JPH0820543A - Topical oral drug for controlling helicobacter pylori - Google Patents

Abstract

PURPOSE:To provide a topical oral medicine which contains a bismuth compound, thus is effective in treatment and recurrence prevention for gastrointestinal injury, treatment and prevention for ozostomia, further disinfection of Helicobacter pylori. CONSTITUTION:This (medicinal) preparation contains 5-500mg, every preparation unit, of a bismuth compound such as colloidal bismuth citrate, tripotassium bismuthate dicitrate. This compound is prepared in a pharmaceutical preparation in which the bismuth compound can be suitably released, for example, chewing gum, a chewable preparation, troche, tooth paste, gargling gel, oral rinse or the like. The releasing time of the bismuth compound is at least 2 minutes, preferably 2-15 minutes, although it depends on the preparations. Simultaneously, it can kill Campylobacter rectus and Treponema denticola, too.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an agent for oral administration,
More specifically, it relates to a topical oral administration agent for sterilizing Helicobacter pylori bacteria and / or Campylobacter rectus and Treponema denteicola in the oral cavity. The topical oral administration agent of the present invention can be used for treating, preventing recurrence or prevention of gastrointestinal disorders by sterilizing Helicobacter pylori, and the topical oral administration agent is Campylobacter rectus and Treponema. By sterilizing denteicola, it can be used for treating or preventing halitosis.

[0002]

[Prior Art] Helicobacter pylori
Pylori) is a Gram-negative bacillus, and is found to be closely attached to the gastrointestinal wall and closely associated with disorders such as gastritis, gastric ulcer, and duodenal ulcer (K.L.G. et al. Helicobacter pylori infection and non-ulcer dyspepsia: Effect of treatment with colloidal bismuth (“Helicobacter pylori Infection and Non-Ulcer
Dyspepsia: The Effectof Treatment with Colloidal B
ismuth Subcitrate ")" Scandinavian Journal of Gastroenterology, 26; 1123-
1131, 1991). Therefore, it has been clarified that the sterilization and extermination of this H. pylori is an important element for the treatment, prevention of recurrence and prevention of the above-mentioned disorders. Furthermore, recently, research reports on H. pylori and gastric cancer have been published (for example, J.A.Personenet "Helicobacter.
Pirori and gastric cancer (“HELICOBACTER PYLORI AND GASTRI
C CANCER ”)” Gastroenterology Clinics of North America, 22 (1); 89-104, 1
See March 993).

In the field of gastrointestinal ulcer treatment, a histamine H ₂ receptor antagonist (hereinafter referred to as H ₂ blocker) has been recently used.
Although acid secretion inhibitors such as and proton pump inhibitors have been developed to cure ulcers at a high rate and at an early stage, prevention of recurrence after healing remains a major issue to date.

According to follow-up studies, 75-80% of patients with gastrointestinal ulcer who once healed have been reported to repeat healing / recurrence over a long period of 13 to 25 years thereafter (Void et al., “Recurrent ulcer disease”). (“Recurrent ulcer dise
ase ”)” Exceptor Medica, 14-42, 1
984).

