WO2016148046A1 - Gastric volume-reducing agent - Google Patents

Gastric volume-reducing agent Download PDF

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Publication number
WO2016148046A1
WO2016148046A1 PCT/JP2016/057714 JP2016057714W WO2016148046A1 WO 2016148046 A1 WO2016148046 A1 WO 2016148046A1 JP 2016057714 W JP2016057714 W JP 2016057714W WO 2016148046 A1 WO2016148046 A1 WO 2016148046A1
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Prior art keywords
glutamine
phenylalanine
methionine
amino acids
stomach
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PCT/JP2016/057714
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French (fr)
Japanese (ja)
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内田　勝幸
千鶴 岩本
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株式会社明治
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Priority to JP2017506513A priority Critical patent/JP6764856B2/en
Publication of WO2016148046A1 publication Critical patent/WO2016148046A1/en

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    • 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
    • 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, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]

Definitions

  • the present invention relates to a gastric capacity reducing agent containing one or more selected from glutamine, methionine and phenylalanine as an active ingredient.
  • Lifestyle-related diseases are diseases that develop or progress due to genetic factors (originally predisposing to the disease, etc.) and lifestyle-related factors (such as eating and drinking too much, lack of exercise, and smoking).
  • examples of lifestyle-related diseases include hypertension, hyperlipidemia, diabetes and the like, and important factors include obesity associated with excessive eating, excessive drinking, and lack of exercise.
  • Dietary therapy and exercise therapy are known as treatment methods for obesity, but the actual situation is that these therapies do not have a sufficiently effective effect.
  • the present inventors screened a material that reduces the stomach volume by using a non-invasive screening method for the stomach.
  • glutamine, methionine, and phenylalanine which are major amino acids with dietary experience, are found in the stomach. It was found that it is effective for capacity reduction.
  • the present inventors used this test system to monitor adaptive relaxation when an amino acid was administered to give an animal a gastric stretch stimulus. Glutamine, methionine and phenylalanine were adapted to the gastric stretch stimulus. It was found that the relaxation of the stomach bottom and / or the upper body of the stomach was suppressed (when a stomach stretching stimulus was applied). The present invention is based on the above findings.
  • the object of the present invention is to provide a gastric volume reducing agent that is safe and can be taken for a long time.
  • a gastric volume reducing agent comprising as an active ingredient one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine.
  • the agent according to the above [1] which suppresses relaxation of the stomach bottom and / or stomach upper body adapted to gastric stretch stimulation.
  • a prophylactic, therapeutic and / or ameliorating agent for obesity containing, as an active ingredient, one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine.
  • [5] The agent according to any one of [1] to [4] above, which is formulated so that the daily intake or dosage of amino acids in humans is 0.2 to 5 g in terms of solid content of amino acids. .
  • [6] The agent according to any one of [1] to [5] above, which is in a package unit form per one intake or dose.
  • a method for reducing gastric volume comprising orally ingesting one or more amino acids selected from glutamine, methionine and phenylalanine.
  • a method for preventing, treating and / or improving obesity comprising administering one or more amino acids selected from glutamine, methionine and phenylalanine to mammals including humans in need thereof .
  • Example 1 The outline
  • the adaptive relaxation (% vs. control) when the internal pressure of the barostat back is 8 mmHg is shown. *: P ⁇ 0.05 vs. Control group (Student's t-test)
  • the present inventors have found a new screening method characterized by indwelling an intragastric balloon in a non-human mammal non-invasively.
  • this screening method as shown in the test (Example 1) described later, in an in vivo test using a non-human mammal such as a rat, a balloon is forcibly placed in the stomach of the animal under anesthesia, and a test sample After administration, the stomach pressure of the stomach is evaluated by increasing the internal pressure of the stomach of the animal to give the stomach a stretch stimulus and monitoring adaptive relaxation.
  • the conventional screening method since a non-human mammal was opened, the stomach was incised and a balloon was placed, it was invasive to the stomach and it was difficult to say that the physiological situation was reproduced.
  • adaptive relaxation refers to the reflex action of the stomach in which the bottom of the stomach expands in response to an increase in the internal pressure of the stomach when food enters the stomach.
  • the present inventors screened 20 kinds of amino acids in the test described later (Example 1), and 3 kinds of amino acids (glutamine (Gln), methionine (Met) and phenylalanine (Phe)) are adapted for gastric stretch stimulation. It has been found to inhibit relaxation of the fundus and / or upper stomach. That is, the present inventors have found that glutamine, methionine and phenylalanine reversibly reduce gastric volume.
  • the gastric capacity reducing agent of the present invention contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient.
  • it may be an agent containing only one or more selected from glutamine, methionine and phenylalanine as an active ingredient, and one or more selected from glutamine, methionine and phenylalanine
  • the agent containing only 2 or more types can also be illustrated.
  • “decrease in gastric volume” can be evaluated by indicating relaxation of the stomach bottom and / or upper gastric body adapted to gastric stretch stimulation (see Example 1). For example, in the screening system of Example 1, it can be determined that the gastric volume has been reduced when gastric dilation is suppressed as compared to gastric dilatation due to adaptive relaxation during administration of the control sample. Specifically, in the screening system of Example 1, when the increased volume of the stomach due to adaptive relaxation is 80% or less (preferably 70% or less, more preferably 60% or less) of the increased volume when the control sample is administered In addition, it can be determined that the stomach volume has been reduced.
  • the agent of the present invention can be preferably used for suppressing the relaxation of the stomach, and more preferably used for suppressing the relaxation of the stomach bottom and / or the upper body of the stomach adapted to gastric stretch stimulation. it can. From another point of view, the agent of the present invention can be used to decrease gastric volume without promoting gastric emptying (while suppressing gastric emptying).
  • Glutamine is one of the essential amino acids, and there are D-form and L-form.
  • L-glutamine Cas No. Is 56-85-9, and its alternative names are (S) -2-amino-4-carbamoylbutanoic acid, glutamine, ⁇ -glutamine, and L-(+)-glutamine. Gln and Q may be used as an abbreviation for glutamine.
  • Glutamine is easily soluble in formic acid, slightly soluble in water, and hardly soluble in ethanol (16th revision Japanese Pharmacopoeia). It is known that glutamine is contained in various materials and foods such as wheat protein, casein, soybean, and pork.
  • Methionine is one of the essential amino acids, and there are D-form and L-form.
  • Cas No. of L-methionine Is 63-68-3, and its alias is (S) -4- (methylthio) -2-aminobutyric acid, (S) -2-amino-4- (methylthio) butanoic acid, (S) -3 -Phenyl-2-aminopropionic acid, L-(-)-methionine.
  • Met and M may be used as abbreviations for methionine.
  • Methionine is easily soluble in formic acid, slightly soluble in water, soluble in dilute hydrochloric acid, and extremely insoluble in ethanol (16th revision Japanese Pharmacopoeia). Methionine is known to be contained in various materials and foods such as casein, bonito, and soybean.
  • Phenylalanine is one of the essential amino acids, and there are D-form and L-form.
  • L-Phenylalanine Cas No. Are 63-91-2, and their alias names are (S) - ⁇ -aminobenzenepropanoic acid, (2S) -2-amino-3-phenylpropanoic acid, (S) -3-phenyl-2-amino Propionic acid, L- ⁇ -phenylalanine, and L-( ⁇ )-phenylalanine.
  • Phe and F are used as abbreviations for phenylalanine.
  • Phenylalanine is easily soluble in formic acid, slightly insoluble in water, soluble in dilute hydrochloric acid, and hardly soluble in ethanol (16th revision Japanese Pharmacopoeia). It is known that phenylalanine is contained in various materials such as various proteins and foods.
  • glutamine, methionine and phenylalanine may be free bases or hydrates, organic acids (acetic acid, tartaric acid, fatty acids, etc.), organic bases, inorganic acids (hydrochloric acid, hydrobromic acid, nitric acid). , Sulfuric acid, perchloric acid, etc.) and inorganic bases (potassium, sodium, zinc, etc.) may form a salt.
  • organic acids acetic acid, tartaric acid, fatty acids, etc.
  • organic bases inorganic acids (hydrochloric acid, hydrobromic acid, nitric acid).
  • Sulfuric acid, perchloric acid, etc.) and inorganic bases may form a salt.
  • glutamine, methionine, and phenylalanine either D-form or L-form may be used, but L-form is preferably used.
  • glutamine, methionine, and phenylalanine can be obtained by squeezing, concentrating, purifying, crystallizing, or extracting with various solvents from materials and foods that are rich in glutamine, methionine, and phenylalanine.
  • various solvents water or commonly used solvents such as alcohols, hydrocarbons, organic acids, organic bases, inorganic acids, inorganic bases, supercritical fluids, etc. may be used alone or in combination. Is possible. Moreover, it is also possible to use what was produced with microorganisms. A chemically synthesized product can also be used.
  • the agent of the present invention contains one or more selected from glutamine, methionine, and phenylalanine as an active ingredient, and is a composition that is combined with other additive components that are acceptable in food hygiene or medicine You may comprise as. Therefore, the agent of the present invention contains one or more selected from glutamine, methionine, and phenylalanine as an active ingredient, and further contains other additives that are acceptable in food hygiene or pharmaceutically.
  • the composition is selected from glutamine, methionine and phenylalanine in an effective amount for reducing gastric volume, or an effective amount for prevention, treatment and / or amelioration of the diseases and symptoms described below (especially obesity).
  • Comprising one or more amino acids are selected from glutamine, methionine and phenylalanine in an effective amount for reducing gastric volume, or an effective amount for prevention, treatment and / or amelioration of the diseases and symptoms described below (especially obesity).
  • Comprising one or more amino acids are selected from glutamine, methionine and phenylalanine in an effective amount for reducing gastric volume, or an effective amount for prevention, treatment and / or amelioration of the diseases and symptoms described below (especially obesity).
  • additive components are not particularly limited, and those that promote the effect of the agent of the present invention or those that do not inhibit the agent can be used preferentially.
  • Other additive components of the present invention include, for example, excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, solubilizers, suspension agents or coating agents, vitamins, minerals, organic Examples include acids, sugars, peptides, sweeteners, acidulants, emulsifiers, and fragrances.
  • the actual form is not particularly limited, and one that promotes the effect of the agent of the present invention or one that does not inhibit can be preferentially used.
  • examples of the actual form of the agent of the present invention include tablets (tablets), capsules, granules, powders, syrups, solutions, suspensions, drinks, and supplements.
  • the amount of one or more selected from glutamine, methionine, and phenylalanine is not particularly limited because it varies depending on the dosage form, symptom, body weight, use, and the like.
  • One or more amino acids selected from phenylalanine in terms of solid content), with a lower limit of 0.1%, 0.2%, 0.5%, 0.8%, 1%, 2%, 5 %, 8%, and the upper limit can be set to 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 15%.
  • “%” is “w / w%” unless otherwise specified.
  • the daily intake and dose of one or more amino acids selected from glutamine, methionine, and phenylalanine are not particularly limited because they vary depending on age, symptoms, body weight, use, etc.
  • one or more amino acids selected from glutamine, methionine, and phenylalanine in terms of solid content
  • examples include ingestion or administration by setting 0.9 g and an upper limit of 5 g, 4 g, 3 g, 2.5 g, 2 g, or 1.5 g.
  • the daily intake and dose of the above amino acids can be 0.2 to 5 g, preferably 0.3 to 4.0 g, more preferably 0.7 to 2. 0 g, particularly preferably 0.9 to 1.5 g.
  • the amino acid of the agent of the present invention is 0.2 g, 0.5 g, 1 g, This means that 1.5 g, 2.5 g, and 5 g have been ingested.
  • Example 3 amino acid content: 200 mg / tablet, about 33 w / w%) are ingested, 0.2 g of amino acid of the agent of the present invention, 0. 4g, 0.6g, 1g, 2g, 4g were taken.
  • Example 4 when the supplement (amino acid content: 300 mg / grain) shown in Example 4 is ingested 1, 2, 3, 5, 10 grains, 0.3 g, 0.6 g, 0.9 g, 1. It means that 5g and 3g were ingested.
  • the amino acid content of the agent of the present invention in the supplement was about 79 w. / W%.
  • the agent of the present invention may be used in combination with or before or after intake of a conventionally known composition, food or drink, or medicine having a gastric volume reducing effect, or reduction in gastric volume. It may be used at the same time as treatment (fertilization surgery, balloon placement, etc.) or before or after those treatments. Specific examples include satiety central stimulants, dietary fiber, fertilization surgery, balloon placement, and the like, but are not limited to these examples.
