WO2015167002A1 - Composition pour atténuer les troubles gastro-intestinaux - Google Patents

Composition pour atténuer les troubles gastro-intestinaux Download PDF

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WO2015167002A1
WO2015167002A1 PCT/JP2015/063041 JP2015063041W WO2015167002A1 WO 2015167002 A1 WO2015167002 A1 WO 2015167002A1 JP 2015063041 W JP2015063041 W JP 2015063041W WO 2015167002 A1 WO2015167002 A1 WO 2015167002A1
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exercise
serine
gastrointestinal
composition
histidine
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PCT/JP2015/063041
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English (en)
Japanese (ja)
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義人 野草
亜実 水柿
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味の素株式会社
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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
    • A61K31/33—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
    • 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
    • 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]

Definitions

  • the present invention relates to a composition for improving gastrointestinal disorders. Specifically, the present invention relates to oral compositions that improve gastrointestinal disorders.
  • the digestive tract has not only digestive absorption of ingested food but also a barrier function that prevents foreign substances from entering the body. It is known that a decrease in the barrier function leads to invasion of enteric bacteria into the body, causing inflammation and causing not only a malfunction of the digestive tract but also a general deterioration of the physical condition. In severe cases, bacteria may migrate to the organ and cause multiple organ failure. Such a decrease in the barrier function of the digestive tract is caused by intense exercise (Non-patent Document 1). Although the decrease in gastrointestinal function during exercise is similar to Crohn's disease, ulcerative colitis, and stress-related diseases, the detailed mechanism is unclear.
  • barrier function is lowered due to physiological phenomena peculiar to exercise such as blood gathering in muscles and heart and blood supply to the digestive tract is reduced, and body temperature is increased. Since this decrease in barrier function leads to a decrease in athlete's condition and performance, it is important for athletes to maintain the gastrointestinal barrier function.
  • Cow colostrum, glutamine, and arginine have been reported to improve exercise-induced degradation of gastrointestinal barrier function.
  • cow colostrum it has been reported that stress resistance of the intestinal tract is increased by growth factors such as TGF-1 contained therein (Patent Document 1).
  • Cow colostrum is valuable and has the problem of lack of versatility.
  • Non-Patent Documents 2 and 3 it is necessary to take glutamine and arginine for a long time, and it is complicated to use during exercise. Furthermore, the use of glutamine is limited because of its low stability in aqueous solution.
  • An object of the present invention is to provide an agent for improving gastrointestinal disorders that can exhibit an improvement effect equivalent to or better than that of the prior art and can be easily ingested for gastrointestinal disorders including a decrease in gastrointestinal barrier function. It is in.
  • amino acids such as histidine, serine, branched chain amino acids (leucine, isoleucine, valine) and fat-soluble antioxidants are useful as materials for improving gastrointestinal disorders.
  • amino acids such as histidine, serine, branched chain amino acids (leucine, isoleucine, valine) and fat-soluble antioxidants are useful as materials for improving gastrointestinal disorders.
  • the present invention has been completed.
  • the present invention is as follows.
  • An oral composition for improving gastrointestinal disorders (hereinafter referred to as “this”) containing as an active ingredient at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant. Also referred to as “the composition of the invention”).
  • the composition according to (1) which contains serine as an active ingredient.
  • the composition according to (1) or (2), wherein the gastrointestinal tract disorder is at least one selected from reduced gastrointestinal barrier function, gastrointestinal inflammation and gastrointestinal upset.
  • composition according to any one of (2) to (4), wherein the serine content per unit dose of human being is 10 mg to 10 g.
  • the composition according to (1), wherein the gastrointestinal disorder is exercise-induced degradation of the gastrointestinal barrier function.
  • composition according to (1) wherein the gastrointestinal disorder is exercise-induced degradation of the gastrointestinal barrier function.
  • a food or pharmaceutical comprising the composition according to any one of (1) to (20).
  • a composition containing, as an active ingredient, at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant is orally administered to a subject in need thereof at least once.
  • a method for improving gastrointestinal disorders is orally administered to a subject in need thereof at least once.
  • the composition contains at least one selected from the group consisting of histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an active ingredient, (23) The method according to (23), wherein the gastrointestinal tract disorder is exercise-induced gastrointestinal barrier function decline.
  • the composition contains at least one selected from the group consisting of serine, histidine, valine, leucine and isoleucine as an active ingredient, (23) The method according to (23), wherein the gastrointestinal tract disorder is exercise-induced gastrointestinal barrier function decline.
  • the method according to (30) or (31), wherein the composition contains valine, leucine and isoleucine as active ingredients.
  • the method according to (31), wherein the composition contains serine and histidine as active ingredients.
  • composition contains 0.1 to 100 g of an active ingredient per unit amount of human intake.
  • composition is taken at least once before exercising.
  • composition is taken during exercise or immediately after the end of exercise.
  • composition is taken at least once before exercising, and further at least once during or immediately after exercising.
  • composition of the present invention is suitably used for improving gastrointestinal disorders.
  • the compositions of the present invention are effectively used to ameliorate exercise-induced gastrointestinal disorders.