Until now, the mainstream of gastrointestinal ulcer treatment has been the administration of acid secretion inhibitors such as H ₂ blockers. However, as the causal relationship between Helicobacter pylori and gastrointestinal disorders, in particular gastrointestinal ulcer, has been elucidated, H ₂ blocker has no antibacterial action. Therefore, extermination of Helicobacter pylori is related to prevention of recurrence of gastrointestinal ulcer. It has become a matter of predecessor, and now there is a big change in the administration method for treating gastrointestinal ulcer. In other words, bismuth compounds have a long history as therapeutic agents for gastrointestinal disorders, but their antibacterial action against Helicobacter pylori has been confirmed (eg, McNultay A.M. et al. "Clinical isolation of Campylobacter pyloridis against 11 antibacterial agents. Infectivity of “Susceptibility of Clinical Isolates of C
ampylobacter pyloridis to 11 Antimicrobial Agent
s ")" Antimicrovial Agent Chemotherapy, 28, 837-838, 1985)), and in many cases it has been used in combination with a gastrointestinal ulcer drug for its eradication. It was For example, triple dosing in which a bismuth compound is combined with a first antibiotic such as penicillins and a second antibiotic such as metronidazole or a bactericide (JP-A-3-503404), H ₂ blocker agents such as famotidine, etc. Alternatively, double-dose combination of a proton pump inhibitor such as omeprazole and a bismuth compound (JP-A-4-288015) has been attempted. Also, in one attempt, it was reported that quadruple dosing (bismuth, two kinds of antibiotics, proton pump inhibitor) increased the eradication of H. pylori to an average of 90% or more (Rouse E.A.J. et al. Healing of duodenal ulcers associated with exterminating Helicobacter pylori (“Cure
of duodenal ulcer associated with eradication of
Helicobacter pylori ")" Lancet, 335, 12
23-35, 1990; Ciba et al., F-D-C Report, p. 21, February 14, 1994; Bee Rassoborn, "H. Pylori Shakes the Anti-ulcer Market (" H pylori sha
kes up the anti-ulcer market ”)” Therapeutics, 1993, etc.). As described above, these medications have a high eradication rate, and in particular, it has been found that the combination of the bismuth compound and the antibiotic is most effective in the extermination of gastrointestinal Helicobacter pylori, and it is also effective to prevent recurrence to some extent. I raised it.

However, all of them are aimed at exterminating Helicobacter pylori in the gastrointestinal tract by oral administration, and have the following various drawbacks. For example, administering various kinds of drugs such as four kinds requires prescribing with a high degree of caution, and is not practical as a general prescription. In addition, these medications have side effects such as vomiting and diarrhea, which may require discontinuation of the medication. In addition, there is the emergence of resistant bacteria as a problem associated with the use of antibiotics,
There have already been reports of H. pylori resistant to metronidazole (eg, Anti-microvial, Agent, Chemotherapy, McNultay Am, et al., 2 above).
8, 837-838, 1985). It should be noted here that even if the gastrointestinal Helicobacter pylori is eradicated by combination drug therapy with antibiotics, recurrence within one year is reported at a rate of 10 to 20%. (Lance, L.E.A.J., et al., Supra, 335,
1223-35, 1990; Henschel et al., FD-
See C Report, p. 21, February 14, 1994). Therefore, in order to prevent recurrence, it may be possible to continue the above-mentioned medication for a long period of time, but long-term administration cannot be performed due to the problems of these side effects, the problem of resistant bacteria and the like.

On the other hand, as a result of research on the infection route of H. pylori,
It has been proved that the one caused by oral infection is predominant (A.M.Aitch Nguyen et al. "Detection by reverse transcription-polymerase chain reaction of Helicobacter pylori in oral dental plaque (" DETECTION OF HELICOBACTER PYLORI
IN DENTAL PLAQUE BY REVERSE TRANSCRIPTION-POLYMERA
SE CHAIN REACTION ”)” Journal of Clinical Microbiology, 31 (4), 783-7, 19
1993). Among them, in reports of human-to-human infections, there are many cases in which Helicobacter pylori is found to be infected in humans in the old age group, and since it is relatively small in the young age group, Helicobacter pylori is It is suggested that the infection affects humans from the elderly to the young and even to children. More specifically, since the recurrence rate of gastrointestinal ulcer is high even after eradication of Helicobacter pylori in the gastrointestinal tract, there is a hidden place for Helicobacter pylori other than in the gastrointestinal tract to avoid antibacterial therapy. Based on the hypothesis that it may be carried out, a number of separate studies have been conducted (see A. M. Aitch Nguyen, et al., Journal of Clinical Microbiology, 31 (4), 783-7, 1993; Kay Olson et al., "H. pylor in oral plaque"
i in dental plaque ”)” Lancet, 341, 956
-7, 1993, etc.), it was recently confirmed that Helicobacter pylori is present in the dental plaque (Dental Plaque) (J. A. Mitchie Nguyen, et al., Supra). -See Clinical Microbiology, 31 (4), 783-7, 1993). The presence of Helicobacter pylori is confirmed in the human gastrointestinal tract, and the proportion of the oral cavity of Helicobacter pylori in the same person is reported to be 38% to 100%. Then, after eradication of Helicobacter pylori in the gastrointestinal tract by the combination with the above-mentioned antibiotics, since Helicobacter pylori is still present in the oral cavity, the gastrointestinal Helicobacter pylori extermination therapy is Helicobacter pylori in the oral cavity. Has been confirmed to have almost no effect on
It is thought to be greatly involved in the recurrence of gastric and duodenal ulcers, etc. (Journal of Clinical Microbiology, A.M.
31 (4), 783-7, 1993; Eitchie G.
Desai et al. “Dental Plaque: A Permanent Resevoir?
of Helicobacter Pylori? ”)” Scandinavian Journal of Gastroenterology, 26, 12
05-1208, 1991).

