WO2000010581A1 - Medicaments comprenant une combinaison d'une bacterie produisant de l'acide butyrique, et d'un constituant d'acide biliaire - Google Patents

Medicaments comprenant une combinaison d'une bacterie produisant de l'acide butyrique, et d'un constituant d'acide biliaire Download PDF

Info

Publication number
WO2000010581A1
WO2000010581A1 PCT/JP1999/004448 JP9904448W WO0010581A1 WO 2000010581 A1 WO2000010581 A1 WO 2000010581A1 JP 9904448 W JP9904448 W JP 9904448W WO 0010581 A1 WO0010581 A1 WO 0010581A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
bile
butyric acid
intestinal
medicament
Prior art date
Application number
PCT/JP1999/004448
Other languages
English (en)
Japanese (ja)
Inventor
Kikuo Yamazaki
Akio Maeda
Original Assignee
Miyarisan Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Miyarisan Pharmaceutical Co., Ltd. filed Critical Miyarisan Pharmaceutical Co., Ltd.
Priority to AU53013/99A priority Critical patent/AU5301399A/en
Publication of WO2000010581A1 publication Critical patent/WO2000010581A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Definitions

  • the present invention relates to a medicine comprising a combination of bile acid, a conjugate thereof or a pharmaceutically acceptable salt thereof, and a butyric acid-producing bacterial cell or a spore thereof, and more particularly, an excellent gallstone formation-preventing action
  • the present invention relates to a medicament having a gallstone dissolving action, a protective and repairing effect on mucous membranes in inflammatory bowel disease and the like, an improvement in indigestion, and an excellent growth promoting action.
  • butyric acid-producing bacteria have a strong antagonistic action against putrefactive bacteria present in the intestine (Clinical Medicine 4,973-980 (1 9 3 5)). Some of these butyric acid-producing bacteria have excellent ameliorating effects on diarrhea caused by various causes such as acute digestive insufficiency, neonatal diarrhea, pseudo-cholera cholera, and acute enteritis. is there. Intestinal flora equilibrium is necessary to maintain gut health; for example, an increase in intestinal pH favors the growth of spoilage and other pathogens, but usually the intestinal contents produce acids Suppresses pH rise and maintains biological equilibrium. However, the intestinal flora may be unbalanced due to diarrhea or antibiotics given in various diseases.
  • butyric acid-producing bacteria belonging to the genus Clostridium or spores thereof (hereinafter, simply referred to as butyric acid-producing bacteria) against such intestinal microflora imbalance causes the growth of lactic acid bacteria. It promotes the growth of lactic acid bacteria, prevents intestinal putrefaction and fermentation, and secondarily inhibits the growth of enterococci, such as Escherichia coli, so that it is close to the state of the fecal flora of healthy people. Revert (New Drug and Clinical 25, 1505-1509 (1976)).
  • butyric acid produced by butyric acid-producing bacteria and the like becomes energy for the colonic mucosa and proliferates and protects damaged colonic mucosal cells (Experimental Medicine 2,483 489 (1 984)).
  • Bile acid is the final product of cholesterol, which is bound in the liver to glycine-epinephrine and is excreted as a glycine conjugate, for example, glycocholate-eternal phosphorus conjugate, for example, eluted as cholocholic acid.
  • the bile acids and their conjugates which are mainly produced in the liver, are converted into their sodium and potassium salts in bile, which has a strong lipophilicity. It cleanses and emulsifies and helps digest and absorb fat.
  • bile acids and their conjugates or salts thereof have a gallstone dissolving effect and a bile effect.
  • gallstone dissolving action is that the formation of gallstones depends on the correlation between free cholesterol, bile acids, and lecithin in bile. It is thought to rectify the dissolution and dissolve gallstones (edited by Isao Makino, Gastrointestinal Disease Seminar 56, pl 40-; L50, (1994)).
  • bile acid drugs include ursodesoxycholic acid, which is a chemically synthesized medicinal component of the gallbladder of Japanese black bear, which is useful in biliary tract (bile duct 'gallbladder) diseases and liver diseases with cholestasis.
  • Ursodesoxycholic acid has the above-mentioned digestive and absorptive effects by increasing the hepatic bile flow and bilirubin excretion, as well as by increasing the hepatic blood flow, promoting fat absorption, and bile cholesterol desaturation.
  • Has a gallstone dissolving effect, a bile effect, etc. No. 13 Revised Japanese Pharmacopoeia Manual, Hirokawa Shoten, Ursodesoxycholic acid section).
  • bile acid component medicines containing bile acids, their conjugates or pharmacologically acceptable salts thereof (hereinafter simply referred to as “bile acid component”) may irritate the gastric mucosa in patients with peptic ulcer. Therefore, careful administration is currently required. Furthermore, it is known that side effects such as diarrhea, abdominal pain, and constipation may occur. The use of bile acid components is generally taken for a long period of time, and the side effects such as diarrhea and loose stools that occur during that period halve the therapeutic effect.
  • the gallstone dissolving action of the bile acid component is closely related to the quantitative composition ratio of free cholesterol in bile to bile acids and lecithin. Therefore, in order to dissolve calculi generated in the living body, it is necessary to make the composition ratios of the above three different, and it is necessary to administer a large amount of bile acid components such that this composition ratio reaches the gallstone dissolution zone. Desired. For this reason, it is difficult to reduce the dose under the current conditions, and it is difficult to treat and prevent gallstone disease, which is particularly prone to chronicity and relapse, and to reduce the above-mentioned side effects. Furthermore, if the bile acid component is used to improve indigestion of food that occurs during inflammatory bowel disease, there is no point in causing diarrhea or loose stool due to side effects.
