WO1998019669A1 - Chewing gum containing colloidal bismuth subcitrate - Google Patents
Chewing gum containing colloidal bismuth subcitrate Download PDFInfo
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- 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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- bismuth
- chewing gum
- subcitrate
- colloidal
- compound
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/29—Antimony or bismuth compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/245—Bismuth; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/88—Polyamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth 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
- A61K9/0058—Chewing gums
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier 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
- A61Q17/005—Antimicrobial 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
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002270520A CA2270520A1 (en) | 1996-11-01 | 1997-10-31 | Chewing gum containing colloidal bismuth subcitrate |
PL97333101A PL333101A1 (en) | 1996-11-01 | 1997-10-31 | Chewing gum containing colloidal basic bismuth citrate |
BR9712730-2A BR9712730A (en) | 1996-11-01 | 1997-10-31 | Chewing gum containing colloidal bismuth subcitrate |
AU50976/98A AU730881B2 (en) | 1996-11-01 | 1997-10-31 | Chewing gum containing colloidal bismuth subcitrate |
HU0000163A HUP0000163A3 (en) | 1996-11-01 | 1997-10-31 | Chewing gum containing colloidal bismith subcitrate |
EP97913910A EP0956007A4 (en) | 1996-11-01 | 1997-10-31 | Chewing gum containing colloidal bismuth subcitrate |
IL12959997A IL129599A0 (en) | 1996-11-01 | 1997-10-31 | Chewing gum containing colloidal bismuth subcitrate |
RO99-00502A RO117415B1 (en) | 1996-11-01 | 1997-10-31 | Chewing gum pharmaceutical composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/741,781 US5834002A (en) | 1994-05-02 | 1996-11-01 | Chewing gum containing colloidal bismuth subcitrate |
US08/741,781 | 1996-11-01 |
Publications (1)
Publication Number | Publication Date |
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WO1998019669A1 true WO1998019669A1 (en) | 1998-05-14 |
Family
ID=24982168
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/019765 WO1998019669A1 (en) | 1996-11-01 | 1997-10-31 | Chewing gum containing colloidal bismuth subcitrate |
Country Status (13)
Country | Link |
---|---|
US (3) | US5834002A (en) |
EP (1) | EP0956007A4 (en) |
KR (1) | KR20000052950A (en) |
CN (1) | CN1140264C (en) |
AU (1) | AU730881B2 (en) |
BR (1) | BR9712730A (en) |
CA (1) | CA2270520A1 (en) |
HU (1) | HUP0000163A3 (en) |
ID (1) | ID22353A (en) |
IL (1) | IL129599A0 (en) |
PL (1) | PL333101A1 (en) |
RO (1) | RO117415B1 (en) |
WO (1) | WO1998019669A1 (en) |
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KR100440918B1 (en) * | 2001-10-12 | 2004-07-21 | 롯데제과주식회사 | A chewing gum and its composition |
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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 |
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EP1469867A4 (en) * | 2001-11-28 | 2005-10-05 | Terry Dorcen Bolin | Method of treating halitosis |
Also Published As
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HUP0000163A3 (en) | 2001-02-28 |
BR9712730A (en) | 1999-12-21 |
HUP0000163A2 (en) | 2000-06-28 |
CA2270520A1 (en) | 1998-05-14 |
EP0956007A4 (en) | 2001-09-05 |
IL129599A0 (en) | 2000-02-29 |
EP0956007A1 (en) | 1999-11-17 |
AU5097698A (en) | 1998-05-29 |
PL333101A1 (en) | 1999-11-08 |
RO117415B1 (en) | 2002-03-29 |
ID22353A (en) | 1999-09-30 |
US6616938B2 (en) | 2003-09-09 |
CN1140264C (en) | 2004-03-03 |
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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