WO1998009652A1 - COMPOSITION, ANTIMICROBIAL AGENT, INFECTION PREVENTIVE, AND FOOD AGAINST $i(HELICOBACTER PYLORI) - Google Patents

Abstract

The following pharmaceuticals or foods (1) to (3) suitable for the treatment or prevention of gastritis, gastric ulcer and other diseases caused by Helicobacter pylori: (1) a composition, an antimicrobial agent, an infection preventive, and a food against Helicobacter pylori, comprising as the active ingredient a material having an antimicrobial activity against Helicobacter pylori and at least one member selected from the group consisting of free fatty acids, salts thereof, and esters thereof; (2) an antimicrobial agent, an infection preventive, and a food against Helicobacter pylori, comprising as the active ingredient at least one member selected from the group consisting of iron citrate, ammonium iron citrate, sodium ferrous citrate, iron lactate, and ferric pyrophosphate; and (3) an antimicrobial agent and an infection preventive against Helicobacter pylori, comprising as the active ingredient iron citrate and aqueous ammonia.

Description

 Specification

 Helicobacter pylori composition, antibacterial agent, infection preventive agent and food <Technical field>

 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.

 <Background technology>

 Recently, it has been revealed that helicobacter pylori, a gram-negative bacterium, is deeply involved in the development of 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)).

 The mechanism of gastric mucosal injury caused by the above-mentioned H. pylori has been studied variously in the past, and is almost as follows.

 In other words, 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. Here, urea is decomposed by the urease produced by itself to produce ammonia, neutralizing stomach acid, establishing a favorable living environment, and starting proliferation.

 According to the adhesion (infection) of H. pylori to gastric mucosal epithelial cells, firstly, 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.

 Third, 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.

Conventionally, the treatment of ulcerative disease, antiulcer agents such sofalcone, Purouno Torr; Omepurazo Ichiru, pro Tonponpu inhibitors such as lansoprazole (PPI); famotidine, gastric acid secretion inhibitor such as cimetidine (H ₂ blockers) Was used. However, these drugs are not effective in suppressing the growth of H. pylori, and require separate treatment with antibacterial agents.

 By the way, 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.

 However, these chemotherapeutic agents cannot exert sufficient antibacterial effects in vivo, and at present, triple therapy (triple therapy) with antibiotics, insect repellents and bismuth preparations is regarded as the most effective means.

 However, even in the above-mentioned tribble therapy, satisfactory treatment cannot be performed for patients such as gastric ulcer and duodenal ulcer, and the dose of the drug becomes larger than usual. Therefore, the drug must be administered for a long period of time. As a result, there are concerns about the side effects of drugs or the formation of resistant bacteria.

 In addition, the use of 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.

 Therefore, 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.

 Disclosure of the Invention>

 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. pylori with one selected from the group consisting of free fatty acids, salts and esters thereof, The present inventors have found that the synergistic action enhances the antibacterial action against H. pylori, and completed the present invention. That is, according to the present invention, 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.

More specifically, according to the present invention, 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;上 記 The above composition containing an oily extract; has an antibacterial activity against H. pylori Having a antibacterial action against H. pylori; that the 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.

 Further, the 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.

 Further, the present inventors have proposed iron salts (iron citrate, iron citrate ammonium, ferrous sodium citrate, iron lactate, iron lactate) conventionally contained in powdered milk, flour, biscuits and the like as iron fortifying agents for foods. And ferric pyrophosphate), or when 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.

 That is, according to the present invention, there is provided 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.

 Also provided is 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.

 <Brief description of drawings>

 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%.

<Best mode for carrying out the invention>

 In the composition of the present invention, the substance having an antibacterial activity against H. pylori includes polyphenols and various chemotherapeutic agents in addition to the above crude drugs.

 Examples of the polyphenols include flavones, catechins, propolis, tannin, anthocyanin, flavan and the like.

 Examples of the chemotherapeutic agent include known chemotherapeutic agents such as aminopenicillin, tetracycline, and macrolide.

 As the crude drugs, those already known as Chinese herbs or food additives can be appropriately selected, and there are no particular limitations on the place of production, production method, form, component composition, and the like. The herbal medicines and their names in this specification may be the ones described in “Natural Products Handbook” (13th edition) published by Food and Science Co., Ltd. (1995), or It is based on.