  • the composition of the present invention is suitably used for maintaining the condition during training of an athlete.
  • the compositions of the present invention are effectively used to ameliorate exercise-induced degradation of gastrointestinal barrier function.
  • the composition of the present invention is extremely advantageous because it is highly safe and has few side effects.
  • Example 1 Lipopolysaccharide.
  • the outline of the experimental method of Example 1 etc. is shown.
  • Sed non-exercise group
  • Exercise exercise group
  • Water water
  • Gln L-glutamine
  • ArgHCL L-arginine hydrochloride
  • HisHCL L-histidine hydrochloride
  • CHO maltodextrin.
  • Sedentary non-exercise group
  • Water water, 0.5 g / kg His: L-histidine hydrochloride aqueous solution, 0.25 g / kg Arg + 0.25 g / kg His: aqueous solution of L-arginine hydrochloride and L-histidine hydrochloride, 0.25 g / kg His + 0.25 g / kg
  • Ser An aqueous solution of L-serine and L-histidine hydrochloride. The effect of serine on exercise-induced gastrointestinal barrier function decline is shown.
  • Water water, Ser: L-serine, Gly: glycine.
  • Sedentary non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution.
  • 2 shows the effect of serine (measurement result of blood endotoxin concentration) on exercise-induced gastrointestinal barrier function decline.
  • Sedentary non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution.
  • the effect of serine on the inflammation of the gastrointestinal tract is shown.
  • Sedentary non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution.
  • the effect of serine on the inflammation of the gastrointestinal tract is shown.
  • the effect of serine on the inflammation of the gastrointestinal tract is shown.
  • the effect of serine on inflammation of the gastrointestinal tract is shown.
  • Sedentary non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution. The combined effect (measurement result of FD4 concentration in blood) of serine and other amino acids exerted on exercise-induced gastrointestinal barrier function lowering is shown.
  • Sedentary non-exercise group, Water: water, Ser: L-serine aqueous solution, Ser + His: aqueous solution of L-serine and L-histidine hydrochloride, Ser + Arg: aqueous solution of L-serine and L-arginine hydrochloride.
  • Sedentary non-exercise group
  • Ex-Water water
  • Ex-His 0.5 g / kg L-histidine hydrochloride aqueous solution
  • Ex-chlorogenic acid chlorogenic acid aqueous solution
  • Ex-His + chlorogenic acid L-histidine hydrochloride and chlorogenic acid Aqueous solution.
  • digestive tract disorder refers to tissue damage and functional deterioration in the digestive tract (pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine) and symptoms caused by them. Examples thereof include a decrease in gastrointestinal barrier function, inflammation of the gastrointestinal tract, and gastrointestinal upset.
  • the transport pathway of substances through the digestive tract epithelial cells is roughly classified into intracellular and paracellular pathways. Intracellular pathways contribute to the absorption of nutrients through transporters and channels on the cell membrane.
  • the cell-to-cell pathway has selective permeability controlled by adhesion molecules between adjacent cells, which is useful for absorption of minerals such as calcium, as well as intestinal bacteria and diet-derived antigens that exist in large quantities in the lumen.
  • it shows a barrier function that does not enter the body.
  • the adhesive molecular structure responsible for this selective permeability is a tight junction.
  • Tight junctions are large protein complexes that are located in the vicinity of the brush border membrane of the epithelial cell side bottom membrane, and are composed of transmembrane proteins such as occludin and claudin and intracellular lining proteins such as zonula occludens.
  • “digestive tract barrier function reduction” means that the barrier between epithelial cells of the digestive tract breaks down, and the permeability of the digestive tract is increased to produce a foreign substance, intestinal bacterium, or enteric bacterium. The state where it is easy to enter the body through the digestive tract. It is considered that the deterioration of the gastrointestinal barrier function is caused by, for example, a decrease in blood supply to the gastrointestinal tract during exercise. Moreover, it is thought that the fall of a digestive tract barrier function is caused by the rise in body temperature etc., for example. A schematic diagram of the degradation of the gastrointestinal barrier function is shown in FIG.
  • the deterioration of the gastrointestinal barrier function and whether or not the gastrointestinal barrier function is improved can be confirmed when the gastrointestinal barrier function is maintained normally, but the transition from the gastrointestinal tract to the body is suppressed. Confirmed by orally administering to the animal a labeled compound having a molecular weight that passes through the digestive tract and enters the blood (for example, a molecular weight of about 4000) and measures the amount (concentration) of the labeled compound in the blood can do. In the case of humans, it can be confirmed by measuring the permeation amount of non-metabolizable sugar molecules such as mannitol, rhamnose, lactulose through the intestinal mucosa.
  • the term “inflammation of the digestive tract” includes any inflammation observed in the digestive tract regardless of the cause.
  • the inflammation may be acute or chronic. It may be accompanied by one or more inflammatory symptoms such as redness, pain, fever, swelling, etc., or may not be accompanied by these inflammatory symptoms.
  • gastrointestinal upset is a general term for pathological symptoms that occur in the gastrointestinal tract and pathological symptoms that occur due to decreased function of the gastrointestinal tract, such as stomach pain, nausea, diarrhea, etc. Can be mentioned.
