5: Two or more relatively large ulcers or inflammation. Or an ulcer or inflammation of about 1 to 2 cm. Score 6: Ulcer or inflammation of about 2 to 3 cm. Score 7: Ulcer or inflammation of about 3-4 cm. Score 8: Ulcer or inflammation of about 4-5 cm. Score 9: Ulcer or inflammation of about 5-6 cm. Score 10: Ulcer or inflammation over 6 cm. Damage score: The average value of the above 10 animals was determined.
  • the amino acid does not contain a non-essential amino acid and does not contain a non-essential amino acid as compared with the case where a nutritional composition A containing all amino acid mixtures is administered as an amino acid (Comparative Example 1).
  • a nutritional composition A containing all amino acid mixtures is administered as an amino acid
  • Comparative Example 1 In the case of administering the nutritional compositions B and C containing only (Examples 1 and 2), it was revealed that pathological conditions such as intestinal adhesions, dilation, and ulcers were greatly improved.
  • the nutritional composition C of Example 2 containing 20% by weight (as a free amino acid) of essential amino acids, but also the nutritional composition B of Example 1 (15) in which the amount of amino acids is less than the composition of Comparative Example 1.
  • Example 3 which added arginine to the essential amino acid, it became clear that a disease state improved further.
  • the ulcer area is particularly small, the thickness of the intestinal tract wall and the weight of the small intestine are remarkably reduced, and it can be said that the pathological condition improving effect is remarkable.
  • Example 4 in which fructooligosaccharides were blended into the composition having almost the same amino acid composition as the nutritional composition of Example 3 and vitamins C, D and E were blended at high values, even better results were obtained. As a result, an effect of improving the pathological condition of inflammatory bowel disease was obtained.
  • the nutritional composition for inflammatory diseases of the present invention is more excellent in the pathological condition improving effect on inflammatory bowel disease than the composition using all amino acid compositions as amino acids, 2) When arginine is added to the essential amino acid, a better disease state improving effect can be obtained, 3) It was found that the effect of improving the pathological condition was further improved by blending fructooligosaccharides as carbohydrates and blending vitamins C, D and E at high values.
  • Test Example 2 In this test example, general mouse colitis (TNBS solution was administered into the colon approximately 4 cm from the anus) was prepared, and evaluation of inflammatory cytokines in the intestinal tissue including the lesion site was performed.
  • the test procedure was as follows. (Acclimation) SJL / J male mice (weighing about 20 g) were acclimated for 7 days, during which they were fed the AIN-93G diet. (Fasting) Prior to TNBS administration, the mice were fasted for 1 day from 6 pm one day before TNBS colon administration in order to temporarily eliminate the contents of the intestinal tract.
  • mice were pre-anesthetized with isoflurane (gas anesthesia system for small experimental animals; manufactured by DS Pharma Biomedical Co., Ltd.) and then left for 3 minutes or more under maintenance anesthesia to lower the abdominal pressure.
  • isoflurane gas anesthesia system for small experimental animals; manufactured by DS Pharma Biomedical Co., Ltd.
  • a 4Fr nutritional catheter manufactured by Atom Medical Co., Ltd.
  • insert a TNBS solution which is turned upside down with the mouse's tail, into the colon lumen about 4 cm from the anus, and slowly inject 100 ⁇ l. It left still for 1 minute as it was. Thereafter, in order to prevent leakage of TNBS, the patient was placed on his back with his hind legs warped upward, returned to the state of maintenance anesthesia, and allowed to stand for 5 minutes.
  • TNBS mouse of this test example dissection was performed 4 days after TNBS colon administration, the colon was removed, and inflammatory cytokines in the colon tissue including the lesion site were analyzed by ELISA (R & D systems kit).
  • the large intestine tissue was homogenized in TBST (Tris-Buffered Saline + 1% Triton X-100 + Protease inhibitor), and then the supernatant was recovered as a protein extract by centrifugation (20,000 ⁇ g, 4 ° C., 30 minutes). And subjected to ELISA.
  • TNF- ⁇ is an inflammatory cytokine that works in concert with interleukin-1 (IL-1) and interleukin-6 (IL-6) to induce cell invasion, adhesion molecule expression induction, and cell death.
  • IL-6 is a cytokine that is produced in the early stages of inflammation, induces the production of chemokines that induce cell invasion, and induces the expression of adhesion molecules.
  • interleukin-1a induces inflammatory cytokines such as IL-6 and TNF- ⁇ , and is itself a neutrophil-inducing cytokine. Therefore, if the amount of these cytokines is reduced by administering the nutritional composition, it is indicated that inflammation is suppressed.
  • Table 6 The results are shown in Table 6.
  • composition B Example 1
  • composition E Example 4
  • fructooligosaccharide as a carbohydrate and containing vitamins C, D and E at high values
  • composition B and composition E the amino acid composition containing only the essential amino acid without containing the non-essential amino acid
  • composition E contains fructooligosaccharides, and vitamins C, D and E at high levels further suppress the production of these cytokines. That is, it was found that the amino acid composition of the present invention is effective in suppressing inflammation of inflammatory diseases.
  • Test Example 3 In this test example, the effect of the amino acid composition of the present invention administered together with normal food on the pathology of small intestinal inflammation caused by TNBS was examined.
  • the types of rats used and the test procedures were the same as in Test Example 1.
  • CRF-1 (manufactured by Oriental Yeast Co., Ltd.) was used as a normal bait.
  • CRF-1 is a general powder feed used for laboratory animals such as mice, rats, hamsters, and has the following composition in 100 g. Moisture 7.8g Crude protein 22.4g 5.7g of crude fat 6.6 g of crude ash Coarse fiber 3.1g Soluble nitrogen free 54.5g
  • CRF-1 contains a large amount of fiber and fat, and a nitrogen source is contained not as an amino acid but as a protein, and is essentially a composition (feed) that is not suitable for an inflammatory bowel disease model. It is.