 As the 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. ) Clough. -Formula (5) 4 '-0-Methyl methyl' rough '

Equation (2) Rough 'Rishi' Equation (6) Rough

Formula (3) Synfraphone Formula (7) Formononetin

ローズマリー抽出物としては、 シソ科マンネンソゥ （Rosmarinus officinalis し ） の花または葉を二酸化炭素、 エタノールまたは他の有機溶剤で抽出して得 られるローズマノール、 力ルバクロール等を成分とするものを利用でき、 これら は酸化防止剤として食品分野で知られている。 Formula (4) 3'-Frenylk ♦ Rough ♦ Rishi ♦

As the 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.

 As the salvia extract, those containing brabonoids as a main component obtained by extracting leaves of Salvia officinalis (eg, Salvia officinal is) with 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.

 As a ginger extract, gingerol-shogaol obtained by extracting the rhizome of ginger ginger (Zingiber officinale ROSC.) With an organic solvent such as ethanol is a main component, and is known as a food additive (lifetime improver). Things are available.

 As the wagon extract, 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.

 As the 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 (Quillan extract) includes Rosaceae (Quil laia saponaria) MOLINA) can be obtained by extracting the bark with water, and these are known as food additives (emulsifiers).

 As the 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 (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.

As for tamarind extract, 50 of leguminous tamarind. / ₀ ethanol extract is available, which is known as a thickener.

 As the 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.

As 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). As 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.

 In the composition of the present invention, 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 (ω-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. Such 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. Choline, ethanolamine, serine, inosit, etc. And phosphodiester-linked phospholipids. Examples of such phospholipids include lecithin, kephalin, phosphatidylserine, sphingolipid, sphingomyelin and the like.

Representative saturated fatty acids (free form) 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 (free form), 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.

 In the 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. However, when 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. Also, when 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.

On the other hand, 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. In particular, when the crude drugs and free fatty acids are used in combination, the weight ratio is preferably selected from the range of about 100: 1 to 1: 1100.

 The 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. Depending on the form of use of the formulation, 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

 Various forms of the above pharmaceutical preparations 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.

 In the form of tablets, 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. Further, 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.

 In the case of molding into pill form, 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.

When molding into suppository form, 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.

 When forming into liquid form, 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.

 When shaping into a suspension, 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.

 When prepared as an injection, 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. In the composition of the present invention, 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.

 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.

 In addition, the 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. At that time, except that 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.

 There are no particular restrictions on the other food ingredients as long as they are commonly used in the food field.Examples include various proteins such as flour, starch, sugar, oils and fats, lipids, sugar raw materials, and other vitamins and minerals. Can be

 Further, 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. Next, an antibacterial agent containing iron citrate and aqueous ammonia as active ingredients will be described.

 In such an antibacterial agent, 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.

 On the other hand, as the 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.

Further, in the present invention, instead of iron citrate and aqueous 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.

 Examples of iron lactate include ferrous lactate and ferric lactate, and these may be used alone or in combination.

 When the 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.

 When the iron salt is 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. Can be

 In addition, as an active ingredient of the antibacterial agent, 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.

 Further, 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.

 <Industrial applicability>

As described above, 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.

 Examples>

 Hereinafter, the present invention will be described in detail with reference to Test Examples and Formulation Examples.

 Crude drug samples and their preparation are based on those described in the “Natural Products Handbook” (13th edition) published by Food and Science Co., Ltd. (1995), or according to them.

Test Example 1 [Measurement of minimum growth inhibitory concentration (MIC) of H. pylori extract against H. pylori]

 (Isolation of flavonoid compounds contained in Kanzo oil extract)

 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.

Next, as shown in Fig. 2, fractions 7 and (lg) corresponding to the fraction 7 having the highest fraction were analyzed by silica gel chromatography (eluate) in the same manner as above to search for the main components of the kanzo oily extract. : Hexane: acetone = 3:] → cloth form: methanol = 9: 1) and the resulting fraction 7'-B is separated into 7 fractions 7'-AF. The fractions were separated into fractions 7'-B-:! -4 using silica gel chromatography (supra, eluent: black-mouthed form). Further, the fraction 7'-B-1 was purified by preparative thin-layer chromatography (PTL C, developing solvent: chloroform: methanol = 97: 3) to obtain the compound 1, and the fraction 7 ' -Compound B-2 was obtained by crystallization of B-4. These compounds were identified as Compound 1 as the above-mentioned glabrol (1) and Compound 2 as the above-mentioned glabridine (2). Solvent ratio at the time of collecting each of the above fractions and each fraction Figure 2 shows the amount of recovered chillons.

