[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO1995032720A1 - Composition for treating gastrointestinal disorders - Google Patents

Composition for treating gastrointestinal disorders Download PDF

Info

Publication number
WO1995032720A1
WO1995032720A1 PCT/AU1995/000319 AU9500319W WO9532720A1 WO 1995032720 A1 WO1995032720 A1 WO 1995032720A1 AU 9500319 W AU9500319 W AU 9500319W WO 9532720 A1 WO9532720 A1 WO 9532720A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
lactobacillus
bismuth
composition
bacteria
Prior art date
Application number
PCT/AU1995/000319
Other languages
French (fr)
Inventor
Gregory Murray Winn
John Benjamin Borushek
Original Assignee
Hybrid Scientific Pty. 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 Hybrid Scientific Pty. Ltd. filed Critical Hybrid Scientific Pty. Ltd.
Priority to AU25578/95A priority Critical patent/AU2557895A/en
Publication of WO1995032720A1 publication Critical patent/WO1995032720A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
    • A23C9/13—Fermented milk preparations; Treatment using microorganisms or enzymes using additives
    • A23C9/1322—Inorganic compounds; Minerals, including organic salts thereof, oligo-elements; Amino-acids, peptides, protein-hydrolysates or derivatives; Nucleic acids or derivatives; Yeast extract or autolysate; Vitamins; Antibiotics; Bacteriocins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • 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
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients

Definitions

  • This invention relates to compositions and methods for the symptomatic treatment or amelioration of gastrointestinal disease induced by pathogenic infection.
  • Gastrointestinal disorders may arise in the upper or lower gastrointestinal tract or both.
  • causes of gastrointestinal disorders include genetic, physiological, environmental and psychogenic factors. In view of this, the diagnosis and management of such disorders can be exceptionally difficult.
  • ulcers are those which may be generally categorised as causing gastritis and more particularly peptic ulcer disease (especially in the lower gastrointestinal tract).
  • Gastritis is, typified by inflammation of the stomach mucosa. In practice this disorder manifests itself in symptoms such as dyspepsia, indigestion, heartburn and excessive reflux disorders.
  • Peptic ulcers on the other hand manifest themselves as lesions of the gastrointestinal tract lining and are often characterised by loss of tissue due to the action of digestive acids and pepsin. They are thought to be caused either by gastric hyposecretion or more often by decreased resistance of the gastric lining to digestive acids and pepsin. Approximately twenty per cent of the world's population suffers from these chronic disease states.
  • sufferers obtained temporary symptomatic relief from the disease states caused by Helicobacter pylori with anti-acid drugs.
  • This form of treatment alleviates the gastritis but does not remove the underlying causative agent, viz the bacteria.
  • healing is often followed by a relapse of the disease after about 6-12 weeks resulting in inflammation often leading to ulcers again.
  • patients must stay on the anti-acid treatment for life otherwise the gastritis will often return.
  • antibiotic combinations include tinidazole, amoxicillin and metronidazole.
  • Antibiotic combinations are a powerful form of treatment which generally kill the helicobacter in situ after which the gastritis goes away naturally.
  • side effects of such combinations include nausea, devastation of the microflora in the gastrointestinal tract leading to a microflora imbalance and occasionally diarrhoea.
  • treatment with an appropriate antibiotic combination will clear the pathogen, recurrence of infection occasionally >ccurs within one to six months following drug therapy.
  • devastion of the microflora in the gastrointestinal tract often leaves the patient susceptible to other forms of bacterial attack.
  • Bismuth salts Such compounds have been used to treat various Helicobacter induced diseases, including gastritis and peptic ulcers. Bismuth therapy is as effective as anti-acids, but much cheaper.
  • i_ vitro Helicobacter pylori is inhibited by bismuth compounds at concentrations of 25 mg/L or less. In biopsies taken two hours after ingestion of bismuth compounds marked changes are evident in the Helicobacter pylori bacteria and in their relationship to a patient's epithelium. Many of the organisms appear irregular or fragmented or show structural degradation and deposits of electron- dense material are often present on the external surface and to a lesser extent, within the damaged bacteria.
  • compositions comprising bismuth and bacteria from the genus Lactobacillus species and or Bifidobacterium are effective in treating or ameliorating gastrointestinal disorders induced by pathogenic agents.
  • the present invention provides a substantially natural cure or affords lower relapse rates of gastritis and peptic ulcer disease as compared to other methods of treatment.
  • the present invention consists in a composition effective in treating or ameliorating gastrointestinal disorders caused by a pathogenic agent, the said composition comprising;
  • compositions of the present invention are employed to treat gastrointestinal disorders caused by Helicobacter bacteria colonising the gastrointestinal tract. More preferably the present invention is used to treat gastrointestinal disorders caused by Helicobacter pylori.
  • the bismuth salt is preferably administered as a pharmaceutically acceptable salt.
  • Bismuth salts that may be used in the present invention include; for example, bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, bismuth subgalate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, tripotassium dicitrato bismuthate or any other colloidal or soluble bismuth salt.
  • the pharmaceutically acceptable bismuth salt is bismuth citrate, bismuth subcitrate, bismuth tartrate, bismuth subsalicylcate or tripotassium dicitrate bismuthate.
  • Bismuth salts are preferably administered in dose amounts of between 1 and 5000 mg and more preferably between about 50 and 1500 mg per dosage form depending on the age and weight of the person and severity of the gastrointestinal disorder that needs to be treated. More preferably the dose is between 100 and 500 mg per dosage form.
  • a typical dosage amount of Bismuth subcitrate effective in treating Helicobacter pylori infection in an adult human would be about 100-200 mg administered two to three times daily.
  • the most common recommended therapeutic Lactobacillus are Lactobacillus acidophilus, Lactobacillus casei and Lactobacillus bul ⁇ aricus.
  • Lactobacillus acidophillus should not be mixed with Lactobacillus bul ⁇ aricus. Lactobacillus fermentum, Lactobacillus helveticus. or Lactobacillus plantarium.
  • Bifidobacterium bacteria that may be used in the present invention include: Bifidobacterium bifidum. Bifidobacterium adolescentis. Bifidobacterium breve. Bifidobacterium infantis and Bifidobacterium longum.
  • the bacterial species employed in the composition is either Lactobacillus acidophilus or Bifidobacterium bifidum of both.
  • the bacteria may be employed in either a freeze dried or live culture form.
  • the bacterial is provided in a freeze dried form.
  • the bacteria is preferably provided as a live culture.
  • Gastrointestinal disorders that may be treated by the present invention include but are not limited to; non-ulcerated disorders such as chronic or atrophic gastritis; non-ulcerative dyspepsia; oesophogeal reflux disorders; gastric motility disorders; peptic ulcer disease such as duodenal ulcers, gastric ulcers, jejunal ulcers or gastric cancer.
  • the composition of the present invention will normally be administered as a pharmaceutical composition in combination with a pharmaceutically acceptable carrier therefore.
  • the composition may have added thereto other pharmacological active compounds known to be useful in treating gastrointestinal disorders.
  • the composition may include antacid compounds such as pH buffering agents that are capable of neutralising acid pH build up (eg magnesium trisilicate or aluminium hydroxide gel); H 2 receptor antagonists such as omeprazole, cimetidine, or ranitidine that suppress acid production by the cells of the stomach mucosa; rafting compounds that increase the viscocity of the gastrointestinal content particularly in the stomach; mucus membrane stomach protectants such as sucralfate; or mucilaginous agents or dispersants that would be effective in dispersing and settling the stomach, reducing gastric reflux and coating the stomach and intestines with the composition.
  • antacid compounds such as pH buffering agents that are capable of neutralising acid pH build up (eg magnesium trisilicate or aluminium hydroxide gel); H 2 receptor antagonist
  • the present invention may also include antiulcer agents or adhesion inhibitors of helicobacter pylori comprising for example fucoidan or a phaeophyceae chordariales nemacystus extract containing fucoidan where the fucoidan is optionally degraded.
  • Fucoidan is an extract of red or brown algae that prevents ulcers on the gastric mucosa by inhibiting adhesion of helicobacter pylori to the gastric mucosa.
  • the composition may additionally include one or more antimicrobial agents.
  • an antimicrobial agent is included in the composition then preferably the Lactobacillus and/or Bifidobacterium bacteria are encapsulated in slow release microcapsules which are degraded by acid pH. Any means of microencapsulation known in the art may be employed for this purpose. Desirably, both the bismuth salt and the bacteria are encapsulated in slow release microcapsules. In this form the antimicrobial agent is able to effectively inhibit helicobacter pylori activity prior to the release of the composition of the present invention.
  • Antimicrobial agents which may be employed in such a composition include; gentamycin, neomycin, kanamycin, streptomycin, erythromycin, clindamycin, rifampin, penicillin, ampicillin, amoxycillin, bacitracin, polymyxin, tetracyclin, chlortetracycline, oxyteracycline, doxycycline, cephalexin, cephalothin, chloramphenicol, sulphonamides, nitrofurazone, nitrofuractoin, furozolidone, metronidazole, tinidazole, nimorazole and mixtures thereof.
  • Highly preferred antimicrobial agents include erythromycin, penicillin, ampicillin, amoxycillin, doxycycline, nitrofuratoin, metranidazole and tinidazole.
