JP2021113187A - Gastric or duodenal submucosal microinflammation improving drug and gastric excretion improving drug - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a gastric or duodenal submucosal microinflammation improving agent and a gastric excretion improving agent.
SOLUTION: A gastric or duodenal submucosal microinflammation improving agent containing a gastric mucosa protective agent as an active ingredient and a gastric excretion improving agent containing a gastrointestinal mucosa protective agent as an active ingredient.
[Selection diagram] Fig. 1

Description

The present invention relates to a gastric or duodenal submucosal microinflammation improving agent and a gastric excretion improving agent.

Drugs that form a protective film on the injured area and have the effect of healing inflammation and ulcers are classified as gastrointestinal mucosal protective agents, and drugs such as sucralfate, sodium alginate, and aldioxa are known. On the other hand, the gastrointestinal mucosa protective agent is known to be effective when there is an injury on the surface of the gastrointestinal tract such as gastritis or gastric ulcer.
Non-Patent Document 1 shows the clinical effects of aggressor-based drugs and protective-factor-based drugs on acute exacerbation cases of chronic gastritis, and the disappearance of findings that gastric acid secretion inhibitors are superior to gastric acid erosion. It has been reported that protective factor enhancers such as Benexate Hydrochloride Betadex show excellent elimination in superficial gastritis.
On the other hand, submucosal microinflammation, unlike superficial injuries, persists for a long period of time even after the mucosal surface has normalized, causing chronic leaning pathology. Further, although the above mucosal protective agent is known to be effective for wound repair, it is not known to improve submucosal microinflammation and gastric motor function (gastric excretion ability).

Pharmacology and Treatment Vol. 20, No. 12, pp. 5031-5044 (1992)

The present invention has been made in view of the above circumstances, and is effective not only for damage to the surface layer of the gastric or duodenal mucosa but also for inflammation of the gastric or subduodenal mucosa (hereinafter, also referred to as gastric or duodenal submucosal microinflammation). It is an object of the present invention to provide the above-mentioned drug, and further to provide a drug capable of improving the decrease in gastric emptying ability associated with the submucosal microinflammation.

The present inventors are effective in improving the gastrointestinal mucosal protective agent not only for damage to the surface of the gastrointestinal tract such as gastritis and gastric ulcer, but also for improvement of gastric or duodenal submucosal microinflammation and improvement of gastric emptying ability. The present invention has been completed by finding that a gastrointestinal mucosal protective agent can effectively improve gastric pain and stomach upset.

The present invention has the following aspects.
[1] A gastric or duodenal submucosal microinflammation improving agent containing a gastrointestinal mucosal protective agent as an active ingredient.
[2] The gastrointestinal mucosa protective agent is selected from the group consisting of sucrose octasulfate and its pharmaceutically acceptable salt, rebamipide and its pharmaceutically acceptable salt, teprenone, and methylmethionine sulfonium chloride. The gastric or duodenal submucosal microinflammation improving agent according to [1], which is at least one kind.
[3] The agent for improving gastric or duodenal submucosal inflammation according to [1] or [2], which further contains at least one selected from the group consisting of inorganic salts, organic acids and salts thereof.
[4] A gastric excretion improving drug containing a gastrointestinal mucosa protective agent as an active ingredient.
[5] The agent for improving gastric emptying ability according to [4], wherein the improvement of gastric emptying ability is due to improvement of microinflammation of the stomach or duodenal submucosa.
[6] The gastrointestinal mucosa protective agent is selected from the group consisting of sucrose octasulfate and its pharmaceutically acceptable salt, rebamipide and its pharmaceutically acceptable salt, teprenone, and methylmethionine sulfonium chloride. The gastric emptying ability improving agent according to at least one of [4] or [5].
[7] The agent for improving gastric emptying ability according to any one of [4] to [6], which further contains at least one selected from the group consisting of an inorganic salt, an organic acid and a salt thereof.

According to the present invention, it is possible to provide a drug capable of efficiently improving gastric pain and gastric leaning by improving gastric or duodenal submucosal microinflammation and gastric emptying ability.

It is a figure which showed the vascular permeability suppressing effect of sucrose octasulfate aluminum salt (sucralfate) in the stomach. It is a figure which showed the correlation of the vascular permeability suppressing effect and the acid infiltration suppressing effect in the stomach of the sucrose octasulfate aluminum salt (sucralfate) and the mixture of sucralfate and an organic acid and an inorganic salt. It is a figure which compared the acid infiltration inhibitory effect in the stomach of a sucrose octasulfate aluminum salt (sucralfate) and a mixture of sucralfate, an organic acid and an inorganic salt. It is a figure which showed the gastric excretion improving effect of a mixture of sucralfate, an organic acid and an inorganic salt, and itopride.

<Stomach or duodenal submucosal microinflammation improving drug>
The gastric or duodenal submucosal microinflammation improving agent of the present invention contains a gastrointestinal mucosal protective agent as an active ingredient. The gastrointestinal mucosa protective agent is a drug that improves the damage to the gastrointestinal mucosa by physically protecting the damaged part of the gastrointestinal mucosa and promoting the secretion of mucus in the gastrointestinal tract, and is used for treating gastrointestinal ulcers and the like. It is a drug used. The gastrointestinal tract in the gastrointestinal mucosal protective agent is not particularly limited, and examples thereof include stomach and duodenum.
Specific examples of the gastrointestinal mucosa protective agent include teprenone, a drug in which the drug itself, such as sucrose octasulfate, sodium alginate, and dry aluminum hydroxide gel, forms a physical barrier by gelling at the damaged part of the gastrointestinal mucosa. , Rebamipide, methylmethionine sulfonium chloride, cetraxate, sofalcone, Benexate hydrochloride betadex and other drugs that form a biological barrier in the injured part of the gastrointestinal mucosa due to increased gastrointestinal mucosa and their pharmaceutically acceptable salts. However, sucrose octasulfate and its pharmaceutically acceptable salt, rebamipide and its pharmaceutically acceptable salt, teprenone, methylmethionine sulfonium chloride are preferred, and sucrose octasulfate and its pharmaceutically acceptable salt are preferred. Acceptable salts are more preferred.
These gastrointestinal mucosa protective agents can form a physical barrier such as gelation of the drug itself or a biological barrier such as an increase in gastrointestinal mucus, and infiltrate the gastrointestinal mucosa of acid. By suppressing the above, not only the damage to the surface layer of the gastric or duodenal mucosa but also the microinflammation under the gastric or duodenal mucosa can be improved by acting on the gastric or duodenal mucosa.

