MXPA99004186A - Chewing gum containing colloidal bismuth subcitrate - Google Patents
Chewing gum containing colloidal bismuth subcitrateInfo
- Publication number
- MXPA99004186A MXPA99004186A MXPA/A/1999/004186A MX9904186A MXPA99004186A MX PA99004186 A MXPA99004186 A MX PA99004186A MX 9904186 A MX9904186 A MX 9904186A MX PA99004186 A MXPA99004186 A MX PA99004186A
- Authority
- MX
- Mexico
- Prior art keywords
- bismuth
- chewing gum
- subcitrate
- colloidal
- compound
- Prior art date
Links
- 235000015218 chewing gum Nutrition 0.000 title claims abstract description 106
- 229940112822 Chewing Gum Drugs 0.000 title claims abstract description 104
- 229960004645 bismuth subcitrate Drugs 0.000 title claims description 38
- BJTMZHBPYPNQSV-UHFFFAOYSA-L bismuth;3-carboxy-3,5-dihydroxy-5-oxopentanoate;3-carboxy-5-hydroxy-3-oxido-5-oxopentanoate;potassium Chemical compound [K].[K].[K].[Bi+3].OC(=O)CC(O)(C(O)=O)CC([O-])=O.OC(=O)CC([O-])(C(O)=O)CC([O-])=O BJTMZHBPYPNQSV-UHFFFAOYSA-L 0.000 title claims 18
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims abstract description 69
- 239000000203 mixture Substances 0.000 claims abstract description 67
- 229910052797 bismuth Inorganic materials 0.000 claims abstract description 65
- 239000000796 flavoring agent Substances 0.000 claims abstract description 23
- 206010006326 Breath odour Diseases 0.000 claims abstract description 14
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001622 bismuth compounds Chemical class 0.000 claims description 40
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- ZREIPSZUJIFJNP-UHFFFAOYSA-K Bismuth subsalicylate Chemical compound C1=CC=C2O[Bi](O)OC(=O)C2=C1 ZREIPSZUJIFJNP-UHFFFAOYSA-K 0.000 claims description 12
- 229960000782 bismuth subsalicylate Drugs 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- ANERHPOLUMFRDC-UHFFFAOYSA-K 5-hydroxy-2,8,9-trioxa-1-bismabicyclo[3.3.2]decane-3,7,10-trione Chemical compound [Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O ANERHPOLUMFRDC-UHFFFAOYSA-K 0.000 claims description 10
- 230000003115 biocidal Effects 0.000 claims description 10
- HWSISDHAHRVNMT-UHFFFAOYSA-N Bismuth subnitrate Chemical compound O[NH+]([O-])O[Bi](O[N+]([O-])=O)O[N+]([O-])=O HWSISDHAHRVNMT-UHFFFAOYSA-N 0.000 claims description 9
- 229960001482 bismuth subnitrate Drugs 0.000 claims description 9
- REKWPXFKNZERAA-UHFFFAOYSA-K bismuth;2-carboxyphenolate Chemical compound [Bi+3].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O REKWPXFKNZERAA-UHFFFAOYSA-K 0.000 claims description 9
- 229910000014 Bismuth subcarbonate Inorganic materials 0.000 claims description 8
- MGLUJXPJRXTKJM-UHFFFAOYSA-L bismuth subcarbonate Chemical compound O=[Bi]OC(=O)O[Bi]=O MGLUJXPJRXTKJM-UHFFFAOYSA-L 0.000 claims description 8
- 229940036358 bismuth subcarbonate Drugs 0.000 claims description 8
- -1 busm.uto subnitrate Chemical compound 0.000 claims description 8
- 229940104825 bismuth aluminate Drugs 0.000 claims description 7
- ZWSUTHPTOGDVHM-UHFFFAOYSA-N bismuth;oxido(oxo)alumane Chemical compound [Bi+3].[O-][Al]=O.[O-][Al]=O.[O-][Al]=O ZWSUTHPTOGDVHM-UHFFFAOYSA-N 0.000 claims description 7
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- SULICOHAQXOMED-UHFFFAOYSA-H bis(5,6-dihydroxy-4,7-dioxo-1,3,2-dioxabismepan-2-yl) 2,3-dihydroxybutanedioate Chemical compound [Bi+3].[Bi+3].[O-]C(=O)C(O)C(O)C([O-])=O.[O-]C(=O)C(O)C(O)C([O-])=O.[O-]C(=O)C(O)C(O)C([O-])=O SULICOHAQXOMED-UHFFFAOYSA-H 0.000 claims description 6
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims description 6
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- FEWJPZIEWOKRBE-UHFFFAOYSA-L 2,3-dihydroxybutanedioate Chemical compound [O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-L 0.000 claims 1
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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
MASK RUBBER CONTAINING COLOIDAL BISMUTO SUBC1TRATE
BACKGROUND OF THE INVENTION
This invention relates to chewing gum compositions containing active ingredients. More particularly, this invention relates to the production of chewing gums containing compounds for treating ulcers and halitosis. The 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 administration of active agents. These active agents can be a variety of breath fresheners or medications, such as laxatives, aspirin or nicotine. The administration of these medications through a chewing gum vehicle is desirable for people who have difficulty swallowing pills. Also, the bad taste of some of the agents with stronger flavoring agents than chewing gum can be disguised, which can make the gum a suitable vehicle for the administration of certain medicines. In addition, some medicines can be absorbed directly into the bloodstream through the lining of the mouth tissue, making it easier to take medicine
if it is absorbed through the gastrointestinal walls. Accordingly, many people may benefit from new discoveries of how to effectively administer active ingredients by means of a chewing gum formulation. Unfortunately, said active ingredients are not suitable for administration by means of a chewing gum for a variety of reasons. A chewing gum can not be effective if it has unpleasant medicinal taste, causes a discoloration in the user's mouth or the active ingredient causes deficient chewing characteristics. Chewing gum can not be effective if it is not easily released from the active ingredient in the gum and therefore does not administer either to the mouth or stomach where the current can typically be absorbed. For this reason, many active ingredients can be effectively administered by chewable tablets or deglubal tablets, but not by chewing gum. Recent discoveries have associated bacterial infection in the active cause process of peptic ulcer disease. The bacteria that you have found is associated with peptic ulcers has been identified as Helicobacter pylori. It is no longer thought that excessive gastric acidity and mental tension are the main pathophysiological reasons for the occurrence of peptic ulcers, and doubts have been raised about the paradigms and fully established approaches to the treatment and cure procedures ulcers.