  • composition of the invention is not microencapsulated then it is desirable to minimise or avoid the simultaneous presence of the present invention when used in combination with an antimicrobial agent. This may for example be achieved by staggering the administration of these agents.
  • the antimicrobial agent may be administered via an alternative means to oral administration. Any means which would facilitate such administration may be employed.
  • the present invention includes an antimicrobial agent, then that agent is preferably provided in a dosage of about 100 to 10000 mg per day and preferably about 100 and 1000 mg per day depending on the age and weight of the person and the severity of the gastrointestinal disorder to be treated.
  • the specific preferred quantity of antimicrobical agent, and the duration of treatment with the composition (when containing such an agent) will, in addition to other factors depend upon the particular antimicrobial used and its pharmacology. Further, the speed of degradation of the slow release microcapsules should be varied to account for the pharmacological effect of the antimicrobial and the duration of effect which the selected antimicrobial has on the patient.
  • compositions of the present invention will be made in a dosage unit form appropriate to the desired mode of administration.
  • a dosage unit form appropriate to the desired mode of administration.
  • a dosage unit form appropriate to the desired mode of administration.
  • compositions may be in a form suitable for oral use.
  • aqueous or oily suspensions dispensable powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art. Further, such compositions may contain one or more agents selected from a group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide a pharmaceutical elegant and palatable preparation.
  • Tablets may for example contain the composition in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of such tablets.
  • excipients may be inert diluents, for example lactose, calcium phosphate, calcium carbonate, sodium phosphate; granulating or disintegrating agents, for example maze, starch, or alginic acid; binding agents such as starch, gelatine or acacia; and lubricating agents such as magnesium stearate or stearic acid.
  • Such tablets may be uncoated or they may be coated by known techniques to prolong dispersal and absorption into the gastrointestinal tract thereby providing a sustained action for a longer period.
  • Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solic diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medium such as arachis oil or liquid paraffin or olive oil.
  • an inert solic diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as arachis oil or liquid paraffin or olive oil.
  • Aqueous suspensions may for example contain the active ingredients in admixture with excipients suitable for the manufacture of such suspensions.
  • Excipients suitable for use in the invention might include for example suspending agents such as sodium carboxymethyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, mucillagenous gums (eg plant gum); dispersing or wetting agents such as naturally occurring phosphatides or condensation products of an alkaline oxide with fatty acid or for example polyoxyethylene stearate or condensation products of ethylene oxide with long chain aliphatic alcohols.
  • the composition may also contain one or more preservatives, colouring agents, flavouring agents or sweetening agents.
  • Syrups and elixirs may also be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavouring and colouring agents.
  • composition of this invention may be used by administering the composition from 1 to 10 times per day or every alternate day for a period of between 3 to 28 days.
  • the frequency of administration will largely depend upon the specific bismuth salts used, the physicological state and viability of the bacteria, whether the composition contains such additives as antimicrobial agents, the concentration or amounts in which the components are included in the composition, the nature and severity of the condition to be treated, and the nature of any concurrent therapy (if any).
  • a food supplement effective in treating or ameliorating gastrointestinal disorders caused by a pathogenic agent comprising:
  • the food supplement is provided in a yoghurt or ice cream mixture.
  • the food supplement may be combined with any other food base that will mix with the supplement.
  • the bacteria in the composition is preferably Lactobacillus acidophillus and or Bifidobacterium bifidum.
  • H. pylori Helicobacter pylori
  • a formulation was prepared containing bismuth subcitrate (500mg) and Lactobacillus acidophilus (750 mg) as freeze dried viable bacteria.
  • the composition was mixed and provided in capsules with a base of 1 % by weight of whey, and microcrystalline cellulose.
  • composition according to the present invention is made comprising:
  • composition is made by simply admixing the components and then pressing them into tablets using conventional methods.
  • the composition is then administered to a human subject having gastritis or peptic ulcer lesions three times daily for fourteen days.
  • composition according to the present invention is made comprising:
  • composition is made by simply admixing the components and then pressing them into tablets using conventional methods.
  • the composition is then administered to a human subject having gastritis or peptic ulcer lesions, two or three times daily for two to three weeks.
  • composition according to the present invention is prepared comprising:
  • composition is made by simply admixing the components and adding them to a capsule using convention methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions, three times daily for two weeks.
  • a composition according to the present invention is prepared comprising: Bismuth carbonate 0.5 gm
  • Lactobacillus acidophilus 0.4 gm
  • composition is made by simply admixing the components and then pressing them into a tablet using conventional methods.
  • the composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
  • composition according to the present invention is prepared comprising: Bismuth sub-citrate 0.6 gm
  • composition is made by simply admixing the components and then pressing them into a tablet using conventional methods.
  • the composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks.
  • composition according to the present invention is prepared comprising:
  • composition is made by simply admixing the components and then pressing them into a tablet using conventional methods.
  • the composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
  • composition according to the present invention is prepared comprising:
  • composition is made by simply admixing the components and then pressing them into a tablet using conventional methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks.
  • composition according to the present invention is prepared comprising:
  • composition is made by simply admixing the components and then pressing them into a tablet using conventional methods.
  • the composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
  • composition according to the present invention is prepared comprising:
  • Lactobacillus acidophilus 0.2 gm
  • composition is made by simply admixing the components and then pressing them into a tablet using conventional methods.
  • the composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
  • composition according to the present invention is prepared comprising: Bismuth sub-citrate 0.12 gm
  • composition is made by simply admixing the components and then pressing them into a tablet using conventional methods.
  • the composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
  • composition according to the present invention is prepared comprising:
  • composition is made by simply admixing the components and then pressing them into a tablet using conventional methods.
  • the composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
  • a food supplement according to the present invention is prepared comprising:
  • the food supplement is made by simply admixing the components.
  • the supplement is then ingested by a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks.
  • a food supplement according to the present invention is prepared comprising:
  • the food supplement is made by simply admixing the components.
  • the supplement is then ingested by a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Mycology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Nutrition Science (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to compositions and methods for the symptomatic treatment of gastrointestinal disease by pathogenic infection. The composition comprising: (i) a bismuth salt in an amount effective for treating the gastrointestinal disorder; and (ii) at least a bacteria selected from the genus Lactobacillus and/or Bidobacterium.

