JP3288550B2 - Oral topical formulation for killing Helicobacter pylori - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an orally administered drug,
More specifically, the present invention relates to a topical oral preparation for killing Helicobacter pylori and / or Campylobacter lectus and Treponema denteicolla in the oral cavity. The topical oral preparation of the present invention can be used for the treatment, prevention or prevention of recurrence of gastrointestinal disorders by killing Helicobacter pylori, and the topical oral preparation is Campylobacter lectus and Treponema. It can also be used for the treatment or prevention of halitosis by disinfecting denticolla.

[0002]

2. Description of the Related Art Helicobacter pylori
Pylori) is a gram-negative bacillus that adheres to the gastrointestinal wall and has been found to be closely related to disorders such as gastritis, gastric ulcer, and duodenal ulcer (K.L. Helicobacter pylori infection and non-ulcer dyspepsia: effects 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 found that disinfection and eradication of the H. pylori is an important factor in treating, preventing, and preventing recurrence of the above-mentioned disorders. Furthermore, research reports on H. pylori and gastric cancer have recently been made (for example, J.P.S.
H. pylori and gastric cancer ("HELICOBACTER PYLORI AND GASTRI
C CANCER ")" Gastroenterology Clinics of North America, 22 (1); 89-104, 1
993).

In the field of gastrointestinal ulcer treatment, histamine H ₂ receptor antagonists (hereinafter referred to as H ₂ blockers) have recently been used.
Secretion inhibitors such as urea and proton pump inhibitors have been developed, and ulcers have been healed at a high rate and at an early stage. However, prevention of recurrence after healing is still a major issue.

Follow-up studies have reported that 75-80% of gastrointestinal ulcer patients who have healed once have repeatedly healed / recurred over a prolonged period of 13-25 years (see Void et al. (“Recurrent ulcer dise
ase ")" Extracter Medica, 14-42, 1
984).

Heretofore gastrointestinal ulcer treatment of the mainstream of H ₂ blocker - was due to the administration of an acid secretion inhibitor such as agents. However, Helicobacter pylori and gastrointestinal disorders, as coming specifically elucidated causal relationship between gastrointestinal ulcers, H ₂ blocker - because there is no antimicrobial effect on such, combating Helicobacter pylori on Prevention gastrointestinal ulcer recurrence It became a matter of prejudice, and now there has been a major change in the dosing regimen for the treatment of gastrointestinal ulcers. In other words, bismuth compounds have a long history as therapeutic agents for gastrointestinal disorders, but their antibacterial activity against Helicobacter pylori has been confirmed (for example, the clinical isolation of Campylobacter pyloridis against 11 antibacterial agents such as McNartay AM) Infectivity (“Susceptibility of Clinical Isolates of C
ampylobacter pyloridis to 11 Antimicrobial Agent
s ")" (see Antimicrovial Aging Chemotherapy, 28, 837-838, 1985), and in many cases it has been used in combination with gastrointestinal ulcer drugs for its eradication. Was. For example, a first antibiotic and a second antibiotic or triple combination bactericidal medication or (JP 3-503404), such as metronidazole, such as bismuth compound and penicillins, H ₂ blockers such as famotidine - agents Alternatively, double dosing combining a proton pump inhibitor such as omeprazole and a bismuth compound (JP-A 4-288015) has been attempted. In one attempt, quadruple-dose (bismuth, two antibiotics, and a proton pump inhibitor) reported that pylori eradication was increased to over 90% on average (Rouse E.A.J. Healing of duodenal ulcer associated with Helicobacter pylori eradication (“Cure
of duodenal ulcer associated with eradication of
Helicobacter pylori ")" Lancet, 335, 12
23-35, 1990; Ciba et al., FDC Report, page 21, February 14, 1994; B. Rassoborn, "H. pylori shakes the anti-ulcer market (" H pylori sha
kes up the anti-ulcer market ")" Therapeutics, 1993, etc.). Thus, these medications have a high eradication rate, and in particular, the combination of bismuth compounds and antibiotics has been found to be the most effective in controlling gastrointestinal H. pylori, and has some effect in preventing recurrence. I raised it.