Previously, ulcers were treated by suppressing the secretion of acid in the stomach. H2-receptor blockers, such as cimetidine (Tragamet®) and Ranitidine (Zantac®), suppress acid secretion and have been used to treat and cure duodenal ulcers. However, these H2 receptor bleaches do not eliminate the bacterium Helicobacter pylori ("H.
Pylori ") .These drugs do not reverse the tendency for ulcers to form.For many years, bismuth compounds have been used in the form of swallowable tablets and in liquid form to treat ulcers.The therapeutic efficacy of bismuth compounds, such as Colloidal bismuth subcitrate (SBC), also known as tripotassium tripithium bismutate, to cure duodenal ulcers and decrease relapse rates is attributed to its specific antibacterial activity against H. pylori, however, using bismuth compounds alone, it has been reported to about H. pylori radiation indices and approximately 10 to 40% .Also, patients would suffer a relapse of ulcers after discontinuing bismuth compounds.Although as a single agent the SBC is significantly more effective at eradicating H. pylori than many other antibiotics, have been formed to near multiple therapies and bismuth compounds combined with other antibiotics which result in more than 95% of the H. pylori radiation index and have reduced the relapse rate of ulcers by at least 10% during a 12-month continuity period. For example, it has been reported that one such common triple therapy, consisting of
SBC, amoxicillin and metronidazole, has a high start of effectiveness. However, it would be desirable to achieve so much effectiveness in the eradication of H. pylori with simple therapies of single agents. None of the many unique agents have proven to be effective so far.
BRIEF DESCRIPTION OF THE INVENTION
The present invention therefore relates to the development of a chewing gum formulation to effectively eradicate H. pylori colonies without the need for antibiotic therapies in combination. This invention relates to a chewing gum formation containing a water soluble bulk portion, a water-insoluble 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 subgalate, bismuth aluminate, and combinations thereof. It has been found that this chewing gum eradicates or reduces H. pyiori in deposits of the oral cavity and in citium infection and ulceration in the gastric mucosa. The emission further provides a method for treating H. pylori infection by administering a chewing gum containing an amount of bismuth in a bismuth-containing compound equivalent to between about 10 and 200 mm of colloidal bismuth subcitrate. The emission
further provides the method for treating halitosis by administering a chewing gum containing bismuth compounds. DETAILED DESCRIPTION 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 portion on the water is dissipated with a portion of the flavoring agents for a period while chewing. The base portion of gum in the mouth is retained throughout the chewing process. The insoluble gum base generally includes elastomers, resins, fats, oils, waxes, inorganic fillers and inorganic fillers. The elastomers may include polyisobutylene, isobutylene-isoprene copolymer, styrene and butadiene rubber and natural latexes, such as chewing gum. The resins may include polyvinyl acetate and terpene resins. Low molecular weight polyvinyl acetate is a preferred resin. Fats and oils may include animal fat such as lard and pork, 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 beeswax, candelia, carnauba and polyethylene wax. Preferably, the waxes have a melting point between 35 ° C and 115.5 ° C.
The gum base typically also includes a filler component such as calcium carbonate, magnesium carbonate, talus, dicalcium phosphate and the like; elastomers, including glycerol monostearate and glierol triacetate; optional ingredients such as antioxidants, colors and emulsifiers. The gum base constitutes between 5 and 95% by weight of the composition of the chewing gum, more typically 10 and 50% by weight of the chewing gum commonly 25-35% by weight of the chewing gum. The water soluble portion of the chewing gum can include softeners, bulk sweeteners, high density sweeteners and combinations thereof. The softeners are added to the chewing gum in order to optimize the chewiness and the feel of the gum in the mouth. The softeners, which are also known as classifiers or plasticizing agents, generally constitute and between about 0.5 and 15% by weight of the chewing gum. Softeners may include glycerin, lecithin and combinations thereof. The softeners may also include aqueous coloring solutions such as those containing sorbitol, hydrogenated starch hydrolysates, corn syrup and combinations thereof. Mass sweeteners constitute between 20 and 80% by weight of the chewing gum and can include both sugar and sweeteners and sugar-free components. Sugar sweeteners may include components containing saccharides including, but not limited to, sucrose, dextrose, maltose, dextrin, invert sugar
dry, fructose, levulose, galactose, corn syrup solids and the like, alone or in combination. Sweeteners without sugar include components with sweetening characteristics, but they are devoid of the sugars commonly known. Sweeteners without sugar include but are not eliminated to the same 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, aspartame, acesulfame salts, alitame, saccharins and their salts, cyclamic acid and its salts, dihydrochalcones, thaumatin, monelin and the like, alone or in combination. Combinations of sweeteners with sugar and / or without sugar can be used in chewing gum. The sweetener may also function in the chewing gum as a whole or in part as a water-soluble filler. Additionally, the softener can also provide additional sweetness such as aqueous sweeteners of sugar or alditol. 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 0.5-3% by weight of the chewing gum. Flavoring agents may include essential oils, synthetic flavors and mixtures thereof including, but not limited to, oils derived from
plants and fruits such as citrus oils, fruit essences, peppermint oil, spearmint oil, other peppermint oils, clove oil, gualteria oil such as anise and the like. Flavoring agents and components may also be used. Natural and artificial flavoring agents can be combined in any sensibly acceptable manner. All the flavors salts and flavor mixtures are contacted for the present invention. Optional ingredients such as colors, such as titanium dioxide and the like, emulsifiers and pharmaceutical agents may also be included in the chewing gum. The pharmaceutical agents active in this chewing gum formulation of this invention include bismuth non-H2 antagonist compounds. These bismuth compounds include colloidal bismuth subcitrate (SBC), bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartar, bismuth subgalate and bismuth aluminant. Preferably, the bismuth compound is selected from colloidal bismuth subcitrate (SBC), bismuth subcitrate, bismuth subsalicylate and combinations thereof. More preferably, the bismuth compound is colloidal bismuth subcitrate (SBC). The structural formula of the SBC is:
[Bi (OH3)] 3BiC6H6? 7 (ACIDO1, 2,3-PROPANOTRICARBONIC, 2-HYDROXY, BISMUTO (3T) POTASSIUM); CAS # 57644-54-9
The colloidal bismuth substrate and other bismuth compounds may be coated, microencapsulated or agglomerated, before incorporating the chewing gum formulation to cause in addition to slow dissolution and sustained concentration of the saliva compounds.