Microinflammation under the gastric or duodenal mucosa is caused by various causes, and examples thereof include stress and viral infection.
For example, stress disrupts tight junctions in the gastrointestinal mucosa, thereby increasing material permeability of the mucosa and infiltrating acids and irritants under the mucosa. As a result, microinflammation occurs under the gastric or duodenal mucosa. The gastrointestinal mucosal protective agent not only suppresses the infiltration of acids and irritants into the gastrointestinal mucosa due to this stress, but also suppresses the breakdown of tight junctions in the gastric or duodenal mucosa due to stress, and the gastric or duodenal mucosa. By acting directly on the microinflammation of the stomach, the microinflammation under the gastric or duodenal mucosa can be improved.

Regarding the action of the gastrointestinal mucosa protective agent on the breakdown of the tight junction of the gastric or duodenal mucosa, for example, occludin, which is a transmembrane protein constituting the tight junction, is used in the gastric or duodenal mucosa after stress loading. The expression level can be evaluated by measuring it by electrophoresis or the like. For comparison after stress loading, if the expression level of occludin in the gastric or duodenal mucosa after administration of the gastrointestinal mucosa protective agent is increased, it is evaluated that it has an inhibitory effect on the breakdown of tight junctions in the gastric or duodenal mucosa. be able to.
Regarding the action of the gastrointestinal mucosa protective agent on the substance permeability of the gastrointestinal mucosa, for example, the mucosal protective layer is formed by gelling the drug or mucin production, and the permeability of mannitol to the mucosal protective layer is measured. It can be evaluated by doing. If the transmittance 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 transmittance of mannitol to the mucosal protective layer is high, the substance permeability of the gastrointestinal mucosa can be evaluated. It can be evaluated that the inhibitory effect on the disease is low. The direct improving effect of the gastrointestinal mucosal inhibitor on microinflammation under the gastric or duodenal mucosa is evaluated, for example, by measuring the inhibitory effect on the infiltration of eosinophils into the gastric or duodenal mucosa due to stress. be able to. 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 these eosinophils infiltrated, it acts directly on microinflammation under the gastric or duodenal mucosa. Therefore, it can be evaluated that it has an improving effect on the microinflammation.

The single dose of the gastrointestinal mucosal protective agent in the gastric or duodenal submucosal microinflammation improving agent of the present invention is not particularly limited, but is preferably 2 to 2000 mg, more preferably 30 to 1000 mg, and particularly 75 to 1000 mg. preferable. When the dose is equal to or more than the above dose, the effect of improving microinflammation under the gastric or duodenal mucosa is enhanced, and when the dose is not more than the above upper limit, the size of the drug can be easily taken. The content of the gastrointestinal mucosal protective agent in the gastric or duodenal submucosal microinflammation improving agent of the present invention is not particularly limited, but is preferably 0.1 to 80% by mass, more preferably 1 to 70% by mass. 2 to 60% by mass is particularly preferable. When the content is equal to or higher than the above content, the concentration is increased and the single dose is reduced, so that the ingestibility is improved and the effect of improving microinflammation under the gastric or duodenal mucosa is enhanced. , The physical properties can be made excellent in moldability, disintegration property, and elution property, and side effects can be further reduced.

The pharmaceutically acceptable salt of sucrose octasulfate is not particularly limited, and one selected from alkali metal or alkaline earth metal oxides, hydroxides and carbonates may be used alone or in combination of two or more. Can be used in appropriate combinations, but sodium salt, potassium salt and aluminum salt are preferable. Sucralfate, an aluminum salt of sucrose octasulfate, is a drug that binds to proteins in the mucosal inflamed area and has the effect of covering and protecting the inflamed area while repairing it, and is also called a "stomach adhesive plaster". In the present invention, sclarfert has an effect on the inflamed part of the stomach, can suppress the invasion of the gastrointestinal mucosa of acid, and acts on the gastric or duodenal submucosa to cause microinflammation of the gastric or duodenal submucosa. It can exert an excellent effect on improvement. The sucralfate is not particularly limited and may be a hydrate or an anhydride, but in the present invention, the sucralfate is listed in the Japanese Pharmacopoeia unless otherwise specified. It means Japanese food. Unlike sucralfate, which is an aluminum salt, sucrose octasulfate sodium salt does not have gel-forming ability, but has an action of suppressing gastric or duodenal submucosal microinflammation like sucralfate. Teprenone and methylmethionine sulfonium chloride promote the secretion of gastric mucosa, cover the mucosal surface to maintain lubricity, and suppress gastric or duodenal submucosal microinflammation caused by gastric acid infiltration.
The pharmaceutically acceptable salts of levamipide are not particularly limited, and are sodium salts, potassium salts, or other common basic substances (tromethamole (tris [hydroxymethyl] aminomethane), monoethanolamine, diethanolamine, etc. Examples thereof include salts formed together with triethanolamine, diisopropanolamine, meglumin, etc.), and one type can be used alone or two or more types can be used in combination as appropriate. In the present invention, rebamipide is preferable as a pharmaceutically acceptable salt thereof because a more remarkable effect can be obtained.
In the present invention, one type of gastrointestinal mucosa protective agent may be used alone, or two or more types may be used in combination.

In the present invention, the gastrointestinal mucosal protective agent alone can exert an effect of improving gastric or duodenal submucosal microinflammation, but contains at least one selected from the group consisting of inorganic salts, organic acids and salts thereof. Therefore, the effect of improving microinflammation under the gastric or duodenal mucosa can be further improved.

