JPH06500571A - Oral composition consisting of antibiotic material and clay material - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Oral compositions consisting of antibiotic materials and clay materials (useful remedies against gastrointestinal inflammation) Medical compositions) - Technical field 1 The present invention is directed to the treatment of Helicobacter in humans and animals. and by bacteria belonging to the group Campylobacter. The present invention relates to novel compositions useful for treating gastrointestinal inflammation.

-Background technology- In humans, gastric ulcers are characterized by damage to the affected tissue of the stomach wall under the influence of the gastric mucosa. Inside, Helicobacter pylori (Helicobacter pylori) It is abbreviated as r　Hp　J. Old name: Campylobacter pylori Campylobacter pyloridi and Campylobac terpyloridis) is known to exist. Regarding this point , B.J. Marshall et al. al,, Digestion, 37.5upp1.2. p, 15-30 ( (1987)) and the paper by C. Nis. Guttwin et al. (C, S., Goodw. in et al.

Journal of Antimicrobial Chemotherapy , 17. p, 309-314 (1986)) Ru.

According to current knowledge, in particular the following publications: J. L. Fauchere et. al., Campylobacter and Helicochacter in human gastrointestinal pathology (Campylobacter et Helicobacter enpa thologie digestivehumane) J, Medec ine/5science, 2.1), 138-152 (1991), M, V eron et al, Bacteriology J, p, 694-722.　Flammarion.

Paris (1989), 2e edition.

J., L., Penner. genus Campylobactera decade of progr ess) J, Cl1n, Microbial, Rev, , ↓, p, 157-172 (19W8), G, E, Buck, r Helicobacter pylori and gastroduodenal disease (Helic obacter py-1ori and gastroducxlennal disease) J, Cl1n, Microbial, Rev,, 3. Blow A1-12 (1990), The presence of Hp on the surface of the stomach wall has an extremely high incidence in all countries2. It is known to be associated with gastric inflammation, type B, and gastrointestinal ulcers. It is being Other gastric inflammation (particularly non-ulcerative indigestion) is also associated with the presence of Hp. It is estimated that there is. Also, certain types of gastritis caused by Hp can progress to gastric cancer. Are listed. And also, some Hp carriers show no symptoms but have gastric growth. Histological examination reveals lesions characteristic of gastritis. This lesion is present in non-carriers. This is something that is not normally seen. The lesions of the gastric mucosa observed during the course of these diseases are When it becomes clear that the bacteria Hp is the direct cause, there is no doubt that It is starting to grow. The bacterium Hp colonizes humans, especially in humans; of bacteria are adaptable to mucus, and the bacteria produce large amounts of urea-degrading enzymes to absorb gastric fluid. This is because it provides resistance to acidity. Bacteria adhere to the surface of mucosal cells is due to bacterial colonization factors, some of which have not been identified and isolated. separated. The mechanism of lesion generation is not well known. Caused by colony formation an inflammatory reaction caused by this, alteration of the mucous membrane as a barrier by the action of mucoid bacterial enzymes, or This may result in the production of large amounts of ammonia or cytotoxic substances that are harmful to the mucous membranes. It is thought that this may cause lesions.

On the other hand, the above-mentioned J. L. Faucher et al. According to the report, Campylobacter, an enteric pathogen, is taxonomically classified as Helicobacter. , and is the cause of enteritis, which is common in all countries. the current, Campylobacter, an enteric pathogen, is the primary or primary cause of bacterial diarrhea in some countries. This is thought to be the cause of 2. The method to prevent enteritis caused by Campylobacter is to This is less problematic than how to prevent gastritis caused by succictor. However, Campylobacter - are also mucus-adapted bacteria, so if antibacterial drugs are used in the intestinal mucosa (especially the upper intestinal tract), If the drug can more easily penetrate the mucus layer that covers the mucous membrane agents would be significantly more likely to reach the source of infection. Campylobacter is under the mucus layer This is because they proliferate and exert pathogenic effects.

In animals, especially warm-blooded animals such as mammals, Campylobacter and Bacterial gastrointestinal inflammation caused by licorice was observed.

