Drugs for improving minor inflammation of the submucosal lining of the duodenum and drugs for improving gastric discharge

Abstract

To provide an agent for improving gastric or duodenal submucosal minor inflammation and an agent for improving a gastric emptying ability.SOLUTION: The present disclosure provides: an agent for improving gastric or duodenal submucosal minor inflammation, containing a gastric mucosa protectant as an active ingredient; and an agent for improving a gastric emptying ability, containing a gastrointestinal mucosa protectant as an active ingredient.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a drug for improving gastric or duodenal submucosal microinflammation and a drug for improving gastric emptying function. [Background technology]

[0002] Drugs that form a protective film on the injured area and have the effect of curing inflammation and ulcers are classified as gastrointestinal mucosa protective agents, and known drugs include sucralfate, sodium alginate, aldioxa, etc. On the other hand, gastrointestinal mucosa protective agents are known to be effective when there is damage to the surface of the gastrointestinal tract, such as gastritis or gastric ulcers. Non-patent literature 1 reports that, regarding the clinical effects of aggressive factor drugs and defensive factor drugs in cases of acute exacerbation of chronic gastritis, gastric acid secretion inhibitors are effective in eliminating symptoms of erosions caused by strong gastric acid, while defensive factor enhancers such as benexate hydrochloride and betadex are effective in eliminating symptoms of superficial gastritis. On the other hand, unlike superficial damage, submucosal microinflammation remains for a long time even after the mucosal surface has normalized, causing chronic heaviness. In addition, although the above-mentioned mucosal protective agents are known to be effective in repairing wounds, they are not known to improve submucosal microinflammation or gastric motility (gastric emptying function). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Pharmacology and Therapy, Vol. 20, No. 12, pp. 5031-5044 (1992) Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention has been made in consideration of the above circumstances, and aims to provide a drug that is effective not only against damage to the surface layer of the gastric or duodenal mucosa, but also against inflammation under the gastric or duodenal mucosa (hereinafter also referred to as gastric or duodenal submucosal microinflammation), and further to provide a drug that can improve the decrease in gastric emptying function associated with the submucosal microinflammation. [Means for solving the problem]

[0005] The present inventors have discovered that a gastrointestinal mucosa protective agent is not only effective against surface injuries of the gastrointestinal tract such as gastritis and gastric ulcers, but is also effective in improving gastric or duodenal submucosal microinflammation and improving gastric emptying function, and that the gastrointestinal mucosa protective agent can effectively improve stomach pain and heavy stomach feeling, thereby completing the present invention.

[0006] The present invention has the following aspects. [1] A drug for improving gastric or duodenal submucosal microinflammation that contains a gastrointestinal mucosa protective agent as an active ingredient. [2] The gastric or duodenal submucosal microinflammation improving drug described in [1], wherein the gastrointestinal mucosal protective agent is at least one selected from the group consisting of sucrose octasulfate and a pharma- ceutical acceptable salt thereof, rebamipide and a pharma- ceutical acceptable salt thereof, teprenone, and methylmethionine sulfonium chloride. [3] The drug for improving gastric or duodenal submucosal microinflammation according to [1] or [2], further comprising at least one selected from the group consisting of inorganic salts, organic acids and their salts. [4] A drug for improving gastric emptying that contains a gastrointestinal mucosa protective agent as an active ingredient. [5] The gastric emptying function improving drug according to [4], wherein the improvement of gastric emptying function is due to improvement of gastric or duodenal submucosal microinflammation. [6] The gastric emptying function improving drug according to [4] or [5], wherein the gastrointestinal mucosa protecting agent is at least one selected from the group consisting of sucrose octasulfate and a pharma- ceutical acceptable salt thereof, rebamipide and a pharma- ceutical acceptable salt thereof, teprenone, and methylmethionine sulfonium chloride. [7] The gastric emptying function improving drug according to any one of [4] to [6], further comprising at least one selected from the group consisting of inorganic salts, organic acids and salts thereof. Effect of the Invention

[0007] According to the present invention, a drug can be provided that can efficiently ameliorate stomach pain and heavy stomach feeling by improving gastric or duodenal submucosal microinflammation and improving gastric emptying function. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 shows the inhibitory effect of sucrose octasulfate aluminum salt (sucralfate) on vascular permeability in the stomach. [Diagram 2] FIG. 1 shows the correlation between the vascular permeability inhibitory effect and acid infiltration inhibitory effect in the stomach of sucrose octasulfate aluminum salt (sucralfate) and a mixture of sucralfate with an organic acid and an inorganic salt. [Diagram 3] FIG. 1 is a graph comparing the inhibitory effect of aluminum sucrose octasulfate (sucralfate) with that of a mixture of sucralfate with an organic acid and an inorganic salt on acid infiltration into the stomach. [Figure 4] FIG. 1 shows the effect of improving gastric emptying of a mixture of sucralfate with an organic acid and an inorganic salt, and itopride. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] <Gastric or duodenal submucosal microinflammation improving drug> The gastric or duodenal submucosal microinflammation improving drug of the present invention contains a gastrointestinal mucosa protecting agent as an active ingredient. The gastrointestinal mucosa protecting agent is a drug that physically protects the damaged part of the gastrointestinal mucosa or promotes gastrointestinal mucus secretion to improve the damage of the gastrointestinal mucosa, and is a drug used for the treatment of gastric ulcers, etc. The gastrointestinal tract in the gastrointestinal mucosa protecting agent is not particularly limited, and examples thereof include the stomach and duodenum. Specific examples of gastrointestinal mucosa protective agents include drugs that themselves form a physical barrier by gelling at damaged sites of the gastrointestinal mucosa, such as sucrose octasulfate, sodium alginate, and dried aluminum hydroxide gel; drugs that form a biological barrier at damaged sites of the gastrointestinal mucosa by increasing gastrointestinal mucus, such as teprenone, rebamipide, methylmethionine sulfonium chloride, cetraxate, sofalcone, benexate hydrochloride, and betadex, and pharma- ceutical acceptable salts thereof; of these, sucrose octasulfate and its pharma- ceutical acceptable salts, rebamipide and its pharma- ceutical acceptable salts, teprenone, and methylmethionine sulfonium chloride are preferred, and sucrose octasulfate and its pharma- ceutical acceptable salts are more preferred. These gastrointestinal mucosa protective agents can form a physical barrier by gelling, etc., or a biological barrier by increasing gastrointestinal mucus, and by suppressing acid infiltration into the gastrointestinal mucosa, can not only prevent damage to the surface of the gastric or duodenal mucosa but also act on the gastric or duodenal submucosa to improve microinflammation under the gastric or duodenal mucosa.