Description

"COMPOSITION FOR TREATING GASTROINTESTINAL DISORDERS"
This invention relates to compositions and methods for the symptomatic treatment or amelioration of gastrointestinal disease induced by pathogenic infection.
Factors which adversely affect the function of the gastrointestinal system in mammals are diverse in their nature. Gastrointestinal disorders may arise in the upper or lower gastrointestinal tract or both. Causes of gastrointestinal disorders include genetic, physiological, environmental and psychogenic factors. In view of this, the diagnosis and management of such disorders can be exceptionally difficult.
Among the chronic disorders which may be found in the gastrointestinal tract (ie the mouth, oesophagus, stomach, duodenum, jejunum and ilium) are those which may be generally categorised as causing gastritis and more particularly peptic ulcer disease (especially in the lower gastrointestinal tract). Gastritis is, typified by inflammation of the stomach mucosa. In practice this disorder manifests itself in symptoms such as dyspepsia, indigestion, heartburn and excessive reflux disorders. Peptic ulcers on the other hand manifest themselves as lesions of the gastrointestinal tract lining and are often characterised by loss of tissue due to the action of digestive acids and pepsin. They are thought to be caused either by gastric hyposecretion or more often by decreased resistance of the gastric lining to digestive acids and pepsin. Approximately twenty per cent of the world's population suffers from these chronic disease states.
Many of the disorders affecting the gastrointestinal tract are induced by bacteria such as those in the genus Helicobacter. For example, Type B gastritis has been directly linked to Helicobacter pylori infection. Further, the frequency of isolating Helicobacter pylori from patients with duodenal ulcers is near to one hundred per cent and from patients with gastric ulcers near to ninety seven per cent. Helicobacter pylori bacteria are now recognised as one of the major aetiological agents of peptic ulcer disease. There is also accumulating evidence that this bacteria plays a role in the pathogenesis of gastric cancer.
In developed countries about ten per cent of 20 year olds and forty percent of adults by the age of 50 suffer from gastritis or peptic ulcer diseases. In under developed countries such diseases are far more prevalent, with up to eighteen percent of 10 year olds, fifty five percent of 30 year olds and seventy five percent of 50 year olds being infected with Helicobacter bacteria.
Helicobacter pylori was first discovered in 1982 in Western Australia. Medical attention is now focused on this bacteria and the disease states that it induces. Increasing public awareness has created a demand for both effective diagnosis and treatment of this bacteria.
Historically, sufferers obtained temporary symptomatic relief from the disease states caused by Helicobacter pylori with anti-acid drugs. This form of treatment alleviates the gastritis but does not remove the underlying causative agent, viz the bacteria. Thus healing is often followed by a relapse of the disease after about 6-12 weeks resulting in inflammation often leading to ulcers again. As a result patients must stay on the anti-acid treatment for life otherwise the gastritis will often return.
More recently the treatment of helicobacter induced diseases has revolved around the use of antibiotic combinations. Particular antibiotics that have been shown to be effective against for example, Helicobacter pylori, include tinidazole, amoxicillin and metronidazole. Antibiotic combinations are a powerful form of treatment which generally kill the helicobacter in situ after which the gastritis goes away naturally. However, the side effects of such combinations include nausea, devastation of the microflora in the gastrointestinal tract leading to a microflora imbalance and occasionally diarrhoea. Although treatment with an appropriate antibiotic combination will clear the pathogen, recurrence of infection occasionally >ccurs within one to six months following drug therapy. Furthermore, devastion of the microflora in the gastrointestinal tract often leaves the patient susceptible to other forms of bacterial attack.
Another form of treatment that has been shown to be effective against Helicobacter infection involves the use of Bismuth salts. Such compounds have been used to treat various Helicobacter induced diseases, including gastritis and peptic ulcers. Bismuth therapy is as effective as anti-acids, but much cheaper. i_ vitro. Helicobacter pylori is inhibited by bismuth compounds at concentrations of 25 mg/L or less. In biopsies taken two hours after ingestion of bismuth compounds marked changes are evident in the Helicobacter pylori bacteria and in their relationship to a patient's epithelium. Many of the organisms appear irregular or fragmented or show structural degradation and deposits of electron- dense material are often present on the external surface and to a lesser extent, within the damaged bacteria. It has been suggested by various authorities that the apparent concentration of bismuth complexes in the vicinity of the bacteria may perhaps be explained by a change in pH from alkaline to acid immediately adjacent to the bacteria, once the latter become metabolically inhibited. Even though such compounds have a significant metabolic effect on He!: obacter pylori bacteria, bismuth salts alone cure only about thirty per cent of patients infected with this bacteria.
Recently an alternative form of Helicobacter treatment has been proposed which employs a mixture of bismuth salts and an antimicrobial agent such as tinidazole, tetracycline, metronidazole and/or amoxicillin. Such mixtures can achieve a cure rate of eighty to ninety per cent of patients in two to four weeks. However there are contra indications and problems with resistance to such therapies. This treatment can be highly effective but in the case of patient non compliance the effectiveness falls to below sixty per cent. According to the present invention it has now been found that compositions comprising bismuth and bacteria from the genus Lactobacillus species and or Bifidobacterium are effective in treating or ameliorating gastrointestinal disorders induced by pathogenic agents. In particular, the present invention provides a substantially natural cure or affords lower relapse rates of gastritis and peptic ulcer disease as compared to other methods of treatment.
Thus the present invention consists in a composition effective in treating or ameliorating gastrointestinal disorders caused by a pathogenic agent, the said composition comprising;
(i) a bismuth salt in an amount effective for treating the gastrointestinal disorder; and
(ii) at least a bacteria selected from the genus Lactobacillus and or Bifidobacterium.
Preferably compositions of the present invention are employed to treat gastrointestinal disorders caused by Helicobacter bacteria colonising the gastrointestinal tract. More preferably the present invention is used to treat gastrointestinal disorders caused by Helicobacter pylori.
Although the precise methods by which the present invention effects pathogen induced gastrointestinal disorders, such as those cause by Helicobacter pylori, is still under investigation, it is thought that bismuth salts and the Lactobacillus and or Bifidobacterium bacteria in combination inhibit the growth of the pathogen thereby allowing the Lactobacillus or Bifidobacterium bacteria to displace the pathogen and colonise the gastrointestinal mucosa in competition with the pathogen. This provides one explanation for the lower relapse rates observed during testing of the present invention since these organisms appear to contribute to stabilisation of the microflora in the gastrointestinal tract and maintain the colonisation resistance against further pathogenic attack.
In the composition of this invention, the bismuth salt is preferably administered as a pharmaceutically acceptable salt. Bismuth salts that may be used in the present invention include; for example, bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, bismuth subgalate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, tripotassium dicitrato bismuthate or any other colloidal or soluble bismuth salt. Preferably the pharmaceutically acceptable bismuth salt is bismuth citrate, bismuth subcitrate, bismuth tartrate, bismuth subsalicylcate or tripotassium dicitrate bismuthate.
Bismuth salts are preferably administered in dose amounts of between 1 and 5000 mg and more preferably between about 50 and 1500 mg per dosage form depending on the age and weight of the person and severity of the gastrointestinal disorder that needs to be treated. More preferably the dose is between 100 and 500 mg per dosage form. For example a typical dosage amount of Bismuth subcitrate effective in treating Helicobacter pylori infection in an adult human would be about 100-200 mg administered two to three times daily.
