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WO1998009652A1 - COMPOSITION, AGENT ANTIMICROBIEN, AGENT DE PREVENTION DES INFECTIONS, ET PRODUIT ALIMENTAIRE CONTRE L'$i(HELICOBACTER PYLORI) - Google Patents

COMPOSITION, AGENT ANTIMICROBIEN, AGENT DE PREVENTION DES INFECTIONS, ET PRODUIT ALIMENTAIRE CONTRE L'$i(HELICOBACTER PYLORI) Download PDF

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Publication number
WO1998009652A1
WO1998009652A1 PCT/JP1997/003100 JP9703100W WO9809652A1 WO 1998009652 A1 WO1998009652 A1 WO 1998009652A1 JP 9703100 W JP9703100 W JP 9703100W WO 9809652 A1 WO9809652 A1 WO 9809652A1
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WIPO (PCT)
Prior art keywords
extract
helicobacter pylori
citrate
iron
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1997/003100
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English (en)
Japanese (ja)
Inventor
Mikio Kikuchi
Hisao Takizawa
Hirokazu Wakebe
Fumie Mukai
Seiichi Shimizu
Hiroshi Okamatsu
Takao Saito
Satoko Yamadaira
Hiroyuki Kimura
Kanae Sasaki
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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Filing date
Publication date
Priority claimed from JP17247197A external-priority patent/JP4081157B2/ja
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Priority to AU41346/97A priority Critical patent/AU4134697A/en
Publication of WO1998009652A1 publication Critical patent/WO1998009652A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4

Definitions

  • the present invention relates to a composition for Helicobacter pylori, an antibacterial agent, an agent for preventing infection and food, which is suitable for treating or preventing gastrointestinal diseases such as chronic gastritis, stomach and duodenal ulcer caused by Helicobacter pylori. About.
  • helicobacter pylori a gram-negative bacterium
  • gastrointestinal diseases such as chronic gastritis and gastric and duodenal ulcers (Med. J. Aust., 142, 436 (1985), Gastroenterology, 102, 1575 (1992), N. Engl. J. Med., 328, 308 (1993)).
  • H. pylori like E. coli, enters the stomach, for example, through the mouth, swims through the mucus layer using the flagella of the stomach, reaches the gastric mucosal layer, and adheres (adheres) to the gastric mucosal cells.
  • urea is decomposed by the urease produced by itself to produce ammonia, neutralizing stomach acid, establishing a favorable living environment, and starting proliferation.
  • stomach mucosal cells provide the neutrophil chemotactic factor, interleukin-18 (IL-8). Is released and neutrophils collect at the site of infection. -Second, H. pylori produces and releases neutrophil activators, which activates the neutrophils, which are more likely to adhere to endothelial cells of blood vessels, which are responsible for microcirculation of mucous membranes. In addition to causing ring damage, it also produces proteases, free radicals (active oxygen), and leukotrienes, which are known as causative agents of the microcirculation disorder.
  • IL-8 interleukin-18
  • the produced ammonia reacts with free radicals to produce monochloramine, a poison that damages gastric mucosal cells and the like. Thus, inflammation is triggered and progresses.
  • Gastric mucosal injury caused by H. pylori may be caused by, for example, the attack of gaseous mucosa by ammonia itself produced by perease, Vacuolar degeneration of mucosal cells by itotoxin (vacuolar toxin) is also considered to be a factor.
  • the Helicobacter pylori is characterized in that its survival environment is in the epithelium of the gastric mucosa and its division time is many times longer than that of normal bacteria. Therefore, the antibacterial agent effective against the H. pylori is required to be stable to acids, penetrate between gastric mucosa, and have a high antibacterial effect.
  • Drugs having antimicrobial activity against H. pylori in vitro include antibiotics such as amoxicillin and clarithromycin; nitronidazole-based insecticides such as metronidazole and tinidazole; and bismuth preparations. I have.
  • triple therapy triple therapy with antibiotics, insect repellents and bismuth preparations is regarded as the most effective means.
  • antibiotics has a high possibility of excreting toxic substances such as endotoxin of H. pylori and substances causing inflammation around the gastric mucosa as the cells are destroyed. Therefore, these cause new inflammation and mucous membrane injury, gastritis, gastric ulcer relapse, there is a possibility of relapse.
  • the main object of the present invention is to solve all the problems of conventional chemotherapeutic agents, to have an excellent antibacterial activity against H. pylori, and to provide a high level of protection against infection by such bacteria.
  • An object of the present invention is to provide a novel composition having an effect.
