JP2014193832A - Pharmaceutical composition containing mosapride and antacid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To develop a pharmaceutical composition with preservation stability which contains a mosapride or a salt thereof.SOLUTION: In the present invention, there are provided a pharmaceutical composition which has preservation stability by containing 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide or a salt thereof, and antacid as active ingredients, and a method for inhibiting a color change in a pharmaceutical composition containing 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide, or a salt thereof.

Description

  The present invention relates to 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter also simply referred to as “mosapride”) or a salt thereof. And an antacid as an active ingredient, and 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide Or it is related with the discoloration suppression method of the pharmaceutical composition containing the salt.

Mosapride is known as a selective serotonin 5-HT ₄ receptor agonist having gastrointestinal motility promoting action and gastric excretion promoting action. In particular, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide monocitrate dihydrate (hereinafter simply referred to as “quenched”). (Also referred to as “acid mosapride”) is known by the general name “mosapride citrate hydrate” or “mosapride citrate” and is widely used as a typical gastrointestinal drug.

  Here, mosapride citrate, which is the drug substance, has a bitter taste, and also has a problem in stability when formulated, and therefore, a device for formulation has been studied. For example, mosapride citrate and a specific formulation component that promotes degradation and coloration of mosapride citrate are formulated in a form in which both components do not contact (Patent Document 1), and a specific formulation component is blended A technique (Patent Document 2) for producing an intraorally rapidly disintegrating tablet that can be stably stored and has sufficient hardness by mixing spray-dried particles and mosapride citrate is known.

  On the other hand, antacids are known to have an action of chemically neutralizing gastric acid to protect the gastric mucosa, and are widely used as pharmaceuticals against hyperacidic stomach and peptic ulcer. Substances known as antacids are generally inorganic salt compounds, and for example, sodium hydrogen carbonate (sodium bicarbonate), magnesium oxide, aluminum hydroxide and the like are known.

International Publication No. 2006/11638 JP 2011-37767 A

  However, as described above, it is known that a preparation containing mosapride citrate has low storage stability, and specifically, it is known to cause degradation or coloring during storage. Therefore, efforts have been made to maintain storage stability by applying aluminum packaging to the preparation or by applying troublesome coatings, but on the other hand, there have been problems in terms of manufacturing and cost.

  In addition, mosapride or a salt thereof and an antacid are gastrointestinal drugs having different effects as described above, and thus can be prescribed separately. It was also troublesome for the patient, and there was a problem in terms of reduced compliance and increased medical costs.

  As a result of intensive studies to solve the above problems, the present inventors have found that discoloration of tablets can be suppressed by adding an antacid to a composition containing mosapride or a salt thereof to complete the present invention. It came.

  That is, the present invention comprises 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof and an antacid as an active ingredient. A pharmaceutical composition is provided.

That is, although not limited to this, this invention includes invention of the following aspects.
(1) 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof; and an antacid;
A pharmaceutical composition comprising as an active ingredient.
(2) The compounding ratio of the 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof and the antacid is The pharmaceutical composition according to (1), which is 1:20 to 1:80.
(3) The 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof is 4-amino-5-chloro-2 The pharmaceutical composition according to (1) or (2), which is -ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide monocitrate dihydrate.
(4) The antacid is a dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, magnesium alumina alumina, aluminum hydroxide gel, hydroxylation Aluminum / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, metasilica (1) to (1) selected from the group consisting of magnesium acid aluminate, anhydrous calcium hydrogen phosphate, bird band bone, stone name, borei, aminoacetic acid, dihydroxyaluminium aminoacetate, funnel extract, and combinations thereof 3 The pharmaceutical composition according to any one of.
(5) The pharmaceutical composition according to any one of (1) to (4), wherein the content of the antacid is 20 to 80% by weight.
(6) The pharmaceutical composition according to any one of (1) to (5), wherein discoloration is suppressed.
(7) The pharmaceutical composition according to any one of (1) to (6), which is in the form of a powder, granule or tablet.
(8) Method for inhibiting discoloration of a pharmaceutical composition containing 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof Because
4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof; and an antacid;
Mixing at a blending ratio of 1:20 to 1:80;
Including the above method.