Bacteria that cause gastrointestinal inflammation include Helicochacter and Campylobacter. Those belonging to this group consist of an outer cell wall or complex proteins. According to current knowledge For example, this complex protein has an average molecular weight of 14.000, 30.000 and 60. Consists of a peptide subunit of 000 daltons and has strong ureolytic activity (i) specifically adheres to human and animal epithelial cells and in the presence of urea; can kill epithelial cells in a few hours, and (ii) thereby In the case of Bacterium vilori, it makes the bacteria resistant to the acidity of gastric juices and kills them. It is presumed that the applicant can be protected from the environment (but there is no reason to bind the applicant (not a theory). [This information will be published in a future publication by G. L. Fauchier et al. It is thought that this can be confirmed by ] Campylobacter and Helicobacter bacterial gastrointestinal inflammation, such as gastric ulcers, gastritis, monodenal ulcers and duodenal The techniques currently known for the treatment of inflammation, etc. are not the above. - salts of bismuth (not commercially available as a medicine, especially in France and other European countries) banned in Pakistan], such as bismuth aluminate, bismuth subcarbonate. bismuth subcitrate, bismuth citrate, bismuth subnitrate, bismuth citrate Tripotassium tripotassium, bismuth tartrate and bismuth subsalicylate are used as shielding means. Campyloba is effective as a gastric protectant, but has no antibacterial effect. strains of Helicobacter and/or Helicobacter, especially Helicobacter as found in humans. Bacterium virori strains cannot be eradicated as mentioned above as protective substances in the stomach. Coating clay materials, which were similarly recommended, also lack antibacterial efficacy. - EP-A-0206625 (B.G. Marshall) or recommended technology On the other hand, bismuth salts are administered17 to remove deposits or deposits on the surface of the affected area of the gastric mucosa. On the other hand, antibiotics are administered to eliminate pathogenic bacterial strains, i.e. Helicobacter. pylori strains or similar strains (EP-A-0206625, p. 5, p. (see lines 4 to 22) or kill them (bactericidal effect). However, this method is clearly insufficient from the following points. Sunawaji , in the stomach, the recommended antibiotics (EP-A-0206625, No. 7) (see pages 3 to 8, line 1) through the thick gastric mucosal layer and the stomach below the gastric mucosa. It is unable to affect the pathogenic bacteria present in the wall tissue, and when administered by Nikkei, the stomach The antibiotics that enter the stomach have virtually no effect on the tissue of the stomach wall, which remains intact after the injection. Some of the antibiotic given (i.e., the part that passes through the wall of the lower intestinal tract and enters the bloodstream) It only accepts antibiotics (partial antibiotics) through the blood vessels.

On the other hand, as is known, the combination of clay substances and antibiotics can cause bacterial infections in the gastrointestinal system. Although it has already been proposed as a treatment for the disease, sufficient results have not been obtained.

In particular, No. GB-A-826328 includes heat-treated attapulgite and steel. The combination with treptomycin is also described in US-A-2951011 (Example 7). Reference) describes a combination of kaolin and sulfonamide. Furthermore, U As another technical solution, S-A-3352752 describes Describes a method for removing bacterial toxins present in the gastrointestinal system using magnesium icate (see column 2, lines 3 to 20), but the same issue also mentions the above synthetic aluminium Suggests how magnesium silicate can be combined with antibiotics (column 6, no. 5) lines 6-57).

By the way, attapulgite is particularly described in No. GB-A-826328. Pre-heat treated attapulgite and US-A-2951011 The clay substances described, such as kaolin, allow antibiotic materials to pass through the thick mucus layer of the gastrointestinal system. It doesn't really help you do that. Described in US-A-3352752 The same applies to synthetic magnesium aluminosilicate. These clay substances They are not suitable because they do not mix well with mucus and/or they do not form a coating. This is due to the fact that it acts as a barrier to prevent the antibiotic from progressing to the desired site of action.

In short, when using these conventionally known compositions, gastrointestinal mucus, especially Antibiotic materials have a direct effect on bacteria that have invaded the tissue underlying the gastric mucosa. I can't do it. The mucus itself is difficult for gastric cavity products to pass through.

-Object of the invention 1 One of the objects of the present invention is to prevent bacterial infections caused by Campylobacter and Helicobacter. The aim is to provide a novel technical solution for treating gastrointestinal inflammation.

The novel technical solution described above is designed to ensure that antibiotic materials and their use in the gastrointestinal system. It is based on the use in combination with substances that pass through mucus.