As mentioned above, the therapy for exterminating Helicobacter pylori has so far been aimed at exterminating gastrointestinal Helicobacter pylori by oral administration of multiple drugs. It does not attempt to eradicate Helicobacter pylori from the infection route.

On the other hand, a bismuth compound is an effective drug for controlling Helicobacter pylori because it has an excellent antibacterial action against Helicobacter pylori, but liquid products containing bismuth salts are unstable. In addition, it has been reported that the bismuth compound causes a blackish discoloration in the enamel of the tongue and teeth (JP-A-2-145).
523).

Under the above circumstances, a practical and safe means for exterminating Helicobacter pylori bacteria living in the oral cavity must be provided immediately.

There are numerous etiologies for halitosis. This common name for malodors from the mouth includes stench, malodorous substrates,
Halitosis, oral malodor, etc. are included. Many systemic pathological conditions, such as diabetes, uremia, and liver disease, also produce metabolites and cause halitosis. According to Moriyama, there is an important correlation between halitosis and anaerobic spirochators and kinematic rods that inhabit the lower gingival bacterial flora (Moriyama, "Balliosis and lower gingival bacterial flora Research on Correlation of "Dental Bulletin, September, 8
9 (9), 1425-39, 1989). In addition to these oral flora and systemic metabolic disorders, dry mouth is also considered to be the cause of halitosis or bad breath (eg,
Narry F “Intraoral Drying and Haltosis (“ Dry m
"outh halitosis") "practitioner, 234 (1490), 1425-39, 19
See June 8, 1989). Saliva plays a large role in the process leading to halitosis. Saliva has a substrate that is easily oxidizable, and they promote oxygen deficiency in the oral cavity during the process of oxidation (for example, “Creberg Eye, West Bay G., et al.,“ Oral malodor-reassessment ”).
oral review ")" Oral Biology and Medicine, 1 (4), 247-59,1
990). The oxygen-poor environment helps breed anaerobic bacteria that cause halitosis. Also, MacPherson,
According to a simulated experiment in which the effect of chewing gum (sugar-free and sugar-containing) mastication such as Dowes on the pH change in lichen was compared with that without chewing gum, the pH of the lichen of the sample was previously determined to be 4. After reducing to 5, after measuring the time for the pH to return to a standard value depending on whether chewing gum is used or not, the sugar-free chewing gum is the shortest and the next is sugar-containing chewing. Gum,
And it has been found that the order is to use no chewing gum (McPherson L.M., Dowes C. et al., "Stimulating effect of chewing gum without sugar and chewing gum containing sugar on pH change in dental lichen" In vitro experiment ("An in-vitro sti
mulation of the effects o
f chewing sugar-free and
sugar-containing chewing gu
ms on pH changes in denta
l plaque ")" Journal of Dental Research, 72 (10), 1391-7, October 1993). On the other hand, Helicobacter pylori has recently been found to have a strong causal relationship with bad breath, which is represented by bad breath disease (for example, "Helicobacter halitis (" Hli
cobalt halitosis "), Journal of Clinical Gastroenterology, 4
Mon, 16 (3), 274, 1993). Also, Campylobacter rectus and Treponema denteicola are known to cause halitosis.

However, no topical buccal agent effective for halitosis, particularly bad breath disease, has been found yet.
There is a need for such a dosage form.