  • the agent of the present invention includes various foods and beverages (milk, soft drinks, processed milk, dairy drinks, fermented milk, lactic acid bacteria drinks, yogurt, cheese, bread, biscuits, crackers, pizza crusts, gummy, candy, baked goods, pudding , Jelly, bavaroa, prepared milk powder, liquid food, food for the sick, nutritional food, frozen food, processed food, and other commercially available foods).
  • These foods and drinks may be in the form of liquid, paste, gel, solid or powder.
  • 1 type or 2 or more types selected from glutamine, methionine, and phenylalanine clearly higher than usual may be mix
  • Proteins, peptides, amino acids, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, flavors, and the like can be used as components of foods and drinks that contain the agent of the present invention. These are not particularly limited.
  • the protein include whole milk powder, skim milk powder, partially skim milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, whey protein hydrolyzate, ⁇ -casein, ⁇ -casein, ⁇ - Casein, ⁇ -lactoglobulin, ⁇ -lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein and other animal and vegetable proteins, their degradation products, whey, non-protein nitrogen and the like.
  • the peptide include casein phosphopeptide.
  • saccharide examples include saccharides, processed starch (in addition to text phosphorus, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like.
  • lipids for example, animal oils such as lard, fish oil, transesterified oil, palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, etc., fractionated oils thereof, hydrogenated oil, transesterified oil, etc. And vegetable oils and the like.
  • vitamins examples include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, Examples thereof include choline and folic acid.
  • examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium and the like.
  • examples of the organic acid include malic acid, citric acid, lactic acid, tartaric acid, erythorbic acid, and the like.
  • the component of these food-drinks can be used individually or in combination of multiple types. Further, it may be a synthetic product and / or a natural product.
  • the form of these food and drink components may be any of liquid, paste, gel, solid, powder and the like.
  • health functional foods such as foods for specified health use, special purpose foods, nutritional functional foods, nutritional supplements, foods for the sick, health supplements, functional foods, quasi drugs or pharmaceutical products
  • the agent of the present invention is provided as a health functional food such as food for specified health use, special purpose food, nutritional functional food, nutritional supplement, sick food, health supplement or functional food.
  • it is advantageous in reducing stomach volume while clarifying distinction from general (drinking) foods.
  • the foods listed above foods for specified health use, health functional foods, special purpose foods, nutritional functional foods, nutritional supplements, foods for patients, health supplements, functional foods, supplements, agents of the present invention
  • One or more amounts selected from glutamine, methionine and phenylalanine contained in one packaging unit of an agent, quasi-drug, or pharmaceutical consisting only of an auxiliary for formulation are glutamine, methionine And 0.2 g, 0.3 g, 0.4 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, or 1 g, 1.5 g in terms of solid content of phenylalanine.
  • the agent of the present invention can be used not only in healthy subjects but also in those who have symptoms that require food saving such as obesity, diabetes, hyperlipidemia, bulimia, bulimia, etc. Ingestion can prevent, treat and / or improve these diseases and symptoms. Alternatively, those who have other diseases that require dietary savings or physical disorders (such as obesity) can prevent, treat, and / or improve these diseases and symptoms by taking the agent of the present invention.
  • the agent of the present invention can reduce gastric volume without promoting gastric emptying, and can reduce gastric volume as a treatment (weight loss) for obesity as described in the background art section. Is very effective, the agent of the present invention can efficiently prevent, treat and / or improve obesity.
  • the present invention is also the use (use method) of one or more selected from glutamine, methionine and phenylalanine for producing a gastric volume reducing agent. Moreover, this invention is also 1 type (s) or 2 or more types (use method) selected from glutamine, methionine, and phenylalanine for manufacturing the prevention, treatment, and / or improvement agent of obesity.
  • the present invention is also a method for reducing gastric volume, characterized in that one or more selected from glutamine, methionine and phenylalanine are used for oral intake.
  • the present invention is also a method for preventing, treating and / or improving obesity, characterized by using one or more selected from glutamine, methionine and phenylalanine for oral ingestion or oral administration. In the above two methods, medical practices for humans may be excluded.
  • the present invention is also a method for reducing gastric volume, characterized in that one or more selected from glutamine, methionine and phenylalanine are orally ingested (provided commercially).
  • the present invention also relates to a method for preventing, treating and / or improving obesity, characterized in that one or more selected from glutamine, methionine and phenylalanine are orally ingested (commercially provided). But it is. In the above two methods, medical practices for humans may be excluded.
  • the present invention is also a composition for reducing gastric volume, containing one or more selected from glutamine, methionine and phenylalanine as an active ingredient.
  • the present invention is also a composition for preventing, treating and / or improving obesity, which contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient.
  • the present invention includes one or more selected from glutamine, methionine, and phenylalanine as an active ingredient, and contains other additives that are acceptable for food hygiene, and drinks and drinks for reducing gastric capacity But there is.
  • the present invention also includes obesity prevention, treatment and / or containing one or more selected from glutamine, methionine and phenylalanine as an active ingredient and containing other additive components acceptable in food hygiene. It is also a beverage and drink for improvement.
  • Other additive components acceptable in food hygiene that can be used in the beverages and drinks include food additives such as sweeteners and acidulants.
  • the present invention contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient, contains other additive components that are acceptable for food hygiene, and contains a formulation aid. It is also a supplement such as tablets (tablets) to reduce Moreover, the prevention of obesity containing 1 or 2 or more types selected from glutamine, methionine and phenylalanine as an active ingredient, containing other additive ingredients acceptable for food hygiene, and containing a formulation aid, It is also a supplement such as a tablet for treatment and / or improvement. Examples of other food hygiene-acceptable additives that can be used in the supplement include food additives such as sweeteners, acidulants, emulsifiers, and fragrances. Formulation aids that can be used in the supplement include any one or more of excipients, binders, disintegrants, and lubricants.
  • the present invention is also a supplement such as a capsule for reducing gastric volume, which contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient and contains a formulation aid. It is also a supplement such as a capsule for preventing, treating and / or improving obesity containing one or more selected from glutamine, methionine and phenylalanine as an active ingredient and containing a formulation aid.
  • Formulation aids that can be used in the supplement include any one or more of excipients, binders, disintegrants, and lubricants.
  • An inhibitor of relaxation of the bottom of the stomach and / or the upper part of the stomach which contains one or more amino acids selected from the group consisting of glutamine, methionine, and phenylalanine as an active ingredient, and that is adapted to gastric stretch stimulation; Inhibiting the relaxation of the gastric fundus and / or upper gastric body adapted to gastric stretch stimulation comprising ingesting one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine Of one or more amino acids selected from the group consisting of glutamine, methionine, and phenylalanine for the manufacture of a method and a relaxation inhibitor for the stomach bottom and / or upper gastric body adapted to gastric stretch stimulation Use is provided.
  • the above-described invention can be carried out according to the description of the gastric volume reducing agent of the present invention and the preventive, therapeutic and / or ameliorating agents for various diseases and symptoms and the amino acids of the agent of the present invention.
  • a gastric volume reducing agent comprising one or more selected from glutamine, methionine, and phenylalanine as an active ingredient.
  • a gastric volume reducing agent comprising one or more selected from glutamine, methionine, and phenylalanine as an active ingredient.
  • the agent described in [21] above wherein the agent suppresses relaxation of the stomach bottom and / or the upper body of the stomach adapted to gastric stretch stimulation.
  • the agent described in [21] or [22] above which does not promote gastric emptying.
  • the agent according to any one of [21] to [23] above, wherein the daily intake amount of human is 0.2 to 5 g.
  • An agent for preventing and / or improving obesity comprising the agent according to any one of [21] to [23] as an active ingredient.
  • a method for reducing gastric volume (excluding medical practice for humans), wherein one or more selected from glutamine, methionine, and phenylalanine are used for oral intake.
  • a method for reducing gastric volume (excluding medical practice for humans), wherein one or more selected from glutamine, methionine, and phenylalanine are orally ingested.
  • Example 1 Test of gastric volume reduction effect with various amino acids (1) Materials and methods [test sample] 19 kinds of amino acids (L-Phenyl aline (Phe), L-Lycine (Lys), Glycine (Gly), L-Cystein (Cys), L-Serine (Ser), L-Alinene, L-Proline (Pro), L-Arginine (Arg), L-Histine (His), L-Threonine, L-Valine, L-Glutamine, L-Asparagine (Asn), L-Methionine, L-Glutamate acid, L-Apartic acid L-Isolucine, L-Leucine, and L-Tyrosine) were used as test samples.
  • amino acids L-Phenyl aline (Phe), L-Lycine (Lys), Glycine (Gly), L-Cystein (Cys), L-Serine (Ser), L-Alinene, L-Proline (Pro), L
  • amino acids hydrochloride was used for Lys, monohydrate was used for Asn, and free base was used for the other amino acids.
  • hydrochloride was used for Lys
  • monohydrate was used for Asn
  • free base was used for the other amino acids.
  • Rikkunshi-to Tsumura Rikkunshi-to extract granule (medical), Tsumura
  • a Chinese medicine used to improve stomach sag is dissolved and suspended in water for injection (Otsuka Pharmaceutical) at a concentration of 500 mg / 5 ml. Used.
  • Barostat bag A barostat bag in which two polyethylene tubes were connected to a polyethylene bag (maximum capacity: 7 ml, maximum diameter: 3 cm) was used.
  • the barostat bag was inflated while connected to a barostat device (Barostat Diistender IIR, G & J Electronics) while maintaining breathing, and the internal pressure and volume of the barostat bag were measured. . Specifically, the internal pressure of the barostat bag was set to 0 mmHg as an initial value, and the internal pressure was increased stepwise to give a stretching stimulus from the bottom of the stomach to the upper part of the stomach.
  • a barostat device Barostat Diistender IIR, G & J Electronics
  • the internal pressure of the barostat bag is set to 1 mmHg, 2 mmHg, 4 mmHg, and 8 mmHg at 0 to 1 minute, 1 to 2 minutes, 2 to 3 minutes, and 3 to 4 minutes after the start of measurement. Was measured (FIG. 1).
  • the abdomen was incised with the barostat bag inflated, and the stomach was observed to confirm the insertion state (position, etc.) of the barostat bag, the swelling state of the barostat bag, the presence of bleeding, etc. .
  • FIG. 2 shows adaptive relaxation when the internal pressure of the barostat back is 8 mmHg.
  • Gln group and the Met group both values were significantly lower than those in the Control group.
  • Phe group the contraction action from the stomach bottom to the stomach upper part was strong, and the barostat bag was pushed out from the stomach bottom to the stomach upper part and moved to the stomach body. This phenomenon shows that Phe has a stronger action than Gln and Met.
  • Example 2 Process for producing a beverage containing the agent of the present invention L-glutamine 0.5 w / v%, sweetener 1.0 w / v%, acidulant 0.9 w / v%, and thickener 0.2 w
  • a beverage was prepared according to a conventional method. When 40 ml, 100 ml, 200 ml, 300 ml, 500 ml and 1000 ml of this beverage are ingested, L-glutamine can be ingested in 0.2 g, 0.5 g, 1 g, 1.5 g, 2.5 g and 5 g.
  • a beverage containing 0.5 w / v% L-methionine a beverage containing 0.5 w / v% L-phenylalanine, 0.2 w / v L-glutamine and 0.1 w / v L-methionine % And L-phenylalanine 0.2 w / v%, and a drink containing L-glutamine 0.1 w / v% and L-phenylalanine 0.4 w / v%.
  • Example 3 Manufacturing method of tablet containing the agent of the present invention 200 mg L-glutamine was mixed with excipient, binder, disintegrant, lubricant, acidulant, emulsifier, flavor, sweetener, etc. About 600 mg of a tablet was produced according to the above (L-aspartic acid content: about 33 w / w%). When these tablets 1, 2, 3, 5, 10, 20 tablets are taken, L-glutamine can be taken 0.2 g, 0.4 g, 0.6 g, 1 g, 2 g, 4 g.
  • a tablet containing 200 mg of L-methionine, a tablet containing 200 mg of L-phenylalanine, a tablet containing 50 mg of L-glutamine, 50 mg of L-methionine and 100 mg of L-phenylalanine, and 100 mg of L-methionine and L- A tablet containing 100 mg of phenylalanine was produced.
  • Example 4 Method for producing a supplement containing the agent of the present invention An excipient or the like was added to 300 mg of L-glutamine and filled into capsules to produce a supplement. Ingestion of 1, 2, 3, 5, 10 capsules of this supplement can ingest 0.3 g, 0.6 g, 0.9 g, 1.5 g, 3 g of L-glutamine.
  • a supplement filled with 300 mg of L-methionine a supplement filled with 300 mg of L-phenylalanine, a supplement filled with 50 mg of L-glutamine, 100 mg of L-methionine and 150 mg of L-phenylalanine, and 200 mg of L-glutamine and L- A supplement filled with 100 mg of methionine was produced.