  • Another object of the present invention is to provide high safety for the human body and excellent anti-H. Pylori resistance. It is an object of the present invention to provide a novel drug having a bactericidal action and having a high protective effect against the infection of H. pylori.
  • the inventors of the present invention have conducted intensive studies to achieve the above-mentioned object, and as a result, have found an effective antibacterial activity against H. pylori (an infection-preventing activity) in herbal medicines conventionally known as Kampo medicines or food additives. And the same shall apply hereinafter).
  • the efficacy of such crude drugs against H. pylori is classified into antibacterial action, urease activity inhibitory action, and adhesion inhibitory action on gastric mucosal epithelial cells. It has been found that the combination of the crude drugs possesses the ability to suppress the growth of H. pylori and thus provide a medicinal product or food that is effective for the treatment of gastritis and gastric / duodenal ulcer (Japanese Patent Application Laid-Open No. Hei 8-1-19787). No. 2). In subsequent studies, the present inventors have found that combining a substance such as the herbal medicine having antibacterial activity against H.
  • a composition for Helicobacter pylori which comprises as an active ingredient a substance having an antibacterial activity against H. pylori and at least one selected from the group consisting of free fatty acids and salts and esters thereof Is provided.
  • substances having antibacterial activity against H. pylori include glycyrrhizin, licorice extract, rosemary extract, salvia extract, ginger extract, thyme extract, and ginger extract. , Wagon extract, ju extract, sicon extract, kilanin, rooibos tea dry extract, mugwort dry extract, pear pear extract powder, tamarind extract, guava extract, yukinoshita leaf extract, ceramide, enmeiso extract, mukuroje
  • a composition comprising at least one crude drug selected from the group consisting of kiss powder, yucca extract powder and lemon extract, and wherein the free fatty acid is a long-chain fatty acid, more preferably linolenic acid; ⁇ ⁇
  • the above composition containing an oily extract has an antibacterial activity against H.
  • composition material is a polyphenol compound
  • An antibacterial agent against Helicobacter pylori which comprises, as active ingredients, an active substance and at least one member selected from the group consisting of free fatty acids, salts and esters thereof; and a prophylactic agent for infections containing the active ingredients.
  • composition of the present invention can be prepared in a food form such as a beverage or a block, instead of a pharmaceutical form such as an antibacterial agent.
  • iron salts iron citrate, iron citrate ammonium, ferrous sodium citrate, iron lactate, iron lactate
  • ferric pyrophosphate ferric pyrophosphate
  • ferric citrate is used in combination with aqueous ammonia, which is a surprisingly good antibacterial against H. pylori The fact that it has an effect was found.
  • a pyrrole containing, as an active ingredient, at least one selected from the group consisting of iron citrate, iron citrate ammonium, ferrous sodium citrate, iron lactate and ferric pyrophosphate.
  • An antibacterial agent against bacteria; an infection preventive agent containing the active ingredient; and a food containing the active ingredient are provided.
  • an antibacterial agent against Helicobacter pylori containing iron citrate and aqueous ammonia as active ingredients; a prophylactic agent for infection containing the active ingredients.
  • the antibacterial agent, infection preventive agent and food of the present invention can exert an excellent preventive effect over conventional chemotherapeutic agents, and have the advantages of being safe and having few side effects. Therefore, it is suitable for the prevention and treatment of gastritis and gastric / duodenal ulcer caused by H. pylori.
  • FIG. 1 is a flowchart showing a method for isolating flavonoids in a licorice extract.
  • Fig. 2 is a flow chart showing a method for isolating flavonoids, which is the main component in a citrus oily extract.
  • FIG. 3 is a flow chart showing a method for isolating flavonoids, which show excellent antibacterial activity, especially against H. pylori, among flavonoids contained in a licorice extract.
  • Fig. 4 shows the results after administration of each reagent (Experiment 1) to H. pylori-infected mice for 3 days.
  • 4 is a graph showing the number of H. pylori in the stomach (log (CFUZ stomach)).
  • FIG. 5 is a graph showing the number of H. pylori in the stomach (log (CFUZ stomach)) after administration of each reagent (Experiment 2) for 3 days to H. pylori-infected mice.
  • FIG. 6 is a graph showing the number of H. pylori in the stomach (log (CFU / stomach)) after 10 days of administration of each reagent (Experiment 3) to H. pylori-infected mice.
  • FIG. 7 is a graph showing the infection rate of each reagent (Experiment 3) when the infection rate of H. pylori in the control group was 100%.
  • the substance having an antibacterial activity against H. pylori includes polyphenols and various chemotherapeutic agents in addition to the above crude drugs.