The polymers used for the coating or encapsulation may include methylene chloride, carboxymethyl cellulose, hydroxylpropylmethylcellulose, ethylcellulose, carbocera, polyethylene glycols, acrylic polymers, to name a few.
For example, the SBC may be coated with a coating solution containing hydroxypropylene and polyethyleneglycol in a hydroalcoholic solvent using a coating equipment with the fluid fact. The coated SBC particles should be analyzed in terms of SBC content and dissolution characteristics. It is preferred that the chewing gum formulation containing bismuth compound be able to release the drug accurately and reproducibly during a fifteen minute chewing time. The preparation of the bismuth compound using any of the above techniques can achieve such uniform release. The chewing gum formulations may also include anti-plaque agents. Antiplaque agents also contribute to improved efficiency by breaking down the plaque and exposing the bacterial colonies of
H. pylori the bacterial agents. Antiplaque agents include, but not
they are limited to them, which is not glucose anhydroglucosidase, glucose oxidase, calcium kaolin, silicone oil, bloodthirsty, and the like. Optionally, an antibiotic, such as metronidazole, can be added to the chewing gum formulation to extend the antimicrobial activity against H. pylori. However, a preferred form of chewing gum comprises an active pharmaceutical agent consisting essentially of a bismuth compound selected from the group consisting of colloidal bismuth subcitrate (SBC), bismuth citrate, bismuth subcitrate, bismuth salicylate, subsalicylate of bismuth, bismuth subnitrate, bismuth subcarbonate, bismuth tartar, bismuth sabgalate and bismuth aluminate. The chewing gum is generally manufactured by sequentially adding the various chewing gum ingredients to any commercially available mixture known in the art. Generally, the ingredients are mixed by first melting the gum base and adding it to the working mixture. The gum base can be melted alternately in the mixture. Color and emulsifiers can be added at this time. A softener such as glycerin can be added together with a syrup and part of the bulk portion. Additional portions of the bulk portion can then be added to the mixer. Flavoring agent, pharmaceutical agent and other optional ingredients of this kind are typically added to the final portion of the bulk portion. The entire mixing process typically takes five to fifteen minutes,
although sometimes longer mixing times are required. The aspects of the art will recognize that variations of this mixing procedure or other mixing procedures can be followed. After the ingredients have been mixed thoroughly, the gum mass is discharged from the mix and shaped in the desired manner such as filling to form sheets and cutting to form bars by pulling out to form coarse and short pieces or emptying to form pellets. The rubber in pellet or in ball is prepared like a conventional chewing gum, but it is formed either as pellets that have a pillow shape or as balls. The pellets / balls can be coated or coated by conventional dragee techniques to make a single gum coated with sugar. Conventional dragee processes generally apply a liquid coating to a pellet, which then solidifies, usually drying the coating. The hard bark coating layer is formed by successive coating and drying steps. Conventional dragee processes generally coat sucrose, but recent advances in dragee have allowed the use of other carbohydrate materials that are used in place of sucrose, but nonetheless obtain a hard crust coating. Some of these components include, but are not limited to, dextrose, maltose, xylitol, lactitol, palatinit, and other novel alditols or a combination thereof. You can mix these materials like
grafting modifiers including, but not limited to, gum arabic, maltodextrins, corn syrup, gelatin, cellulose-type materials such as carboxymethylcellulose or hydroxymethylcellulose, modified starch and starches, vegetable gums such as alginates, acacia bead gum, guar gum and tragacanth gum, insoluble carbonates such as calcium carbonate or magnesium carbonate, and talc. Anti-scalping agents can also be added as grafting modifiers, which allow the use of a variety of carbohydrates and sugar alcohols that can be used in the development of new grafted or coated rubber products. Flavors can be added with the sugar coating and with the mass sweetener to produce unique characteristics of the product. The chewing gum formulation of the present invention is superior to conventional therapy for treating ulcers. It turns out that conventional therapy with bismuth proved to be only slightly effective in the removal of H. pylori from the gastric mucosa, but had no effect on H. pylori colonies in dental pl. The colloidal bismuth subcitrate (SBC), an effective agent against H. pylori, is not, however, significantly absorbed from the gastrointestinal tract and therefore produces insufficient salivary concentrations through systemic recirculation to affect H. pylori in the mouth. This continued presence of H. pylori in the dental pl impossibly the throat and esophagus, raises the question whether relapse of ulcers was inevitable with conventional therapy with bismuth.
