JPS62277322A - Stabilized pharmaceutical composition and production thereof - Google Patents

Abstract

PURPOSE:To obtain the titled composition, by blending a benzimidazole based compound with a specific basic inorganic salt. CONSTITUTION:A stabilized pharmaceutical composition obtained by blending 1pts.wt. compound expressed by formula I (R<1> is H, alkyl, halogen, cyano, etc.; R<2> is H, alkyl, acyl, carboalkoxy, etc.; R<3> and R<5> are H, alkyl, alkoxy, etc.; R<4> is H, alkyl, alkoxy which may be fluorinated, etc.; m is 0-4) or a derivative thereof with 0.3-20pts.wt. basic inorganic salt of magnesium and/or calcium. This composition is a remedy for peptic ulcer having inhibition of gastric acid secretion as main action. The compound expressed by formula I can be obtained by a method for subjecting a compound expressed by formula II prepared by reacting a compound expressed by formula III with a compound expressed by formula IV (X is halogen) to oxidative reaction, etc. The dose thereof is 0.01-30mg/kg/day, preferably 0.1-3mg/kg/day expressed in terms of the compound expressed by formula I.

Description

Detailed Description of the Invention 3. Detailed Description of the Invention Industrial Field of Application The present invention relates to 2-C(2-pyridyl)methylsulfinylcopenzimidazole or its derivatives (hereinafter referred to as benzimidazole) useful as an anti-ulcer agent. (sometimes abbreviated as a compound based on magnesium) and magnesium
IJ-Jq+1)AI-/7'll#,"T-)l'r
The present invention relates to a stabilized pharmaceutical composition comprising im and 4-subfertile f-LM 1, and a method for producing the same.

BACKGROUND OF THE INVENTION Penzimidazole compounds have recently been clinically studied as gastric acid secretion inhibitors. The pharmacological effect of this compound is that it is a therapeutic agent for peptic ulcers whose main effect is to suppress gastric acid secretion based on the (H"+K")-ATPase inhibitory effect.
It has a strong and long-lasting action compared to a receptor antagonist, and also has gastric mucosal protective action, so it is attracting attention as a next-generation powerful therapeutic agent for whitening ulcers.

Examples of benzimidazole compounds having anti-ulcer effects include JP-A-52-62275 and JP-A-5
Publication No. 4-141783 1 Japanese Unexamined Patent Publication No. 57-53406.

Publication of JP-A-58-13588, JP-A-58-192
Compounds described in JP-A-880, JP-A-59-181277, etc. are known.

However, the stability of these compounds is poor; in a solid state, they are unstable with respect to temperature, humidity, and light, and in an aqueous solution or suspension, the lower the pH, the more unstable they are. on the other hand,
The stability of formulations, such as tablets, powders, fine granules, granules, and capsules, is unstable due to stronger interactions with other ingredients in the formulation than with the compound alone, and may vary during manufacturing and over time. There is a significant decrease in content and color change. Formulation components that adversely affect stability include, for example, microcrystalline cellulose,
Polyvinylpyrrolidone (PVP), carboxymethylcellulose calcium, polyethylene glycol 6000
．． Examples include Pluronic F68 (polyoxyethylene-polyoxypropylene copolymer). Furthermore, when coating tablets and granules among these preparations, for example, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate, salanate 9 eudragit (methacrylic acid/acrylic acid copolymer)
It also has poor compatibility with enteric-coated bases such as, resulting in a decrease in content and color change. However, in the production of oral preparations, although it is essential to mix one or more of these components, the stability is adversely affected as described above, making it difficult to formulate the preparation.

In order to eliminate these instabilities, conventionally, benzimidazole compounds have been converted into salts of lithium, sodium, potassium, magnesium, calcium, titanium, and the like. (Japanese Unexamined Patent Publication No. 59-167587) Problems to be Solved by the Invention However, according to the above method, in order to stabilize the benzimidazole compound, the step of converting it into a salt as described above was necessary. .

Means for Solving the Problems In view of the above circumstances, the present inventors investigated the stabilization of penzimidazole compound-containing preparations, and as a result, completed the present invention.

That is, the present invention provides: (1) A pharmaceutical composition comprising 2-[(2-pyridyl)methylsulfinyl]benzimidazole or a derivative thereof having an anti-ulcer effect and a basic inorganic salt of magnesium and/or calcium. and (2) a stabilized product characterized by blending basic inorganic salts of magnesium and/or calcium with 2-[(2-pyridyl)methylsulfinyl]benzimigsol or its derivatives having an anti-ulcer effect. This is a method for producing a pharmaceutical composition.

