WO2002055092A1 - Preventives and/or remedies for digestive diseases - Google Patents

Abstract

It is intended to provide novel preventives and/or remedies usable in preventing and/or treating digestive diseases. Thus, preventives and/or remedies for digestive diseases which contain a cyclic and/or chain-form polylactic acid mixture having a degree of condensation of 3 to 20 are provided.

Description

 Specification

 Agent for prevention and / or treatment of gastrointestinal diseases.

 The present invention relates to a prophylactic and / or therapeutic agent for gastrointestinal tract diseases containing a polydiacid mixture as an active ingredient. More specifically, the present invention relates to a prophylactic and / or therapeutic agent for inflammation, ulcer or tumor in the esophagus, stomach or duodenal mucosa, such as esophagitis, gastritis, gastric ulcer, duodenal ulcer, gastric cancer or duodenal cancer. The present invention also relates to a food or drink for the prevention and / or treatment of gastrointestinal tract diseases, comprising a poly-lactic acid mixture. Background art

This as the ulcer therapeutic agents that have been developed to, antacids, anticholinergic agents, anti-gassing Trinh agents, gastrointestinal hormone agents, anti-pepsin agents, histamine H ₂ receptor antagonists, tissue repair agents, mucosal protective agents Microcirculation improvers, proton pump inhibitors and the like are known. Among these ulcer treatments, the development of histamine H ₂ receptor antagonists and proton pump inhibitors, which have particularly strong acid secretion inhibitory effects, has dramatically improved the treatment results for ulcers. However, 'these ulcer treatments have a very high rate of ulcer recurrence after discontinuation of medication, which remains a major problem to be solved now. Helicobacter pylori is a gram-negative microaerobic bacterium belonging to the genus Helicobacter and is said to be one of the major causes of recurrence such as gastritis, duodenal ulcer, gastric ulcer or gastric cancer. For the purpose of treating or preventing these diseases, the search for substances having antibacterial activity against Helicobacter pylori has been conducted.

Currently, the treatment of various diseases caused by Helicobacter pylori includes the combination of bismuth and antibiotics, bismuth, metronidazole (US Patent No. 2,944,061) andに For triple use of tetracycline (US Pat. No. 2,712,517) or amoxicillin (US Pat. No. 3,192,198) Chemotherapy has been performed. These bismuth preparations, antibiotics and metronidazole are administered orally.

 Antimicrobial agents used as anti-Helicobacter pylori agents need to be administered in large amounts to maintain a concentration sufficient to inhibit the growth of Helicobacter pylori at the site of growth. For this reason, there was a problem that many side effects such as vomiting and diarrhea occurred. For these reasons, there has been a keen need for the development of a drug that is easy to administer, has few side effects, and has an excellent eradication activity against Helicobacter pylori.

 Previous studies have reported that cyclic and / or chain poly-L-lactic acid mixtures having a degree of condensation of 3 to 20 are useful as antineoplastic agents (Japanese Patent Application Laid-Open No. 9-22727). Japanese Patent Publication No. 3888/1998, Japanese Patent Application Laid-Open No. Hei 10-130153). However, there has been no report on the evaluation of whether a cyclic and Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 20 exerts the preventive and therapeutic effects on gastrointestinal diseases. Disclosure of the invention

 An object of the present invention is to provide a novel prophylactic and / or therapeutic agent which can be used for prevention and / or treatment of gastrointestinal tract diseases. Another object of the present invention is to provide a food and drink for preventing and / or treating digestive tract diseases.

 The present inventors, in order to conduct a study aimed at solving the above problems, first,

After infecting Mongolian gerbils with Helicobacter pylori and breeding them for a month, the number of viable bacteria in the gerbils' stomach and duodenum is measured to determine the number of viable bacteria against Helicobacter pylori. The infection protective effect of a cyclic or linear polylactic acid mixture having a condensation degree of 3 to 20 was examined. As a result, it was found that the above polyacid mixture showed a protective effect against Helicobacter pylori infection.

Furthermore, the present inventors have found that, in a model rat having 7_ immersion-restrained stress-induced gastric mucosal damage, the formation of the gastric mucosal damage has a cyclic, linear or chain form having a degree of condensation of 3 to 20. The effect of the polylactic acid mixture was investigated. As a result, it was found that the administration of the polylactic acid mixture significantly suppressed the occurrence of gastric mucosal damage.

 The present invention has been completed based on these findings.

 According to the present invention, there is provided a preventive and / or therapeutic agent for gastrointestinal tract diseases, comprising a cyclic and / or zonal or linear polylactic acid mixture having a condensation degree of 3 to 20.

 The gastrointestinal diseases referred to in the present specification are, for example, inflammation, ulcer or tumor in the esophagus, stomach or duodenal mucosa, and more specifically, for example, esophagitis, gastritis, gastric ulcer, duodenal ulcer, gastric cancer or duodenum Cancer and the like.

 The agent for preventing and / or treating a gastrointestinal tract disease of the present invention can be used for preventing and treating or treating a gastrointestinal tract disease caused by a helicopter, particularly a gastrointestinal tract disease caused by a helicobacter pylori. It can be used for prevention and treatment of Z.