  • a total amino acid composition (1), an essential amino acid composition (2), and a composition (3) containing an essential amino acid and arginine containing amino acids in the proportions shown in Table 7 (as free amino acids (% by weight)) were prepared.
  • Each of the amino acid compositions (1) to (3) was mixed with normal bait (CRF-1) as shown in Table 8.
  • the amounts of amino acids in the mixed feeds A to D shown in Table 8 are as follows. “Mixed feed A”: 20% of the total amino acid composition (1) added to the total amount of mixed feed. That is, the amount of the total amino acid composition (1) in 100 g of mixed feed is 20 g (as a free amino acid).
  • “Mixed diet B” a mixture obtained by adding 15% of the essential amino acid composition (2) to the total amount of the mixed diet. That is, the amount of the essential amino acid composition (2) in 100 g of mixed feed is 15 g (as a free amino acid).
  • “Mixed diet C” 20% of the essential amino acid composition (2) added to the total amount of the mixed diet. That is, the amount of the essential amino acid composition (2) in 100 g of mixed feed is 20 g (as a free amino acid).
  • “Mixed diet D” 15% of the above (essential amino acids and arginine) composition (3) added to the total amount of the mixed diet.
  • the amount of the (essential amino acids and arginine) composition (3) in 100 g of mixed feed is 15 g (as free amino acids).
  • amino acids shown in Table 7 are expressed as the amount of amino acids when actually used, they are as shown in Table 9. Normal diet and mixed diets AD were fed to the mice so that all energy intakes were equal.
  • an amino acid composition containing only essential amino acids as amino acids and an amino acid composition containing only essential amino acids and arginine have a better therapeutic effect on inflammatory bowel disease than when all amino acid compositions are used.
  • the mixed diet C containing 20% by weight of essential amino acids but also the mixed diet B in which the amount of amino acid is smaller than that of the composition A the therapeutic effect superior to the mixed diet A is obtained, and the amino acid of the present invention It can be seen that the excellent anti-inflammatory effect of the composition is obtained by not containing non-essential amino acids.
  • the effect in Test Example 3 is not so remarkable as compared with the result obtained in Test Example 1, this is considered to be caused by ingestion of normal food.
  • the normal diet (CRF-1) used in Test Example 3 is a diet containing a large amount of fat and fiber that is not suitable for the inflammatory bowel disease model, and the nitrogen source is not included as an amino acid but as a protein. Yes.
  • These fats, fibers, and proteins are components that cause deterioration of inflammatory bowel disease.
  • the mixed food B group, the mixed food C group, and the mixed food D group were used in this order, rather than the normal food group fed only with the normal food and the mixed food A added with the whole amino acid composition. Similar to Test Example 1, the effect of the present invention was increased.
  • the composition of the present invention is inflammatory by ingesting an amino acid composition containing only essential amino acids or an amino acid composition containing only essential amino acids and arginine, even in animals that have been fed a feed that is not suitable for inflammatory bowel disease. It has been found that it has the effect of improving bowel disease.
  • Example 5 Manufacture of powder containing human essential amino acid composition as active ingredient
  • the composition ratio of essential amino acids is the amino acid of milk whey protein described in Heine WE, Klein PD, Reeds PJ. Et.al. (1991) The importance of alpha-lactalbumin in infant nutrition. 121 (3): 277-83.
  • a net amino acid amount (as a free amino acid, ie, subtracting the amount of salt), histidine 3.7% by weight, isoleucine 11.5% by weight, leucine, 18.8% by weight, Lysine 16.7 wt%, methionine 4.1 wt%, cysteine 4.1 wt%, phenylalanine 6.5 wt%, tyrosine 6.0 wt%, threonine 13.6 wt%, tryptophan 3.5 wt% and valine The amount was 11.5% by weight. A mixture consisting only of these essential amino acids was prepared and used as an active ingredient of the powder.
  • the above components were weighed by a conventional powder preparation method, premixed, pulverized using a pulverizer, and mixed again to produce 10 kg of an amino acid mixture.
  • the obtained amino acid mixture was weighed and packaged so as to be 5.0 g per package to obtain a powder containing the amino acid composition for inflammatory diseases of the present invention.
  • Example 6 Manufacture of powders containing a mixture of human essential amino acids and arginine as active ingredients
  • a powder containing the amino acid composition for inflammatory diseases of the present invention was prepared in the same manner as in Example 1 except that L-arginine hydrochloride (manufactured by Kyowa Hakko) was added.
  • composition ratio of each amino acid is the net amino acid amount (as a free amino acid, that is, the salt is subtracted), histidine 3.5 wt%, isoleucine 11.0 wt%, leucine 17.9 wt% Lysine 15.9 wt%, methionine 3.9 wt%, cysteine 3.9 wt%, phenylalanine 6.2 wt%, tyrosine 5.7 wt%, threonine 12.9 wt%, tryptophan 3.4 wt%, The content was 11.0% by weight of valine and 4.8% by weight of arginine.
  • the nutritional composition for inflammatory diseases of the present invention is very effective for the treatment, prevention, induction and maintenance of inflammatory diseases such as inflammatory bowel diseases represented by Crohn's disease and ulcerative colitis. Can maintain patient body protein and can improve nutrition.
  • the nutritional composition for inflammatory diseases of the present invention is inexpensive and can contribute to a reduction in medical costs without worrying about side effects like existing drugs.
  • the amino acid composition for inflammatory diseases of the present invention is very effective for the treatment, prevention, induction and maintenance of inflammatory diseases represented by Crohn's disease and ulcerative colitis.
  • the amino acid composition for inflammatory diseases of the present invention can be administered orally with no side effects or drug resistance as compared with existing drugs, and can improve nutrition of patients.
  • the amino acid composition of the present invention is cheaper than existing pharmaceuticals, it can contribute to a reduction in medical costs.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Nutrition Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pediatric Medicine (AREA)
  • Cardiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heart & Thoracic Surgery (AREA)