The benzimidazole compound having an anti-ulcer effect used in the present invention is a compound described in the above-mentioned publications, etc., and has the following general formula (1)% formula% [wherein R1 is hydrogen, Alkyl, halogen, cyano, carboquine, carbalkoxy, carbalkoxyalkyl, carbamoyl, carbamoylalkyl, n
A
4,000 + Lkll fluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl, R1 is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl, alkylcarbonylmethyl,
alkoxycarbonylmethyl, alkylsulfonyl,
R3 and R5 are the same or different and represent hydrogen, alkyl, alkoxy or alkoxyalkoxy; R4 is hydrogen;
alkyl, alkoxy which may be fluorinated or alkoxyalcogine; m represents an integer of 0 to 4; ) The compound of general formula (1) can be produced by the method described in the above-mentioned publication or a method involving therein.

The substituents of the known compound in general formula (1) will be briefly explained below.

In the above formula, the alkyl represented by R1 has 1 carbon number
Carboalkoxy has 1 to 7 carbon atoms, alkoxy of carboalkoxy has 1 to 4 carbon atoms, alkoxy of carboalkoquinoalkyl has 1 to 4 carbon atoms, alkyl has 1 to 4 carbon atoms, carbamoylalkyl The alkyl having 1 to 4 carbon atoms is
Alkoxy has 1 to 5 carbon atoms, alkyl in hydroxoalkyl has 1 to 7 carbon atoms, acyl has 1 to 4 carbon atoms, and acyl in acyloxo has 1 to 4 carbon atoms. The thing is
Examples of aryl include phenyl, aryloquino aryl includes phenyl, alkylthio includes those having 1 to 6 carbon atoms, and alkylsulfinyl includes those having 1 to 6 carbon atoms.

Furthermore, the alkyl represented by R2 has 1 to 5 carbon atoms, the acyl has 1 to 4 carbon atoms, the alkoxy in carboalkoxy has 1 to 4 carbon atoms, and the alkyl in alkylcarbamoyl has 1 to 4 carbon atoms. The alkyl of dialkylcarbamoyl has 1 to 4 carbon atoms, and the alkylcarbonylmethyl has 1 to 4 carbon atoms, and the alkylcarbonylmethyl of sulfonylmethyl has 1 to 4 carbon atoms. has 1 to 4 carbon atoms, and the alkyl of alkylsulfonyl has 1 to 4 carbon atoms.
I can give you 4 things.

The alkyl represented by R', R' and R5 has 1 to 4 carbon atoms, the alkyne has 1 to 8 carbon atoms, and the alkoxy of alkinoalkoxy has 1 to 4 carbon atoms. can give.

Further, the alkoxy represented by R' which may be fluorinated includes those having I to 8 carbon atoms.

Among the compounds represented by the above formula (1), ■R1 or hydrogen. A compound in which R' is hydrogen or methoxy or trifluoromethyl, R3 and R5 are the same or different hydrogen or methyl, R4 is a fluorinated alkokino having 2 to 5 carbon atoms, and m is 1; R1 is hydrogen. Compounds in which R2 is hydrogen, R3 is hydrogen or methyl, R4 is alkokyne having 3 to 8 carbon atoms, R5 is hydrogen, and m is 1, and ■ R1 is hydrogen, Fluorine. Metquin or trifluoromethyl, R2 is hydrogen, R3 is alkoxy having 1 to 8 carbon atoms, R4 is optionally fluorinated alkoxy having 1 to 8 carbon atoms, R5 is hydrogen and m months. The compound is a new compound.

The substituents of the above novel compound will be explained in detail.

The lower alkoxy group represented by R3 is preferably a lower alkoxy group having 1 to 8 carbon atoms, such as metquine, ethoquino, broboxo. Examples include isopropoquine 2-butoxy, isobutoxy, pentyloquino, pequinluoquino, heptyloxy, octyloquino, and among these, a lower alkokino group having 1 to 4 carbon atoms is preferred.

The lower alkokino group in the optionally fluorinated lower alkokino group represented by R4 is Hirako Ut l
fX L)i R low-Q alkokino JIL is included, and preferred examples thereof include the same alkokino group as R3 above. Examples of fluorinated lower alkoxy groups include 2.2.

2-trifluoroethquino, 2.2,3.3.3-pentafluoropropoxy, 1-(trifluoromethyl)-2,
2.2-trifluoroethoquino, 2.2.3.3-tetrafluoropropoxy, 2.2.3.3.4. , 1.1 hebutaflokubutkin, 2.2.3.3.4, = 1.5.5
Examples include -octafluoropentoxy, but a fluorinated lower alkoxy group having 2 to 4 carbon atoms is preferred.

Examples of the position of R+ include the 4th and 5th positions, of which the 5th position is preferred.

Next, a method for producing the above novel compound [hereinafter referred to as formula (do) 1] will be described.

The compound has the general formula [wherein R1 to R5 have the same meanings as above. ] can be produced by subjecting the compound represented by the formula to an oxidation reaction.

Examples of the oxidizing agent used here include metachloroperbenzoic acid, peracetic acid, and trifluoroperacetic acid.

Examples include peracids such as permaleic acid, sodium bromite, and sodium hypochlorite.

Chloroform is used as a solvent for the reaction.