 According to another aspect of the present invention, there is provided an 'anti-helicopter agent comprising a cyclic and / or linear polylactic acid mixture having a degree of condensation of 3 to 20.

 The anti-helicopter agent of the present invention can be particularly used as an anti-Helicobacter pylori agent, and can be used, for example, as a prophylactic and / or therapeutic agent for helicopter infection.

 Preferably, the lactic acid which is a repeating unit in the polylactic acid is substantially L? Consists of L-acid.

Preferably, a cyclic and Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 20 is subjected to dehydration condensation of lactic acid under an inert atmosphere, and the ethanol- and methanol-soluble components of the obtained reaction solution are subjected to reverse phase column chromatography. subjected to mouth Matogurafi one, after eluting with 2 5-5 0% by weight of Asetonitoriru aqueous p H 2 to 3,; fractions eluted with 9 0 weight _^0/0 or more Asetonitori Le aqueous solution of p H 2 to 3 It is.

Preferably, the dehydration condensation is carried out in a nitrogen gas atmosphere by stepwise reduction in pressure and temperature. Preferably, the reverse phase column chromatography is performed by ODS column chromatography. According to still another aspect of the present invention, there is provided a food or drink for prevention of gastrointestinal diseases and treatment of Z or ^^, which comprises a cyclic and / or chain polylactic acid mixture having a condensation degree of 3 to 20. It is.

 '' According to still another aspect of the present invention, in the manufacture of a food or drink for the prevention and treatment of gastrointestinal diseases or Z or a therapeutic agent for gastrointestinal diseases, There is provided the use of cyclic and / or linear polyamic acid mixtures.

 According to still another aspect of the present invention, a method for preventing gastrointestinal diseases, comprising administering to a mammal such as a human an effective amount of a cyclic and / or chain polylactic acid mixture having a condensation degree of 3 to 20. And / or methods for treatment are provided. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 shows a mass spectrum of the polylactic acid mixture obtained in Production Example 1.

 FIG. 2 is a graph showing the results of measuring the viable bacterial count of H. pylori in the stomach (foregutrum, hind stomach) and duodenum of the CPL administration group and the control group. White bars indicate the control group (n = 5), and black bars indicate the CPL group (n = 6).

 Figure 3 shows the effect of CP on the development of water immersion restraint stress-induced gastric mucosal injury in rats.

6 is a graph showing the effect of L. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, embodiments and a method of implementing the present invention will be described in detail.

The prophylactic and / or therapeutic agent for gastrointestinal tract disease of the present invention or the therapeutic agent (also referred to as the “agent of the present invention” in this specification) is a mixture of cyclic and / or linear polylactic acid having a condensation degree of 3 to 20. For the prevention and / or treatment of esophagus, gastritis, gastric ulcer, duodenal ulcer, esophagus such as gastric cancer or duodenal cancer, inflammation, ulcer or tumor of gastric or duodenal mucosa. Can be used. In addition, the agent for preventing and / or treating gastrointestinal tract diseases of the present invention includes a helicobacter bacterium (particularly, a helicobacter --H. pylori) is also useful as an anti-Helicobacter agent (especially anti-Helicobacter pylori agent).

The gastrointestinal tract disease referred to in the present specification has the broadest meaning, and all inflammatory diseases, ulcers or tumors in the esophagus, stomach or duodenal mucosa such as esophagitis, gastritis, gastric ulcer, duodenal ulcer, gastric cancer or duodenal cancer are included. Included. - Herikopakuta pylori (Helicobacter pylori) are activity 'is a Gram-negative bacteria isolated from & raw chronic gastritis崽者gastric mucosa. (Warren, JR & Marshall, BJ Lanceti: 1273-1275, 1983) 0 present bacteria Have a higher rate of isolation than stomach * duodenal ulcer patients, and show evidence of active gastritis apparent from infection experiments with human porantia (Morris, A. & Mcholoson, G. Am. J. Gastroenterology, 82: 192-199, 1987), and experimental animals with Helicobacter pylori infection also show symptoms of gastritis similar to humans. Therefore, it has become clear that they are associated with upper gastrointestinal diseases. Helicobacter pylori has also been attracting attention as an important risk factor for gastric cancer (Parsonnet, J. et al. N. Eng. J. Med. 325: 1127-1131, 1991).

 The cyclic and / or chain polylactic acid mixture having a degree of condensation of 3 to 20 used as an active ingredient in the present invention exhibits a good eradication activity even in an animal model of Helicobacter pylori infection. It is effective for the prevention and treatment of gastrointestinal diseases caused by Helicobacter pylori (especially gastritis, gastric ulcer or gastric cancer).

The preventive and / or therapeutic agent for gastrointestinal tract disease or the therapeutic agent of the present invention is effective for protection against helicopter infection. Therefore, if taken before infection, it is difficult to cause infection and cures even if infected. It has a preventive effect of 'easy'. Therefore, it is also preferable that the preventive and / or therapeutic agent for gastrointestinal tract diseases of the present invention is routinely taken as a health food or pharmaceutical. In the preventive and / or therapeutic agent for gastrointestinal tract disease and the food and drink for prevention and / or treatment of gastrointestinal tract disease of the present invention, a cyclic and Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 20 is preferably used. Used as an active ingredient.