  • polyphenols examples include flavones, catechins, propolis, tannin, anthocyanin, flavan and the like.
  • chemotherapeutic agent examples include known chemotherapeutic agents such as aminopenicillin, tetracycline, and macrolide.
  • glycyrrhizin a water-extracted solid mainly composed of glycyrrhizin, which is known as a food additive (sweetener), can be used.
  • the oil extract of licorice includes legume licorice (glyeyrrhiza glabra., G. uralensis FISCH), and flavonoids obtained by extracting the root or rhizome of the same plant with an organic solvent such as ethanol from the water extraction residue. Which are known as food additives (antioxidants).
  • the flavonoids include, for example, glabrol, grabradine, synflavone, 3,1-prenyl glabridine, 4 '_- methylglycuradine, glabrene, and formononetin represented by the following formulas (1) to (1).
  • the method for isolating these flavonoid compounds (1) to (7) will be described in the examples below.
  • Formula (4) 3'-Frenylk ⁇ Rough ⁇ Rishi ⁇
  • rosemary extract there can be used those containing rosemanol, oleucachlor, and the like obtained by extracting flowers or leaves of Rosmarinus officinalis with the carbon dioxide, ethanol, or other organic solvents. These are known in the food field as antioxidants.
  • those containing brabonoids as a main component obtained by extracting leaves of Salvia officinalis eg, Salvia officinal is
  • ethanol or other organic solvents can be used.
  • These are known in the food field as antioxidants, similar to the Rosemary extract.
  • the extract of cucumbers (clove extract) is mainly composed of eugenol, which is obtained by extracting buds and leaves of Syzygium aromaticum MERR. Et PERRY with an organic solvent such as ethanol. What is known as is available.
  • Thyme extract liquid is mainly composed of flavonoids obtained by extracting the dried leaves of a plant belonging to the Labiatae family Thymus vulgaris with 90% ethanol, and is also known as a food additive (flavor, spice) Can be used.
  • gingerol-shogaol obtained by extracting the rhizome of ginger ginger (Zingiber officinale ROSC.)
  • an organic solvent such as ethanol
  • ethanol is a main component, and is known as a food additive (lifetime improver). Things are available.
  • a flavonoid-based extract obtained by extracting roots of Scutellaria baicalensis Georigi. With 90% ethanol can be used.
  • Polyphenols obtained by extracting the roots and rhizomes of Remoko (Sanguisorba officinalis) with 50% ethanol can be used as the main component of the extract.
  • sicon extract a naphthoquinone-based shikonin obtained by extracting the roots of purple mussels (Lithospermum erythrorhizon SIEB.) With ethanol can be used as the main pigment component, and what is known as a food additive (colorant) can be used. .
  • Quilanin includes Rosaceae (Quil laia saponaria) MOLINA) can be obtained by extracting the bark with water, and these are known as food additives (emulsifiers).
  • rooibos tea dry extract those obtained by extracting rooibos tea leaves with an organic solvent such as water or ethanol can be used.
  • the dried mugwort extract can be used as a main component, including caffeine tannins and essential oils obtained by extracting water or ethanol from the stems and leaves of Artemisia princeps PAMPAN. Also known as things (bitters).
  • the pear extract powder is extracted from water from Rosaceae pear and can be used as food.
  • tamarind extract 50 of leguminous tamarind. / 0 ethanol extract is available, which is known as a thickener.
  • guava extract a 50% ethanol extract known as a food additive (flavor) can be used.
  • Saxifraga leaf extract is the same as the above guava extract.
  • ceramides those obtained by water extraction from wheat cell walls can be used (> 50% ethanol extract as enmeiso extract, and 80% ethanol extract as muclojex pada).
  • a yucca extract powder an aqueous extract containing saponin as a main component and used as a food additive (emulsifier), and as a lemon extract, used as a food additive (spice) 50 % Ethanol extract is available respectively.
  • the free fatty acids, salts and esters thereof include, for example, linolenic acid, oleic acid, arachidonic acid, eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and palmitoleic acid (POA). And various kinds of saturated fatty acids, unsaturated fatty acids ( ⁇ -based fatty acids, CLA conjugated fatty acids), free fatty acids such as essential fatty acids, salts thereof such as alkali metal salts, alkaline earth metal salts and esters thereof. Included.
  • the esters of the above fatty acids include glycerin esters (glycerides) generally called fats and oils, lipids and the like.
  • glycerides include, for example, monog It may be any of lyceride, diglyceride, triglyceride (TG), MCT (medium fatty acid glyceride), STRACTURED TRIGLYCERIDE and the like.