The composition ratio of the organic acid and / or its salt and the gastrointestinal mucosa protective agent in the gastric or duodenal submucosal microinflammation improving agent of the present invention is the composition ratio of the organic acid and / or its salt: the gastrointestinal mucosa protective agent. = 0.05 to 1: 1 is preferable, and 0.1 to 0.33: 1 is more preferable. By setting the composition ratio of the organic acid and / or its salt to the above range or more, 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, and the gastrointestinal tract is improved. As well as enhancing the protective function of the gastrointestinal tract, the retention in the digestive tract is enhanced and the effect can be sustained or enhanced. By setting the content to the upper limit or less, the irritation of the gastrointestinal mucosa protective agent by the organic acid and / or its salt can be suppressed. These organic acids and / or salts thereof may be in a powder state in the preparation or may be in a solution. Further, the gastrointestinal mucosa protective agent and the organic acid and / or a salt thereof may be present separately in the preparation, or may be used in a state of being reacted in advance.

The inorganic salt is not particularly limited, and one selected from alkali metal or alkaline earth metal oxides, hydroxides and carbonates can be used alone or in combination of two or more as appropriate, but acid suppository. Ingredients that act as agents are preferred. In the present invention, the antacid is an agent that neutralizes hydrochloric acid in gastric juice to lower the 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, sodium carbonate, sodium hydrogencarbonate, calcium carbonate and magnesium carbonate. In addition to carbonates such as, synthetic hydrotalcite, magnesium aluminomerate, magnesium oxide, aluminum hydroxide, magnesium hydroxide, and the like can be used. In the present invention, sodium hydrogen carbonate, calcium carbonate, sodium hydroxide, magnesium carbonate and magnesium hydroxide can be preferably used from the viewpoint of improving gastric or duodenal submucosal microinflammation effect and manufacturability. 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).

The content of the inorganic salt adjusts the pH of the gastric or duodenal submucosal microinflammation improving agent of the present invention within a predetermined range when the gastrointestinal protective agent and the organic acid and / or a salt thereof are contained and administered. The amount obtained is preferred. In the present invention, the pH of the gastric or duodenal submucosal microinflammation improving agent is preferably 5.0 to 8.0, more preferably 5.5 to 7.4, and particularly preferably 5.5 to 7 by the inorganic salt. By blending an amount that can be adjusted to 0.0, the effect of the gastrointestinal mucosal protective agent, for example, in the case of sclarfate, has good adhesion and is excellent in takeability with reduced mucosal irritation due to organic acid. Alternatively, a drug for improving microinflammation under the duodenal mucosa can be obtained, and the gastric acid neutralization itself can exert an injurious alleviating effect. In addition, by neutralizing gastric acid by blending an inorganic salt, the gastrointestinal mucosa protective agent and the organic acid can selectively react in the gastrointestinal tract, and the effect of the gastrointestinal mucosa protective agent such as high adhesion in the non-acidic region Can be a higher gastric or duodenal submucosal microinflammation improver.

The organic acid and / or a salt thereof is not particularly limited, and one kind alone or two or more kinds may be used in combination as appropriate. Organic acids include alginic acid, citric acid, malic acid, ascorbic acid, glucuronic acid, aspartic acid, glutamic acid, adipic acid, gluconic acid, tartaric acid, from the viewpoint of improving microinflammation under the gastric or duodenal mucosa and dispersion stability. One or more selected from succinic acid, lactic acid, acetic acid, butyric acid, maleic acid and fumaric acid is preferable, and citric acid, malic acid and lactic acid are particularly preferable. Examples of the organic acid salt include the above-mentioned sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt and the like, and from the viewpoint of gel-forming property on the mucous membrane of the gastrointestinal mucosa protective agent, sodium salt and potassium. Salt is preferred.

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

Further, in the present invention, the gastrointestinal mucosal invasion inhibitory action of acid is such that the stomach or duodenum is attached to a chamber under anesthesia from an animal such as a rat in which a proton pump inhibitor is administered to suppress physiological gastric acid secretion. It can be confirmed by evaluating the inhibitory effect of the test drug on the acid infiltration when the AITC is administered to the exposed stomach or duodenum to induce acid infiltration of the gastric or duodenal mucosa. ..

<Stomach excretion improving drug>
The gastric emptying ability improving agent of the present invention contains a gastrointestinal mucosa protective agent as an active ingredient. As the gastrointestinal mucosa protective agent, the gastrointestinal mucosal protective agent mentioned in the section of the gastric or duodenal submucosal microinflammation improving agent can be used. The gastric emptying ability improving agent of the present invention preferably has an effect of improving gastric emptying ability by improving microinflammation of the stomach or duodenal submucosa.
In contrast to the agent that improves gastric emptying ability by repairing the surface of the gastric or duodenal mucosa, the gastric emptying ability improving agent that has the effect of improving gastric emptying ability by improving gastric or duodenal microinflammation according to the present invention is a gastrointestinal mucosal protective agent. Since microinflammation of the stomach or duodenum can be improved in a short period of time without waiting for the repair of the gastric or duodenal mucosal surface, which requires a relatively long period of time, the gastric emptying ability is improved by repairing the gastric or duodenal mucosal surface. Compared with drugs, it can be expected to improve gastric emptying ability in a short period of time.
In addition, drugs that repair the surface of the gastric or duodenal mucosa are not expected to improve the delay in gastric emptying due to microinflammation of the stomach or duodenum, and the autonomic nervous system that controls movement symptomatically, etc. It is common to employ drugs that activate exercise. The gastric emptying ability improving agent having a gastric or duodenal submucosal microinflammation improving effect of the present invention can improve gastric or duodenal submucosal microinflammation, which is a pathological site of decreased gastric motility, and thus acts on the autonomic nervous system and the like. As compared with a drug that promotes exercise and a drug that has an effect of suppressing gastric acid secretion, it improves the root cause of the pathological condition, so that it can be expected to surely develop the effect and prevent recurrence.

