WO1998019669A1 - Chewing gum containing colloidal bismuth subcitrate - Google Patents

Chewing gum containing colloidal bismuth subcitrate Download PDF

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Publication number
WO1998019669A1
WO1998019669A1 PCT/US1997/019765 US9719765W WO9819669A1 WO 1998019669 A1 WO1998019669 A1 WO 1998019669A1 US 9719765 W US9719765 W US 9719765W WO 9819669 A1 WO9819669 A1 WO 9819669A1
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WIPO (PCT)
Prior art keywords
bismuth
chewing gum
subcitrate
colloidal
compound
Prior art date
Application number
PCT/US1997/019765
Other languages
French (fr)
Inventor
Narayan K. Athanikar
Original Assignee
Josman Laboratories, Inc.
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 Josman Laboratories, Inc. filed Critical Josman Laboratories, Inc.
Priority to CA002270520A priority Critical patent/CA2270520A1/en
Priority to PL97333101A priority patent/PL333101A1/en
Priority to BR9712730-2A priority patent/BR9712730A/en
Priority to AU50976/98A priority patent/AU730881B2/en
Priority to HU0000163A priority patent/HUP0000163A3/en
Priority to EP97913910A priority patent/EP0956007A4/en
Priority to IL12959997A priority patent/IL129599A0/en
Priority to RO99-00502A priority patent/RO117415B1/en
Publication of WO1998019669A1 publication Critical patent/WO1998019669A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/28Compounds containing heavy metals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/28Compounds containing heavy metals
    • A61K31/29Antimony or bismuth compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/425Thiazoles
    • A61K31/429Thiazoles condensed with heterocyclic ring systems
    • A61K31/43Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/245Bismuth; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42Amides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64Proteins; Peptides; Derivatives or degradation products thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/88Polyamides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058Chewing gums
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005Antimicrobial preparations

Definitions

  • This invention relates to chewing gum compositions containing active ingredients. More particularly, this invention relates to producing chewing gums that contain compounds for treating ulcers and halitosis.
  • Chewing gum compositions typically, include a water soluble bulk portion, a water insoluble chewing gum base portion and water insoluble flavoring agents.
  • chewing gum compositions can be formulated to provide the delivery of active agents.
  • active agents may be a variety of breath fresheners, or medicaments, such as laxatives, aspirin or nicotine. Delivering these medicaments through a chewing gum vehicle is desirable for people who have difficulty swallowing pills. Also, the bad taste of some of the agents may be disguised by stronger flavoring agents in the chewing gum, which may make gum a suitable vehicle for delivery of certain medicines.
  • H2-receptor blockers such as cimetidine (Tagamet®) and Ranitidine (Zantac®), suppress acid secretion and have been used to treat and heal duodenal ulcers.
  • H2-receptor blockers do not eliminate the Helicobacter pylori bacteria ("H. pylori"). These drugs do not reverse the tendency for ulcers to form.
  • bismuth compounds have been used in swallowable tablet form and liquid form for treating ulcers.
  • the therapeutic efficacy of bismuth compounds such as colloidal bismuth subcitrate, CBS, (also known as tripotassium dicitrato bismuthate), in healing duodenal ulcers and lowering relapse rates is attributed to its specific antibacterial activity against H. pylori.
  • CBS colloidal bismuth subcitrate
  • H. pylori eradication rates of about 10 to 40% has been reported.
  • patients would suffer a relapse of ulcers after discontinuing taking the bismuth compounds.
  • the present invention is related to development of a chewing gum formulation to effectively eradicate H. pylori colonies without the need for combination antibiotic therapies.
  • This invention is related to a chewing gum formulation containing a water soluble bulk portion, a water insoluble chewing gum base portion, a flavoring agent, and compounds selected from the group consisting of colloidal bismuth subcitrate, bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, bismuth aluminate, and combinations thereof.
  • This chewing gum has been found to eradicate or reduce H.
  • the invention further provides for a method of treating H. pylori infection by the administration of a chewing gum containing an amount of bismuth in a bismuth-containing compound equivalent to between about 10 and 200 milligrams of colloidal bismuth subcitrate.
  • the invention further provides for the method of treating halitosis by the administration of a chewing gum containing bismuth compounds.
  • chewing gum compositions include a water soluble bulk portion, a water insoluble chewing gum base portion and, typically, water insoluble flavoring agents.
  • the water soluble portion dissipates with a portion of the flavoring agents over a period of time during chewing.
  • the gum base portion is retained in the mouth throughout the chewing process.
  • the insoluble gum base generally includes elastomers, resins, fats, oils, waxes, softeners and inorganic fillers.
  • the elastomers may include polyisobutylene, isobutylene-isoprene copolymer, styrene butadiene rubber and natural latexes such as chicle.
  • the resins may include polyvinyl acetate and terpene resins. Low molecular weight polyvinyl acetate is a preferred resin.
  • Fats and oils may include animal fats such as lard and tallow, vegetable oils such as soybean and cottonseed oils, hydrogenated and partially hydrogenated vegetable oils, and cocoa butter.
  • waxes include petroleum waxes such as paraffin and microcrystalline wax, natural waxes such as paraffin and microcrystalline wax, natural waxes such as beeswax, candellia, carnauba and polyethylene wax.
  • the waxes Preferably, the waxes have a melting point between 95° F. and
  • the gum base typically also includes a filler component such as calcium carbonate, magnesium carbonate, talc, dicalcium phosphate and the like; elastomers, including glycerol monostearate and glycerol triacetate; and optional ingredients such as antioxidants, colors and emulsifiers.
  • the gum base constitutes between 5 and 95% by weight of the chewing gum composition, more typically 10-50% by weight of the chewing gum, and commonly 25-35%) by weight of the chewing gum.
  • the water soluble portion of the chewing gum may include softeners, bulk sweeteners, high intensity sweeteners and combinations thereof. Softeners are added to the chewing gum in order to optimize the chewability and mouth feel of the gum.
  • the softeners which are also known as plasticizers or plasticizing agents, generally constitute between about 0.5-15% by weight of the chewing gum.
  • the softeners may include glycerin, lecithin, and combinations thereof.
  • the softeners may also include aqueous sweetener solutions such as those containing sorbitol, hydrogenated starch hydrolysates, corn syrup and combinations thereof.
  • Bulk sweeteners constitute between 20-80% by weight of the chewing gum and may include both sugar and sugarless sweeteners and components.
  • Sugar sweeteners may include saccharide containing components including but not limited to sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose levulose, galactose, corn syrup solids, and the like, alone or in combination.
  • Sugarless sweeteners include components with sweetening characteristics but are devoid of the commonly known sugars.
  • Sugarless sweeteners include but are not limited to sugar alcohols such as sorbitol, mannitol, xylitol, hydrogenated, starch hydrolysates, maltitol, and the like, alone or in combination.
  • High intensity sweeteners may also be present. These may include but are not limited to sucralose, aspartarne, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, dihydrochalcones, thaumatin, monellin, and the like, alone or in combination.
  • Combinations of sugar and/or sugarless sweeteners may be used in chewing gum.
  • the sweetener may also function in the chewing gun in whole or in part as a water soluble bulking agent. Additionally, the softener may also provide additional sweetness such as with aqueous sugar or alditol solutions.
  • One or more flavoring agents are generally present in the chewing gum in an amount within the range of about 0.1-10% by weight of the chewing gum, preferably between about 0.5-3% by weight of the chewing gum.
  • the flavoring agents may include essential oils, synthetic flavors or mixtures thereof including but not limited to oils derived from plants and fruits such as citrus oils, fruit essences, peppermint oil, spearmint oil, other mint oils, clove oil, oil of wintergreen, anise and the like.
  • Artificial flavoring agents and components may also be used. Natural and artificial flavoring agents may be combined in any sensorally acceptable fashion. All such flavors and flavor blends are contemplated by the present invention.
  • the active pharmaceutical agents in this chewing gum formulation of this invention include non-H2 antagonist bismuth compounds.
  • These bismuth compounds include colloidal bismuth subcitrate (CBS), bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, and bismuth aluminate.
  • CBS colloidal bismuth subcitrate
  • bismuth citrate bismuth subcitrate
  • bismuth subcitrate bismuth salicylate
  • bismuth subsalicylate bismuth subnitrate
  • bismuth subcarbonate bismuth tartrate
  • bismuth subgallate bismuth aluminate
  • the bismuth compound is selected from Colloidal Bismuth Subcitrate
  • CBS Colloidal Bismuth Subcitrate
  • Colloidal bismuth subcitrate and other bismuth compounds may be coated, micro-encapsulated, or agglomerated before incorporating in the chewing gum formulation to further cause the slow dissolution and sustained concentration of the compounds in the saliva.
  • the polymers used for coating or encapsulation may include methylcellulose, carboxymethylcellulose, hydroxy-propylmethylcellulose, ethylcellulose, carbowax, polyethyleneglycols, acrylic polymers, to name a few.
  • CBS can be coated with a coating solution containing hydroxy-propylcellulose and polyethylene glycol in hydro-alcoholic solvent employing a fluid-bed coating equipment. The coated
  • CBS particles should be assayed for CBS content and dissolution characteristics.
  • the chewing gum formulation containing bismuth compounds be capable of releasing the drug in a precise and reproducible fashion during a fifteen- minute chewing time. Preparing the bismuth compound using any of the above techniques may achieve such uniform release.
  • the chewing gum formulations may also include anti-plaque agents.
  • the anti- plaque agents further contribute to improved efficacy by breaking down the plaque and exposing the H. pylori bacterial colonies to the anti-bacterial agents.
  • Anti-plaque agents include, but are not limited to, glucanase anhydroglucosidase, glucose oxidase, calcium kaolin, silicone oil, sanguinarine, and the like.
  • an antibiotic such as metronidazole
  • a preferred form of the chewing gum comprises an active pharmaceutical agent that consists essentially of a bismuth compound selected from the group consisting of colloidal bismuth subcitrate (CBS), bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, and bismuth aluminate.
  • CBS colloidal bismuth subcitrate
  • CBS colloidal bismuth subcitrate
  • bismuth citrate bismuth subcitrate
  • bismuth salicylate bismuth subsalicylate
  • bismuth subnitrate bismuth subcarbonate
  • bismuth tartrate bismuth subgallate
  • bismuth aluminate bismuth aluminate
  • Chewing gum is generally manufactured by sequentially adding the various chewing gum ingredients to any commercially available mixer known in the art. Generally, the ingredients are mixed by first melting the gum base and adding it to the running mixer. The gum base may alternatively be melted in the mixer. Color and emulsifiers can be added at this time. A softener such as glycerin can be added next along with syrup and part of the bulk portion. Further parts of the bulk portion may then be added to the mixer. The flavoring agent, pharmaceutical agent, and other optional ingredients of this ilk, are typically added with the final part of the bulk portion. The entire mixing process typically takes from five to fifteen minutes, although longer mixing times are sometimes required. Those skilled in the art will recognize that variations of this mixing procedure, or other mixing procedures, may be followed.