 As used herein, the term “polylactic acid mixture” refers to a mixture in which cyclic and Z- or chain-like polylactic acid having a condensation degree of 3 to 20 is present at an arbitrary ratio. That is, the term "mixture" means a mixture of polylactic acids having any of the degrees of condensation of 3 to 20, and is also used as a concept including a mixture of cyclic and chain-like polylactic acids. . Such a “polylactic acid mixture” can be obtained by dehydrating and condensing a diacid and purifying it by an appropriate method, as described later in this specification. In this specification, the term "polylactic acid mixture" is used for convenience, but includes a single component such as cyclic polylactic acid having a certain degree of condensation or chain polylactic acid having a certain degree of condensation. And polylactic acid consisting of

 The degree of condensation means the number of lactic acid units which are repeating units in polylactic acid. For example, it is presumed that the cyclic polylactic acid has the following structural formula, where n represents the degree of condensation (that is, n = 3 to 20).

I)

When simply referred to herein as "lactic acid", the lactic acid includes all of L-lactic acid, D-lactic acid, or a mixture of these in any proportion. In the present invention, preferably, the lactic acid consists essentially of: L-lactic acid. Here, “substantially” means the ratio of L-lactic acid units in the polylactic acid mixture [that is, (L-lactic acid unit number ZL-lactic acid unit number + D-lactic acid unit number) XI 0 0] 70% or more, preferably 80% or more, more preferably 85% or more, further preferably 90% or more, particularly preferably 95% It means above. The ratio of L-lactic acid units in the polylactic acid mixture depends on the ratio of L-lactic acid and D-lactic acid present in lactic acid used as a starting material.

 The method for producing a cyclic and / or chain polylactic acid mixture having a degree of condensation of 3 to 20 is not particularly limited. For example, Japanese Patent Application Laid-Open Nos. Japanese Patent Application No. 0-1303053 or Japanese Patent Application No. 11-39894 (all contents described in these patent specifications are incorporated herein by reference). It can be obtained by the production method described below.

 More specifically, for example, a cyclic and Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 20 can be obtained by the following method A. Method A:

 First, lactic acid (preferably, lactic acid substantially consisting of L-lactic acid) is dehydrated and condensed under an inert atmosphere. As the inert atmosphere, for example, nitrogen gas, argon gas, etc. can be used, but it is preferable to use nitrogen gas.

The dehydration / condensation reaction is carried out at a temperature of 110 to 210 ° C, preferably 130 to 190 ° C, under reduced pressure of normal pressure to about 1 mmHg. It is particularly preferable to carry out the heating stepwise. The reaction time can be appropriately set, and for example, the reaction can be performed for 1 to 20 hours. When stepwise decompression or stepwise heating is used, the reaction time is divided into two or more partial reaction times, and the reaction is performed by setting the pressure and temperature in each part. When stepwise decompression is used, the pressure can be reduced, for example, from normal pressure to 150 mmHg to 3 mmHg. ° C → 185 ° C. In practice, these may be combined, for example, for 3 hours at ambient pressure at 145 ° C, 3 hours at 150 mmHg at 150 mmHg, and 3 hours at 155 ° C at 3 mmHg. The reaction can be carried out for 1.5 hours at 3 mmHg at 185 ° C for 1.5 hours. Next, ethanol / methanol is added to the reaction mixture obtained by the dehydration / condensation reaction, and the mixture is filtered and the filtrate is dried to obtain ethanol and methanol soluble components. That is, the term "ethanol- and methanol-soluble matter" as used herein means a fraction soluble in a mixed solution of ethanol and methanol. In addition, when ethanol and methanol soluble components are obtained, the reaction mixture of the dehydration condensation reaction is mixed with ethanol and methanol, and the ratio of ethanol to methanol can be set as appropriate. : Methanol = 1: 9. The order and method of adding ethanol and methanol to the reaction mixture are not limited, and may be appropriately selected.For example, it is possible to first add ethanol to the reaction mixture for the dehydration condensation reaction, and then add methanol. it can.

The ethanol-methanol soluble matter obtained above was subjected to reversed phase column chromatography, in particular, chromatography using an octadecylsilane (ODS) column. removing the fractions eluting with Asetonitoriru solution weight _^0/0, then 9 0 weight p H 2 to 3. When the fraction eluted with an aqueous solution of acetonitrile of ₀ % or more, preferably 99% by weight or more of an aqueous solution of acetonitrile is collected, a cyclic, linear or linear polylactic acid mixture having a condensation degree of 3 to 20 is obtained. Can be

 The cyclic and / or chain-like polylactic acid mixture obtained as above is neutralized with an alkali substance such as sodium hydroxide, dried under reduced pressure, and then formulated into a desired form as described below by a conventional method. Can be

 As another method for producing a cyclic and / or chain-like polylactic acid mixture having a condensation degree of 3 to 20 used in the present invention, for example, Japanese Patent Application No. 11-265571 / 1999 describes the method. The proposed method (Method B) or the method described in the specification of Japanese Patent Application No. 11-26673 (Method C) can be used (these patent specifications are not included). The contents of the description are all incorporated herein by reference.) Hereinafter, Method B and Method C will be specifically described.