Since the gastric emptying ability improving agent of the present invention can act on the gastric or duodenal submucosa to improve the gastric or duodenal submucosal microinflammation, the cause of repeated gastric leaning can be directly repaired. In addition, since the gastric excretion improving agent of the present invention can improve smoldering inflammation under the gastric or duodenal mucosa, it can further improve the gastric leaning constitution, relieve or normalize the hypersensitivity state of the mucosa. can do.

As a specific example of the gastrointestinal mucosa protective agent in the gastrointestinal mucosa protective agent of the present invention, the drug itself such as sucrose octasulfate, sodium alginate, and dry aluminum hydroxide gel is physically formed by gelling at the damaged part of the gastrointestinal mucosa. Drugs that form a biological barrier to the injured part of the gastrointestinal mucosa due to increased gastrointestinal mucosa, such as teprenone, rebamipide, cetraxate, and sulcon, and their pharmaceutically acceptable salts. Sucrose octasulfate and its pharmaceutically acceptable salt, rebamipide and its pharmaceutically acceptable salt, teprenone, methylmethionine sulfonium chloride are preferred, and sucrose octasulfate and its pharmaceutically acceptable salt are preferred. Possible salts are more preferred.
Examples of the pharmaceutically acceptable salt of sucrose octasulfate, rebamipide and the pharmaceutically acceptable salt thereof include the salts described in the section of the above-mentioned gastric or duodenal submucosal microinflammation improving drug.

The single dose of the gastrointestinal mucosa protective agent in the gastric excretion improving agent 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. When the dose is equal to or higher than the above dose, the effect of improving gastric emptying ability is enhanced, and when the dose is equal to or higher than the upper limit, the size of the drug can be easily taken.
The content of the gastrointestinal mucosa protective agent in the gastric emptying ability improving agent 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 2 to 60% by mass. % Is particularly preferable. When the content is equal to or higher than the above content, the concentration is increased and the single dose is reduced, so that the ingestibility is improved and the effect of improving gastric excretion is enhanced. By setting the content to the above content or less, physical properties having excellent moldability, disintegration property, and elution property can be obtained, and side effects can be further reduced.

In the present invention, the gastrointestinal mucosa protective agent alone can exert an effect of improving gastric emptying ability, but by containing at least one selected from the group consisting of inorganic salts, organic acids and salts thereof, gastric emptying ability can be exhibited. The improvement effect can be improved. Examples of the inorganic salt, the organic acid and the salt thereof include those described above. The composition ratio of the organic acid and / or its salt and the gastrointestinal mucosa protective agent in the gastric emptying ability improving agent of the present invention includes the composition ratio described in the section of the gastric or duodenal submucosal microinflammation improving agent. .. In addition, the content of the inorganic salt in the gastric emptying ability improving agent of the present invention includes the content described in the section of the gastric or duodenal submucosal microinflammation improving agent.

The gastric emptying ability improving action of the gastric emptying ability improving agent of the present invention is described in, for example, "Medical Treatment and New Drugs" 1997, 8, 51-58 by administering AITC to fasted mice to induce gastric emptying delay. It can be confirmed by evaluating the inhibitory effect of administration of the test drug when the gastric emptying ability is evaluated by the phenol red method according to the method.

The gastric or duodenal submucosal microinflammation improving agent and the gastric emptying ability improving agent of the present invention may appropriately contain arbitrary components as long as the effects of the present invention are not impaired. Optional ingredients include other active ingredients, polyols, polymeric compounds, excipients, binders, disintegrants, sweeteners, lubricants, preservatives, flavors, flavoring agents, pigments and the like.

Other active ingredients include ranitidine or ranitidine hydrochloride, famotidine, simethidine, loxatidine hydrochloride acetate, nizatidine, laftidine, lansoprazole, labeprazole, omeprazole, bonoplazan and other gastric acid secretion inhibitors, roto extract, pyrenzepine, atropin, and In addition to muscarinic receptor antagonists such as scopolamine, it contains healthy stomach biomedical ingredients such as Koboku style extract, Sojutsu style extract, Ukon style extract, Kanzo extract, Carrot style extract, Ourentinki, Choujitinki, Gentiana tinki, and Keihi tinki. You may.

The polyol can contain sugar alcohols such as mannitol, erythritol, xylitol, sorbitol, palatinit and lactitol, monosaccharides, oligosaccharides and polysaccharides, as well as polyethylene glycol (PEG) and polyhydric alcohols such as glycerin and propylene glycol. It can also contain lower alcohols such as ethanol.

As the polymer compound, xanthan gum, alginate ester, HM pectin, carrageenan and the like can be contained.

Examples of the mold release agent include lactose, cornstarch, crystalline cellulose, potato starch and the like. Examples of the binder include hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethyl cellulose, gum arabic, pregelatinized starch, carboxyvinyl polymer, agar, gelatin, honey and the like.
Examples of the disintegrant include crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose and the like.
Examples of the sweetener include sucrose, fructose, aspartame, sucralose, thaumatin, acesulfame potassium, sorbitol, stevia, purified sucrose, saccharin, glycyrrhizin and the like.
Examples of the lubricant include magnesium stearate, stearyl sodium fumarate, sucrose fatty acid ester, and light anhydrous silicic acid.
Examples of the preservative include parabens such as alkylparaben, benzoic acid, sodium benzoate and the like.
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, grapefruit flavor and the like.
Examples of the flavoring agent include menthol and the like.
Examples of the pigment include caramel, carmine, carotene solution, β-carotene, copper chlorophyll, sodium copper chlorophyllin and the like.
By blending these additives, it is possible to obtain a preparation having excellent moldability, storage stability, dissolution property, disintegration property, flavor, stability thereof, ingestibility and the like.