[0013]

DISCLOSURE OF THE INVENTION The present invention provides a topical buccal preparation for combating Helicobacter pylori present in the oral cavity by using a pharmaceutically acceptable bismuth compound having an excellent bactericidal action against Helicobacter pylori. The purpose is to

Another object of the present invention is to increase the probability of removal of H. pylori to provide a more useful therapy for treating, preventing and preventing recurrence of gastrointestinal disorders caused by H. pylori infection, such as gastritis, gastric ulcer, duodenal ulcer and the like. Especially. In particular, the topical buccal administration agent of the present invention is to provide a useful therapy in combination with a conventional bismuth-containing oral agent and / or anti-ulcer agent.

Still another object of the present invention is to provide an administration agent useful for treating or preventing halitosis by removing Helicobacter pylori in the oral cavity.

[0016]

Accordingly, the present invention is a topical buccal preparation for sterilizing Helicobacter pylori containing a pharmaceutically acceptable bismuth compound.

The bismuth compound used in the present invention can be used as a drug having antibacterial properties against Helicobacter pylori, and for example, colloidal bismuth subcitrate (hereinafter sometimes referred to as "CBS"). , Bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, tripotassium bismuth dicitrate and bismuth aluminate and mixtures thereof. . Colloidal bismuth subcitrate, tripotassium dicitrate bismuthate, bismuth subcitrate, bismuth subsalicylate and mixtures thereof are preferred. Further preferred are colloidal bismuth subcitrate and tripotassium bismuth dicitrate. Most preferred is colloidal bismuth subcitrate. The colloidal bismuth subcitrate has the formula: [Bi (OH) ₃ ] ₃ BiC ₆ H ₅
O ₇ (1,2,3-propanetricarboxylic acid, 2-hydroxy, bismuth (3T) potassium salt (Cas-576
44-54-9)).

The dosage form that can be used in the topical buccal preparation of the present invention is one in which the bismuth compound can be appropriately released in the oral cavity.
Examples include troches, toothpastes, mouthwash gels, and mouth rinses. Chewing gums and lozenges are preferred. Chewing gum is most preferred because of its ease of use, predictability of drug release, and high degree of drug contact with the tooth surface.

The topical buccal preparation of the present invention must release the bismuth compound in an amount sufficient to kill Helicobacter pylori. Minimum inhibitory concentration of bismuth compounds against Helicobacter pylori (MI
C) depends on the type of bismuth compound used,
For example, in the case of colloidal bismuth subcitrate, 4 to 3
It was reported to be 2 mg / liter (S. Lee "The Mode of Action of Colloidal Bismuth Subcitr
ate ”)” Scandinavian Journal Gastroenterology, 26 (Supplement 185), 1-6, 1
991; CS Goodin et al., "The minimum inhibitory and bactericidal concentrations of antibiotics and anti-ulcer agents against Campylobacter pyloridis.
tericidal concentrations of antibiotics and anti-u
lcer agents against Campylobacter pyloridis ”)”
See Journal of Antimicrovial Agent Chemotherapy, 17, 309-314, 1986). Therefore, the amount of the bismuth compound released is at least about 1 times its minimum inhibitory concentration, preferably about 2 times to about 300 times, and most preferably 2 times to 170 times, while the administration agent is applied in the oral cavity. Double. To achieve such release, the content of bismuth compound per unit dosage form is from about 5 mg to about 500 mg, preferably 10 mg.
mg to 300 mg, most preferably 25 mg to 100 m
g. For example, when the chewing gum is made of colloidal bismuth subcitrate, the unit dosage form may contain from about 5 mg to about 200 mg of colloidal bismuth subcitrate, preferably from 10 mg to about 200 mg.
Contains 100 mg, most preferably 25 mg to 75 mg.

The release time of the bismuth compound of the topical buccal administration agent of the present invention is as follows:
There must be enough time to kill H. pylori. This depends on the bismuth compound administered and the dosage form, but is at least about 2 minutes, preferably 2 minutes to 15 minutes, most preferably 10 minutes to 15 minutes. For example, when using a colloidal hypobismuth citrate in the chewing gum, it is at least about 2 minutes, preferably 2 minutes to 15 minutes, most preferably 10 minutes to 15 minutes.