  • butyric acid itself is a substance that is absorbed before it reaches the large intestine, even if it becomes energy for the colonic mucosa. Therefore, simply oral administration cannot be used effectively for inflammatory bowel disease and the like.
  • the present inventors have met the above requirements and have conducted intensive pharmacological research.As a result, a drug combining butyric acid-producing bacteria and a bile acid component can solve the above problems and further digest Excellent effect with promotion and intestinal action And completed the present invention.
  • a medicine comprising a combination of a butyric acid-producing bacterium and a bile acid component.
  • the butyric acid-producing bacteria are Clostridium butyricum Miyali 585 (FE RM BP—68 15), Clostridium butyricum Miyali 595 (FE RM BP—68 16), At least one member selected from the group consisting of resp.
  • Pulicum miyai 63 Pulicum miyai 63 (FE RM BP—68 17) and cross-stream butyl liquor miyai 58 8 (FERMBP— 27 89)
  • the bile acid, the conjugate thereof or a pharmaceutically acceptable salt thereof is ursodesoxycholic acid, dehydrocholic acid, chenodeoxycholic acid, or ureursodeoxycholate;
  • the above-mentioned (1) which is at least one selected from the group consisting of glycoursodeoxycholic acid, ursodeoxycholic acid-3-glucuronide or salts or conjugates thereof.
  • pharmaceutical (3) cholelithiasis
  • the pharmaceutical according to (1) or (2) is ⁇ .
  • the present invention is a medicament comprising a combination of cells of a butyric acid-producing bacterium belonging to the genus Clostridium or a spore thereof, and a bile acid, a conjugate thereof or a pharmaceutically acceptable salt thereof.
  • the butyric acid-producing bacterium used in the medicament is not particularly limited as long as it belongs to the genus Clostridium and mainly produces butyric acid.
  • Butyric acid producing bacteria, etc. Strongly antagonizes intestinal putrefactive bacteria with butyric acid produced by the plant, assists spontaneous healing of intestinal diseases, prevents intestinal putrefactive fermentation, provides energy for colonic mucosa, and has a protective effect on the proliferation of colonic mucosal cells This is because the disease can be prevented before it occurs.
  • clostridium produces spores, it is particularly excellent in stability when used as a medicament and viability in the intestine.
  • Clostridium butyricum 588 (Clostridium but yricum MIYAIRI 588: Hereinafter referred to as “CbM588”. ) Is particularly preferred. Each of these strains is described in the document Bifidobacteria Microflora vol 7, 57-60, 1988.
  • the butyric acid-producing bacteria are used in the present invention because they promote the increase of lactic acid bacteria, reduce the number of Escherichia coli and enterococci, and are excellent in correcting the imbalance of the intestinal flora. Furthermore, these butyric acid-producing bacteria have the properties of acid-resistant spores, survive as spores in gastric juice, and grow and grow in the intestinal tract.
  • butyric acid-producing bacteria when used, they have acid resistance, and therefore their activity is rarely suppressed even when they are mixed with the following bile acid components. Among them, CbM588 is particularly preferable. In addition to the excellent properties described above, it is also resistant to aminoglycoside antibiotics, etc., has already been widely used as a pharmaceutical, has a proven track record of pharmacological effects such as intestinal effects, and has no side effects It is.
  • the butyric acid-producing bacteria may be used alone or in combination of two or more.
  • the method for identifying butyric acid-producing bacterium Clostridium butyricum used in the present invention was as follows.
  • the butyric acid-producing bacterium Clostridium butyricum used in the present invention was identified as a butyric acid-producing bacterium Clostridium butyricum by the following characteristics. Morphological features: Straight or slightly curved obtuse rods at both ends, forming oval sub-terminal spores, 3-5 m in length, 0.9-1.1 lm in width, colo The first is a white or milky white round or irregularly shaped, opaque, rough raised settlement,
  • Milk medium produces acid and gas, with coagulation
  • the cells or spores of butyric acid-producing bacteria belonging to the genus Clostridium used in the present invention can be obtained by a known culture method.
  • An example is as follows. That is, carbon sources such as corn starch, ground starch, potato starch, soluble starch and glucose, and nitrogen sources such as meat extract, peptone, casamino acid, amino acid mixture, corn steep liquor, and yeast extract.
  • carbon sources such as corn starch, ground starch, potato starch, soluble starch and glucose
  • nitrogen sources such as meat extract, peptone, casamino acid, amino acid mixture, corn steep liquor, and yeast extract.
  • bimine sources are selected, and a medium consisting of manganese sulfate, iron sulfate, calcium carbonate, etc. as an inorganic salt is subjected to high-pressure steam sterilization at 120 ° C.
  • bile acids, conjugates or salts thereof used in the medicament of the present invention are components of animal bile.
  • ursodesoxycholic acid hereinafter sometimes referred to as “ursodeoxycholic acid” in some cases
  • dehydrocholic acid chenodeoxycholic acid
  • lithocholic acid So-called cholic acid derivatives are included.
  • Cholic acid derivatives are synthesized as glycin-taurine conjugates in the liver, but after excretion in the gallbladder, they are generally present as these sodium salts due to the alkaline nature of bile.