[0010] Microinflammation under the gastric or duodenal mucosa can be caused by a variety of factors, including stress and viral infection. For example, stress causes the breakdown of tight junctions in the gastrointestinal mucosa, which increases the permeability of the mucosa to substances, allowing acids and irritants to infiltrate under the mucosa. As a result, microinflammation occurs under the mucosa of the stomach or duodenum. The gastrointestinal mucosa protective agent not only suppresses the infiltration of acids and irritants under the mucosa of the gastrointestinal tract caused by stress, but also suppresses the breakdown of tight junctions in the gastrointestinal or duodenal mucosa caused by stress and acts directly on the microinflammation under the mucosa of the stomach or duodenum, thereby improving the microinflammation under the mucosa of the stomach or duodenum.

[0011] The effect of the gastrointestinal mucosa protective agent on the breakdown of tight junctions in the gastric or duodenal mucosa can be evaluated, for example, by measuring the expression level of occludin, a transmembrane protein that constitutes tight junctions, in the gastric or duodenal mucosa after stress loading by electrophoresis, etc. If the expression level of occludin in the gastric or duodenal mucosa after administration of the gastrointestinal mucosa protective agent is increased compared to after stress loading, it can be evaluated that the agent has an inhibitory effect on the breakdown of tight junctions in the gastric or duodenal mucosa. In addition, the action of the gastrointestinal mucosa protective agent on the substance permeability of the gastrointestinal mucosa can be evaluated, for example, by forming a mucosal protective layer by gelling the drug or producing mucin, and measuring the permeability of mannitol to the mucosal protective layer. If the permeability of mannitol to the mucosal protective layer is low, it can be evaluated that the inhibitory effect on the substance permeability of the gastrointestinal mucosa is high, and if the permeability of mannitol to the mucosal protective layer is high, it can be evaluated that the inhibitory effect on the substance permeability of the gastrointestinal mucosa is low. In addition, the direct improving effect of the gastrointestinal mucosa inhibitor on the microinflammation under the gastric or duodenal mucosa can be evaluated, for example, by measuring the inhibitory effect on the infiltration of eosinophils into the gastric or duodenal mucosa due to stress. For example, if eosinophils are infiltrated into the gastric or duodenal mucosa by stress, and the gastrointestinal mucosa protective agent can reduce the number of infiltrating eosinophils, it can be evaluated that the agent acts directly on the microinflammation under the gastric or duodenal mucosa and has an improving effect on the microinflammation.

[0012] The single dose of the gastrointestinal mucosa protective agent in the gastric or duodenal submucosal microinflammation improving drug of the present invention is not particularly limited, but is preferably 2 to 2000 mg, more preferably 30 to 1000 mg, and particularly preferably 75 to 1000 mg. By making it more than the above dose, the effect of improving gastric or duodenal submucosal microinflammation is enhanced, and by making it less than the above upper limit, the size of the drug can be made easy to take. The content of the gastrointestinal mucosa protective agent in the gastric or duodenal submucosal microinflammation improving drug of the present invention is not particularly limited, but is preferably 0.1 to 80 mass%, more preferably 1 to 70 mass%, and particularly preferably 2 to 60 mass%. By making it more than the above content, the concentration is increased and the single dose is reduced, so that the ease of taking is improved and the effect of improving gastric or duodenal submucosal microinflammation is enhanced, and by making it less than the above content, the physical properties can be excellent in moldability, disintegration, and dissolution, and side effects can be further reduced.

[0013] The medicamentically acceptable salt of sucrose octasulfate is not particularly limited, and one selected from oxides, hydroxides and carbonates of alkali metals or alkaline earth metals can be used alone or in combination of two or more, but sodium salt, potassium salt and aluminum salt are preferred. Sucralfate, which is an aluminum salt of sucrose octasulfate, has the effect of binding to proteins in inflamed mucosa to cover and protect the inflamed mucosa while repairing it, and is also called a "stomach bandage". In the present invention, sucralfate can suppress the infiltration of acid into the digestive tract mucosa in addition to its effect on inflamed stomach, and can exert an excellent effect on improving microinflammation under the stomach or duodenal mucosa by acting on the stomach or duodenal submucosa. Sucralfate is not particularly limited, and may be a hydrate or anhydrous, but in the present invention, sucralfate means sucralfate hydrate listed in the Japanese Pharmacopoeia, unless otherwise specified. Unlike sucralfate, an aluminum salt, sodium sucrose octasulfate does not have gel-forming ability, but like sucralfate, it has the effect of suppressing gastric or duodenal submucosal microinflammation. Teprenone and methylmethionine sulfonium chloride promote the secretion of gastric mucus, cover the mucosal surface to maintain lubrication, and suppress gastric or duodenal submucosal microinflammation caused by gastric acid infiltration. The pharma- ceutically acceptable salt of rebamipide is not particularly limited, and examples thereof include sodium salts, potassium salts, and salts formed with other common basic substances (trometamol (tris[hydroxymethyl]aminomethane), monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, meglumine, etc.), and one type may be used alone or two or more types may be used in appropriate combination. In the present invention, rebamipide and its pharma- ceutically acceptable salts are preferably rebamipide, since more significant effects can be obtained. In the present invention, the gastrointestinal mucosa protective agent may be used alone or in combination of two or more kinds.

[0014] In the present invention, the gastrointestinal mucosa protective agent alone can exhibit the effect of improving gastric or duodenal submucosal microinflammation, but by containing at least one selected from the group consisting of inorganic salts, organic acids and their salts, the effect of improving gastric or duodenal submucosal microinflammation can be further improved.

[0015] The composition ratio of the organic acid and / or its salt to the gastrointestinal mucosa protective agent in the gastric or duodenal submucosal microinflammation improving drug of the present invention is preferably 0.05 to 1:1 by weight, more preferably 0.1 to 0.33:1. By making the composition ratio of the organic acid and / or its salt greater than the above range, the effect of the gastrointestinal mucosa protective agent, for example, in the case of sucralfate, the adhesion of sucralfate to the gastrointestinal mucosa is improved, the protective function of the gastrointestinal tract is enhanced, and the retention in the gastrointestinal tract is increased, so that the effect can be sustained and enhanced. By making the composition ratio less than the upper limit, the irritation of the gastrointestinal mucosa protective agent caused by the organic acid and / or its salt can be suppressed. These organic acids and / or their salts may be in a powdered state or in a solution in the preparation. In addition, the gastrointestinal mucosa protective agent and the organic acid and / or its salt may be present separately in the preparation, or may be used in a state of being reacted in advance.