Examples include halogenated hydrocarbons such as nochloromethane, ethers such as tetrahydrofuran and nooxane, amides such as dimethylformamide, and water, which may be used alone or in combination. The amount of the oxidizing agent to be used is preferably approximately equivalent to or slightly in excess of the amount of compound (II). That is, about 1 to 3 equivalents, more preferably about 1 to 1.5 equivalents. The reaction temperature is from water cooling to around the boiling point of the solvent used, usually from water cooling to room temperature, more preferably from about 0°C to 10°C. The reaction time is usually about 0.1 to 24 hours, more preferably about 0.1 to 4 hours.

The novel target compound (1') produced by the above reaction is
It can be isolated and purified by conventional means such as recrystallization and chromatography.

The compound may be converted into a pharmacologically acceptable salt by commonly used means. Examples of the salt include hydrochloride, bromate, iodate, phosphate, nitrate, sulfate,
Examples include acetate and citrate.

Compound (I[) has the general formula [wherein R1 and R2 have the same meanings as defined above]. ] and the general formula [wherein R3-R5 have the same meanings as above, and X represents a halogen atom. ] It can be produced by reacting with the raw material compound represented by.

Examples of the halogen atom represented by X include chlorine, bromine, and iodine.

This reaction is conveniently carried out in the presence of a base. The base is, for example, sodium hydride.

Alkali metal hydrides such as potassium hydride, alkali metal hydrides such as sodium metal, sodium methoxide,
Examples include sodium alcoholades such as sodium methoxide, alkali metal carbonates such as potassium carbonate and sodium carbonate, and organic amines such as triethylamine.

Examples of the solvent used in the reaction include alcohols such as methanol and ethanol, and dimethylformamide. The amount of base used in the above reaction is usually slightly in excess of the equivalent amount, but a large excess of base may also be used. That is, about 2 to 10 equivalents, more preferably about 2 to 4 equivalents. The above reaction temperature is
The temperature is usually about 0°C to around the boiling point of the solvent used, more preferably about 20°C to 80°C. The reaction time is about 0.2 to 24 hours, more preferably about 0.
, 5 to 2 hours.

Next, a method for producing raw material compound (IV) will be explained.

Among compounds (IV), compounds in which R3 and R5 are the same or different and are hydrogen or methyl, and R4 is a fluorinated alkoxy having 2 to 5 carbon atoms or alkoxy having 3 to 8 carbon atoms, can be prepared as follows. It can be manufactured by

(Left below) Manufacturing method l) (■) (■) General formula (V
) In the formula, R3゜R5 represents the same meaning as the previous 5 self] In the presence of a base, alcohol derivative R"0H (Vr) [wherein R" is a fluorinated carbon] It represents alkyl having 2 to 5 carbon atoms or alkyl having 3 to 8 carbon atoms. ] By avoiding the reaction, the general formula (■) [
In the formula, R3, R', and R5 have the same meanings as defined above]. Bases used in the reaction include, for example, alkali metals such as lithium, sodium, and potassium, alkali metal hydrides such as sodium hydride and potassium hydride, alcolades such as butogynopotassium and propoxysodium, potassium carbonate, and carbonate. lithium. sodium carbonate.

Alkali metal carbonates or bicarbonates such as potassium bicarbonate, sodium bicarbonate, and alkali metals such as potassium disodium and lithium.

Examples include alkali hydroxides such as sodium hydroxide and potassium hydroxide. Examples of alcohol derivatives used in the reaction include propatool, isopropatool, butanol, pentanol, hexanol, 2,2
．． 1-trifluoroethanol, 2.2,3.3.3-pentafluoropropertool.

2.2.3.3-tetrafluoropropanol, 1-(h
lifluoromedyl)-2,2,1-trifuroethanol, 2,2.3,3,4,4.4-hebucfluorobutanol, 2.2,3.3,4,4,5.5-octafluoro Examples include pentanol. Examples of solvents used in the reaction include R', 'OH, ethers such as tetrahydrofuran dinooxane, ketones such as acetone and methyl ethyl ketone, acetonitrile, trimethylformamide, and hexamethylphosphoric triamide. It will be done. The reaction temperature is appropriately selected from water cooling to around the boiling point of the solvent. Reaction time is about 1 to 48 hours.

The compound (■) obtained in this way is heated in the presence of a mineral acid such as sulfuric acid or perchloric acid (approx.
0 to 120°C) to obtain the general formula ('vl)
A 2-acetoquinomethylbilitz derivative represented by [wherein R3, R4, and R5 represent the same meanings as above]. ] is obtained. The reaction time is usually about 0.1 to 10 hours.

Then, a 2-hydroquinomethylpyrinone derivative represented by the general formula (IK) can be produced by subjecting compound (Vl) to alkaline hydrolysis. Examples of the alkali include sodium hydroxide.

Examples of potassium hydroxide, potassium carbonate, and sodium carbonate include methanol, ethanol, and water.

The reaction temperature is usually about 20 to 60°C, and the reaction time is about 0.
．． It takes 1 to 2 hours.