Method B: In this method, a lactide is polymerized in the presence of a lithium compound represented by RYL i (where R represents an aliphatic group or an aromatic group, and “Y represents an oxygen atom or an iodine atom) to form a cyclic compound. When a polymerization reaction is carried out, the proportion of the lithium compound (RYL i) used is 1 to 0.1 mol, preferably 0.2 to 0.3, per mol of lactide. The reaction temperature is 1 1

The temperature is from 0 to 0 ° C., preferably 1 780 ° C. The reaction is preferably started at a temperature between 178 and 150 ° C. and gradually raised to room temperature. The reaction is preferably performed in the presence of a reaction solvent. As a reaction solvent, in addition to cyclic ethers such as tetrahydrofuran, getyl ether, dimethoxetane and the like can be used. As the reaction atmosphere, an inert gas atmosphere such as nitrogen gas or argon is used. The reaction pressure is not particularly limited, and is preferably normal pressure.

 The composition of the lactic acid oligomer obtained as described above (that is, the mixing ratio of the cyclic lactic acid oligomer and the chain lactic acid oligomer) varies depending on the lithium compound used as the reaction aid. When a lithium compound having 1 to 3 carbon atoms (ROL i) (where R is an alkyl group having 1 to 3 carbon atoms) is used as the lithium compound, a cyclic lactic acid oligomer and a chain oligomer are used. (Proportion of cyclic lactic acid oligomer: 80 to 85% by weight) is obtained. On the other hand, when a lithium compound of an alkyl alcohol having 4 or more carbon atoms such as t-butyl alcohol or a thiophenol compound is used as the lithium compound, substantially only a cyclic lactic acid oligomer can be selectively obtained. Method C:

 This method comprises the steps of (i) heating lactic acid to a temperature in the range of 120 to 140 ° C under a pressure of 350 to 400 mmHg to cause a dehydration-condensation reaction and to distill lactide. First heating step to distill and remove only by-product water without

(ii) After completion of the first heating step, the reaction product is calo-heated to a temperature of 150 to 160 ° C., and the reaction pressure is reduced to a rate of 15 to 20 at a rate of 0.5 to 1 mmHgZ min. down to mmH g When the pressure is lowered, only by-product water is distilled off while avoiding the distillation of lactide. After the reaction pressure drops to 15 to 2 OmmHg, the same pressure condition and reaction temperature of 150 to 160 are applied. C, a second heating step in which the reaction is further continued to produce a dehydrated condensate mainly composed of a linear lactic acid oligomer,

 (iii) After the completion of the second heating step, the linear lactic acid oligomer is cyclized by heating at 15 to 16 '0 ° C under a pressure condition of 0.1 to 3 mmHg to form a cyclic oligomer. Third heating step,

The method is characterized by comprising:

 In this method, first, in a first heating step, acetic acid is heated under reduced pressure to cause a dehydrocondensation reaction. The reaction time in this case is 3 to 12 hours, preferably 5 to 6 hours. In the reaction under the first heating, by-product water generated by dehydration-condensation of lactic acid is distilled off so that the reaction proceeds smoothly.In this case, lactide which is a dehydration-condensate of two molecules of lactic acid is removed. Carry out so as not to evaporate. For this purpose, the reaction pressure is reduced, preferably kept at 300 to 500 mmHg, more preferably at 350 to 400 mmHg, and under this pressure condition, 100 to 140 ° C, preferably 130 to 140 ° C. It is good to heat to the range. The reaction in the first heating step mainly produces a reaction product mainly composed of a dehydration condensate of 3 to 23 molecules of lactic acid.

 After the completion of the first heating step, in the second heating step, a temperature higher than the reaction temperature in the first heating step, preferably 145 to 180, so as to obtain an oligomer having an increased average degree of polymerization. C., more preferably at a temperature of 150 to 160.degree. C., and the reaction pressure is lowered to a pressure of 10 to 50 mmHg, preferably 15 to 20 mmHg, and the dehydration condensation reaction is further continued.

This reaction is also carried out under the same conditions as in the case of the reaction in the first heating step, in which by-product water is distilled off to make the reaction proceed smoothly, but lactide is not distilled off. The rate at which the reaction pressure is reduced to a pressure within the above range (the pressure reduction rate) is 0.25 to 5 mniHgZ, preferably 0.5, in order to avoid lactide distilling and to increase the reaction efficiency. It is usually necessary to keep it in the range of 11 mmH gZ. Above the range If the pressure reduction rate is lower, the time required to reduce the pressure to the predetermined pressure becomes longer, which is not preferable.On the other hand, if the pressure reduction rate is higher than the above range, lactide is distilled off together with by-product water. Not preferred.

 After the reaction pressure has dropped to a predetermined pressure, the reaction is continued at this reaction pressure. The heating time in this case is 3 to 12 hours, preferably 5 to 6 hours. By the reaction in the second heating step, a lactic acid oligomer having an average degree of polymerization of 3 to 30, preferably 3 to 2 ′ 3 is obtained. In this case, the ratio of the cyclic oligomer in the oligomer is usually 7 It is about 0 to 80% by weight. After completion of the second heating step, in the third heating step, the reaction pressure is maintained at 0.25 to 5 mmHg, preferably 0.5 to 1 mmHg, and The reaction is further continued at a temperature of C, preferably 150-160 ° C. The reaction time is 3 to 12 hours, preferably 5 to 6 hours. The by-product water generated in this case is also distilled off. In this case, it is preferable to avoid the distillation of lactide, but since the reaction product contains almost no lactide, it is not necessary to reduce the pressure-reducing rate significantly.