[0016] The inorganic salt is not particularly limited, and one selected from oxides, hydroxides, and carbonates of alkali metals or alkaline earth metals can be used alone or in appropriate combination of two or more, but a component that acts as an antacid is preferable. In the present invention, an antacid is a drug that neutralizes hydrochloric acid in gastric juice to reduce acidity. In the present invention, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, carbonates such as sodium carbonate, sodium bicarbonate, calcium carbonate, and magnesium carbonate, as well as synthetic hydrotalcite, magnesium aluminosilicate, magnesium oxide, aluminum hydroxide, and magnesium alumina hydroxide can be used. In the present invention, from the viewpoint of the effect of improving microinflammation under the gastric or duodenal mucosa and manufacturability, sodium bicarbonate, calcium carbonate, sodium hydroxide, magnesium carbonate, and magnesium hydroxide can be preferably used. In addition, when a water-soluble inorganic salt is contained as the inorganic salt, the inorganic salt is dissolved in water and consumed (metal ions, hydroxide ions, carbonate ions, etc. remain in the system).

[0017] The content of the inorganic salt is preferably an amount capable of adjusting the pH of the gastric or duodenal submucosal microinflammation improving drug of the present invention to a predetermined range when the gastrointestinal protective agent and the organic acid and / or its salt are contained and administered. In the present invention, the inorganic salt is added in an amount capable of adjusting the pH of the gastric or duodenal submucosal microinflammation improving drug to preferably 5.0 to 8.0, more preferably 5.5 to 7.4, particularly preferably 5.5 to 7.0, to obtain a gastric or duodenal submucosal microinflammation improving drug having excellent digestibility and excellent adhesiveness in the case of sucralfate, which has good adhesiveness and reduced mucosal irritation caused by organic acids, and can exert a damage alleviating effect due to gastric acid neutralization itself. In addition, by neutralizing gastric acid by adding an inorganic salt, the gastrointestinal mucosal protective agent and the organic acid can selectively react in the gastrointestinal tract, and a gastric or duodenal submucosal microinflammation improving drug having a higher effect as a gastrointestinal mucosal protective agent, such as high adhesiveness in non-acidic regions, can be obtained.

[0018] The organic acid and / or its salt is not particularly limited, and can be used alone or in combination of two or more. As the organic acid, from the viewpoint of the effect of improving microinflammation under the gastric or duodenal mucosa and the dispersion stability, one or more selected from alginic acid, citric acid, malic acid, ascorbic acid, glucuronic acid, aspartic acid, glutamic acid, adipic acid, gluconic acid, tartaric acid, succinic acid, lactic acid, acetic acid, butyric acid, maleic acid and fumaric acid are preferred, and citric acid, malic acid and lactic acid are particularly preferred. As the organic acid salt, the above-mentioned sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, etc. can be mentioned, and from the viewpoint of the gel forming property of the digestive tract mucosa protective agent on the mucosa, sodium salt and potassium salt are preferred.

[0019] The gastric or duodenal submucosal microinflammation improving effect of the gastric or duodenal submucosal microinflammation improving drug of the present invention can be confirmed, for example, by administering a proton pump inhibitor to an animal such as a rat to suppress physiological gastric acid secretion, exposing the stomach or duodenum in a chamber under anesthesia, administering allyl isothiocyanate (hereinafter also referred to as AITC), a drug that induces microinflammation under the gastric or duodenal mucosa, to the exposed stomach or duodenum, and evaluating the inhibitory effect of the test drug on the microinflammation induced by AITC when the test drug is administered to the exposed stomach or duodenum.

[0020] In addition, in the present invention, the inhibitory effect of acid infiltration into the digestive mucosa can be confirmed, for example, by exposing the stomach or duodenum of an animal such as a rat in which a proton pump inhibitor has been administered to suppress physiological gastric acid secretion by attaching it to a chamber under anesthesia, administering AITC to the exposed stomach or duodenum, and inducing acid infiltration of the gastric or duodenal mucosa, and evaluating the inhibitory effect of the test drug on the acid infiltration.

[0021] <Drugs that improve gastric emptying> The drug for improving gastric emptying function of the present invention contains a gastrointestinal mucosa protective agent as an active ingredient. As the gastrointestinal mucosa protective agent, the gastrointestinal mucosa protective agents listed in the section on the drug for improving gastric or duodenal submucosal microinflammation can be used. The drug for improving gastric emptying function of the present invention preferably has an effect of improving gastric emptying function by improving gastric or duodenal submucosal microinflammation. In contrast to drugs that improve gastric emptying function by repairing the gastric or duodenal mucosal surface, the gastric emptying function improving drug of the present invention, which has the effect of improving gastric emptying function by improving gastric or duodenal microinflammation, can be expected to have an improving effect on gastric emptying function in a short period of time compared to drugs that improve gastric emptying function by repairing the gastric or duodenal mucosal surface, because the gastrointestinal mucosa protecting agent can improve gastric or duodenal microinflammation in a short period of time without waiting for the gastric or duodenal mucosal surface to be repaired, which takes a relatively long period of time. In addition, drugs that repair the surface of the gastric or duodenal mucosa are not expected to improve the delayed gastric emptying caused by gastric or duodenal submucosal microinflammation, and drugs that activate the movement of the autonomic nervous system, etc., which controls movement as a symptomatic treatment, are generally adopted. The gastric emptying function improving drug of the present invention, which has an effect of improving gastric or duodenal submucosal microinflammation, can improve gastric or duodenal submucosal microinflammation, which is the pathological site of gastric hypomotility, and therefore can be expected to improve the root cause of the pathology and thus to ensure the expression of effects and the prevention of recurrence, compared with drugs that act on the autonomic nervous system, etc. to enhance movement, or drugs that have a gastric acid secretion inhibitory effect.

[0022] The gastric emptying function improving drug of the present invention can act on the submucosa of the stomach or duodenum to improve the microinflammation of the stomach or duodenum, and therefore can directly repair the cause of recurrent heavy stomach. In addition, the gastric emptying function improving drug of the present invention can improve inflammation smoldering in the submucosa of the stomach or duodenum, and can further improve the predisposition to heavy stomach, and relieve or normalize the hypersensitive state of the mucosa.