Further, by halogenating compound (IX) with a chlorinating agent such as thionyl chloride, a 2-halogenomedylpyrinono derivative represented by the general formula ([V)] [wherein R', R'
, R5 represents the same meaning as above, and X is chlorine.

Represents bromine or iodine. ] can be manufactured. Examples of the solvent used include chloroform, dichloromethane, and tetrachloroethane.

The reaction temperature is usually about 20 DEG to 80 DEG C. and the reaction time is about 0.1 f-C to 2 hours.

The produced compound (IV) was obtained by using the halokenolating agent [
7-hydrogenide salt, which is usually directly converted into the compound (
It is preferable to use it in the reaction with II).

Also, among compounds a), compounds in which Fz''' is a low carbon alkokino having 1 to 8 carbon atoms, R4 is a fluorinated high-carbon alcoquino, and R5 is hydrogen: produced as follows. You can do it in a row.

Production method 2) When maltol (X) is reacted with an alkyl halide represented by R''X in the presence of silver oxide, the compound (X[
) is obtained, and the pyridone derivative (X[) can be produced by reacting (XI) with aqueous ammonia. Compound(
(2) is converted into a halogen derivative (XI'/) by direct alkylation with an alkyl halide or with a halogenating agent such as phosphorus oxychloride, and then converted to a lower plate alcohol represented by R4''OH in the presence of a base. Compound (XIII) is induced by conducting the reaction.

Next, compound (X
V), react with acetic anhydride to form compound (XV[), and then hydrolyze to produce compound (X■), which is led to compound (It/) with a halogenating agent such as thionyl chloride. You can also do that.

Examples of the alkyl halide used in the production of compound (X[) include methyl iodide and ethyl iodide.

Propyl iodide, isopropyl iodide, butyl iodide,
Pentyl iodide, hexyl iodide, etc.
As the alkyl halide used in the production of I), in addition to those similar to the alkyl halide used in the production of compound (X[), for example, 2,2.2
- Trifluoroethyl iodite.

2.2,3,3.3-pentafluoropropyl iodite, 2,2.3.3-tetrafluoropropyl iodide,
l-(trifluoromethyl)-2,2,2-trifluoroethyl iodite, 2.2,3,3,4,4.4-hebutafluorobutyl iodite, 2,2.3.3°4 .4,5
．． Examples include 5-octafluoropentyl iodite,
The amount used is about 1 to 10 equivalents.

Further, examples of the deoxidizing agent include silver oxide, potassium carbonate, sodium carbonate, etc., and examples of the solvent include dimethylformamide, trimethylacetamide, etc., and room temperature is usually used as the reaction condition.

Examples of the halogenating agent used in the production of compound (XIV) include phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, etc. The amount used is an equivalent to a large excess, and the reaction temperature is about 50℃. ~150°C.

7shiΔrou tv I'Ir) store, 1-l Rem A4x/
VIT+) Small Fr5ml1-m+11L Alcohols include methanol, ethanol, and manufacturing method 1
Examples include alcohol derivatives similar to those used in alcohol derivatives, and the amount used is an equivalent to a large excess, and bases include sodium or potassium alcoholade of each alcohol, potassium t-butoxide, sodium hydride, etc. . The reaction temperature should be selected from room temperature to the boiling point of the alcohol used.

When compound (XII[) is directly brominated with N-bromosuccinic acid, the reaction is preferably carried out under light irradiation, and carbon tetrachloride, chloroform, tetrachloroethane, etc. are used as the solvent.

Examples of the oxidizing agent used in the reaction of compound (XII[) to compound (XV) include peracids such as metachloroperoxymonocarboxylic acid, peracetic acid, trifluoroperacetic acid, and permaleic acid, and hydrogen peroxide. etc. Solvents used in the reaction include halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as tetrahydrofuran and dioxane, and amides such as dimethylformamide.
Examples include acids and water damage, and they can be used alone or in combination. The amount of the oxidizing agent used is preferably approximately equivalent to an excess amount relative to compound (XI). Preferably it is about 1 to 10 equivalents. The reaction is carried out at an appropriate temperature ranging from water cooling to around the boiling point of the solvent used. The reaction time is usually about 0.1 to 24 hours, more preferably about 0.1 to 4 hours.

Compound (XVI) is produced from compound (XV) by heating (about 80 to 120'C) compound (XV) in the presence of acetic anhydride alone or a mineral acid such as sulfuric acid or perchloric acid. . The reaction time is usually 0.1 to 10
It's time.

Compound (X■) can be produced by alkaline hydrolysis of Compound (XV[), and examples of the alkali that can be used include sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. Examples of solvents used include methanol, ethanol,
Examples include water. The reaction temperature is usually about 20 to 60
C1 reaction time is about 0.1 to 2 hours.

To produce compound (1■) from compound (X■), a chlorinating agent such as thionyl chloride, an organic sulfonic acid such as methanesulfonyl chloride, p-toluenesulfonyl chloride, nophenylphosphoryl chloride, or This is done by using acid chlorides of organophosphoric acids. In the case of chlorinating agents such as thionyl chloride, the compound (X■
) is used in a small to large excess of chlorinating agent. Examples of solvents that can be used include chloroform, dichloromethane, and tetrachloroethane.