  • “exercise-induced gastrointestinal dysfunction” refers to gastrointestinal dysfunction that develops with exercise (particularly intense exercise).
  • severe exercise means, for example, exercise for a long time, exercise every day, exercise of relatively high intensity, exercise in a harsh environment such as under high temperature, or the like.
  • As a method for determining whether or not a gastrointestinal disorder is exercise-induced for example, a significant increase in TNF- ⁇ cannot be confirmed, but when a gastrointestinal disorder occurs, the gastrointestinal disorder is exercise-induced. It can be determined that there is. Whether or not the gastrointestinal tract disorder is exercise-induced is determined not only from TNF- ⁇ , but also from, for example, an increase in body temperature, blood shortage, inflammation (particularly inflammation in which the increase in TNF- ⁇ is not significant), etc. It may be determined.
  • “exercise-induced decrease in gastrointestinal barrier function” refers to a decrease in gastrointestinal barrier function that occurs with exercise (particularly intense exercise). “Exercise-induced degradation of gastrointestinal barrier function” is thought to be mainly due to increased body temperature and decreased blood flow due to exercise. On the other hand, stress-related intestinal diseases and inflammatory bowel diseases are caused by inflammation, and these and the exercise-induced decrease in gastrointestinal barrier function are considered to differ in mechanism and state.
  • “exercise-induced inflammation of the gastrointestinal tract” refers to inflammation of the gastrointestinal tract that occurs with exercise (particularly intense exercise). Also, “exercise-induced gastrointestinal upset” refers to gastrointestinal upset that develops with exercise (particularly intense exercise).
  • “improvement” means “prevention or treatment”.
  • exercising ⁇ exercise-induced barrier function decline '' which is a type of gastrointestinal disorder
  • ⁇ improvement '' of exercise-induced barrier function decline is exercise-induced gastrointestinal barrier function during exercise
  • prevention of gastrointestinal inflammation or gastrointestinal upset means preventing or delaying the onset of gastrointestinal inflammation or gastrointestinal upset
  • treatment refers to the gastrointestinal tract. It means to reduce inflammation or gastrointestinal upset symptoms, or to prevent or delay the progression (aggravation) of symptoms.
  • Serine, histidine, valine, leucine and isoleucine which are amino acids contained as an active ingredient in the composition of the present invention, can be used in any of L-form, D-form and DL-form, respectively. , L-form and DL-form, and more preferably L-form.
  • the amino acid can be used not only in a free form but also in a salt form.
  • the salt form include acid addition salts and salts with bases, and pharmacologically acceptable salts are preferably selected.
  • serine salts include salts with inorganic bases, salts with inorganic acids, and salts with organic acids.
  • Examples of the salt with an inorganic base include a salt with an alkali metal such as sodium, potassium and lithium, a salt with an alkaline earth metal such as calcium and magnesium, and an ammonium salt.
  • Examples of the salt with an inorganic acid include salts with hydrohalic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid and the like.
  • Examples of the salt with an organic acid include salts with formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, glutamic acid, aspartic acid and the like.
  • histidine salts include salts with inorganic bases, salts with inorganic acids, and salts with organic acids.
  • the salt with an inorganic base include a salt with an alkali metal such as sodium, potassium and lithium, a salt with an alkaline earth metal such as calcium and magnesium, and an ammonium salt.
  • the salt with an inorganic acid include salts with hydrohalic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid and the like.
  • Examples of the salt with an organic acid include salts with formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid and the like.
  • Examples of acids that form pharmacologically acceptable salts by adding to the branched chain amino acids of isoleucine, leucine, and valine include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; acetic acid, lactic acid, citric acid, and the like. Examples thereof include organic acids such as acid, tartaric acid, maleic acid, fumaric acid and monomethyl sulfuric acid.
  • Examples of pharmacologically acceptable bases for branched chain amino acids of isoleucine, leucine and valine include, for example, metal hydroxides or carbonates such as sodium, potassium and calcium, or inorganic bases such as ammonia; ethylenediamine, propylenediamine and ethanol.
  • Organic bases such as amine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine are listed.
  • the fat-soluble antioxidant contained as an active ingredient in the composition of the present invention is not particularly limited as long as it has an action capable of improving gastrointestinal disorders.
  • chlorogenic acid compound, ⁇ -lipoic acid compound, vitamin E, astaxanthin and the like can be mentioned, and a chlorogenic acid compound and an ⁇ -lipoic acid compound are preferable.
  • the chlorogenic acid compound used in the present invention includes 5-caffeoylquinic acid (chlorogenic acid) in which caffeic acid is ester-bonded to the hydroxyl group at the 5-position of quinic acid and derivatives thereof.
  • the derivatives include 4-caffeoylquinic acid (cryptochlorogenic acid) in which caffeic acid is ester-bonded to the 4-position hydroxyl group of quinic acid, and 3-caffeic acid in which caffeic acid is ester-bonded to the 3-position hydroxyl group of quinic acid.