It has been observed that multiple therapies of bismuth compounds combined with other antibiotics are superior to conventional bismuth therapy. Typical combinations include bismuth subsaiccylate, metronidazole and amoxicillin or tetracycline. A possible explanation of the observed clinical efficacy of the combination of antibiotic and bismuth that has not been anticipated by the scientific community that metronidazole is actively secreted in saliva where it may be exerting antimicrobial action against H. pyiori colonies limited to ia dental plaque that can not reach bismuth compounds administered alone in deglutible tablets. Interestingly, antibiotics administered as single agents were only partially effective. Although metronidazole is secreted in saliva and can eradicate H. pylori in the mouth, it is not effective in eradicating single H. pylori management in the gastric mucosa, ie the stomach. Therefore, assuming that the explanation is correct, it is reasonable to believe that in order to achieve the almost complete eradication of H. pylori and prevent relapse of ulcers, it is essential to eradicate the bacteria from the oral cavity, and possibly the throat and esophagus. , as well as the gastric mucosa. However, it was not known if the bismuth compounds would be therapeutically effective in the oral cavity. In the previous use of CBV against ulcers, it was known that CBV underwent conversion to bismuth trioxide under the influence of gastric acids in the stomach.
Conventional wisdom accepted that bismuth trioxide was the product
in the eradication of H. pylori duodenal. Therefore, it was not expected that the
SBC in a chewing gum will show efficacy in the eradication of H. pylori in the mouth. In addition, it was not known at what dose levels the bismuth compounds would provide therapeutic effectiveness, if at all, for topical use in the mouth. The chewing gum formulations in this invention have since been shown to be therapeutically effective in clinical studies. Preferably, the chewing gum releases sufficient bismuth to the saliva for the eradication of H. pylori in the oral cavity. The minimum inhibitory concentration (MIC) of bismuth for H. pylori varies for each bismuth compound. For example, it is established that the CIM of the SBC for H. pylori is 8 μg / ml and its range is from 4 to 32 μg / ml. Therefore, to ensure effectiveness, the chewing gum formulation preferably releases bismuth to the saliva at least up to twice the MIC, preferably a minimum of 2 to 10 times the MIC, more preferably 2 to 250 times the CIM. To achieve these concentrations in the saliva, the bismuth content per dose of the chewing gum may 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 approximately 28 mg. The amount of bismuth-containing compound per dose is then determined by the bismuth content of that particular compound. For example, each piece of chewing gum that
contains SBC contains between about 10 mg and about 200 mg of SBC, preferably between about 10 mg and about 100 mg, and more preferably between about 25 mg and about 25 mg. Accordingly, each piece of gum may include amounts of other bismuth compounds that provide the same bismuth equivalent as the above-mentioned ranges of SBC. Of course, the amount of bismuth compound in each piece can be divided in half, so that a person would chew two pieces at a time to have the same effective amount of bismuth. Also, the chewing gum would 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 a day, more preferably between two and six times a day. In addition, the chewing gum administered may comprise an active pharmaceutical agent consisting essentially of a bismuth compound selected from the group consisting of colloidal bismuth subcitrate (SBC) bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subagalate 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 which is itself administered. The bismuth content of the swallowable tablet may be equivalent to between about 300 mg and 1200 mg of colloidal bismuth subcitrate per day, preferably. The concomitant treatment can be administered once or twice a day, more preferably once a day. A wide variety of changes and modifications to the embodiments of the invention described above will be apparent to those skilled in the art. The following examples are not to be construed as limitations imposed on the invention, but are merely included to illustrate the preferred embodiments.
EXAMPLE 1 PREPARATION OF THE ACTIVE AGENT
To an aqueous solution of ammonia is 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 solution is added.
ammonia to make the solution transparent. The solution is then filtered on a carbon bed and dried by expression to obtain the free-flowing powder material. The product is packaged in a glass container that is proof of air and moisture.
EXAMPLE 2 PREPARATION OF THE MASCARA RUBBER
A brief general description is set forth as follows. Completely melted rubber base (at approximately 90 ° C) is bartender mixer, mixer with cover and sigma blades. Remove the hot water from the mixer cover, let cool, and add lecithin and honey mixtures. Continue to cool approximately 50 ° C and add liquid flavor and mannitol. Mix until uniform. Dry mix the colloidal bismuth subcitrate in sorbitol and mix sodium citrate in serba syrup. Add mixtures of sorbitol and serba syrup to the gum base. Chill the product at 35 ° C, add flavor and sweetener and mix until homogeneous. Remove the product from the mixer, go over to form a sheet of uniform thickness and mark to produce rubber bars of macar weighing 2.5 g each. Turn the individual rubber bars into aluminum foil and place them on plastic sheets.
EXAMPLE 3 COMPOSITION OF RUBBER CONTAINING SBC
Two varieties of gum are prepared with 50 mg of SBC, 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 RUBBER (APPROXIMATELY 2.5 GM PER PIECE)
Formula -1 Formula-2 SBC 50.0 mg SBC 50.0 mg
Crystal Sorbitol 910.0 Crystal Sorbitol 910.0
Rubber base 575.0 Rubber base 575.0
Sorbitol solutions 500.0 Sorbitol solutions 500.0
Mannitol 400.0 Mannitol 400.0
Peppermint oil 25.0 Peppermint oil 25.0
Spray dried mint 12.5 Spray dried mint 12.5
Lecithin grade t 10.0 Lecithin grade t 10.0
Aspartame 10.0 Aspartame 10.0
Sodium Citrate 10.0 Total 2502.5mg Total 2492.5mg
EXAMPLE 4 MEASUREMENT OF THE SPEED OF LIBERATION OF THE BISMUTO IN SALIVA
Among five healthy human subjects, who gave informed consent, three masks contained gum containing SBC with sodium cerate and the other three gum masks containing SBC without sodium citrate. The objects mask the rubber bags for a total of 15 minutes. Earlier saliva samples were collected from time 0, 1, 5, 10 and 15 minutes of chewing. The saliva sample was then presented to an analytical laboratory for the analysis of the same bismuth. The results of table 2 below are shown.