The reaction temperature is usually about 20 to 80°C and the reaction time is about 0.1 to 2 hours. In the case of an acid chloride of an organic sulfonic acid or an organic phosphoric acid, the chloride is used in an amount of M to a small excess of the compound (X), and the reaction is usually carried out in the presence of a base. Examples of the base used include triethylamine, organic bases such as triethylamine, and inorganic bases such as sodium carbonate, potassium carbonate, and sodium bicarbonate, and the amount used is an equivalent to a small excess.

Examples of the solvent to be used include chloroform, dichloromethane, carbon tetrachloride, acetonitrile, etc., and appropriate conditions are selected for the reaction temperature and reaction time, from water cooling to around the boiling point, and from several minutes to several hours.

The novel benzimidazole compound exhibits excellent gastric acid secretion suppressing action, gastric mucosal protective action, and anti-ulcer action,
Furthermore, since the toxicity is low, it can be used to treat gastrointestinal ulcers in mammalian animals (eg, mice, rats, rabbits, dogs, cats, humans, etc.).

Next, the basic inorganic salts of magnesium and calcium used in the present invention will be explained.

Examples of the basic inorganic salt of magnesium include heavy magnesium carbonate and magnesium carbonate.

Magnesium oxide, magnesium hydroxide, magnesium aluminate metasilicate, magnesium aluminate silicate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [MgflA12 (○) 4.・
Examples of the basic inorganic salts of calcium include precipitated calcium carbonate, hydroxide, and the like. These basic inorganic salts of magnesium and calcium have a pH of 1% aqueous solution or suspension.
7 or more).

The basic inorganic salts of magnesium and calcium may be blended singly or in combination of two or more, and the blend m varies depending on the type, but is about 0.3 to 20% by weight per 1 part by weight of the Benraimigsol compound. parts by weight, preferably about 0.6 to 7 parts by weight.

The composition of the present invention may further contain additives, such as excipients (eg, lactose, corn starch, light silicic anhydride, microcrystalline cellulose, white sugar, etc.).

Binders (e.g. pregelatinized starch, methylcellulose).

Calpoquine methylcellulose, hydroquinopropylcellulose, troquinebrovir methylcellulose, polyvinylpyrrolidone), disintegrants (e.g. carpoquine methylcellulose, starch, low-substituted hydroxypropylcellulose, etc.).

Surfactant (e.g. Tween 80 (manufactured by Kao Atlas)
, Pluronic F68 (manufactured by Asahi Denka Kogyo Co., Ltd., polyoxyethylene/polyoxypropylene copolymer, etc.), antioxidants (e.g., L-nestain, sodium sulfite, sodium ascorbate, etc.), lubricating agents (e.g., magnesium stearate, talc, etc.) are used as additives.

The composition of the present invention comprises the above-mentioned benzimidazole compound,
It can be obtained by uniformly mixing a basic inorganic salt of magnesium and/or calcium and the above-mentioned additives. Additives may be mixed with the benzimidazole compound, or basic inorganic salts of magnesium and/or calcium may be mixed with the additive and the benzimidazole compound. Any method that uniformly contacts the basic inorganic salt of magnesium and/or calcium may be used.

The mixture can be formulated into dosage forms suitable for oral administration, such as tablets, capsules, powders, granules, and fine granules, by means known per se.

Tablets, granules, and fine granules may be coated by methods known per se for the purpose of taste masking, enteric coating, or persistence. Examples of the coating agent include hydroquinepropyl methylcellulose, edyl cellulose, hydroquine methylcellulose, hydroquinepropylcellulose, polyoxine ethylene glycol, Tween 80. Pluronic F68. Cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, West Germany, methacrylic acid/acrylic acid copolymer) and titanium oxide,
Pigments such as red iron are used.

For tablets, granules, powders, fine granules, and capsules,
It can be manufactured by a conventional method (for example, the method described in the General Preparations of the Japanese Pharmacopoeia, 10th Amendment 1). That is,
For tablets, benzimidazole compound and excipient,
A basic inorganic salt of magnesium and/or calcium is added to the disintegrant, mixed, and a binder is added to form granules. A lubricant and the like are added to the granules, which are then compressed to form tablets. For granules, extrusion granulation is carried out in almost the same manner as for tablets, or non-barrel (containing 75% sucrose (W/W) and corn starch 25% (W/W)) is mixed with water or sucrose. , hydroxypropylcellulose, hydroquinepropylmethylcellulose, etc. (approximately 0 degrees
．． Benzimidazole-based compounds, basic inorganic salts of magnesium and/or calcium, and additives (e.g., white sugar, cornstarch, crystalline cellulose, hydroquinopropylcellulose, methylcellulose, hydroxyl) while spraying 5-70% (W/V). propylcellulose,
It can be obtained by coating a powdered dusting agent containing naturally occurring polyhinylpyrrolidone (polyhinylpyrrolidone, etc.). In the case of capsules, m may be mixed and filled.