  • Oil quinic acid (neochlorogenic acid), dicaffeoylquinic acid (isochlorogenic acid) in which caffeic acid is ester-bonded to any two of hydroxyl groups at positions 3, 4 and 5 of quinic acid, Ferryl quinic acid in which ferulic acid is ester-bonded to any one of hydroxyl groups at positions 3, 4 and 5, and caffeic acid at any two of hydroxyl groups at positions 3, 4 and 5 of quinic acid And ferulic caffeoyl quinic acid in which erulic acid and ferulic acid are ester-bonded.
  • physiologically acceptable salts eg, alkali metal salts, alkaline earth metal salts, etc.
  • esters, and amides may also be used.
  • the chlorogenic acid compound used in the present invention may be any one of these compounds or a mixture of two or more compounds.
  • the chlorogenic acid compound used in the present invention is preferably chlorogenic acid.
  • the ⁇ -lipoic acid compound used in the present invention includes ⁇ -lipoic acid (thioctic acid (1,2-dithiolane-3-pentanoic acid)) and derivatives thereof.
  • the derivative include dihydrolipoic acid (6,8-dimercaptooctanoic acid).
  • physiologically acceptable salts eg, alkali metal salts, alkaline earth metal salts, etc.
  • esters, and amides may also be used.
  • the ⁇ -lipoic acid compound used in the present invention may be any one of these compounds or a mixture of two or more compounds.
  • the ⁇ -lipoic acid compound used in the present invention is preferably ⁇ -lipoic acid.
  • the fat-soluble antioxidant eg., chlorogenic acid compound, ⁇ -lipoic acid compound, etc.
  • those extracted from nature may be used, or those chemically synthesized chemically may be used.
  • a commercially available product may be used, which is preferable because it is simple.
  • composition of the present invention contains, as an active ingredient, at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant (eg, chlorogenic acid compound, ⁇ -lipoic acid compound, etc.). To do.
  • the composition of the present invention may contain, as an active ingredient, two or more combinations selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant.
  • composition of the present invention may contain at least one selected from the group consisting of serine, histidine, valine, leucine and isoleucine as an active ingredient, and is a group consisting of serine, histidine, valine, leucine and isoleucine Two or more selected combinations may be contained as active ingredients.
  • composition of the present invention may contain serine as an essential active ingredient.
  • composition of the present invention may further contain at least one selected from the group consisting of histidine, arginine and a fat-soluble antioxidant as an active ingredient.
  • composition of the present invention may contain at least one selected from the group consisting of histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an essential active ingredient.
  • composition of the present invention may further contain arginine and / or serine as an active ingredient.
  • Arginine that can be contained as an active ingredient in the composition of the present invention can be used in any of L-form, D-form, and DL-form, preferably L-form and DL-form, and more preferably Is the L-form.
  • arginine salts include salts with inorganic bases, salts with inorganic acids, and salts with organic acids.
  • the salt with an inorganic base include a salt with an alkali metal such as sodium, potassium and lithium, a salt with an alkaline earth metal such as calcium and magnesium, and an ammonium salt.
  • Examples of the salt with an inorganic acid include salts with hydrohalic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid and the like.
  • Examples of the salt with an organic acid include salts with formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid and the like.
  • composition of the present invention may contain serine as an essential component and at least one amino acid selected from the group consisting of histidine, valine, leucine and isoleucine as an active ingredient.
  • amino acids amino acids, fat-soluble antioxidants
  • Serine and histidine amino acids, fat-soluble antioxidants
  • serine and arginine amino acids, histidine and arginine
  • Histidine and chlorogenic acid compounds preferably chlorogenic acid
  • Three amino acids valine, leucine and isoleucine
  • Serine, valine, leucine and isoleucine amino acids, valine, leucine and isoleucine
  • four amino acids histidine, valine, leucine and isoleucine
  • the content of the active ingredient is human in view of the effect of improving gastrointestinal disorders (eg, exercise-induced degradation of the gastrointestinal barrier function).
  • it is preferably 0.1 g or more, more preferably 0.5 g or more, particularly preferably 1 g or more per unit amount taken once.
  • the content is preferably 100 g or less, more preferably 10 g or less.
  • the amino acid content is calculated after converting the salt into a free form.
  • the content of the active ingredient is, for example, 1 when the composition contains only one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an active ingredient.
  • the content of the one component per unit dose.
  • the combination per unit dose The total amount.
  • the “unit dose once taken” is an amount taken or administered at a time.
  • the content of serine is preferably 10 mg or more per unit dose when applied to humans from the viewpoint of the effect of improving gastrointestinal disorders, More preferably, it is 50 mg or more, Most preferably, it is 100 mg or more. Further, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.
  • the content of serine is preferably 10% by weight or more, more preferably 20% by weight or more, based on all amino acids in the composition of the present invention. And particularly preferably 50% by weight or more.
  • the content of serine is preferably 100% by weight or less, more preferably 95% by weight or less, and particularly preferably 90% by weight or less, based on all amino acids in the composition of the present invention. .
  • the content of histidine is preferably 10 mg or more per unit dose when applied to humans from the viewpoint of the effect of improving gastrointestinal disorders, More preferably, it is 50 mg or more, Most preferably, it is 100 mg or more. Further, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.