Abstract

The present invention addresses the problem of providing a gastric volume-reducing agent which is safe and can be ingested for a long period. According to the present invention, a gastric volume-reducing agent is provided, which contains, as an active ingredient, at least one type of amino acid selected from the group consisting of glutamine, methionine and phenylalanine. The gastric volume-reducing agent according to the present invention can suppress the relaxation of fundus and/or an upper part of stomach which is adapted to a stretch stimulus to the stomach.

Description

胃容量の減少剤Gastric volume reducing agent 関連出願の参照Reference to related applications
　本願は、先行する日本国出願である特願２０１５－５０５８３（出願日：２０１５年３月１３日）の優先権の利益を享受するものであり、その開示内容全体は引用することにより本明細書の一部とされる。 This application enjoys the benefit of priority of Japanese Patent Application No. 2015-50583 (filing date: March 13, 2015), which is a prior application in Japan, the entire disclosure of which is incorporated herein by reference. To be part of
　本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有する胃容量の減少剤に関する。 The present invention relates to a gastric capacity reducing agent containing one or more selected from glutamine, methionine and phenylalanine as an active ingredient.
　生活習慣病は、遺伝による要因（もともと、その病気になりやすい体質など）と、生活習慣による要因（食べすぎや飲みすぎ、運動不足、喫煙など）により、発病・進行する病気である。ここで、生活習慣病としては、高血圧、高脂血症、糖尿病などが挙げられ、これらの重要な要因として、食べすぎや飲みすぎ、運動不足などに伴う、肥満が挙げられる。 Lifestyle-related diseases are diseases that develop or progress due to genetic factors (originally predisposing to the disease, etc.) and lifestyle-related factors (such as eating and drinking too much, lack of exercise, and smoking). Here, examples of lifestyle-related diseases include hypertension, hyperlipidemia, diabetes and the like, and important factors include obesity associated with excessive eating, excessive drinking, and lack of exercise.
　肥満の治療法として、食事療法（ダイエット）や運動療法が知られているが、これらの療法では、なかなか十分に有効な効果が見られないのが実情である。 Dietary therapy and exercise therapy are known as treatment methods for obesity, but the actual situation is that these therapies do not have a sufficiently effective effect.
　最近では、約８００人を試験対象とした臨床研究により、肥満の治療方法として、食事療法や運動療法に比べて、外科手術では、有効な効果が見られることが示されている。具体的には、肥満の人達を被験者とした１１項目の臨床研究を分析したところ、外科手術を伴わない減量法（食事療法、運動療法、行動療法、投薬など）に比べて、胃バンディング（緊縛）、胃バイパス、胃切除などの外科手術では、２年間で体重が平均して２６キロも多く減少したことが示されている（非特許文献１）。 Recently, clinical studies on approximately 800 people have shown that surgical treatment has a more effective effect as a method of treating obesity than diet therapy or exercise therapy. Specifically, an analysis of 11 clinical studies involving obese subjects revealed that gastric banding (binding) compared to weight loss methods that do not involve surgery (diet therapy, exercise therapy, behavioral therapy, medication, etc.) ) In surgical operations such as gastric bypass and gastrectomy, it has been shown that the average body weight has decreased by as much as 26 kg in two years (Non-patent Document 1).
　また、外科手術以外の方法では、食物繊維が水分を吸収して、胃に留まることにより、膨満感が得られる結果として、食欲を抑える方法などが報告されている（例えば、特許文献１）。 Also, in methods other than surgery, a method of suppressing appetite has been reported as a result of obtaining a feeling of fullness by the dietary fiber absorbing moisture and staying in the stomach (for example, Patent Document 1).
特表２００４－５０８３１０号公報Japanese translation of PCT publication No. 2004-508310
　本発明者らは、胃に対して非侵襲的なスクリーニング方法を用いて、胃容量を減少させる素材についてスクリーニングを行ったところ、食経験のある主要なアミノ酸である、グルタミン、メチオニンおよびフェニルアラニンが胃容量の減少に有効であることを見出した。 The present inventors screened a material that reduces the stomach volume by using a non-invasive screening method for the stomach. As a result, glutamine, methionine, and phenylalanine, which are major amino acids with dietary experience, are found in the stomach. It was found that it is effective for capacity reduction.
　具体的には、ラットを用いたインビボ（in vivo）試験において、麻酔下で強制的に動物の胃内にバルーンを留置して、動物の胃の内圧を高めることを特徴とするスクリーニング方法を用いた。この試験系は胃に対して非侵襲的であるため、胃の生理的状況により近いといえる。 Specifically, in an in vivo test using rats, a screening method characterized by increasing the internal pressure of the animal's stomach by forcibly placing the balloon in the animal's stomach under anesthesia is used. It was. Since this test system is non-invasive to the stomach, it can be said that it is closer to the physiological situation of the stomach.
　本発明者らは、この試験系を用いて、アミノ酸を投与して動物に胃の伸展刺激を与えたときの適応弛緩をモニターしたところ、グルタミン、メチオニンおよびフェニルアラニンが、胃の伸展刺激に適応した（胃の伸展刺激を与えたときに）胃底部および／または胃体上部の弛緩を抑制することを見出した。本発明は上記知見に基づくものである。 The present inventors used this test system to monitor adaptive relaxation when an amino acid was administered to give an animal a gastric stretch stimulus. Glutamine, methionine and phenylalanine were adapted to the gastric stretch stimulus. It was found that the relaxation of the stomach bottom and / or the upper body of the stomach was suppressed (when a stomach stretching stimulus was applied). The present invention is based on the above findings.
　本発明は、安全で長期摂取が可能な胃容量の減少剤の提供を目的とする。 The object of the present invention is to provide a gastric volume reducing agent that is safe and can be taken for a long time.
　また、本発明によれば以下の発明が提供される。
［１］グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸を有効成分として含有する、胃容量の減少剤。
［２］胃の伸展刺激に適応した胃底部および／または胃体上部の弛緩を抑制する、上記［１］に記載の剤。
［３］胃排出を促進しないことを特徴とする、上記［１］または［２］に記載の剤。
［４］グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸を有効成分として含有する、肥満の予防、治療および／または改善剤。
［５］ヒトの１日当たりのアミノ酸の摂取量または投与量がアミノ酸の固形分換算で０．２～５ｇとなるよう配合されてなる、上記［１］～［４］のいずれかに記載の剤。
［６］１回の摂取量または投与量当たりの包装単位形態からなる、上記［１］～［５］のいずれかに記載の剤。
［７］グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のアミノ酸を経口摂取させることを含んでなる、胃容量を減少させる方法。
［８］胃容量の減少剤の製造のための、グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸の使用。
［９］グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のアミノ酸を、それを必要とするヒトを含む哺乳類に投与することを含んでなる、肥満の予防、治療および／または改善方法。
［１０］肥満の予防、治療および／または改善剤の製造のための、グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸の使用。 Further, according to the present invention, the following inventions are provided.
[1] A gastric volume reducing agent comprising as an active ingredient one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine.
[2] The agent according to the above [1], which suppresses relaxation of the stomach bottom and / or stomach upper body adapted to gastric stretch stimulation.
[3] The agent according to [1] or [2] above, which does not promote gastric emptying.
[4] A prophylactic, therapeutic and / or ameliorating agent for obesity containing, as an active ingredient, one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine.
[5] The agent according to any one of [1] to [4] above, which is formulated so that the daily intake or dosage of amino acids in humans is 0.2 to 5 g in terms of solid content of amino acids. .
[6] The agent according to any one of [1] to [5] above, which is in a package unit form per one intake or dose.
[7] A method for reducing gastric volume, comprising orally ingesting one or more amino acids selected from glutamine, methionine and phenylalanine.
[8] Use of one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine for the manufacture of a gastric volume reducing agent.
[9] A method for preventing, treating and / or improving obesity comprising administering one or more amino acids selected from glutamine, methionine and phenylalanine to mammals including humans in need thereof .
[10] Use of one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine for the manufacture of an agent for preventing, treating and / or improving obesity.
　本発明によれば、安全で長期摂取が可能な胃容量の減少剤を提供することができる。 According to the present invention, it is possible to provide a gastric volume reducing agent that is safe and can be taken for a long time.
例１のバロスタット試験の概要を示す。試験装置、バロスタットバッグにかけた内圧（Ｐｒｅｓｓｕｒｅ）の経時的変化、およびバロスタットバッグの容量（Ｖｏｌｕｍｅ）の経時的変化の一例を示す。The outline | summary of the barostat test of Example 1 is shown. An example of the time-dependent change of the internal pressure (Pressure) applied to the test apparatus, the barostat bag, and the time-dependent change of the volume of the barostat bag (Volume) is shown. 例１における、バロスタットバックの内圧が８ｍｍＨｇのときの　適応弛緩（％対コントロール）を示す。＊：ｐ＜０．０５　ｖｓ．　Ｃｏｎｔｒｏｌ群（Ｓｔｕｄｅｎｔ‘ｓ　ｔ－ｔｅｓｔ）In Example 1, the adaptive relaxation (% vs. control) when the internal pressure of the barostat back is 8 mmHg is shown. *: P <0.05 vs. Control group (Student's t-test)
　本発明者らは、非ヒト哺乳動物に非侵襲的に胃内バルーンを留置することを特徴とする、新たなスクリーニング方法を見出した。このスクリーニング方法は、後述の試験（例１）で示すように、ラットなどの非ヒト哺乳動物を用いたインビボ試験において、麻酔下で強制的に動物の胃内にバルーンを留置し、被検試料の投与の後に動物の胃の内圧を高めて胃に伸展刺激を与え、Ａｄａｐｔｉｖｅ　ｒｅｌａｘａｔｉｏｎ（適応弛緩）をモニターすることで、胃底部の弛緩を評価することを特徴とする。従来のスクリーニング方法では、非ヒト哺乳動物を開腹し、胃を切開してバルーンを留置していたため、胃に対して侵襲的であり、生理的状況を再現しているとは言い難かった。それに対し、このスクリーニング方法は胃に対して非侵襲的であるため、胃の生理的状況により近い試験系であるといえる。ここで、「適応弛緩」（適応性弛緩）とは、食物が胃に入ったときに胃の内圧の増加に応答して胃底部が膨張する胃の反射作用をいう。 The present inventors have found a new screening method characterized by indwelling an intragastric balloon in a non-human mammal non-invasively. In this screening method, as shown in the test (Example 1) described later, in an in vivo test using a non-human mammal such as a rat, a balloon is forcibly placed in the stomach of the animal under anesthesia, and a test sample After administration, the stomach pressure of the stomach is evaluated by increasing the internal pressure of the stomach of the animal to give the stomach a stretch stimulus and monitoring adaptive relaxation. In the conventional screening method, since a non-human mammal was opened, the stomach was incised and a balloon was placed, it was invasive to the stomach and it was difficult to say that the physiological situation was reproduced. On the other hand, since this screening method is non-invasive to the stomach, it can be said that it is a test system closer to the physiological condition of the stomach. Here, “adaptive relaxation” (adaptive relaxation) refers to the reflex action of the stomach in which the bottom of the stomach expands in response to an increase in the internal pressure of the stomach when food enters the stomach.