Unlike previously known methods, the present invention recommends a novel technique for eradicating pathogenic bacteria. Surgical solutions allow treatment without passage through blood vessels, especially through absorption in the lower gastrointestinal system. This allows an effective amount of antibiotic material to be delivered directly to the treatment site.

Another object of the invention is to use the same antibiotic material in the treatment of bacterial inflammation of the gastrointestinal system. Novel antibiotic materials used in combination with substances that ensure the material passes through mucus. The purpose is to provide instructions on how to use it.

Another object of the present invention is to provide a method for producing the above composition.

-Object of the invention- Thus, the present invention provides compositions useful for the treatment of bacterial inflammation of the gastrointestinal system in humans and animals. wherein the composition comprises (a) an antibiotic in combination with a physiologically acceptable excipient; quality materials, and (b)/<beidellite, smectite ite), halloysite), lithomage (lit homarge), benzimite and mixtures thereof selected from the group consisting of We present a novel composition characterized in that it contains a clay substance that actually passes through mucus. This is what we provide.

The invention also relates to methods of using antibiotic materials in human and animal treatment. , the antibiotic material and the antibiotic material must pass through the gastrointestinal mucus, and on the effect of combination with substances selected from earth substances and mixtures thereof; Campylobacter and Helicobacter, especially Helicobacter pylori It is characterized by providing medicines suitable for treating specific areas of bacterial gastrointestinal inflammation. The present invention provides a new method for using antibiotic materials.

To obtain the composition of the invention, the antibiotic material is added to the clay material until completely saturated. Provided is a manufacturing method characterized by adsorption with.

- Detailed description of the invention The "gastrointestinal system" used in the present invention refers to EP-A-020662 unless otherwise specified. Refers to the upper part of the gastrointestinal tract, especially the stomach, duodenum and jejunum, as defined in No. 5. This includes:

The antibiotic material used in the present invention is selected from the following group: antibiotics, especially streptomycin, gentamicin, neomycin, Icin, penicillins (penicillin G, penicillin V, etc.), ampicillin, ammo Xycillin, tetracyclines (tetracycline, chlortetracycline) , oxytetracycline, doxycycline, etc.), cephalosporins (ceph arexin, cephalothin, etc.), chloramphenicol, sulfonamides, their addition salts, and mixtures thereof; - Inhibition of bacterial adhesion in tissues of the gastrointestinal system; Antibiotics (i.e., structural analogs of bacterial colonization factors and their cellular receptors) - inhibitors of bacterial enzymes (i.e. in special cases ureolytic activity or other bacterial products that inhibit enzyme activity); - Inhibitor of bacterial toxin; antibodies against one bacterial antigen; and - mixtures thereof.

Ensuring the passage of antibiotic materials through the gastrointestinal mucus, or the use of substances that aid in their passage. Among these are beidellite, smectite, halloysite, lithomage, and benjimy. and mixtures thereof are suitable. Gastrointestinal mucus, especially mucus that is miscible with gastric juices It is important that it is an earthy substance. In the composition of the present invention, the antibiotic material is Preferably, it is adsorbed to soil material and penetrates a thick layer of mucus to reach the infected area of the tissue. Yes.

Of course, in the composition of the present invention containing the components (a) and (b), the components (a) In other words, antibiotic materials are those that act effectively at doses that exhibit medicinal efficacy. It is.

Therapeutic compositions useful in the treatment of humans and animals, especially humans and warm-blooded animals such as mammals. Things are beidellite, smectite, halloysite, lithomage, benzimite and mixtures thereof, preferably 8 to 20 parts by weight of a clay material selected from the group consisting of 0.05 to 15 parts by weight (preferably 10 to 12 parts by weight) of the antibiotic material (0.1 to 1.2 parts by weight).

- Preferred form 1 According to the best mode for carrying out the invention, the present invention provides Orally useful compositions include: (a) Antibiotics (streptomycin sulfate or hydrochloride, etc.) 01-12 parts, and (b) 10 to 12 parts by weight of a finely divided clay material in combination with a physiologically acceptable excipient. It is characterized by containing:

Used as a carrier for antibiotic materials (antibiotics in the above) in the above best form The average particle size of the clay material is preferably 10 μm or less, more preferably 5 μm. m or less.

By using the antibiotic material of component (a) in combination with component (b), gastrointestinal It can be applied directly to the infection site of pathogenic bacteria that causes system inflammation.