  • these bile acids, conjugates thereof, or pharmacologically acceptable salts thereof can be used.
  • examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid.
  • Preferable examples of the salt with an inorganic base include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with aluminum, ammonium and the like.
  • Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, genoleamine, trienoamine, dicyclohexylamine, N, N-dibenzylethylenediamine.
  • salts with You Preferable examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, lingic acid, methanesulfonic acid, benzene
  • salts with basic amino acids include, for example, salts with arginine, lysine, ordinine, etc., and salts with acidic amino acids.
  • Preferable examples thereof include, for example, salts with aspartic acid, glutamic acid and the like.
  • a sodium salt, a potassium salt, a calcium salt, and a sulfate are preferable.
  • the ratio of bile acid to cholesterol in bile can be shifted in the direction of dissolving gallstones, thereby suppressing gallstone formation and dissolving gallstones.
  • a single bile acid component may be used, or two or more bile acid components may be used in combination.
  • ursodeoxycholic acid ursodeoxycholic acid, dehydrocholic acid, chenodeoxycholic acid, tauroursodeoxycholic acid, glycoursodeoxycholic acid, ursodeoxycholic acid-3-glucuronic acid
  • ursodeoxycholic acid dehydrocholic acid, and chenodeoxycholic acid.
  • bile acid components that show a non-dissociated state are excellent in their absorption, but the use of bile acids themselves, rather than bile acid conjugates or salts thereof, provides a quick absorption effect from the intestinal tract. It is.
  • bile acids themselves return to the liver via enterohepatic circulation in the living body, where they are reconjugated to glycoconjugates and tauroconjugates, and excreted again in the gallbladder and further to the duodenum to perform functions such as emulsification. Therefore, administration of bile acids in a non-dissociated state provides a more rapid absorption effect in the proximal small intestine, and does not require the use of conjugates or salts as bile acid components from the beginning.
  • ursodeoxycholic acid is excellent in terms of weak cytotoxicity, and is particularly preferable.
  • the medicament of the present invention is obtained by combining the butyric acid-producing bacterium and the like with a bile acid component.
  • a bile acid component By combining butyric acid-producing bacteria, etc., which do not always produce sufficient effects when administered alone, and bile acid components, gallstone dissolution, gallstone formation prevention, and bile action are synergistically demonstrated. This is because it has been found that the combination exerts excellent digestive and intestinal regulating effects and ameliorating effects of inflammatory bowel disease which have not been found conventionally.
  • the gallstone formation inhibitory effect of the present invention is based on the fact that butyric acid-producing bacteria and the like are present in the intestinal tract, thereby altering the enterohepatic circulation of bile acids and promoting excretion of bile acids from the body, and suppressing gallstone formation.
  • Bile acid components such as bile acids and conjugates of these are metabolites of cholesterol. The cholesterol metabolites are excreted outside the body by promoting the excretion of bile acid components outside the body.
  • the bile action of the bile acid component is synergistically exerted.
  • the mechanism of the bile action of ursodeoxycholic acid includes the theory of increased bicarbonate ion concentration, the theory of osmotic pressure, and the theory of secretion, but the combination of both drugs results in an excellent inhibitory effect on gallstone formation. It is believed that the bile effect is also exerted effectively.
  • the medicament of the present invention containing a bile acid component and a butyric acid-producing bacterium exhibited a growth promoting effect that could not be obtained when these were used alone. It was known that butyric acid-producing bacteria and the like exert an intestinal action in the intestinal tract, but there were no reports of observing the digestive absorption action. However, it is considered that the combination with the bile acid component promotes digestion and absorption of fats in the intestinal tract, resulting in an extremely excellent growth promoting effect. This is thought to be related to the use of butyric acid produced by butyric acid-producing bacteria and the like as energy, but the details are unknown.
  • the bile acid component used in the present invention can be obtained by drying and finely chopping a bile acid component containing a large amount of a bile acid component, such as bear bile used in herbal medicine, and chemically by a known method. It can also be synthesized. For example, using ursodeoxycolic acid as an example, methyl cholate is acetylated and then oxidized to form a 12-ketone, which is then exposed to excess hydrazide.
  • chenodeoxycholic acid Heat with hydrate to form chenodeoxycholic acid and then oxidize with potassium chromate in acetic acid or react with N-bromosuccinic acid imide in acetone to form the 7-ketone. Reduction of this with sodium metal in n-propanol yields a 7? Hydroxyl substrate, ursodeoxycholate.
  • a natural product or a chemically synthesized product may be used.
  • the medicament of the present invention has low toxicity and can be used safely in mammals (eg, humans, mice, rats, puppies, dogs, cats, puppies, puppies, bush, monkeys, etc.).
  • the dose of the medicament of the present invention may be determined according to the dose of each drug, and depends on the administration subject, age and weight of the administration subject, symptoms, administration time, dosage form, administration method, drug combination, and the like. It can be selected as appropriate.