  According to the present invention, it is advantageous in that the storage stability of the preparation is improved and discoloration can be particularly suppressed. Moreover, since the said effect of this invention is acquired only by mixing a mosapride or its salt, and an antacid, it is advantageous also at the point that the simplification of a manufacturing process and also the effect of cost reduction are acquired.

  In addition, since mosapride or a salt thereof and an antacid are gastrointestinal agents having different effects as described above, the combination of these agents is expected to enhance efficacy, and moreover, a plurality of gastrointestinal agents can be used. Since it is not necessary to take, prescription by a doctor is simplified, and it is advantageous in that it can contribute to improvement of medication compliance and reduction of medical costs.

Hereinafter, embodiments of the present invention will be described in detail.
The pharmaceutical composition of the present invention comprises mosapride or a salt thereof and an antacid as active ingredients. Here, the term “containing as an active ingredient” means that mosapride or a salt thereof and an antacid are each contained in the composition in an amount effective as a drug.

As used herein, “4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide” (mosapride) is
The following formula (I):

In the present invention, it may be a free form or a salt thereof. In addition, either a racemate or an optically active substance can be used.
Although the salt of mosapride is not particularly limited, a pharmaceutically acceptable salt is preferable, and examples thereof include organic acids such as formic acid, acetic acid, lactic acid, adipic acid, citric acid, tartaric acid, fumaric acid, methanesulfonic acid, and maleic acid. And addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, oxalic acid and phosphoric acid, and citrate is particularly preferred.

  Furthermore, mosapride or a salt thereof may form a solvate, particularly a hydrate. Mosaprid / monocitrate / dihydrate represented by the following formula (II) is preferably used in the pharmaceutical composition of the present invention.

  The content of mosapride or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, but is 0.5 to 10% by weight, preferably 1 to 5% with respect to 100% by weight of the total amount of the pharmaceutical composition of the present invention. % By weight. In addition, the dose of mosapride or a salt thereof varies depending on the administration subject, administration route, dosage form, symptom, etc., but when converted to mosapride citrate, for example, 7.5 to 22.5 mg orally per day for adults, Preferably it is 7.5-15 mg, More preferably, it is 15 mg, and it may be administered in a single dose or divided into multiple doses.

  The “antacid” used in the present invention is not particularly limited as long as it is a substance having an action of adjusting the pH in the stomach. For example, a fast-acting type (sodium bicarbonate, magnesium carbonate, magnesium hydroxide, etc.) Type (magnesium aluminate metasilicate, magnesium aluminate silicate, dry aluminum hydroxide gel, synthetic aluminum silicate, natural aluminum silicate, aluminum hydroxide gel, magnesium silicate, magnesium oxide, precipitated calcium carbonate, etc.), sustained Type that has both properties and rapid action (synthetic hydrotalcite, magnesium aluminate metasilicate, dihydroxyaluminum aminoacetate, magnesium hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate If dry gel, aluminum oxide, magnesium carbonate, calcium carbonate co-precipitation product) Various antacids such may be formulated according to the purpose. The antacid may be alkaline or neutral, for example, dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, Alumina magnesium hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium hydroxide, Examples include sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, magnesium aluminate metasilicate, anhydrous calcium hydrogen phosphate, bird bandit, stone name, volley, aminoacetic acid, dihydroxyaluminium aminoacetate, funnel extract, etc. In may be used in combination plurality also be used. Particularly preferred are antacids selected from sodium bicarbonate, magnesium aluminate metasilicate, and combinations thereof.