The gastric or duodenal submucosal microinflammation improving agent and gastric excretion improving agent of the present invention include tablets, granules, fine granules, capsules, powders, powders, lozenges, pills, chewables, solutions, emulsions, etc. It can be used in a dosage form such as a suspension agent or a jelly agent. Suitable pharmaceutically acceptable liquid or solid carriers, excipients, dispersants, fillers, bulking agents, solvents, emulsifiers, additives, lubricants, preservatives to be formulated into these dosage forms. , Auxiliary agents such as fragrances, wetting agents, flavor modifiers, dyes and buffers can be added.
To prepare solid formulations such as tablets, granules, fine granules, capsules, powders, powders, troches, pills, chewables, for example, sodium bicarbonate, calcium carbonate, starch, sucrose, mannitol, etc. It can be carried out by a conventional method by adding additives such as carboxymethyl cellulose, calcium stearate, magnesium stearate and glycerin. Such preparations are preferred for oral administration and can effectively act on the stomach or duodenum. In addition, an enteric coating such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, styrene-maleic anhydride copolymer, and methacrylate-methyl methacrylate copolymer is applied to prepare an enteric preparation that disintegrates in the small intestine. It can also be converted to.

The gastric or duodenal submucosal microinflammation improving agent and the gastric emptying ability improving agent of the present invention can be orally administered, and the dose thereof can be appropriately selected depending on the dosage type, the gender, body type, constitution, age, etc. of the patient. However, it is usually 0.1 to 50 mg / kg once 1 to 4 times a day, preferably 0.5 to 20 mg / kg. When the dose is equal to or higher than the above dose, the improvement effect is obtained, and when the dose is lower than the above dose, side effects are reduced, and moldability, storage stability, elution, disintegration, flavor and its stability are exhibited. It can be a preparation having excellent ingestibility and the like.

In order to prepare the gastric or duodenal submucosal microinflammation improving agent and the gastric emptying ability improving agent of the present invention, for example, a gastrointestinal mucosal protective agent and an organic acid and / or a salt thereof are added with appropriate excipients and the like. It can be processed such as granulation, mixed in a powder state, and formed as a powder or molded into capsules, tablets, etc. to form a preparation.
It is also possible to add an organic acid and / or a salt thereof to a gastrointestinal mucosa protective agent dispersed in water, dry the organic acid and / or a salt thereof, dry the powder, and then mold the organic acid into capsules, tablets and the like to form a formulation. When further inorganic salts are added, the order is not particularly specified, and the organic acid and / or the salt thereof and the inorganic salt may be added first, or the gastrointestinal mucosa protective agent and the organic acid and / or the salt thereof. Inorganic salts may be added to the mixture to formulate the mixture. Further, the liquid preparation can be prepared by using, for example, purified water, physiological saline, alcohols such as ethanol, propylene glycol, glycerin and polyethylene glycol, and a solvent such as triacetin. To prepare a liquid preparation, put the gastrointestinal mucosa protective agent and the organic acid and / or its salt in a suspension, solution or powder, respectively, in a container, add water at the time of use if necessary, and then both. To prepare a liquid preparation. Further, both components may be reacted in advance to prepare a liquid preparation.

Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[Examples 1 to 4]
<Stomach or duodenal submucosal microinflammation improving effect>
Intraperitoneal injection of 60 mg / kg of omeprazole, a proton pump inhibitor, into fasted SD rats according to the method described in Tajima et al. The abdomen was opened after suppressing the physiological gastric acid secretion, and the stomach was incised and attached to the chamber so that the mucous membrane was on the upper side, and 10% direct blue (pigment) was intravenously administered. Then, a physiological saline solution containing 50 mM hydrochloric acid (50 mM HCl / 0.9% NaCl) was treated on the mucosal side as a chamber solution, and the mixture was allowed to stand for 1 hour to be in a steady state, and then 50 mM allyl isothiocyanate (AITC) was used. The chamber solution was changed to a physiological saline solution containing 50 mM hydrochloric acid and submucosal inflammation (microinflammation) was induced. AITC was removed after 30 minutes, the mucosa was washed with saline, and then the chamber solution was changed to saline containing 50 mM hydrochloric acid again, and 3 mg, 10 mg, 30 mg or 100 mg of scralfert (sucrose octasulfate aluminum ester) was used. Salt, manufactured by 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 adjust the final concentration of hydrochloric acid in the chamber to 50 mM. After 15 minutes, the chamber solution was removed, and every 30 minutes thereafter, sampling and addition of the chamber solution (2 mL of physiological saline containing 50 mM hydrochloric acid) were repeated. Using the sampled chamber solution as a measurement sample, the amount of acid infiltration and vascular permeability were measured immediately after the administration of AITC, 30 minutes after the administration of AITC, and 120 minutes after the administration of AITC.
The amount of acid infiltration is an index of acid permeation under the mucosa, and the amount of NaOH required to reach pH 7.0 was determined using a potentiometric titrator (AT-710S) manufactured by Kyoto Denshi Kogyo Co., Ltd. The amount of acid infiltrated under the mucosa was determined by determining the difference in acidity between the physiological saline containing 50 mM hydrochloric acid and the solution after sampling. Vascular permeability is an index of submucosal microinflammation, and the amount of pigment leaking from the mucosa to the lumen side due to vasodilation due to inflammation is measured by an absorbance measuring device at 594 nm, and a known concentration of direct blue is used. It was measured by quantifying the amount of dye leaked into the sampling solution from the calibration curve of. The results are shown in Table 1.

[Example 5]
The acid infiltration amount and vascular permeability were determined 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. It was measured. The results are shown in Table 1.

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

[Comparative Example 1]
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). The results are shown in Table 1.

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

Next, the acid infiltration suppression rate by the drug was calculated by the following formula (1), and the vascular permeability suppression rate by the drug was calculated by the following formula (2).