The formulation thus obtained exhibits excellent stability upon long-term storage.

The pharmaceutical composition of the present invention thus obtained exhibits excellent gastric acid secretion suppressing action, gastric mucosal protective action, and anti-ulcer action,
Furthermore, since the toxicity is low, it can be used to treat gastrointestinal ulcers in mammals (eg, mice, rats, rabbits, dogs, cats, pigs, humans, etc.).

When the pharmaceutical composition of the present invention is used for the treatment of gastrointestinal ulcers in mammals, it is mixed with pharmacologically acceptable carriers, excipients, diluents, etc. as described above, and prepared into 5 tablets of capsules. It can be administered orally in the form of granules and the like.

The dosage is approximately 0 as a benzimidazole compound.
．． 01 mg to 30 mg/kg/day, preferably about 0,
The dose is 1 mg to 3 mg/kg/day.

EXAMPLES The present invention will be explained in more detail by reference examples, practical examples, and experimental examples below, but these are not intended to limit the present invention.

Reference Example I 2.3-dimethyl-4-nitropyridine-1-oquinodo (2.0 g), methyl ethyl ketone (30d).

2.2, 3.3.3-Pentafluoropropertool (30
5 years old), anhydrous potassium carbonate (3,29 g), and hexamethylphosphoric acid triamide (2,07 g).
After heating and stirring at 0°C for 4.5 days, insoluble matter was filtered off and aggregation was performed. Water was added to the residue, extracted with ethyl acetate, dried over magnesium sulfate, the solvent was distilled off, the residue was applied to a column of solica gel (50 g), eluted with chloroform-methanol (10:l), and extracted with acetic acid. Recrystallization from ethyl ester-hexane yielded 24 g of colorless needle-like crystals of 2,3-methyl-4-(2,2,3,3,3-pentafluoropropoquine)pyridine-1-oquinodo. Melting point: 148-149°C Compound (■) was produced from starting compound (V) in the same manner as above.

Compound (■) R'R5R' Melting point (°C) C11,I
I 0C112CF3131.0~131.5 Note 1)
++ It 0CII2C112CH3II
Lt note 2) C113II 0C112CII2
CH3,1 + l-form Note 1) NMR spectrum (CDCQ
, ) δ 1,01 (30,t.

J=711z), 1.81(211,m), 2.
50 (311, s), 3.93 (211, t, J-
=7Hz), 6.50-6.80(211,m),
8.10 (lit, d, J = 7tlz) 12) NMR spectrum (CDC 3) 61.07 (
311,t.

J=7.5Hz), 1.65-2.02 (211, m
), 2.21 (311°S), 2.52 (3+1.
S), 3.99 (2H, t, J=6112).

6.68 (ill, d, J=611z), 8
．． 15 (Ill, d, J=611z) Reference example 2 2.3-tmethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyrinone-1-oquinodo (2.5 g
), acetic anhydride (8%) was added with j:I and aqueous acid (2 drops), stirred at 11θ0C for 2 hours, and then concentrated.

The residue was dissolved in methanol (30+J), a 2N solution of sodium hydroxide in water (2i) was added, and the mixture was stirred at room temperature for 2 hours. After concentration, water was added and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent was distilled off and
It was applied to a column of Tsuka gel (50 g), eluted with chloroporm-methanol (10 l), and recrystallized from isopropyl ether to give 2-hydroquinomedy-3-medy-4-(2,2,3,3,3- 16 g of brown flakes of pentafluoropropoquino)pyrinone were obtained.

NMR spectrum (CD C1,) δ: 2.07 (
311, s), 4.28 (111, brs), 4.49
(211, t, J= 1211z), 4.67 (2h,
s).

6.69 (Ill, d, J = 511z), 8.34 (
iff, d, J=511z) Compound (■) was produced from compound (■) by the same method as above.

Compound (IX) R3R5R' Melting point (°C) CI13H0C
11, CF393.5~940 Note 1) II I
I 0CIt2CIItC113 Oily 2) C1+
3 ++ ocl12cl12ci+, curved shape = 7.511z), 1.79 (211, m),
3.92 (211, L, J-6Hz), 4.5
1-4.90 (IH, br), 4.68 (211,
s).

6.68 (11, dd, J=2 and 611z
), 630 (ift.

d, J=211z), 8.28(Ill,
d, J = 6tlz) Note 2) NMR spectrum (CD (
J! ,)61.03(3+1.t.

J=7.5tlz), 1.82(211,m),
2.02 (311, s), 3.95 (211, t
, J=611z), 4.62(211,s),
5.20 (III.

brd, s), 6.68(ill, d,
J=611z), 8.25 (Ill, d.