  • the gum mass is discharged from the mixer and shaped into the desired form such as by rolling into sheets and cutting into sticks, extruding into chunks, or casting into pellets.
  • Pellet or ball gum is prepared as conventional chewing gum, but formed either into pellets that are pillow- shaped or into balls.
  • the pellets/balls can then be coated or panned by conventional panning techniques to make a unique sugar-coated pellet gum.
  • Conventional panning procedures generally apply a liquid coating to a pellet, which is then solidified, usually by drying the coating.
  • the hard-shell coating layer is built up by successive coating and drying steps.
  • panning modifiers including, but not limited to, gum arabic, maltodextrins, corn syrup, gelatin, cellulose type materials like carboxymethyl cellulose or hydroxymethyl cellulose, starch and modified starches, vegetable gums like alginates, locust bean gum, guar gum, and gum tragacanth, insoluble carbonates like calcium carbonate or magnesium carbonate, and talc.
  • Antitack agents may also be added as panning modifiers, which allow the use of a variety of carbohydrates and sugar alcohols to be used in the development of new panned or coated gum products. Flavors may also be added with the sugar coating and with the bulk sweetener to yield unique product characteristics.
  • the chewing gum formulation of the present invention is superior to conventional therapy for treating ulcers. It turns out that the conventional bismuth therapy was shown to be only somewhat effective in eliminating H. pylori from the gastric mucosa, but had no effect on the H. pylori colonies in dental plaque. Colloidal bismuth subcitrate (CBS), an effective agent against H. pylori, however, is not absorbed significantly from the gastrointestinal tract, and therefore produces insufficient salivary concentrations through systemic recycling to affect H. pylori in the mouth. This continued presence of H. pylori in the dental plaque, and possibly the throat and esophagus, raises the question of whether the relapse of ulcers was inevitable with conventional bismuth therapy.
  • CBS Colloidal bismuth subcitrate
  • Chewing gum formulations in this invention have since been shown to be therapeutically effective in clinical studies.
  • the chewing gum releases enough bismuth into saliva for eradication of H. pylori in the oral cavity.
  • the rninimum inhibitory concentration (MIC) of bismuth for H. pylori varies for each bismuth compound. For instance, it is established that the MIC of CBS for H. pylori is 8 ⁇ g/mL, and its range is 4 to 32 ⁇ g/mL. Therefore, to ensure its effectiveness, the chewing gum formulation preferably releases bismuth into saliva up to at least 2 times the MIC, preferably a minimum of 2 to 10 times the MIC, most preferably 2 to 250 times the MIC.
  • the bismuth content per dosage of chewing gum can be between about 3.5 mg and about 75 mg, preferably between about 3.5 mg and about 37 mg, more preferably between about 9 mg and about 28 mg.
  • the amount of bismuth-containing compound per dosage thus is determined by the bismuth content of that particular compound.
  • each piece of CBS-containing chewing gum may contain between about 10 mg and about 200 mg of CBS, preferably between about 10 mg and about 100 mg, and more preferably between about 25 mg and about 75 mg. Accordingly, each piece of gum may include amounts of other bismuth compounds that provide the same bismuth equivalent as the aforementioned ranges of CBS.
  • the amount of bismuth compound in each piece may be halved so that a person would chew on two pieces at a time to have the same effective amount of bismuth.
  • the chewing gum should be chewed multiple times throughout the day to prevent the H. pylori colonies from returning to their original size.
  • the chewing gum will be administered in sequential doses of between one and ten times per day, more preferably between two and six times per day.
  • the chewing gum administered may comprise an active pharmaceutical agent that consists essentially of a bismuth compound selected from the group consisting of colloidal bismuth subcitrate (CBS), bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, and bismuth aluminate and combinations thereof.
  • CBS colloidal bismuth subcitrate
  • the chewing gum containing a previously described bismuth compound is administered simultaneously (or concomitantly) with a peroral dosage form, such as a swallowable tablet, containing a previously described bismuth compound.
  • the bismuth content of the chewing gum used for the concomitant treatment of the present invention may be the same as that of the chewing gum that is administered by itself.
  • the bismuth content of the swallowable tablet can be equivalent to between about 300 mg - 1200 mg of colloidal bismuth subcitrate per day, preferably.
  • the concomitant treatment can be administered once or twice per day, more preferably once per day.
  • a brief general description of the chewing gum is set forth as follows. Fully melt the gum base (at approximately 90°C) in Bartender mixer, a jacketed mixer with sigma blades. Remove the hot water from the mixer jacket, allow to cool, and add lecithin and mix well. Cool further to approximately 50°C, and add liquid flavor and mannitol. Mix until uniform.
  • Peppermint Oil 25.0 Peppermint Oil 25.0
  • Saliva samples were analyzed for elemental bismuth in ppm units. The results were then converted to ⁇ g of active CBS per mL of saliva, and also expressed as a multiple of minimum inhibitory concentration (MIC) of CBS for H. pylori. As can be seen from the results for formula-2, the salivary concentrations of CBS are about 156, 64, 5, and 1.8 times the MIC at 1, 5, 10 and 15 minutes, respectively. The constant bathing of the oral cavity from saliva containing sufficient concentration of CBS (2 to 5 times the MIC) for up to 15 minutes can be expected to further reduce the population of viable cells of H. pylori.
  • Example 5 Sensory Analysis of Chewing Gum
  • Topical safety was evaluated in the six volunteers for up to 60 minutes after administration of the gum. The subjects were asked to report any adverse effects such as discomfort or irritation in the oral cavity.
  • Example 7 Storage Stability Study
  • the test saliva was prepared by dissolving 0.500 g of colloidal bismuth subcitrate in 100 mL of the above artificial saliva.
  • 500 mL of artificial saliva at room temperature was placed in one of two identical glass jars with lids.
  • 500 mL of the artificial saliva at room temperature containing 0.50% of CBS was placed in each of the jars.
  • the denture material block and a magnetic stirrer was placed in each of the jars. The jars were then placed on the magnetic platform and set to agitate at a minimum rate for four hours.
  • the denture materials that were exposed to artificial saliva containing either CBS or placebo are listed in Table 10 below.
  • the four hour exposure of natural tooth and other denture materials to 0.5% CBS in artificial saliva with mild agitation did not cause any staining, discoloration, or changes in texture.
  • the MERETEK UBTTM (urea breath test kit) from MERETEK Diagnostics, Inc. can be used to detect the presence of H. pylori in the stomach for the diagnosis of ulcers.
  • the patient is given a liquid containing urea that is enriched with the carbon- 13 isotope.
  • H. pylori is a urease positive bacteria. If the carbon- 13 isotope is present in heavy concentrations in later breaths, it signifies the presence of H. pylori in the stomach.
  • Duodenal ulcer patients with a positive urea breath test were randomized into active and placebo groups and entered into a 15-day clinical trial. These patients did not receive any antibiotic therapy during the clinical trial.
  • the patients in the active group received gum containing 50 mg of colloidal bismuth subcitrate per piece.
  • the patients in the placebo group received gum not containing colloidal bismuth subcitrate.
  • the patients were further subdivided into high dose and low dose groups.
  • the patients in the high dose group chewed gum 6 times per day and the patients in the low dose group chewed gum 2 times per day. After 15 days, the urea breath test was repeated. The results are reported in Table 12 below.
  • the average change in urea breath test data was a decrease of 64% in the six patients on the low active dose (range of 22% to 98%).
  • the average change in urea breath test data was a decrease of 91% in the six patients on the high active dose (range of 79% to 98%). 5.
  • Six of six patients in the high active drug group had a decrease (p ⁇ 0.05 by chi- square analysis).
  • VSCs Volatile Sulfur Compounds
  • a halitosis meter can be used to detect the presence of bad breath. This meter uses an analyzer that can detect the levels of VSCs. Most individuals feel that odor is coming from their stomach, when really 80 percent originates from the mouth and tongue. Typically, breath mints, chewing gum, mouth washes and toothpastes that you buy at the store merely mask your bad breath. These breath fresheners are only able to cover up the odor for a short time. In order to permanently eliminate bad breath it is necessary to attack the source of the VSCs.
  • Campylobacter rectus, Helicobacter pylori, and Treponema denticola are bacteria that have been demonstrated to be associated with Halitosis (bad breath).
  • the bismuth- containing compounds and methods of the present invention including CBS as well as ascorbyl bismuth derivative, have demonstrated in vitro activity against all three bacteria, as indicated by their minimum effective concentrations (MICs) presented in Table 13 below.
  • a chewing gum containing CBS should be effective in reducing Halitosis caused by bacteria. It is expected that a person may treat halitosis by chewing gum containing preferably between about 10 mg CBS and about 100 mg CBS, and preferably between about one and four times per day. Also, the chewing gum may contain an amount of bismuth in the aforementioned bismuth compound or combinations thereof equivalent to between about 10 and about 100 milligrams of colloidal bismuth subcitrate.
  • CBS Long term safety of CBS and treatment of peptic ulcers at a standard dose of 480 mg (expressed as bismuthtrioxide) in four daily divided doses has been examined by Bader, Digestion 37(Supplement 2):53-59 (1987), incorporated herein by reference. CBS was first introduced in Europe in 1971 and since that time 1.5 million treatments have been dispensed. During eight years of use of CBS tablets [De-Nol®] in Europe between 1978 and 1986 under a more comprehensive adverse reaction monitoring system, only 13 adverse reaction forms were completed. Five of these adverse reactions were ascribed to CBS: one case of headache, one case of stomach pain, one case of diarrhea, and two cases of allergy (mainly in the form of skin rashes).
  • compositions and methods of the present invention are capable of being incorporated in the form of a variety of embodiments, only a few of which have been illustrated and described above.
  • the invention may be embodied in other forms without departing from spirit or essential characteristics.
  • the described embodiments are to be considered in all respects only as illustrative and not restrictive, and the scope of the invention is, therefore, indicated by the appended claims rather that the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Abstract

The invention provides a chewing gum composition containing a water soluble bulk portion, a water insoluble chewing gum base portion, a flavoring agent, and bismuth-containing compounds. The invention provides a bismuth-containing gum which when chewed multiple times per day, over the period of two weeks, is effective in reducing peptic ulcers by eradicating H. pylori. The chewing gum is also effective in eliminating forms of halitosis. The chewing gum does not have undesirable side effects, unpleasant taste and poor chewing characteristics.