  • the above ester has a basic skeleton of phosphatidic acid in which two fatty acids are ester-bonded to the hydroxyl group of glycerin and phosphoric acid is bonded to the third hydroxyl group.
  • phosphodiester-linked phospholipids examples include lecithin, kephalin, phosphatidylserine, sphingolipid, sphingomyelin and the like.
  • Representative saturated fatty acids include, for example, n-butanoic acid, n-pentanoic acid, 3-methylbutanoic acid, n-hexanoic acid, n-heptanoic acid, n-octanoic acid, n-nonanoic acid, n- Decanoic acid, n-dodecanoic acid, n-tetradecanoic acid, n-octadecanoic acid, n-eicosanoic acid, n-docosanoic acid, n-tetracosanoic acid, n-hexacosanoic acid, n-octacosanoic acid, n-triacosanoic acid And the like.
  • Representative unsaturated fatty acids for example, delta 9 - decenoic acid, Stringfellows acid, delta 9 - dodecene acid, palmitic Torein acid, Orein acid, elaidic acid, Rishino Lumpur acid, petroselinic acid, vaccenic acid, Reno —Lulic acid, Linolenic acid, Eleostearic acid, Punicic acid, Ricanic acid, Nono, Examples include linalic acid, gadolinic acid, arachidonic acid, 5-eicosenoic acid, 5-docosenoic acid, cetolic acid, 5,13-docosagenic acid, and seracholic acid.
  • composition of the present invention it is important to combine a substance having an antibacterial activity against H. pylori and at least one selected from the group consisting of free fatty acids, salts and esters thereof as essential active ingredients.
  • the combination ratio of each of the above active ingredients can be appropriately selected according to the type of each component to be used.
  • the substance having an antibacterial activity against H. pylori is a crude drug, it is usually about 0.0. 1-500mg / kg, preferably about 0 :!
  • the dose is preferably in the range of about 50 mg / kg to about 50 mg / kg.
  • a polyphenol or a chemotherapeutic agent is used in place of the above crude drugs, it is sufficient to administer the amount within the above range.
  • the free fatty acids, salts and esters thereof, which are other active ingredients are administered in a range of about 0.001 to 10 mg / kg, preferably about 0.01 to 0.5 mg / kg. You can give it.
  • the weight ratio is preferably selected from the range of about 100: 1 to 1: 1100.
  • composition of the present invention is usually in the form of a general pharmaceutical preparation using a pharmaceutical carrier together with the above-mentioned active ingredient.
  • the formulation carrier used may be a commonly used diluent or excipient such as a filler, extender, binder, humectant, disintegrant, surfactant, lubricant, etc. It is prepared using
  • compositions, suspensions, etc. can be selected according to the purpose of treatment.
  • Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections Agents (solutions, suspensions, etc.), ointments and the like. These are all prepared according to a conventional method using the above-mentioned appropriate carrier.
  • those conventionally known in the art can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica, etc.
  • Excipients water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dried sodium starch alginate, agar powder , Laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, disintegrators such as monoglyceride stearate, starch, sugar, sucrose, stearin, cacao batata, hydrogenated oil, etc.
  • Collapse control Agents quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, adsorbents such as glycerin, starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene Glycols and other lubricants.
  • the tablets can be made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets as required.
  • a wide variety of carriers conventionally known in this field can be used as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, power oil, and talc; Disintegrants such as rubber powder, tragacanth powder, gelatin, ethanol and the like.
  • a wide variety of known carriers can be used. Examples include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.
  • preservatives such as sodium benzoate, methyl p-oxybenzoate, sodium dehydroacetate, solubilizing agents such as sodium salicylate, sodium acetate, sodium benzoate, and coloring agents. It is prepared by blending flavors, flavors, sweeteners and the like as needed, and further adding a diluent such as water or ethanol as needed.
  • a suspending agent such as gum arabic, tragacanth, carboxymethylcellulose, sodium alginate, bentonite magma, and zinc is added, and a coloring agent, a flavor, a flavoring agent, It is prepared by mixing a sweetener and the like as needed, and adding a diluent such as water or ethanol as needed.
  • the solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. Therefore, a sufficient amount of salt, glucose, or glycerin to adjust the isotonic solution may be included in the drug, and the usual dissolution aids, buffers, soothing agents, etc. may be added. Good. Further, if necessary, coloring agents, preservatives, flavors, flavoring agents, sweetening agents and the like and other pharmaceuticals can be contained.