　本発明者らは、後述の試験（例１）で２０種類のアミノ酸をスクリーニングし、３種のアミノ酸（グルタミン（Ｇｌｎ）、メチオニン（Ｍｅｔ）およびフェニルアラニン（Ｐｈｅ））が、胃の伸展刺激に適応した胃底部（Ｆｕｎｄｕｓ）および／または胃体上部（Ｆｏｒｅｓｔｏｍａｃｈ）の弛緩を抑制することを見出した。つまり、本発明者らは、グルタミン、メチオニンおよびフェニルアラニンが、胃容量を可逆的に減少させることを見出した。 The present inventors screened 20 kinds of amino acids in the test described later (Example 1), and 3 kinds of amino acids (glutamine (Gln), methionine (Met) and phenylalanine (Phe)) are adapted for gastric stretch stimulation. It has been found to inhibit relaxation of the fundus and / or upper stomach. That is, the present inventors have found that glutamine, methionine and phenylalanine reversibly reduce gastric volume.
　本発明の胃容量の減少剤は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有する。あるいは本発明の剤の態様として、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のみを有効成分として含有する剤であってもよく、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のみを含有する剤を例示することもできる。 The gastric capacity reducing agent of the present invention contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient. Alternatively, as an aspect of the agent of the present invention, it may be an agent containing only one or more selected from glutamine, methionine and phenylalanine as an active ingredient, and one or more selected from glutamine, methionine and phenylalanine The agent containing only 2 or more types can also be illustrated.
　本発明において「胃容量の減少」は、胃の伸展刺激に適応した胃底部および／または胃体上部の弛緩を指標して評価することができる（例１参照）。例えば、例１のスクリーニング系において、対照試料投与時の適応弛緩による胃の拡張と比較して胃の拡張が抑制された場合に、胃容量を減少させたと判断することができる。具体的には、例１のスクリーニング系において、適応弛緩による胃の増加体積が、対照試料投与時の増加体積の８０％以下（好ましくは７０％以下、より好ましくは６０％以下）であった場合に、胃容量を減少させたと判断することができる。 In the present invention, “decrease in gastric volume” can be evaluated by indicating relaxation of the stomach bottom and / or upper gastric body adapted to gastric stretch stimulation (see Example 1). For example, in the screening system of Example 1, it can be determined that the gastric volume has been reduced when gastric dilation is suppressed as compared to gastric dilatation due to adaptive relaxation during administration of the control sample. Specifically, in the screening system of Example 1, when the increased volume of the stomach due to adaptive relaxation is 80% or less (preferably 70% or less, more preferably 60% or less) of the increased volume when the control sample is administered In addition, it can be determined that the stomach volume has been reduced.
　本発明の剤は好ましくは胃の弛緩を抑制するために用いることができ、より好ましくは、胃の伸展刺激に適応した胃底部および／または胃体上部の弛緩を抑制するために用いることができる。また別の観点から、本発明の剤は胃排出を促進せずに（胃排出を抑制しつつ）胃容量を減少させるために用いることができる。 The agent of the present invention can be preferably used for suppressing the relaxation of the stomach, and more preferably used for suppressing the relaxation of the stomach bottom and / or the upper body of the stomach adapted to gastric stretch stimulation. it can. From another point of view, the agent of the present invention can be used to decrease gastric volume without promoting gastric emptying (while suppressing gastric emptying).
　グルタミン（Ｇｌｕｔａｍｉｎｅ）は、必須アミノ酸の１つであり、それには、Ｄ体とＬ体が存在する。Ｌ－グルタミンのＣａｓ　Ｎｏ．は、５６－８５－９であり、その別名は、（Ｓ）－２－アミノ－４－カルバモイルブタン酸、グルミン、γ－グルタミン、Ｌ－（＋）－グルタミンである。グルタミンの略号として、Ｇｌｎ、Ｑを用いる場合もある。グルタミンは、蟻酸に溶けやすく、水にやや溶けやすく、エタノールにほとんど溶けない（第十六改正日本薬局方）。グルタミンは、小麦たんぱく、カゼイン、大豆、豚肉など様々な素材や食品に含まれていることが知られている。 Glutamine is one of the essential amino acids, and there are D-form and L-form. L-glutamine Cas No. Is 56-85-9, and its alternative names are (S) -2-amino-4-carbamoylbutanoic acid, glutamine, γ-glutamine, and L-(+)-glutamine. Gln and Q may be used as an abbreviation for glutamine. Glutamine is easily soluble in formic acid, slightly soluble in water, and hardly soluble in ethanol (16th revision Japanese Pharmacopoeia). It is known that glutamine is contained in various materials and foods such as wheat protein, casein, soybean, and pork.
　メチオニン（Ｍｅｔｈｉｏｎｉｎｅ）は、必須アミノ酸の１つであり、それには、Ｄ体とＬ体が存在する。Ｌ－メチオニンのＣａｓ　Ｎｏ．は、６３－６８－３であり、その別名は、（Ｓ）－４－（メチルチオ）－２－アミノ酪酸、（Ｓ）－２－アミノ－４－（メチルチオ）ブタン酸、（Ｓ）－３－フェニル－２－アミノプロピオン酸、Ｌ－（－）－メチオニンである。メチオニンの略号として、Ｍｅｔ、Ｍを用いる場合もある。メチオニンは、蟻酸に溶けやすく、水にやや溶けやすく、希塩酸に溶け、エタノールには極めて溶けにくい（第十六改正日本薬局方）。メチオニンは、カゼイン、かつお、大豆など様々な素材や食品に含まれていることが知られている。 Methionine is one of the essential amino acids, and there are D-form and L-form. Cas No. of L-methionine Is 63-68-3, and its alias is (S) -4- (methylthio) -2-aminobutyric acid, (S) -2-amino-4- (methylthio) butanoic acid, (S) -3 -Phenyl-2-aminopropionic acid, L-(-)-methionine. Met and M may be used as abbreviations for methionine. Methionine is easily soluble in formic acid, slightly soluble in water, soluble in dilute hydrochloric acid, and extremely insoluble in ethanol (16th revision Japanese Pharmacopoeia). Methionine is known to be contained in various materials and foods such as casein, bonito, and soybean.
　フェニルアラニン（Ｐｈｅｎｙｌａｌａｎｉｎｅ）は、必須アミノ酸の１つであり、それには、Ｄ体とＬ体が存在する。Ｌ－フェニルアラニンのＣａｓ　Ｎｏ．は、６３－９１－２であり、その別名は、（Ｓ）－α－アミノベンゼンプロパン酸、（２Ｓ）－２－アミノ－３－フェニルプロパン酸、（Ｓ）－３－フェニル－２－アミノプロピオン酸、Ｌ－β－フェニルアラニン、Ｌ－（－）－フェニルアラニンである。フェニルアラニンの略号として、Ｐｈｅ、Ｆを用いる場合もある。フェニルアラニンは、蟻酸に溶けやすく、水にやや溶けにくく、希塩酸に溶け、エタノールにはほとんど溶けない（第十六改正日本薬局方）。フェニルアラニンは、多種のタンパク質などの様々な素材や食品に含まれていることが知られている。 Phenylalanine is one of the essential amino acids, and there are D-form and L-form. L-Phenylalanine Cas No. Are 63-91-2, and their alias names are (S) -α-aminobenzenepropanoic acid, (2S) -2-amino-3-phenylpropanoic acid, (S) -3-phenyl-2-amino Propionic acid, L-β-phenylalanine, and L-(−)-phenylalanine. In some cases, Phe and F are used as abbreviations for phenylalanine. Phenylalanine is easily soluble in formic acid, slightly insoluble in water, soluble in dilute hydrochloric acid, and hardly soluble in ethanol (16th revision Japanese Pharmacopoeia). It is known that phenylalanine is contained in various materials such as various proteins and foods.
　本発明において、グルタミン、メチオニンおよびフェニルアラニンは、フリーベースや水和物であってもよく、また、有機酸（酢酸、酒石酸、脂肪酸など）、有機塩基、無機酸（塩酸、臭化水素酸、硝酸、硫酸、過塩素酸など）、無機塩基（カリウム、ナトリウム、亜鉛など）と塩を形成していても構わない。そして、グルタミン、メチオニンおよびフェニルアラニンには、Ｄ体とＬ体のいずれを用いてもよいが、Ｌ体 を用いることが好ましい。 In the present invention, glutamine, methionine and phenylalanine may be free bases or hydrates, organic acids (acetic acid, tartaric acid, fatty acids, etc.), organic bases, inorganic acids (hydrochloric acid, hydrobromic acid, nitric acid). , Sulfuric acid, perchloric acid, etc.) and inorganic bases (potassium, sodium, zinc, etc.) may form a salt. For glutamine, methionine, and phenylalanine, either D-form or L-form may be used, but L-form is preferably used.
　本発明において、グルタミン、メチオニンおよびフェニルアラニンは、グルタミン、メチオニン、フェニルアラニンを多く含む素材や食品などから、搾汁、濃縮、精製、結晶化または各種の溶媒で抽出するなどして得ることができる。各種の溶媒として、水や通常に用いられる溶媒、例えば、アルコール類、炭化水素類、有機酸、有機塩基、無機酸、無機塩基、超臨界流体等を単独で、あるいは複数を組み合わせて用いることが可能である。また、微生物で生産したものを用いることも可能である。そして、化学的に合成されたものを用いることも可能である。 In the present invention, glutamine, methionine, and phenylalanine can be obtained by squeezing, concentrating, purifying, crystallizing, or extracting with various solvents from materials and foods that are rich in glutamine, methionine, and phenylalanine. As various solvents, water or commonly used solvents such as alcohols, hydrocarbons, organic acids, organic bases, inorganic acids, inorganic bases, supercritical fluids, etc. may be used alone or in combination. Is possible. Moreover, it is also possible to use what was produced with microorganisms. A chemically synthesized product can also be used.
　本発明の剤は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有してなり、食品衛生上または医薬上で許容可能な他の添加成分とを組み合わせた組成物として構成してもよい。したがって、本発明の剤は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有し、さらに、食品衛生上または医薬上で許容可能な他の添加成分とを含有する、胃容量を減少させるための組成物、あるいは後記疾患や症状（特に肥満）の予防、治療および／または改善のための組成物として提供される。この場合、上記組成物は胃容量を減少させるための有効量、あるいは、後記疾患や症状（特に肥満）の予防、治療および／または改善のための有効量、のグルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のアミノ酸を含んでなるものである。 The agent of the present invention contains one or more selected from glutamine, methionine, and phenylalanine as an active ingredient, and is a composition that is combined with other additive components that are acceptable in food hygiene or medicine You may comprise as. Therefore, the agent of the present invention contains one or more selected from glutamine, methionine, and phenylalanine as an active ingredient, and further contains other additives that are acceptable in food hygiene or pharmaceutically. Provided as a composition for reducing gastric volume, or a composition for preventing, treating and / or improving diseases and symptoms (especially obesity) described later. In this case, the composition is selected from glutamine, methionine and phenylalanine in an effective amount for reducing gastric volume, or an effective amount for prevention, treatment and / or amelioration of the diseases and symptoms described below (especially obesity). Comprising one or more amino acids.
　本発明において、他の添加成分は、特に限定されず、本発明の剤の効果を促進するものや阻害しないものを優先的に用いることができる。本発明の他の添加成分として、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、矯臭剤、溶解補助剤、懸濁剤またはコーティング剤などの製剤化補助剤、ビタミン、ミネラル、有機酸、糖類、ペプチド類、甘味料、酸味料、乳化剤または香料などが挙げられる。 In the present invention, other additive components are not particularly limited, and those that promote the effect of the agent of the present invention or those that do not inhibit the agent can be used preferentially. Other additive components of the present invention include, for example, excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, solubilizers, suspension agents or coating agents, vitamins, minerals, organic Examples include acids, sugars, peptides, sweeteners, acidulants, emulsifiers, and fragrances.
　本発明において、実際の形態は、特に限定されず、本発明の剤の効果を促進するものや阻害しないものを優先的に用いることができる。本発明の剤の実際の形態として、例えば、錠剤（タブレット）、カプセル剤、顆粒剤、散剤、シロップ剤、水剤、懸濁剤、ドリンク剤またはサプリメントが挙げられる。 In the present invention, the actual form is not particularly limited, and one that promotes the effect of the agent of the present invention or one that does not inhibit can be preferentially used. Examples of the actual form of the agent of the present invention include tablets (tablets), capsules, granules, powders, syrups, solutions, suspensions, drinks, and supplements.