Description

CHEWING GUM CONTAINING COLLOIDAL BISMUTH SUBCITRATE
BACKGROUND OF THE INVENTION
This invention relates to chewing gum compositions containing active ingredients. More particularly, this invention relates to producing chewing gums that contain compounds for treating ulcers and halitosis. Chewing gum compositions, typically, include a water soluble bulk portion, a water insoluble chewing gum base portion and water insoluble flavoring agents. Also, chewing gum compositions can be formulated to provide the delivery of active agents. These active agents may be a variety of breath fresheners, or medicaments, such as laxatives, aspirin or nicotine. Delivering these medicaments through a chewing gum vehicle is desirable for people who have difficulty swallowing pills. Also, the bad taste of some of the agents may be disguised by stronger flavoring agents in the chewing gum, which may make gum a suitable vehicle for delivery of certain medicines. Moreover, some medicines may be absorbed directly into the bloodstream through the tissue lining the mouth, making the medicine more readily available than if absorbed through the gastrointestinal walls. Accordingly, many people can benefit from new discoveries of how to effectively deliver active ingredients through a chewing gum formulation. Unfortunately, many active ingredients are not suitable for administration through a chewing gum for a variety of reasons. A chewing gum cannot be effective if it has unpleasant medicinal taste, causes discoloration in the user's mouth, or the active ingredient causes poor chewing characteristics. A chewing gum cannot be effective if the active ingredient is not readily released from the gum, and thus, not delivered either into the mouth or the stomach where it can be absorbed or act topically. For this reason, many active ingredients may be effectively delivered by chewable tablets, or swallowable tablets, but not by chewing gum. Recent discoveries have associated bacterial infection in the causation of peptic ulcer disease. The bacterium found to be associated with peptic ulcers has been identified as Helicobacter pylori. Excessive gastric acidity and mental stress are no longer thought to be the major pathophysiological reasons for the occurrence of peptic ulcers. Thus, questions regarding the previously established paradigms of and approaches for ulcer treatment and healing processes have been raised.
Previously, ulcers were treated by suppressing secretion of acid in the stomach. H2-receptor blockers, such as cimetidine (Tagamet®) and Ranitidine (Zantac®), suppress acid secretion and have been used to treat and heal duodenal ulcers. However, these H2-receptor blockers do not eliminate the Helicobacter pylori bacteria ("H. pylori"). These drugs do not reverse the tendency for ulcers to form.
For many years bismuth compounds have been used in swallowable tablet form and liquid form for treating ulcers. The therapeutic efficacy of bismuth compounds such as colloidal bismuth subcitrate, CBS, (also known as tripotassium dicitrato bismuthate), in healing duodenal ulcers and lowering relapse rates is attributed to its specific antibacterial activity against H. pylori. However, using bismuth compounds alone, H. pylori eradication rates of about 10 to 40% has been reported. Also, patients would suffer a relapse of ulcers after discontinuing taking the bismuth compounds.
Even though, as a single agent, CBS is significantly more effective in eradicating H. pylori than many other antibiotics, multiple therapies of bismuth compounds combined with other antibiotics have been reported to result in more than a 95% eradication rate for H. pylori and reduced ulcer relapse rate to less than 10% during a twelve-month follow-up period. For example, one such common triple therapy, comprised of CBS, amoxicillin and metronidazole, has been reported to have a high rate of effectiveness. However, it would be desirable to achieve such effectiveness in eradicating H. pylori with simple single agent therapies. No such single agent heretofore has been shown to be effective.
SUMMARY OF THE INVENTION
The present invention, therefore, is related to development of a chewing gum formulation to effectively eradicate H. pylori colonies without the need for combination antibiotic therapies. This invention is related to a chewing gum formulation containing a water soluble bulk portion, a water insoluble chewing gum base portion, a flavoring agent, and compounds selected from the group consisting of colloidal bismuth subcitrate, bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, bismuth aluminate, and combinations thereof. This chewing gum has been found to eradicate or reduce H. pylori in reservoirs in the oral cavity and at the cite of infection and ulceration in the gastric mucosa. The invention further provides for a method of treating H. pylori infection by the administration of a chewing gum containing an amount of bismuth in a bismuth-containing compound equivalent to between about 10 and 200 milligrams of colloidal bismuth subcitrate. The invention further provides for the method of treating halitosis by the administration of a chewing gum containing bismuth compounds.
DETAILED DESCRD?TION OF THE INVENTION
In general, chewing gum compositions include a water soluble bulk portion, a water insoluble chewing gum base portion and, typically, water insoluble flavoring agents. The water soluble portion dissipates with a portion of the flavoring agents over a period of time during chewing. The gum base portion is retained in the mouth throughout the chewing process.
The insoluble gum base generally includes elastomers, resins, fats, oils, waxes, softeners and inorganic fillers. The elastomers may include polyisobutylene, isobutylene-isoprene copolymer, styrene butadiene rubber and natural latexes such as chicle. The resins may include polyvinyl acetate and terpene resins. Low molecular weight polyvinyl acetate is a preferred resin. Fats and oils may include animal fats such as lard and tallow, vegetable oils such as soybean and cottonseed oils, hydrogenated and partially hydrogenated vegetable oils, and cocoa butter. Commonly used waxes include petroleum waxes such as paraffin and microcrystalline wax, natural waxes such as paraffin and microcrystalline wax, natural waxes such as beeswax, candellia, carnauba and polyethylene wax. Preferably, the waxes have a melting point between 95° F. and
240° F.
The gum base typically also includes a filler component such as calcium carbonate, magnesium carbonate, talc, dicalcium phosphate and the like; elastomers, including glycerol monostearate and glycerol triacetate; and optional ingredients such as antioxidants, colors and emulsifiers. The gum base constitutes between 5 and 95% by weight of the chewing gum composition, more typically 10-50% by weight of the chewing gum, and commonly 25-35%) by weight of the chewing gum. The water soluble portion of the chewing gum may include softeners, bulk sweeteners, high intensity sweeteners and combinations thereof. Softeners are added to the chewing gum in order to optimize the chewability and mouth feel of the gum. The softeners, which are also known as plasticizers or plasticizing agents, generally constitute between about 0.5-15% by weight of the chewing gum. The softeners may include glycerin, lecithin, and combinations thereof. The softeners may also include aqueous sweetener solutions such as those containing sorbitol, hydrogenated starch hydrolysates, corn syrup and combinations thereof.
Bulk sweeteners constitute between 20-80% by weight of the chewing gum and may include both sugar and sugarless sweeteners and components. Sugar sweeteners may include saccharide containing components including but not limited to sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose levulose, galactose, corn syrup solids, and the like, alone or in combination. Sugarless sweeteners include components with sweetening characteristics but are devoid of the commonly known sugars. Sugarless sweeteners include but are not limited to sugar alcohols such as sorbitol, mannitol, xylitol, hydrogenated, starch hydrolysates, maltitol, and the like, alone or in combination.
High intensity sweeteners may also be present. These may include but are not limited to sucralose, aspartarne, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, dihydrochalcones, thaumatin, monellin, and the like, alone or in combination.
Combinations of sugar and/or sugarless sweeteners may be used in chewing gum. The sweetener may also function in the chewing gun in whole or in part as a water soluble bulking agent. Additionally, the softener may also provide additional sweetness such as with aqueous sugar or alditol solutions.
One or more flavoring agents are generally present in the chewing gum in an amount within the range of about 0.1-10% by weight of the chewing gum, preferably between about 0.5-3% by weight of the chewing gum. The flavoring agents may include essential oils, synthetic flavors or mixtures thereof including but not limited to oils derived from plants and fruits such as citrus oils, fruit essences, peppermint oil, spearmint oil, other mint oils, clove oil, oil of wintergreen, anise and the like. Artificial flavoring agents and components may also be used. Natural and artificial flavoring agents may be combined in any sensorally acceptable fashion. All such flavors and flavor blends are contemplated by the present invention.
Optional ingredients such as colors, such as titanium dioxide and the like, emulsifiers and pharmaceutical agents may also be included in chewing gum. The active pharmaceutical agents in this chewing gum formulation of this invention include non-H2 antagonist bismuth compounds. These bismuth compounds include colloidal bismuth subcitrate (CBS), bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, and bismuth aluminate. Preferably, the bismuth compound is selected from Colloidal Bismuth Subcitrate
(CBS), bismuth subcitrate, bismuth subsalicylate and their combination. Most preferably, the bismuth compound is Colloidal Bismuth Subcitrate (CBS). The structural formula of CBS is:
[Bi(OH)3]3BiC6H6θ7 (1,2,3-PROPANETRICARBONIC ACID,
2-HYDROXY, BISMUTH(3T)POTASSIUM); CAS#57644-54-9
Colloidal bismuth subcitrate and other bismuth compounds may be coated, micro-encapsulated, or agglomerated before incorporating in the chewing gum formulation to further cause the slow dissolution and sustained concentration of the compounds in the saliva. The polymers used for coating or encapsulation may include methylcellulose, carboxymethylcellulose, hydroxy-propylmethylcellulose, ethylcellulose, carbowax, polyethyleneglycols, acrylic polymers, to name a few. For example, CBS can be coated with a coating solution containing hydroxy-propylcellulose and polyethylene glycol in hydro-alcoholic solvent employing a fluid-bed coating equipment. The coated
CBS particles should be assayed for CBS content and dissolution characteristics.
It is preferred that the chewing gum formulation containing bismuth compounds be capable of releasing the drug in a precise and reproducible fashion during a fifteen- minute chewing time. Preparing the bismuth compound using any of the above techniques may achieve such uniform release.
The chewing gum formulations may also include anti-plaque agents. The anti- plaque agents further contribute to improved efficacy by breaking down the plaque and exposing the H. pylori bacterial colonies to the anti-bacterial agents. Anti-plaque agents include, but are not limited to, glucanase anhydroglucosidase, glucose oxidase, calcium kaolin, silicone oil, sanguinarine, and the like.
Optionally, an antibiotic, such as metronidazole, can be added to the chewing gum formulation to broaden the anti-microbial activity against H. pylori. However, a preferred form of the chewing gum comprises an active pharmaceutical agent that consists essentially of a bismuth compound selected from the group consisting of colloidal bismuth subcitrate (CBS), bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, and bismuth aluminate.
Chewing gum is generally manufactured by sequentially adding the various chewing gum ingredients to any commercially available mixer known in the art. Generally, the ingredients are mixed by first melting the gum base and adding it to the running mixer. The gum base may alternatively be melted in the mixer. Color and emulsifiers can be added at this time. A softener such as glycerin can be added next along with syrup and part of the bulk portion. Further parts of the bulk portion may then be added to the mixer. The flavoring agent, pharmaceutical agent, and other optional ingredients of this ilk, are typically added with the final part of the bulk portion. The entire mixing process typically takes from five to fifteen minutes, although longer mixing times are sometimes required. Those skilled in the art will recognize that variations of this mixing procedure, or other mixing procedures, may be followed.