[0006] However, these are all aimed at controlling Helicobacter pylori in the gastrointestinal tract by oral administration, and have the following various disadvantages. For example, the administration of four types of drugs must be prescribed with great care, and is not practical as a general prescription. In addition, these medications have side effects such as vomiting and diarrhea, which may necessitate discontinuing the medication. Another problem associated with the use of antibiotics is the emergence of resistant bacteria,
There have already been reports of H. pylori resistant to metronidazole (for example, antimicrovial agent chemotherapy such as McNartay AM, 2).
8, 837-838, 1985). It should be noted that 10 to 20% of cases in which gastrointestinal H. pylori relapse within one year even after eradication by combination therapy with antibiotics are reported. (Lancet, such as Rouse E.A.J., 335,
1223-35, 1990; Henschel et al., FD-
C report, page 21, February 14, 1994). Therefore, in order to prevent recurrence, it is conceivable that the above-mentioned medication is continued for a long period of time.

[0007] On the other hand, as a result of research on the infection route of H. pylori,
Oral infection has been found to be promising (A.M.H. Nguen et al., “Detection of Helicobacter pylori in oral plaque by reverse transcription-polymerase chain reaction (“ DETECTIONOF HELICOBACTER PYLORI ”).
IN DENTAL PLAQUE BY REVERSE TRANSCRIPTION-POLYMERA
SE CHAIN REACTION ")" Journal of Clinical Microbiology, 31 (4), 783-7, 19
1993). In particular, reports on human-to-human transmission have shown that H. pylori is often found in humans of older age groups and is relatively rare in younger people. It is suggested that the disease can be transmitted to older to younger people and even children. More specifically, since the recurrence rate of gastrointestinal ulcers is high even after eradication of Helicobacter pylori in the gastrointestinal tract, there is a hidden place in Helicobacter pylori other than in the gastrointestinal tract to avoid antibacterial therapy. Based on the hypothesis that this might be the case, a number of separate studies have been conducted (see Journal of Clinical Microbiology, such as AM HC Nguyen, supra, 31 (4), 783-7, 1993; Kay Olson et al., "H. pylor in oral plaque.
i in dental plaque ")" Lancet, 341,956
-7, 1993, etc.), and it has recently been confirmed that Helicobacter pylori is present in the dental plaque (Dental Plaque) (see Journal of AMC Nguyen et al., Supra).・ Clinical microbiology, 31 (4), 783-7, 1993). The presence of Helicobacter pylori in the human gastrointestinal tract has been confirmed, and the percentage of Helicobacter pylori in the oral cavity of the same person is reported to be 38% to 100%. And, after eradication of Helicobacter pylori in the gastrointestinal tract by the combination with the above-mentioned antibiotics, since Helicobacter pylori still exists in the oral cavity, gastrointestinal Helicobacter pylori eradication therapy is performed in the oral cavity. Has little effect on
It is thought to be greatly involved in the recurrence of stomach and duodenal ulcers (see Journal of Clinical Microbiology, such as AMC Nguyen, supra)
31 (4), 783-7, 1993;
Desai et al. “Dental Plaque: A Permanent Resevoir: A Permanent Storage Room for Helicobacter pylori?
of Helicobacter Pylori? ")" Scandinavian Journal of Gastroenterology, 26, 12
05-1208, 1991).

[0008] As described above, therapies for controlling Helicobacter pylori so far have been all aimed at controlling gastrointestinal H. pylori by oral administration of a plurality of drugs. It does not seek to eradicate Helicobacter pylori from the route of infection.

On the other hand, bismuth compounds have excellent antibacterial activity against Helicobacter pylori, so they are effective drugs for controlling Helicobacter pylori, but liquid products containing bismuth salts are unstable. In addition, it has been reported that bismuth compounds cause dark discoloration of the enamel of the tongue and teeth (JP-A-2-145).
No. 523).

Under the circumstances described above, a practical and safe means for eliminating Helicobacter pylori living in the oral cavity must be provided promptly.