　本発明において、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上の配合量は、剤型、症状、体重、用途などによって異なるため、特に限定されないが、あえて挙げるなら、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のアミノ酸（固形分換算）で、下限値を０．１％、０．２％、０．５％、０．８％、１％、２％、５％、８％、上限値を１００％、９０％、８０％、７０％、６０％、５０％、４０％、３０％、２０％または１５％の配合量に設定することができる。本発明において、「％」は、特に記載がない限り「ｗ／ｗ％」である。 In the present invention, the amount of one or more selected from glutamine, methionine, and phenylalanine is not particularly limited because it varies depending on the dosage form, symptom, body weight, use, and the like. One or more amino acids selected from phenylalanine (in terms of solid content), with a lower limit of 0.1%, 0.2%, 0.5%, 0.8%, 1%, 2%, 5 %, 8%, and the upper limit can be set to 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 15%. In the present invention, “%” is “w / w%” unless otherwise specified.
　本発明において、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のアミノ酸の一日当たりの摂取量および投与量は、年齢、症状、体重、用途などによって異なるため、特に限定されないが、あえて挙げるなら、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のアミノ酸（固形分換算）で、下限値を０．２ｇ、０．３ｇ、０．４ｇ、０．５ｇ、０．６ｇ、または０．９ｇ、上限値を５ｇ、４ｇ、３ｇ、２．５ｇ、２ｇ、または１．５ｇ、に設定して摂取あるいは投与する例が挙げられる。より具体的には、胃容量を減少させるための、あるいは、後記疾患や症状（特に肥満）の予防、治療および／または改善のための、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のアミノ酸（固形分換算）のヒト一日当たりの摂取量および投与量は、０．２～５ｇとすることができ、好ましくは０．３～４．０ｇ、より好ましくは０．７～２．０ｇ、特に好ましくは０．９～１．５ｇである。 In the present invention, the daily intake and dose of one or more amino acids selected from glutamine, methionine, and phenylalanine are not particularly limited because they vary depending on age, symptoms, body weight, use, etc. For example, one or more amino acids selected from glutamine, methionine, and phenylalanine (in terms of solid content), with a lower limit of 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, Alternatively, examples include ingestion or administration by setting 0.9 g and an upper limit of 5 g, 4 g, 3 g, 2.5 g, 2 g, or 1.5 g. More specifically, one or two selected from glutamine, methionine and phenylalanine for decreasing gastric volume or for preventing, treating and / or ameliorating the diseases and symptoms described below (especially obesity) The daily intake and dose of the above amino acids (in terms of solid content) can be 0.2 to 5 g, preferably 0.3 to 4.0 g, more preferably 0.7 to 2. 0 g, particularly preferably 0.9 to 1.5 g.
　例えば、例２に示す飲料（アミノ酸含量：０．５ｗ／ｖ％）を４０ｍｌ、１００ｍｌ、２００ｍｌ、３００ｍｌ、５００ｍｌ、１０００ｍｌ摂取すると、本発明の剤のアミノ酸を０．２ｇ、０．５ｇ、１ｇ、１．５ｇ、２．５ｇ、５ｇ摂取したことになる。 For example, when 40 ml, 100 ml, 200 ml, 300 ml, 500 ml, 1000 ml of the beverage shown in Example 2 (amino acid content: 0.5 w / v%) is ingested, the amino acid of the agent of the present invention is 0.2 g, 0.5 g, 1 g, This means that 1.5 g, 2.5 g, and 5 g have been ingested.
　例えば、例３に示すタブレット（アミノ酸含量：２００ｍｇ／錠、約３３ｗ／ｗ％）を１、２、３、５、１０、２０錠摂取すると、本発明の剤のアミノ酸を０．２ｇ、０．４ｇ、０．６ｇ、１ｇ、２ｇ、４ｇ摂取したことになる。 For example, when 1, 2, 3, 5, 10, 20 tablets of the tablet shown in Example 3 (amino acid content: 200 mg / tablet, about 33 w / w%) are ingested, 0.2 g of amino acid of the agent of the present invention, 0. 4g, 0.6g, 1g, 2g, 4g were taken.
　例えば、例４に示すサプリメント（アミノ酸含量：３００ｍｇ／粒）を１、２、３、５、１０粒摂取すると、本発明の剤のアミノ酸を０．３ｇ、０．６ｇ、０．９ｇ、１．５ｇ、３ｇ摂取したことになる。 For example, when the supplement (amino acid content: 300 mg / grain) shown in Example 4 is ingested 1, 2, 3, 5, 10 grains, 0.3 g, 0.6 g, 0.9 g, 1. It means that 5g and 3g were ingested.
　また、例４に示すサプリメントの類型として、本発明の剤のアミノ酸３００ｍｇを０．０８ｇの１号カプセルに充填してサプリメントを製造した場合、サプリメント中の本発明の剤のアミノ酸含量は、約７９ｗ／ｗ％となる。 Further, as a supplement type shown in Example 4, when a supplement was prepared by filling 300 mg of the amino acid of the agent of the present invention into 0.08 g of No. 1 capsule, the amino acid content of the agent of the present invention in the supplement was about 79 w. / W%.
　なお、本発明の剤は、従来公知の胃容量の減少効果がある組成物、飲食品、または医薬品などの摂取と同時または、それらの摂取の前後に併用してもよいし、胃容量の減少処置（減肥手術、バルーン留置など）などと同時または、それらの処置の前後に併用してもよい。具体的には、満腹中枢刺激剤、食物繊維、減肥手術、バルーン留置などが挙げられるが、これらの例に限定されない。 The agent of the present invention may be used in combination with or before or after intake of a conventionally known composition, food or drink, or medicine having a gastric volume reducing effect, or reduction in gastric volume. It may be used at the same time as treatment (fertilization surgery, balloon placement, etc.) or before or after those treatments. Specific examples include satiety central stimulants, dietary fiber, fertilization surgery, balloon placement, and the like, but are not limited to these examples.
　本発明の剤は、各種の飲食品（牛乳、清涼飲料、加工乳、乳性飲料、発酵乳、乳酸菌飲料、ヨーグルト、チーズ、パン、ビスケット、クラッカー、ピッツァクラスト、グミ、飴、焼き菓子、プリン、ゼリー、ババロア、調製粉乳、流動食、病者用食品、栄養食品、冷凍食品、加工食品その他の市販食品など）に配合して、これを摂取してもよい。これらの飲食品の形態として、液状、ペースト状、ゲル状、固形状、粉末状などを問わない。また、各種の飲食品に通常より明らかに高濃度のグルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を配合し、これを摂取するものであってもよい。 The agent of the present invention includes various foods and beverages (milk, soft drinks, processed milk, dairy drinks, fermented milk, lactic acid bacteria drinks, yogurt, cheese, bread, biscuits, crackers, pizza crusts, gummy, candy, baked goods, pudding , Jelly, bavaroa, prepared milk powder, liquid food, food for the sick, nutritional food, frozen food, processed food, and other commercially available foods). These foods and drinks may be in the form of liquid, paste, gel, solid or powder. Moreover, 1 type or 2 or more types selected from glutamine, methionine, and phenylalanine clearly higher than usual may be mix | blended with various food-drinks, and you may take this.
　本発明の剤を配合する飲食品の成分には、水、タンパク質、ペプチド、アミノ酸、糖質、脂質、ビタミン類、ミネラル類、有機酸、有機塩基、果汁、フレーバー類等を用いることができるが、これらには特に限定されない。タンパク質として、例えば、全脂粉乳、脱脂粉乳、部分脱脂粉乳、カゼイン、ホエイ粉、ホエイタンパク質、ホエイタンパク質濃縮物、ホエイタンパク質分離物、ホエイタンパク質加水分解物、α－カゼイン、β－カゼイン、κ－カゼイン、β－ラクトグロブリン、α－ラクトアルブミン、ラクトフェリン、大豆タンパク質、鶏卵タンパク質、肉タンパク質等の動植物性タンパク質、これらの分解物、ホエイ、非タンパク態窒素等が挙げられる。また、ペプチドとして、例えば、カゼインホスホペプチド等が挙げられる。 Water, proteins, peptides, amino acids, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, flavors, and the like can be used as components of foods and drinks that contain the agent of the present invention. These are not particularly limited. Examples of the protein include whole milk powder, skim milk powder, partially skim milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, whey protein hydrolyzate, α-casein, β-casein, κ- Casein, β-lactoglobulin, α-lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein and other animal and vegetable proteins, their degradation products, whey, non-protein nitrogen and the like. Examples of the peptide include casein phosphopeptide.
　また、糖質として、例えば、糖類、加工澱粉（テキストリンのほか、可溶性澱粉、ブリティッシュスターチ、酸化澱粉、澱粉エステル、澱粉エーテル等）、食物繊維等が挙げられる。また、脂質として、例えば、ラード、魚油、エステル交換油等の動物性油脂、パーム油、サフラワー油、コーン油、ナタネ油、ヤシ油等、これらの分別油、水素添加油、エステル交換油等の植物性油脂等が挙げられる。また、ビタミン類として、例えば、ビタミンＡ、カロチン類、ビタミンＢ群、ビタミンＣ、ビタミンＤ群、ビタミンＥ、ビタミンＫ群、ビタミンＰ、ビタミンＱ、ナイアシン、ニコチン酸、パントテン酸、ビオチン、イノシトール、コリン、葉酸等が挙げられる。 Examples of the saccharide include saccharides, processed starch (in addition to text phosphorus, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like. Further, as lipids, for example, animal oils such as lard, fish oil, transesterified oil, palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, etc., fractionated oils thereof, hydrogenated oil, transesterified oil, etc. And vegetable oils and the like. Examples of vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, Examples thereof include choline and folic acid.
　また、ミネラル類として、例えば、カルシウム、カリウム、マグネシウム、ナトリウム、銅、鉄、マンガン、亜鉛、セレン等が挙げられる。また、有機酸として、例えば、リンゴ酸、クエン酸、乳酸、酒石酸、エリソルビン酸等が挙げられる。なお、これらの飲食品の成分は、単独で、または複数種類を組み合わせて用いることがでる。また、合成品および／または天然物であってもよい。これらの飲食品の成分の形態として、液状、ペースト状、ゲル状、固形状、粉末状などのいずれであってもよい。 Further, examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium and the like. Examples of the organic acid include malic acid, citric acid, lactic acid, tartaric acid, erythorbic acid, and the like. In addition, the component of these food-drinks can be used individually or in combination of multiple types. Further, it may be a synthetic product and / or a natural product. The form of these food and drink components may be any of liquid, paste, gel, solid, powder and the like.
　本発明の剤では、特定保健用食品等の保健機能食品、特別用途食品、栄養機能食品、栄養補助食品、病者用食品、健康補助食品、機能性食品、医薬部外品または医薬品等の製品として提供して、あるいはそれら製品に配合して、対象に投与することできる。特に、本発明の剤では、特定保健用食品等の保健機能食品、特別用途食品、栄養機能食品、栄養補助食品、病者用食品、健康補助食品または機能性食品として提供することは、消費者に対して一般（飲）食品との区別を明確にしながら、胃容量を減少させる上で有利である。 In the agent of the present invention, health functional foods such as foods for specified health use, special purpose foods, nutritional functional foods, nutritional supplements, foods for the sick, health supplements, functional foods, quasi drugs or pharmaceutical products Can be provided as or in combination with these products and administered to a subject. In particular, the agent of the present invention is provided as a health functional food such as food for specified health use, special purpose food, nutritional functional food, nutritional supplement, sick food, health supplement or functional food. On the other hand, it is advantageous in reducing stomach volume while clarifying distinction from general (drinking) foods.
　本発明において、上記に挙げた食品、特定保健用食品、保健機能食品、特別用途食品、栄養機能食品、栄養補助食品、病者用食品、健康補助食品、機能性食品、サプリメント、本発明の剤および製剤化のための補助剤のみからなる剤、医薬部外品、または医薬品の、１包装単位に含まれるグルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上の量は、グルタミン、メチオニンおよびフェニルアラニンの固形分換算で０．２ｇ、０．３ｇ、０．４ｇ、０．６ｇ、０．７ｇ、０．８ｇ、０．９ｇ、または１ｇ、１．５ｇに設定することができる。 In the present invention, the foods listed above, foods for specified health use, health functional foods, special purpose foods, nutritional functional foods, nutritional supplements, foods for patients, health supplements, functional foods, supplements, agents of the present invention One or more amounts selected from glutamine, methionine and phenylalanine contained in one packaging unit of an agent, quasi-drug, or pharmaceutical consisting only of an auxiliary for formulation are glutamine, methionine And 0.2 g, 0.3 g, 0.4 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, or 1 g, 1.5 g in terms of solid content of phenylalanine.