[0023] Specific examples of the gastrointestinal mucosa protecting agent in the gastric emptying function improving drug of the present invention include drugs which themselves form a physical barrier by gelling at damaged sites of the gastrointestinal mucosa, such as sucrose octasulfate, sodium alginate, and dried aluminum hydroxide gel, and drugs which form a biological barrier at damaged sites of the gastrointestinal mucosa by increasing gastrointestinal mucus, such as teprenone, rebamipide, cetraxate, and sofalcone, and pharma- ceutically acceptable salts thereof. Of these, sucrose octasulfate and pharma-ceutically acceptable salts thereof, rebamipide and pharma-ceutically acceptable salts thereof, teprenone, and methylmethionine sulfonium chloride are preferred, and sucrose octasulfate and pharma-ceutically acceptable salts thereof are more preferred. Examples of the pharma- ceutically acceptable salt of sucrose octasulfate, rebamipide and its pharma- ceutical acceptable salts include the salts described in the section on gastric or duodenal submucosal microinflammation ameliorators.

[0024] The single dose of the gastrointestinal mucosa protecting agent in the gastric emptying function improving drug of the present invention is not particularly limited, but is preferably 2 to 2000 mg, more preferably 30 to 1000 mg, and particularly preferably 75 to 1000 mg. By making the dose above the above range, the effect of improving gastric emptying function is enhanced, and by making the dose below the above range, the size of the drug can be made easy to take. The content of the gastrointestinal mucosa protective agent in the gastric emptying function improving drug of the present invention is not particularly limited, but is preferably 0.1 to 80% by mass, more preferably 1 to 70% by mass, and particularly preferably 2 to 60% by mass. By making the content above the above range, the concentration is increased and the single dose is reduced, resulting in good dosability and a high effect of improving gastric emptying function. By making the content below the above range, the drug can have physical properties that are excellent in moldability, disintegration, and dissolution, and further side effects can be reduced.

[0025] In the present invention, the gastrointestinal mucosa protective agent can exhibit the effect of improving gastric emptying function even when used alone, but the effect of improving gastric emptying function can be improved by containing at least one selected from the group consisting of inorganic salts, organic acids and their salts. Examples of inorganic salts, organic acids and their salts include those mentioned above. The composition ratio of the organic acid and / or its salt to the gastrointestinal mucosa protective agent in the gastric emptying function improving drug of the present invention may be the composition ratio described in the section on the gastric or duodenal submucosal microinflammation improving drug. In addition, the content of the inorganic salt in the gastric emptying function improving drug of the present invention may be the content described in the section on the gastric or duodenal submucosal microinflammation improving drug.

[0026] The gastric emptying function improving effect of the gastric emptying function improving drug of the present invention can be confirmed, for example, by administering AITC to fasted mice to induce delayed gastric emptying, and evaluating the gastric emptying function by the phenol red method in accordance with the method described in "Diagnostics and New Drugs" 1997,8,51-58, and evaluating the inhibitory effect of administration of the test drug.

[0027] The gastric or duodenal submucosal microinflammation improving drug and gastric emptying function improving drug of the present invention may contain optional ingredients as appropriate within the scope of not impairing the effects of the present invention. The optional ingredients include other active ingredients, polyols, polymeric compounds, excipients, binders, disintegrants, sweeteners, lubricants, preservatives, flavors, flavorings, colorants, etc.

[0028] Other active ingredients may include gastric acid secretion inhibitors such as ranitidine or ranitidine hydrochloride, famotidine, cimetidine, roxatidine acetate hydrochloride, nizatidine, lafutidine, lansoprazole, rabeprazole, omeprazole, and vonoprazan, muscarinic receptor antagonists such as Scopolia extract, pirenzepine, atropine, and scopolamine, as well as stomachic herbal medicine ingredients such as Magnolia bark fluid extract, Sophora Root fluid extract, Turmeric fluid extract, Licorice extract, Carrot fluid extract, Coptis tincture, Clove tincture, Gentian tincture, and Cinnamon tincture.

[0029] The polyol may include sugar alcohols such as mannitol, erythritol, xylitol, sorbitol, palatinite, lactitol, etc., monosaccharides, oligosaccharides, and polysaccharides, as well as polyhydric alcohols such as polyethylene glycol (PEG), glycerin, and propylene glycol, etc. Also, lower alcohols such as ethanol may be included.

[0030] Polymer compounds that can be included include xanthan gum, alginate ester, HM pectin, and carrageenan.

[0031] Examples of excipients include lactose, corn starch, crystalline cellulose, potato starch, etc. Examples of binders include hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethylcellulose, gum arabic, pregelatinized starch, carboxyvinyl polymer, agar, gelatin, honey, etc. Examples of disintegrants include crospovidone, croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose. Examples of sweeteners include sucrose, fructose, aspartame, sucralose, thaumatin, acesulfame potassium, sorbitol, stevia, refined white sugar, saccharin, and glycyrrhizin. Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid esters, light anhydrous silicic acid, and the like. Examples of preservatives include parabens such as alkylparabens, benzoic acid, and sodium benzoate. Examples of the flavoring include known essential oils, such as limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, and grapefruit flavor. The flavoring agent includes menthol. Examples of pigments include caramel, carmine, carotene liquid, β-carotene, copper chlorophyll, and sodium copper chlorophyllin. By incorporating these additives, it is possible to obtain a preparation that is excellent in moldability, storage stability, dissolution property, disintegration property, flavor and its stability, ease of administration, and the like.

[0032] The gastric or duodenal submucosal microinflammation improving agent and gastric emptying ability improving agent of the present invention can be used in the dosage forms of tablets, granules, fine granules, capsules, powders, powders, troches, pills, chewable agents, liquids, emulsions, suspensions, jellies, etc. Preparation into these dosage forms can be carried out by adding auxiliaries such as pharma- ceutically acceptable liquid or solid suitable carriers, excipients, dispersants, fillers, extenders, solvents, emulsifiers, additives, lubricants, preservatives, flavors, wetting agents, flavor correctors, dyes, and buffer substances. To prepare solid preparations such as tablets, granules, fine granules, capsules, powders, powders, troches, pills, and chewables, additives such as sodium bicarbonate, calcium carbonate, starch, sucrose, mannitol, carboxymethylcellulose, calcium stearate, magnesium stearate, and glycerin can be added in a conventional manner. Such preparations are preferably administered orally and can effectively affect the stomach or duodenum. They can also be formulated as enteric preparations that disintegrate in the small intestine by applying an enteric coating such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate, styrene-maleic anhydride copolymer, and methacrylic acid-methyl methacrylate copolymer.

