WO1996024342A1 - Traitement concomitant a base de composes au bismuth par voie orale - Google Patents

Traitement concomitant a base de composes au bismuth par voie orale Download PDF

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WO1996024342A1
WO1996024342A1 PCT/US1995/016171 US9516171W WO9624342A1 WO 1996024342 A1 WO1996024342 A1 WO 1996024342A1 US 9516171 W US9516171 W US 9516171W WO 9624342 A1 WO9624342 A1 WO 9624342A1
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bismuth
antibacterial
compounds
group
pylori
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Narayan Krishnarao Athanikar
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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
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    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/29—Antimony or bismuth compounds
    • A—HUMAN NECESSITIES
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    • 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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    • 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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    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof
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    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
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    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
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    • 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
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    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
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    • A—HUMAN NECESSITIES
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    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A61K8/66—Enzymes
    • A—HUMAN NECESSITIES
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    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
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    • A61K8/67—Vitamins
    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
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    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • 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

  • Helicobacter pylori (Goodwin et al., Int. J. Syst. Bacteriol. 39:397-405, 1989), have been demonstrated to be associated with gastritis and peptic ulcers (Buck et al. , J. Infect. Dis. 153:664-669, 1986 and Graham, Gastroenterology 96:615-625, 1989), and are thought to be transmitted by person-to-person contact.
  • H 2 receptor blockers which suppress acid secretion such as cimetidine (Tagamet ® ) and ranitidine (Zantac ® ), have been used to treat and heal duodenal ulcers (Jones et al., Gut. 28: 1120-1127, 1987; Mclsaac et al., Aliment. Pharmacol. Therap. 1:369-381, 1987; and Boyed et al., Amsterdam:Excerpta Medica, 14-42, 1984). Recently, however, a number of clinical investigations have demonstrated that 70-80% of healed duodenal ulcers reoccur within the next year (Goodwin et al., Int. J. Syst.
  • pylori is reported to be 8 mg/L (Lambert et al., Antimicrob. Agents Chemotherapy 3:510-511) and the range is 4-32 mg/L (Lambert et al. , Antimicrob. Agents Chemotherapy 3:510-511).
  • CBS has been demonstrated to enhance mucus glycoprotein secretion, strengthen viscoelastic gel properties of mucus, cause increased concentration of epithelial growth factor (EGF) in ulcer tissue, and stimulate prostaglandin synthesis in the gastric antral mucosa (Lee, Scandinavian Journal of Gastroenterology 26(Supplement 185): 1-6, 1991).
  • EGF epithelial growth factor
  • These gastroprotective properties of CBS may contribute to the initial healing of duodenal ulcers and the observed lower rates of relapse by returning the gastric mucosal cells to normal physiologic function.
  • Triple therapy consisting of an antibiotic (amoxicillin, tetracycline or erythromycin), metronidazole, and bismuth compounds, has 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 12-month follow-up period (Graham et al. , Gastroenterology 102:493-496, 1992 and Borody et al. , Gastroenterology 102:A 44, 1992). It is interesting to note that metronidazole as a single agent has only 5 % eradication rate for H.
  • metronidazole is actively secreted in the saliva (Mustofa et al., International Journal of Clinical Pharmacology, Therapy, and Toxicology 29(12): 474-478, 1991) where it might be exerting its antimicrobial action against dental plaque-bound H. pylori colonies.
  • the typical steady state saliva represent 10 to 20 times the MIC for H. pylori.
  • Clarithromycin a new-generation macrolide, which has shown a 40 to 60% cure rate as a single agent, is also secreted in the saliva. Therefore, it is reasonable to believe that in order to achieve nearly complete eradication of H.
  • CBS Colloidal bismuth subcitrate
  • the invention relates to concomitant treatment with bismuth compounds and/or with other antibacterial compounds and/or with antibiotics in topical oral and peroral dosage forms to eradicate H. pylori from its niches both in the dental plaque and in the gastric mucosa in order to improve the ulcer cure rate and prevent ulcer relapse.
  • the invention also provides oral topical dosage forms with pharmaceutically usable bismuth compounds and/or antibacterial compounds and/or antibiotics that eradicate or reduce H. pylori in dental plaque.
  • the invention further provides for treatment with bismuth compounds and/or antibacterial compounds and/or antibiotics which are effective against Campylobacter rectus and Treponema denticola which are responsible for causing halitosis.