　本発明の剤は、健常者はもとより、肥満、糖尿病、高脂血症、過食症、多食症等の節食が必要な症状を有する者において、飲食の前、飲食と同時、または飲食の後に摂取することで、これらの疾患や症状を予防、治療および／または改善することができる。あるいは、他の節食が必要な疾患や身体の不調（肥満など）を有する者が、本発明の剤を摂取することで、これらの疾患や症状を予防、治療および／または改善することができる。特に、本発明の剤は、胃排出を促進せずに、胃容量を減少させることができ、また、背景技術の欄に記載したように肥満の治療法（減量）として胃容量を減少させることが非常に有効であることから、本発明の剤は肥満を効率的に予防、治療および／または改善することができる。 The agent of the present invention can be used not only in healthy subjects but also in those who have symptoms that require food saving such as obesity, diabetes, hyperlipidemia, bulimia, bulimia, etc. Ingestion can prevent, treat and / or improve these diseases and symptoms. Alternatively, those who have other diseases that require dietary savings or physical disorders (such as obesity) can prevent, treat, and / or improve these diseases and symptoms by taking the agent of the present invention. In particular, the agent of the present invention can reduce gastric volume without promoting gastric emptying, and can reduce gastric volume as a treatment (weight loss) for obesity as described in the background art section. Is very effective, the agent of the present invention can efficiently prevent, treat and / or improve obesity.
　本発明は、胃容量の減少剤を製造するための、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上の使用（使用方法）、でもある。また、本発明は、肥満の予防、治療および／または改善剤を製造するための、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上の使用（使用方法）、でもある。 The present invention is also the use (use method) of one or more selected from glutamine, methionine and phenylalanine for producing a gastric volume reducing agent. Moreover, this invention is also 1 type (s) or 2 or more types (use method) selected from glutamine, methionine, and phenylalanine for manufacturing the prevention, treatment, and / or improvement agent of obesity.
　本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を経口摂取に用いることを特徴とする、胃容量を減少させる方法、でもある。また、本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を経口摂取あるいは経口投与に用いることを特徴とする、肥満を予防、治療および／または改善する方法、でもある。上記二つの方法においては、ヒトに対する医療行為が除かれていてもよい。 The present invention is also a method for reducing gastric volume, characterized in that one or more selected from glutamine, methionine and phenylalanine are used for oral intake. The present invention is also a method for preventing, treating and / or improving obesity, characterized by using one or more selected from glutamine, methionine and phenylalanine for oral ingestion or oral administration. In the above two methods, medical practices for humans may be excluded.
　本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を（商業的に提供して）経口摂取させることを特徴とする、胃容量を減少させる方法、でもある。また、本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を（商業的に提供して）経口摂取させることを特徴とする、肥満を予防、治療および／または改善する方法、でもある。上記二つの方法においては、ヒトに対する医療行為が除かれていてもよい。 The present invention is also a method for reducing gastric volume, characterized in that one or more selected from glutamine, methionine and phenylalanine are orally ingested (provided commercially). The present invention also relates to a method for preventing, treating and / or improving obesity, characterized in that one or more selected from glutamine, methionine and phenylalanine are orally ingested (commercially provided). But it is. In the above two methods, medical practices for humans may be excluded.
　本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有する、胃容量の減少用の組成物でもある。また、本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有する、肥満の予防、治療および／または改善用の組成物でもある。 The present invention is also a composition for reducing gastric volume, containing one or more selected from glutamine, methionine and phenylalanine as an active ingredient. The present invention is also a composition for preventing, treating and / or improving obesity, which contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient.
　本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有し、食品衛生上許容可能な他の添加成分を含有する、胃容量の減少用の飲料やドリンク剤でもある。また、本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有し、食品衛生上許容可能な他の添加成分を含有する、肥満の予防、治療および／または改善用の飲料やドリンク剤でもある。上記飲料およびドリンク剤に使用できる食品衛生上許容可能な他の添加成分としては、甘味料、酸味料などの食品添加物が挙げられる。 The present invention includes one or more selected from glutamine, methionine, and phenylalanine as an active ingredient, and contains other additives that are acceptable for food hygiene, and drinks and drinks for reducing gastric capacity But there is. The present invention also includes obesity prevention, treatment and / or containing one or more selected from glutamine, methionine and phenylalanine as an active ingredient and containing other additive components acceptable in food hygiene. It is also a beverage and drink for improvement. Other additive components acceptable in food hygiene that can be used in the beverages and drinks include food additives such as sweeteners and acidulants.
　本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有し、食品衛生上許容可能な他の添加成分を含有し、製剤化補助剤を含有する、胃容量の減少用の錠剤（タブレット）などのサプリメントでもある。また、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有し、食品衛生上許容可能な他の添加成分を含有し、製剤化補助剤を含有する、肥満の予防、治療および／または改善用の錠剤（タブレット）などのサプリメントでもある。上記サプリメントに使用できる食品衛生上許容可能な他の添加成分としては、甘味料、酸味料、乳化剤、香料などの食品添加物が挙げられる。上記サプリメントに使用できる製剤化補助剤としては、賦形剤、結合剤、崩壊剤、滑沢剤の何れか１種又は２種以上が挙げられる。 The present invention contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient, contains other additive components that are acceptable for food hygiene, and contains a formulation aid. It is also a supplement such as tablets (tablets) to reduce Moreover, the prevention of obesity containing 1 or 2 or more types selected from glutamine, methionine and phenylalanine as an active ingredient, containing other additive ingredients acceptable for food hygiene, and containing a formulation aid, It is also a supplement such as a tablet for treatment and / or improvement. Examples of other food hygiene-acceptable additives that can be used in the supplement include food additives such as sweeteners, acidulants, emulsifiers, and fragrances. Formulation aids that can be used in the supplement include any one or more of excipients, binders, disintegrants, and lubricants.
　本発明は、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有し、製剤化補助剤を含有する、胃容量の減少用のカプセルなどのサプリメントでもある。また、グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上を有効成分として含有し、製剤化補助剤を含有する、肥満の予防、治療および／または改善用のカプセルなどのサプリメントでもある。上記サプリメントに使用できる製剤化補助剤としては、賦形剤、結合剤、崩壊剤、滑沢剤の何れか１種又は２種以上が挙げられる。 The present invention is also a supplement such as a capsule for reducing gastric volume, which contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient and contains a formulation aid. It is also a supplement such as a capsule for preventing, treating and / or improving obesity containing one or more selected from glutamine, methionine and phenylalanine as an active ingredient and containing a formulation aid. Formulation aids that can be used in the supplement include any one or more of excipients, binders, disintegrants, and lubricants.
　本発明の好ましい態様によれば、
　グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸を有効成分として含有する、胃の伸展刺激に適応した胃底部および／または胃体上部の弛緩抑制剤、
　グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸を摂取させることを含んでなる、胃の伸展刺激に適応した胃底部および／または胃体上部の弛緩を抑制する方法、および
　胃の伸展刺激に適応した胃底部および／または胃体上部の弛緩抑制剤の製造のための、グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸の使用
が提供される。上記発明は本発明の胃容量減少剤および各種疾患や症状の予防、治療および／または改善剤並びに本発明の剤のアミノ酸に関する記載に従って実施することができる。 According to a preferred embodiment of the present invention,
An inhibitor of relaxation of the bottom of the stomach and / or the upper part of the stomach, which contains one or more amino acids selected from the group consisting of glutamine, methionine, and phenylalanine as an active ingredient, and that is adapted to gastric stretch stimulation;
Inhibiting the relaxation of the gastric fundus and / or upper gastric body adapted to gastric stretch stimulation comprising ingesting one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine Of one or more amino acids selected from the group consisting of glutamine, methionine, and phenylalanine for the manufacture of a method and a relaxation inhibitor for the stomach bottom and / or upper gastric body adapted to gastric stretch stimulation Use is provided. The above-described invention can be carried out according to the description of the gastric volume reducing agent of the present invention and the preventive, therapeutic and / or ameliorating agents for various diseases and symptoms and the amino acids of the agent of the present invention.
　本発明によれば下記発明が提供される。
［２１］グルタミン、メチオニン、フェニルアラニンから選択される１種または２種以上を有効成分として含有する、胃容量の減少剤。
［２２］胃の伸展刺激に適応した胃底部および／または胃体上部の弛緩を抑制することを特徴とする、上記［２１］に記載の剤。
［２３］胃排出を促進しないことを特徴とする、上記［２１］または［２２］に記載の剤。
［２４］ヒトの１日当たりの摂取量が０．２～５ｇである、上記［２１］～［２３］のいずれかに記載の剤。
［２５］上記［２１］～［２３］のいずれかに記載の剤を有効成分とする、肥満の予防および／または改善剤。
［２６］グルタミン、メチオニン、フェニルアラニンから選択される１種または２種以上を経口摂取に用いることを特徴とする、胃容量を減少させる方法（ヒトに対する医療行為を除く）。
［２７］グルタミン、メチオニン、フェニルアラニンから選択される１種または２種以上を経口摂取させることを特徴とする、胃容量を減少させる方法（ヒトに対する医療行為を除く）。 According to the present invention, the following inventions are provided.
[21] A gastric volume reducing agent comprising one or more selected from glutamine, methionine, and phenylalanine as an active ingredient.
[22] The agent described in [21] above, wherein the agent suppresses relaxation of the stomach bottom and / or the upper body of the stomach adapted to gastric stretch stimulation.
[23] The agent described in [21] or [22] above, which does not promote gastric emptying.
[24] The agent according to any one of [21] to [23] above, wherein the daily intake amount of human is 0.2 to 5 g.
[25] An agent for preventing and / or improving obesity comprising the agent according to any one of [21] to [23] as an active ingredient.
[26] A method for reducing gastric volume (excluding medical practice for humans), wherein one or more selected from glutamine, methionine, and phenylalanine are used for oral intake.
[27] A method for reducing gastric volume (excluding medical practice for humans), wherein one or more selected from glutamine, methionine, and phenylalanine are orally ingested.
　以下、本発明に関して、例を挙げて説明するが、本発明は、これにより限定されるものではない。 Hereinafter, although an example is given and demonstrated regarding this invention, this invention is not limited by this.
例１：各種アミノ酸における、胃容量の減少効果の試験
（１）材料および方法
［被検試料］