[0033] The gastric or duodenal submucosal microinflammation improving drug and gastric emptying function improving drug of the present invention can be orally administered, and the dosage can be appropriately selected depending on the dosage form, the sex, body type, constitution, age, etc. of the patient, but is usually 1 to 4 times a day, 0.1 to 50 mg / kg per dose, preferably 0.5 to 20 mg / kg. By administering at or above the above dosage, the improving effect can be obtained, and by administering at or below the above dosage, side effects can be reduced and a preparation excellent in moldability, storage stability, dissolution, disintegration, flavor and its stability, ease of administration, etc. can be obtained.

[0034] To prepare the gastric or duodenal submucosal microinflammation improving drug and gastric emptying function improving drug of the present invention, for example, the gastrointestinal mucosa protecting agent and the organic acid and / or its salt are each added with an appropriate excipient, etc., and processed by granulation or the like, mixed in a powdered state, and then the powder can be used as is or molded into capsules, tablets, etc. to form a formulation. Alternatively, an organic acid and / or its salt may be added to the gastrointestinal mucosa protective agent dispersed in water, dried to a powder, and then similarly molded into capsules, tablets, etc. to prepare a formulation. When an inorganic salt is added, there is no particular order to add the organic acid and / or its salt and the inorganic salt first, or the inorganic salt may be added to a mixture of the gastrointestinal mucosa protective agent and the organic acid and / or its salt to prepare a formulation. To prepare a liquid formulation, for example, purified water, physiological saline, alcohols such as ethanol, propylene glycol, glycerin, polyethylene glycol, and solvents such as triacetin may be used. To prepare a liquid formulation, the gastrointestinal mucosa protective agent and the organic acid and / or its salt are placed in a container in the form of a suspension, solution, or powder, and water is added at the time of use, if necessary, and then the two are mixed to prepare a liquid formulation. The two components may also be reacted in advance to prepare a liquid formulation. EXAMPLES

[0035] The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[0036] [Examples 1 to 4] <Improvement of gastric or duodenal submucosal microinflammation> According to the method described in "Ulcer" by Tajima et al. (2189-7956), Vol. 40, pp. 13-16 (May 2013), 60 mg / kg of omeprazole, a proton pump inhibitor, was administered intraperitoneally to fasted SD rats to suppress physiological gastric acid secretion, and then the abdomen was opened, the stomach was incised, and the mucosa was attached to the chamber with the mucosa facing up, and 10% direct blue (dye) was administered intravenously. After that, saline containing 50 mM hydrochloric acid (50 mM HCl / 0.9% NaCl) was applied to the mucosa side as the chamber liquid, and after leaving it for 1 hour to reach a steady state, the chamber liquid was changed to saline containing 50 mM allyl isothiocyanate (AITC) and 50 mM hydrochloric acid, and inflammation (microinflammation) was induced under the mucosa. AITC was removed after 30 minutes, and the mucosa was washed with physiological saline. The chamber fluid was then changed again to physiological saline containing 50 mM hydrochloric acid, and 3 mg, 10 mg, 30 mg, or 100 mg of sucralfate (sucrose octasulfate aluminum salt, Fuji Chemical Industry Co., Ltd.) was suspended in 1 mL of purified water and added, and 1 mL of physiological saline containing 100 mM hydrochloric acid was added to make the final concentration of hydrochloric acid in the chamber 50 mM. The chamber fluid was removed after 15 minutes, and thereafter, sampling and addition of chamber fluid (2 mL of physiological saline containing 50 mM hydrochloric acid) was repeated every 30 minutes. The sampled chamber fluid was used as a measurement specimen, and the amount of acid infiltration and vascular permeability were measured immediately after AITC administration, 30 minutes after AITC administration, and 120 minutes after AITC administration. The amount of acid infiltration is an index of acid permeation into the submucosa. The amount of NaOH required to reach pH 7.0 was calculated using a potentiometric titrator (AT-710S) manufactured by Kyoto Electronics Manufacturing Co., Ltd., and the amount of acid infiltration into the submucosa was calculated by calculating the difference in acidity between the physiological saline containing 50 mM hydrochloric acid that had not been used and the liquid after sampling. Vascular permeability is an index of microinflammation in the submucosa. The amount of dye leaking from the mucosa to the luminal side due to vasodilation caused by inflammation was measured by measuring the absorbance at 594 nm using an absorbance measuring device, and the amount of dye leaking into the sampling liquid was quantified using a calibration curve of Direct Blue of known concentration. The results are shown in Table 1.

[0037] [Example 5] The amount of acid infiltration and vascular permeability were measured in the same manner as in Example 1, except that 16.7 mg of sucrose octasulfate sodium salt (hereinafter also referred to as SOS) was used instead of sucralfate. The results are shown in Table 1.

[0038] [Examples 6 to 9] The amount of acid infiltration and vascular permeability were measured immediately after AITC administration and 120 minutes after AITC administration in the same manner as in Example 1, except that a mixture of sucralfate, an organic acid (malic acid or lactic acid), and an inorganic salt (calcium carbonate or sodium bicarbonate) was used instead of sucralfate. When 3 mg of sucralfate was used, malic acid and calcium carbonate were mixed at 0.75 mg each, and lactic acid and sodium bicarbonate were mixed at 0.84 mg each. When 30 mg of sucralfate was used, malic acid and calcium carbonate were mixed at 7.5 mg each, and lactic acid and sodium bicarbonate were mixed at 8.4 mg each. The results are shown in Table 2.

[0039] [Comparative Example 1] Except for using physiological saline instead of the drug (sucralfate), the amount of acid infiltration and vascular permeability were measured in the same manner as in Example 1. The results are shown in Table 1.

[0040] [Comparative Example 2] The amount of acid infiltration and vascular permeability were measured in the same manner as in Example 1, except that physiological saline was used instead of the drug (sucralfate) and 0.9% NaCl was used as the chamber fluid instead of physiological saline containing 50 mM hydrochloric acid. The results are shown in Table 1.

[0041] Next, the inhibition rate of acid infiltration by the drug was calculated according to the following formula (1), and the inhibition rate of vascular permeability by the drug was calculated according to the following formula (2).

[0042] Acid infiltration inhibition rate by drug (%) = (acid infiltration amount immediately after AITC addition – acid infiltration amount at sampling time) / acid infiltration amount immediately after AITC addition × 100 (1) Vascular permeability inhibition rate by drug (%) = (vascular permeability of Comparative Example 1 at the time of sampling - vascular permeability at the time of sampling) / vascular permeability of Comparative Example 1 at the time of sampling × 100 (2)

[0043] The inhibition rate of acid infiltration (%) and the inhibition rate of vascular permeability (%) were judged according to the following criteria. <Effectiveness Assessment Criteria> × (no effect); less than 15% △ (weak effect); 15% to less than 40% ○ (moderate effect); 40% to less than 75% ◎ (Strong effect): 75% or more The results are shown in Tables 1 and 2 and FIGS.