  • the invention also provides bismuth compounds which have applications in wound healing, particularly in ocular and dermal wound healing.
  • Figure 1 is a generalized reaction diagram for the synthesis of bismuth sulfates.
  • Figure 2 is a graph of human saliva concentration versus time which shows the release of bismuth from CBS chewing gum.
  • bismuth compound used in this invention should be a pharmaceutically acceptable antimicrobacterial agent against H. pylori, such as colloidal bismuth subcitrate (CBS), bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, tripotassium dicitrato bismuthate and bismuth aluminate.
  • CBS colloidal bismuth subcitrate
  • tripotassium dicitrato bismuthate bismuth subcitrate, bismuth subsalicylate and their combination are chosen. More preferably, CBS and tripotassium dicitrato bismuthate are chosen. And further selection is made for CBS.
  • bismuth compounds namely complexes of polysulfates, of polyhydroxy compounds such as sugars, sugar alcohols, and ascorbic acid and its derivatives, as well as alpha-D-glucopyranoside bismuth complex, beta-D-fructofuranosyl-oktakis (hydrogen sulfate) bismuth complex, and L-dihydro ascorbyl-tetrakis (hydrogen sulfate) bismuth complex are part of the present invention.
  • a generalized reaction diagram for the synthesis of bismuth sulfates is shown in Figure 1.
  • Chemical structures of the compounds conceived in this invention are complexes of poly-sulfates and of poly-hydroxy compounds such as sugars, sugar alcohols, and ascorbic acid and its derivatives. These novel compounds will deliver bismuth more effectively and will have less side effects in treating H. Pylori positive duodenal ulcers and gastritis. These compounds moreover lend themselves to controlled release oral dosage forms and oral topical dosage forms for eradication of H. Pylori in dental plaque. Chemical structures of the compounds conceived in this invention are illustrated below:
  • the ascorbic acid-derived molecules are synthesized in a manner completely analogous to the reaction diagram for synthesis of bismuth sulfates set forth above. These compounds can also be used in embodiments relating to would healing as described below.
  • Antibiotics useful herein include, but are not limited to, Tetracycline, Amoxicillin, Ampicillin, Doxycycline, Erythromycin, Clarithromycin, Metronidazole, Tinidazole, Ciproflaxacin, Oflaxacin, Norflaxacin, Furazolidine, Nitrofurantoin.
  • Antibacterials useful herein include, but are not limited to naturally occurring peptides and synthetic peptide antibacterials such as Lanthocins, and particularly, Circuitn and related peptides, Proton pump inhibitors such as Omeprazole and Lansoprazole, Sanguinaria and other antibacterials obtained from plant sources, as well as bismuth-containing compounds.
  • the present methods utilize topical oral dosage forms to deliver bismuth compounds, antibiotics, and/or antibacterials directly to the oral cavity in concentrations sufficient to reduce or eliminate H. pylori in tn oral cavity.
  • Each oral-topical dosage form of this invention is the one which can make it possible to release bismuth compound and/or antibacterial compounds and/or antibiotics into oral cavity in a predictable manner and result in appropriate antibacterial concentration.
  • Those examples of such forms include a chewing-gum form, a chewable form including chewable tablets, lozenges, dental paints, viscous gels, dental implants, polymer film adhesives, a troche form, a toothpaste form, a gargling-gel form and mouth-rinse form.
  • a chewing-gum form and a troche form are chosen.
  • a chewing-gum form is most preferred due to its easy-to-use characteristic, predictable drug release and increased drug contact with dental surface.
  • the chewing gum delivery system especially enables sustained contact of the antibacterial agents with the entire oral cavity and therefore, enhance bactericidal/bacteriostatic efficacy.
  • chewing gum formulation containing an antibacterial agent, colloidal bismuth subcitrate releases the drug in a precise and reproducible fashion during a 15 minute chewing time.
  • Chewable tablets, Viscous get formulations and dental paint formulations also will be able to provide sustained concentration of antibacterial agents in the oral cavity .
  • Oral-topical dosage forms containing bismuth in this invention must release enough bismuth, antibiotic, and/or antibacterial into saliva for eradication of H. pylori in the oral cavity.
  • the minimum inhibitory concentration (MIC) of bismuth for H. pylori varies in each bismuth compound. For instance, it is reported that the MIC of CBS for H. pylori is 8 mg/L and its range is 4 to 32 mg/L.
  • the dosage form is required to release bismuth into saliva up to at least two times the MIC, preferably a minimum of 2 to 10 times, most preferably 2 to 250 times.
  • the bismuth content per dosage form should be about 50 mg to 200 mg, preferably a minimum of 10 mg to 50 mg, most preferably 25 mg to 50 mg.
  • each piece of CBS-containing chewing gum should contain approximately 50 mg to 200 mg of CBS, preferably a minimum of 10 mg to 50 mg, most preferably 25 mg to 50 mg.
  • Time release of each dosage form in this invention must be long enough to eradicate H. pylori. Although the duration of time release varies in each bismuth compound and in each dosage form, it is required at least 75 % of the dose is released within 2 minutes, preferably within 2 to 15 minutes, most preferably within 10 to 15 minutes.
  • a chewing gum drug delivery system is utilized to provide sustained concentration of bismuth compounds, antibiotics, and/or antibacterial compounds which are proven antibacterial agents against H. pylori and anti-plaque agents to help these compounds penetrate the dental plaques to reach the site of H. pylori infection.