J=611z) Reference Example 3 2-hydroxymethyl-3-methyl-,? -(2゜2.
3.3.3-Pentafluoropropoquine) Birituno (35
Add dionyl chloride (0.2〃J) to a chloroform solution (lo, J) of 0 mg) for 30 minutes] L11 Heat to reflux f
It was then concentrated and the residue was dissolved in methanol (El rn!:l
), 2-mercaptobenzimidazole (2
00mg).

The mixture was added to a 28% sodium methoxyd solution (1 rut) and methanol (6 ruts), and heated under reflux for 30 minutes. Methanol was distilled off, water was added, and the mixture was dried over magnesium Δ′ acid ethyl ester.
) and recrystallized from ethyl acetate-hexane.
2- ([3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-bilinol]methylthio]
Colorless plate crystals of benzimidazole hemihydrate 370
mg was obtained. Melting point 145-146°C.

Thereafter, Compound (In) and (IV) were reacted in the same manner as above to produce Compound (II).

Compound (n) HHC11a HOCH*CFs 149-1
50HII II H0CI1. CH2CH284
~86 Note) II HCH3H0C11, CH, CH
3 oily) NMR spectrum (CDCQ3) δ: 0
．． 9g (3H, t.

J=7.5Hz), 1.54-1.92(2)1.
m), 2.15 (3H1s), 3.80 (2H,t
+ J=6tlz), 4.43(2i1.s), 6
．． 55 (IH, d, J=6Hz), 7.09 (2H
, m), 7.50 (2)1゜m), 8.21 (LH
, -d, J=6)1z) Reference Example 4 2- ([3-medyru-4-(2,2,3,3,3-pentafluoropropoquine)-2-pyridyl]methylthio]
Benzimidazole (2.2 g) in chloroform (20
d) Add m-chloroperbenzoic acid (1.3 g) to the solution under water cooling.
A chloroform (15%) solution was added dropwise over 30 minutes, and the reaction solution was washed with a saturated aqueous sodium bicarbonate solution. After drying with magnesium sulfate and concentrating, silica gel (5
0g) column and eluted with acetic acid ethyl ester.
Recrystallization from acetone-isopropyl ether yields 2
- Pale yellow prism of ([3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-bilinol]methylsulfinyl]benzimidazole (hereinafter sometimes referred to as compound ■) 1.78 g of the product was obtained. Melting point: 161-163°C (decomposition) Compound (■) (hereinafter sometimes referred to as compound ■, compound ■, and compound ■, respectively) was obtained from compound (n) in the same manner. Manufactured.

Compound (I) R'R''R3R'R' Melting point (
℃）■HIt Cll3 H0CIhCFz
178~1g2 (decomp,)■HHIt HO
CH, Ctl*CHa 123-125 (decomp
,)■+1 11 C113H0CHICI1. CH
381-83 Example 1 Among the following compositions, compound (1), magnesium hydroxide,
Nostein, corn starch, and lactose were mixed, and 172 amounts of microcrystalline cellulose, light anhydrous silicic acid, and magnesium stearate were added and mixed well, and then processed using a dry granulator (roller convector).

Compression molding was performed using Freund Co., Ltd. (1 Japan). After crushing this material in a mortar and passing it through a round surface (+6 mesh), the remaining amount is microcrystalline cellulose and light anhydrous silicic acid.

Magnesium stearate was added and mixed, and tablets of 250 mg per tablet were produced using a rotary tablet press (manufactured by Kikusui Seisakusho).

Compound composition in 1 tablet: 50 mgl (3
4 L-cysteine 20 mg-cornstarch 20 mg lactose
65.2mg light silicic anhydride t, gmg magnesium stearate 3.0mg total
250.0mg Example 2 Tablets were manufactured using the method of Example i, but using omebrazole (note) in place of compound (1).

(Note) 5-Methoxy-2-[(4-methoquine-3゜5-dimethyl-2-pyridyl)methylsulfinyl]penzimidazole Example 3 Among the following compositions, compound ■, precipitated calcium carbonate, cornstarch, lactose and hydroquino Mix propyl cellulose, add water and knead, then 40℃
The mixture was vacuum dried for 16 hours, ground in a mortar, and passed through a 16-mesh sieve to form granules.

Tablets each weighing 200 mg were produced using a Lee 2 tablet press (manufactured by Kikusui Seisakusho).

Compound composition in 1 tablet: 30 mg precipitated carbonate 50 mg cornstarch 40 mg lactose
73.4 mg hydroquinepropyl cellulose 6 mg Magnenium stearate
0.6mg water
(0.05m1) total
200.0 mg Example 4 Tablets were manufactured using the method of Example 3, but using (Sho) Timobrasol instead of Compound (1).

(Note) [(2-bilinol)methylsulfinyl]benzimidazole Example 5 After thoroughly mixing the substances in the composition ratios below, water was added and kneaded, and the extrusion granulator (manufactured by Kikusui Seisakusho, screen diameter 1.
0 mmφ), immediately turned into spherical granules using Marumerizer (manufactured by Fuji Paradal Co., Ltd., 101,000 rp), vacuum-dried at 40°C for 16 hours, and dried on a round surface for 12-4 hours.
2 metsunyu! One grain of lI' was obtained.