The topical buccal preparation of the present invention is necessary for preparing a topical buccal preparation such as an excipient, a sweetener, a gum base, a flavoring agent and a coloring agent. Other additives can be added.

The preparation for topical buccal administration of the present invention is manufactured by a method which is commonly used for the preparation to be manufactured.

The topical buccal preparation of the present invention is highly safe, does not blacken the enamel of the tongue and teeth, and has no side effects such as vomiting and diarrhea unlike oral preparations. Suitable for regular use, Helicobacter in dental plaque
It can be administered over a long period of time while observing the habitation status of H. pylori.

The topical buccal administration agent of the present invention is more effective when used in combination with a conventional oral bismuth compound-containing antiulcer agent. That is, while treating a peptic ulcer with a conventional oral drug, eradicates Helicobacter pylori in the stomach, and eradicates Helicobacter pylori in the oral cavity with the topical oral administration agent of the present invention. Cut off the source of infection,
Further, after that, while observing the presence or absence of Helicobacter pylori bacteria in the oral dental plaque, if necessary, the topical buccal administration agent of the present invention is administered to prevent recurrence.

When the topical buccal preparation of the present invention is used for patients with halitosis, Helicobacter pylori, Campylobacter lectus and Treponema denteicola are sterilized, and in particular, chewing gum is used. Occasionally, it further stimulates saliva production to help bring saliva pH to neutrality and chewing gum chewing improves dry mouth, another factor in halitosis. Furthermore, the topical buccal preparation of the present invention can be used for the prevention of halitosis.

The topical preparation for oral administration of the present invention has high storage stability and has a shelf life that can be sufficiently endured for application by a patient according to a doctor's prescription through a normal distribution route.

The present invention will be further described below with reference to examples.

[0028]

【Example】

Example 1 A flavored chewing gum formulation having the following two formulations and containing no sugar was prepared. The gum piece weighed about 2.5 g and contained 50 mg CBS per piece.

[0029]

[Table 1] <Production of chewing gum> The gum base was sufficiently melted (about 104 ° C) in a Brabender mixer, heating was stopped, and lecithin was added and mixed well. Cool to about 66 ° C., add liquid flavor and mannitol and mix for about 5 minutes until homogeneous. CBS was dry blended with crystalline sorbitol. Sodium citrate was blended into the sorbitol solution. Crystalline sorbitol and sorbitol liquid were added alternately over a 5 minute period. About 49
Cooled to ° C. The flavor and sweetener were added and mixed until smooth.

Regarding the chewing gum formulation having the above-mentioned formulation,
Six healthy persons were used to 1) measure the release rate of bismuth into saliva, 2) evaluate the feeling of using chewing gum, and 3) evaluate the local safety.

The 6 persons were divided into 2 groups of 3 persons, and the chewing gum containing sodium citrate (formulation A) was added to one of the groups.
The other was a chewing gum containing no sodium citrate (Formulation B). Sodium citrate was included to slightly increase the firmness of the chewing gum.

1) Measurement of release rate of bismuth into saliva Chewing gum for a total of 15 minutes, saliva was collected at the start, 1 minute, 5 minutes, 10 minutes and 15 minutes later, The amount of bismuth can be determined by the American Federation of Analytical Chemists (AO.
A. C. ) "Official Method
15th Edition (1990)
Year).

The results are shown in Table 2 and FIG. Here, the bismuth element in the saliva sample is measured in ppm concentration,
From the numerical value of the result, the activated CBS [(Bi (O
H) ₃ ) ₃ ] content in μg / mL unit
The C magnification was calculated. Here, 1 mg of bismuth element corresponds to 1.41 mg of active CBS, and the minimum inhibitory concentration (MIC) of CBS against Helicobacter pylori is 8 mg /
Calculated as L.