Bacteria that may be used in the present invention should be selected from the genus Lactobacillus and Bifidobacterium. Lactobacillus bacteria that may be used in the present invention include: Lactobacillus casei. Lactobacillus acidophilus. Lactobacillus plantarium. Lactobacillus helveticus. Lactobacillus bulαaricus. Lactobacillus brevis. Lactobacillus buchneri. and Lactobacillus fermenti. Preferably a combination of Lactobacillus bacteria are used in the composition. The most common recommended therapeutic Lactobacillus are Lactobacillus acidophilus, Lactobacillus casei and Lactobacillus bulαaricus. To avoid unnecessary competition between the Lactobacillus bacteria when in situ in a patient Lactobacillus acidophillus should not be mixed with Lactobacillus bulαaricus. Lactobacillus fermentum, Lactobacillus helveticus. or Lactobacillus plantarium.
Bifidobacterium bacteria that may be used in the present invention include: Bifidobacterium bifidum. Bifidobacterium adolescentis. Bifidobacterium breve. Bifidobacterium infantis and Bifidobacterium longum.
In a highly preferred form of the invention the bacterial species employed in the composition is either Lactobacillus acidophilus or Bifidobacterium bifidum of both.
The bacteria may be employed in either a freeze dried or live culture form. Preferably when the composition is formed as tablets or capsules, the bacterial is provided in a freeze dried form. On the other hand when the composition is provided as a food supplement, in for example yoghurt or ice cream, the bacteria is preferably provided as a live culture.
Gastrointestinal disorders that may be treated by the present invention include but are not limited to; non-ulcerated disorders such as chronic or atrophic gastritis; non-ulcerative dyspepsia; oesophogeal reflux disorders; gastric motility disorders; peptic ulcer disease such as duodenal ulcers, gastric ulcers, jejunal ulcers or gastric cancer.
For therapeutic use the composition of the present invention will normally be administered as a pharmaceutical composition in combination with a pharmaceutically acceptable carrier therefore. In addition, the composition may have added thereto other pharmacological active compounds known to be useful in treating gastrointestinal disorders. For example the composition may include antacid compounds such as pH buffering agents that are capable of neutralising acid pH build up (eg magnesium trisilicate or aluminium hydroxide gel); H2 receptor antagonists such as omeprazole, cimetidine, or ranitidine that suppress acid production by the cells of the stomach mucosa; rafting compounds that increase the viscocity of the gastrointestinal content particularly in the stomach; mucus membrane stomach protectants such as sucralfate; or mucilaginous agents or dispersants that would be effective in dispersing and settling the stomach, reducing gastric reflux and coating the stomach and intestines with the composition.
In addition to the above, the present invention may also include antiulcer agents or adhesion inhibitors of helicobacter pylori comprising for example fucoidan or a phaeophyceae chordariales nemacystus extract containing fucoidan where the fucoidan is optionally degraded. Fucoidan is an extract of red or brown algae that prevents ulcers on the gastric mucosa by inhibiting adhesion of helicobacter pylori to the gastric mucosa.
Depending on the severity of infection, the composition may additionally include one or more antimicrobial agents. When an antimicrobial agent is included in the composition then preferably the Lactobacillus and/or Bifidobacterium bacteria are encapsulated in slow release microcapsules which are degraded by acid pH. Any means of microencapsulation known in the art may be employed for this purpose. Desirably, both the bismuth salt and the bacteria are encapsulated in slow release microcapsules. In this form the antimicrobial agent is able to effectively inhibit helicobacter pylori activity prior to the release of the composition of the present invention. Antimicrobial agents which may be employed in such a composition include; gentamycin, neomycin, kanamycin, streptomycin, erythromycin, clindamycin, rifampin, penicillin, ampicillin, amoxycillin, bacitracin, polymyxin, tetracyclin, chlortetracycline, oxyteracycline, doxycycline, cephalexin, cephalothin, chloramphenicol, sulphonamides, nitrofurazone, nitrofuractoin, furozolidone, metronidazole, tinidazole, nimorazole and mixtures thereof. Highly preferred antimicrobial agents include erythromycin, penicillin, ampicillin, amoxycillin, doxycycline, nitrofuratoin, metranidazole and tinidazole.
The presence of bismuth is known to adversely affect the efficiency of some antimicrobial agents. Further antimicrobial agents are known to inhibit Lactobacillus and Bifidobacteria growth. If the composition of the invention is not microencapsulated then it is desirable to minimise or avoid the simultaneous presence of the present invention when used in combination with an antimicrobial agent. This may for example be achieved by staggering the administration of these agents. Alternatively, the antimicrobial agent may be administered via an alternative means to oral administration. Any means which would facilitate such administration may be employed.
If the present invention includes an antimicrobial agent, then that agent is preferably provided in a dosage of about 100 to 10000 mg per day and preferably about 100 and 1000 mg per day depending on the age and weight of the person and the severity of the gastrointestinal disorder to be treated.
The specific preferred quantity of antimicrobical agent, and the duration of treatment with the composition (when containing such an agent) will, in addition to other factors depend upon the particular antimicrobial used and its pharmacology. Further, the speed of degradation of the slow release microcapsules should be varied to account for the pharmacological effect of the antimicrobial and the duration of effect which the selected antimicrobial has on the patient.
Advantageously compositions of the present invention will be made in a dosage unit form appropriate to the desired mode of administration. For example, as a tablet, capsule, sustained released type, oral suspension or any form of food supplement suitable for combination with the composition of the present invention.
Desirably when the composition is formulated as either tablets or capsules it contains a dispersant to aid in effective distribution of the composition throughout the gastrointestinal tract. The pharmaceutical compositions may be in a form suitable for oral use. For example, as tablets, lozenges, aqueous or oily suspensions, dispensable powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art. Further, such compositions may contain one or more agents selected from a group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide a pharmaceutical elegant and palatable preparation.
Tablets may for example contain the composition in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of such tablets. Such excipients may be inert diluents, for example lactose, calcium phosphate, calcium carbonate, sodium phosphate; granulating or disintegrating agents, for example maze, starch, or alginic acid; binding agents such as starch, gelatine or acacia; and lubricating agents such as magnesium stearate or stearic acid. Such tablets may be uncoated or they may be coated by known techniques to prolong dispersal and absorption into the gastrointestinal tract thereby providing a sustained action for a longer period.
Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solic diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medium such as arachis oil or liquid paraffin or olive oil.
Aqueous suspensions may for example contain the active ingredients in admixture with excipients suitable for the manufacture of such suspensions. Excipients suitable for use in the invention might include for example suspending agents such as sodium carboxymethyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, mucillagenous gums (eg plant gum); dispersing or wetting agents such as naturally occurring phosphatides or condensation products of an alkaline oxide with fatty acid or for example polyoxyethylene stearate or condensation products of ethylene oxide with long chain aliphatic alcohols. The composition may also contain one or more preservatives, colouring agents, flavouring agents or sweetening agents.
Syrups and elixirs may also be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavouring and colouring agents.