Acid infiltration suppression rate by chemicals (%) = (acid infiltration immediately after AITC addition-acid infiltration at sampling time) / acid infiltration immediately after AITC addition × 100 ... (1)
Vascular Permeability Suppression Rate by Drug (%) = (Vascular Permeability of Comparative Example 1 at Sampling Time-Vascular Permeability at Sampling Time) / Vascular Permeability of Comparative Example 1 at Sampling Time x 100 ... (2)

The acid infiltration suppression rate (%) and the vascular permeability suppression rate (%) were determined according to the following criteria.
<Effect criteria>
× (no effect); less than 15% △ (weak effect); 15% or more and less than 40% ○ (moderate effect); 40% or more and less than 75% ◎ (strong effect); 75% or more 2 and FIGS. 1 to 3 show.

As shown in Table 1 and FIG. 1, administration of AITC caused acid infiltration and increased vascular permeability, and caused submucosal microinflammation, although it did not cause gross injury. On the other hand, in the group to which sucrose octasulfate aluminum salt (sucralfate) and sucrose octasulfate sodium salt (SOS) were administered, vascular permeability, which is an index of inflammation, was decreased.
As a control, 60 mg / kg of omeprazole, which is a proton pump inhibitor, was intraperitoneally administered, and the chamber fluid was used as NaCl to completely block acid stimulation (Comparative Example 2). High vascular permeability improving effect was obtained. Therefore, this effect cannot be obtained with a drug that suppresses acid secretion, such as an H2 blocker or a proton pump inhibitor. That is, 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 from a low dose of 0.72 μmol / mL this time (75 mg when converted to human dose), and the effect was in a dose range that could be sufficiently used for humans.

Further, as shown in Table 2, in the mixture of sucralfate and the organic acid and the inorganic salt, the vascular permeability was similarly significantly reduced, and the acid infiltration was also significantly reduced. Moreover, the vascular permeability improving effect and the acid infiltration improving effect are improved as compared with the effect of sucralfate alone as shown in FIGS. 2 and 3, and the vascular permeability improving effect and the acid infiltration improving effect are shown as shown in FIG. There was a positive correlation with the improvement effect. Since the mixture of sucralfate and organic acid and inorganic salt forms a gel-like substance stronger than sucralfate alone, it suppresses the permeation of acids and irritants in addition to the above-mentioned submucosal microinflammation improving effect. Further enhancement of the biological barrier function can be expected to further improve submucosal microinflammation.
From the above results, the gastrointestinal mucosal protective agent represented by sucralfate has the effect of improving the biological barrier function of suppressing the permeation of acids and irritants and repairing submucosal microinflammation, thereby causing the gastric or duodenal submucosa. It has been shown that microinflammation can be improved.

[Example 10]
<Stomach excretion improving effect>
AITC 80 mg / kg was orally administered to fasted ddY mice (8 weeks old, male) according to the method described in Tajima et al.'S "Urture" 2016, 43, 87-90 to induce gastric emptying delay. The gastric emptying ability was evaluated by the phenol red method according to the method described in "Medical Treatment and New Drugs" by Ueki et al., 1997, 8, 51-58. That is, 20 minutes after the administration of AITC, a mixture of 1500 mg / kg of sucralfate, 375 mg / kg of malic acid and 375 mg / kg of calcium carbonate (hereinafter, also referred to as SF organic acid mixture) was suspended as a drug in purified water, and 5 mL / kg thereof. kg was orally administered, and 0.5 mL / 1 animal of 1.5% carboxymethyl cellulose (CMC) solution containing 0.05% phenol red was administered 40 minutes after administration of the SF organic acid mixture. Twenty minutes after the administration of phenol red, the stomach was collected under anesthesia, and the phenol red contained in the stomach contents was quantified by measuring the absorbance at a wavelength of 565 nm. The results are shown in Table 3.

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

[Comparative Example 3]
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 as a medium was administered instead of the SF organic acid mixture.

[Comparative Example 4]
Gastric contents in the same manner as in Example 10 except that 10 mg / kg of itopride (manufactured by Tokyo Chemical Industry Co., Ltd.), which is a medical ingredient having a gastrointestinal motility improving effect, is subcutaneously administered instead of the SF organic acid mixture. Phenol red contained in the substance was quantified by measuring the absorbance at a wavelength of 565 nm.

[Comparative Example 5]
Absorbance measurement of phenol red contained in the stomach contents at a wavelength of 565 nm was carried out in the same manner as in Example 10 except that a mixture of 375 mg / kg of malic acid and 375 mg / kg of calcium carbonate was administered instead of the SF organic acid mixture. Quantified by doing.

Next, using a sample of the gastric contents collected immediately after administration of phenol red into the stomach as a reference, the gastric emptying capacity (%) is calculated by the following formula (3), and the gastric emptying capacity (%) is calculated by the following formula (4). The suppression rate (%) was calculated by the following formula (5), and the gastric emptying improvement rate (%) was calculated.

Gastric excretion capacity (%) = (1-Amount of phenol red in sample / Amount of reference phenol red) x 100 ... (3)
Gastric excretion suppression rate (%) = [1- (Stomach excretion rate of drug-administered group / Gastric excretion rate of reference example)] × 100 ... (4)
Gastric excretion improvement rate (%) = (Stomach excretion suppression rate of Comparative Example 3-Stomach excretion suppression rate of drug-administered group) / Gastric excretion suppression rate of Comparative Example 3 × 100 ... (5)

The effect of improving gastric excretion was determined according to the following criteria.
<Effect criteria>
× (no effect); gastric excretion improvement rate less than 15% △ (weak effect); gastric excretion improvement rate 15% or more and less than 40% ○ (moderate effect); gastric excretion improvement rate 40% or more and less than 75% ⊚ (strong effect); Gastric excretion improvement rate is 75% or more The results are shown in Table 3 and FIG.

As shown in Table 3 and FIG. 4, the gastric emptying ability was significantly decreased by the administration of AITC, and the gastric emptying ability was significantly improved by the administration of the SF organic acid mixture. In addition, the effect was higher than that of itopride, which is a medical ingredient having an effect of improving gastrointestinal motility function.
From the above results, it is considered that a gastrointestinal mucosal protective agent such as sucralfate improves gastric motor dysfunction by suppressing microinflammation under the gastric mucosa.