 By the way, when the antibacterial activity against H. pylori in 11 fractions 1 to 11 shown in FIG. 1 was measured in vitro, the fractions 3 to 6 having a lower polarity than the above-mentioned fraction 7, which is the main fraction, were measured. However, it was found that it shows strong antibacterial activity against H. pylori. Therefore, a search was made for active substances contained in the above fractions 3 to 6. The search method will be described with reference to FIG.

 First, the Kanzo oil extract (10 g) was fractionated using silica gel chromatography (eluent: black-mouthed honolem → hexane: acetone = 2: 1 ~ → chloropho / rem: methanolic = 9: 1). It was separated into 1-4. The fraction 11 obtained (corresponding to fractions 3 and 4 in FIG. 1) was fractionated again using silica gel chromatography (eluent: hexane: acetone = 3: 1). 1 1 1 Separated into AC. Further, the obtained fraction 1] —B was first purified by silica gel chromatography (eluent: hexane: acetone = 3: 1) to obtain a fraction 11—B ′, and then this fraction 11—1 B ′ was obtained. Was purified by silica gel chromatography (eluent: hexane: acetone = 3: 1) to obtain fractions 11-B'-1 and 11-B, -2.

 The above fraction 11 1—Β′-1 was subjected to silica gel chromatography (eluent: hexane: ethyl acetate = 4: 1) to obtain five fractions 11 1—Β′-1 a to e, and fraction 11 1— Compound 3 was obtained from B′_1 e.

 On the other hand, when 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-Β'-2a, and compound 5 was obtained from fraction 11-B'-2b.

Compounds 3, 4, and 5 obtained above were identified as the above-mentioned synflavone (3), 3′-prenyl dalabridine (4), and 4′-O-methylglabridine (5), respectively. Further, when crystallization was performed on the fractions 11 1-Β'-1a and 11-Β'-1b, the fraction 11 1-Β'-la was converted to the 4'-O-methyldallabridin ( 5) and further from the fraction 11_B'-1b, the 3'-prenyl glabridine described above. (4) was obtained. Figure 3 shows the amount of each fraction recovered, along with the solvent ratio when each fraction was recovered.

 (Measurement of minimum inhibitory concentration (M I C) against H. pylori)

 For the flavonoid compounds represented by the above-obtained formulas (1) to (5), 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.

That is, 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). Each strain was inoculated, and the minimum drug concentration at which no growth was observed was defined as MIC (μg / m 1). Table 1 shows the test results.

cn o

table 1

 (gZm 1) Flavonoids ^ Gravrol (1) Gravlidine (2) Synflavone (3) 3'-Prenylg 4'-0-Methylg strain Lablabridine (4) Lablabridine (5) Human clinical 001 12.50 1 2.50 12.50 6.25 6.25 Human clinical 0014 12.50 12.50 6.25 3.13 3.13

ATCC 43504 12.50 12.50 6.25 6.25 6.25

Test Example 2 [Antibacterial test using H. pylori-infected mice]

 (Preparation of reagents)

 The following 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%].

 In addition, when a licorice oil extract and α-linolenic acid were used in combination, the licorice oil extract was finely divided in a mortar and used after being suspended in α-linolenic acid. Experiment 1:

 Control group

1 group · '· 20πι _β Ζΐί 8 group

 2 groups • • • l Omg / kg α-linolenic acid administration group

 3 groups 500 mg Zkg g kanzo oily extract + 1 O mg / kg α-linolenic acid combination administration group

Experiment 2:

 Control group

 1 group • • 20 mg / kg meth-mouth nidazole group

 2 groups • • 50 O mg / kg g kanzo oily extract + 1 O mg / kg a-Lino

 Lenoic acid combination administration group

 3 groups10 O mg / kg g kanzo oily extract + 10 mg Zkg α-linolenic acid combination administration group

 4 groups20 mg Zkg g kanzo oily extract + 1 Omg / kg α-linolenic acid combination administration group

Experiment 3:

 An active ingredient of each group shown below was added to distilled water (600 ml) and mixed to prepare a reagent agent having an iron content of 0.007 to 0.01 mg / m1.