[0044] [Table 1]

[0045] [Table 2]

[0046] As shown in Table 1 and Figure 1, administration of AITC caused acid infiltration and increased vascular permeability, resulting in submucosal microinflammation, despite not causing any macroscopic damage. In contrast, administration of sucrose octasulfate aluminum salt (sucralfate) and sucrose octasulfate sodium salt (SOS) reduced vascular permeability, an indicator of inflammation. As a control, 60 mg / kg of omeprazole, a proton pump inhibitor, was administered intraperitoneally, and the chamber liquid was changed to NaCl to completely block acid stimulation (Comparative Example 2). In comparison, the sucralfate and SOS administration group showed a sufficiently high vascular permeability improvement effect. Therefore, this effect cannot be obtained with drugs that suppress acid secretion, such as H2 blockers and proton pump inhibitors. In other words, it was suggested that this effect is a specific effect obtained by directly approaching the suppression of submucosal microinflammation. In addition, the effect was observed at a low dose of 0.72 μmol / mL (equivalent to 75 mg in human dose), which is an effect at a dose range that can be fully considered for use in humans.

[0047] Similarly, as shown in Table 2, a mixture of sucralfate with an organic acid and an inorganic salt also significantly reduced vascular permeability and acid infiltration. Moreover, the effects of improving vascular permeability and acid infiltration were improved compared to the effects of sucralfate alone, as shown in Figures 2 and 3, and there was a positive correlation between the effects of improving vascular permeability and acid infiltration, as shown in Figure 2. Since a mixture of sucralfate with an organic acid and an inorganic salt forms a stronger gel than sucralfate alone, in addition to the above-mentioned effect of improving submucosal microinflammation, a further effect of improving submucosal microinflammation can be expected by enhancing the biological barrier function that inhibits the permeation of acids and irritants. These results indicate that gastrointestinal mucosal protective agents, such as sucralfate, can improve gastric or duodenal submucosal microinflammation by improving the biological barrier function that inhibits the permeation of acids and irritants, and by repairing submucosal microinflammation.

[0048] [Example 10] <Improving effect on gastric emptying ability> According to the method described in "Ulcer" by Tajima et al., 2016, 43, 87-90, AITC 80mg / kg was orally administered to fasted ddY mice (8 weeks old, male) to induce delayed gastric emptying, and gastric emptying was evaluated by the phenol red method according to the method described in "Diagnosis and New Drugs" by Kamiki et al., 1997, 8, 51-58. That is, 20 minutes after AITC administration, a mixture of sucralfate 1500mg / kg, malic acid 375mg / kg, and calcium carbonate 375mg / kg (hereinafter referred to as SF organic acid mixture) was suspended in purified water and orally administered at 5mL / kg, and 40 minutes after administration of the SF organic acid mixture, 1.5% carboxymethylcellulose (CMC) solution containing 0.05% phenol red was administered at 0.5mL / mouse. The stomach was collected under anesthesia 20 minutes after administration of phenol red, and the amount of phenol red in the stomach contents was quantified by measuring the absorbance at a wavelength of 565 nm. The results are shown in Table 3.

[0049] [Reference example 1] The phenol red contained in the stomach contents was quantified by measuring the absorbance at a wavelength of 565 nm in the same manner as in Example 10, except that purified water and 1% Tween 80 aqueous solution were administered as the suspension medium instead of the SF organic acid mixture and AITC, respectively.

[0050] [Comparative Example 3] The amount of phenol red contained in the stomach contents was quantified by measuring the absorbance at a wavelength of 565 nm in the same manner as in Example 10, except that purified water was administered as a vehicle instead of the SF organic acid mixture.

[0051] [Comparative Example 4] The same procedure as in Example 10 was repeated, except that 10 mg / kg of itopride (Tokyo Chemical Industry Co., Ltd.), a medical ingredient that improves gastrointestinal motility, was administered subcutaneously instead of the SF organic acid mixture, and the amount of phenol red contained in the gastric contents was quantified by measuring the absorbance at a wavelength of 565 nm.

[0052] [Comparative Example 5] The same procedure as in Example 10 was repeated, except that a mixture of 375 mg / kg malic acid and 375 mg / kg calcium carbonate was administered instead of the SF organic acid mixture, and the amount of phenol red contained in the stomach contents was quantified by measuring the absorbance at a wavelength of 565 nm.

[0053] Next, a sample of gastric content collected immediately after administration of phenol red into the stomach was used as a reference to calculate gastric emptying ability (%) using the following formula (3), gastric emptying inhibition rate (%) using the following formula (4), and gastric emptying improvement rate (%) using the following formula (5).

[0054] Gastric emptying (%) = (1 - amount of phenol red in sample / amount of phenol red in reference) × 100 (3) Gastric emptying inhibition rate (%) = [1 - (gastric emptying rate of drug-administered group / gastric emptying rate of control group)] × 100 (4) Gastric emptying improvement rate (%) = (gastric emptying inhibition rate in Comparative Example 3 - gastric emptying inhibition rate in drug administration group) / gastric emptying inhibition rate in Comparative Example 3 × 100 (5)

[0055] The effect of improving gastric emptying was evaluated according to the following criteria. <Effectiveness Assessment Criteria> × (no effect); gastric emptying improvement rate is less than 15% △ (weak effect): Gastric emptying improvement rate is 15% or more but less than 40% ○ (moderate effect); gastric emptying improvement rate is 40% or more but less than 75% ◎ (Strong effect): Gastric emptying improvement rate of 75% or more The results are shown in Table 3 and FIG.

[0056] [Table 3]

[0057] As shown in Table 3 and Figure 4, gastric emptying was significantly decreased by administration of AITC, and gastric emptying was significantly improved by administration of the SF organic acid mixture. Moreover, the effect was higher than that of itopride, a medical ingredient that has the effect of improving gastrointestinal motility. These results suggest that gastrointestinal mucosa protective agents such as sucralfate may improve gastric motility disorders by suppressing microinflammation under the gastric mucosa.

[0058] [Examples 11 to 12] <Improvement of gastric or duodenal submucosal microinflammation> The amount of acid infiltration and vascular permeability were measured in the same manner as in Example 1, except that 1 mg or 3 mg of methylmethionine sulfonium chloride (hereinafter also referred to as MMSC) was used instead of sucralfate. The results are shown in Table 4.

[0059] [Examples 13-14] The amount of acid infiltration and vascular permeability were measured in the same manner as in Example 1, except that 1 mg or 3 mg of teprenone was used instead of sucralfate. The results are shown in Table 4.