The amount of antacid contained in the pharmaceutical composition of the present invention can be appropriately determined by those skilled in the art based on the type of antacid and the amount of mosapride or salt thereof used in combination. For example, the content of the antacid relative to the total amount of the composition is 20 to 80% by weight, preferably 40 to 80% by weight, and in the case of a persistent antacid, 20 to 80% by weight, preferably 40 to 40% by weight. 80 to 80% by weight, preferably 26 to 80% by weight for fast acting antacids, more preferably 40 to 80% by weight, and 20 to 67 for both long-lasting and fast acting antacids % By weight is preferred, more preferably 26 to 60% by weight. The antacids having both rapid action and durability can be used alone or in combination. The blending ratio of mosapride or a salt thereof and the antacid is 1:20 to 1:80, preferably 1:40 to 1:80. In the case of a long-lasting antacid, 1:20 to 1: 80, preferably 1: 40-1: 80, and in the case of fast acting antacids, preferably 1: 26-1: 80, more preferably 1: 40-1: 80, In the case of an antacid having both durability and rapid action, it is preferably 1:20 to 1:67, more preferably 1:26 to 1:60. Each of the antacids having both rapid efficacy and sustainability may be used alone or in combination.
The dosage of the antacid is also different depending on the type of antacid, administration subject, administration route, dosage form, symptom and the like, but for example, 0.3 to 4.0 g, preferably 0 .4 to 3.0 g, more preferably 0.6 to 3.0 g, which may be administered in a single dose or divided into multiple doses.

  The pharmaceutical composition of the present invention may further contain an additive. The additive is not particularly limited as long as it is pharmaceutically acceptable, and for example, an excipient, a binder, a disintegrant, a lubricant, a fluidizing agent, an anti-caking agent, etc. may be used. it can.

Examples of the excipient include D-mannitol and lactose hydrate.
Examples of the binder include gum arabic, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and the like.

  Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, and carboxymethyl starch sodium.

  Examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.

Examples of the fluidizing agent or anti-caking agent include hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide, heavy anhydrous silicic acid, tricalcium phosphate, talc and the like.
As further additives, buffering agents, acidulants, foaming agents, artificial sweeteners, fragrances, flavoring agents, coloring agents, antioxidants, surfactants, stabilizers and the like can also be used.

Moreover, these additives can be added in combination. The compounding amount of the additive can be used in an amount within the range in which the desired effect of the present invention is achieved.
In one embodiment, the pharmaceutical composition of the present invention contains light silicic anhydride or hydrous silicon dioxide as an additive component. The component functions as a fluidizing agent or an anti-caking agent and is particularly useful when preparing granules, powders, and tablets.

As another aspect of the present invention, the additional active ingredients may be administered simultaneously, sequentially or separately with the pharmaceutical composition of the present invention. For example, H ₂ blockers (cimetidine, ranitidine hydrochloride, famotidine, etc.), gastric acid secretion receptor antagonists such as muscarinic receptor antagonists (pirenzepine hydrochloride hydrate, etc.), gastric mucosa protective components (sucralfate, dipotassium glycyrrhizinate, etc.) , Local anesthetics (such as ethyl aminobenzoate), smooth muscle relaxants (such as papaverine hydrochloride), antifoams (such as dimethylpolysiloxane), stomach medicines (aloe, turmeric, keihi, skin, etc.), dry yeast, hydrochloric acid Digestives such as carnitine and trimebutine maleate), digestive enzymes (diastase, lipase, etc.), bile components (ursodeoxycholic acid, dehydrocholic acid, etc.), intestinal regulating agents (lactic acid bacteria, butyric acid bacteria, natto bacteria, etc.), proton pump inhibition Drugs (omeprazole, lansoprazole, rabeprazole sodium , Esomeprazole, etc.) can be used in combination. These additional active ingredients can also be combined and formulated into the pharmaceutical composition of the present invention.

  The pharmaceutical composition of the present invention comprises irritable bowel syndrome, flaccid constipation, habitual constipation, chronic constipation, functional dyspepsia, acute / chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastroneuropathy, senile ileus , Non-diffuse gastroesophageal reflux disease, NSAID ulcer, loss of appetite in esophageal / biliary diseases, nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, heartburn, ambiguity, schizophrenia, depression, or anxiety It can be used for the treatment and prevention of various diseases or symptoms such as. The pharmaceutical composition of the present invention is also useful for the treatment and prevention of various digestive system abnormalities associated with the treatment of digestive system diseases and the various diseases and symptoms described above. That is, the pharmaceutical composition of the present invention is useful as a gastrointestinal motility promoting agent or a gastrointestinal function improving agent. Preferably, the pharmaceutical composition of the present invention comprises functional dyspepsia, acute / chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastroneuropathy, senile ileus, non-diffuse gastroesophageal reflux disease, NSAID ulcer, esophagus -Particularly useful for the treatment and prevention of various diseases or symptoms such as loss of appetite, nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, heartburn, or ambiguity in biliary tract diseases.