 1 group · · · Ferric quenate (Wako Pure Chemical Industries, Ltd., 26 mg) + 28% ammonia water (Wako Pure Chemical Industries, Ltd., 26 µ1) Group

2 groups.. 'Ferric citrate (Kishida Chemical Co., 34 mg) administration group 3 groups · · · Ferric pyrophosphate (Tomita Pharmaceutical Co., Ltd., 20mg) administration group

 4 groups · · · Ferrous lactate (Musashino Chemical, 35mg) administration group

 5 groups · · Ferrous sodium citrate (manufactured by Sansei Pharmaceutical Co., Ltd., 58 mg) administration group 6 groups · · ferric ammonium citrate (manufactured by Kishida Chemical Co., 40 mg) administration group Control group · · · distilled water Single dose group

 (Preparation of H. pylori solution for inoculation)

 Clinical isolate Helicobacter pylori CO 001 cryopreservation solution (Bruce 11 abrot h + 1 5% glycerol in which H. pylori is suspended) 0.1 ml applied to 7% FBS-supplemented B rucellaagar The cells were cultured at 37 for 2 days in an atmosphere of 85% nitrogen, 10% carbon dioxide, and 5% oxygen.

 Next, 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.

Furthermore, 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.

Note that in Experimental Example 3, a pre-culture solution 5 m 1, performs cultured as above except inoculation into 7% FBS added B rucellabroth 45m 1, so that the final number of bacteria is about 1 0 ⁷ CFU / m 1 Was used.

 (experimental method)

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. 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 α-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.

 In Experimental Example 3, the above mice (10 mice per group) were forcibly orally administered the inoculated bacterial solution and infected with H. pylori. For 10 days from the 7th to the 16th day after infection, 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.

 Of this, 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, and 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.

 Further, in Experiment 3, the infection rate (%) of each of the reagents when the infection rate of Helicobacter pylori in the control group was set to 100% was represented by a bar graph. Figure 7 shows the results.

 As is clear from FIGS. 4 and 5, it was found that the combined administration of the licorice oil extract and α-linolenic acid reduced the number of H. pylori in the mouse stomach below the limit.

In addition, as is clear from FIGS. 6 and 7, the group administered with the reagent was more effective than the control group. It was found that the number of H. pylori in the mouse stomach decreased.

 In particular, a significant difference (p <0.01) was observed between the control group and one group in FIG. 6 in Dunnet Two—tailedTest. Further, between the control group and the first and second groups in FIG. 7, F i s h e r ′ s e x a c t p r o b a b i l i t y

A significant difference (p <0.05) was observed for Te st.

 Hereinafter, formulation examples of the composition of the present invention into various forms will be described.

Formulation Example 1

The components shown in Table 2 below were mixed, and the mixture was formed into a tablet form by a direct powder compression method to prepare a foaming agent-form composition of the present invention.

to

 o o

Table 2

Product No.

 1

 1 9 Δ 0 4 5 6 7 Granulated sugar 3 0 3 0 3 0 3 4 3 0 3 6 3 2 2 5

L-ascorbic acid 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 3

L-Montaric acid 2 3 2 3 2 3 2 3 2 3 2 3 2 3 2 5 Sodium bicarbonate 2 2 2 2 2 2 2 2 2 0 2 1 2 1 1 1 Licorice oil extract 1 3 5 0.5 1 2 1.53 Linolenic acid 5 8 5 3 6 2 4 5 Linoleic acid 5 2 5 3 4 2 4 5 Sweetener Appropriate amount Appropriate amount Appropriate amount Appropriate weight mm Appropriate amount堇 Appropriate potassium carbonate 0.3 0.3 0.4 0.5 0.5 1.0 0.2 0.5 0.6 13.0

Weight per tablet (g) 4. 8 6. 8 8. 9 4. 3 4. 4 5. 5 5. 4 7. 7

Formulation Example 2

 Operation of mixing each component shown in Table 3 below and tableting directly (tablet) Operation of weighing and mixing each component and packaging (powder), and weighing and mixing of each component, granulation and drying, and packaging By the following procedure (granules), the compositions of the present invention in the form of respective preparations were prepared.