After the ingredients have been thoroughly mixed, the gum mass is discharged from the mixer and shaped into the desired form such as by rolling into sheets and cutting into sticks, extruding into chunks, or casting into pellets. Pellet or ball gum is prepared as conventional chewing gum, but formed either into pellets that are pillow- shaped or into balls. The pellets/balls can then be coated or panned by conventional panning techniques to make a unique sugar-coated pellet gum. Conventional panning procedures generally apply a liquid coating to a pellet, which is then solidified, usually by drying the coating. The hard-shell coating layer is built up by successive coating and drying steps.
Conventional panning procedures generally coat with sucrose, but recent advances in panning have allowed the use of other carbohydrate materials to be used in the place of sucrose, yet still obtain a hard-shell coating. Some of these components include, but are not limited to, dextrose, maltose, xylitol, lactitol, palatinit and other new alditols or a combination thereof. These materials may be blended with panning modifiers including, but not limited to, gum arabic, maltodextrins, corn syrup, gelatin, cellulose type materials like carboxymethyl cellulose or hydroxymethyl cellulose, starch and modified starches, vegetable gums like alginates, locust bean gum, guar gum, and gum tragacanth, insoluble carbonates like calcium carbonate or magnesium carbonate, and talc. Antitack agents may also be added as panning modifiers, which allow the use of a variety of carbohydrates and sugar alcohols to be used in the development of new panned or coated gum products. Flavors may also be added with the sugar coating and with the bulk sweetener to yield unique product characteristics.
The chewing gum formulation of the present invention is superior to conventional therapy for treating ulcers. It turns out that the conventional bismuth therapy was shown to be only somewhat effective in eliminating H. pylori from the gastric mucosa, but had no effect on the H. pylori colonies in dental plaque. Colloidal bismuth subcitrate (CBS), an effective agent against H. pylori, however, is not absorbed significantly from the gastrointestinal tract, and therefore produces insufficient salivary concentrations through systemic recycling to affect H. pylori in the mouth. This continued presence of H. pylori in the dental plaque, and possibly the throat and esophagus, raises the question of whether the relapse of ulcers was inevitable with conventional bismuth therapy.
Multiple therapies of bismuth compounds combined with other antibiotics have been found to be superior to conventional bismuth therapy. Typical combinations include bismuth subsalicylate, metronidazole and amoxicillin or tetracycline. One possible explanation for the observed clinical efficacy of the antibiotic and bismuth combination that has not been advanced by the scientific community is that the metronidazole is actively secreted in the saliva where it may be exerting anti-microbial action against dental plaque-bound H. pylori colonies that the bismuth compounds administered alone in swallowable tablets cannot reach.
Interestingly, the antibiotics administered as single agents were only partially effective. Even though metronidazole is secreted in the saliva and may eradicate H. pylori in the mouth, it is not effective in single-handedly eradicating H. pylori in the gastric mucosa, i.e., the stomach. Therefore, assuming this explanation is correct, it is reasonable to believe that in order to achieve nearly complete eradication of H. pylori, and prevent relapses of ulcers, it is essential to eradicate the bacterium from the oral cavity, and possibly the throat and esophagus, as well as from the gastric mucosa.
However, it was not known whether bismuth compounds would be therapeutically effective in the oral cavity. In prior use of CBS against ulcers, it was known that CBS undergoes conversion to bismuth trioxide under the influence of gastric acids in the stomach. Conventional wisdom accepted that bismuth trioxide was the active product in the eradication of duodenal H. pylori. Therefore, it was not expected that CBS in a chewing gum would show efficacy in eradicating H. pylori in the mouth. Moreover, it was not known at what dose levels bismuth compounds would provide therapeutic effectiveness, if at all, for topical use in the mouth.
Chewing gum formulations in this invention have since been shown to be therapeutically effective in clinical studies. Preferably, the chewing gum releases enough bismuth into saliva for eradication of H. pylori in the oral cavity. The rninimum inhibitory concentration (MIC) of bismuth for H. pylori varies for each bismuth compound. For instance, it is established that the MIC of CBS for H. pylori is 8 μg/mL, and its range is 4 to 32 μg/mL. Therefore, to ensure its effectiveness, the chewing gum formulation preferably releases bismuth into saliva up to at least 2 times the MIC, preferably a minimum of 2 to 10 times the MIC, most preferably 2 to 250 times the MIC. To achieve these concentrations in the saliva, the bismuth content per dosage of chewing gum can be between about 3.5 mg and about 75 mg, preferably between about 3.5 mg and about 37 mg, more preferably between about 9 mg and about 28 mg. The amount of bismuth-containing compound per dosage thus is determined by the bismuth content of that particular compound. For instance, each piece of CBS-containing chewing gum may contain between about 10 mg and about 200 mg of CBS, preferably between about 10 mg and about 100 mg, and more preferably between about 25 mg and about 75 mg. Accordingly, each piece of gum may include amounts of other bismuth compounds that provide the same bismuth equivalent as the aforementioned ranges of CBS. Of course, the amount of bismuth compound in each piece may be halved so that a person would chew on two pieces at a time to have the same effective amount of bismuth. Also, the chewing gum should be chewed multiple times throughout the day to prevent the H. pylori colonies from returning to their original size. Preferably, the chewing gum will be administered in sequential doses of between one and ten times per day, more preferably between two and six times per day. Also, the chewing gum administered may comprise an active pharmaceutical agent that consists essentially of a bismuth compound selected from the group consisting of colloidal bismuth subcitrate (CBS), bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, and bismuth aluminate and combinations thereof.
In another embodiment of the present invention, the chewing gum containing a previously described bismuth compound is administered simultaneously (or concomitantly) with a peroral dosage form, such as a swallowable tablet, containing a previously described bismuth compound.
The bismuth content of the chewing gum used for the concomitant treatment of the present invention may be the same as that of the chewing gum that is administered by itself. The bismuth content of the swallowable tablet can be equivalent to between about 300 mg - 1200 mg of colloidal bismuth subcitrate per day, preferably. The concomitant treatment can be administered once or twice per day, more preferably once per day.
A wide range of changes and modifications to the embodiments of the invention described above will be apparent to persons skilled in the art. The following examples are not to be construed as imposing limitations on the invention, but are included merely to illustrate preferred embodiments. Example 1 - Preparation of Active Agent
To an aqueous solution of ammonia are added bismuth citrate, citric acid, and caustic potash in specific stoichiometric proportions, and at specific temperatures. The solution is examined for turbidity and, if required, additional volume of ammonia solution is added to render the solution clear. The solution is then filtered on a carbon bed and spray dried to obtain free-flowing powder material. The product is packaged in an air and moisture proof glass container. Example 2 - Preparation of Chewing Gum
A brief general description of the chewing gum is set forth as follows. Fully melt the gum base (at approximately 90°C) in Bartender mixer, a jacketed mixer with sigma blades. Remove the hot water from the mixer jacket, allow to cool, and add lecithin and mix well. Cool further to approximately 50°C, and add liquid flavor and mannitol. Mix until uniform.
Dry blend colloidal bismuth subcitrate in sorbitol, and blend sodium citrate in sorbo syrup. Add sorbitol and sorbo syrup blends to the gum base. Cool the product to 35°C, add flavor and sweetener and mix until smooth. Remove the product from the mixing kettle, roll to form a sheet of uniform thickness and score to produce chewing gum sticks weighing 2.5 g each. Wrap individual gum sticks in aluminum foil and place in plastic bags.
Example 3 - Composition of CBS-Containing Gum
Two variations of 50 mg CBS gum were prepared as shown in Table 1 below. Both formulations used were identical with the exception that Formula-2 contained sodium citrate to impart a firmer texture, while Formula- 1 did not.
Table 1.
FORMULATIONS OF THE GUM (APPROX. 2.5 gm A PD2CE)
Formula- 1 Formula-2
CBS 50.0mg CBS 50.0mg
Crystalline Sorbitol 910.0 Crystalline Sorbitol 910.0
GumBase 575.0 GumBase 575.0
Sorbitol Solution 500.0 Sorbitol Solution 500.0
Mannitol 400.0 Mannitol 400.0
Peppermint Oil 25.0 Peppermint Oil 25.0
Spray Dried Peppermint 12.5 Spray Dried Peppermint 12.5
Grade t Lecithin 10.0 Grade t Lecithin 10.0
Aspartame 10.0 Aspartame 10.0
Sodium Citrate 10.0
Total: 2502.5mg Total: 2492.5mg Example 4 - Measurement of Release Rate of Bismuth into Saliva
Among six healthy human subjects, who gave informed consent, three chewed the CBS-containing gum with sodium citrate, and the other three chewed CBS-containing gum without sodium citrate. The subjects chewed the gum samples for a total of 15 minutes. Saliva samples were collected at time interval of 0, 1, 5, 10, and 15 minutes of chewing. The saliva samples were then submitted to an analytical laboratory for bismuth analysis. Results are shown in Table 2 below.
Table 2.
IN VTVO SALIVARY CONCENTRATION OF
CBS FROM THE CHEWING GUM
chewing time saliva cone of Bi cone of active
Formula (min.) vol. fmL) (Ppm) < CBS ( μe/m ) X MIC
0 4.4 (±0.5)
1 3.3 (±1.4) 900.7 (±239.1) 1270.3 (±334.7) 148.7 (±42.0) formula- 1 5 5.4 (±1.5) 257.7 (±112.3) 363.3 (±158.9) 45.0 (±19.9)
10 4.9 (±1.3) 28.0 (±5.0) 40.0 (±6.6) 5.0 (±1.0)
15 5.2 (±2.1) 15.8 (±17.8) 25.7 (±23.0) 3.1 (±2.7)
0 7.2 (±0.5)
1 4.8 (±1.9) 888.3 (±329.5) 1257.0 (±464.5) 156.3 (±58.0) formula-2 5 8.5 (±1.7) 326.0 (±113.3) 572.7 (±159.7) 63.7 (±19.9)
10 7.5 (±3.4) 30.0 (±9.5) 42.3 (±13.6) 5.0 (± 1.7)
15 7.7 (±3.8) 10.7 (±6.7) 14.7 (±9.2) 1.8 (±1.2)
Saliva samples were analyzed for elemental bismuth in ppm units. The results were then converted to μg of active CBS per mL of saliva, and also expressed as a multiple of minimum inhibitory concentration (MIC) of CBS for H. pylori. As can be seen from the results for formula-2, the salivary concentrations of CBS are about 156, 64, 5, and 1.8 times the MIC at 1, 5, 10 and 15 minutes, respectively. The constant bathing of the oral cavity from saliva containing sufficient concentration of CBS (2 to 5 times the MIC) for up to 15 minutes can be expected to further reduce the population of viable cells of H. pylori. Example 5 - Sensory Analysis of Chewing Gum
Sensory characteristics of the chewing gum were evaluated by the subjects during the 15 minutes of chewing. Again, three subjects chewed the CBS gum containing sodium citrate and three subjects chewed the CBS gum without sodium citrate. A nine point rating scale was used to evaluate each category. The results are shown in Tables 3 and 4 below.