Composition in 200 mg of granules Compound ■ 30 mg Heavy magnesium carbonate 20 mg.

Cornstarch 80 mg Microcrystalline Cellulose 20 mg Carpoquine Memethycellulose Carnoum 0 mg Hydroquine Propyl Cellulose 10 mg Pluronic F 68 4 mg Lactose
26 mg water
(0,1,ml) total
200 mg Example 6 In the method of Example 5, compound ■ instead of compound ■
Granules were manufactured using

Example 7 An enteric coating liquid having the following composition was applied to the granules obtained in Example 3 in a fluidized spray dryer (manufactured by Okawara Co., Ltd.) at a supply air temperature of 50°C.
1 Enteric coated granules were obtained by coating at a granule temperature of 40°C. 260 mg of this product was filled into No. 1 hard capsules using a capsule filling machine (manufactured by Parke Davis, USA) to produce capsules.

Enteric coating liquid composition Eudragit L-300 138 mg (solid component 41.
4mg) Talc 4.1
mg polyethylene glycol 6000 12.4m
gtween 80 2.1mg water
Composition of 276μQ Enteric Coated Granules Granules of Example 5 200mg enteric coating 60mg total
Composition of 260mg capsule Enteric coated granule 260mg No. 1 hard capsule 76mg total
336B Song Liyou 1 You 3 Self composition includes compound ■, Magnenoum carbonate.

White sugar, cornstarch, and crystalline cellulose were mixed well to prepare a dispersant. Centrifugal fluid coating? Place the non-barrel into an i-grain device (CF-360, manufactured by Freund Sangyo Co., Ltd.), and add hydroquine propyl cellulose solution a (4%
(W/V) was coated with the above dispersing agent to obtain spherical granules.

The spherical granules were vacuum dried at 40° C. for 16 hours and examined on a round surface to obtain granules of 2 to 32 mesunyu.

Composition in granules 190mg Non-barrel 75mg compound ■
15mg Magnenium Carbonate 15mg White Sugar
29mg corn starch 27mg crystalline cellulose 27mg hydroquinepropylcellulose 2mg total
190 mg Example 9 An enteric coating liquid having the following composition was added to the granules obtained in Example 8 in a fluidized spray dryer (manufactured by Okawara Co., Ltd.) at a supply air temperature of 50°.
Enteric coated granules were obtained by coating at a C2 granule temperature of 40°C. Capsules were prepared by filling 240 mg of the granules into No. 2 hard capsules using a capsule filling machine (manufactured by Parke Davis).

Enteric coating liquid composition Eudragit L-30D 104.7 mg (solid component 31.4 mg) Talc 9,6 mg
Polyethylene glycol 6000 3.2mg Tween 80 1.6mg titanium oxide
4.2mg water
(220μQ) Composition of enteric granules Granules of Example 8 190mg total
Composition of 240mg capsule Enteric coated granules 240mg total
305mg Experimental Example 1 Granules were produced according to the method of Example 5 and heated at 50°C, 375%R.
Changes in appearance were observed after 1 week. However, products in which heavy magnesium carbonate was replaced with lactose or the following attachments were produced in the same manner and aged over time.

(See margins below) Table 1: No change in appearance + Yes + + Significant As a result, almost no change in appearance was observed in the samples to which the additives of the present invention were added.

Experimental Example 2 According to the method of Example 5, Compound ■ was replaced with Compound ■, Compound ■
Compound (1) Granules containing omebrazole and demoprazole were prepared, and changes in appearance were observed after one week at 50° C. and 175% RH. In addition, as a control, heavy magnesium carbonate was replaced with lactose, which was then manufactured and administered orally in the same manner.

(The following margins are blank) -, No change in appearance ++ ・〃 The above results showed that all of the compositions of the present invention, Compound (1), Omeprazole 2 Demoprazole, Compound (2), and Compound (2), were stable.

Experimental Example 3 In Examples 3 and 5, various basic Mg inorganic salts or Ca inorganic salts were used, or lactose was used as a lamp, and the preparations of Example and # were prepared and heated at 50°C 175 % fl l-I, change in appearance after storage for 1 week and 6 months at 40°C, and m content (residual q ratio) were measured (see margin below). As shown in Table 2 and above, the composition of the present invention showed There was no change, and it was clear that the content was stable.

In the present invention, a physically stable pharmaceutical composition can be obtained by blending a basic inorganic salt of magnesium and/or calcium with a penzimidazole compound.

Claims (2)

[Claims] (1) A pharmaceutical composition comprising a basic inorganic salt of magnesium and/or calcium mixed with 2-[(2-pyridyl)methylsulfinyl]benzimidazole or a derivative thereof having an anti-ulcer effect. (2) A stabilized pharmaceutical composition characterized by blending 2-[(2-pyridyl)methylsulfinyl]benzimidazole or its derivative, which has an anti-ulcer effect, with a basic inorganic salt of magnesium and/or calcium. How things are manufactured.