  • the chewing gum delivery system enables sustained contact of the antibacterial agents with the entire oral cavity and therefore, enhances bacteriocidal efficacy.
  • oral-topical dosage form in this invention must release enough antibiotic/antibacterial into saliva for eradication of H. pylori from the oral cavity.
  • the minimum inhibitory concentration (MIC) varies for each antibiotic/antibacterial agent. However, for most of the antibiotics listed in this invention, the MIC values are between less than 1 to 10 mcg/mL, or 1 to 10 mg/L.
  • the topical-oral dosage from is required to release the antibacterial agent into saliva up to at least 2 times the MIC, preferably a minimum of 2 to 10 times, most preferably 2 to 100 times.
  • the antibacterial content per unit of dosage form should be about 10 to 100 mg, preferably a minimum of 5 to 50 mg, most preferably 10 to 25 mg.
  • each piece of chewing gum should contain approximately 10 to 100 mg. of the antibiotic or antibacterial agent.
  • the topical-oral dosage forms of this invention must release the antibiotic/antibacterial over an extended time.
  • the duration of release must be at least 5 minutes, preferably 10 minutes, most preferably 15 minutes. Further 75 % of the antibiotics/antibacterial content is required to be released within 5 minutes, preferably within 2 to 15 minutes, most preferably within 10 to 15 minutes.
  • a chewing gum delivery system is utilized to provide sustained concentration of antibiotic/antibacterial agent several times above its MIC for H. pylori over at least 10 times.
  • the anti-plaque agents further contribute to improved efficacy by breaking down the plaque and exposing the bacterial colonies to the antibacterial agents.
  • the chewing gum formulation containing CBS, antibiotic, and/or antibacterial releases the drug in a precise and reproducible fashion during a 15-minute chewing time.
  • Anti-plaque agents include, but are not limited to, glucanase anhydroglucosidase, glucose oxidase, silicon oil, sanguinarine, and the like.
  • Chewing gum formulations may optionally include crystalline sorbitol, sorbitol solution, mannitol, Nova-base TM , or any other gum base, dextrans, cellulose derivatives, buffer salts, sweeteners, flavors, and the like.
  • metronidazole can be added to CBS chewing gum to broaden the antimicrobial activity against H. pylori.
  • Bismuth compounds embodied in these inventions also have been found to stimulate cellular production of growth factors, and therefore have applications in wound healing, specifically in ocular and dermal wound healing. Therefore, the present invention also contemplates use of novel bismuth complexes with sulfated polyhydroxy hydrophilic film-forming polymers to accelerate wound healing in ulcerative diseases of the eye, skin, and other mucosal tissues.
  • the invention involves synthesis of unique complexes of bismuth with partially sulfated hydrophilic film-forming polymers such as hydroxyprobal cellulose, hydroxyethyl cellulose, hydroxypropyl-methyl cellulose, carboxymethyl cellulose, and poly vinyl alcohol.
  • chewing gum Brief general description of the preferred topical dosage form, chewing gum, is set forth as follows. Fully melt the gum base (at approximately 90°C) in Brabender 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.
  • the product 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. Where the gum is to include antibiotic or antibacterial compounds, the agent is coated with a polymeric substance to mask any untoward taste or odor, and to further regulate its release in the saliva.
  • CBS Colloidal Bismuth Subcitrate
  • other bismuth compounds including bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, tripotassium dicitrato bismuthate and bismuth aluminate.
  • colloidal bismuth subcitrate (CBS), tripotassium dicitrato bismuthate, bismuth subcitrate, bismuth subsalicylate are coated with the following coating agent to regulate their dissolution and salivary release: bee's wax, carnauba wax, shellac, cellulose acetate phthalate, methyl cellulose, propyl cellulose, hydroxy propyl- cellulose, ethyl cellulose, hydroxy propylmethylcellulose, ethylcellulose, polymethyl methacrylate, and Eudragit® polymers, polyvinyl pyrohidone, polyvinyl alcohol, etc.
  • CBS colloidal bismuth subcitrate
  • tripotassium dicitrato bismuthate bismuth subcitrate
  • bismuth subsalicylate are coated with the following coating agent to regulate their dissolution and salivary release: bee's wax, carnauba wax, shellac, cellulose acetate phthalate, methyl cellulose
  • Moderately water soluble bismuth compounds such as bismuth ascorbyl sulfate, bismuth sucrose sulfate, bismuth subascorbate, cyclodextrin bismuth sulfate are used in the chewing gum dosage form to produce sustained concentration in the saliva.
  • Synthetic and natural latex-based chewing gum bases are used to tightly enclose bismuth compounds and other antibacterial/antibiotic compounds to cause their gradual release in the saliva.
  • Saliva samples were analyzed for elemental bismuth in ppm units. The results were then converted to mg 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 (formula-2 of Table-3), the salivary concentrations of CBS are 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 viable cells of H. pylori. These results are plotted in Figure 2 which shows a graph of human saliva concentration versus time.
  • 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.