  • the content of histidine is preferably 10% by weight or more, more preferably 20% by weight or more, based on all amino acids in the composition of the present invention. And particularly preferably 50% by weight or more.
  • the content of histidine is preferably 100% by weight or less, more preferably 95% by weight or less, and particularly preferably 90% by weight or less, based on the total amino acids in the composition of the present invention. .
  • composition of the present invention may contain, as an active ingredient, a mixture of three kinds of branched chain amino acids of isoleucine, leucine and valine (may be abbreviated as BCAA in the present invention).
  • BCAA branched chain amino acids
  • the content of BCAA is preferably 10 mg or more per unit of ingestion when applied to humans, from the viewpoint of the effect of improving gastrointestinal disorders, More preferably, it is 50 mg or more, Most preferably, it is 100 mg or more. Further, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.
  • the content of BCAA is preferably 50% by weight or more, more preferably 60% by weight or more, based on all amino acids in the composition of the present invention. And particularly preferably 70% by weight or more.
  • the content of BCAA is preferably 100% by weight or less, more preferably 95% by weight or less, and particularly preferably 90% by weight or less, based on all amino acids in the composition of the present invention. .
  • the content of the chlorogenic acid compound is preferably 1 mg per unit dose taken when applied to humans from the viewpoint of the effect of improving gastrointestinal disorders. Or more, more preferably 5 mg or more, particularly preferably 50 mg or more. Further, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.
  • the content of the ⁇ -lipoic acid compound is such that, when applied to humans, from the viewpoint of the effect of improving gastrointestinal disorders, , Preferably 10 mg or more, more preferably 50 mg or more, particularly preferably 100 mg or more. Further, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.
  • composition of the present invention contains histidine, serine and BCAA
  • composition of the present invention contains histidine and a fat-soluble antioxidant (for example, a chlorogenic acid compound), the ratio of histidine to the fat-soluble antioxidant is a weight ratio, usually histidine: lipid-soluble antioxidant.
  • Oxidizing agent is in the range of 1: 0.001 to 5, preferably in the range of 1: 0.01 to 2.
  • composition of the present invention can be used in combination with a therapeutic agent for gastrointestinal ulcer (hereinafter sometimes referred to as a concomitant drug).
  • a therapeutic agent for gastrointestinal ulcer hereinafter sometimes referred to as a concomitant drug.
  • the concomitant drug is not particularly limited as long as it is a therapeutic drug usually used in the treatment of digestive system diseases, and specific examples include rebamipide.
  • composition of the present invention can be used in combination with good bacteria such as lactic acid bacteria and bifidobacteria.
  • good bacteria such as lactic acid bacteria and bifidobacteria.
  • Specific examples include VSL # 3 (registered trademark).
  • composition of the present invention can be used in combination with glutamine or arginine.
  • composition of the present invention can be applied to mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).
  • mammals eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.
  • the intake of the composition of the present invention may be appropriately set according to the weight or size of the animal.
  • composition of the present invention is usually used orally, but can be administered through administration routes such as enteral tube administration and infusion administration according to the symptoms of the subject.
  • dosage forms for oral use include granules, fine granules, powders, coated tablets, tablets, powders, (micro) capsules, chewables, syrups, juices, liquids, suspensions, and emulsions. Etc.
  • Preparation into these dosage forms is performed by formulating by a conventional method.
  • Various pharmaceutical substances that are pharmacologically acceptable can be blended as required in the preparation.
  • the substance for the preparation can be appropriately selected depending on the dosage form of the preparation.
  • the excipient, the diluent, the additive, the disintegrant, the binder, the coating agent, the lubricant, the lubricant, the lubricant, and the corrigent. Flavoring agents, sweetening agents, solubilizing agents and the like.
  • the pharmaceutical substance examples include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents, Examples include sterilized water and mono- or polyhydric alcohols such as glycerol.
  • the intake or dose of the composition of the present invention varies depending on the subject's symptoms, age, body weight or dosage form, intake method or administration method, etc., but histidine is 0.005 g / kg body weight to 5 g / day per adult.
  • the standard is 5 g / kg body weight and 0.001 g / kg body weight to 1 g / kg body weight of a fat-soluble antioxidant (eg, chlorogenic acid compound, ⁇ -lipoic acid compound, etc.).
  • a fat-soluble antioxidant eg, chlorogenic acid compound, ⁇ -lipoic acid compound, etc.
  • histidine 0.01 g / kg body weight to 1 g / kg body weight
  • serine 0.01 g / kg body weight to 1 g / kg body weight
  • isoleucine 0.01 g / kg body weight to 1 g / kg per day for an adult.
  • composition of the present invention contains arginine
  • the intake or dose of arginine is usually 0.005 g / kg body weight to 5 g / kg body weight, preferably 0.01 g / kg body weight to 1 g / day, per adult day. kg body weight.
  • the daily dose can be taken or administered at once or in several divided doses.
  • the composition of the present invention may be taken or administered before exercise, after exercise, or during exercise.
  • the intake or administration time of the composition of the present invention is preferably before the start of exercise, during exercise or immediately after the end of exercise.