The reaction in the third heating step, the average degree of polymerization 3 to 3 0, preferably at 3-2 3, and the proportion of cyclic oligomers 9 0 wt% or more, preferably 9 9 weight _^0/0 more lactic acid oligomers Is generated.

 Note that the above methods A, B and C are only a part of specific examples of the method for producing the polylactic acid mixture used in the present invention, and in the present invention, the polylactic acid mixture produced by another method is used. It can also be used.

The prophylactic and / or therapeutic agent for gastrointestinal tract diseases of the present invention may be used in the form of pharmaceuticals, quasi-drugs, etc., in addition to the above essential components, if necessary, as long as the effects of the present invention are not impaired. The components and additives used can be arbitrarily selected and used in combination. The prophylactic and / or therapeutic agent for gastrointestinal tract diseases of the present invention or Z or therapeutic agent can be used as a single pharmaceutical product, and can also be used by blending it with a pharmaceutical product or a quasi-drug. The agent of the present invention contains a cyclic or Z- or chain-like polylactic acid mixture having a degree of condensation of 3 to 20 as an active ingredient. If necessary, other active ingredients, for example, a gastric acid secretion inhibitor, a gastric mucous membrane Protective agents, antacids, stomachic drugs, digestive drugs, stomachic digestive drugs, intestinal drugs, enzyme preparations such as anti-urease enzyme, anti-Helicobacter pylori, antibody preparations, and antibacterial agents.

More particularly, the agents of the present invention, histamine H ₂ receptor antagonist, Purotonpo pump inhibitors, gastric Neba鹰defense type gastritis and peptic ulcer therapeutic agents, antacids, such as antidiarrheals and combines viewed Can be used.

The histamine H ₂ receptor antagonists, for example cimetidine, ranitidine, Famo cytidine, mouth Kisachijin, nizatidine, etc., and Shioa Rui allowed their pharmaceutically may include derivatives, one or more selected from these Can be used. Examples of the pharmaceutically acceptable salt or derivative include ranitidine hydrochloride and the like as ranitidine salts, and oral xatidine hydrochloride and the like as oral xatidine derivatives.

 Examples of the proton pump inhibitor include lansoprazole, omebrazole, pantoprazole, labebrazole, reminoprazole, palibrazole, and the like, and pharmaceutically acceptable salts thereof, and one or more selected from these may be used. it can. Preferably, lansoprazole, omebrazole or rabebrazole is used. Proton pump inhibitors are used in combination with the following antacids to reduce the effects of stomach acid by methods such as the use of antacids or enteric-coated preparations or stabilized preparations (eg, basic inorganic salts of magnesium or calcium). It is preferred that

Gastric mucosa-protective gastritis and peptic ulcer treatment agents include, for example, aldiquosa, aldioxa ', magnesium aluminate metasilicate, sucralfate, proglumide, teprenone, cetraxate hydrochloride, pranotol, sofacalcon, and venexate hydrochloride beta. Examples thereof include desks, illsogladine maleate, levapimide, fetobena sodium, polaprezinc, ecapapide, prostaglandin derivatives (misoprostol, ornoprosteel, etc.) and the like, and one or more selected from these are used. Examples of the antacid include dry hydroxide aluminum gel, magnesium aluminate magnesium, magnesium silicate, synthetic aluminum silicate, synthetic hydrosite, acid magnesium, magnesium aluminate hydroxide, aluminum hydroxide gel, aluminum hydroxide. , Sodium hydrogen carbonate co-precipitated product, aluminum hydroxide 'dried magnesium carbonate mixed gel, aluminum hydroxide / magnesium carbonate / carbonic acid rusidium co-precipitated product, magnesium hydroxide, sodium bicarbonate, magnesium carbonate Inorganic antacids such as calcium carbonate, calcium carbonate, magnesium aluminate metasilicate, calcium hydrogen phosphate and calcium hydrogen phosphate, amino acid agents such as amino acetic acid, dihydroxy aluminum amino acetate, and roto extract Gera is one or more selected from these are used.

 Examples of antidiarrheals include bismuth agents (for example, bismuth hyposalicylate, bismuth hyponitrate, bismuth hypocarbonate, bismuth hypogallate, etc.) and tanning agents (for example, tannic acid, albumin tannate, methylene thymol tannin, etc.) And the like, and one or more selected from these can be used. Of these, bismuth agents that effectively act on Helicobacter pylori are particularly preferred.