  • 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 (RT) was placed in one of two identical glass jars with lids. In the other jar was placed 500 mL of the Artificial Saliva (RT) containing 0.50% of CBS.
  • RT Artificial Saliva
  • 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.
  • 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 (R) ] 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).
  • Example 11 Composition of Antibiotic or Antibacterial-Containing Gum
  • the chewing gum formulation comprises antibiotic or antibacterial agents in concentration ranges from 10 to 50 mg per piece of gum.
  • the chewing gum-base consists of Crystalline Sorbitol, Gum Base, Sorbitol Solution, Mannitol, Peppermint Oil, Spray Dried Peppermint, Grade t Lecithin, Aspartame, and Sodium Citrate, as set forth in Table 1 above.
  • the formulation may also contain Glucanase, Anhydroglucosidase, Glucose oxidase, Silicon oil, Sanguinarine and related compounds as anti-plaque agents.
  • Saliva samples are analyzed for antibiotic or antibacterial agents in ppm units. The results are then converted to mg of active agent per mL of saliva and also expressed as a multiple of minimum inhibitory concentration (MIC) of the agent for H. pylori.
  • the salivary concentrations of the agent are 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 the agent (2 to 5 times the MIC) for up to 15 minutes can be expected to further reduce the viable cells of H. pylori. These results are plotted to show a graph of human saliva concentration versus time.
  • Sensory characteristics of the chewing gum are evaluated by the subjects during the 15 minutes of chewing. Again, three subjects chews the gum containing sodium citrate and three subjects chewed the gum without sodium citrate. A nine point rating scale is used to evaluate each category.
  • Topical safety is evaluated in the six volunteers for up to 60 minutes after administration of the gum. The subjects are asked to report any adverse effects such as discomfort or irritation in the oral cavity.
  • Samples of the agent-containing gum (50mg) are wrapped individually in foil wrappers. The sticks of gum are 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 is 90 days.
  • the test saliva is prepared by dissolving 0.500 g of the antibiotic or antibacterial agent in 100 mL of the above artificial saliva.
  • 500 mL of Artificial Saliva (RT) is placed in one of two identical glass jars with lids. In the other jar is placed 500 mL of the Artificial Saliva (RT) containing 0.50% of the agent.
  • RT Artificial Saliva
  • the denture material block and a magnetic stirrer is placed. The jars are then placed on the magnetic platform and set to agitate at a minimum rate.
  • the denture materials that are were exposed to artificial saliva containing the agent or placebo are included.
  • the four hour exposure of natural tooth and other denture materials to 0.5% of the agent in artificial saliva with mild agitation does not cause any staining, discoloration, or changes in texture.
  • H. pylori patients with positive response for the presence of H. pylori in the dental plaque/oral cavity are divided into two treatment groups.
  • Group I is given placebo chewing gum to be chewed 2 or 6 times a day for 2 or 4 weeks.
  • Group II is given chewing gum containing antibiotic/antibacterial agent to be chewed 2 or 6 times a day for 2 or 4 weeks.
  • Patient's dental plaque/saliva samples are collected at time 0 (Pre-treatment) on days 7, 14, 28, and tested for H .pylori presence and density. The incidence of H. pylori presence in the placebo group and the active treatment group is compared.
  • the group receiving the chewing gum containing antibiotic/antibacterial shows significantly lower incidence of H. pylori presence in the dental plaque/saliva compared to placebo chewing gum group after 2 and 4 weeks of treatment.
  • Campylobacter rectus, Helicobacter pylori, and Treponema denticola have been demonstrated to be associated with Halitosis (bad breath).
  • the 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 12 below.
  • Colloidal bismuth subcitrate and other bismuth compounds are known to accelerate wound healing by increasing the concentration of epithelial growth factor (EGF) and fibroblast growth factor (FGF) in the wounded tissue.
  • EGF epithelial growth factor
  • FGF fibroblast growth factor
  • rat mesentery culture model (Wu et al., Annals of Plastic Surgery 12(2): 155-161 (1994), incorporated herein by reference) and a medium containing 2% fetal calf serum, wound closure rates are measured.
  • This tissue culture model is useful for gaining insights into growth factor interactions and wound healing.
  • CBS or bismuth ascorbyl sulfate or glucose (placebo) are added to the medium in concentration ranges from 10 mcg/mL to 1,000 mcg/mL, and the wound closure is assessed at 24-hour, 48-hour and 72-hour intervals. Significantly higher concentrations of growth factors EGF and FGF are observed.
  • a significantly faster wound closure rate and complete closure is seen in the culture to which CBS or bismuth ascorbyl sulfate are added, compared to the placebo.
  • wound healing potential of the above bismuth compounds is evaluated using a diabetic mouse wound healing model (Matuszewska et al., Pharmaceutical Research 11(1):65-71 (1994), incorporated herein by reference).
  • Wounds treated with CBS and bismuth ascorbyl sulfate formulations at concentration ranges of 10 mcg/mL to 1 ,000 mcg/mL heal faster compared to placebo treated wound.
  • the wound healing rates produced by the bismuth compounds are comparable to the wound healing rate produced by 0.5 to 5 mcg/mL concentration of basic fibroblast growth factor (bFGF).
  • bFGF basic fibroblast growth factor