  • the bile acid component can be selected in the range of 0.1 to 3600 mg, preferably in the range of 0.5 to 3 mg when oral administration per adult per day.
  • a drug containing butyric acid-producing bacteria and the like to be used in combination therewith can be appropriately selected based on the clinically used dose.
  • the clinical dose can be selected in the range of 11 sxiosxio, preferably 1 lxiossxio11. The appropriate number of doses is 1 to 3 times a day.
  • the compounding ratio of each active ingredient can be appropriately selected depending on the administration subject, age and weight of the administration subject: symptoms, administration time, dosage form, administration method, combination of drugs, and the like. It can be used for the treatment of cholelithiasis, digestive and intestinal medicine, inflammatory bowel disease treatment and growth promoter.
  • the combination drug of the present invention comprises mixing these active ingredients separately or simultaneously with a physiologically acceptable carrier, excipient, binder, diluent, or the like. It can be administered orally or parenterally as a pharmaceutical composition.
  • the active ingredients are separately formulated as pharmaceuticals, they can be separately formulated and administered using a diluent at the time of use, but the separately formulated ones can be administered separately and simultaneously. Alternatively, they may be administered to the same subject at different times.
  • the butyric acid-producing bacterium and the bile acid component are mixed in an amount of 1 ⁇ 10 6 to 1 ⁇ 10 11 butyric acid-producing bacteria in 1 g of the composition. preferably contains, more preferably 1 0 1 X 1 0 ⁇ ⁇ ⁇ ⁇ ⁇ .
  • the amount of the bile acid component in the composition lg is preferably from 5 to 600 mg, more preferably from 20 to 400 mg.
  • the dose when using c pharmaceutical composition proportion of butyrate producing bacteria with bile acid component can be appropriately selected depending on the intended use as human subjects is 1 day. 20 to 6000 mg, more preferably 1 00 to 5000 mg, particularly preferably 250 to 4000 mg.
  • the dose is 100 to 600 mg / day, more preferably 500 to 5000 mg / day, particularly preferably 1500 to 4000 mg / day for use in the prevention and treatment of so-called gallstone disease such as gallstone dissolution and prevention of gallstone formation.
  • the dose is 100 to 6000 mg / day, more preferably 500 to 3000 mg / day, particularly preferably 1,000 to 2000 mg / day.
  • the amount is 100 to 600 mg / day, more preferably 500 to 3000 mg / day, particularly preferably 1,000 to 2000 mg / day.
  • the dose is 20 to 1,500 mg per day, preferably 100 to 800 mg, particularly preferably 250 to 500 mg. Is preferred.
  • the medicament of the present invention can be used for animals.
  • the target animals include various animals, such as bush, dog, cat, monkey, bird, bird, pest and so on. When these animals are used as subjects, the dosage is preferably 5 to 350 mg / kg, more preferably 10 to 250 mg / kg, particularly preferably 25 to 200 mg / kg. It can be appropriately selected according to the target animal, symptoms, age, sex, body weight, etc. of the administration.
  • oral administration is preferable, and it is preferable to take the above daily dose in one to three divided doses, but the number may be increased or decreased as appropriate according to the symptoms.
  • the daily dose may be administered once or more in the feed.
  • the pharmaceutical composition can be used as it is as a powder or granule by mixing it directly with feed, and furthermore, corn flour, soybean meal, barley flour, naked barley flour, soy flour, rice bran, potato flour, tofu grounds, starch, It can also be administered beforehand in animal feed such as fish meal.
  • the pharmaceutical composition can be used as an oral preparation, for example, a pharmaceutical preparation such as granules, powders, tablets, capsules, syrups, emulsions and suspensions.
  • a pharmaceutical preparation such as granules, powders, tablets, capsules, syrups, emulsions and suspensions.
  • These medicaments can be produced by a method known per se that is generally used in the pharmaceutical process. Hereinafter, a specific method for producing a pharmaceutical will be described in detail.
  • the oral preparation contains a bile acid component as an active ingredient and the above-mentioned butyric acid-producing bacterium and the like, and can further be mixed with a pharmaceutically acceptable excipient to prepare a composition for oral administration.
  • a pharmaceutically acceptable excipient to prepare a composition for oral administration.
  • Other additives that can be blended include lactose, sucrose, mannite, corn starch, synthetic or natural gum, excipients such as crystalline cellulose, gelatin, cellulose derivatives, arabia gum, polyvinylpyrrolidone.
  • Binders such as carboxymethyl cell mouth —Disintegrants such as scalcium, sodium carboxymethylcellulose, starch, corn starch, sodium alginate, polyethylene glycol 600, lubricants such as talc, magnesium stearate, sodium stearate, calcium carbonate, sodium carbonate There are fillers or diluents such as lium, phosphoric acid, sodium phosphate, etc. In addition, other ingredients can be added depending on the purpose and symptoms.
  • disintegrants such as scalcium, sodium carboxymethylcellulose, starch, corn starch, sodium alginate, polyethylene glycol 600, lubricants such as talc, magnesium stearate, sodium stearate, calcium carbonate, sodium carbonate
  • fillers or diluents such as lium, phosphoric acid, sodium phosphate, etc.
  • other ingredients can be added depending on the purpose and symptoms.