 The agent of the present invention may further include, if necessary, for example, bottle mouth maggot (Areca), seki ruzukahi (Punica granatum), power, nose, / ゥ (Licorice root;, shoma (Cimicifuga rhizome;), herba ;, engokek (Corydalis tuber), senna (Senna), perilla herb (perilla herb), burdock (Actium lappa), tannon (Salviae miltiorrhizae), renyo (Forsythiae fructus), tanhi (Moutan cor) (Crataegus), Hofun (Aconitum carmichae 丄 i Kinguin power (Louicwra japonica), Kobun (yperus rhizome), Kozuka (Carthami f los), Zakaku (Lindera strychhifolia), Rennik seed , Dhuo (Rhubarb), Ginger, Kujin

(Sophora root), Aloe (Aloe), Peony (Peony root), Chiyouji (Clove), Okon (Scutellaria root), Kissim (Is atureorange), Kogoboku (Magnolia bark), etc. Crude drug powder or its extract component, preferably May further include at least one of powdered crude or extracted components of ginger, ozone, kid, chili, licorice or engosaku. The drug of the present invention can be used in combination with drugs such as other anti-ulcer drugs (for example, proton pump inhibitors) as described above, but can also be used in combination with antibacterial drugs. '

 Examples of the antibacterial agent that can be used in combination with the agent of the present invention include amoxicillin, clarithromycin, tetracycline, metronidazole, tinidazole and the like.

 In some cases, the two or three-drug combination therapy described above can achieve better eradication, anti-ulcer, and ulcer relapse / relapse prevention effects than when each drug alone is used. is there.

 The form of the prophylactic and / or therapeutic agent for gastrointestinal tract disease of the present invention is not particularly limited, and an appropriate form most suitable for the purpose is selected from a form for oral or parenteral administration. It is possible to

 Pharmaceutical forms suitable for oral administration include, for example, tablets, capsules, powders, drinks, granules, fine granules, syrups, solutions, emulsions, suspensions, tuples, etc. Pharmaceutical forms suitable for parenteral administration include, for example, injections (subcutaneous injection, intramuscular injection, intravenous injection, etc.), external preparations, drops, inhalants, sprays, etc. It is not limited to.

Liquid preparations suitable for oral administration, such as solutions, emulsions, and syrups, include water, sucrose, sorbitol, fructose and other sugars, polyethylene glycol, propylene glycol and other glycols, sesame oil, olive oil, It can be produced using oils such as soybean oil, preservatives such as p-hydroxybenzoic acid esters, and flappers such as strawberry flapper and peppermint. For the production of solid preparations such as capsules, tablets, powders, or granules, excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrants such as sodium alginate, and stearic acid Lubricants such as magnesium and tanolek, polyvinyl alcohol, hydroxy Binders such as propylcellulose and gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin can be used.

 Formulations for injection or infusion suitable for parenteral administration preferably contain the above-mentioned substances, which are the active ingredient, dissolved or suspended in a sterile aqueous medium isotonic with the blood of the recipient. For example, in the case of an injection, a solution can be prepared using an aqueous medium composed of a salt solution, glucose, or a mixture of Δτ and pudose solution. Formulations for enteral administration can be prepared using a carrier such as cocoa butter, hydrogenated fat, or hydrogenated carboxylic acid, and are provided as suppositories. In the production of a propellant, the above-mentioned substance as an active ingredient can be dispersed as fine particles, which does not irritate the oral and respiratory mucosa of the recipient and facilitates the absorption of the active ingredient. The body can be used. Specific examples of the carrier include lactose and glycerin. Formulations in the form of aerosol or dry powder can be prepared depending on the substance as the active ingredient and the properties of the carrier used. These parenteral preparations are selected from glycos, oils, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc.1 Seeds or two or more foods can be added.

 The dose and frequency of administration of the agent for preventing and / or treating a gastrointestinal tract disease of the present invention may be appropriately determined depending on various factors including the purpose of administration, administration form, conditions such as the age, weight, and sex of the ingestor. In general, the dose of the active ingredient is 1 to 100 mg / kg, preferably 10 to 200 mg / kg, more preferably 10 to 1 mg / kg per day. 0 O mg Z kg. It is preferable to administer the above dosage amount of the preparation in 1 to 4 divided doses per day.

The timing of administration of the prophylactic and / or therapeutic agent for gastrointestinal tract disease of the present invention is not particularly limited. The present invention further relates to a food for preventing and / or treating gastrointestinal diseases, comprising a mixture of cyclic and linear or linear polylactic acids having a degree of condensation of 3 to 20. That is, the cyclic and Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 20 used in the present invention is as described above. It can be used not only in the form of a single preparation but also in food and drink. '

 The food and drink for prevention and / or treatment of gastrointestinal tract diseases of the present invention are not particularly limited as long as they can be blended without decomposing the polylactic acid mixture.

 Specific examples of food and drink products for preventing and / or treating gastrointestinal diseases according to the present invention include soft drinks, drinks, health foods, foods for specified health uses, functional foods, functionally active foods, Health foods or supplements, including beverages, commonly referred to as dietary supplements, supplements, feed, feed additives, and the like. '

 The food and drink for prevention and / or treatment of gastrointestinal tract diseases of the present invention includes food and drink of all forms, and the type thereof is not particularly limited. A composition, for example, various oral or enteral nutritional supplements, beverages, and the like, can be provided as a food or drink by blending a cyclic, Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 20. The composition of such foods and drinks may include proteins, lipids, carbohydrates, vitamins and / or minerals, etc. in addition to the cyclic and Z- or chain-like polylactic acid mixtures having a degree of condensation of 3 to 20. it can. The form of the food or drink is not particularly limited, and may be any of solid, powder, liquid, gel, and slurry forms as long as it is easy to take.