  • the mixing ratio of the above-mentioned active ingredients is appropriately determined according to the kind and combination of the active ingredients, the pharmacological action of the active ingredients, and the like. For example, in the case of crude drugs and polyphenols, the amount may be determined appropriately based on the amount of daily intake (administration) of about 1 mg to 2 g.
  • the administration method of the above pharmaceutical preparation is not particularly limited, and is determined according to various preparation forms, patient age, gender and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered.
  • injections In the case of injections, they are intravenously administered alone or mixed with normal replenishers such as glucose and amino acids, and further administered intramuscularly, intradermally, subcutaneously or intraperitoneally as needed. In the case of suppositories, they are administered rectally.
  • the dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, age, sex and other conditions of the patient, the degree of the disease, etc., but usually the total amount of the active ingredient is about 1 kg / kg of body weight per day. An amount of about 0.5 to 100 mg can be administered in 1 to 4 times a day.
  • composition of the present invention may be in the form of a food, such as a drink or a block, instead of the pharmaceutical form.
  • a food such as a drink or a block
  • the combination of the essential active ingredients is contained, it is prepared by appropriately using other food materials (raw material components), excipients, diluents and the like according to a conventional method.
  • the above-mentioned composition is obtained by combining a foaming component such as sodium hydrogencarbonate and sodium or sodium carbonate with citric acid, tartaric acid, fumaric acid, and ascorbic acid in a conventional blending amount as a neutralizing agent, for example, by direct powdering.
  • the food can be prepared in the form of a foaming agent according to a conventional method such as a compression method, a dry or wet granulation method.
  • an antibacterial agent containing iron citrate and aqueous ammonia as active ingredients will be described.
  • examples of the iron citrate include ferrous citrate and ferric citrate, which may be used alone or in combination.
  • the iron citrate may contain water of crystallization, and such a case is also included in the scope of the present invention.
  • aqueous ammonia for example, commercially available concentrated aqueous ammonia (28% by weight) or aqueous ammonia water (10% by weight) of the Pharmacopoeia B can be used as appropriate.
  • the amount of ammonia water used relative to iron citrate is at least 0.1 to 1 mole, preferably 2 to 10 mole, in terms of ammonia.
  • an iron salt specifically, iron citrate, iron citrate ammonium, ferrous sodium citrate, iron lactate, and ferric pyrophosphate are used. At least one selected from the group may be used as an active ingredient. These iron salts may contain water of crystallization, and such cases are also included in the scope of the present invention. Examples of the iron citrate ammonium include ferrous citrate ammonium and ferric citrate ammonium, and these may be used alone or in combination.
  • iron lactate examples include ferrous lactate and ferric lactate, and these may be used alone or in combination.
  • iron citrate and aqueous ammonia are used as the active ingredients in the antibacterial agent of the present invention, they are prepared in the form of the above-mentioned liquid preparation. Iron citrate and aqueous ammonia may be mixed in advance, or may be mixed at the time of administration.
  • iron salt When used as an active ingredient, it is used in the form of general pharmaceutical preparations such as tablets, pills, powders, granules, capsules, suppositories, liquids, and suspensions described above.
  • general pharmaceutical preparations such as tablets, pills, powders, granules, capsules, suppositories, liquids, and suspensions described above.
  • an iron salt other than the above-mentioned iron citrate may be used together with iron citrate and aqueous ammonia, and in this case, a solution or suspension is prepared.
  • the amount of the active ingredient to be contained in the antibacterial agent is not particularly limited, and is selected from a wide range.
  • the amount is usually 1 to 90% by weight, preferably 10 to 70% by weight in the preparation.
  • the dosage is not particularly limited, but may be appropriately selected depending on the conditions such as the usage, the age of the patient, the sex, and the degree of the disease.
  • the iron content in the active ingredient is 0.01 to 0 per 1 kg of body weight. 4 mg, preferably 0.1 to 0.2 mg, is administered in 1 to 4 times a day.
  • the antibacterial agent of the present invention includes other pharmacological agents such as antibiotics such as amoxicillin and clarithromycin; imidazole-based antiprotozoal agents such as tinidazole and thiabendazole; bismuth preparations ⁇ sofalcone, prounothol; It may be used in combination with antiulcer agents such as omebrazole, lansoprazole, and other proton pump inhibitors.
  • antibiotics such as amoxicillin and clarithromycin
  • imidazole-based antiprotozoal agents such as tinidazole and thiabendazole
  • bismuth preparations ⁇ sofalcone, prounothol bismuth preparations ⁇ sofalcone, prounothol
  • antiulcer agents such as omebrazole, lansoprazole, and other proton pump inhibitors.