  • the term “immediately after exercise” means within 1 hour after the exercise ends.
  • the intake or administration frequency is at least once. More preferably, it is ingested or administered at least once before exercising, and at least once more during or immediately after exercising.
  • the ingestion or administration period is not particularly limited, but the composition of the present invention can exert its effect significantly by a single administration before exercise.
  • composition of the present invention contains two or more selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant (eg, chlorogenic acid compound, ⁇ -lipoic acid compound, etc.) as active ingredients
  • active ingredients may be contained alone or in any combination in the preparation, or all of them may be contained in one kind of preparation.
  • the timing which administers each may be simultaneous, or may be separate. When there are drugs to be used in combination, the timing of administration is appropriately determined according to the type and effect. That is, the composition of the present invention may be a preparation containing at least two active ingredients at the same time, or may be a concomitant preparation that is separately formulated and used together. In particular, an embodiment in which all active ingredients are contained in the same preparation is preferable because it can be easily administered.
  • weight ratio indicates the weight ratio of each component in the preparation. For example, when at least two kinds of active ingredients are included in one preparation, the ratio of the individual contents, and when each of the active ingredients is included in a plurality of preparations alone or in any combination Is the ratio of the weight of each active ingredient included in each formulation.
  • the actual dose ratio is a ratio of a single dose or a daily dose of each active ingredient per application target.
  • the weight ratio corresponds to the dose ratio.
  • the ratio of the total amount of each active ingredient in each preparation administered once or daily corresponds to the weight ratio.
  • the composition of the present invention can be used by adding to various foods.
  • a foodstuff when adding to a foodstuff, there is no restriction
  • drinks such as soft drinks and powdered drinks can be prepared by adding an appropriate flavor.
  • it can be added to a juice, milk, confectionery, jelly, yogurt, rice cake, etc. to eat and drink.
  • the foodstuff which added such a composition of this invention as a health functional food or a dietary supplement.
  • This health functional food includes food for specified health use and food with nutritional function.
  • the food for specified health is a food that can indicate that a specific health purpose can be expected, for example, improvement of gastrointestinal disorders.
  • the nutritional functional food is a food that can display the function of the nutritional component when the amount of the nutritional component included in the daily intake standard amount conforms to the standard standards of the upper and lower limits set by the country.
  • Dietary supplements include so-called nutritional supplements or health supplements.
  • foods for specified health use are foods labeled as being used for applications such as gastrointestinal disorders, and documents (so-called indications of efficacy) describing that they are used for such applications. Foods that include the product as a package are also included.
  • composition of the present invention can be used by adding it to a concentrated liquid food or a food supplement.
  • food supplements When added to food supplements, it can be prepared together with other ingredients in the form of tablets, capsules, powders, granules, suspensions, chewables, syrups and the like.
  • the food supplement in the present invention refers to those taken for the purpose of supplementing nutrition in addition to those taken as food, and also includes nutritional supplements and supplements.
  • “rich liquid food” is adjusted to a concentration of about 1 kcal / ml, and the qualitative composition of each nutrient is sufficiently considered so that no significant excess or deficiency of nutrients is caused even by long-term single intake. It is a comprehensive nutritional food (liquid food) designed based on the nutritional requirements of food.
  • the composition of the present invention can be in a unit packaging form.
  • the “unit packaging form” refers to a form in which a specific amount (for example, a single ingestion unit amount) is one unit, and one unit or two or more units are contained in one package.
  • the unit packaging form in which the unit intake amount is 1 unit is referred to as “unit packaging form per unit intake unit amount”.
  • the packaging used for the unit packaging form may be appropriately selected according to the form of the composition, and examples thereof include paper containers, plastic containers, aluminum cans, steel cans, glass bottles, PET bottles, PTP sheets and the like.
  • a gastrointestinal disorder for example, exercise-induced gastrointestinal barrier function
  • a gastrointestinal disorder for example, exercise-induced gastrointestinal barrier function
  • at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an active ingredient.
  • Commercial packages are also included, including descriptions.
  • the composition of the present invention can improve gastrointestinal disorders by oral administration at least once to a subject in need thereof.
  • the composition of the present invention can effectively improve exercise-induced gastrointestinal disorders.
  • the composition of the present invention is orally administered to a subject in need thereof at least once to reduce the digestive tract barrier function, inflammation of the digestive tract (preferably the small intestine (duodenum, jejunum, ileum)), and Gastrointestinal upset can be improved.
  • the compositions of the present invention can effectively ameliorate exercise-induced gastrointestinal barrier function decline, exercise-induced gastrointestinal inflammation, and exercise-induced gastrointestinal upset.
  • the composition of the present invention is particularly suitably used for improving gastrointestinal disorders (preferably exercise-induced gastrointestinal disorders).
  • the composition of the present invention contains, as an active ingredient, at least one selected from the group consisting of histidine, valine, leucine, isoleucine and a fat-soluble antioxidant, the gastrointestinal barrier function is lowered (preferably exercise-induced It is particularly preferably used for improving the gastrointestinal barrier function lowering.