　１９種類のアミノ酸（Ｌ－Ｐｈｅｎｙｌ　ａｌａｎｉｎｅ（Ｐｈｅ）、Ｌ－Ｌｙｓｉｎｅ（Ｌｙｓ）、Ｇｌｙｃｉｎｅ（Ｇｌｙ）、Ｌ－Ｃｙｓｔｅｉｎｅ（Ｃｙｓ）、Ｌ－Ｓｅｒｉｎｅ（Ｓｅｒ）、Ｌ－Ａｌａｎｉｎｅ、Ｌ－Ｐｒｏｌｉｎｅ（Ｐｒｏ）、Ｌ－Ａｒｇｉｎｉｎｅ（Ａｒｇ）、Ｌ－Ｈｉｓｔｉｄｉｎｅ（Ｈｉｓ）、Ｌ－Ｔｈｒｅｏｎｉｎｅ、Ｌ－Ｖａｌｉｎｅ、Ｌ－Ｇｌｕｔａｍｉｎｅ、Ｌ－Ａｓｐａｒａｇｉｎｅ（Ａｓｎ）、Ｌ－Ｍｅｔｈｉｏｎｉｎｅ、Ｌ－Ｇｌｕｔａｍｉｃ　ａｃｉｄ、Ｌ－Ａｓｐａｒｔｉｃ　ａｃｉｄ（Ａｓｐ）、Ｌ－Ｉｓｏｌｅｕｃｉｎｅ、Ｌ－Ｌｅｕｃｉｎｅ、およびＬ－Ｔｙｒｏｓｉｎｅ）を被検試料として用いた。 Example 1: Test of gastric volume reduction effect with various amino acids (1) Materials and methods [test sample]
19 kinds of amino acids (L-Phenyl aline (Phe), L-Lycine (Lys), Glycine (Gly), L-Cystein (Cys), L-Serine (Ser), L-Alinene, L-Proline (Pro), L-Arginine (Arg), L-Histine (His), L-Threonine, L-Valine, L-Glutamine, L-Asparagine (Asn), L-Methionine, L-Glutamate acid, L-Apartic acid L-Isolucine, L-Leucine, and L-Tyrosine) were used as test samples.
　前記のアミノ酸のうち、Ｌｙｓには、塩酸塩、Ａｓｎには、一水和物、他のアミノ酸には、ｆｒｅｅ　ｂａｓｅ を用いた。これらアミノ酸を、各々１ｇ／５ｍｌの濃度で注射用水（大塚製薬）に溶解・懸濁して用いた。 Among the amino acids, hydrochloride was used for Lys, monohydrate was used for Asn, and free base was used for the other amino acids. These amino acids were dissolved and suspended in water for injection (Otsuka Pharmaceutical) at a concentration of 1 g / 5 ml each.
［陽性対照試料］
　陽性対照として、胃もたれの改善に用いられる漢方薬である、六君子湯（ツムラ六君子湯エキス顆粒(医療用)、ツムラ）を５００ｍｇ／５ｍｌの濃度で注射用水（大塚製薬）に溶解・懸濁して用いた。
［バロスタットバッグ］
　ポリエチレン製の袋（最大容量：７ｍｌ、最大直径：３ｃｍ）にポリビニル製のチューブの２本を接続したバロスタットバッグを用いた。 [Positive control sample]
As a positive control, Rikkunshi-to (Tsumura Rikkunshi-to extract granule (medical), Tsumura), a Chinese medicine used to improve stomach sag, is dissolved and suspended in water for injection (Otsuka Pharmaceutical) at a concentration of 500 mg / 5 ml. Used.
[Barostat bag]
A barostat bag in which two polyethylene tubes were connected to a polyethylene bag (maximum capacity: 7 ml, maximum diameter: 3 cm) was used.
［動物実験］
　内田らの論文（Ｍａｓａｙｕｋｉ　ＵＣＨＩＤＡ、Ｋｉｍｉｋｏ　ＳＨＩＭＩＺＵ、「Ｍｅｔｈｏｄ　ｔｏ　ｅｖａｌｕａｔｅ　ａｄａｐｔｉｖｅ　ｒｅｌａｘａｔｉｏｎ　ｏｆ　ｔｈｅ　ｓｔｏｍａｃｈ　ｂｙ　ｕｓｉｎｇ　Ｂａｒｏｓｔａｔ　ｉｎ　ｒａｔｓ　ｗｉｔｈｏｕｔ　ｓｕｒｇｉｃａｌ　ｏｐｅｒａｔｉｏｎ，ａｎｄ　ｔｈｅ　ｅｆｆｅｃｔｓ　ｏｆ　ｃａｐｓａｉｃｉｎ　ａｎｄ　Ｎω－ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ－ｍｅｔｈｙｌｅｓｔｅｒ　ｏｎ　ａｄａｐｔｉｖｅ　ｒｅｌａｘａｔｉｏｎ．」、Ｊ．Ｓｍｏｏｔｈ　Ｍｕｓｃｌｅ　Ｒｅｓ．、（２０１２）４８（４））を参考に行った。 [Animal experimentation]
Uchida et al (Masayuki UCHIDA, Kimiko SHIMIZU, "Method to evaluate adaptive relaxation of the stomach by using Barostat in rats without surgical operation, and the effects of capsaicin and Nω-nitro-L-arginine-methylester on adaptive relaxation." J. Smooth Muscle Res., (2012) 48 (4)).
　すなわち、８週齢のＳＤ系雄性ラット（ＳＬＣ社）を１週間で予備飼育して試験に用いた。試験開始日の前日に、体重に基づいて群分けし（全２０群、各ｎ＝４～８匹）、１８～２０時間で絶食した（ただし、水を自由摂取とした）。
　被検試料投与群に、前記の各種アミノ酸の溶解・懸濁液を５ｍｌ／ｋｇ（被検試料の用量１ｇ／ｋｇ）、Ｃｏｎｔｒｏｌ群に、注射用水を５ｍｌ／ｋｇ、陽性対照群に、六君子湯の溶解・懸濁液を５ｍｌ／ｋｇ（六君子湯の用量　５００ｍｇ／ｋｇ）で強制的に経口摂取させた。 That is, 8-week-old SD male rats (SLC) were preliminarily raised for 1 week and used for the test. On the day before the test start date, the animals were divided into groups based on body weight (20 groups in total, n = 4 to 8 animals each), and fasted for 18 to 20 hours (however, water was ad libitum).
In the test sample administration group, the above-mentioned various amino acid dissolution / suspension was 5 ml / kg (test sample dose 1 g / kg), in the Control group, water for injection was 5 ml / kg, in the positive control group, Rikkunko. The dissolution / suspension of hot water was forcibly ingested at 5 ml / kg (Rikkunshi-to dose of 500 mg / kg).
　被検試料または注射用水の投与２０分後に、ウレタンにて麻酔（２０％ウレタン、６ｍｌ／ｋｇ、腹腔内投与）を行い、被検試料または注射用水の投与２５分後に、バロスタットバッグを経口より胃内に挿入した。一方のチューブを閉じた状態で、もう一方のチューブから空気７ｍｌをバロスタットバッグに注入し、バロスタットバッグが胃底部～胃体上部に位置するように調整した。その後、速やかにバロスタットバッグの空気を抜いた。 20 minutes after administration of the test sample or water for injection, anesthesia with urethane (20% urethane, 6 ml / kg, intraperitoneal administration) was performed, and a barostat bag was orally administered 25 minutes after administration of the test sample or water for injection. Inserted into the stomach. With one tube closed, 7 ml of air was injected into the barostat bag from the other tube and adjusted so that the barostat bag was located from the stomach bottom to the upper stomach. Thereafter, the air of the barostat bag was quickly evacuated.
　被検試料または注射用水の投与３０分後に、バロスタット装置（Ｂａｒｏｓｔａｔ　Ｄｉｓｔｅｎｄｅｒ　ＩＩＲ、Ｇ＆Ｊ　Ｅｌｅｃｔｒｏｎｉｃｓ）に接続して、呼吸を保持しつつ、バロスタットバッグを膨らませて、バロスタットバッグの内圧および容量を測定した。具体的には、バロスタットバッグの内圧を初期値で０ｍｍＨｇとし、段階的に内圧を増加させて、胃底部～胃体上部に伸展刺激を与えた。 Thirty minutes after administration of the test sample or water for injection, the barostat bag was inflated while connected to a barostat device (Barostat Diistender IIR, G & J Electronics) while maintaining breathing, and the internal pressure and volume of the barostat bag were measured. . Specifically, the internal pressure of the barostat bag was set to 0 mmHg as an initial value, and the internal pressure was increased stepwise to give a stretching stimulus from the bottom of the stomach to the upper part of the stomach.
測定開始後０～１分、１～２分、２～３分、３～４分におけるバロスタットバッグの内圧を、１ｍｍＨｇ、２ｍｍＨｇ、４ｍｍＨｇ、８ｍｍＨｇに設定して、継続的にバロスタットバッグの容量を測定した（図１）。 The internal pressure of the barostat bag is set to 1 mmHg, 2 mmHg, 4 mmHg, and 8 mmHg at 0 to 1 minute, 1 to 2 minutes, 2 to 3 minutes, and 3 to 4 minutes after the start of measurement. Was measured (FIG. 1).
　測定終了後に、バロスタットバッグを膨らしたままで腹部を切開し、胃部を観察して、バロスタットバッグの挿入具合（位置など）、バロスタットバッグの膨らみ具合、出血の有無等を確認した。 After the measurement was completed, the abdomen was incised with the barostat bag inflated, and the stomach was observed to confirm the insertion state (position, etc.) of the barostat bag, the swelling state of the barostat bag, the presence of bleeding, etc. .
［評価］
　各段階のバロスタットバッグの内圧を約１分間で維持する間に増加したバロスタットバッグの容量（ｍｌ）を算出し、これをＡｄａｐｔｉｖｅ　ｒｅｌａｘａｔｉｏｎ（ｍｌ）とした（図１）。さらに、各内圧で得られた値をｃｏｎｔｒｏｌ群の値で除して、適応弛緩（％対コントロール群）を算出した。 [Evaluation]
The volume (ml) of the barostat bag increased while maintaining the internal pressure of the barostat bag at each stage for about 1 minute was calculated, and this was referred to as Adaptive relaxation (ml) (FIG. 1). Further, adaptive relaxation (% vs. control group) was calculated by dividing the value obtained at each internal pressure by the value of the control group.
（２）結果
　図２にバロスタットバックの内圧が８ｍｍＨｇのときの、適応弛緩（Ａｄａｐｔｉｖｅ　ｒｅｌａｘａｔｉｏｎ）を示す。Ｇｌｎ群、Ｍｅｔ群では、いずれも、Ｃｏｎｔｒｏｌ群より有意に低い値を示した。また、Ｐｈｅ群では、胃底部～胃体上部の収縮作用が強く起こり、バロスタットバッグが胃底部～胃体上部から押し出されて胃体部に移動した。この現象では、Ｐｈｅは、ＧｌｎやＭｅｔよりもさらに強い作用を有することを示している。 (2) Results FIG. 2 shows adaptive relaxation when the internal pressure of the barostat back is 8 mmHg. In the Gln group and the Met group, both values were significantly lower than those in the Control group. In the Phe group, the contraction action from the stomach bottom to the stomach upper part was strong, and the barostat bag was pushed out from the stomach bottom to the stomach upper part and moved to the stomach body. This phenomenon shows that Phe has a stronger action than Gln and Met.
　このことから、Ｇｌｎ、Ｍｅｔ、Ｐｈｅは、胃の伸展刺激に適応した胃底部および／または胃体上部の弛緩を抑制し、可逆的に胃容量を減少させることがわかった。 From this fact, it was found that Gln, Met, and Phe reversibly reduce the gastric volume by suppressing the relaxation of the stomach bottom and / or the upper body of the stomach adapted to the gastric stretch stimulation.
例２：本発明の剤を配合した飲料の製造方法
　Ｌ－グルタミンを０．５ｗ／ｖ％、甘味料１．０ｗ／ｖ％、酸味料０．９ｗ／ｖ％、および増粘剤０．２ｗ／ｖ％の濃度で配合し、常法に従って飲料を製造した。この飲料を４０ｍｌ、１００ｍｌ、２００ｍｌ、３００ｍｌ、５００ｍｌ、１０００ｍｌを摂取すると、Ｌ－グルタミンを０．２ｇ、０．５ｇ、１ｇ、１．５ｇ、２．５ｇ、５ｇ摂取することができる。 Example 2: Process for producing a beverage containing the agent of the present invention L-glutamine 0.5 w / v%, sweetener 1.0 w / v%, acidulant 0.9 w / v%, and thickener 0.2 w A beverage was prepared according to a conventional method. When 40 ml, 100 ml, 200 ml, 300 ml, 500 ml and 1000 ml of this beverage are ingested, L-glutamine can be ingested in 0.2 g, 0.5 g, 1 g, 1.5 g, 2.5 g and 5 g.
　同様にして、Ｌ－メチオニンを０．５ｗ／ｖ％配合した飲料、Ｌ－フェニルアラニンを０．５ｗ／ｖ％配合した飲料、Ｌ－グルタミン０．２ｗ／ｖ％とＬ－メチオニン０．１ｗ／ｖ％とＬ－フェニルアラニン０．２ｗ／ｖ％を配合した飲料、および、Ｌ－グルタミン０．１ｗ／ｖ％とＬ－フェニルアラニン０．４ｗ／ｖ％を配合した飲料を製造した。 Similarly, a beverage containing 0.5 w / v% L-methionine, a beverage containing 0.5 w / v% L-phenylalanine, 0.2 w / v L-glutamine and 0.1 w / v L-methionine % And L-phenylalanine 0.2 w / v%, and a drink containing L-glutamine 0.1 w / v% and L-phenylalanine 0.4 w / v%.
例３：本発明の剤を配合したタブレットの製造方法
　Ｌ－グルタミン２００ｍｇに賦形剤、結合剤、崩壊剤、滑沢剤、酸味料、乳化剤、香料、および甘味料などを配合し、常法に従って約６００ｍｇのタブレットを製造した（Ｌ－アスパラギン酸含量：約３３ｗ／ｗ％）。このタブレット１、２、３、５、１０、２０錠を摂取すると、Ｌ－グルタミンを０．２ｇ、０．４ｇ、０．６ｇ、１ｇ、２ｇ、４ｇ摂取することができる。 Example 3: Manufacturing method of tablet containing the agent of the present invention 200 mg L-glutamine was mixed with excipient, binder, disintegrant, lubricant, acidulant, emulsifier, flavor, sweetener, etc. About 600 mg of a tablet was produced according to the above (L-aspartic acid content: about 33 w / w%). When these tablets 1, 2, 3, 5, 10, 20 tablets are taken, L-glutamine can be taken 0.2 g, 0.4 g, 0.6 g, 1 g, 2 g, 4 g.
　同様にして、Ｌ－メチオニンを２００ｍｇ配合したタブレット、Ｌ－フェニルアラニンを２００ｍｇ配合したタブレット、Ｌ－グルタミン５０ｍｇとＬ－メチオニン５０ｍｇとＬ－フェニルアラニン１００ｍｇを配合したタブレット、および、Ｌ－メチオニン１００ｍｇとＬ－フェニルアラニン１００ｍｇを配合したタブレット製造した。 Similarly, a tablet containing 200 mg of L-methionine, a tablet containing 200 mg of L-phenylalanine, a tablet containing 50 mg of L-glutamine, 50 mg of L-methionine and 100 mg of L-phenylalanine, and 100 mg of L-methionine and L- A tablet containing 100 mg of phenylalanine was produced.
例４：本発明の剤を配合したサプリメントの製造方法
　Ｌ－グルタミン３００ｍｇに賦形剤などを添加して、カプセルに充填してサプリメントを製造した。このサプリメント１、２、３、５、１０粒摂取すると、Ｌ－グルタミンを０．３ｇ、０．６ｇ、０．９ｇ、１．５ｇ、３ｇ摂取することができる。 Example 4: Method for producing a supplement containing the agent of the present invention An excipient or the like was added to 300 mg of L-glutamine and filled into capsules to produce a supplement. Ingestion of 1, 2, 3, 5, 10 capsules of this supplement can ingest 0.3 g, 0.6 g, 0.9 g, 1.5 g, 3 g of L-glutamine.
　同様にして、Ｌ－メチオニンを３００ｍｇ充填したサプリメント、Ｌ－フェニルアラニンを３００ｍｇ充填したサプリメント、Ｌ－グルタミン５０ｍｇとＬ－メチオニン１００ｍｇとＬ－フェニルアラニン１５０ｍｇを充填したサプリメント、および、Ｌ－グルタミン２００ｍｇとＬ－メチオニン１００ｍｇを充填したサプリメントを製造した。 Similarly, a supplement filled with 300 mg of L-methionine, a supplement filled with 300 mg of L-phenylalanine, a supplement filled with 50 mg of L-glutamine, 100 mg of L-methionine and 150 mg of L-phenylalanine, and 200 mg of L-glutamine and L- A supplement filled with 100 mg of methionine was produced.