  The administration route and dosage form of the pharmaceutical composition of the present invention are not particularly limited, but oral administration of solid preparations is preferred, powders, granules or tablets are more preferred, and granules are more preferred. Examples of the tablet include preparations such as film-coated tablets, capsule tablets, chewable tablets, orally disintegrating tablets, and sustained-release tablets.

  The manufacturing method of the pharmaceutical composition of this invention can be suitably selected according to the dosage form of the formulation to manufacture from a grinding | pulverization process, a mixing process, a granulation process, a shaping | molding process (tablet process), a film coating process, etc. For example, in the case of a powder or granule, a pulverization step, a mixing step, and a granulation step can be included. In the case of a tablet, a molding step and, if necessary, a film coating step are included.

  The pulverization step is not particularly limited to any device and means as long as the drug and appropriate additives can be pulverized using a conventional method in the field of pharmaceutical preparations. Examples of the pulverizer include an impact pulverizer, a hammer mill, a ball mill, a jet pulverizer, and a colloid mill. The pulverizing conditions are not particularly limited.

In the mixing step, a conventional method in the pharmaceutical field can be used, and there is no particular limitation on the apparatus and means as long as each component can be uniformly mixed.
In the granulation step, a conventional method in the pharmaceutical field can be used. The pulverized product obtained in the pulverization step and various additives are put into a granulator, and a binder solution is added. You may dry during a granulation process. As granulation methods, for example, fluidized bed granulation method, melt granulation method, high speed stirring granulation method, crushing (pulverization) granulation method, extrusion granulation method, rolling granulation method, spray granulation method, dry method Examples thereof include a granulation method and an apparatus used by those methods.

The drying method is not particularly limited, and a conventional method in the pharmaceutical field can be used.
In the mixing step, the granulated product and various additives are mixed.
In the compression molding process (tablet process), the mixed product is tableted using a rotary tableting machine, a single-shot tableting machine or the like to obtain a tableted product. The process is not particularly limited to any device or means as long as it is a method for molding the pharmaceutical composition of the present invention.

As the film coating step, a film coating may be applied to the tablet surface after tableting as appropriate, and a conventional method in the pharmaceutical field can be used as the method.
Moreover, the other aspect of the pharmaceutical composition of this invention is a pharmaceutical composition by which discoloration was suppressed. By containing an antacid, discoloration of the pharmaceutical composition containing mosapride or a salt thereof can be suppressed and stored stably over a long period of time. Here, the term “discoloration” as used in the present invention means that the color of the pharmaceutical composition is changed, and the degree thereof is not particularly limited, but the pharmaceutical composition is colored, and further, browning or yellowing. Say. According to the present invention, discoloration of a pharmaceutical composition can be suppressed for a long time. In addition, this effect can be confirmed, for example, by performing a test under conditions of 60 ° C. for 2 months, more preferably 60 ° C. for 4 weeks after opening.

  Moreover, from another viewpoint, this invention relates to the discoloration inhibitor containing an antacid for suppressing discoloration of the pharmaceutical composition containing mosapride or its salt. The content of the discoloration inhibitor relative to the total amount of the pharmaceutical composition can be calculated based on the blending ratio of mosapride or a salt thereof and an antacid.

  From still another aspect, the present invention relates to a method for suppressing discoloration of a pharmaceutical composition containing mosapride or a salt thereof. This method is characterized in that antacid is mixed with mosapride or a salt thereof in a mixing ratio of 1:20 to 1:80. The method of the present invention makes it possible to suppress discoloration of a pharmaceutical composition containing mosapride or a salt thereof and to stably store it over a long period of time.

  Hereinafter, although the content of the present invention is explained in detail, referring to the example of the present invention, the present invention is not limited to the following example. Unless otherwise specified, numerical ranges in this specification are described as including the end points.