Table 3.
RESULTS OF SENSORY ANALYSIS RATING OF CBS GUM
WITHOUT SODHJM CITRATE
(Formula-1)
CHEWING TIME
SENSORY CHARACTERISTICS l MIN 5 MIN lO MIN 15 MEN
Overall Flavor 6.3 6.0 5.3 5.0
(0 = dislike extremely, (±1.2) (±1.0) (±1.5) (±1.0) 8 = like extremely)
Flavor Intensity 5.7 4.7 3.7 3.0
(0 = none, 8 = very strong) (±1.5) (±1.2) (±0.6) (±1.0)
Chew Qualities 6.0 6.0 5.3 5.0
(0 = dislike extremely, (±1.0) (±1.0) (±1.5) (±1.0)
8 = like extremely)
Unpleasant Aftertaste 0.0 0.0 0.0 0.0
(0 = none, 8 = very strong) (±0.0) (±0.0) (±0.0) (±0.0)
Overall Qualities 6.3 6.0 5.7 5.3
(0 = dislike extremely, (±1.2) (±1.0) (±1.2) (±1.5)
8 = like extremely)
Table 4.
RESULTS OF SENSORY ANALYSIS RATING OF CBS GUM
WITH SODRJM CITRATE
(Formula-2)
CHEWING TIME
SENSORY CHARACTERISTICS 1 MIN 5 MIN 10 MIN 15 MIN
Overall Flavor 6.7 5.7 4.7 4.7
(0 = dislike extremely, (±0.6) (±1.5) (±1.2) (±1.2)
8 = like extremely)
Flavor Intensity 6.7 6.0 5.0 3.7
(0 = none, 8 = very strong) (±0.6) (±0.0) (±1.0) (±1.5)
Chew Qualities 4.7 5.0 4.3 4.3
(0 = dislike extremely, (±2.1) (±2.0) (±1.5) (±0.6)
8 = like extremely)
Unpleasant Aftertaste 0.7 1.7 1.7 2.0
(0 = none, 8 = very strong) (±1.2) (±2.1) (±2.1) (±2.0)
Overall Qualities 6.3 5.7 4.7 4.0
(0 = dislike extremely, (±0.6) (±1.2) (±1.2) (±1.0)
8 = like extremely)
In general, there were no dramatic differences in the sensory analysis between the two formulas. The sensory panel clearly shows that both chewing gum formulations have a desirable level of flavor and taste, and cause a minimal unpleasant aftertaste after chewing.
Example 6 - Topical Safety
Topical safety was evaluated in the six volunteers for up to 60 minutes after administration of the gum. The subjects were asked to report any adverse effects such as discomfort or irritation in the oral cavity.
There were no reports of any discomfort or irritation in the oral cavity by any of the subjects at either the 15 or 60 minute post administration time periods. Example 7 - Storage Stability Study
Samples of chewing gum containing 50 mg of CBS were wrapped individually in foil wrappers. The pieces of gum were then placed in foil laminate bags, sealed, and placed in storage. Storage conditions include 40°C and room temperature (RT). The duration of the stability testing was 90 days. The results are shown in Tables 5-8 below.
Table 5.
THREE MONTH STABILITY DATA IN VIVO SALIVARY CONCENTRATIONS IN HUMAN SUBJECTS OF CBS FROM THE 50 MG CBS CHEWING GUM
Figure imgf000017_0001
CHEWING CONC OF
TIME/ TIME SALIVA CONC OF Bi CONC OF Bi ACTIVE CBS
CONDITION (min) VOLUME (mL) (ppm) (μg/mL) (μg/mL) X MIC
ZERO TIME 0 4.2 (±1.6) NA NA NA NA
1 4.9 (±4.5) 1937.3 (±753.5) 1937.3 (±753.5) 2729.0 (±1060.2) 341.0 (±132.7)
5 6.4 (±3.1) 437.0 (±152.1) 437.0 (±152.1) 615.7 (±214.5) 77.0 (±26.9)
10 3.9 (±0.1) 36.0 (±28.6) 36.0 (±28.6) 50.7 (±40.5) 6.4 (±5.0)
15 4.5 (±1.3) 5.0 (±4.6) 5.0 (±4.6) 7.0 (±6.6) 0.9 (±0.8)
3 MONTHS AT 40°C 0 5.6 (±1.4) NA NA NA NA
1 2.9 (±1.8) 1922.3 (±511.8) 1922.3 (±511.8) 2710.0 (±791.9) 338.6 (±90.3)
5 5.6 (±1.7) 399.3 (±278.1) 363.7 (±1 13.3) 563.0 (±329.3) 70.3 (±49.1)
10 5.3 (±1.4) 25.7 (±11.4) 30.0 (±9.5) 362.0 (±160.5) 45.4 (±20.1)
15 4.9 (±0.4) 7.9 (±4.9) 10.7 (±6.7) 10.8 (±6.8) 1.4 (±0.9)
3 MONTHS AT ROOM TEMP. 0 5.1 (±1.3) NA NA NA NA
1 4.1 (±1.5) 1240.0 (±458.7) 1240.0 (±458.7) 1748.0 (±646.6) 218.0 (±80.6)
5 7.2 (±2.3) 518.7 (±118.7) 518.7 (±118.7) 731.3 (±167.6) 91.0 (±21.8)
10 6.0 (±2.2) 12.5 (±10.6) 12.5 (±10.6) 17.7 (±14.6) 2.1 (±1.8)
15 5.6 (±1.6) 4.5 (±2.2) 4.5 (±2.2) 6.0 (±2.6) 0.7 (±0.3) n = 3 for each group
Table 6.
THREE MONTH STABILITY DATA RESULTS OF SENSORY ANALYSIS RATING OF 50 MG CBS GUM
CHEWING TIME
SENSORY CHARACTERISTIC 1 MIN 5 MIN 10 MIN 15 MIN
ZERO TIME OVERALL FLAVOR 6.7 (±0.6) 6.3 (±0.6) 5.3 (±0.6) 5.3 (±0.6)
FLAVOR INTENSITY 6.3 (±1.2) 5.3 (±1.2) 4.0 (±1.0) 4.0 (±1.0)
CHEW QUALITIES 6.7 (±0.6) 6.3 (±0.6) 5.7 (±0.6) 5.3 (±0.6)
UNPLEASANT AFTERTASTE 0.0 (±0.0) 0.0 (±0.0) 0.0 (±2.1) 0.0 (±0.0)
OVERALL QUALITIES 6.7 (±0.6) 6.3 (±0.6) 5.7 (±0.6) 5.3 (±1.2)
_ 3 MONTHS AT σ, 4o°c OVERALL FLAVOR 6.0 (±0.0) 4.7 (±0.6) 2.7 (±1.2) 2.7 (±1.2)
1 FLAVOR INTENSITY 5.3 (±1.2) 3.0 (±0.0) 2.3 (±0.6) 2.0 (±1.0)
CHEW QUALITIES 5.7 (±0.6) 5.0 (±1.0) 4.3 (±0.6) 4.3 (±0.6)
UNPLEASANT AFTERTASTE 0.3 (±0.6) 0.3 (±0.6) 0.0 (±0.0) 0.0 (±0.0)
OVERALL QUALITIES 6.0 (±0.0) 4.3 (±0.6) 2.7 (±0.6) 2.3 (±0.6)
3 MONTHS AT ROOM TEMP. OVERALL FLAVOR 6.3 (±0.6) 6.3 (±0.6) 5.3 (±0.6) 4.3 (±0.6)
FLAVOR INTENSITY 5.7 (±1.5) 5.3 (±1.5) 4.3 (±1.5) 4.0 (±1.7)
CHEW QUALITIES 6.0 (± 1.0) 6.0 (±1.0) 5.3 (±0.6) 4.3 (±0.6)
UNPLEASANT AFTERTASTE 0.0 (±0.0) 0.0 (±0.0) 0.0 (±0.0) 0.0 (±0.0)
OVERALL QUALITIES 6.3 (±0.6) 6.3 (±0.6) 5.3 (±0.6) 4.7 (±1.2)
Note: n = 3 for each analysis
Rating Scale:
0=disTike extremely, 9-like extremely for: Overall Flavor, Chew Quality, Overall Quality 0=none, 9-like extremely for: Flavor Intensity 0=none, 9=very strong for: Unpleasant Aftertaste
Table 7.
Figure imgf000019_0001
EXPONENTIAL REGRESSION DATA OF TIME VS SALIVARY CONCENTRATIONS
EXPRESSED AS MULTIPLES OF MIC
Initial Test Lot Stability Lot Clinical Lot
# CBS-50-CG-0001 # CBS-50CG-0002 # CBS-50CG-0003
Zero Time 3 mo./RT 3 mo./40°C
A (intercept) 240.0 563.1 575.7 422.3 446.5 b (slope) -0.339 -0.432 -0.361 -0.448 -0.426 r (correlation 0.992 0.998 0.948 0.971 0.959 coefficient)
K (pseudo first order -0.339 0.432 0.361 0.448 0.426 rate constant)
'0.5 (min.) 2.04 1.60 1.92 1.55 1.63
Mean t 0, .5 = 1.748 (±0.218)
Table 8.
RELEASE OF CBS FROM THE CHEWING GUM AFTER
15 MINUTES OF CHEWING BY HUMAN SUBJECTS
Stability Lot Clinical Lot
# CBS -50CG-0002 # CBS-50CG-0003
Zero Time 3 mo./RT 3 mo./40°C
Mg CBS/2.5 g gum 45.6 (100) 44.5 (100) 46.1 (100) 46.2 (100)
Before chewing (%)
Mg CBS/2.5 g gum 3.5 (7.6) 4.0 (9.0) 4.5 (9.8) 3.8 (8.5)
After 15 min chewing (%)
Mean % of CBS Remaining in the gum after 15 min of chewing = 8.6 (±1.0)
Figure imgf000020_0001
Figure imgf000020_0002
Each piece of the gum used for the stability study (one for zero-time, two for three months, total three) was from the same lot number. The results show that bismuth concentration remains stable over the tested time period.
Example 8 - Denture Material Exposure Study
An evaluation of CBS salivary concentration on various denture materials was conducted in order to test any potential staining effect of the CBS on denture materials. Artificial saliva was used. The results are reported at Table 9 below.
Table 9.