TABLE 2 IN VIVAL SALIVAL CONCENTRATION OF MASK GUM
Volume Times Concentration Concentration Mask of active SBC Formula (min) (mL) (ppm) (μq / mL) XCIM 0 4.4 (+0.5) 3.3 (+1.4) 900.7 (+239.1) 1270.3 (± 334.7) 148.7 ( +42.0) formula -1 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) 572.2 (± 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)
The saliva samples were analyzed as elemental bismuth of units of ppm. The results were then converted to μg of
SBC active for my saliva and were also expressed with a multiple of concentration and minimum inhibitory (MIC) of SBC for H: pylori. As can be seen from the results for formula 2, the salivary concentrations of SBC are approximately 156, 64, 5, and 1.8 times the MIC at 1, 5, 10 and 15 minutes, respectively. It can be expected that constant bathing of the oral cavity by exit containing sufficient concentration of SBC (2 to 5 times the MIC) for up to 15 minutes will last longer the population of viable cells of H. pylori.
EXAMPLE 5 SENSORI ANALYSIS OF THE MASCARA RUBBER
The sensory characteristics of the chewing gum were devalued by subjects for 15 minutes of the cell. Again, three subjects chewed gum with SBC containing sodium citrate and three subjects chewed gum by SBC without sodium citrate. A 9-point evaluation scale was used to assess each category. The results of tables 3 and 4 below are shown.
TABLE 3
RESULTS OF THE ANALYSIS EVALUATION
SBC RUBBER SENSORI
WITHOUT SODIUM CITRATE
(FORMULA 1) Masking time Sensory characteristics 1 Min 5 Min 10 Min 15 Min
General insurance 6.3 6.0 5.3 5.0
(0 = extremely upset, (± 1 -2) (± 1.0) (± 1 -5) (± 1.0)
8 = extremely liked) Intensity of taste 5.7 4.7 3.7 3.0
(0 = none, 8 = very strong) (± 1 -5) (± 1 -2) (+0.6) (+1.0) Masking qualities 6.0 6.0 5.3 5.0
(0 = extremely upset, (+1.0) (+1.0) (+1.5) (+1.0) 8 = extremely liked) Unpleasant taste 0.0 0.0 0.0 0.0
(0 = none, 8 = very strong) (+0.0) (± 0.0) (+0.0) (± 0.0) General qualities 6.3 6.0 5.7 5.3
(0 = extremely upset, (+1.2) (+1.0) (+1.2) (+1.5) 8 = extremely liked)
TABLE 4
RESULTS OF THE EVALUATION OF THE SENSOR ANALYSIS! OF THE SBC RUBBER WITH SODIUM CITRATE (FORMULA 2)
Chewing time Sensory characteristics 1 Min 5 Min 10 Min 15 Min General insurance 6.7 5.7 4.7 4.7
(0 = extremely upset, (+0.6) (+1.5) (+1.2) (+1.2) 8 = extremely liked) Intensity of taste 6.7 6.0 5.0 3.7 (0 = none, 8 = very strong) (± 0.6) (± 0.0) (± 1 -0) (± 1 -5) Masking qualities 4.7 5.0 4.3 4.3
(0 = extremely upset, (± 2-1) (+2.0) (± 1 -5) (+0.6) 8 = extremely liked) Unpleasant taste 0.7 1.7 1.7 2.0 (0 = none, 8 = very strong) (± 1 -2) (± 2-1) (± 2.1) (± 2.0) General qualities 6.3 5.7 4.7 4.0
(0 = extremely upset, (+0.6) (± 1 -2) (± 1 -2) (+1.0) 8 = extremely liked)
In general, there were no notable differences in the sensory analysis between the two formulas. In the sensory jury it clearly shows that both formulations of gum have a desirable level of taste and taste and cause a minimum unpleasant taste after chewing.
EXAMPLE 6 TOPICAL SAFETY
Topical safety was evaluated in 6 volunteers for 60 minutes after the administration of the gum. The subjects that will form a fence of any adverse effects, discomfort or irritation in the oral cavity were fired. There were no reports of discomfort or irritation in the oral cavity of any of the subjects at 15 or 60 minutes after the administration periods.
EXAMPLE 7 THE STUDY ON STABILITY DURING STORAGE
Chewing gum samples containing 50 mg of SBC in wraps and foil were individually wrapped. The rubber pieces were then placed in metal bags, sealed and placed in storage. Storage conditions include 40 ° C and ambient temperature (RT). The duration of the stability tests was 90 days. The results are shown in Tables 5-8 below.