[0011] Halitosis has many etiologies. This common name for malodor from the mouth includes malodor, malodorous substrates,
Bad breath disease (Halitosis), oral malodor, and the like are included. Many systemic pathological conditions, such as diabetes, uremia, and liver disease, also produce metabolic substances and cause halitosis. According to Moriyama, there is an important correlation between halitosis and anaerobic spirochetes and motile rods that inhabit the lower gingival bacterial flora (Moriyama, “Halitosis and lower gingival bacterial flora Clinical Study on the Correlation of Dental Science ”, Dental Science Report, September, 8
9 (9), 1425-39, 1989). In addition to these oral bacterial flora and systemic metabolic disorders, dry mouth is also considered a cause of bad breath or bad breath (eg,
Narry F. "Dry Mouth and Haritosis (" Dry m
outside halitosis ")" practitioner, 234 (1490), 1425-39, 19
June 8, 1989). Saliva plays a major role in the process leading to halitosis. Saliva has oxidizable substrates that promote oxygen deprivation in the oral cavity during the oxidation process (see, for example, "Oral malodor-c" by Clayberg Eye, West Bay G., et al.
oral review ")" Oral Biology and Medicine, 1 (4), 247-59, 1
990). An oxygen-diluted environment helps the growth of anaerobic bacteria that cause halitosis. Also, McPherson,
According to a simulated experiment comparing the effect of chewing gum (eg sugar-free and sugar-containing) chewing on pH change in dental plaque without using chewing gum by Dowes et al. After reducing the pH to 5, the time required for the pH to return to the standard value was measured depending on whether chewing gum was used or not, and the result was the shortest time for the sugar-free chewing gum, followed by the sugar-containing chewing gum. Gum,
It has been found that the order of chewing gum is not used (see MacPherson LM, Dowes C., et al., "Stimulative effect of sugar-free chewing gum and sugar-containing chewing gum on pH change in dental plaque." In-vitro experiments ("An in-vitro sti"
modulation of the effects o
f chewing sugar-free and
sugar-container cooling gu
ms on pH changes in denta
lplaque ")", Journal of Dental Research, 72 (10), 1391-7, October 1993). On the other hand, it has recently been found that Helicobacter pylori has a strong causal relationship with halitosis typified by bad halitosis among halitosis (for example, "Helicobacter halitosis (" Hli
journal halitosis ")" Journal of Clinical Gastroenterology, 4
Mon, 16 (3), 274, 1993). Campylobacter lectus and Treponema denteicolla are also known to cause halitosis.

[0012] However, no topical orally administered agent effective for halitosis, particularly bad halitosis, has yet been found.
There is a need for such dosages.

[0013]

DISCLOSURE OF THE INVENTION The present invention provides a topical oral administration agent for controlling H. pylori present in the oral cavity by using a pharmaceutically acceptable bismuth compound having an excellent H. pylori bactericidal action. The purpose is to:

Another object of the present invention is to increase the probability of eliminating H. pylori and to provide a more useful therapy for the treatment of gastrointestinal disorders due to H. pylori infection, such as gastritis, gastric ulcer, and duodenal ulcer, and for preventing and preventing recurrence. It is in. In particular, the topical oral preparation of the present invention is to provide a useful therapy in combination with a conventional bismuth-containing oral preparation and / or an anti-ulcer agent.

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

[0016]

SUMMARY OF THE INVENTION Accordingly, the present invention is directed to a topical oral dosage form for killing Helicobacter pylori, which contains a pharmaceutically acceptable bismuth compound.

The bismuth compound used in the present invention can be used as a drug having antibacterial activity against Helicobacter pylori, and for example, colloidal bismuth hypocitrate (hereinafter sometimes referred to as "CBS"). Bismuth hypocitrate, bismuth citrate, bismuth salicylate, bismuth hyposalicylate, bismuth hyponitrate, bismuth hypocarbonate, bismuth tartrate, bismuth hypogallate, tripotassium bismuthate and bismuth aluminate and mixtures thereof . Preference is given to colloidal bismuth subcitrate, tripotassium bismuthate, bismuth subcitrate, bismuth subsalicylate and mixtures thereof. Colloidal bismuth subcitrate and tripotassium bismuthate dicitrate are more preferred. Colloidal bismuth subcitrate is most preferred. 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 which can be used in the topical oral preparation of the present invention is one in which the bismuth compound can be appropriately released in the oral cavity, for example, chewing gum, chewable,
There are troche, toothpaste, gargle gel, oral rinse and the like. Chewing gums and lozenges are preferred. Chewing gums are most preferred because of their ease of use, predictability of drug release, and high degree of drug contact with tooth surfaces.

The topical oral preparation of the present invention must release the bismuth compound in an amount sufficient to kill Helicobacter pylori. Minimum inhibitory concentration of bismuth compound 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
2 mg / litre (SP 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 bacterial concentration of antibiotics and anti-ulcer agents against Campylobacter pyloridis"
tericidal concentrations of antibiotics and anti-u
lcer agents against Campylobacter pyloridis ”)”
Journal of Antimicrovial Agent Chemotherapy, 17, 309-314, 1986). Thus, while the dosage form is being applied orally, the release of the bismuth compound will be at least about 1 time, preferably from about 2 times to about 300 times, and most preferably from 2 times to 170 times, its minimum inhibitory concentration. It is twice. To achieve such release, the content of bismuth compound per unit dosage form should be 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 colloidal bismuth subcitrate is used in the chewing gum, about 5 mg to about 200 mg of colloidal bismuth subcitrate can be contained per unit dosage form, preferably 10 mg to about 200 mg.
It contains 100 mg, most preferably 25 mg to 75 mg.

The release time of the bismuth compound of the topical oral preparation of the present invention is as follows.
It must be long enough to kill H. pylori. This depends on the bismuth compound to be 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 colloidal bismuth subcitrate is used in the chewing gum, it is at least about 2 minutes, preferably 2 minutes to 15 minutes, and most preferably 10 minutes to 15 minutes.

[0021] The topical oral preparation of the present invention includes, for example, excipients, sweeteners, gum bases, flavoring agents, coloring agents and the like necessary for preparing the topical oral administration preparation. Other additives can be added.

The method for producing the topical oral preparation of the present invention is carried out by a method commonly used for the preparation to be produced.

The topical oral 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 or diarrhea unlike oral preparations. It is suitable for everyday use,
It can be administered over a long period of time while observing the status of H. pylori inhabitation.

The topical oral preparation of the present invention is more effective when used in combination with a conventional oral bismuth compound-containing antiulcer agent. That is, while treating peptic ulcer with conventional oral drugs, eradication of Helicobacter pylori in the stomach, and eradication of 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 cavity, the topical oral administration agent of the present invention is administered as needed to prevent recurrence.

When the topical oral preparation of the present invention is used for patients with halitosis, Helicobacter pylori, Campylobacter lectus and Treponema denteicolla are eradicated, and in particular, a chewing gum is used. Sometimes it further stimulates saliva production to help neutralize saliva pH and chewing gum chewing improves mouth dryness, another factor in halitosis. Furthermore, the topical oral preparation of the present invention can also be used for prevention of halitosis.

The topical oral preparation of the present invention has high storage stability and has a shelf life that can withstand enough to be applied to patients according to the prescription of a physician via an ordinary distribution channel.

Hereinafter, the present invention will be further described with reference to examples.

[0028]

【Example】

(Example 1) A chewing gum containing fragrance and containing no sugar was prepared, having the following two prescriptions. Each gum piece weighed about 2.5 g and contained 50 mg of CBS per piece.

[0029]

[Table 1] <Production of chewing gum> The gum base was sufficiently melted (about 104 ° C.) in a Brabender mixer, the heating was stopped, and lecithin was added to mix well. Cool to about 66 ° C., add the 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 solution were added alternately over 5 minutes. About 49
Cooled to ° C. Add flavor and sweetener and mix until smooth.

Regarding the chewing gum of the above formula,
Using 6 healthy persons, 1) measurement of the release rate of bismuth into saliva, 2) evaluation of feeling of use of chewing gum, and 3) evaluation of local safety.

The six persons were divided into two groups of three persons. One of them was a chewing gum containing sodium citrate (formulation A).
On the other hand, a chewing gum containing no sodium citrate (formulation B) was used. Sodium citrate was included to slightly increase the firmness of the chewing gum.

1) Measurement of release rate of bismuth into saliva The gum was chewed for a total of 15 minutes, and saliva was collected at the start, 1 minute, 5 minutes, 10 minutes, and 15 minutes. The amount of bismuth was determined by the National Federation of Official Analytical Chemists (A.O.
A. C. ) "Official Meth Method"
ods of Analysis) ", 15th edition (1990)
Year).

The results are shown in Table 2 and FIG. Here, the bismuth element in the saliva sample was measured in ppm concentration,
From the numerical value of the result, the active CBS [(Bi (O
H) ₃ ) ₃ ] The content was determined in μg / mL.
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 / C.
Calculated as L.

[0034]

[Table 2] As can be seen from the above results, the concentration of CBS in saliva showed little difference between Formulations A and B, and was about 150 times the MIC at 1 minute, about 55 times the MIC at 5 minutes,
After 5 minutes, it was 5 times, and 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 almost complete 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, Helicobacter pylori can be further reduced because saliva containing CBS at an appropriate concentration (2 to 5 times the MIC) constantly rinses the oral cavity by 15 minutes.

2) Evaluation of the feeling of use of chewing gum The time-lapse feeling during chewing for 15 minutes was evaluated by comparing the gum of Formula A containing sodium citrate with the gum of Formula B not containing the same as described above. Six gum users, divided into two groups, evaluated. The rating is the overall flavor / taste rating (0 = very bad to 8 = very good 9
Grade), flavor / taste intensity (0 = not at all ~ 8 =
9 steps of very strong), chewing feeling (0 = not at all preferable to 8 = 9 steps of very preferable), discomfort after use (0
= Not feeling at all ８ 8 = 9 levels of very uncomfortable) and overall feeling of use (0 = completely unfavorable ~ 8 levels of very favorable 9). Table 3 shows the results.

[0036]

[Table 3] The results in Table 3 show that there was no significant difference in the feeling of use depending on the presence or absence of sodium citrate, that the feeling of use as a whole was maintained to a considerable extent from the start of mastication to 15 minutes, and that there was no problem with discomfort after use. Is shown.

3) Evaluation of Local Safety The same six subjects were asked 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. Was.

The results were 15 minutes and 60 minutes after using both formulations.
None of them reported any discomfort or irritation.

(Example 2) Example 1 Using a chewing gum of Formula A (containing 50 mg of CBS in one piece), the CBS content before mastication and the CBS residual content after mastication for 15 minutes were measured. CBS content is bismuth content in ppm
It was calculated in units and converted to CBS content (mg). Table 4 shows the results.

[0040]

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

(Example 3) Example 1 A storage stability test was performed on a chewing gum having the same formulation as the formulation A.

The chewing gum containing CBS was wrapped in a metal foil, and a predetermined number of gums were put in a metal foil laminated bag, sealed, and stored. Storage conditions were 90 days at different temperatures of room temperature and 40 degrees Celsius, respectively. The stability test was 9
The CBS content was measured after 0 days, the CBS content in the gum after chewing for 15 minutes, the amount of CBS released into saliva, and the feeling of use of the chewing gum was evaluated. The test method and the evaluation method were performed 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 ° C at room temperature and 40 ° C.
There was no change in the CBS content even after storage for 1 day, and the CBS content after chewing 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 the start, even after storage at room temperature and 40 ° C. for 90 days. Further, as can be seen from Table 7, the feeling of use of the chewing gum was not changed from that at the start even after storage at room temperature and 40 ° C. for 90 days.

Example 4 An in vitro test was conducted to determine whether there is a possibility of staining dental materials including teeth in the oral cavity at the CBS concentration in saliva that can be used in the present invention. As saliva, artificial saliva having the following composition was used.

[0045] Note) Control artificial saliva was prepared by dissolving the above 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.

[0046] 500 mL of control artificial saliva (room temperature) was placed in one of two glass vials with a lid. 5 in the other glass bottle
00 mL of test artificial saliva (room temperature) was placed. Each bottle contained the following dental material pieces and magnetic stirrer. The contents of each bottle were then agitated using a magnetic stirrer at minimal speed. After stirring for 1 hour, visual observation was made for any staining or coloring. At this point,
There was no difference between the pieces of dental material in both bottles. Each bottle was then allowed to stir for an additional 3 hours and the dental material strip was removed and rinsed using control artificial saliva. The dental material pieces were dried at room temperature.