THE COMPOSITION OF ARTIFICIAL SALIVA
Ingredients Concentration per Liter
Sodium Bicarbonate 0.50 g
Sodium Phosphate, Dibasic, Dihydrate 0.85 g Calcium Chloride 0.44 g
Magnesium Chloride 0.06 g
Potassium Chloride 1.40 g
Sodium Carboxyl Methyl Cellulose 2.00 g
Phosphoric Acid to adjust pH to 6.4 Distilled Water QS
The test saliva was prepared by dissolving 0.500 g of colloidal bismuth subcitrate in 100 mL of the above artificial saliva. 500 mL of artificial saliva at room temperature was placed in one of two identical glass jars with lids. In the other jar was placed 500 mL of the artificial saliva at room temperature containing 0.50% of CBS. In each of the jars the denture material block and a magnetic stirrer was placed. The jars were then placed on the magnetic platform and set to agitate at a minimum rate for four hours. The denture materials that were exposed to artificial saliva containing either CBS or placebo are listed in Table 10 below. The four hour exposure of natural tooth and other denture materials to 0.5% CBS in artificial saliva with mild agitation did not cause any staining, discoloration, or changes in texture.
Table 10.
DENTURE MATERIALS
1) Natural tooth with silver amalgam filling
2) Composite resin (used on anterior teeth for filling)
3) Denture base acrylic resin 4) Porcelain fused to metal
5) Partial denture metal frame
6) Acrylic tooth (artificial)
7) Natural tooth
Example 9 - Clinical Efficacy Data
An open label, placebo-controlled pilot clinical study in ten patients with initial positive response for H. pylori in the dental plaque has been initiated. Data from six patients (four patients treated with CBS 50 mg chewing gum six times-a-day and two patients treated with placebo chewing gum six times-a-day for fifteen days) has been obtained. The dental plaque samples from the patients were collected before treatment, at day 7 and at day 15 after treatment, and tested by microbiological culture and CLO test. The results are set forth in Table 11 below:
Table 11.
Figure imgf000023_0001
Mean CLO response time after 15 days = 2.0 HR
NA = Not available
NE = Not evaluated (before chewing) The data show that for patients treated with CBS 50 mg chewing gum and placebo chewing gum on day 15 the mean CLO response times are 4.125 hours and 2.0 hours, respectively. The longer CLO test response time for CBS 50 mg chewing gum group compared to the placebo chewing gum group is indicative of substantial reduction in H. pylori density in the oral cavity of the active treatment group.
Example 10- Clinical Trial Data
The MERETEK UBT™ (urea breath test kit) from MERETEK Diagnostics, Inc. can be used to detect the presence of H. pylori in the stomach for the diagnosis of ulcers. To perform the test, the patient is given a liquid containing urea that is enriched with the carbon- 13 isotope. H. pylori is a urease positive bacteria. If the carbon- 13 isotope is present in heavy concentrations in later breaths, it signifies the presence of H. pylori in the stomach.
Duodenal ulcer patients with a positive urea breath test were randomized into active and placebo groups and entered into a 15-day clinical trial. These patients did not receive any antibiotic therapy during the clinical trial. The patients in the active group received gum containing 50 mg of colloidal bismuth subcitrate per piece. The patients in the placebo group received gum not containing colloidal bismuth subcitrate. The patients were further subdivided into high dose and low dose groups. The patients in the high dose group chewed gum 6 times per day and the patients in the low dose group chewed gum 2 times per day. After 15 days, the urea breath test was repeated. The results are reported in Table 12 below.
Table 12.
Figure imgf000025_0001
* Overall assessment is a qualitative result (either positive or negative) based on a numerical value established for the test. ** Overall change in data refers to the difference in numerical values from initial test to day 15.
Results of Overall Assessment: 1. All three patients receiving placebo (100%) had positive urea breath tests at the conclusion of the trial.
2. Eight of eleven patients receiving active gum (73%) had negative urea breath tests at the conclusion of the trial.
3. One patient with negative results at the start (i.e., below threshold value to consider the test positive) was not included. Results of Overall Changes in Data:
1. The average change in urea breath test data was an increase of 23% in the three placebo patients.
2. The average change in urea breath test data was a decrease of 64% in the six patients on the low active dose (range of 22% to 98%).
3. Six of six patients in the low active drug group had a decrease (p<0.05 by chi- square analysis).
4. The average change in urea breath test data was a decrease of 91% in the six patients on the high active dose (range of 79% to 98%). 5. Six of six patients in the high active drug group had a decrease (p<0.05 by chi- square analysis).
Summary of Results:
1. Twelve of twelve patients on active gum had decreases in urea breath test data results (ranging from 22% to 98%), whereas three placebo patients had an average increase of 23%).
2. There was a dose-response relationship between the two doses of gum used. The data suggest that the doses are near the peak of the dose-response relationship. 3. The data strongly suggest that H. pylori has been eradicated from the stomach by the active gum used in this clinical trial.
Example 11 - Antibacterial Efficacy for Treatment of Halitosis
Halitosis is caused by the buildup of Volatile Sulfur Compounds (VSCs). These VSCs arise from the breakdown of bacteria, tissue, and food particles trapped in the mouth. Other contributing factors include digestive problems, nose, throat and/or lung infections, and the intake of medications.
A halitosis meter can be used to detect the presence of bad breath. This meter uses an analyzer that can detect the levels of VSCs. Most individuals feel that odor is coming from their stomach, when really 80 percent originates from the mouth and tongue. Typically, breath mints, chewing gum, mouth washes and toothpastes that you buy at the store merely mask your bad breath. These breath fresheners are only able to cover up the odor for a short time. In order to permanently eliminate bad breath it is necessary to attack the source of the VSCs.
Campylobacter rectus, Helicobacter pylori, and Treponema denticola are bacteria that have been demonstrated to be associated with Halitosis (bad breath). The bismuth- containing compounds and methods of the present invention, including CBS as well as ascorbyl bismuth derivative, have demonstrated in vitro activity against all three bacteria, as indicated by their minimum effective concentrations (MICs) presented in Table 13 below.
Table 13.
Figure imgf000027_0001
Based on the in vitro activity, a chewing gum containing CBS should be effective in reducing Halitosis caused by bacteria. It is expected that a person may treat halitosis by chewing gum containing preferably between about 10 mg CBS and about 100 mg CBS, and preferably between about one and four times per day. Also, the chewing gum may contain an amount of bismuth in the aforementioned bismuth compound or combinations thereof equivalent to between about 10 and about 100 milligrams of colloidal bismuth subcitrate.
Example 12 - Toxicology
A number of animal toxicity studies and human clinical investigations have demonstrated safety of bismuth compounds, especially CBS, in therapeutic dose ranges. No toxicity has been reported in chronic daily administration of high doses of CBS (160, 320, and 640 mg/kg body weight representing 2, 4, and 8 times the human therapeutic dose, respectively) in rats treated for three months or dogs treated for six months. See Wieriks et al., Journal of Gastroenterology 17(Supplement 80): 11B16 (1982), incorporated herein by reference.
Long term safety of CBS and treatment of peptic ulcers at a standard dose of 480 mg (expressed as bismuthtrioxide) in four daily divided doses has been examined by Bader, Digestion 37(Supplement 2):53-59 (1987), incorporated herein by reference. CBS was first introduced in Europe in 1971 and since that time 1.5 million treatments have been dispensed. During eight years of use of CBS tablets [De-Nol®] in Europe between 1978 and 1986 under a more comprehensive adverse reaction monitoring system, only 13 adverse reaction forms were completed. Five of these adverse reactions were ascribed to CBS: one case of headache, one case of stomach pain, one case of diarrhea, and two cases of allergy (mainly in the form of skin rashes). A high degree of safety of CBS in therapeutic applications for the treatment of peptic ulcers is reported in a review of pharmacology of bismuth-containing compounds by Lambert, Review of Infectious Diseases 13 (Supplement 8): 691-695 (1991), incorporated herein by reference. In reviewing safety and pharmacokinetics of CBS, Bennet, Scandinavian Journal of Gastroenterology 26_(Supplement 185):29-35 (1991), incorporated herein by reference, has calculated the systemic bioavailability of bismuth after oral dosing of CBS to be in the range of 0.16 to 0.28% of the administered dose, and concluded that steady-state blood levels of 50-100 ng/mL are unlikely to cause any neurotoxicity. It should be appreciated that the compositions and methods of the present invention are capable of being incorporated in the form of a variety of embodiments, only a few of which have been illustrated and described above. The invention may be embodied in other forms without departing from spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive, and the scope of the invention is, therefore, indicated by the appended claims rather that the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

WHAT IS CLAIMED IS:
1. A chewing gum composition comprising a water soluble bulk portion, a water insoluble chewing gum base portion, a flavoring agent, and a therapeutically effective amount of a compound selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, bismuth aluminate, and combinations thereof.
2. The chewing gum of claim 1 wherein the bismuth compound is selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth subsalicylate and combinations thereof.
3. The chewing gum of claim 2 wherein the bismuth compound is colloidal bismuth subcitrate.
4. The chewing gum of claim 3 wherein the chewing gum includes between about 10 mg and 200 mg of colloidal bismuth subcitrate per piece.
5. The chewing gum of claim 4 wherein the chewing gum includes between about 10 mg and about 100 mg of colloidal bismuth subcitrate per piece.
6. The chewing gum of claim 5 wherein the chewing gum includes between about 25 mg and about 75 mg of colloidal bismuth subcitrate per piece.
7. The chewing gum of claim 1 further comprising an antibiotic.
8. The chewing gum of claim 7 wherein the antibiotic is metronidazole.
9. The chewing gum of claim 1 further comprising an anti-plaque agent.
10. The chewing gum of claim 9 wherein said antiplaque agent is selected from gluconase and hydroglucosidase, glucose oxidase, calcium kaolin, silicone oil, and sanguinarine.
11. A chewing gum formulation comprising a bismuth compound selected from the group consisting of colloidal bismuth subcitrate (CBS), bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, and bismuth aluminate.
12. The chewing gum of claim 11 wherein the chewing gum includes an amount of bismuth in said bismuth compound or combinations thereof equivalent to between about 10 and about 200 milligrams of colloidal bismuth subcitrate.
13. The chewing gum of claim 12 wherein the chewing gum includes an amount of bismuth in said bismuth compound or combinations thereof equivalent to between about
25 and about 75 milligrams of colloidal bismuth subcitrate.
14. The chewing gum of claim 13 wherein the chewing gum includes an amount of bismuth in said bismuth compound or combinations thereof equivalent to about 50 milligrams of colloidal bismuth subcitrate.
15. A method of treating Helicobacter pylori infection comprising the step of administering a chewing gum containing a water soluble bulk portion, a water insoluble chewing gum base portion, a flavoring agent, and a therapeutically effective amount of a compound selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, bismuth aluminate and combinations thereof.