TABLE 5 STABILITY DATA OF THREE MONTHS IN VIVID SALIVARIAN CONCENTRATIONS IN HUMAN SUBJECTS OF SBC OF THE MASK GUM WITH 50 MG OF SBC
TIME / VOLUME TIME CONCENTRATION CONCENTRATION CONCENTRATION CONDITION BIV SALIVA (Bi) ppm Bi (μg / ml) SBC ACTIVE (min) (mi) (μg / ml) X MIC TIME 0 4.2 (± 1.6) ND ND ND ND ZERO 1 4.9 (± 4.5) 1937.3 (± 753.5) 1937.3 (1753.5) 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) ND ND ND ND 15 1 2.9 (± 1.8) 1922.3 (± 511.8) 1922.3 (1511.8) 2710.0 (± 791.9) 338.6 (± 90.3) 5 5.6 (± 1.7) 399.3 (± 278.1) 363.7 (± 113.3) 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) 54.4 (± 20.1) 10.7 (± 6.7) 10.8 (± 6.8) 1.4 (± 0.9)
TABLE 5 (CONTINUED) 3 MONTHS AT AMBIENT TEMPERATURE
. 1 (± 1.3) ND ND ND ND
1 4.1 (± 1.5) 1240.0 (± 458.7) 1240.0 (1458.7) 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 10
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TABLE 6 STABILITY DATA FOR THREE MONTHS RESULTS OF THE RATING SENSOR ANALYSIS ASSESSMENT WITH 50 MG OF SBC
MASCURE TIME
CHARACTERISTIC
SENSOR 1 MIN 5 MIN 10 MIN 15 MIN = C5 GENERAL 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)
MASCULTURAL QUALITIES 6.7 (± 0.6) 6.3 (± 0.6) 5.7 (± 0.6) 5.3 (± 0.6) UNUSUAL THRUST OO (± OO) OO (± OO) 0.0 (± 2.1) 0.0 (± 0.0) GENERATING QUALITIES 6.7 ( ± 0.6) 6.3 (± 0.6) 5.7 (± 0.6) 5.3 (± 1.2)
3 MONTHS AT 40 ° C GENERAL SAVER 6.0 (± 0.0) 4.7 (± 0.6) 2.7 (± 1.2) 2.7 (± 1.2)
TASTE INTENCITY 5.3 (± 1.2) 3.0 (10.0) 2.3 (± 0.6) 2.0 (± 1.0)
MASCULTURAL QUALITIES 5.7 (± 0.6) 5.0 (± 1.0) 4.3 (± 0.6) 4.3 (± 0.6) UNPLEASANT THRILL 0.3 (± 0.6) 0.3 (± 0.6) 0.0 (± 0.0) 0.0 (± 0.0)
TABLE 6 (CONTINUED) GENERAL QUALITIES 6.0 (± 0.0) 4.3 (± 0.6) 2.7 (± 0.6) 2.3 (± 0.6)
3 MONTHS AT AMBIENT TEMPERATURE GENERAL TASTE 6.3 (± 0.6) 6.3 (± 0.6) 5.3 (± 5.6) 4.3 (± 0.6) 5 TASTE INTENCITY 5.7 (± 1.5) 5.3 (± 1.5) 4.3 (± 1.5) 4.0 (± 1.7 ) MASCURE QUALITIES 6.0 (± 1.0) 6.0 (± 1.0) 5.3 (± 0.6) 4.3 (± 0.6) DISADVANTABLE TUNE OO (± OO) OO (± OO) OO (± OO) OO (± OO) GENERAL QUALITIES 6.3 ( ± 0.6) 6.3 (± 0.6) 5.3 (± 0.6) 4.7 (± 1.2) Note: n = 3 for each analysis 10 Assessment scale: 0 = extremely distasteful, 9 = extremely liked in terms of: general flavor, quality of chewing, general quality. 0 = none, 9 = extremely liked in terms of: intensity of taste. 0 = n¡nguno, 9 = very strong in terms of: unpleasant taste.
TABLE 7
DATA EXPONENTIAL REGRESSION OF TIME WITH RESPECT TO SALIVAL CONCENTRATIONS AS MULTIPLES OF
LOT OF TEST LOT STABILITY CLINICAL LOT
INITIAL # SBC-50-CG-0001 # SBC-50CG-0002 # SBC-50CG-003 ZERO TIME 3 mo./TA 3 mo./40°C A (intersection) 240.0 563.1 575.7 422.3 446.5 b. (slope) -0.339 -0.339 -0.361 -0.448 -0.426 10 r (coefficient) 0.992 0.998 0.948 0.971 0.959 of correlation k (pseudoconstant -0.339 0.432 0.361 0.448 0.426 of first order evaluation) 15 10.5 (min) 2.04 1.60 1.92 1.55 1.63 t average 0.5 = 1.748 (± 0.218)
TABLE 8
DELIVERY OF SBC FROM THE MASK GUM AFTER 15 MINUTES OF MASCURE BY HUMAN SUBJECTS = C7 LOT OF STABILITY CLINICAL LOT # SBC-50CG-0002 # SBC-50CG-003 TIME ZERO 3 mo / TA 3 mo./40°C Rubber of MgCBS / 2.5 g Before chewing (%) 45.6 (100) 44.5 (100) 46.1 (100) 46.2 (100) Gum of MgCBS / 2.5 g 10 After chewing (%) .35 (7.6) 4.0 (9.0) 4.5 (9.8) 3.8 (8.5)
% SBC average remaining in the gum after 15 min. Chewing = 8.6 (± 1.0)
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Each piece of a rubber used for the stability study (one for time zero, two for three months total three) was the same lot number. The results show that the bismuth concentration remains stable during the period under test.
EXAMPLE 8 STUDY ON EXPOSURE OF DENTAL EQUIPMENT
An evaluation of the SBC salivary concentration on various denture materials was conducted in order to test any potential staining effect of the SBC on the denture materials. Artificial saliva was used. The results are presented in table 9 below.
TABLE 9 THE COMPOSITION OF ARTIFICIAL SALIVA Ingredients Concentration per liter
0.50 g Sodium Bicarbonate Sodium phosphate, dibasic, dihydrate 0.85 g Calcium chloride 0.44 g Magnesium chloride 0.06 g Potassium chloride 1.40 g Sodium carboxymethylcellulose 2.00 g phosphoric acid to adjust pH to 6.4, distilled water as sufficient
A test saliva is prepared by dissolving 0.500 g of colloidal bismuth subcitrate in 100 ml of the previous artificial saliva. 500 ml of artificial saliva was placed at room temperature in one of two identical glass jars with lids. In the other jar 500 ml of the artificial saliva was placed at room temperature containing 0.50% of SBC. In each of the jars, the block of denture material and a magnetic stirrer were placed. The jars were then placed on the magnetic platform and started to stir at a minimum speed for 4 hours. Denture materials that were exposed to artificial saliva that contained either SBC or placebo are listed in Table 10 below. Exposure for 4 hours of natural tooth and other denture materials to 0.5% SBC in artificial saliva with mild agitation did not cause any staining, discoloration or changes in texture.
TABLE 10 MATERIALS DENTURE 1) Natural tooth with amalgam fillings silver 2) Mixed resin (used on anterior teeth for filling) 3) acrylic resin for denture base 4) Porcelain fused to metal 5) Metal frame for partial denture 6) Acrylic tooth (artificial) 7) Natural tooth
EXAMPLE 9 DATA ON CLINICAL EFFICACY
An open-label, placebo-controlled pilot clinical study has been initiated in ten patients with an initial positive response for H. pylori. Data were obtained from six patients (four patients treated with SBC chewing gum of 50 ml six times a day and two patients treated with chewing gum with placebo six times a day for fifteen days). Samples of patients' dental plaques were collected before treatment, on day seven and on day fifteen after treatment and were tested by microbiological culture and CLO test. The results are shown in table 11 below:
TABLE 11
Average CLO response time after 15 days = 4.125 HR
average response time of CLO after 15 days = 2.0 HR NA = Not applicable NE = Not evaluated (before chewing) The data show that patients treated with gum SBC 50 ml and gum placebo daily 15, the mean CLO response times are 4.125 hours and 2.0 hours, respectively, and the longest CLO test response time for the 50 ml SBC chewing gum groups compared to the group of Chewing gums with placebo is indicative of a substantial reduction in the density of H. pylori in the oral cavity of the active treatment group.
EXAMPLE 10 DATA ON CLINICAL EXPERIMENT
The MERETEK UBT ™ (urea and 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 which is enriched with the carbon 13 isotope. H. pyiori is a positive urease bacterium. If the isotope of carbon 13 is present in dense concentrations and of subsequent breaths, means the presence of H. pylori in the stomach. Patients with duodenal ulcer were randomized with a positive urea and breath test to active and placebo groups and were included in a 15-day clinical trial. These patients did not receive any antibiotic therapy during the clinical trial. Patients in the active group received gum containing 50 ml of colloidal bismuth subcitrate per piece. Patients in the placebo group received, gum that did not contain colloidal bismuth subcitrate. Patients were also subdivided into high dose and low dose groups. Patients in the high-dose group chewed gums 6 times a day and patients in low-dose groups chewed gum twice a day. After 15 days, the urea and breath test was repeated. The results are presented in table 12 below.
TABLE 12
Overall assessment is a qualitative result (either positive or negative) based on numerical value setting for the test. ** Change refers to the difference of the numerical values from the initial test until day 15.
Results of the general assessment: 1.- The three patients who received placebo (100%) had urea and breath tests at the conclusion of the experiment. 2. Eight of the eleven patients who received active gum (73%) had negative urea and breath tests at the conclusion of the experiment. 3.- A patient with negative results at the beginning (that is, low minimum value to consider the positive test) was not included.
Results of the general data changes 1.- The mean change in the urea and breath test data was an increase of 23% in three patients with placebo. 2.- The mean change of the urea and breath test data was a 64% decrease in the six patients in the low active dose (range 22% to 98%). 3.- Six out of six patients in the low active drug group had a decrease (p <0.05 by chi square analysis).
4. - The mean change in the urea and breath test data was a 91% decrease in the six patients over the high active dose (range 79% to 98%). 5.- Six out of six patients in the high active drug group had a decrease (p <0.05 by the analysis of the square of chi).
Summary of the results: 1.- Twelve of the twelve patients with active gum had decreases in the results of the urea and breath test data (ranging from 22% to 98% ñ, while three patients with placebo had an increase average of 23% 2.- There was a dose response relationship between the two doses of gum used.The data suggest that the doses are close to 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 experiment.
EXAMPLE 11 ANTIBACTERIAL EFFICACY FOR THE TREATMENT OF HALITOSIS
Halitosis is caused by the formation of volatile sulfur compounds (VSC's). These VSCs originate from the decomposition of bacteria, tissue and food particles trapped in the mouth. Other contributing factors include digestive problems, nose, throat and / or lung infections, and medication use. 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 the odor comes from their stomach, when the 80% unit originates in the mouth and tongue. Typically, breath mints, chewing gum, mouth rinses and toothpastes that are bought at the store simply disguise bad breath. These breath fresheners are able to cover the smell only for a short time. In order to permanently eliminate bad breath it is necessary to attack the source of the VSCs. Campylobacter rectus, Heiocobacter pylori and Treponema denticola are bacteria that have been shown to be associated with halitosis (bad breath). The bismuth-containing compounds and methods of the present invention, including the SBC as well as an ascorbyl bismuth derivative, have demonstrated in vitro activity against the three bacteria, as indicated by
minimum effective concentrations (MICs) presented in Table 13 below.
TABLE 13
Based on in vitro activity, a chewing gum containing CBAS should be effective in reducing halitosis caused by bacteria. It is expected that a person can release halitosis by chewing gum preferably containing between about 10 mg of SBC of about 100 mg of SBC and preferably between about 1 and 4 times a day. Also, a chewing gum may contain a previously mentioned amount of bismuth or bismuth compound or combinations of the same equivalent between about 10 and about 100 milligrams of colloidal bismuth subcitrate.
EXAMPLE 12 TOXICOLOGY
A number of studies on animal toxicity in human clinical investigations have shown safety of bismuth compounds, especially SBC, in the range of therapeutic doses. No toxicity has been reported in the chronic daily administration of high doses of SBC (160, 320, and 640 mg / kg of body weight representing 2, 4 and 8 times the human therapeutic dose, respectively) in treated rats respectively) treated rats for 5 months. See Wieriks et al. Journal of Gastroenterology 17 (Supplement ° 80): 11B16 (1982), incorporated herein by reference. The safety in prolonged relation of the SBC and the treatment of peptic ulcers at a normal dose of 480 mg (interlaced as bismuth trioxide) in four divided daily doses has been examined by Bader, Digestion 37 (supra 2): 53-59 ( 1987), incorporated herein by reference. The SBC was first introduced to Europe in 1971 and since then it has supplied 1.5 million treatments. During 8 years of use of the SBC [De-Nol®] tablets in Europe between 1978 and 1986 under a comprehensive system of adverse reaction inspection, only thirteen forms of adverse reactions were completed. Five of these adverse reactions were attributed to SBC: one case of headache, one case of stomach pain, one case of diarrhea and two cases of allergy (mainly in
form of skin rashes). A high degree of safety of SBC in therapeutic applications for the treatment of peptic ulcers is reported in a specialized journal of pharmacology of compounds containing bismuth by Lambert, Review of Infectious Diseases 13 (supplement 8): 8691-695 (1991), incorporated in the present by reference. In reexamining the safety and pharmacokinetics of SBC, Bennet, Scandinavian Journal of Gastroenterology 27 (Supplement 185): 29-35 (1991), incorporated herein by reference, has calculated the systemic bioavailability of bismuth after oral dosing of SBC that is in the range of 0.16 to 0.28% of the dose administered and concluded that steady-state blood levels of 50-100 ng / ml are unlikely to cause 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 modalities, only a few of which have been illustrated and described above. The invention can be modalized in other forms without deviating from the spirit or essential characteristics. The described embodiments are to be considered in all respects only as administrative and restrictive, and scope of the invention is therefore indicated by the appended claims rather than by the foregoing description. All changes that fall within the meaning and range of equivalency of the claims must be encompassed within their scope.