[0060] [Examples 15 to 16] The amount of acid infiltration and vascular permeability were measured in the same manner as in Example 1, except that 2 mg or 6 mg of repamipide was used instead of sucralfate. The results are shown in Table 4.

[0061] Next, the inhibition rate of acid infiltration by the drug (%) and the inhibition rate of vascular permeability by the drug (%) were calculated in the same manner as in Example 1, and the inhibition rates of acid infiltration and vascular permeability were evaluated in the same manner as in Example 1. The results are shown in Table 4.

[0062] [Table 4]

[0063] As shown in Table 4, methylmethionine sulfonium chloride, teprenone, and rebamipide, which are drugs that form a biological barrier in the gastrointestinal mucosa by increasing gastrointestinal mucus, also reduced vascular permeability and acid infiltration. The above results show that in addition to gastrointestinal mucosal protective agents such as sucralfate, which form a physical barrier by gelling at damaged areas of the gastrointestinal mucosa, gastrointestinal mucosal protective agents such as methylmethionine sulfonium chloride, teprenone, and rebamipide, which form a biological barrier in the gastrointestinal mucosa by increasing gastrointestinal mucus, can also improve gastric or duodenal submucosal microinflammation by improving the biological barrier function that suppresses the permeation of acids and irritants and by repairing submucosal microinflammation.

[0064] [Example 17] <Improving effect on gastric emptying ability> Phenol red contained in the gastric contents was quantified by measuring absorbance at a wavelength of 565 nm in the same manner as in Example 10, except that 1500 mg / kg of sucralfate was administered instead of the SF organic acid mixture. Next, gastric emptying function (%), gastric emptying improvement rate, and gastric emptying improvement rate were calculated in the same manner as in Example 10. In addition, the gastric emptying improvement effect was evaluated in the same manner as in Example 10. The results are shown in Table 5.

[0065] [Example 18] Phenol red contained in the stomach contents was quantified by measuring absorbance at a wavelength of 565 nm in the same manner as in Example 10, except that 150 mg / kg of methylmethionine sulfonium chloride was administered instead of the SF organic acid mixture. Next, gastric emptying function (%), gastric emptying improvement rate, and gastric emptying improvement rate were calculated in the same manner as in Example 10. In addition, the gastric emptying improvement effect was evaluated in the same manner as in Example 10. The results are shown in Table 5.

[0066] [Example 19] Phenol red contained in the gastric contents was quantified by measuring absorbance at a wavelength of 565 nm in the same manner as in Example 10, except that 150 mg / kg of teprenone was administered instead of the SF organic acid mixture. Next, gastric emptying function (%), gastric emptying improvement rate, and gastric emptying improvement rate were calculated in the same manner as in Example 10. In addition, the gastric emptying improvement effect was evaluated in the same manner as in Example 10. The results are shown in Table 5.

[0067] [Table 5]

[0068] As shown in Table 5, the administration of AITC significantly decreased gastric emptying, while the administration of sucralfate, methylmethionine sulfonium chloride, or teprenone improved gastric emptying.

[0069] [Example 20] <Improvement effect on stress-induced breakdown of tight junctions in the gastrointestinal mucosa> SD rats were subjected to tail stimulation stress for 30 minutes, three times a day, for seven consecutive days. Tail stimulation stress was applied by clamping the rat's tail with sponge forceps and fixing the other end of the forceps to the edge of a circular enclosure (60 cm in diameter) used for open field testing, restricting the rat's movement. The rats were divided into two groups on the last day of stress application, and sucralfate was administered at a dose of 200 mg / kg at 2 mL / kg for seven days from the following day. The rats were fasted from the evening after the end of the sucralfate administration period, and the stomach and duodenum were removed the next day and subjected to the following Western blotting analysis.

[0070] <Western blotting analysis> The duodenal mucosa of the rat obtained above was scraped off, placed in lysis buffer, and crushed on ice using a biomasher, and left to stand for 15 minutes. After centrifugation, the amount of protein in the supernatant was quantified, and the concentration was adjusted so that the total protein concentration in each lane was similar, and then electrophoresis was performed on an acrylamide gel and transferred to a PVDF membrane. After blocking with skim milk for 30 minutes, an occludin antibody (manufactured by Thermoscientific) was added and incubated at 4°C for one day and night. After washing three times with 1% TBS-T, a secondary antibody (manufactured by Thermoscientific) was added and incubated for 2 hours, and chemiluminescence using a Western luminescence detection reagent (manufactured by GE Healthcare Life Sciences) was detected with a CCD camera to quantify the amount of occludin protein.

[0071] [Reference example 2] The amount of occludin protein in the duodenal mucosa was quantified in the same manner as in Example 20, except that rats that had been raised normally for 7 days without being subjected to stress were used.

[0072] [Comparative Example 6] The amount of occludin protein in the duodenal mucosa was quantified in the same manner as in Example 20, except that purified water was administered as a vehicle instead of sucralfate.

[0073] Next, the band intensity of the Western blotting was measured, and the relative band intensity was calculated based on the band intensity measured in non-stressed rats in Reference Example 2. The barrier function decrease rate was calculated using the following formula (6), and the barrier function improvement rate was calculated using the following formula (7).

[0074] Barrier function decrease rate (%) = [(1 - (relative band intensity of drug administration group / relative band intensity of Reference Example 2)] × 100 (6) Barrier function improvement rate (%) = (barrier function decrease rate in Comparative Example 6 - barrier function decrease rate in drug administration group) / barrier function decrease rate in Comparative Example 6 × 100 (7)

[0075] The improving effect on the breakdown of tight junctions in the gastrointestinal mucosa due to stress was evaluated according to the following criteria. <Effectiveness Assessment Criteria> × (no effect); Barrier function improvement rate is less than 15% △ (weak effect): Barrier function improvement rate is 15% or more but less than 40% ○ (moderate effect); Barrier function improvement rate is 40% to 75% ◎ (Strong effect): Barrier function improvement rate is 75% or more The results are shown in Table 6.

[0076] [Table 6]

[0077] As shown in Table 6, sucralfate improved stress-induced breakdown of tight junctions. These results indicate that gastrointestinal mucosa protective agents such as sucralfate can improve stress-induced breakdown of tight junctions, thereby improving microinflammation under the gastric or duodenal mucosa.