[0034]

[Table 2] As can be seen from the above results, the concentration of CBS in saliva was almost the same in Formulations A and B, and was about 150 times higher than MIC after 1 minute and about 55 times after 5 minutes.
After 5 minutes, it was 5 times, and even after 15 minutes, it was about 2 times. The release rate followed a pseudo-first-order rate with a correlation coefficient of -0.99, with most release after 15 minutes with standard chewing. The first high concentration in saliva has a strong bactericidal effect on Helicobacter pylori in dental plaque. Furthermore, since the saliva containing CBS at an appropriate concentration (2 to 5 times the MIC) up to 15 minutes constantly rinses the oral cavity, Helicobacter pylori can be further reduced.

2) Evaluation of the feeling of use of the chewing gum The feeling of use over time while chewing for 15 minutes was the same as that of the gum of the formula A containing sodium citrate and the gum of the formula B not containing the same as above. Six gum users who were divided into two groups were evaluated. The overall rating is perfume / flavor (0 = very bad to 8 = very good 9
Grade evaluation), intensity of flavor / taste (0 = not felt at all-8 =
Very strong 9 levels), chewing sensation (0 = not at all ~ 8 = very preferred 9 levels), discomfort after use (0)
= No feeling ~ 8 = 9 stages of very uncomfortable) and overall feeling of use (0 = totally unfavorable ~ 8 9 stages of very preferable). The results are shown in Table 3.

[0036]

[Table 3] The results in Table 3 show that there was no great difference in the feeling of use depending on the presence or absence of sodium citrate, and the feeling of use as a whole was maintained substantially for 15 minutes from the start of chewing, and there was no problem with discomfort after use. Indicates.

3) Topical Safety Evaluation Similarly, six test subjects were requested to report the presence or absence of side effects such as discomfort or irritation in each oral cavity for 60 minutes after using the gum. It was

The results show that both formulations are 15 minutes and 60 minutes after use.
There was no report of discomfort or irritation in any of the minutes.

Example 2 The chewing gum formulation of Example 1 formulation A (containing 50 mg of CBS in one piece) was used to measure the CBS content before chewing and the residual CBS content after chewing for 15 minutes. CBS content is bismuth content in ppm
It was calculated in units and converted to CBS content (mg). The results are shown in Table 4.

[0040]

[Table 4] From the results of Table 4, it can be seen that the residual content of CBS in the gum after 15 minutes of chewing is 7.6% of the content before chewing, indicating that CBS is almost released from the gum. This result is consistent with the result of the release test of CBS of Example 1 in saliva.

Example 3 Example 1 A chewing gum having the same formulation as Formula A was subjected to a storage stability test.

The CBS-containing chewing gum agent was wrapped in a metal foil, and then a predetermined number of gums were placed in a metal foil laminated bag, sealed and stored. The storage conditions were room temperature and different temperatures of 40 degrees Celsius for 90 days. The stability test is 9
The CBS content was measured after 0 days, the CBS content in the gum after 15 minutes of chewing, the amount of CBS released into saliva, and the feeling of use of the chewing gum were evaluated. The test method and evaluation method were carried out according to Example 1. The results are shown in Tables 5, 6 and 7, respectively.

[0043]

[Table 5]

[Table 6]

[Table 7] As can be seen from the results in Table 5, 90 at room temperature and 40 ° C
There was no change in the CBS content even after storage for a day, and the CBS content after mastication for 15 minutes was not different from that at the start. Table 6
As can be seen, the release of CBS from the chewing gum into saliva was unchanged from that at the beginning after 90 days storage at room temperature and 40 ° C. Further, as can be seen from Table 7, the feeling of use of the chewing gum agent was the same as that at the start even when it was stored at room temperature and 40 ° C. for 90 days.

Example 4 An in-vitro test was conducted to determine whether the CBS concentration in saliva that can be used in the present invention might stain a dental material including teeth in the oral cavity. As the saliva, artificial saliva having the composition shown below was used.

[0045] Note) A control artificial saliva was prepared by dissolving the above composition components in distilled water. Test artificial saliva (0.5% CB
S-containing) was prepared by dissolving 0.500 g of colloidal bismuth subcitrate in 100 mL of the above-mentioned control artificial saliva.

500 mL of control artificial saliva (room temperature) was placed in one of the two glass bottles with lids. 5 in the other glass bottle
00 mL of test artificial saliva (room temperature) was added. Each bottle was filled with a piece of dental material and a magnetic stirrer shown below. The contents of each bottle were then agitated with a magnetic stirrer at minimum speed. After stirring for 1 hour, visual observation was made for dyeing or coloring. At this point,
There was no difference in the dental material pieces in both bottles. Each bottle was then allowed to stir for an additional 3 hours and the piece of dental material was removed and rinsed using control artificial saliva. The dental material pieces were dried at room temperature.

[0047] Dental material piece exposed to control artificial saliva and CBS 0.5%
There was no difference by visual observation between it and the dental material piece that was exposed to the test artificial saliva contained therein.

(Example 5) Opening of 6 patients showing a positive reaction to Helicobacter pylori in dental plaque
Labeled, placebo-controlled, pilot clinical trials were conducted. Tests were carried out using the formulation A of Example 1 (containing 50 mg of CBS) chewing gum, and a placebo chewing gum containing no CBS as a control. Chewing gum is administered 6 times / day for 15 days by giving 1 sheet of chewing gum at a time.
6 patients (4 with the CBS containing gum of the present invention and 2 with C
Placebo chewing gum containing no BS was given)
The data was obtained from Dental plaque samples were collected from patients before and 7 and 15 days after the treatment, and were subjected to microbial culture and Campylobacter approximate tissue determination method (Campylobacte).
r Like Organism Test (CLO test) (the test method is Eitch G. Desai et al., “Intraoral Dental Plaque: Permanent Resevoir of Helicobacter pylori?” (“Dental Plaque: A Permanent Resevoir of
Helicobacter Pylori? ”)” Scandinavian Journal of Gastroenterology, 26, 120
5-1208, 1991). Here, the longer response time in the CLO test is the helicobacter
It shows that the antibacterial activity against H. pylori is large. Table 8 shows the results.

[0049]

[Table 8] The data in Table 8 show that the average CLO response time on day 15 of patients treated with CBS 50 mg chewing gum of the present invention and placebo chewing gum was 4.125 hours and 2.0 hours, respectively. C of the chewing gum group containing 50 mg of CBS in comparison with the placebo chewing gum group
It can be seen that the LO test response time was long and the density of Helicobacter pylori in the oral cavity of the CBS-containing chewing gum treatment group was significantly reduced.

Example 6 A lozenge having the following composition was prepared.

[0051] (Example 7) A mouthwash gel having the following composition was prepared.

[0052] (Example 8) An oral rinse agent having the following composition was prepared.

[0053] (Example 9) The in vitro activity of CBS against Helicobacter pylori, Campylobacter rectus and Treponema denteicola is shown in Table 9 below as the minimum inhibitory concentration (MIC).

[0054]

[Table 9] As can be seen from Table 9, CBS has antibacterial activity not only against Helicobacter pylori but also against Campylobacter rectus and Treponema denteicola and is effective against halitosis.

[Brief description of drawings]

FIG. 1 is a graph showing the release rate of CBS from the chewing agent of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 9/68 31/29 ADZ 9455-4C 31/60 ACJ

Claims (6)

[Claims] 1. A topical buccal agent for sterilizing Helicobacter pylori containing a pharmaceutically acceptable bismuth compound. 2. The bismuth compound is colloidal bismuth subcitrate, bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth carbonate, bismuth tartrate, bismuth subgallate, bismuth acid. A selected from the group consisting of tripotassium dicitrate and bismuth aluminate.
The described administration agent. 3. The dosage form according to claim 1, wherein the dosage form of the dosage form is a chewing gum agent, a chewable agent, a troche agent, a toothpaste agent, a mouthwash gel agent or an oral rinse agent. 4. The dosage form according to claim 1, wherein the bismuth compound is colloidal bismuth subcitrate and the dosage form is a chewing gum. 5. The administration agent according to any one of claims 1 to 4, which is used for treating, preventing or preventing recurrence of gastrointestinal disorders. 6. The administration agent according to claim 1, which is used for treating or preventing halitosis by sterilizing Campylobacter rectus and Treponema denteicola.