16. The method of claim 15 wherein said bismuth compound is selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth subsalicylate, and a combination thereof.
17. The method of claim 16 wherein the bismuth compound is colloidal bismuth subcitrate.
18. The method of claim 17 wherein the chewing gum includes between about
10 mg and 200 mg of colloidal bismuth subcitrate.
19. The methd of claim 18 wherein the chewing gum includes between about 10 mg and about 100 mg of colloidal bismuth subcitrate per piece.
20. The chewing gum of claim 19 wherein the chewing gum includes between about 25 mg and about 75 mg of colloidal bismuth subcitrate per piece.
21. The method of claim 15 wherein the chewing gum further comprises an antiplaque agent.
22. The method of claim 15 wherein the chewing gum is administered between about one and ten times per day.
21. A method of treating Helicobacter pylori infection comprising the step of administering a chewing gum containing a therapeutically effective amount of a bismuth compound selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, bismuth aluminate and combinations thereof.
22. The method of claim 21 wherein the chewing gum includes an amount of bismuth in said bismuth compound or combinations thereof equivalent to between about 10 and about 200 milligrams of colloidal bismuth subcitrate.
23. The method of claim 22 wherein the chewing gum includes an amount of bismuth in said bismuth compound or combinations thereof equivalent to between about 25 and about 75 milligrams of colloidal bismuth subcitrate.
24. The method of claim 23 wherein the chewing gum includes an amount of bismuth in said bismuth compound or combinations thereof equivalent to about 50 milligrams of colloidal bismuth subcitrate.
25. A method for treating halitosis comprising administering a chewing gum containing a water soluble bulk portion, a water insoluble chewing gum base portion, a flavoring agent, and a therapeutically effective amount of a compound selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, bismuth aluminate and combinations thereof.
26. The method of claim 25 wherein said bismuth compound is selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth subsalicylate, and combinations thereof.
27. The method of claim 26 wherein the bismuth compound is colloidal bismuth subcitrate.
28. The method of claim 27 wherein the chewing gum is administered between about one and ten times per day.
29. The method of claim 28 wherein the chewing gum is administered between about one and four times per day.
30. The method of claim 25 wherein the chewing gum includes an amount of bismuth in said bismuth compound or combinations thereof equivalent to between about 10 and about 100 milligrams of colloidal bismuth subcitrate.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1300148A2 (en) * 2001-08-27 2003-04-09 Hedonist Biochemical Technologies Inc. Use of bismuth subgallate in inhibition of production of nitric oxide synthase
WO2003045403A1 (en) 2001-11-28 2003-06-05 Terry Dorcen Bolin Method of treating halitosis
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Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6426085B1 (en) 1994-05-02 2002-07-30 Josman Laboratories Inc. Use of bismuth-containing compounds in topical oral dosage forms for the treatment of halitosis
US6902738B2 (en) * 1994-05-02 2005-06-07 Josman Laboratories, Inc. Topical oral dosage forms containing bismuth compounds
US5834002A (en) 1994-05-02 1998-11-10 Josman Laboratories, Inc. Chewing gum containing colloidal bismuth subcitrate
US6379651B1 (en) * 1995-02-07 2002-04-30 Josman Laboratories Oral-topical dosage forms for delivering antibacterials/antibiotics to oral cavity to eradicate H. pylori as a concomitant treatment for peptic ulcers and other gastro-intestinal diseases
US6372784B1 (en) 1995-02-07 2002-04-16 Josman Laboratories, Inc. Bismuth-containing compounds in topical dosage forms for treatment of corneal and dermal wounds
US5955054A (en) * 1998-04-29 1999-09-21 Hartmann; John F. Diagnostic assay for localizing H. pylori
US6677129B1 (en) * 1998-07-22 2004-01-13 Richard S. Blume Method for detecting Helicobacter pylori infection
US6358060B2 (en) 1998-09-03 2002-03-19 Jsr Llc Two-stage transmucosal medicine delivery system for symptom relief
US6586023B1 (en) 1998-12-15 2003-07-01 Wm. Wrigley Jr. Company Process for controlling release of active agents from a chewing gum coating and product thereof
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US6322806B1 (en) 1999-04-06 2001-11-27 Wm. Wrigley Jr. Company Over-coated chewing gum formulations including tableted center
US6355265B1 (en) 1999-04-06 2002-03-12 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
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US6773716B2 (en) 1999-04-06 2004-08-10 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
EP1181010A4 (en) * 1999-04-06 2003-03-26 Wrigley W M Jun Co Pharmaceutical chewing gum formulations
US6663849B1 (en) 2000-09-01 2003-12-16 Wm. Wrigley Jr. Company Antacid chewing gum products coated with high viscosity materials
US6569472B1 (en) 2000-09-01 2003-05-27 Wm. Wrigley Jr. Company Coated chewing gum products containing antacid and method of making
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US6491540B1 (en) 1999-09-20 2002-12-10 Jack Barreca Center-filled supplement gum
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US9253991B2 (en) 1999-09-20 2016-02-09 Jack Barreca Chewing gum with B vitamins
WO2001052667A2 (en) 2000-01-18 2001-07-26 Societe Des Produits Nestle S.A. Pet food composition for treating helicobacter species in pets
US6647549B2 (en) 2000-04-06 2003-11-18 Kimberly-Clark Worldwide, Inc. Finger glove
US6721987B2 (en) 2000-04-06 2004-04-20 Kimberly-Clark Worldwide, Inc. Dental wipe
WO2001089476A1 (en) * 2000-05-19 2001-11-29 Npd Llc Chewing gums, lozenges, candies, tablets, liquids, and sprays for efficient delivery of medications and dietary supplements
US6572900B1 (en) 2000-06-09 2003-06-03 Wm. Wrigley, Jr. Company Method for making coated chewing gum products including a high-intensity sweetener
US6444241B1 (en) 2000-08-30 2002-09-03 Wm. Wrigley Jr. Company Caffeine coated chewing gum product and process of making
US6579545B2 (en) 2000-12-22 2003-06-17 Wm. Wrigley Jr. Company Coated chewing gum products containing an antigas agent
USD494369S1 (en) 2001-04-04 2004-08-17 Kimberly-Clark Worldwide, Inc. Dental wipe
US6613346B2 (en) 2001-06-28 2003-09-02 Wm. Wrigley, Jr. Company Chewable product including active ingredient
AU2002342421B2 (en) * 2001-11-28 2007-09-06 Terry Dorcen Bolin Method of treating halitosis
US20030158752A1 (en) * 2001-12-19 2003-08-21 1747, Inc. System and method for designing and running of clinical trials
US8602774B2 (en) 2002-12-04 2013-12-10 Bryan Wasylucha Process of tooth whitening and apparatus therefor
US7041311B2 (en) * 2003-02-28 2006-05-09 International Flavors & Fragrances Inc. Preparation for saliva flow
US20050066463A1 (en) * 2003-09-25 2005-03-31 Brunner Michael S. Substrates and devices for applying a lip care formulation
US20050241089A1 (en) * 2004-04-30 2005-11-03 Kimberly-Clark Worldwide, Inc. Device for treating surfaces
US20060018842A1 (en) * 2004-06-25 2006-01-26 Gary Blumenthal Composition and method for delivery of phytochemicals
US20060115266A1 (en) * 2004-12-01 2006-06-01 Gil Levi All-optical protection signaling systems and methods in optical communication networks
US20060243409A1 (en) * 2005-04-29 2006-11-02 Fish Jeffrey E Edge-stiffened sheet material probe
US7674058B2 (en) 2005-08-30 2010-03-09 Kimberly-Clark Worldwide, Inc. Disposable wipe with liquid storage and application system
JP5035865B2 (en) * 2005-09-26 2012-09-26 国立大学法人高知大学 Method for inhibiting growth and movement of Helicobacter pylori strain
US8642016B2 (en) 2006-07-21 2014-02-04 Jsrnti, Llc Medicinal delivery system, and related methods
CN102590123A (en) * 2012-02-17 2012-07-18 长治学院 Method for detecting content of bismuth in bismuth potassium citrate medicament
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4801608A (en) * 1981-09-22 1989-01-31 Gist-Brocades N. V. Bismuth containing composition and method for the preparation thereof
US4822597A (en) * 1987-07-13 1989-04-18 Warner-Lambert Company Anesthetic-containing chewing gum compositions

Family Cites Families (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR70408E (en) 1955-06-01 1959-05-06 Int Standard Electric Corp Two-way communication system
US3011949A (en) * 1958-06-10 1961-12-05 Anthony G Bilotti Method of promoting release of active ingredients from slab chewing gum and product
NL301743A (en) 1962-12-13
FR4961M (en) 1965-03-29 1967-04-03
US3352689A (en) * 1966-02-14 1967-11-14 Warner Lambert Pharmaceutical Sugarless gum
GB1144915A (en) 1966-11-24 1969-03-12 Armour Pharma Improvements in or relating to pastille formulations
US3577533A (en) 1968-02-21 1971-05-04 Joseph Alfred Rider Antacid compositions containing bismuth aluminate and coprecipitated aluminum hydroxide and magnesium carbonate
US3824006A (en) * 1968-04-23 1974-07-16 F Voit Optical spectacles including adhesive bonding means between metal spectacle frames and ophthalmic lenses
US4153685A (en) * 1968-11-23 1979-05-08 Schering Corporation Bismuth complex preparations
DE1963496A1 (en) 1969-12-18 1971-06-24 Hans Voigt Chemisch Pharmazeut Stomach and intestinal disorders treatment - compsn
DE2012187A1 (en) * 1970-03-14 1971-09-23 Welding & Co, 2000 Hamburg Bismuth compounds for dental care particular
US3651208A (en) * 1970-12-14 1972-03-21 Lafant Research Co Dentifrice for periodontia purposes
US3982023A (en) 1972-10-05 1976-09-21 General Foods Corporation Chewing gums of longer lasting sweetness and flavor
US3943258A (en) * 1972-10-05 1976-03-09 General Foods Corporation Chewing gums of longer lasting sweetness and flavor
US4118480A (en) 1973-02-09 1978-10-03 Charles V. Stoelker Pharmaceutical preparation for treating hemorrhoids and anal fissures
US3929449A (en) * 1973-12-10 1975-12-30 Gulf Oil Corp Method of alleviating dermal toxicity of pesticide compositions
ZA74385B (en) 1974-01-18 1975-08-27 Gist Brocades Nv Pharmaceutical compositions
US4055655A (en) * 1975-07-21 1977-10-25 National Research Laboratories Complexes of heavy metal ions and polyfunctional organic ligands used as antimicrobial agents
US4180473A (en) * 1975-07-21 1979-12-25 National Research Laboratories Method of transporting metal ions
US4016268A (en) 1975-10-06 1977-04-05 Morton-Norwich Products, Inc. Method of combatting gastric ulceration
US3973041A (en) * 1976-03-03 1976-08-03 Ici United States Inc. Sugarless chewing gum having improved shelf life
US4217368A (en) * 1977-07-08 1980-08-12 Life Savers, Inc. Long-lasting chewing gum and method
US4208431A (en) * 1978-05-05 1980-06-17 Life Savers, Inc. Long-lasting chewing gum having good processibility and method
US4514421A (en) * 1979-08-30 1985-04-30 Herschler R J Dietary and pharmaceutical uses of methylsulfonylmethane and compositions comprising it
US4956386A (en) * 1980-04-25 1990-09-11 Gist-Brocades N.V. Pharmaceutical compositions and process for their preparation
DE3127639A1 (en) 1980-07-12 1982-08-19 Pavel 6000 Frankfurt Kozak Cream for the treatment of skin disorders
PT75550B (en) * 1981-09-22 1984-12-12 Gist Brocades Nv Bismuth containing composition and method for the preparation thereof
US4680309A (en) * 1982-12-06 1987-07-14 National Research Laboratories Methods and compositions for treating inflammation or arthritis
US5002776A (en) 1983-12-22 1991-03-26 Elan Corporation, Plc Controlled absorption diltiazem formulations
US4917899A (en) 1983-12-22 1990-04-17 Elan Corporation Plc Controlled absorption diltiazem formulation
US4670245A (en) * 1984-04-27 1987-06-02 Vasquez Tony E Diagnostic procedures using radiolabeled colloidal bismuth subcitrate and related compounds
US5017367A (en) * 1984-10-01 1991-05-21 Stojkoski Radmila G Skin treatment preparation
US4652444A (en) * 1984-12-14 1987-03-24 National Research Laboratories Methods and compositions for treating dental structures
EP0222834A4 (en) 1985-04-18 1989-10-04 Borody Thomas J Treatment of non-ulcer dyspepsia with bismuth salts.