[0078] [Example 21] <Suppression of stress-induced inflammatory cell infiltration into the duodenal submucosa> The duodenal tissues excised from the stressed rats administered with sucralfate obtained in Example 20 were fixed with 4% paraformaldehyde solution, embedded in cryomount (Muto Chemical Co., Ltd.) to prepare frozen blocks. After preparing thin sections, they were immunostained using major basic protein, an eosinophil marker, as an indicator, and eosinophils were stained using the ABC method and DAB as a staining substrate. Three fields of view were photographed at a magnification of 40 times for each individual, and the average number per field was taken as the number of eosinophils for each individual. The counting was performed blindly so that the evaluator did not know which specimen was being evaluated.

[0079] [Reference example 3] The number of eosinophils was measured in the same manner as in Example 21, except that rats were kept normally for 7 days without being subjected to stress.

[0080] [Comparative Example 7] The number of eosinophils was measured in the same manner as in Example 21, except that rats were administered with purified water as a vehicle instead of sucralfate.

[0081] Next, the increase rate of inflammatory cell count was calculated using the following formula (8), and the inflammation improvement rate was calculated using the following formula (9).

[0082] Increase rate of inflammatory cell count (%)=[(eosinophil count in drug administration group or Comparative Example 7 / eosinophil count in Reference Example 3)−1)]×100 (8) Inflammation improvement rate (%) = (inflammatory cell increase rate in Comparative Example 7 - inflammatory cell increase rate in drug administration group) / inflammatory cell increase rate in Comparative Example 7 × 100 (9)

[0083] The inflammation-ameliorating effect was judged according to the following criteria. <Effectiveness Assessment Criteria> × (no effect); inflammation improvement rate is less than 15% △ (weak effect): Inflammation improvement rate is 15% or more but less than 40% ○ (moderate effect); Inflammation improvement rate is 40% or more but less than 75% ◎ (Strong effect): Inflammation improvement rate of 75% or more The results are shown in Table 7.

[0084] [Table 7]

[0085] As shown in Table 7, stress caused eosinophils to infiltrate from the duodenal mucosa, and the infiltrated eosinophils were reduced by administration of sucralfate. These results indicate that gastrointestinal mucosa protective agents such as sucralfate improve microinflammation in the duodenal submucosa by suppressing stress-induced infiltration of inflammatory cells into the duodenal submucosa.

[0086] [Examples 22 to 28] <Improvement of gastrointestinal mucosa permeability> According to the composition shown in Table 8 below, the components were mixed to prepare the oral compositions of Examples 22 to 28. Specifically, an organic acid or a salt thereof was added to purified water, and the resulting mixture was stirred and dispersed with a Three-One Motor (manufactured by Mizuho Kogyo Co., Ltd.) while sucralfate was added, and a pre-dissolved xanthan gum solution was further added to obtain the oral composition of each Example. In Example 22, no organic acid or a salt thereof was added, and in Examples 22, 23, 25, and 27, precipitated calcium carbonate having the composition shown in Table 8 was added simultaneously with the xanthan gum solution. Next, a membrane filter (pore size 1.0 μm, cellulose mixed ester type) was placed in the Franz cell, and the inside of the receiver was filled with the JP dissolution test first fluid (2.0 g of sodium chloride was dissolved in 7.0 mL of hydrochloric acid and water to make 1000 mL). A donor cap was attached, and a suspension of 5 mL of the first fluid and the oral composition of each Example (equivalent to 100 mg of sucralfate) was added. After leaving it for 3 hours, 5 mL of the first fluid in the donor cap was removed, and 5 mL of the first fluid containing 100 mM mannitol was added. The mannitol concentration in the first fluid in the receiver was quantified using the EnzyChrom D-Mannitol Assay Kit (Funakoshi Co., Ltd.) immediately after the addition and 1 hour later.

[0087] [Reference example 4] The mannitol concentration in the first liquid in the receiver was quantified in the same manner as in Example 22, except that an oral composition not containing an organic acid or a salt thereof and sucralfate was used.

[0088] Next, the permeation inhibition rate was calculated by the following formula (10).

[0089] Permeation inhibition rate (%)=[1-(mannitol concentration in each example / mannitol concentration in Reference Example 4)]×100 (10)

[0090] The improvement in permeability of the gastrointestinal mucosa was evaluated according to the following criteria. <Effectiveness Assessment Criteria> × (no effect); permeation inhibition rate is less than 15% △ (weak effect): Permeation suppression rate is 15% or more but less than 40% ○ (moderate effect): Permeation inhibition rate is 40% or more but less than 75% ◎ (Strong effect): Permeation suppression rate is 75% or more The results are shown in Table 8.

[0091] [Table 8]

[0092] As shown in Table 8, sucralfate formed a gel layer and inhibited the permeation of mannitol. This inhibitory effect on the permeation of mannitol was improved by adding an organic acid and an inorganic salt to sucralfate. From the above results, it has been shown that the gastrointestinal mucosa protective agent such as sucralfate can improve the microinflammation under the gastric or duodenal mucosa by exerting the inhibitory effect on the permeability of gastrointestinal mucosa to substances.In addition, the mixture of sucralfate with organic acid and inorganic salt forms a stronger gel than sucralfate alone, so in addition to the above-mentioned effect of improving the microinflammation under the mucosa, the enhancement of the biological barrier function that inhibits the permeability of the mucosa to substances can be expected to further improve the microinflammation under the gastric or duodenal mucosa.

Claims

1. A drug for improving gastric or duodenal submucosal microinflammation, comprising a gastrointestinal mucosa protective agent as an active ingredient, The gastrointestinal mucosa protecting agent is at least one selected from the group consisting of sucrose octasulfate and a pharma- ceutical acceptable salt thereof, rebamipide and a pharma- ceutical acceptable salt thereof, teprenone, and methylmethionine sulfonium chloride, for improving gastric or duodenal submucosal microinflammation.

2. 2. The drug for improving gastric or duodenal submucosal microinflammation according to claim 1, further comprising at least one selected from the group consisting of inorganic salts, organic acids and their salts.

3. A drug for improving gastric emptying function, comprising a gastrointestinal mucosa protective agent as an active ingredient, The gastric emptying function improving drug, wherein the gastrointestinal mucosa protecting agent is at least one selected from the group consisting of sucrose octasulfate and a pharma- ceutical acceptable salt thereof, rebamipide and a pharma- ceutical acceptable salt thereof, teprenone, and methylmethionine sulfonium chloride.

4. The drug for improving gastric emptying function according to claim 3, wherein the improvement of gastric emptying function is achieved by improving gastric or duodenal submucosal microinflammation.

5. 5. The drug for improving gastric emptying function according to claim 3, further comprising at least one selected from the group consisting of inorganic salts, organic acids and their salts.

Images