  • the present invention includes gastrointestinal disorders (eg, decreased gastrointestinal barrier function, gastrointestinal inflammation, gastrointestinal upset, etc.) comprising orally administering the composition of the present invention to a subject in need thereof at least once. It also provides an improvement method.
  • the present invention also provides a method for ameliorating exercise-induced gastrointestinal disorders, comprising orally administering the composition of the present invention to a subject in need thereof at least once. These methods may exclude medical practices.
  • medical practice refers to an act of treating, operating or diagnosing a human being performed by a doctor or dentist or under the supervision of a doctor or dentist.
  • Example 1 Effect of histidine to improve exercise-induced degradation of gastrointestinal barrier function
  • Seven-week-old male CD2F1 mice (Charles River Japan Co., Ltd.) were administered aqueous solutions of various amino acids or salts thereof at a dose of 1 g / kg body weight, and 30 minutes later, they were run in a rotating car for 4 hours (speed: 10. 5 m / min).
  • FITC-dextran (average molecular weight 4000; FD4, Sigma-Aldrich Japan) was orally administered at a dose of 500 mg / kg body weight, and blood was collected after 1 hour (FIG. 2).
  • FD4 permeability of FD4 was calculated by measuring the fluorescence intensity in the blood, whereby the FD4 permeability of FD4 was evaluated (FIG. 3).
  • blood was collected from mice under anesthesia with isoflurane. The blood was centrifuged to obtain plasma.
  • the plasma was diluted 2-fold with a phosphate buffer, and the fluorescence intensity was measured under the conditions of an excitation wavelength of 485 nm and a detection wavelength of 535 nm (measuring instrument SPECTRA MAX GEMINI EM Molecular Device Japan).
  • the results are shown in FIG.
  • the FD4 concentration in the blood was increased as compared with the animals in the non-exercise group (Sed). From this result, it was confirmed that the gastrointestinal barrier function decreased by running for 4 hours, and a large amount of high molecular weight substance flowed into the blood.
  • the FD4 concentration in the blood did not decrease.
  • the intake of carbohydrate did not improve the barrier function of the digestive tract.
  • the FD4 concentration was decreased in the L-histidine hydrochloride administration group (HisHCL), and thus histidine was found to suppress exercise-induced degradation of the gastrointestinal barrier function. The effect was higher than that of the L-glutamine administration group (Gln) and the L-arginine hydrochloride administration group (ArgHCL).
  • Example 2 Effect of BCAA to improve exercise-induced degradation of gastrointestinal barrier function
  • the group (BCAA, Ex) significantly decreased the FD4 concentration in the blood compared with the group (CMC-Na, Ex) that was exercised by administering only the solvent (FIG. 5). From this result, it was recognized that BCAA has an effect of improving exercise-induced gastrointestinal barrier function.
  • Example 3 Effect of improving exercise-induced degradation of gastrointestinal barrier function of ⁇ -lipoic acid and chlorogenic acid Example for preventing injuries that the toenails peel off during running, except that the mouse nails were cut short In the same manner as in 1, the effects of ⁇ -lipoic acid and chlorogenic acid on exercise-induced degradation of the gastrointestinal barrier function were examined.
  • Example 4 Combined Effect of Histidine and Other Amino Acids
  • the combined effect of L-histidine and other amino acids was examined in the same manner as in Example 3.
  • an exercise group administered with an aqueous solution of L-arginine hydrochloride dose: 0.25 g / kg body weight
  • L-histidine hydrochloride dose: 0.25 g / kg body weight
  • Kg Arg + 0.25 g / kg His compared with the group (0.5 g / kg His) administered with an aqueous solution of L-histidine hydrochloride (dose: 0.5 g / kg body weight) and exercised.
  • Example 5 Effect of improving serine exercise-induced decrease in gastrointestinal barrier function
  • the effects of L-serine and glycine on exercise-induced decrease in gastrointestinal barrier function were examined.
  • blood FD4 concentration was significantly decreased in the group exercised by administering L-serine at 1 g / kg body weight, compared with the group exercised by administering water.
  • no decrease in blood FD4 concentration was observed (FIG. 8). From this result, it was recognized that serine has a mitigating effect on exercise-induced degradation of the gastrointestinal barrier function.
  • Example 6 Effect of improving serine gastrointestinal barrier function decline
  • Seven-week-old male CD2F1 mice (Nippon Charles River Co., Ltd.) were administered water or an L-serine aqueous solution (dose: 1 g / kg body weight). After 30 minutes, the vehicle was run for 4 hours in a rotating vehicle (speed: 10.5 m / min). After running, FITC-dextran (average molecular weight: 4000; FD4, Sigma-Aldrich Japan) was orally administered at a dose of 500 mg / kg body weight, and blood was collected after 1 hour (FIG. 2). In addition, the group (Sed) which was not run after water administration performed fasting and fasting as in the running group. Cani et al.
  • Example 7 Effect of Serine on Gastrointestinal Inflammation
  • 7-week-old male CD2F1 mice Charles River Japan Co., Ltd.
  • water or L-serine aqueous solution dose: 1 g / kg body weight.
  • the vehicle was run for 4 hours in a rotating car (speed 10.5 m / min).