  • sugar-coated tablets, coated tablets, sustained-release preparations, and oral liquid preparations and pastes may be used.
  • An enteric agent may be used by using a coating substrate such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate, cellulose acetate phthalate, and methacrylate copolymer. Since the bile acid component has bitterness, it can be made into capsules using sugar-coated tablets or hard or soft gelatin capsules to prevent bitterness. However, taking advantage of the fact that bitterness acts as a bitter stomachic, powders, granules, tablets, tablets, and the like can be used while having bitterness.
  • the cells or spores of the butyric acid-producing bacterium and the bile acid component are suspended and dissolved in water, alcohol, or the like, and, if necessary, a wetting agent, an emulsifier, a dispersing aid, a surfactant, a sweetener, or a flavor.
  • a syrup, an elixir and the like can be prepared by appropriately adding an aromatic substance or the like.
  • the pharmaceutical composition may be processed into a form suitable for food by adding dietary fiber, oligosaccharides, cereals, biminins, and the like in addition to the above additives, and further adding a flavor, a flavoring agent, and the like. Is also possible.
  • the medicament of the present invention can be used as a therapeutic agent for cholelithiasis, an anti-inflammatory / intestinal treatment agent, a therapeutic agent for inflammatory bowel disease or a growth promoting agent, by the action of the combined active ingredient. That is, the medicament of the present invention exhibits excellent gallstone dissolving action and gallstone formation suppressing action by combining the butyric acid-producing bacterium and the bile acid component. Therefore, when used as a treatment for gallstone disease, gallstones can be easily dissolved, and it is also a preventive agent for cholelithiasis that tends to recur. Furthermore, it can be used as a gallstone preventive agent due to its gallstone formation inhibitory action.
  • the medicament of the present invention With the use of the medicament of the present invention, diarrhea, loose stool, bleeding, etc. caused by intestinal inflammatory diseases such as colitis can be improved, and the damaged site can be cured. Therefore, it is useful as a therapeutic agent for inflammatory bowel disease.
  • infectious Salmonella enteritis, Vibrio parahaemolyticus, Campylobacter enteritis, Yersinia enteritis, staphylococcal gastroenteritis, etc. as therapeutic agents for inflammatory bowel disease
  • non-infectious agents include allergic gastroenteritis, inflammation Ulcerative colitis, ulcerative colitis, Crohn's disease, irritable bowel syndrome, drug-induced enteritis, etc.
  • the medicament of the present invention improves dyspepsia in inflammatory bowel disease, etc. It can be used as a drug that can be added to pharmaceuticals, foods, feed additives, etc., that can be improved at home. For this reason, it promotes digestion and absorption and has an intestinal action, so that it can be used as a general purpose drug and as an intestinal / intestinal medicine.
  • the medicament of the present invention when used by adding it to food and feed, it exhibits a growth promoting effect and is useful as a growth promoter.
  • ursodeoxycholic acid and butyric acid-producing bacteria To investigate the stability of a drug containing ursodeoxycholic acid and butyric acid-producing bacteria, add 0,5 mg of ursodeoxycholic acid to 1 ml of GAM broth medium, and then add C as butyric acid-producing bacteria.
  • b M588 was inoculated at 5.4 ⁇ 10 3 cells / m 3 , maintained in an anaerobic state, and cultured at 37 ° C. for 24 hours. Result of this, the 2 4 hours of culture 2. have proliferated 0 1 0 7, C b M 588 was found to be not inhibited proliferation by Urso de O carboxymethyl cholate.
  • composition of cholic acid other than ursodeoxycholic acid was examined by gas chromatography.As a result, no cholic acid other than ursodeoxycholic acid was detected, and ursodeoxycholic acid was detected by CbM588. No chemical conversion was found.
  • butyric acid-producing bacteria The butyric acid-producing bacteria, ursodeoxycholic acid, and corn starch were mixed in the amounts shown in Table 13 to obtain compositions of Formulations A, B, and C.
  • Butyric acid bacterium was cultured on CsM medium (published in JP-A-59-187787).
  • Seven Wistar male rats (weight: about 200 g) were divided into three groups, each group consisting of 7 Wistar rats, which were freely used in an environment of 22.9 ⁇ 0.5 ° C and a humidity of 52.3% 4.5%. They were bred under solid feed (CE-2, manufactured by CLEA Japan) and tap water.
  • composition of each of the formulations shown in Table 13 (formulations A, B, and C) was suspended in water and orally administered at a dose of 10 mg / head once a day. This was continued for 14 days, and on days 7 and 14, the rats were observed for stool properties, weighed, and weighed on days 0, 7, and 14. Table 14 shows the results.
  • An SD male rat (body weight: about 200 g) was bred under the same conditions as in Example 2, and dextran sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) was used for drinking water at a rate of 3%. It was dissolved in water and taken freely every day to create an ulcerative colitis model.
  • mice Ten days after the start of ingestion, feces were observed, and rats with stool mixed with blood were selected and divided into four groups, each group consisting of five rats. After that, tap water with a sodium dextran sulfate concentration of 1% was given, and each group was given the above formulation A, B, and C once a day at 5 mg / head at 10 mg. The drug was administered daily.
  • Formulation B which used a combination of ursodeoxycholic acid and dung bacillus, as well as Formulation A, successfully suppressed diarrhea and loose stools and suppressed stool bleeding.