  • the present invention has excellent antibacterial activity against H. pylori, and has high safety since the active ingredients used are conventionally used as foods or pharmaceuticals. Therefore, the antibacterial agent, the infection preventive agent and the food of the present invention are suitable for the treatment and prevention of gastrointestinal diseases such as chronic gastritis and gastric / duodenal ulcer caused by H. pylori.
  • the Kanzo oily extract (900 mg) was separated using silica gel chromatography (Merck). At that time, as the eluent, first, a hexane-acetone mixed solvent was used, and the mixing ratio was changed to 4: 1 ⁇ 3: 1 ⁇ 7: 3 ⁇ 65: 35 by volume fraction to obtain fractions 1 to 3. After collecting 10, 10 fractions were obtained in total by using chloroform-methanol (volume ratio: 9: 1) as eluent (total recovery rate: 97%). Figure 1 shows the amount of each fraction recovered and the solvent ratio when the fraction was recovered. Note that Fr. in the figure means fraction.
  • Solvent ratio at the time of collecting each of the above fractions and each fraction Figure 2 shows the amount of recovered chillons.
  • was purified by silica gel chromatography (eluent: hexane: acetone 3: 1) to obtain fractions 11-B'-1 and 11-B, -2.
  • fraction 11-11 ′ ′-2 was separated in the same manner as fraction 111 ⁇ 1′-1, three fractions 111′B′-2 a to c were obtained. Among them, compound 4 was obtained from fraction 11- ⁇ '-2a, and compound 5 was obtained from fraction 11-B'-2b.
  • H. pylori human clinical isolate CO011, human clinical isolate CO014 and ATCC strain 43504
  • the minimum inhibitory concentration (MIC) was determined according to the standard method described in the journal of the Japanese Society of Chemotherapy.
  • the above culture was carried out in 7% FBS (Gibco) -supplemented Brueellaagar (DCM, Brucella agar medium) containing 7% FBS (Gibco) containing a test substance at a fixed concentration, and 7% FSB SB ruce 1 labroth (BBL, Brucella liquid medium).
  • DCM Brucella agar medium
  • BBL Brucella liquid medium
  • Test Example 2 Antibacterial test using H. pylori-infected mice
  • metronidazole was manufactured by dissolving it in distilled water from Sigma.
  • the oil extract was made by Maruzen Pharmaceutical Co., Ltd., and a-linolenic acid was undiluted [manufactured by Wako Pure Chemical Industries, Ltd. (chemical use).
  • Composition stearic acid 1.9%, linoleic acid 2.1.2 %, Linolenic acid 75.4%, other 1.5%].
  • the cells were removed from the agar medium, suspended in Bruce 11 abroth 3 ml containing 7% FBS, and then suspended in an atmosphere of 85% nitrogen, 10% carbon dioxide, and 5% oxygen. Preculture was performed at 7 ° C for 1 day.
  • 0.5 ml of the preculture was inoculated into 50 ml of Brucellabroth containing 7% FBS, and cultured at 37 ° C for 1 day in an atmosphere of 85% nitrogen, 10% carbon dioxide, and 5% oxygen. and inoculum (approximately 1 0 8 CFU / ml) was prepared.
  • a male d dY mouse (3 weeks old, Japan SLC, Inc.) was transported as a test animal to the laboratory on the 5th floor isolator on the 5th floor of the Hiz tower, Otsuka Pharmaceutical Co., Ltd. Sterile CRF-1 solid feed, Oriental Yeast Kogyo Co., Ltd.) and drinking water (distilled water for injection) were available ad libitum and fasted overnight on the 4th day of delivery. Then, 0.5 ml of H. pylori solution for inoculation was forcibly administered orally to the mice to infect H. pylori.
  • mice From day 7 after infection] For 3 days from day 0 to day 0, the above-mentioned mice (5 mice in each group) were treated with 0.1 ml of each reagent at a dose of 10 ml per 10 g body weight (the amount of drug containing ⁇ -linolenic acid was 0.1%). 05ml), forcibly orally twice daily at 8:00 am and 2:00 pm Gave. The mice were fasted overnight on the last day of the administration of the reagents, and the following day, all the test mice were sacrificed and the stomach was removed.
  • mice 10 mice per group were forcibly orally administered the inoculated bacterial solution and infected with H. pylori.
  • each of the reagents was administered to the mice twice daily at a dose of 0.05 ml / kg body weight, divided into 9 am and 3 pm Gavage was administered orally.
  • the mice were fasted overnight on the last day of administration of the test agent, and on the following day, all test mice were sacrificed and their stomachs were removed.