Specific examples of foods and beverages include, for example, sweets such as chewing gum, chocolate, candy, tablet confectionery, jelly, cookies, biscuits, yogurt, ice cream, frozen desserts such as ice desserts, tea, soft drinks (juice, coffee) Cocoa, etc.), drinks such as nutritional drinks, beauty drinks, etc., and any foods and drinks such as bread, ham, soup, jam, spaghetti, frozen foods and the like. Alternatively, the polylactic acid mixture used in the present invention can be used by adding it to a seasoning, a food additive or the like. Ingestion of foods and beverages for the prevention and / or treatment of gastrointestinal tract diseases of the present invention exerts the preventive and therapeutic effects of gastrointestinal tract diseases, and is safe without substantially harmful side effects. Food and drink can be provided. The food and drink for the prevention and / or treatment of gastrointestinal tract diseases of the present invention is obtained by directly mixing and dispersing a polylactic acid mixture into a general raw material used for food, and then processing it into a desired form by a known method. Can be obtained by:

The content of the polylactic acid mixture in the food or drink is not particularly limited, but is generally 0.1 to 20 weight. / ₀ , more preferably about 0.1 to 10% by weight.

 The amount of the polylactic acid mixture contained in the food or drink is preferably such that the effects of the prevention and / or treatment of gastrointestinal tract diseases, which are the objectives of the present invention, can be exerted. 0.1 g to 10 g per serving, more preferably 0.5 g to 3 g per serving.

 All the contents described in the specification of Japanese Patent Application No. 2001-7771, which is the Japanese patent application on which the priority claimed in the present application is based, are incorporated herein as a part of the disclosure of this specification. Shall be.

 The present invention will be described more specifically with reference to the following examples, but the present invention is not limited in any way by the examples. Example

Production Example 1: Production of polylactic acid mixture (hereinafter also referred to as CPL)

 500 ml of L-lactic acid (containing D-lactic acid) was placed in a separable flask contained in a mantle heater. Nitrogen gas was introduced and stirred for 300 ml of Z, and the distilled water was heated at 145 ° C. for 3 hours while being led to a flask equipped with a reflux condenser through a warmed down-type connecting pipe. After further reducing the pressure to 150 mmHg and heating at the same temperature for 3 hours, the mixture was heated under a reduced pressure of 3 mmHg at 155 for 3 hours, and finally heated under a reduced pressure of 3 mmHg at 185 for 1.5 hours. Polylactic acid was obtained.

The obtained polylactic acid was kept at 100 ° C., and after adding 100 ml of ethanol and 40 ml of methanol each, the mixture was allowed to cool. This was added to 500 ml of methanol, stirred well, allowed to stand, and then purified by filtration. The filtrate was dried under reduced pressure and dissolved in acetate nitrile to make a total volume of 200 ml (stock solution). This stock solution was subjected to reverse phase OD S column pre-equilibrated (TSK ge 1 0DS-8 OTM ), 30% containing 0. 01 M hydrochloric acid, the step-wise with 50% and 100% Asetonitoriru _(p H2. 0) Elution was performed to obtain polylactic acid (condensation degree 3 to 20), a fraction eluted with 100% of acetonitrile. Figure 1 shows the mass spectrum of the substance obtained. As is clear from the regular fragment ion peaks in FIG. 1, the obtained polylactic acid mixture is mainly composed of a cyclic condensate and a small amount of a linear condensate. Test example 1:

 (Materials and methods)

Experimental animals used were gerbils (Seak) 9 to 12 weeks old. The CPL group was fed a standard solid diet (CE-2) contaminated with 0.2% CPL freely with sterilized tap water, and the control group was a radioactive sterilized (Cobalt 60) standard solid diet (CE-2). -2) was freely taken with sterilized tap water. H.pylo; ri (.. L 5~3 0 X 10 6 cfu / mo use) a After 3 consecutive days orally administered using a stomach tube, gives CP L obtained by mixing the feed, sacrificed on day 30, The stomach and duodenum were removed, and the number of viable bacteria was measured. To measure the viable cell count, weigh the stomach (divided into the forestomach and the hind stomach) and the duodenum, add 10 times the volume of phosphate buffered saline (PBS), homogenize, perform serial dilution, and perform step dilution. 1 ml of the solution was spread on a helicopter agar medium (Nissui Pharmaceutical) and the number of colonies was counted. ·

 (Result)

 Viable bacterial counts in the stomach and duodenum of gerbils infected with H. pylori

FIG. 2 shows the results of measuring the viable bacterial count of H. pylori in the stomach (fore-gastric, posterior stomach) and duodenum of the CPL administration group and the control group. CPL administration group forestomach (10 ² cfu), post stomach (10 ² cfu) Oyopi duodenum (10 ² cfu) viable cell count in the control group forestomach (1

0 ³ cfu), the number of viable bacteria in the posterior stomach (10 ⁴ cίu) and the duodenum (10 ⁴ cfu) showed a decreasing tendency. From the above results, it was shown that the growth of H. pylori was suppressed in vivo by CPL itself or its metabolite, and that administration of CPL could protect against H. pylori infection. Test Example 2: '

 (Materials and methods)

 Six-week-old male Donryu rats (Japan SLC, weighing 180-200 g at the time of the experiment) were used for the experiment.