  • Body weight gain was also favorable in the group given the prescription B, and colitis was even more strongly suppressed than in the prescriptions A and C, with colitis almost disappearing in 2 out of 5 animals.
  • the three groups receiving the high cholesterol diet were orally administered each of the compositions of Formulations A, B, and C shown in Table 13 once a day, each at 5 mg / head for 30 days.
  • the other group did not receive drug administration as a control.
  • the mice were sacrificed and dissected, the gallbladder was removed, and the formation of gallstones was evaluated.
  • Gallstone formation is: Score 1 0: No gallbladder gallstones, Score 1: 1: Gallbladder occupies 0 to 1/3, Score 1: 2: Gallbladder occupies 1/3 to 1/2, Score 1: 3: Gallbladder It was evaluated as occupying more than 1/2 of them.
  • Table 6 shows the scores of the five mice and the average of the groups administered with each prescription.
  • mice After the same mice as in Example 5 were ingested with the same high cholesterol solid diet for 25 days, the mice were returned to the normal diet and divided into groups of 5 mice and 5 groups. Of the three groups, the A, B, and C agents were orally administered once each day at 5 mg / head for 30 days. The other group did not receive drug administration as a control. The other group was immediately sacrificed, dissected and evaluated for gallstone formation. The drug administration group and the control group were sacrificed in the same manner 30 days later, and gallstone dissolution was evaluated.
  • the present invention in humans and animals, it is possible to prevent and treat side effects such as diarrhea and loose stool that occur during the course of treatment with bile acid components, and to more effectively treat and prevent gallstone disease.
  • the present invention provides a composition for use in medicines, foods, feed additives, etc., which improves indigestion in inflammatory bowel disease and the like, prevents wasting, and improves the condition in a shorter period of time.
  • the combination of bile acid components and butyric acid-producing bacteria, etc. synergistically enhances gallstone dissolving action and gallstone formation inhibitory action, and can shorten the treatment period.
  • the composition of the present invention is capable of protecting and repairing intestinal mucosa by butyric acid-producing bacteria and the like, and promoting digestive absorption by a bile acid component, thereby producing infectious Salmonella enteritis, Vibrio parahaemolyticus, non-infectious It can improve bleeding, inflammation and other symptoms in inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, improve dyspepsia, and shorten the treatment period.
  • the intestinal action of butyric acid-producing bacteria and the like and the action of bile acid components to promote the digestion and absorption of food are useful as a gastrointestinal drug or a digestive / intestinal drug having a digestive / intestinal action.
  • economic animals such as livestock produce It has an excellent growth effect, especially a weight gain effect, through digestion and intestinal regulation by live bacteria and bile acid components.
  • composition of the present invention two components are combined for a disease in which the bile acid component alone is required to take a drug for several months to several years because the component is easily prone to chronicity and recurrence.
  • gallstones can be easily dissolved by the synergistic effect of both.
  • the composition of the present invention can promote digestion and absorption more effectively by combining two agents. Furthermore, in the case of inflammatory bowel disease, digestion and absorption in the intestine are generally poor, and the condition is not easily improved, but becomes chronic. However, the present invention provides digestion and absorption with compositions of components having different mechanisms of action. It can encourage, prevent wasting, and improve the condition in less time. Industrial applicability
  • a medicine for effectively preventing and treating cholelithiasis, improving dyspepsia in inflammatory bowel disease and the like, preventing wasting, and improving the condition in a shorter time You.
  • the gallstone dissolving action and the gallstone formation inhibitory action are synergistically enhanced, which is useful for humans and other animals that can shorten the treatment period.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Mycology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne des médicaments comprenant des cellules ou spores d'une bactérie produisant de l'acide butyrique et appartenant à l'espèce Clostridium, auxquelles on a combiné un acide biliaire, un conjugué, ou des sels de celui-ci acceptables sur le plan pharmacologique. Etant donné que ces médicaments contiennent un acide biliaire, ils possèdent d'excellents effets de prévention de la formation de calculs biliaires et de lyse de ceux-ci. En outre, grâce à la présence de la bactérie produisant de l'acide butyrique, ces médicaments soulagent les digestions difficiles dans les maladies intestinales inflammatoires et exercent d'excellents effets, favorisant notamment la digestion et la croissance et améliorant l'altération intestinale. On peut les utiliser en tant que médicaments de traitement de la lithiase biliaire, en tant que médicaments destinés aux intestins/favorisant la digestion, et de traitement des maladies intestinales inflammatoires, de même qu'en tant qu'agents de promotion de la croissance.
PCT/JP1999/004448 1998-08-20 1999-08-19 Medicaments comprenant une combinaison d'une bacterie produisant de l'acide butyrique, et d'un constituant d'acide biliaire WO2000010581A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53013/99A AU5301399A (en) 1998-08-20 1999-08-19 Rugs comprising butyric acid-producing bacterium combined with bile acid component