Claims (32)
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 , busm.uto subnitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgalate, bismuth aluminate and combinations thereof.
2. The chewing gum according to claim 1, further characterized in that the bismuth compound is selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth subsalicylate and combinations thereof.
3. The chewing gum according to claim 2, further characterized in that the bismuth compound is a colloidal bismuth subcitrate.
4. The chewing gum according to claim 3, further characterized in that the chewing gum includes between about 10 mg and 200 mg of colloidal bismuth subcitrate per piece.
5. - The chewing gum according to claim 4, further characterized in that the chewing gum includes between about 10 mg and about 10 mg of colloidal bismuth subcitrate per piece.
6. The chewing gum according to claim 5, further characterized in that the chewing gum includes between about 25 mg and about 75 mg of colloidal bismuth subcitrate per piece.
7. The chewing gum according to claim 1, further comprising an antibiotic.
8. The chewing gum according to claim 7, further characterized in that the antibiotic is metronidazole.
9. The chewing gum according to claim 1, further comprising an antiplaque agent.
10. The chewing gum according to claim 9, further characterized in that said antiplaque agent is selected from gluconase and hydroglucosidase, glucose oxidase, calcium-kaolin, silicone oil and sanguinarine.
11. A chewing gum formation comprising a bismuth compound selected from the group consisting of colloidal bismuth subcitrate (SBC), bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, subcarbonate of bismuth, bismuth tartarate, bismuth subgalate and bismuth aluminate.
12. - The chewing gum according to claim 11, further characterized in that the chewing gum includes an amount of bismuth of said bismuth compound or combinations thereof equivalent between about 10 and about 200 mg of colloidal bismuth subcitrate.
13. The chewing gum according to claim 12, further characterized in that the chewing gum includes an amount of bismuth of said bismuth compound or combinations thereof equivalent between about 25 and about 75 mg of colloidal bismuth subcitrate.
14. Chewing gum according to claim 13, further characterized in that the chewing gum includes an amount of bismuth of said bismuth compound or combinations thereof equivalent to about 50 of colloidal bismuth subcitrate.
15. The use of 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 subscritrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgalate, bismuth aluminate and combinations thereof, for the manufacture of a chewing gum composition to treat infection with Helicobacter pylori.
16. The use according to claim 15, wherein said bismuth compound is selected from the group consisting of subcitrate in colloidal bismuth, bismuth subcitrate, bismuth subsalicylate and a combination thereof.
17. The use according to claim 16, wherein the bismuth compound is colloidal bismuth subcitrate.
18. The use according to claim 17, wherein the chewing gum includes between about 10 mg and 200 mg of colloidal bismuth subcitrate.
19. The use according to claim 18, wherein the chewing gum includes between about 10 mg and about 100 mg of subcitrate in colloidal bismuth per piece.
20. The use according to claim 19, wherein the chewing gum includes between about 25 mg and about 75 mg of subcitrate in colloidal bismuth per piece.
21. The use according to claim 15, wherein the chewing gum also comprises an antiplaque agent.
22. The use according to claim 15, wherein the chewing gum is administered between approximately one and ten times a day.
23. The use of a therapeutically effective amount of a bismuth compound selected from the group consisting of colloidal bismuth subsnitrate, bismuth subsnitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgalate, bismuth alminate and combinations thereof, for the manufacture of the chewing gum composition to treat infection with Helicobacter pylori.
24. The use according to claim 23, wherein the chewing gum includes an amount of bismuth of said bismuth compound or combinations thereof equivalent to about 10 to about 200 milligrams of subcitrate in colloidal bismuth.
25. The use according to claim 24, wherein the chewing gum includes an amount of bismuth in the bismuth compound or combinations thereof equivalent between about 25 and about 75 milligrams of subcitrate in colloidal bismuth.
26. The use according to claim 25, wherein the chewing gum includes an amount of bismuth of said bismuth compound or combinations thereof equivalent to about 50 milligrams of subcitrate in colloidal bismuth.
27. The use of a water-soluble bulk portion, a water-soluble chewing gum base portion, a flavoring agent and a therapeutically effective amount of a compound selected from the group consisting of subcitrate in colloidal bismuth, subcitrate of bismuth, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgalate, bismuth aluminate and combinations thereof, for the manufacture of a medicament for treating halitosis.
28. - The use according to claim 27, wherein said bismuth compound is selected from the group consisting of subcitrate in colloidal bismuth, bismuth subcitrate, bismuth subsalicylate and combinations thereof.
29. The use according to claim 28, wherein said bismuth compound is subcitrate in colloidal bismuth.
30. The use according to claim 29, wherein said chewing gum is administered between approximately one and ten times a day.
31. The use according to claim 30, wherein said chewing gum is administered between approximately one and four times a day.
32. The use according to claim 27, wherein the chewing gum includes an amount of bismuth in said bismuth compound or combinations thereof equivalent between about 10 and about 100 milligrams of subcitrate in colloidal bismuth.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US08741781 | 1996-11-01 |
Publications (1)
Publication Number | Publication Date |
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MXPA99004186A true MXPA99004186A (en) | 2000-05-01 |
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