  • the stomach isolated above was added to a 15 ml centrifuge tube containing 2 ml of Brucellabroth, and homogenized using a polytron (Kinematica, Homogenizer-1) under ice-cooling.
  • a polytron Nemogenizer-1
  • 0.2 ml was added to 8 ml of Brucellabroth O. dispensed into a 24-well microplate and mixed, and the same operation was repeated twice to obtain a 50-fold or 250-fold amount. A 250-fold dilution was prepared.
  • 0.2 ml of each of the above diluents was applied to a modified skilow agar medium (manufactured by Nippon Suisan Kaisha, Ltd.), and the mixture was heated at 37 ° C in an atmosphere of 85% nitrogen, 10% carbon dioxide, and 5% oxygen. After culturing for 5 days, the number of grown colonies was counted to determine the number of bacteria in the stomach, and the antibacterial effect of each reagent was evaluated.
  • Figure 4 shows the results of Experiment 1
  • Figure 5 shows the results of Experiment 2
  • Figure 6 shows the results of Experiment 3.
  • Figures 4 to 6 show the results of measurements in each group as bar graphs with the number of bacteria (1 og (CFUZ stomach)) on the vertical axis. ND in the figure indicates that the bacterial count is below the detection limit of 50.
  • composition of the present invention in the form of soft capsules was prepared by a punching method.
  • Linolenic acid 1 0.5 0.3 Linoleic acid 0.5
  • MCT Medium chain fatty acids

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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne les produits pharmaceutiques ou aliments (1) à (3) suivants permettant de traiter ou de prévenir la gastrite, l'ulcère gastrique et d'autres maladies provoquées par l'Helicobacter pylori. L'invention concerne (1) une composition, un agent antimicrobien, un agent de prévention des infections, et un produit alimentaire contre l'Helicobacter pylori, comprenant comme ingrédient actif un matériau présentant une activité antimicrobienne contre l'Helicobacter pylori, et au moins un élément sélectionné dans le groupe se composant d'acides gras libres, de sels de ces derniers, et d'esters de ces derniers. L'invention traite aussi (2) d'une composition, d'un agent antimicrobien, d'un agent de prévention des infections, et d'un produit alimentaire contre l'Helicobacter pylori, comprenant comme ingrédient actif au moins un élément sélectionné dans le groupe se composant de citrate de fer, de citrate de fer d'ammonium, de citrate ferreux de sodium, de lactate de fer et de pyrophosphate ferrique. Enfin, l'invention a pour objet (3) un agent antimicrobien et un agent de prévention des infections contre l'Helicobacter pylori, comprenant comme ingrédient actif du citrate de fer et du gaz ammoniac aqueux.
PCT/JP1997/003100 1996-09-06 1997-09-04 COMPOSITION, AGENT ANTIMICROBIEN, AGENT DE PREVENTION DES INFECTIONS, ET PRODUIT ALIMENTAIRE CONTRE L'$i(HELICOBACTER PYLORI) Ceased WO1998009652A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU41346/97A AU4134697A (en) 1996-09-06 1997-09-04 Composition, antimicrobial agent, infection preventive, and food against (helicobacter pylori)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP8/236623 1996-09-06
JP23662396 1996-09-06
JP17247197A JP4081157B2 (ja) 1997-06-27 1997-06-27 ヘリコバクター・ピロリ菌用抗菌剤
JP9/172471 1997-06-27

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003043644A1 (fr) * 2001-11-21 2003-05-30 Eisai Co., Ltd. Agent de traitement de la colite ulcereuse contenant un sel de fer en tant que substance active