Examples 1-5
Mosaprid citrate (product name: Mosapride Citrate, manufacturer name: Zhejiang Sanmen Hengkang Pharmaceutical) and magnesium aluminate metasilicate (product name: neucillin FH1, manufacturer name: Fuji Chemical Industries), D- Mannitol (Product name: PEARLITOL 50 C-MANNITOL, Manufacturer name: Rocket), Magnesium stearate (Product name: Magnesium stearate vegetable, Manufacturer name: Taihei Chemical Industry), Light anhydrous silicic acid (Product name: AdSolider 101, (Manufacturer name: Fuji Silysia Chemical) and hydroxypropyl cellulose (product name: HPC-L Fine Powder, manufacturer name: Nippon Soda) were mixed and granulated by kneading while adding an appropriate amount of purified water. The granulated product was dried and sized to obtain pharmaceutical compositions (granule) of Examples 1 to 5.

  The granules of Examples 1 to 5 were allowed to stand at 4 ° C. and 60 ° C. for 4 weeks, and the degree of discoloration was visually evaluated (++: yellowing, +: slightly yellowing, ±: slightly yellowing, − :No change). As shown in Table 1, when magnesium metasilicate aluminate was blended, the color of the preparation after evaluation was not changed in all Examples of Examples 1 to 5, and yellowing could be completely suppressed. confirmed.

Comparative Examples 1 and 2
The powder of Comparative Example 1 was prepared in the same manner as in Examples 1 to 5, except that the antacid was not added at the compounding amount shown in Table 1. In Comparative Example 2, 1% of commercially available Gasmotin (registered trademark) powder was weighed and used so that the dose of mosapride citrate was 15 mg.

  As shown in Table 2, in the case of Comparative Examples 1 and 2 in which no antacid was added, the color of the preparation was not changed when it was left at 4 ° C. for 4 weeks, but it was left at 60 ° C. for 4 weeks. In this case, it was confirmed that the preparation was yellowed, and it was clarified that the antacid contributes to suppression of discoloration of the preparation.

Examples 6-9
The powders of Examples 6 to 9 are blended in the amounts shown in Table 1, and instead of “magnesium aluminate metasilicate” as an antacid, “sodium hydrogen carbonate” (product name: sodium bicarbonate, P for manufacturer, manufacturer) It was prepared in the same manner as in Examples 1 to 5 except that name: Tosoh) was used.

  As shown in Table 2, in the case of a fast-acting antacid (sodium hydrogen carbonate) as well as a long-lasting antacid (magnesium aluminate metasilicate), it was confirmed that the yellowing of the preparation can be suppressed. As a result, it has been revealed that it has a sufficient discoloration suppressing effect.

  Moreover, it can be expected from these results that the discoloration of the preparation is also suppressed when a long-lasting antacid and a fast-acting antacid are used in combination.

Formulation Examples 1-4
Examples of powders, granules, and tablets are shown below. According to the formulation examples shown in Table 3, each preparation can be prepared by a conventional method.

Claims (8)

4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof; and an antacid;
A pharmaceutical composition comprising as an active ingredient.   The compounding ratio of the 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof and the antacid is 1:20. The pharmaceutical composition according to claim 1, which is ˜1: 80.   The 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof is 4-amino-5-chloro-2-ethoxy- The pharmaceutical composition according to claim 1 or 2, which is N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide monocitrate dihydrate.   The antacid is dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, magnesium alumina alumina, aluminum hydroxide gel, aluminum hydroxide / carbonic acid Sodium hydrogen coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium hydroxide, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate, metasilicate aluminate Any of claims 1-3, selected from the group consisting of magnesium, anhydrous calcium hydrogen phosphate, bird band, stone name, borray, aminoacetic acid, dihydroxyaluminium aminoacetate, funnel extract, and combinations thereof. Or pharmaceutical composition according to item 1.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the content of the antacid is 20 to 80% by weight.   The pharmaceutical composition according to any one of claims 1 to 5, wherein discoloration is suppressed.   The pharmaceutical composition according to any one of claims 1 to 6, which is in the form of a powder, granule or tablet. A method for suppressing discoloration of a pharmaceutical composition containing 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof. ,
4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a salt thereof; and an antacid;
Mixing at a blending ratio of 1:20 to 1:80;
Including the above method.