The composition of this invention may be used by administering the composition from 1 to 10 times per day or every alternate day for a period of between 3 to 28 days. The frequency of administration will largely depend upon the specific bismuth salts used, the physicological state and viability of the bacteria, whether the composition contains such additives as antimicrobial agents, the concentration or amounts in which the components are included in the composition, the nature and severity of the condition to be treated, and the nature of any concurrent therapy (if any).
In another from the present invention may form a food supplement effective in treating or ameliorating gastrointestinal disorders caused by a pathogenic agent, the food supplement comprising:
(i) at least a bismuth salt in an amount effective for treating the gastrointestinal disorder; and
(ii) at least a bacteria selected from the genus Lactobacillus and or
Bifidobacteria.
Preferably the food supplement is provided in a yoghurt or ice cream mixture. However it will be appreciated that the food supplement may be combined with any other food base that will mix with the supplement. When formed as a food supplement the bacteria in the composition is preferably Lactobacillus acidophillus and or Bifidobacterium bifidum. The present invention will now be described by way of the following examples. The examples are presented by way of illustration only.
Example 1
A panel of 15 volunteers were selected from among working colleagues. Ten of these volunteers presented with gastric disturbance that could be associated with Helicobacter pylori (H. pylori) gastritis. To ascertain and confirm the presence of H. pylori infection, a blood screen was used to identify antibodies to H. pylori. The volunteers were not informed of their results.
Of the 15 volunteers, 9 showed a raised titre to H. pylori using a UREASE ELIZA technique. The other 5 volunteers underwent a blind trial to check symptomology during the treatment. Typically, serum levels take 4-5 weeks to fall to normal following successful treatment.
A formulation was prepared containing bismuth subcitrate (500mg) and Lactobacillus acidophilus (750 mg) as freeze dried viable bacteria. The composition was mixed and provided in capsules with a base of 1 % by weight of whey, and microcrystalline cellulose.
All volunteers were given the treatment to compare activity. The formulation was provided three times per day for 2 weeks. Weekly monitoring of serum anti H. pylori antibodies showed a falling titre at about three weeks. After 5 weeks 6 volunteers had exhibited a titre that had fallen to a level accepted as negative and two others titres had fallen to a level regarded as a weak positive reaction. Side effects were minimal and no evidence of gastric disturbance or lower gastrointestinal discomfort and disturbance (ie like that associated with antibiotic treatment) was observed.
Those volunteers who originally had no observable raised anti H. pylori titre did not suffer any ill effects from the composition and showed no gastric discomfort. One patient who was H. pylori negative, and had mild occasional gastric episodes, appeared to show no ill effects and indeed ceased to suffer further symptoms. In this case the Lactobacillus had been effective in normalising his gastrointestinal microflora so reducing any minor discomfort he had previously suffered.
Although the formulation was tested on a small number of volunteers, it was evidence that the formulation induced an anti Helicobacter effect with few side effect. From this assessment it can be seen that the effects of the combined treatment is at least as effective in treating H. pylori as Colloidal Bismuth salts and more so as it had the combined effect of the Lactobacillus stabilising and normalising lower gastrointestinal tract microflora.
Example 2
A composition according to the present invention is made comprising:
Bismuth carbonate 0.3 gm
Lactobacillus acidophilus 0.01 gm Microcrystalline cellulose, whey and Magnesium stearate 10 mg
The composition is made by simply admixing the components and then pressing them into tablets using conventional methods. The composition is then administered to a human subject having gastritis or peptic ulcer lesions three times daily for fourteen days.
Example 3
A composition according to the present invention is made comprising:
Bismuth carbonate 2.5 gm
Lactobacillus acidophilus 1.5 gm (or Bifidobacteria bifida 1.5 gm)
Microcrystalline cellulose 50 mg Magnesium Stearate
The composition is made by simply admixing the components and then pressing them into tablets using conventional methods. The composition is then administered to a human subject having gastritis or peptic ulcer lesions, two or three times daily for two to three weeks.
Example 4
A composition according to the present invention is prepared comprising:
Bismuth carbonate 0.75 gm
Lactobacillus acidophilus 0.75 gm
Bicarbonate soda .50 mg
The composition is made by simply admixing the components and adding them to a capsule using convention methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions, three times daily for two weeks.
Example 5
A composition according to the present invention is prepared comprising: Bismuth carbonate 0.5 gm
Lactobacillus acidophilus 0.4 gm
Bifidobacteria bifidum 0.4 gm
Bicarbonate soda 50 mg
The composition is made by simply admixing the components and then pressing them into a tablet using conventional methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
Example 6
A composition according to the present invention is prepared comprising: Bismuth sub-citrate 0.6 gm
Lactobacillus acidophilus 0.75 gm
Whey powder, malt and maltose dextran 10 mg
The composition is made by simply admixing the components and then pressing them into a tablet using conventional methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks.
Example 7
A composition according to the present invention is prepared comprising:
Bismuth sub-citrate 1 gm Lactobacillus acidophilus 0.5 gm
Bifidobacteria bifidum 0.5 gm
Magnesium Stearate 20 mg
The composition is made by simply admixing the components and then pressing them into a tablet using conventional methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
Example 8
A composition according to the present invention is prepared comprising:
Bismuth sub-citrate 0.12 gm
Lactobacillus acidophilus 0.1 gm Bifidobacteria bifidum 0.1 gm
Omeprazole 7 mg
Whey powder, malt and maltose dextran 10 mg
The composition is made by simply admixing the components and then pressing them into a tablet using conventional methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks Example 9
A composition according to the present invention is prepared comprising:
Bismuth sub-citrate 0.9 gm
Lactobacillus acidophilus 0.1 gm
Bifidobacteria bifidum 0.1 gm
Cimetidine 70 mg
Magnesium Stearate 20 mg
The composition is made by simply admixing the components and then pressing them into a tablet using conventional methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
Example 10
A composition according to the present invention is prepared comprising:
Bismuth sub-citrate 0.5 gm
Lactobacillus acidophilus 0.2 gm
Bifidobacteria bifidum 0.2 gm
Ranitidine 50 mg Whey powder, malt and microcrystalline cellulose 10 mg
Magnesium Stearate 20 mg
The composition is made by simply admixing the components and then pressing them into a tablet using conventional methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
Example 11
A composition according to the present invention is prepared comprising: Bismuth sub-citrate 0.12 gm
Lactobacillus acidophilus 0.1 gm
Bifidobacteria bifidum 0.1 gm
Sucralfate 1 gm
Whey powder, malt and maltose dextran 10 mg
The composition is made by simply admixing the components and then pressing them into a tablet using conventional methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
Example 13
A composition according to the present invention is prepared comprising:
Bismuth sub-citrate 0.12 gm
Lactobacillus acidophilus 0.1 gm
Bifidobacteria bifidum 0.1 gm Magnesium trisilicate 0.1 gm
Magnesium Stearate 20 mg
The composition is made by simply admixing the components and then pressing them into a tablet using conventional methods. The composition is then administered to a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks
Example 14
A food supplement according to the present invention is prepared comprising:
Bismuth sub-citrate 0.75 gm
Lactobacillus acidophilus 50 gm
Bifidobacteria bifidum 50 gm Yoghurt 100ml
The food supplement is made by simply admixing the components. The supplement is then ingested by a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks Example 15
A food supplement according to the present invention is prepared comprising:
Bismuth sub-citrate 1 gm
Lactobacillus acidophilus 100 gm
Bifidobacteria bifidum 100 gm
Yoghurt 500ml
The food supplement is made by simply admixing the components. The supplement is then ingested by a human patient suffering from gastritis or peptic ulcer lesions three times daily for two weeks