Abstract

La présente invention concerne une composition nutritionnelle pour des maladies inflammatoires qui a un excellent effet d'amélioration des symptômes de maladies inflammatoires comprenant le syndrome abdominal inflammatoire, peut retenir les protéines dans le corps d'un patient, et est utile pour améliorer un état nutritionnel ; et une composition d'acides aminés pour des maladies inflammatoires, qui doit être contenue dans la composition nutritionnelle. La composition d'acides aminés pour les maladies inflammatoires comprend des acides aminés essentiels humains et ne contient pas d'acides aminés non essentiels humains autres que l'arginine. La composition nutritionnelle pour des maladies inflammatoires qui comprend la composition d'acides aminés contient de préférence une huile ou une graisse, un glucide, une vitamine et un minéral.
PCT/JP2012/057538 2011-03-25 2012-03-23 Composition nutritionnelle pour maladies inflammatoires WO2012133198A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2011-067459 2011-03-25
JP2011067463A JP5837315B2 (ja) 2011-03-25 2011-03-25 炎症性疾患用栄養組成物
JP2011-067463 2011-03-25
JP2011067459 2011-03-25

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WO2012133198A1 true WO2012133198A1 (fr) 2012-10-04

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EP3006027A1 (fr) * 2014-10-08 2016-04-13 Professional Dietetics S.p.A. Compositions comprenant des acides aminés destinées à être utilisées dans le traitement de l' etat inflammatoire systemique associe a des accidents cérébrovasculaires chez des patients souffrant de dysphagie
CN105685973A (zh) * 2016-02-04 2016-06-22 贺青 一种肠内营养剂
WO2021113762A1 (fr) * 2019-12-06 2021-06-10 Axcella Health Inc. Compositions et procédés excluant la glutamine ou faisant appel à un niveau réduit de glutamine pour le traitement d'hémoglobinopathies et de thalassémies

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JPH07252145A (ja) * 1993-10-28 1995-10-03 Clintec Nutrition Co アミノ酸をベースとする成分
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Publication number Priority date Publication date Assignee Title
EP3006027A1 (fr) * 2014-10-08 2016-04-13 Professional Dietetics S.p.A. Compositions comprenant des acides aminés destinées à être utilisées dans le traitement de l' etat inflammatoire systemique associe a des accidents cérébrovasculaires chez des patients souffrant de dysphagie
US20160101078A1 (en) * 2014-10-08 2016-04-14 Professional Dietetics S.P.A. Compositions comprising amino acids for use in the treatment of stroke in patients with dysphagia
WO2016055948A1 (fr) * 2014-10-08 2016-04-14 Professional Dietetics S.P.A. Compositions comprenant des acides aminés à utiliser dans le traitement d'accident vasculaire cérébral de patients atteints de dysphagie
US9707198B2 (en) * 2014-10-08 2017-07-18 Professional Deitetics S.p.A. Compositions comprising amino acids for use in the treatment of stroke in patients with dysphagia
CN105685973A (zh) * 2016-02-04 2016-06-22 贺青 一种肠内营养剂
WO2021113762A1 (fr) * 2019-12-06 2021-06-10 Axcella Health Inc. Compositions et procédés excluant la glutamine ou faisant appel à un niveau réduit de glutamine pour le traitement d'hémoglobinopathies et de thalassémies

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