製剤例 3

Formulation Example 3

 Using the components shown in Tables 4 and 5 below, the composition of the present invention in the form of soft capsules was prepared by a punching method.

Table 4

Pharmaceutical No. Constituents (g) 17 18 1Q 21 Licorice oil extract 0.8-1-Evening malindo extract 0.8-1

 Metronidazole 0.1-Provolis I 0.5

 Evening 05 Flavones--Bismuth compounds

 Anthocyanin

 Epigallocatechin

 Linolenic acid 1 0.5 0.3 Linoleic acid 0.5

 Conjugated linoleic acid 0.5

 Medium chain fatty acids (MCT) 0.5

 Arachidonic acid

 0.5 0.3

 Docosahexaenoic acid 0.5 0.3

 Lecithin 0.1

 Safflower oil 0.5

 Castor oil

Oleic acid Table 5

Pharmaceutical No. Constituents (g)? 9 94 D Licorice oil-based extract 11-0.5 Evening malindo extract 1-1.-0.5 Metronidazole 1-1-1-Provo 1) S , One-one-one bon 0.5

Bismuth compound 0.5

Anthocyanin 0.5

Epigallocatechin 0.8 linolenic acid 0.3 0.1 0.5 linoleic acid 0.1 conjugated linoleic acid 0.1 medium chain fatty acid (MCT) 0.1 arachidonic acid 0.3 0.1 eicosapentaenoic acid 0.1 docosahexanoic acid 0.1 lecithin 0.1 safflower oil

Castor oil 1

Oleic acid 1

Claims

The scope of the claims  1. A composition for Helicobacter pylori, comprising, as active ingredients, a substance having an antibacterial activity against Helicobacter pylori and at least one selected from the group consisting of free fatty acids, salts thereof and esters thereof.  2. The substances having antibacterial activity against Helicobacter pylori are glycyrrhizin, licorice extract, rosemary extract, salvia extract, goji extract, thyme extract, ginger extract, oegone extract, and ju extract , Siconex, kilanin, rooibos tea dry extract, mugwort dry extract, pear pear extract powder, tamarind extract, guava extract, saxifrage leaf extract, ceramide, enme iso ゥ extract, mukurojexpauda, yucca extract 2. The composition according to claim 1, which is at least one kind of crude drug selected from the group consisting of powder and lemon extract, and wherein the free fatty acid is a long-chain free fatty acid.  3. The composition according to claim 2, wherein the crude drug contains a licorice extract. 4. The substance having an antibacterial activity against Helicobacter pylori is at least one selected from the group consisting of glabrol, glabridin, synflavone, 3'-prenyl glabridine, 4'-O-methyl grabradine, glabrene and formononetin. 2. The composition according to claim 1, which is a flavonoid of the species.  5. The composition according to claim 1, wherein the substance having an antibacterial activity against Helicobacter pylori is a polyphenol.  6. The composition according to any one of claims 1 to 5, wherein the free fatty acid is linolenic acid. 7. An antibacterial agent against Helicobacter pylori, comprising as active ingredients a substance having an antibacterial activity against Helicobacter pylori and at least one selected from free fatty acids, salts thereof and esters thereof.  8. An agent for preventing infection with Helicobacter pylori, comprising as active ingredients a substance having an antibacterial activity against Helicobacter pylori and at least one selected from free fatty acids, salts and esters thereof.  9. The composition according to claim 1, which has a food form.  10. Helicobacter containing iron citrate and aqueous ammonia as active ingredients • Antibacterial agents against H. pylori. 1 1. Helicopter containing iron citrate and aqueous ammonia as active ingredients.  1 2. Antibacterial agent against Helicobacter pylori containing as active ingredient at least one selected from the group consisting of iron citrate, iron ammonium citrate, sodium ferrous citrate, iron lactate and ferric pyrophosphate .  13 3. An agent for preventing infection against Helicobacter pylori, which contains at least one selected from the group consisting of iron citrate, ammonium citrate ammonium, ferrous sodium citrate, iron lactate and ferric pyrophosphate as an active ingredient .  1 4. Food for Helicobacter pylori, containing at least one selected from the group consisting of iron citrate, iron ammonium citrate, sodium ferrous citrate, iron lactate and ferric pyrophosphate as an active ingredient .