DE3686361T3 (en) 1985-06-13 2003-01-09 Barry James Marshall Use of bismuth in the manufacture of medicaments for the treatment of gastrointestinal disorders caused by Campylobacter polyridis.
US5256684A (en) * 1985-06-13 1993-10-26 The Procter & Gamble Company Methods and compositions for the treatment of gastrointestinal disorders
US4801454A (en) * 1986-07-17 1989-01-31 The Proctor & Gamble Company Processes for making colored pharmaceutical compositions
GB2195891A (en) 1986-10-06 1988-04-20 Procter & Gamble Improving palatability of pharmaceutical chewable tablets
US4786502A (en) 1986-10-06 1988-11-22 The Procter & Gamble Company Palatable solid pharmaceutical compositions
GB2195248A (en) 1986-10-06 1988-04-07 Procter & Gamble Coated lipid-containing compositions
GB2195890A (en) 1986-10-06 1988-04-20 Procter & Gamble Improving palatability of pharmaceutical chewable tablets
US4800083A (en) 1986-10-20 1989-01-24 R. P. Scherer Corporation Sustained release method and product
EP0282132B1 (en) * 1987-03-09 1992-09-30 The Procter & Gamble Company Compositions and their use for treating gastrointestinal disorders
US4975270A (en) * 1987-04-21 1990-12-04 Nabisco Brands, Inc. Elastomer encased active ingredients
DE3887353T2 (en) * 1987-10-12 1994-05-05 Exomed Australia Pty Ltd TREATMENT PROCEDURE FOR STOMACH-DISEASES.
US4940695A (en) * 1987-12-10 1990-07-10 The Procter & Gamble Company Bismuth-containing pharmaceutical compositions
US4879116A (en) * 1988-06-13 1989-11-07 Charles Fox Skin protein complexing composition for the potentiation of the substantivity of aluminum acetate through the use of a cationic emulsifier as an aid in skin healing
US5334582A (en) 1988-06-22 1994-08-02 Applied Microbiology, Inc. Pharmaceutical bacteriocin compositions and methods for using the same
US5304540A (en) 1988-06-22 1994-04-19 Applied Microbiology, Inc. Pharmaceutical bacteriocin compositions and methods for using the same
MY106598A (en) 1988-08-31 1995-06-30 Australian Commercial Res & Development Ltd Compositions and methods for drug delivery and chromatography.
AU641903B2 (en) * 1988-10-26 1993-10-07 Glaxo Group Limited Carboxylic acid derivatives
IL92343A0 (en) * 1988-12-20 1990-07-26 Gist Brocades Nv Granulate for multiparticulate controlled release oral compositions,their preparation and oral pharmaceutical compositions containing them
IL92344A0 (en) 1989-01-04 1990-07-26 Gist Brocades Nv Microencapsulation of bioactive substances in biocompatible polymers,microcapsules obtained and pharmaceutical preparation comprising said microcapsules
IT1229502B (en) * 1989-01-25 1991-09-03 Euroresearch Srl COMPOSITIONS CONTAINING BISMUTO SUITABLE FOR THERAPEUTIC USE.
JP2694361B2 (en) * 1989-02-09 1997-12-24 アストラ アクチエボラグ Antibacterial agent
US5013560A (en) * 1989-03-17 1991-05-07 The Procter & Gamble Company Microbially-stable bismuth-containing liquid pharmaceutical suspensions
EP0403048A3 (en) * 1989-06-14 1991-01-30 Warner-Lambert Company Medicated compositions containing sucralfate and processes for their production
ATE98122T1 (en) 1989-09-07 1993-12-15 Gerhard Gergely GASOMIC ACID BINDING PHARMACEUTICAL PREPARATION.
FI910088A (en) * 1990-01-09 1991-07-10 Gist Brocades Nv ORAL PHARMACEUTICAL COMPOSITION.
US5466681A (en) * 1990-02-23 1995-11-14 Microcarb, Inc. Receptor conjugates for targeting penicillin antibiotics to bacteria
GB9010039D0 (en) * 1990-05-03 1990-06-27 Reckitt & Colmann Prod Ltd Medicament preparation
DE69117955T2 (en) * 1990-07-20 1996-09-19 Tillotts Pharma Ag PRODUCTS AND METHODS FOR TREATING THE DIGESTIVE CHANNEL
US5192752A (en) * 1991-01-14 1993-03-09 The Procter & Gamble Company Swallowable pharmaceutical compositions containing colloidal bismuth subcitrate
DK0589893T3 (en) 1991-04-15 1996-09-09 Applied Microbiology Inc Use of a bacteriocin as an antimicrobial agent for the manufacture of a medicament for the treatment of gastric disorders associated with helicobacter pylori
US5286497A (en) 1991-05-20 1994-02-15 Carderm Capital L.P. Diltiazem formulation
AU3073792A (en) 1991-11-25 1993-06-28 Richardson-Vicks Inc. Use of salicylic acid for regulating skin wrinkles and/or skin atrophy
CA2061870C (en) * 1992-02-26 1996-11-12 Mary Hodutu Medicinal compositions for use as a skin moisturizer and the treatment of exzema
IT1254321B (en) * 1992-04-10 1995-09-14 Kemiprogress S R L PHARMACEUTICAL COMPOSITION FOR THE TREATMENT AND PREVENTION OF CUTANEOUS INFLAMMATIONS AND ORAL MUCOSA.
US5294433A (en) * 1992-04-15 1994-03-15 The Procter & Gamble Company Use of H-2 antagonists for treatment of gingivitis
FR2692146B1 (en) * 1992-06-16 1995-06-02 Ethypharm Sa Stable compositions of gastro-protected omeprazole microgranules and process for obtaining them.
MX9304638A (en) * 1992-07-31 1994-05-31 Neose Pharm Inc COMPOSITION TO TREAT AND INHIBIT GASTRIC AND DUODENAL ULCERS.
US5368845A (en) 1993-01-07 1994-11-29 Colgate Palmolive Company Oral composition
IT1264494B1 (en) * 1993-03-23 1996-09-24 Alfa Wassermann Spa USE OF RIFAXIMIN AND FORMULATIONS THAT CONTAIN IT IN THE TREATMENT OF GASTRIC DYSPEPSIES ORIGINATED BY HELICOBACTER
JP3288550B2 (en) 1994-05-02 2002-06-04 オーバーシーズ ファーマテック株式会社 Oral topical formulation for killing Helicobacter pylori
US5834002A (en) 1994-05-02 1998-11-10 Josman Laboratories, Inc. Chewing gum containing colloidal bismuth subcitrate
US5536510A (en) * 1994-12-29 1996-07-16 Wm. Wrigley Jr. Company Chewing gum products containing a liquid aspartame dispersion
AU4596796A (en) * 1995-02-07 1996-08-27 Narayan Krishnarao Athanikar Concomitant treatment with bismuth and antibacterials
JP4497559B2 (en) 1995-06-22 2010-07-07 スリーエム カンパニー Stable hydroalcohol composition
US5804549A (en) 1996-01-05 1998-09-08 Ambi Inc. Compositions with activity against helicobacter
US5788974A (en) 1996-09-11 1998-08-04 D'amico; Steven A. Helicobacter pylori treatment compliance pack

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4801608A (en) * 1981-09-22 1989-01-31 Gist-Brocades N. V. Bismuth containing composition and method for the preparation thereof
US4822597A (en) * 1987-07-13 1989-04-18 Warner-Lambert Company Anesthetic-containing chewing gum compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0956007A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1300148A2 (en) * 2001-08-27 2003-04-09 Hedonist Biochemical Technologies Inc. Use of bismuth subgallate in inhibition of production of nitric oxide synthase
EP1300148A3 (en) * 2001-08-27 2003-05-21 Hedonist Biochemical Technologies Inc. Use of bismuth subgallate in inhibition of production of nitric oxide synthase
KR100440918B1 (en) * 2001-10-12 2004-07-21 롯데제과주식회사 A chewing gum and its composition
WO2003045403A1 (en) 2001-11-28 2003-06-05 Terry Dorcen Bolin Method of treating halitosis
EP1469867A1 (en) * 2001-11-28 2004-10-27 Terry Dorcen Bolin Method of treating halitosis
EP1469867A4 (en) * 2001-11-28 2005-10-05 Terry Dorcen Bolin Method of treating halitosis

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CA2270520A1 (en) 1998-05-14
EP0956007A4 (en) 2001-09-05
IL129599A0 (en) 2000-02-29
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AU5097698A (en) 1998-05-29
PL333101A1 (en) 1999-11-08
RO117415B1 (en) 2002-03-29
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US6616938B2 (en) 2003-09-09
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US5834002A (en) 1998-11-10
US20010036445A1 (en) 2001-11-01
KR20000052950A (en) 2000-08-25
US6258376B1 (en) 2001-07-10
AU730881B2 (en) 2001-03-15
CN1242703A (en) 2000-01-26

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