[Examples 11-12]
<Stomach or duodenal submucosal microinflammation improving effect>
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.

[Examples 13 to 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.

[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 rebamipide was used instead of sucralfate. The results are shown in Table 4.

Next, as in Example 1, the acid infiltration suppression rate (%) by the drug and the vascular permeability suppression rate (%) by the drug are calculated, and the acid infiltration suppression rate and the vascular permeability suppression rate are the same as in Example 1. Judgment was made in the same manner. The results are shown in Table 4.

As shown in Table 4, vascular permeability and acid infiltration are also reduced for methylmethionine sulfonium chloride, teprenone and rebamipide, which are drugs that form a biological barrier on the gastrointestinal mucosa due to increased gastrointestinal mucus. did.
From the above results, in addition to the gastrointestinal mucosa protective agent typified by sclarfert, which forms a physical barrier by gelation at the damaged part of the gastrointestinal mucosa, a biological barrier is created in the gastrointestinal mucosa by increasing gastrointestinal mucus. The gastrointestinal mucosal protective agents represented by methylmethionine sulfonium chloride, teprenone and rebamipide that form also have the effect of improving the biological barrier function that suppresses the permeation of acids and irritants and repairing submucosal microinflammation. It has been shown that gastric or duodenal submucosal microinflammation can be improved.

[Example 17]
<Stomach excretion improving effect>
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 1500 mg / kg of sucralfate was administered instead of the SF organic acid mixture. Next, the gastric excretion ability (%), the gastric excretion improvement rate, and the gastric excretion improvement rate were calculated in the same manner as in Example 10. Moreover, the gastric excretion improving effect was determined in the same manner as in Example 10. The results are shown in Table 5.

[Example 18]
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 150 mg / kg of methylmethionine sulfonium chloride was administered instead of the SF organic acid mixture. Next, the gastric excretion ability (%), the gastric excretion improvement rate, and the gastric excretion improvement rate were calculated in the same manner as in Example 10. Moreover, the gastric excretion improving effect was determined in the same manner as in Example 10. The results are shown in Table 5.

[Example 19]
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 150 mg / kg of teprenone was administered instead of the SF organic acid mixture. Next, the gastric excretion ability (%), the gastric excretion improvement rate, and the gastric excretion improvement rate were calculated in the same manner as in Example 10. Moreover, the gastric excretion improving effect was determined in the same manner as in Example 10. The results are shown in Table 5.

As shown in Table 5, administration of AITC significantly reduced gastric emptying ability, and administration of sucralfate, methylmethionine sulfonium chloride, or teprenone improved gastric emptying ability.

[Example 20]
<Improvement effect on the breakdown of tight junctions of the gastrointestinal mucosa due to stress>
Rats of the SD strain were subjected to tail stimulation stress for 30 minutes at a time, 3 times a day for 7 consecutive days. Tail stimulation stress was applied by sandwiching the rat's tail with sponge forceps, fixing the other end of the forceps to the edge of a circular (60 cm diameter) enclosure for open field testing, and providing behavioral restrictions. The stress-loaded group was divided into two groups on the final day of stress loading, and sucralfate 200 mg / kg was administered at a dose of 2 mL / kg for 7 days from the next day. Fasting was performed in the evening of 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.

<Western blotting analysis>
The rat duodenal mucosa obtained above was scraped off, placed in Lysis buffer, crushed on ice using a biomasher, and allowed to stand for 15 minutes. After centrifugation, the amount of protein in the supernatant was quantified, the concentration was adjusted so that the total protein concentration in each lane was the same, and then electrophoresis was performed with an acrylamide gel and transferred to the 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 3 times with 1% TBS-T, a secondary antibody (manufactured by Thermoscientific) is added, incubated for 2 hours, and chemiluminescence using a Western luminescence detection reagent (manufactured by GE Healthcare Life Sciences) is CCD. The amount of occludin protein was quantified by detecting with a camera.

[Reference example 2]
The amount of occludin protein from the duodenal mucosa was quantified in the same manner as in Example 20 except that rats normally bred for 7 days without stress were used.

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

Next, the band strength of Western blotting was measured, and the relative band strength was calculated based on the band strength of Reference Example 2 measured in rats without stress, and the barrier was calculated by the following formula (6). The function deterioration rate was calculated by the following formula (7), respectively.

Barrier function reduction rate (%) = [(1- (relative band strength of drug-administered group / relative band strength of Reference Example 2)] × 100 ... (6)
Barrier function improvement rate (%) = (barrier function reduction rate of Comparative Example 6-barrier function reduction rate of drug-administered group) / barrier function reduction rate of Comparative Example 6 × 100 ... (7)

The improvement effect on the breakdown of tight junctions of the gastrointestinal mucosa due to stress loading was determined according to the following criteria.
<Effect criteria>
× (No effect); Barrier function improvement rate is less than 15% △ (Weak effect); Barrier function improvement rate is 15% or more and less than 40% ○ (Medium effect); Barrier function improvement rate is 40% or more and less than 75% ⊚ (strong effect); Barrier function improvement rate is 75% or more The results are shown in Table 6.

As shown in Table 6, sucralfate improved the breakdown of tight junctions due to stress.
From the above results, it was shown that a gastrointestinal mucosal protective agent such as sucralfate can improve microinflammation under the gastric or duodenal mucosa by improving the breakdown of tight junctions due to stress.

[Example 21]
<Inhibitory effect on inflammatory cell infiltration under the duodenal mucosa due to stress>
The duodenal tissue excised from the stress-loaded rat to which sucralfate was administered obtained in Example 20 was fixed with a 4% paraformaldehyde solution and then embedded in Cliomount (manufactured by Muto Chemical Co., Ltd.) to prepare a frozen block. After preparing sliced slices, immunostaining was performed using Major Basic Protein, which is an eosinophil marker, as an index, and eosinophils were stained using the ABC method and DAB as a staining substrate. Photographs of three fields of view were taken at a magnification of 40 times for each individual, and the average number per field of view was taken as the number of eosinophils of each individual. Counting was done blindly so that the assessor did not know which sample was being evaluated.