LT5720B (lt) 2009-08-12 2011-04-26 Inovativo Biomedicinas Technologiju Institūts, Sia Maistinis vaisių-uogų produktas, pasižymintis priešmikrobiniu poveikiu prieš helicobacter pylori
CN106309424A (zh) * 2016-08-19 2017-01-11 江苏康缘药业股份有限公司 黄酮类化合物的应用
US9961886B2 (en) 2014-08-13 2018-05-08 Akeso Biomedical, Inc. Antimicrobial compounds and compositions, and uses thereof
US10106567B2 (en) 2015-08-11 2018-10-23 Akeso Biomedical, Inc. Biofilm inhibiting compositions enhancing weight gain in livestock
WO2019136150A1 (fr) * 2016-02-17 2019-07-11 Akeso Biomedical, Inc. Compositions d'inhibition de biofilm destinées à l'amélioration de prise de poids du bétail
JP2021052744A (ja) * 2019-09-27 2021-04-08 エコ−ジオ バイオ−テクノロジー カンパニー リミテッド．Ｅｃｏ−Ｇｅｏ Ｂｉｏ−Ｔｅｃｈｎｏｌｏｇｙ Ｃｏｍｐａｎｙ Ｌｉｍｉｔｅｄ． ヘリコバクターピロリに対する非医薬殺菌組成物及びそれを使用する方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07242560A (ja) * 1994-02-28 1995-09-19 Eisai Co Ltd 抗菌剤
JPH0820543A (ja) * 1994-05-02 1996-01-23 Kaigai Seiyaku Kk ヘリコバクター・ピロリ菌殺菌のための局所用口腔内投与剤
JPH08119872A (ja) * 1994-10-18 1996-05-14 Otsuka Pharmaceut Co Ltd ヘリコバクター・ピロリに対する生薬組成物
JPH08193028A (ja) * 1994-10-04 1996-07-30 Bristol Myers Squibb Co ヘリコバクターの阻害

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07242560A (ja) * 1994-02-28 1995-09-19 Eisai Co Ltd 抗菌剤
JPH0820543A (ja) * 1994-05-02 1996-01-23 Kaigai Seiyaku Kk ヘリコバクター・ピロリ菌殺菌のための局所用口腔内投与剤
JPH08193028A (ja) * 1994-10-04 1996-07-30 Bristol Myers Squibb Co ヘリコバクターの阻害
JPH08119872A (ja) * 1994-10-18 1996-05-14 Otsuka Pharmaceut Co Ltd ヘリコバクター・ピロリに対する生薬組成物

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003043644A1 (fr) * 2001-11-21 2003-05-30 Eisai Co., Ltd. Agent de traitement de la colite ulcereuse contenant un sel de fer en tant que substance active
LT5720B (lt) 2009-08-12 2011-04-26 Inovativo Biomedicinas Technologiju Institūts, Sia Maistinis vaisių-uogų produktas, pasižymintis priešmikrobiniu poveikiu prieš helicobacter pylori
US10264766B2 (en) 2014-08-13 2019-04-23 Akeso Biomedical, Inc. Antimicrobial compounds and compositions, and uses thereof
US10327423B2 (en) 2014-08-13 2019-06-25 Akeso Biomedical, Inc. Antimicrobial compounds and compositions, and uses thereof
US9961886B2 (en) 2014-08-13 2018-05-08 Akeso Biomedical, Inc. Antimicrobial compounds and compositions, and uses thereof
US10106567B2 (en) 2015-08-11 2018-10-23 Akeso Biomedical, Inc. Biofilm inhibiting compositions enhancing weight gain in livestock
US10301339B2 (en) 2015-08-11 2019-05-28 Akeso Biomedical, Inc. Biofilm inhibiting compositions enhancing weight gain in livestock
US10377785B2 (en) 2015-08-11 2019-08-13 Akeso Biomedical, Inc. Biofilm inhibiting compositions enhancing weight gain in livestock
US10555531B2 (en) 2015-08-11 2020-02-11 Akeso Biomedical, Inc. Biofilm inhibiting compositions enhancing weight gain in livestock
US10653658B2 (en) 2015-08-11 2020-05-19 Akeso Biomedical, Inc. Biofilm inhibiting compositions enhancing weight gain in livestock
US10793587B2 (en) 2015-08-11 2020-10-06 Akeso Biomedical, Inc. Biofilm inhibiting compositions enhancing weight gain in livestock
US11311511B2 (en) 2015-08-11 2022-04-26 Akeso Biomedical, Inc. Biofilm inhibiting compositions enhancing weight gain in livestock
WO2019136150A1 (fr) * 2016-02-17 2019-07-11 Akeso Biomedical, Inc. Compositions d'inhibition de biofilm destinées à l'amélioration de prise de poids du bétail
CN106309424B (zh) * 2016-08-19 2019-03-15 江苏康缘药业股份有限公司 黄酮类化合物的应用
CN106309424A (zh) * 2016-08-19 2017-01-11 江苏康缘药业股份有限公司 黄酮类化合物的应用
JP2021052744A (ja) * 2019-09-27 2021-04-08 エコ−ジオ バイオ−テクノロジー カンパニー リミテッド．Ｅｃｏ−Ｇｅｏ Ｂｉｏ−Ｔｅｃｈｎｏｌｏｇｙ Ｃｏｍｐａｎｙ Ｌｉｍｉｔｅｄ． ヘリコバクターピロリに対する非医薬殺菌組成物及びそれを使用する方法

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