  • Plasma was collected after the run, and the levels of interleukin 6 (IL-6) and serum amyloid A (SAA2) in the blood were set to Mouse IL-6 ELISA Ready-SET-Go! (EBioscience), MOUSE SERUM AMYLOID A ELISA TEST KIT (Life Diagnostics).
  • IL-6 and SAA2 are indicators of inflammation, respectively.
  • the small intestine was collected from the mouse after running, and the IL-6 gene expression level in the small intestine (jejunum, ileum) was measured by the real-time PCR method (GAPDH gene was used for housekeeping).
  • 11 and 12 show the measurement results of IL-6 concentration and SAA2 concentration in blood.
  • water In the water group administered with water for 4 hours (Water), blood IL-6 and SAA2 concentrations increased compared to animals in the non-exercise group (“Sedentary” or “Sed”). (FIGS. 11 and 12). From this result, it was found that inflammation was caused by 4 hours of exercise.
  • FIG. 13 shows the measurement results of the IL-6 gene expression level in the jejunum
  • FIG. 14 shows the measurement results of the IL-6 gene expression level in the ileum.
  • the IL-6 gene expression level was increased in both the jejunum and ileum as compared to animals in the non-exercise group (Sedentary). From this result, it was found that inflammation was induced in the small intestine by 4 hours of exercise.
  • Example 8 Combined Effects of Serine and Other Amino Acids Seven-week-old male CD2F1 mice (Nippon Charles River Co., Ltd.) were mixed with water, L-serine aqueous solution (dose: 0.5 g / kg body weight), L-serine ( Dose: 0.25 g / kg body weight) and an aqueous solution of L-histidine hydrochloride (dose: 0.25 g / kg body weight) or L-serine (dose: 0.25 g / kg body weight) and L-arginine hydrochloride ( (Dose: 0.25 g / kg body weight) of the aqueous solution was administered, and after 30 minutes, it was run in a rotating car for 4 hours (speed: 10.5 m / min).
  • FD4 was orally administered at a dose of 500 mg / kg body weight, and blood was collected after 1 hour.
  • Cani et al. , Gut 2009, 58 (8): 1091-1103 the concentration of FD4 leaked into the blood from the digestive tract was calculated by measuring the fluorescence intensity in the blood, whereby the FD4 permeability of FD4 Was evaluated.
  • the specific measurement method is the same as that in Example 1.
  • Plasma is collected after the run, and the IL-6 concentration in the blood is determined as Mouse IL-6 ELISA Ready-SET-Go! (EBioscience) was used for measurement.
  • FIG. 15 shows the evaluation results of gastrointestinal permeability of FD4
  • FIG. 16 shows the measurement results of IL-6 concentration in blood. From these results, it is clear that the effect of improving the degradation of the gastrointestinal barrier function and the effect of suppressing inflammation of the gastrointestinal tract are higher when histidine or arginine is used in combination than when serine is administered alone. It became.
  • Example 9 Combined effect of L-histidine and fat-soluble antioxidant
  • composition of the present invention is suitably used for improving gastrointestinal disorders.
  • the compositions of the present invention are effectively used to ameliorate exercise-induced gastrointestinal disorders.
  • the composition of the present invention is suitably used for maintaining the condition during training of an athlete.
  • the gastrointestinal barrier function is reduced during high-intensity and long-term exercise in a hot environment, and can be used as a composition for protecting the health of athletes during daily practice and games.

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Abstract

　La présente invention vise à fournir un agent permettant d'atténuer les troubles gastro-intestinaux, ledit agent étant aisé à ingérer. A cet effet, l'invention concerne une composition orale pour atténuer les troubles gastro-intestinaux, ladite composition orale contenant comme principe actif, au moins un élément choisi dans le groupe comprenant la sérine, l'histidine, la valine, la leucine, l'isoleucine ainsi que des antioxydants liposolubles.
PCT/JP2015/063041 2014-04-30 2015-04-30 Composition pour atténuer les troubles gastro-intestinaux WO2015167002A1 (fr)

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WO2016199798A1 (fr) * 2015-06-10 2016-12-15 味の素株式会社 Agent d'amélioration pour troubles gastro-intestinaux induits par un exercice physique

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JP2005247841A (ja) * 2004-02-04 2005-09-15 Fancl Corp 抗不安剤
JP2007210907A (ja) * 2006-02-07 2007-08-23 Ajinomoto Co Inc 消化管機能改善用組成物
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JP2005247841A (ja) * 2004-02-04 2005-09-15 Fancl Corp 抗不安剤
JP2007210907A (ja) * 2006-02-07 2007-08-23 Ajinomoto Co Inc 消化管機能改善用組成物
JP2011512828A (ja) * 2008-03-03 2011-04-28 ネステク ソシエテ アノニム 炭水化物ゲル

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016199798A1 (fr) * 2015-06-10 2016-12-15 味の素株式会社 Agent d'amélioration pour troubles gastro-intestinaux induits par un exercice physique
US10898456B2 (en) 2015-06-10 2021-01-26 Ajinomoto Co., Inc. Ameliorating agent for exercise-induced gastrointestinal disorders

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