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

(Example 5) Opening of six patients positive for Helicobacter pylori in dental plaque was performed.
A label placebo control pilot clinical trial was performed. The test was performed using the chewing gum of Formula A of Example 1 (containing 50 mg of CBS) and a placebo chewing gum containing no CBS as a control. The administration method of chewing gum is to give one chewing gum at a time, 6 times / day for 15 days.
Six patients (four with CBS containing gum of the present invention and two with CBS
A placebo chewing gum without BS was given)
Provided data. Before the treatment, and on the 7th and 15th days after the treatment, a plaque sample was collected from the patient, and the microorganism culture and Campylobacter approximate tissue determination method (Campylobacter)
(L Like Organism Test: CLO test) (The test method was described in IG G. Desai et al., “Dental Plaque: A Permanent Storage Room for Helicobacter pylori?” (“Dental Plaque: A Permanent Resevoir of
Helicobacter Pylori? ")" Scandinavian Journal of Gastroenterology, 26, 120
5-1208, 1991). Here, the longer the response time in the CLO test, the helicobacter
It shows a high antibacterial activity against H. pylori. Table 8 shows the results.

[0049]

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

Example 6 A troche having the following composition was prepared.

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

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

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

[0054]

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

[Brief description of the drawings]

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

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 9/68 A61K 9/68 31/29 31/29 31/60 31/60 A61P 1/00 A61P 1/00 1/02 1 / 02 31/04 31/04 (58) Investigated field (Int.Cl. ⁷ , DB name) A61K 33/24 A61K 7/16 A61K 9/06 A61K 9/08 A61K 9/20 A61K 9/68 A61K 31 / 29 A61K 31/60 A61P 1/00 A61P 1/02 A61P 31/04

Claims (8)

(57) [Claims] 1. A chewing gum containing a pharmaceutically acceptable colloidal bismuth compound capable of killing Helicobacter pylori, wherein the chewing gum weighs about 2.5 g per piece of the chewing gum.
When the said bismuth compound is 5mg-200m
g, the use of the chewing gum in the oral cavity allows the bismuth compound to elute into saliva, and the bismuth compound eluted in the saliva causes Helicobacter pylori in the oral cavity and digestive system. Chewing gum for sterilizing bacteria and treating, preventing or preventing gastrointestinal disorders from recurring. 2. The bismuth compound content is 10 mg.
The chewing gum according to claim 1, wherein the amount is from 100 to 100 mg. 3. The bismuth compound content is 25 mg.
3. Chewing gum according to claim 2, characterized in that it is 〜75 mg. 4. The bismuth compound is a colloidal bismuth hypocitrate, bismuth hypocitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth hypogallate, bismuthate 2. The method of claim 1, wherein said compound is selected from the group consisting of tripotassium dicitrate and bismuth aluminate.
4. The chewing gum according to any one of items 1 to 3. 5. The chewing gum according to claim 4, wherein said bismuth compound is colloidal bismuth hypocitrate. 6. The method according to claim 5, wherein the content of the colloidal bismuth subcitrate is such that the release time of the bismuth compound into the oral cavity during chewing the gum is 10 to 15 minutes. The described chewing gum. 7. The content of the colloidal bismuth hypocitrate is determined by determining the amount of colloidal bismuth hypocitrate released into saliva one minute after the chewing gum starts to be chewed,
Minimum inhibitory concentration of colloidal bismuth subcitrate against Helicobacter pylori at least 2 to 170
The chewing gum according to claim 5, wherein the chewing gum is doubled. 8. A chewing gum containing a pharmaceutically acceptable bismuth compound capable of disinfecting Helicobacter pylori, wherein the chewing gum has a weight of one piece of the chewing gum of about 2.5 g. A bismuth compound containing 5 mg to 200 mg,
By using the chewing gum in the oral cavity, the bismuth compound is eluted into saliva, and the amount of the bismuth compound released into saliva one minute after the chewing gum starts to be chewed is reduced by Helicobacter pylori. The minimum inhibitory concentration against bacteria is at least 2- to 170-fold, and the bismuth compound eluted in the saliva causes Helicobacter /
Chewing gum for killing H. pylori and treating, preventing or preventing gastrointestinal disorders from recurring.