Claims

1The CLAIMS defining the invention are as follows:
1. A composition effective in treating or ameliorating gastrointestinal disorders caused by a pathogenic agent, the composition comprising:
(i) at least a bismuth salt in an amount effective for treating the gastrointestinal disorder; and
(ii) at least a bacteria selected from the genus Lactobacillus and or Bifidobacteria.
2. A composition according to claim 1 wherein the composition is effective in treating or ameliorating gastrointestinal disorders caused by Helicobacter bacteria.
3. A composition according to claim 1 wherein the composition is effective in treating or ameliorating gastrointestinal disorders caused by Helicobacter pylori.
4. A composition according to claim 1 wherein the bismuth salt is selected from the group consisting of: bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, bismuth subgalate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, tripotassium dicitrato bismuthate.
5. A composition according to claim 4 wherein the bismuth salt is one of the following compounds: bismuth citrate, bismuth subcitrate, bismuth tartrate, bismuth subsalicylcate or tripotassium dicitrate bismuthate.
6. A composition according to any one of claims 1 to 5 wherein there are a plurality of bismuth salts provided in the composition.
7. A composition according to any one of claims 1 to 6 wherein the bismuth salt is provided in an amount of about 1 to about 5000 mg per dosage form.
8. A composition according to claims 7 wherein the bismuth salt is provided in an amount of about 50 to about 1500 mg per dosage form.
ψ 5
9. A composition according to claims 8 wherein the bismuth salt is provided in an amount of about 100 to about 750 mg per dosage form.
10. A composition according to any one of the preceding claims wherein the bacteria in the composition is a member of the genus Lactobacillus.
10
11. A composition according to claim 10 wherein the Lactobacillus bacteria are selected from the group consisting of: Lactobacillus casei. Lactobacillus acidophilus. Lactobacillus plantarium, Lactobacillus helveticus. Lactobacillus bulαaricus. Lactobacillus brevis. Lactobacillus buchneri. or Lactobacillus
15 fermenti.
12. A composition according to claim 11 wherein the Lactobacillus bacteria is one of the following bacteria: Lactobacillus acidophilus, Lactobacillus casei or Lactobacillus bulgaricus.
13. A composition according to claim 12 wherein the Lactobacillus bacteria is 20 Lactobacillus acidophilus.
14. A composition according to any one of claims 1 to 9 wherein the bacteria in the composition is Bifidobacteria.
25 15. A composition according to claim 14 wherein the Bifidobacteria bacteria is selected from the group consisting of: Bifidobacterium bifidum. Bifidobacterium adolescentis. Bifidobacterium breve, Bifidobacterium infantis and Bifidobacterium longum.
16. A composition according to claim 12 wherein the Bifidobacteria bacteria is Bifidobacterium bifidum.
17. A composition according to any one of claims 1 to 9 wherein the composition contains both Lactobacillus bacteria and Bifidobacteria bacteria.
18. A composition according to claim 17 wherein the composition contains Lactobacillus acidophilus and Bifidobacterium bifidum.
19. A composition according to any one of the preceding claims wherein the bacteria is provided in an amount of about 5 to 5000 mg per dosage form.
20. A composition according claim 19 wherein the bacteria is provided in an amount of about 100 to 2000 mg per dosage form.
21. A composition according claim 20 wherein the bacteria is provided in an amount of about 100 to 700 mg per dosage form.
22. A composition according to any one of the preceding claims which additionally comprises an antacid.
23. A composition according to claim 22 wherein the antacid is selected from the group consisting of: magnesium trisilicate or aluminium hydroxide gel.
24. A composition according to any one of the preceding claims which additionally comprises an H2 receptor antagonist.
25. A composition according to claim 24 wherein the H2 receptor antagonist is selected from the group consisting of: omeprazole, cimetidine or ranitidine.
26. A composition according to any one of the preceding claims which additionally comprises an agent that has the effect of increasing the viscosity of the gastrointestinal contents.
27. A composition according to any one of the preceding claims which additionally comprises a dispersant that is capable of dispersing the composition over the gastrointestinal lining.
28. A composition according to any one of the preceding claims which additionally comprises an antimicrobial agent selected from the group consisting of gentamycin, neomycin, kanamycin, streptomycin, erythromycin, clindamycin, rifampin, penicillin, ampicillin, amoxycillin, bacitracin, polymyxin, tetracyclin, chlortetracycline, oxyteracycline, doxycycline, cephalexin, cephalothin, chloramphenicol, sulphonamides, nitrofurazone, nitrofuractoin, furozolidone, metronidazole, tinidazole or nimorazole.
29. A composition according to claim 28 wherein the composition of claim 1 is contained in microcapsules and thereby separated from the antimicrobial agent.
30. A food supplement effective in treating or ameliorating gastrointestinal disorders caused by a pathogenic agent, the food supplement comprising:
(i) at least a bismuth salt in an amount effective for treating the gastrointestinal disorder; and
(ii) at least a bacteria selected from the genus Lactobacillus and or Bifidobacteria.
31. A food supplement according to claim 30 wherein the supplement is combined with yoghurt.
32. A food supplement according to claim 31 wherein the Lactobacillus bacteria is Lactobacillus acidophilus and Bifidobacterium bifidum.
PCT/AU1995/000319 1994-05-30 1995-05-30 Composition for treating gastrointestinal disorders WO1995032720A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25578/95A AU2557895A (en) 1994-05-30 1995-05-30 Composition for treating gastrointestinal disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPM5968A AUPM596894A0 (en) 1994-05-30 1994-05-30 Composition for treating gastrointestinal disorders - a combination of bismuth salts plus lactobacillus or bifidobacteria species bacteria for treating gastrointestinal disorders
AUPM5968 1994-05-30

Publications (1)

Publication Number Publication Date
WO1995032720A1 true WO1995032720A1 (en) 1995-12-07

Family

ID=3780543

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1995/000319 WO1995032720A1 (en) 1994-05-30 1995-05-30 Composition for treating gastrointestinal disorders

Country Status (2)

Country Link
AU (2) AUPM596894A0 (en)
WO (1) WO1995032720A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995034292A2 (en) * 1994-06-14 1995-12-21 Recordati S.A. Chemical And Pharmaceutical Company Stabilized biologically active compounds contained in coated microgranules which can be suspended in alimentary fluids
US5702729A (en) * 1995-12-07 1997-12-30 The Procter & Gamble Company Methods for the prevention and treatment of gastrointestinal disorders caused or mediated by algae or cyanobacteria
US5744168A (en) * 1995-12-07 1998-04-28 The Procter & Gamble Company Methods and compositions for the prevention and treatment of gastrointestinal disorders
WO1998023272A1 (en) * 1996-11-27 1998-06-04 The Procter & Gamble Company Compositions and methods for the treatment of gastrointestinal disorders
US5827543A (en) * 1995-12-07 1998-10-27 The Procter & Gamble Company Methods and compositions for the prevention and treatment of urogenital disorders
US5882686A (en) * 1995-12-07 1999-03-16 The Procter & Gamble Company Methods for the prevention and treatment of urogenital disorders
WO1999042568A1 (en) * 1998-02-20 1999-08-26 Mendes S.R.L. Use of bacteria endowed with arginine deiminase to induce apoptosis and/or reduce an inflammatory reaction and pharmaceutical or dietetic compositions containing such bacteria
US6051604A (en) * 1995-12-07 2000-04-18 The Proctor & Gamble Company Methods and compositions for the prevention and treatment of gastrointestinal disorders
US6183776B1 (en) 1996-01-08 2001-02-06 Astra Aktiebolag Oral pharmaceutical dosage forms comprising a proton pump inhibitor and an antacid agent or alginate
WO2002005829A2 (en) * 2000-07-17 2002-01-24 Chr. Hansen A/S Methods and formultations with probiotic microorganisms and medicaments
EP1941888A1 (en) * 2005-09-26 2008-07-09 Ako Kasei Co., Ltd. Method of inhibiting the proliferation and migration of helicobacter pylori
WO2009134948A1 (en) * 2008-05-01 2009-11-05 The Procter & Gamble Company Methods and kits for the treatment of inflammatory bowel disorder conditions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR6779M (en) * 1967-07-19 1969-03-10
FR6929M (en) * 1967-11-29 1969-05-05
FR2566664A1 (en) * 1984-06-29 1986-01-03 Nelson Res & Dev Compsn. for treatment of diarrhoea