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Abstract

L'invention concerne un traitement concomitant à l'aide de composés au bismuth, d'autres composés antibactériens et/ou d'antibiotiques, sous administration topique orale et pérorale. Le traitement vise à éliminer la bactérie Helicobacter pylori des niches où elle se loge aussi bien dans la plaque dentaire que dans la muqueuse gastrique, en vue d'améliorer le taux de guérison des ulcères et d'éviter les récidives. On décrit par ailleurs des formulations pour l'administration topique par voie orale à base de composés pharmaceutiquement utilisables au bismuth, d'autres composés antibactériens et/ou d'antibiotiques qui permettent de détruire les bactéries Helicobacter pylori dans la plaque dentaire ou d'en limiter la prolifération. L'invention concerne en outre le traitement à base de composés au bismuth, d'autres composés antibactériens et/ou d'antibiotiques efficaces contre les genres bactériens Campylobacter rectus et Treponema denticola, qui sont à l'origine de l'haleine fétide. On décrit enfin des composés au bismuth applicables au traitement des blessures, en particulier pour la guérison des blessures oculaires et dermiques.
PCT/US1995/016171 1995-02-07 1995-12-08 Traitement concomitant a base de composes au bismuth par voie orale Ceased WO1996024342A1 (fr)

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PCT/US1995/015985 Ceased WO1996024341A1 (fr) 1995-02-07 1995-12-08 Traitement concomitant a base de bismuth and d'antibacteriens

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981499A (en) * 1998-02-20 1999-11-09 Atlantic Biomed Corporation Lesion-directed antibiotics in dry dosage forms for the treatment of shallow ulcers of the oral mucosa
US6017950A (en) * 1997-08-05 2000-01-25 Millennium Pharmaceuticals, Inc. Methods for controlling gram negative bacteria in mammals
US6248718B1 (en) 1999-08-18 2001-06-19 Atlantic Biomed Corporation Lesion-directed dry dosage forms of antibacterial agents for the treatment of acute mucosal infections of the oral cavity
EP0956007A4 (fr) * 1996-11-01 2001-09-05 Josman Lab Inc Chewing-gum contenant du sous-citrate de bismuth colloidal
CN110833561A (zh) * 2019-12-24 2020-02-25 正大制药（青岛）有限公司 一种奥美拉唑复方咀嚼片