[Reference example 3]
The number of eosinophils was measured in the same manner as in Example 21 except that rats normally bred for 7 days without stress were used.

[Comparative Example 7]
The eosinophil count was measured in the same manner as in Example 21 except that rats administered purified water as a medium were used instead of sucralfate.

Next, the rate of increase in the number of inflammatory cells was calculated by the following formula (8), and the rate of improvement in inflammation was calculated by the following formula (9).

Inflammatory cell number increase rate (%) = [(Eosinophil count in drug-administered group or Comparative Example 7 / Eosinophil count in Reference Example 3) -1)] × 100 ... (8)
Inflammation improvement rate (%) = (Inflammation cell increase rate of Comparative Example 7-Inflammation cell increase rate of drug-administered group) / Inflammation cell increase rate of Comparative Example 7 × 100 ... (9)

The inflammation improving effect was determined according to the following criteria.
<Effect criteria>
× (no effect); inflammation improvement rate less than 15% △ (weak effect); inflammation improvement rate 15% or more and less than 40% ○ (moderate effect); inflammation improvement rate 40% or more and less than 75% ◎ (strong) Effect); Inflammation improvement rate is 75% or more. The results are shown in Table 7.

As shown in Table 7, stress infiltrated eosinophils from the duodenal mucosa, and the infiltrated eosinophils decreased by administration of sucralfate.
From the above results, it was shown that a gastrointestinal mucosal protective agent such as sucralfate improves microinflammation under the duodenal mucosa by suppressing infiltration of inflammatory cells under the duodenal mucosa due to stress.

[Examples 22 to 28]
<Permeability improving effect of gastrointestinal mucosa>
Each component was mixed according to the composition shown in Table 8 below to prepare the oral compositions of Examples 22 to 28. Specifically, an organic acid or a salt thereof is added to purified water, sucralfate is added while stirring and dispersing the obtained mixture with a three-one motor (manufactured by Mizuho Kogyo Co., Ltd.), and a pre-dissolved xanthan gum solution is added. Then, the oral composition of each example was obtained. In Example 22, no organic acid or salt thereof was added, and in Examples 22, 23, 25 and 27, precipitated calcium carbonate having the composition shown in Table 8 was added at the same time as the xanthan gum solution.
Next, a membrane filter (pore size 1.0 μm, cellulose mixed ester type) was installed in Franz cell, and the inside of the receiver was dissolved in the first solution of the Japanese Pharmacopoeia dissolution test (2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water). It was filled with 1000 mL). A donor cap was attached, and a suspension was added in which 5 mL of the first solution and the oral composition of each example (equivalent to 100 mg as sucralfate) were mixed. After standing for 3 hours, 5 mL of the 1st solution in the donor cap was removed, and 5 mL of the 1st solution containing 100 mM mannitol was added. Immediately after the addition and 1 hour after the addition, the mannitol concentration in the first liquid in the receiver was quantified using EnzyChrom D-Mannitol Assay Kit (manufactured by Funakoshi Co., Ltd.).

[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.

Next, the permeation suppression rate was calculated by the following formula (10).

Permeation suppression rate (%) = [1- (mannitol concentration of each example / mannitol concentration of reference example 4)] × 100 ... (10)

Judgment of improvement of permeability of gastrointestinal mucosa was made according to the following criteria.
<Effect criteria>
× (no effect); permeation suppression rate less than 15% △ (weak effect); permeation suppression rate 15% or more and less than 40% ○ (medium effect); permeation suppression rate 40% or more and less than 75% ◎ (strong) Effect); Permeation suppression rate is 75% or more The results are shown in Table 8.

As shown in Table 8, the permeation of mannitol was suppressed by the formation of the gel layer by sucralfate. The effect of suppressing the permeability of mannitol was improved by adding an organic acid and an inorganic salt to sucralfate.
From the above results, it was shown that a gastrointestinal mucosal protective agent such as sucralfate can improve microinflammation under the gastric or duodenal mucosa by exerting an inhibitory effect on the substance permeability of the gastrointestinal mucosa. In addition, since the mixture of sucralfate with an organic acid and an inorganic salt forms a gel-like substance stronger than sucralfate alone, in addition to the above-mentioned submucosal microinflammation improving effect, the substance permeability of the mucosa is improved. Further enhancement of the biological barrier function that suppresses can be expected to further improve microinflammation under the gastric or duodenal mucosa.

Claims (7)

A gastric or duodenal submucosal microinflammation improving drug containing a gastrointestinal mucosal protective agent as an active ingredient. The gastrointestinal mucosa protective agent is at least one selected from the group consisting of sucrose octasulfate and its pharmaceutically acceptable salt, rebamipide and its pharmaceutically acceptable salt, teprenone, and methylmethionine sulfonium chloride. The gastric or duodenal submucosal microinflammation improving agent according to claim 1. The gastric or duodenal submucosal microinflammation improving agent according to claim 1 or 2, further comprising at least one selected from the group consisting of inorganic salts, organic acids and salts thereof. A gastric excretion improving drug containing a gastrointestinal mucosa protective agent as an active ingredient. The agent for improving gastric emptying ability according to claim 4, wherein the improvement of gastric emptying ability is due to improvement of microinflammation of the gastric or duodenal submucosa. The gastrointestinal mucosa protective agent is at least one selected from the group consisting of sucrose octasulfate and its pharmaceutically acceptable salt, rebamipide and its pharmaceutically acceptable salt, teprenone, and methylmethionine sulfonium chloride. The gastric emptying ability improving agent according to claim 4 or 5. The gastric emptying ability improving agent according to any one of claims 4 to 6, further comprising at least one selected from the group consisting of an inorganic salt, an organic acid and a salt thereof.

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