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR6779M (en) * 1967-07-19 1969-03-10
FR6929M (en) * 1967-11-29 1969-05-05
FR2566664A1 (en) * 1984-06-29 1986-01-03 Nelson Res & Dev Compsn. for treatment of diarrhoea

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995034292A3 (en) * 1994-06-14 2001-12-06 Recordati Chem Pharm Stabilized biologically active compounds contained in coated microgranules which can be suspended in alimentary fluids
WO1995034292A2 (en) * 1994-06-14 1995-12-21 Recordati S.A. Chemical And Pharmaceutical Company Stabilized biologically active compounds contained in coated microgranules which can be suspended in alimentary fluids
US6051604A (en) * 1995-12-07 2000-04-18 The Proctor & Gamble Company Methods and compositions for the prevention and treatment of gastrointestinal disorders
US5702729A (en) * 1995-12-07 1997-12-30 The Procter & Gamble Company Methods for the prevention and treatment of gastrointestinal disorders caused or mediated by algae or cyanobacteria
US5744168A (en) * 1995-12-07 1998-04-28 The Procter & Gamble Company Methods and compositions for the prevention and treatment of gastrointestinal disorders
US5827543A (en) * 1995-12-07 1998-10-27 The Procter & Gamble Company Methods and compositions for the prevention and treatment of urogenital disorders
US5882686A (en) * 1995-12-07 1999-03-16 The Procter & Gamble Company Methods for the prevention and treatment of urogenital disorders
US6183776B1 (en) 1996-01-08 2001-02-06 Astra Aktiebolag Oral pharmaceutical dosage forms comprising a proton pump inhibitor and an antacid agent or alginate
WO1998023272A1 (en) * 1996-11-27 1998-06-04 The Procter & Gamble Company Compositions and methods for the treatment of gastrointestinal disorders
WO1999042568A1 (en) * 1998-02-20 1999-08-26 Mendes S.R.L. Use of bacteria endowed with arginine deiminase to induce apoptosis and/or reduce an inflammatory reaction and pharmaceutical or dietetic compositions containing such bacteria
AU754483B2 (en) * 1998-02-20 2002-11-14 Actial Farmaceutica S.R.L. Use of bacteria endowed with arginine deiminase to induce apoptosis and/or reduce an inflammatory reaction and pharmaceutical or dietetic compositions containing such bacteria
US6572854B1 (en) 1998-02-20 2003-06-03 Mendes S.R.L. Use of bacteria endowed with arginine deiminase to induce apoptosis and/or reduce an inflammatory reaction and pharmaceutical or dietetic compositions containing such bacteria
US7147847B2 (en) 1998-02-20 2006-12-12 Vsl Pharmaceuticals, Inc. Use of bacteria endowed with arginine deiminase to induce apoptosis and/or reduce an inflammatory reaction and pharmaceutical or dietetic compositions containing such bacteria
WO2002005829A2 (en) * 2000-07-17 2002-01-24 Chr. Hansen A/S Methods and formultations with probiotic microorganisms and medicaments
WO2002005829A3 (en) * 2000-07-17 2002-05-02 Hansens Lab Methods and formultations with probiotic microorganisms and medicaments
EP1941888A1 (en) * 2005-09-26 2008-07-09 Ako Kasei Co., Ltd. Method of inhibiting the proliferation and migration of helicobacter pylori
EP1941888A4 (en) * 2005-09-26 2012-05-30 Ako Kasei Co Ltd Method of inhibiting the proliferation and migration of helicobacter pylori
WO2009134948A1 (en) * 2008-05-01 2009-11-05 The Procter & Gamble Company Methods and kits for the treatment of inflammatory bowel disorder conditions

Also Published As

Publication number Publication date
AUPM596894A0 (en) 1994-06-23
AU2557895A (en) 1995-12-21

Similar Documents

Publication Publication Date Title
RU2685226C2 (en) Composition containing probiotic bacteria capable of restoring the barrier effect of the stomach, lost in process of pharmacological treatment of increased acidity of the stomach
US5229137A (en) Methods and pharmaceutical compositions for treating episodic heartburn
JP2733849B2 (en) Improved method for treating gastrointestinal disorders
US20120053239A1 (en) Treatment for intestinal gas, bloating, microscopic colitis, inflammatory bowel disease and traveler's diarrhea using colloidal bismuth subcitrate
AU773459B2 (en) Dietary or pharmaceutical composition for use for the prevention or treatment of hyperoxaluria
US20100247489A1 (en) Use of a composition made of mineral nutrients and optionally acetogenic and/or butyrogenic bacteria in order to avoid or reduce the formation of gas in the large intestine of a mammal and the resulting abdominal problems
AU590578B2 (en) Treatment of non-ulcer dyspepsia with bismuth salts
JPS6248623A (en) Method and composition for treating gastro-intestinal disease
JP2003500451A5 (en)
AU719090B2 (en) Oral preparation for the prophylactic and therapeutic treatment of helicobacter sp. infection
WO1995032720A1 (en) Composition for treating gastrointestinal disorders
EP0282132A2 (en) Compositions and their use for treating gastrointestinal disorders
JP4981208B2 (en) Taurolidine and / or taurultam for infectious ulcers or gastritis
KR100282166B1 (en) Pharmaceutical Bacteriocin Compositions
JPH0692850A (en) Remedy for gastrointestinal disturbance
US4689229A (en) Gastrointestinal compositions
RU2737891C2 (en) Use of antibiotics with specific therapeutic activities in combination with simultaneous use of lactobacilli and/or bifidobacteria with non-transient resistance to antibiotics having the same therapeutic value
JPH07242560A (en) Antimicrobial
RU2182008C1 (en) Perorally, rectally or intravaginally injected composition containing alive bacteria
CN116036123A (en) Compound montmorillonite granule for treating helicobacter pylori infection and preparation method thereof
KR100375342B1 (en) A natural antimicrobial agents for the improvement of gastrointestinal disease.
Miehlke et al. Two-Year Follow Up of Duodenal Ulcer Patients Treated with Omeprazole and Amoxicillin
RU2315596C1 (en) Pharmaceutical composition possessing antiacid and reparative effect, its preparing and using
EP0715520B1 (en) Use of a suspension based on sucralphate gel as antacid
RU2184558C2 (en) Method to treat ulcerous duodenal disease

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

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

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA