JP2001081049A - Therapeutic agent/prophylactic for gastritis/stomach ulcer or duodenal ulcer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject therapeutic agent/prophylactic developing a strongly bactericidal effect on a specific bacterium, safer and more effective than a conventional therapy of concomitant use of medicines by making the therapeutic agent/prophylactic include an agglutination active factor to the bacterium and an acid secretion, inhibitor. SOLUTION: The therapeutic agent/prophylactic comprises (A) an agglutination active factor to a bacterium of the genus Helicobacter and (B) an acid secretion inhibitor. The component A is preferably a polyclonal body derived from an egg of fowl. The component B is preferably a histamine H2 receptor blocking agent and/or a proton pump inhibitor. The bacterium is preferably at least one kind selected from the group consisting of Helicobacter pylori, Helicobacter cinaedi, Helicobacter fennelliae, Helicobacter heilmannii, Helicobacter rappini, etc. In the component A, in the case of a polyclonal antibody having >=256 agglutination antibody titer, preferably 10 mg to 10 g/50 kg B.W. per time of the polyclonal antibody is orally administered.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for treating / preventing gastritis / stomach or duodenal ulcer, which comprises an agglutinating factor for Helicobacter bacteria and an acid secretion inhibitor.

[0002]

BACKGROUND OF THE INVENTION Mershall and Warr, 1983
en was found to be able to efficiently detect Helicobacter pylori from gastric biopsies of patients with gastritis and gastric ulcer (Warren)
JR, Maskall BJ: Lancet, 1273
~ 1275 (1983)), it has become increasingly clear that Helicobacter bacteria are involved in the development of gastritis, stomach or duodenal ulcer. At present, eradication of Helicobacter bacteria as a treatment for gastric ulcer is considered to be a complete treatment for preventing ulcer recurrence. Various methods have been considered for eradication therapy for Helicobacter bacteria. Helicobacter bacteria are i
N-vitro is sensitive to antibiotics such as penicillin, cephalosporin, macrolide and nitroimidazole, but in vivo, even if the drug is administered alone, a sufficient eradication effect cannot be obtained. The reason is that the antibacterial activity of the administered antibiotic is attenuated by stomach acid, that the effective concentration of antibiotics does not reach the cells present in the mucus layer, and that the cells acquire drug resistance And so on. Therefore, treatments using a combination of several antibiotics were performed. When three drugs were used in combination, a high eradication rate could be obtained, but the incidence of side effects such as diarrhea was high, which led to a decrease in drug compliance, and the incidence of resistant bacteria was high, so they were not widely used. Was.

[0003] Subsequently, proton pump inhibitor (PPI), a new acid secretion inhibitor, was known to have an antibacterial effect against Helicobacter bacteria, and was used as a eradication therapy. However, since the antibacterial activity of PPI is lower than that of antibiotics, the method of removing bacteria by adding antibiotics and antiprotozoal agents has been adopted. As antibiotics, β-lactam agents (penicillin, ampicillin, etc.), macrolide agents (erythromycin, clarithromycin, etc.), aminoglycoside agents (streptomycin), tetracycline agents, bismuth agents have been used. At present, the combination of PPI and two antibiotics, which is a new three-drug combination therapy, is the mainstream, and shows a considerably high eradication effect.
The incidence of side effects is lower than in previous triple therapy. But,
This method still has many problems of producing antibiotic-resistant bacteria and problems of side effects, and cannot be said to be an absolutely safe treatment. Therefore, a method that is safe and has a high eradication effect is desired.

[0004] Acid secretion inhibitor as recently may histamine are used H ₂ receptor blockers, no antibacterial effect on Helicobacter bacteria. As a method for solving these problems, it has been reported that an antibody of a mammal immunized with a specific bacterium or an antibody derived from a bird has been effective for prevention of infection and eradication of the bacterium (H. Hatta, M.
Kim and T.S. Yamamoto: Japane
se Journal of Dairyand Fo
od Science, 41 (16), 217-221
(1992)). Furthermore, it has been argued that mammalian antibodies or bird-derived antibodies against the Helicobacter genus bacteria are safe and effective methods for food components (Kaihei 4-275232). However, a more efficient method is desired.

[0005]

SUMMARY OF THE INVENTION The present invention relates to the treatment of gastritis, stomach or duodenal ulcer caused by Helicobacter bacteria.
It is to provide a safe and effective drug for prevention.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, the use of a factor having an agglutinating activity against Helicobacter spp. The inventors have found that the bacteria can be effectively removed, and have completed the present invention. That is, the present invention is an agent for treating / preventing gastritis / stomach or duodenal ulcer which is safer and more effective than conventional drug combination therapy.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The genus Helicobacter according to the present invention is Helicobacter pylori.
c. pylori), Helicobacter cinnaedi, Helicobacter feneriae (Helicobacter)
er funnelliae), Helicobacter heilmanni
nnii), Helicobacter Rapiini (Helic)
obaptor rappini), Helicobacter
Refers to bacteria classified into the genus Helicobacter in bacterial taxonomy, such as Helicobacter felis.

[0008] The agglutinating activity factor in the present invention refers to a substance having an aggregating activity against the aforementioned Helicobacter bacterium, and is not particularly limited. And a polyclonal antibody derived from an avian egg, and preferably a polyclonal antibody derived from an avian egg which is highly safe and can be mass-produced. The acid secretion inhibitor in the present invention include PPI or H ₂ receptor blocker, preferably a PPI. The PPI is not particularly limited, but includes omeprazole, lansoprazole, rabeprazole and the like, and preferably omeprazole. Moreover, famotidine as H ₂ receptor antagonists, ranitidine hydrochloride, cimetidine, and the like, preferably famotidine.

The agglutinating activity in the present invention refers to the agglutinating activity observed by specifically reacting with Helicobacter bacteria. Specifically, it refers to the cohesive force caused by the antigen-antibody reaction. In the present invention, the concentration of the agglutinating factor is not particularly limited as long as it is not less than the concentration that specifically agglutinates Helicobacter bacteria. Depending on the purpose of use, age, weight, symptoms, etc., in the case of a polyclonal antibody with an aggregate antibody titer of 256 or more, 10 mg to 1 mg / time
0 g / 50 kg B. W. Has a specific and powerful therapeutic and preventive effect on the upper gastrointestinal tract such as gastritis and duodenal ulcer, and has no side effects. The concentration of the acid secretion inhibitor is not particularly limited as long as the pH in the digestive tract in an acidic environment is 4 or more. Although it depends on the drug, age, body weight, symptoms, etc., it is preferable that omeprazole be administered in a dose of 20 mg to 50 mg / 5 at a time.
0 kgB. W. It is desirable to administer. The agent for treating / preventing gastritis / stomach or duodenal ulcer of the present invention is not limited to a dosage form, and a dosage form such as a tablet, a capsule, and a powder can be appropriately selected. The excipient used for the preparation is not particularly limited, and can be appropriately selected from excipients used in general preparations. Oral administration is effective for the administration route of this drug. Hereinafter, the present invention will be described in more detail. However, these do not limit the invention.

[0010]

[Embodiment 1] Preparation of Helicobacter pylori Helicobacter pylori ATCC4
Using 3504 cells, select medium (Blood Agar)
Base No. 2 (manufactured by OXOID) and 7% horse defibrinated serum (manufactured by NBL), 37 ° C., 10% CO ₂
The cells were cultured under the conditions for 5 days. Embodiment 2. FIG. Helicobacter pylori of Example 1, wherein the anti-pylori egg yolk antibodies prepared to include about 10 ⁸ cells per 1 ml, which was used as antigen solution. One ml of this antigen was intramuscularly injected into one laying hen, and then the antigen was administered again (booster) 8 weeks later. From the 4th week after the booster, chicken eggs were collected for 3 months and the yolk was separated. The yolk is homogenized with a homomixer,
This solution was used as an egg yolk solution. 1 kg of water was added to 1 kg of the obtained egg yolk liquid, homogenized, and 4 kg of 0.15% λ-carrageenan aqueous solution was added thereto, followed by stirring and left for 2 hours. After standing, about 5 kg of egg yolk water-soluble protein was obtained from the supernatant by centrifugation at 8000 rpm for 20 minutes.
To 1 L of the obtained egg yolk water-soluble protein solution, add sodium sulfate 1
After 50 g is added little by little to dissolve, the mixture is left standing for 30 minutes and centrifuged (normal temperature, 8000 rpm × 15 minutes). The supernatant is discarded, and the precipitate is added to 10 mM Na ₂ HPO ₄ buffer 2
Add 00 ml and dissolve. Using the obtained solution, salting out was performed again in the same manner as described above. This solution is 10 mM Na
Dialysis was performed overnight using ₂ HPO ₄ buffer, and the obtained solution was freeze-dried to obtain an anti-H. Pylori egg yolk antibody. The obtained powder was subjected to gel filtration ("Protein I", edited by The Japanese Biochemical Society,
(Chapter 11, Tokyo Kagaku Dojin (1990)) confirmed that the ratio of antibodies to all proteins was 90% or more.

Test Example 1 Aggregation activity of anti-H. Pylori egg yolk antibody The agglutination antibody titer of the anti-H. Pylori egg yolk antibody obtained in Example 2 was measured using the cells obtained in Example 1. In addition, S.P. mutans bacteria (JP-A-4-7146)
Using 5), the agglutinating antibody titer of the anti-H. Pylori egg yolk antibody obtained in Example 2 was measured in the same manner. Table 1 shows the results.

[0012]

[Table 1]

From the results shown in Table 1, the anti-H. Pylori egg yolk antibody obtained in Example 2 does not show agglutination activity against mutans bacteria under neutral (pH 7) conditions, but does not show any activity against H. pylori cells. It was confirmed that they exhibited high aggregating activity. Test example 2. Helicobacter pylori eradication effect test using Helicobacter pylori-infected gerbils Mongolian gerbil (Me
riones unguiculatus) MGS / S
ea (SPF)), a 7-week-old male (manufactured by CLEA Japan, Inc.), and the H. cerevisiae obtained by the method described in Example 1. p
yoriri's method (Journal of G)
astroenterology, 31 (5), 755
(1996)). pylori infection. One month after administration, the above gerbils infected with H. pylori were divided into five groups (1). Physiological saline, (2). Example 2
Anti-H. Pylori IgY solution (2 mg / 10 g)
B. W. ), (3). PPI (20 μg / 10 g B.I.
W. ), (4). Anti-H. Pylori IgY obtained in Example 2
(2 mg / 10 g BW) + PPI (20 μg / 1
0 g B. W. ), (5). Each sample of the antibody granules (JP-A-4-16939) coated with sugar was administered twice a day for 40 days. After sacrifice, the stomach is opened, gross findings, CLO test of gastric surface tissue (manufactured by Kokusai Reagent Co., Ltd.), and H. pylori culture method in gastric tissue (Skirow medium, 37 ° C., 48 hours, microaerobic culture) The number of positive animals was counted to determine the eradication effect (positive number / total number (14)). The results are shown in Table 2.

[0014]

[Table 2]

From the results shown in Table 2, it was not possible to eliminate H. pylori bacteria infected with the stomach by IgY alone, but it was possible to effectively eliminate the bacteria by using PPI together.

The embodiments of the present invention and the desired products are as follows. (1) A therapeutic or prophylactic agent for gastritis, stomach or duodenal ulcer, comprising an agglutinating factor for Helicobacter bacteria and an acid secretion inhibitor. (2) The therapeutic / prophylactic agent for gastritis / stomach or duodenal ulcer according to (1) above, wherein the agglutinating activity factor is a polyclonal antibody derived from avian eggs. (3) an acid secretion inhibitor is histamine H ₂ receptor blockers (1) or (2) gastritis, stomach or duodenal ulcer treatment and prevention agent according. (4) The therapeutic or prophylactic agent for gastritis, stomach or duodenal ulcer according to the above (1) or (2), wherein the acid secretion inhibitor is a proton pump inhibitor (PPI). (5) The above-mentioned (1), wherein the Helicobacter bacterium is at least one selected from the group consisting of Helicobacter pylori, Helicobacter sinaedi, Helicobacter fenneliae, Helicobacter helmannii, Helicobacter rapini, and Helicobacter ferris.
(5) The therapeutic or prophylactic agent for gastritis, stomach or duodenal ulcer according to any one of (1) to (5).

[0017]

Industrial Applicability The present invention expresses a strong eradication effect on Helicobacter bacteria by using an agglutinating factor and an acid secretion inhibitor against Helicobacter bacteria, and provides safe and effective Helicobacter bacteria. This will lead to the eradication method.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Yoshiko Tanaka 9-5 Akabori Shinmachi, Yokkaichi City, Mie Prefecture (72) Inventor Kenji Horie 9-5 Akabori Shinmachi, Yokkaichi City, Mie Prefecture Incorporated (72) Inventor Jinji Sanaka 9-5 Akabori Shinmachi, Yokkaichi City, Mie Prefecture Inside Taiyo Kagaku Co., Ltd. F-term in Gaku Co., Ltd. (reference) 4C084 AA20 MA02 MA52 NA05 NA07 ZA681 ZA682 ZC411 ZC441 4C085 AA13 BA20 CC05 DD38 DD41 EE03 GG08

Claims (5)

[Claims] 1. A therapeutic / prophylactic agent for gastritis, stomach or duodenal ulcer, comprising an agglutinating activator against Helicobacter bacteria and an acid secretion inhibitor. 2. The therapeutic / prophylactic agent for gastritis / stomach or duodenal ulcer according to claim 1, wherein the agglutinating activity factor is a polyclonal antibody derived from avian eggs. 3. The therapeutic or preventive agent for gastritis, stomach or duodenal ulcer according to claim 1, wherein the acid secretion inhibitor is a histamine H ₂ receptor blocker. 4. The therapeutic / prophylactic agent for gastritis, stomach or duodenal ulcer according to claim 1, wherein the acid secretion inhibitor is a proton pump inhibitor (PPI). 5. The Helicobacter bacterium is at least one selected from the group consisting of Helicobacter pylori, Helicobacter sinaedi, Helicobacter fenneliae, Helicobacter heilmanny, Helicobacter rapinii, and Helicobacter ferris. The agent for treating or preventing gastritis, stomach or duodenal ulcer according to any one of the above.