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5753711A (en) * 1997-03-18 1998-05-19 Collagenex Pharmaceuticals, Inc. Method for treatment of H. pylori
FR2778104B1 (fr) * 1998-05-04 2002-08-30 Synthelabo Utilisation d'un vecteur d'ions fluorure pour la preparation d'un medicament destine a la prevention ou au traitement de maladies associees a helicobacter pylori
IN190017B (fr) 1999-01-25 2003-05-31 Panacea Biotech Ltd
CA2379040C (fr) * 1999-03-05 2010-01-26 Shanbrom Technologies, Llc Concentres solubles de couleurs naturelles et nutraceutiques antimicrobiens a base de plantes
AU784898B2 (en) * 2000-01-18 2006-07-20 Societe Des Produits Nestle S.A. Pet food composition for treating helicobacter species in pets
US6576625B2 (en) 2001-03-16 2003-06-10 Panacea Biotic Limited Targeted vesicular constructs for cytoprotection and treatment of H. pylori infections
US20030130225A1 (en) * 2001-10-16 2003-07-10 Nawaz Ahmad Novel methods of treating local fungal and bacterial infections

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0075992A1 (fr) * 1981-09-22 1983-04-06 Gist-Brocades N.V. Composition contenant du bismuth et sa préparation
US5196205A (en) * 1987-10-12 1993-03-23 Borody Thomas J Method for treatment of gastro intestinal disorders
US5264222A (en) * 1990-01-09 1993-11-23 Gist-Brocades N.V. Oral pharmaceutical compositions in unit dosage form

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2694361B2 (ja) * 1989-02-09 1997-12-24 アストラ アクチエボラグ 抗菌剤
US5466681A (en) * 1990-02-23 1995-11-14 Microcarb, Inc. Receptor conjugates for targeting penicillin antibiotics to bacteria
IT1254321B (it) * 1992-04-10 1995-09-14 Kemiprogress S R L Composizione farmaceutica per il trattamento e la prevenzione delle infiammazioni cutanee e della mucosa orale.
FR2692146B1 (fr) * 1992-06-16 1995-06-02 Ethypharm Sa Compositions stables de microgranules d'omeprazole gastro-protégés et leur procédé d'obtention.
IT1264494B1 (it) * 1993-03-23 1996-09-24 Alfa Wassermann Spa Uso di rifaximin e di formulazioni che la contengono nel trattamento delle dispepsie gastriche originate da helicobacter

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0075992A1 (fr) * 1981-09-22 1983-04-06 Gist-Brocades N.V. Composition contenant du bismuth et sa préparation
US5196205A (en) * 1987-10-12 1993-03-23 Borody Thomas J Method for treatment of gastro intestinal disorders
US5264222A (en) * 1990-01-09 1993-11-23 Gist-Brocades N.V. Oral pharmaceutical compositions in unit dosage form

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SCAND. J. GASTROENTEROL., Volume 26, (Suppl. 185), issued 1989, AXON, "Campylobacter Pylori - Therapy Review", pages 35-38. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0956007A4 (fr) * 1996-11-01 2001-09-05 Josman Lab Inc Chewing-gum contenant du sous-citrate de bismuth colloidal
US6017950A (en) * 1997-08-05 2000-01-25 Millennium Pharmaceuticals, Inc. Methods for controlling gram negative bacteria in mammals
US6271256B1 (en) 1997-08-05 2001-08-07 Millennium Pharmaceuticals, Inc. Methods for controlling gram negative bacteria in mammals with bicyclo spiroether compounds
US5981499A (en) * 1998-02-20 1999-11-09 Atlantic Biomed Corporation Lesion-directed antibiotics in dry dosage forms for the treatment of shallow ulcers of the oral mucosa
AU762585B2 (en) * 1998-02-20 2003-06-26 Kee Hung Hau Antibiotics in dry dosage forms for the treatment of shallow ulcers of the oral mucosa
US6248718B1 (en) 1999-08-18 2001-06-19 Atlantic Biomed Corporation Lesion-directed dry dosage forms of antibacterial agents for the treatment of acute mucosal infections of the oral cavity
CN110833561A (zh) * 2019-12-24 2020-02-25 正大制药（青岛）有限公司 一种奥美拉唑复方咀嚼片

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AU5019196A (en) 1996-08-27

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