 CPL was dissolved in glycerin heated to 40 ° C., and then adjusted to 10 Omg / m 1 by adding propylene glycol. Thereafter, it was diluted with distilled water to give a dose of 50 mgZkg. The drug was orally administered once a day for 1 day at a rate of 1 ml per 200 g body weight. As a control group, only the solvent was orally administered at the same dose.

 Water immersion restrained stress-induced gastric mucosal damage was prepared as follows. The rats fasted for 18 hours before the start of the experiment, had free access to water up to 2 hours before the start of the experiment, and then fasted. Rats were placed in a Tokyo University medicinal stress cage (Natsume Seisakusho), immersed in a water tank at 22 to 23 ° C for 10 hours up to the height of the sphenoid process, and subjected to stress loading. The drug was re-administered 30 minutes before stress loading.

 The measurement of the gastric damage area was performed as follows. The abdomen was opened under ether anesthesia, and the stomach was removed. After ligation of the cardia, 8 ml of a 2% formalin solution was injected into the stomach from the duodenum and fixed for 10 minutes. It was also fixed from the serosal side by immersion in the same solution for 10 minutes. After that, an incision was made along the greater curvature and the length of the lesion (mm) was measured with a stereomicroscope.

 The results were expressed as mean soil standard error (mean soil S.E .; N = 10 to 11). Statistical significance was evaluated using the Student's t-test, with a value of P <0.05 being significant.

 (Result)

The measurement results are shown in Table 1 below and FIG. Stomach mucosa injury J

 Μ "τ VOUJIlg / Jig

 Q

 ο ·

 o 1 Q

 9 η

 Δ · υ

 Q

 9 η π

 / 1 Q π υ 1 a

 Ό .π u

o Ο, π υ ο. A U

 Ό Ό, o n

 ,

 7 n

 . Π u

 8 12.0 16.0

 Q

 O. U U.

 10 28. 0 15. 0

 1 1 1 1.0

Average "1 7.9 13.1

As shown in Table 1 and Fig. 3, the average of the sum of the damages induced by stress loading was 17.9 ± 1.6ππππι, whereas the average The administration of water-immersion restraint stress-induced gastric mucosal damage was significantly suppressed by continuous administration for 10 days, and the average of the total damage was: L3.1 ± 1.3 mm. Potential for industrial use '

 The prophylactic and / or therapeutic agent for gastrointestinal tract disease of the present invention includes, for example, esophagitis, gastritis, gastric ulcer, duodenal ulcer, esophagus such as gastric cancer or duodenal cancer, inflammation in stomach or duodenal mucosa, ulcer or tumor Can be used for the prevention and treatment of Z. In addition, the polylactic acid mixture used as an active ingredient in the present invention is a low condensate of lactic acid derived from a biological component, has high biocompatibility, and has few side effects.

Claims

The scope of the claims 1. A preventive and / or therapeutic agent for gastrointestinal tract diseases, comprising a mixture of cyclic and Z- or chain-like polylactic acids having a degree of condensation of 3 to 20. ' 2. The prophylactic and / or therapeutic agent for gastrointestinal tract disease according to claim 1, wherein the gastrointestinal tract disease is inflammation, ulcer or tumor in the esophagus, stomach or duodenal mucosa. ·  3. The preventive or therapeutic agent for gastrointestinal disease according to claim 1 or 2, wherein the gastrointestinal disease is esophagitis, gastritis, gastric ulcer, duodenal ulcer, gastric cancer or duodenal cancer.  4. The preventive and / or therapeutic agent for gastrointestinal tract disease according to any one of claims 1 to 3, wherein the gastrointestinal tract disease is a disease caused by Helicobacter.  5. The preventive and / or therapeutic agent for a gastrointestinal tract disease according to claim 4, wherein the helicobacter is Helicobacter pylori.  6. An anti-helicopter agent comprising a cyclic and Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 20.  7. The anti-helicopter agent according to claim 6, wherein the helicopter is Helicobacter pylori.  8. The anti-Helicobacter agent according to claim 6 or 7, which is a prophylactic and / or therapeutic agent for helicopter infection.  9. The drug according to any one of claims 1 to 8, wherein the lactic acid that is a repeating unit in the polylactic acid substantially consists of L-lactic acid. 10. A cyclic and / or chain polylactic acid mixture having a degree of condensation of 3 to 20 is subjected to dehydration condensation of lactic acid under an inert atmosphere, and reverses the ethanol and methanol soluble components of the resulting reaction solution. subjected to phase column chromatography, after eluting with § Se Tonitoriru aqueous 2 5-5 0 weight _^0/0 p H 2 to 3, and eluted with 9 0 wt% or more Asetonitoriru aqueous solution of p H 2 to 3 10. The agent according to any one of claims 1 to 9, which is a fraction. 11. The agent according to claim 10, wherein the dehydration condensation is carried out in a nitrogen gas atmosphere by stepwise decompression and temperature increase. 12. The drug according to claim 10 or 11, wherein the reverse phase column chromatography is performed by ODS column chromatography.  13. A food or drink product for preventing and / or treating digestive tract diseases, comprising a cyclic and / or linear polylactic acid mixture having a condensation degree of 3 to 20.