Other advantages and features of the invention are further illustrated by examples. Of course, these They are given by way of example only and are not intended to limit the invention.

Example 1 Pilgrimage composition made in 9 weeks Antibiotic materials are used to treat inflammation caused by Helicobacter vilori in humans. A gastrointestinal composition adsorbed onto an earth material was prepared by the following method.

(1) Beidellite (average particle size 5 μm or less) as a clay material at pH 7,50-7 60 (preferably 7.58) to a phosphate buffer to make a suspension, and Streptomycin hydrochloride was added at a final concentration of 10 g/l of beidellite and streptomycin. Add treptomycin hydrochloride at 1 g/l.

(2) The resulting mixture was stirred at 37 °C for 12 h, then at 5,0 OOG for 04 h. Perform centrifugation for a while. The clay material obtained from the mixture was adjusted to pH 7,50-760 as above. (preferably 758) phosphate buffer to detect antibiotics or in the wash solution. (Detection is by maltol reaction or streptomycin-specific (performed by other negative coloring reactions).

(3) Desorption in McIlvaine buffer at pH 3.20 [the raw material obtained in step (2)] After stirring 10 mg of the product in 10 ml of buffer for 2 hours, it shows bacteriological activity. Quantify streptomycin (by biological method using expansion in agar plates) .

(4) until the concentration of active antibiotic no longer increases in the desorption buffer; Repeat steps (1) to (3).

(5) Since the product consists of beidellite saturated with antibiotics as mentioned above, Dry and store at 2-5°C until use.

The product obtained in step (5) is administered at a dosage of 10 g for 7 days, preferably 2 to 4 times/day. Administer orally in divided doses.

Example 2 Preparation of gastrointestinal compositions beidellite to smectite, streptomycin hydrochloride to tetracycline The procedure is as described in Example 1, substituting the hydrochloride. Helicobuff tape in humans A preparation is obtained which is useful in treating gastric ulcers and gastritis due to B. lori strains.

Example 3 Shigaru Sukekoji r1 tail The power of beidellite to benzimite, streptomycin hydrochloride to penicillin■ The same procedure as described in Example 1 is carried out except that the lJ'7mu salt is used. of cattle, sheep, dogs and cats etc. In class 1, it is caused by bacteria belonging to the Helicobacter and Campylobacter groups. The resulting preparation is useful in treating gastrointestinal inflammation.

international search report Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number A 61 K 4510 0 8415-4CI

Claims (7)

[Claims] 1. In compositions useful for the treatment of bacterial inflammation of the gastrointestinal system in humans and animals, characterized in that the composition contains the following substances in combination with physiologically acceptable excipients: a composition, (a) an antibiotic material, and (b) beidellite, smectite, halloysite, lithomage, benzimite and mixtures thereof, and is easily miscible with gastrointestinal mucus and A clay substance that ensures the passage of antibiotic materials through mucus. 2. Claim characterized in that the antibiotic material is selected from the group of: The composition according to item 1, - antibiotics, - an agent for inhibiting bacterial adhesion in tissues of the gastrointestinal system; - an agent for inhibiting bacterial toxins; - antibodies against bacterial antigens, and - mixtures thereof. 3. Composition according to claim 1, characterized in that the clay material is beidellite. thing. 4. The composition may contain 0.05 to 1.0 parts by weight of antibiotic material to 8 to 20 parts by weight of clay material. A composition according to any one of claims 1 to 3, characterized in that it contains 5 parts by weight. 5. The composition is (a) 0.1 to 1.2 parts by weight of antibiotic, and (b) viscosity with an average particle size of 10 μm or less Containing 10-12 parts by weight of earth material in combination with physiologically acceptable excipients The composition according to any one of claims 1 to 4, characterized in that: 6. In Methods of Use of Antibiotic Materials in Human and Animal Treatment, Antibiotics material and the antibiotic material to ensure passage through the gastrointestinal mucus, and beidellite, Smectite, halloysite, lithomage, benzimite and mixtures thereof Campylobacter in combination with a clay material selected from the group consisting of and against bacterial gastrointestinal inflammation caused by Helicobacter and especially Helicobacter pylori. A method of using antibiotic materials characterized by providing medicines suitable for specific site treatment. Law. 7. The antibiotic material is adsorbed onto the clay material until completely saturated. A method for producing a composition according to any one of claims 1 to 5.