Claims (10)

  1. 　グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸を有効成分として含有する、胃容量の減少剤。 A gastric capacity reducing agent comprising one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine as an active ingredient.
  2. 　胃の伸展刺激に適応した胃底部および／または胃体上部の弛緩を抑制する、請求項１に記載の剤。 The agent according to claim 1, which suppresses relaxation of the stomach bottom and / or stomach upper body adapted to gastric stretch stimulation.
  3. 　胃排出を促進しないことを特徴とする、請求項１または２に記載の剤。 3. The agent according to claim 1 or 2, which does not promote gastric emptying.
  4. 　グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸を有効成分として含有する、肥満の予防、治療および／または改善剤。 An obesity preventive, therapeutic and / or ameliorating agent containing one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine as an active ingredient.
  5. 　ヒトの１日当たりのアミノ酸の摂取量または投与量がアミノ酸の固形分換算で０．２～５ｇとなるよう配合されてなる、請求項１～４のいずれか一項に記載の剤。 The agent according to any one of claims 1 to 4, which is formulated so that the daily intake or dose of amino acids in humans is 0.2 to 5 g in terms of solid content of amino acids.
  6. 　１回の摂取量または投与量当たりの包装単位形態からなる、請求項１～５のいずれか一項に記載の剤。 The agent according to any one of claims 1 to 5, which is composed of a packaged unit form per intake or dose.
  7. 　グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のアミノ酸を経口摂取させることを含んでなる、胃容量を減少させる方法。 A method for reducing gastric volume, comprising orally ingesting one or more amino acids selected from glutamine, methionine and phenylalanine.
  8. 　胃容量の減少剤の製造のための、グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸の使用。 Use of one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine for the production of a gastric volume reducing agent.
  9. 　グルタミン、メチオニンおよびフェニルアラニンから選択される１種または２種以上のアミノ酸を、それを必要とするヒトを含む哺乳類に投与することを含んでなる、肥満の予防、治療および／または改善方法。 A method for preventing, treating and / or improving obesity, comprising administering one or more amino acids selected from glutamine, methionine and phenylalanine to mammals including humans in need thereof.
  10. 　肥満の予防、治療および／または改善剤の製造のための、グルタミン、メチオニンおよびフェニルアラニンからなる群から選択される１種または２種以上のアミノ酸の使用。
     
          Use of one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine for the manufacture of an agent for preventing, treating and / or improving obesity.

PCT/JP2016/057714 2015-03-13 2016-03-11 Gastric volume-reducing agent WO2016148046A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4833128A (en) * 1984-12-28 1989-05-23 Neil Solomon Dietary supplement
JP2008291002A (en) * 2007-05-28 2008-12-04 House Wellness Foods Kk Composition for prophylaxis, ameliorate or therapy of metabolic syndrome

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4833128A (en) * 1984-12-28 1989-05-23 Neil Solomon Dietary supplement
JP2008291002A (en) * 2007-05-28 2008-12-04 House Wellness Foods Kk Composition for prophylaxis, ameliorate or therapy of metabolic syndrome

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EKA FUJIMOTO ET AL.: "Himan Model Mouse ni Okeru Gultamine Hokyu no Eikyo", EIYOGAKU ZASSHI, vol. 72, no. 5, 2014, pages 310 *

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