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP23461698 1998-08-20
JP10/234616 1998-08-20

Publications (1)

Publication Number Publication Date
WO2000010581A1 true WO2000010581A1 (fr) 2000-03-02

Family

ID=16973845

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/004448 WO2000010581A1 (fr) 1998-08-20 1999-08-19 Medicaments comprenant une combinaison d'une bacterie produisant de l'acide butyrique, et d'un constituant d'acide biliaire

Country Status (2)

Country Link
AU (1) AU5301399A (fr)
WO (1) WO2000010581A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004501095A (ja) * 2000-05-11 2004-01-15 アンスティテュ　ナショナール　ド　ラ　ルシェルシュ　アグロノミク 消化器系障害の予防または治療のための水素依存性酢酸生成株の使用
CN112335798A (zh) * 2019-08-08 2021-02-09 徐州新奥生物科技有限公司 饲料用组合物及其制备方法和应用
CN114698750A (zh) * 2022-04-20 2022-07-05 潍坊柯能生物科技有限公司 一种水产饲料复合短链脂肪酸靶向抗菌产品及其应用方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5248169B1 (fr) * 1968-12-03 1977-12-08
JPS61158995A (ja) * 1984-12-28 1986-07-18 Takara Shironaga 脂肪肝，胆石，胃粘膜障害発生の予防薬または治療薬
EP0456418A2 (fr) * 1990-05-07 1991-11-13 Kabushiki Kaisha Miyarisan Seibutsu Igaku Kenkyusho Traitement de diarrhée à Clostridium difficile de colite pseudomembranaire
JPH04264032A (ja) * 1991-02-18 1992-09-18 Miyarisan Seibutsu Igaku Kenkyusho:Kk しゃ下剤組成物
JPH05262657A (ja) * 1992-01-22 1993-10-12 Miyarisan Seibutsu Igaku Kenkyusho:Kk 酪酸菌含有液剤の製造法
JPH06166626A (ja) * 1992-05-12 1994-06-14 Taiyo Kagaku Co Ltd 生菌粉末

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5248169B1 (fr) * 1968-12-03 1977-12-08
JPS61158995A (ja) * 1984-12-28 1986-07-18 Takara Shironaga 脂肪肝，胆石，胃粘膜障害発生の予防薬または治療薬
EP0456418A2 (fr) * 1990-05-07 1991-11-13 Kabushiki Kaisha Miyarisan Seibutsu Igaku Kenkyusho Traitement de diarrhée à Clostridium difficile de colite pseudomembranaire
JPH04264032A (ja) * 1991-02-18 1992-09-18 Miyarisan Seibutsu Igaku Kenkyusho:Kk しゃ下剤組成物
JPH05262657A (ja) * 1992-01-22 1993-10-12 Miyarisan Seibutsu Igaku Kenkyusho:Kk 酪酸菌含有液剤の製造法
JPH06166626A (ja) * 1992-05-12 1994-06-14 Taiyo Kagaku Co Ltd 生菌粉末

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 110, Columbus, Ohio, US; abstract no. 147260, ITSUKI FUJITA ET AL.: "Effects of Berberine Chloride on Viability of Intestinal Controller Clostridium Butyricum Miyari II588" *
CHEMICAL ABSTRACTS, vol. 118, Columbus, Ohio, US; abstract no. 45772 *
CHEMICAL ABSTRACTS, vol. 120, Columbus, Ohio, US; abstract no. 62277 *
CHEMICAL ABSTRACTS, vol. 121, Columbus, Ohio, US; abstract no. 187295 *
CHEMICAL ABSTRACTS, vol. 88, Columbus, Ohio, US; abstract no. 94810 *
PHARMACEUTICS AND TREATMENT, vol. 17, no. 1, 1989, pages 185 - 189 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004501095A (ja) * 2000-05-11 2004-01-15 アンスティテュ　ナショナール　ド　ラ　ルシェルシュ　アグロノミク 消化器系障害の予防または治療のための水素依存性酢酸生成株の使用
CN112335798A (zh) * 2019-08-08 2021-02-09 徐州新奥生物科技有限公司 饲料用组合物及其制备方法和应用
CN114698750A (zh) * 2022-04-20 2022-07-05 潍坊柯能生物科技有限公司 一种水产饲料复合短链脂肪酸靶向抗菌产品及其应用方法
CN114698750B (zh) * 2022-04-20 2023-08-25 潍坊柯能生物科技有限公司 一种水产饲料复合短链脂肪酸靶向抗菌产品及其应用方法

Also Published As

Publication number Publication date
AU5301399A (en) 2000-03-14

Similar Documents

Publication Publication Date Title
Kanauchi et al. Modification of intestinal flora in the treatment of inflammatory bowel disease
US6241983B1 (en) Bacteria-and fiber-containing composition for human gastrointestinal health
US6180099B1 (en) Method of using immunoglobulin and fiber-containing compositions for human health
BR112012008005B1 (pt) composição compreendendo cepas de lactobacillus plantarum
JP2010120945A (ja) 栄養性の改良されたイヌリン製品
JP2002508772A (ja) 健康補助剤
JP2010248185A (ja) 血糖降下作用増強剤
US20160354387A1 (en) Pharmaceutical composition based on a hepatoprotector and a prebiotic, and production and application thereof
US20090311227A1 (en) Composition
JP3746522B2 (ja) イネ科植物の発芽種子由来のタンパク質および不溶性食物センイを含有する物質並びにその用途
US20040197352A1 (en) Methods of improving or augmenting kidney function
US7026160B2 (en) Oral bacteriotherapy compositions and methods
KR102000170B1 (ko) 체지방 감소 및 장관면역활성 증진을 위한 건강보조식품
WO2000010581A1 (fr) Medicaments comprenant une combinaison d'une bacterie produisant de l'acide butyrique, et d'un constituant d'acide biliaire
CN110869035B (zh) 沙氏别样杆菌在制备预防和/或治疗脂质代谢性相关疾病组合物中的应用
JPH08509211A (ja) 菌、卵白及びにんにくの２種以上を含有する免疫賦活・感染防御剤
JPS62103022A (ja) 化学療法剤の副作用低減化剤
WO2006038613A1 (fr) Composition orale contenant un anhydride de difructose
US10398717B2 (en) Pharmaceutical composition based on a hepatoprotector and prebiotic, and method for administrating
US6488969B1 (en) Method for reducing blood ammonia concentration
JP3572103B2 (ja) 二次胆汁酸低下剤
KR100523661B1 (ko) 결장 내에서 프로피온산 및/또는 프로피오네이트를생성하기 위한 프로피온 박테리아의 용도
CN106974940B (zh) 厚壁菌类益生菌在治疗和预防肥胖及其相关疾病中的应用
AU774675B2 (en) Compositions and methods for human gastrointestinal health
US20170014443A1 (en) Compositions and methods for treating gastrointestinal disorders for humans and animal husbandry

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase