CA1338377C - Stabilized pharmaceutical composition and its production - Google Patents

Abstract

A stabilized pharmaceutical composition for the inhibition of gastric acid secretion, which comprises an effective amount of 2[(2-pyridyl)methylsulfinyl]benzimidazole derivative selected from the group consisting of 2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-benzimidazole, or a pharmaceutically acceptable salt thereof;
a basic inorganic salt stabilizing agent which is present in an amount effective to stabilize the composition; and an enteric coating for the composition, is physically stable.

Description

This application is a division of application Serial No. 529,605 filed February 12, 1987.
This invention relates to a pharmaceutical composition which comprises 2-[(2-pyridyl)methylsulphinyl]benzimidazole or a derivative thereof (hereinafter sometimes referred to collectively as "benzimidazole compounds"), particularly 2-[C3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl]-benzimidazole or 5-methoxy-2-[(4-methoxy-3,5-dimethyl)-2-pyridyl)-methylsulfinyl]benzimidazole or a pharmaceutically acceptable salt thereof. The composition is useful as an antiulcer agent.
The composition is stabilized by incorporation of an effective amount of a basic inorganic salt stabilizing agent, with basic inorganic salts of magnesium, calcium, potassium and sodium being useful, the magnesium, and calcium salts being preferred.
Certain benzimidazole compounds are recently under clinical study as gastric acid secretion inhibitors. They serve as therapeutic agents for digestive ulcer. Their principal pharmacological effect consists in gastric acid secretion suppression based on (H + K )-ATPase inhibition and is more potent and durable as compared with histamine H2 receptor antagonists such as cimetidine and ranitidine. They also have gastric mucosa protecting activity. Therefore, they have attracted attention as next-generation potent therapeutic agents for digestive ulcer.

Those benzimidazole compounds which are descri~ed in Japanese Unexamined ratent laid open Nos. 62275/77, 141783/79, 53406/82, 135881/83, 192880/83 and 181277/84, corresponding to U.S. Patent No. 4,045,563, U.S. Patent No.
4,255,431, European Patent Publication No. 45,200, U.S. ~atent No.
No. 4,472,409, European Patent Publication No. 5,129 and G.B. Patent Publication No. 2,134,523A, respectively, among others are known to have antiulcer activity.
These compounds, however, are poor in stability. In solid state, they are susceptible to heat, moisture and light and, in aqueous solution or suspension, their stabil-ity decreases with decreasing pH. In dosage forms, i.e.
tablets, powders, fine granules, granules and capsules, said compounds are apt to interact with other components contained in said dosage forms and accordingly are in less stable state as ~ompared with the case where they occur alone. Thus, the content decreases and the color changes significantly in the manufacturing process of dosage form and with the lapse of time. Microcrystalline cellulose, polyvinylpyrrolidone (PVP), carboxymethylcellulose calcium, polyethylene glycol 6000 and Pluronic F68 (polyoxyethylene-polyoxypropylene copolymer), for instance are dosage form components adversely affecting the stability of said com-pounds. Furthermore, in the case of coated tablets and S coated granules among the above dosage forms, enteric coat-ing bases such as cellulose acetate phthalate, hydroxy-propylmethylcellulose acetate succinate and Eudragit (meth-acrylic acid-acrylic acid copolymer) have poor compatibility with said compounds and cause content decrease and color change. Nevertheless, one or more of these components or ingredients, which, as mentioned above, can produce adverse effects on the stability of said compounds, are essential in the manufacture of oral preparations and therefore dif-ficulties are inevitably encountered in dosage form manu-facture.
The prior art avoids the above-mentioned stability problem by using said benzimidazole compounds in a salt form, say in the form of a lithium, sodium, potassium, magnesium, calcium or titanium salt [Japanese Unexamined Patent laid open No. 167587/84 (European Patent Publication No. 124,495A)]
However, the above prior art method requires, for the stabilization of the benzimidazole compounds, a step of converting said compounds to such a salt form as mentioned above in advance.

In view of the above, the present inventors made in-vestlgatlons ln an attempt to stablllze pharmaceutlcal preparatlons contalnlng benzlmldazole compounds and, as a result, have completed the present lnventlon.
Thus, the sub~ect matter of thls dlvlslonal appll-catlon relates to a stablllzed pharmaceutlcal composltlon for the lnhlbltlon of gastrlc acld secretlon, comprlslng:
an effectlve amount of a 2[(2-pyrldyl)methylsulflnyl]-benzlmldazole derlvatlve selected from the group conslstlng of 2-[[~-methyl-4-(2,2,2-trlfluoroethoxy)-2-pyrldyl]methylsulflnyl]benzlmldazole and 5-methoxy-2-[(4-methoxy-3,5-dlmethyl-2-pyrldyl)methylsulflnyl]benzlmldazole, or a pharmaceutlcally acceptable salt thereof;
a baslc lnorganlc salt stablllzlng agent whlch ls selected from the group conslstlng of potasslum, sodlum and alumlnum salts and whlch ls present ln an amount effectlve to stablllze the composltlon; and an enterlc coatlng for the composltlon.
It should be noted that the expresslon "thls lnventlon" or the llke ln thls speclflcatlon lncludes sub~ect matter of thls dlvlslonal appllcatlon as well as that of the parent appllcatlon and another dlvlslonal appllcatlon.
The benzlmldazole compounds havlng an antlulcer actlvlty used ln the lnventlon of thls dlvlslonal appllcatlon are those two speclflc compounds mentloned lmmedlately above.
They are lncluded among such compounds represented by the formula:

C

- 4a -~R~ CH2 ~ R (I) wherein Rl is hydrogen, alkyl, halogen, cyano, carboxy, carbo-alkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, - 5 - ~338377 hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl, R2 is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonyl-methyl, alkoxycarbonylmethyl or alkylsulfonyl, R3 and R5are the same or different and each is hydrogen, alkyl, alkoxy or alkoxyalkoxy,R4 is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy,and m is an integer of 0 through 4.
The compounds of the formula(I) can be produced by the methods described in the above-cited laid-open patent specifications or modifications thereof.
In the following, brief mention is made of the sub-stituents in those compounds which have the for-mula (I) and are already known.
Referring to Rl in the above formula, Cl 7 alkylsmay be mentioned as the alkyl represented by Rl; Cl 4 alkoxys as the alkoxy moiety of the carboalkoxy; Cl 4 alkoxys as the alkoxy moiety of the carboalkoxyalkyl and Cl 4 alkyls as the alkyl moiety; C1 4 alkyls as the alkyl moiety of the carbamoylalkyl; Cl 5 alkoxys as the alkoxy; Cl 7 alkyls as the alkyl moiety of the hydroxy-alkyl; Cl_4alkanoyls as the acyl; phenyl as the aryl; phenyl as the aryl moiety of the aryloxy; Cl 6 alkyls as the alkyl moiety of the alkylthio; and Cl 6 alkyls as the alkyl moiety of the alkylsulfinyl.
Referring to R2, Cl 5 alkyls may be mentioned as the alkyl represented by R2; Cl-4alkanoyls as the acyl;
Cl 4 alkoxys as the alkoxy moiety of the carboalkoxy;
Cl 4 alkyls as the alkyl moiety of the alkylcarbamoyl;
Cl 4 alkyls as each of the alkyl moieties of the dialkyl-carbamoyl; Cl 4 alkyis as the al~yl moiety of the alkyl-carbonylmethyl; Cl 4 alkoxys as the alkoxy moiety of the alkoxycarbonylmethyl; and C1 4 alkyls as the alkyl moiety of the alkylsulfonyl.
Referrring to R3, R4 and R5, Cl 4 alkyls may be men-tioned as the alkyl represented by any of them; Cl 8alkoxys as the alkoxy; and Cl 4 alkoxys as each of the alkoxy moieties of the alkoxyalkoxy.
Referring to R4, Cl 8 alkoxys may be mentioned as the alkoxy, which may optionally be fluorinated.
lS Among those compounds of the above forumula (I), (1) the compounds of which Rl is hydrogen, methoxy or trifluoromethyl, R2 is hydrogen, R3 and RS are the same or different and each is hydrogen or methyl, R4 is fluorinated C2_s alkoxy and m is 1, t2) the compounds of which Rl is hydrogen, fluorine, methoxy or trifluoro-methyl, R2 is hydrogen, R3 is hydrogen or methyl, R4 is C3-8 alkoxy, RS is hydrogen and m is 1, and (3) the compounds of ~7hich Ri is hydrogen, fluorine, methoxy or trifluoromethyl; R2 is hydrogen, R3 is Cl_g alkoxy, R4 is Cl 8 alkoxy wilich may be fluorinated, R5 is hydrogen and m is 1 are novel.
Detailed mention is now made of the substituents . ~ 7 24205-714D

in such novel compounds.
Referring to R3, the lower alkyl represented thereby is preferably Cl 8 lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyl-oxy, heptyloxy or octyloxy and more preferably Cl 4 loweralkoxy.
Referring to R4, C1 8 lower alkoxys may be mentioned as the lower alkoxy, which may optionally be fluorinated, and preferred examples are as mentioned above for R3. As the fluorinated lower alkoxy, there may be mentioned, for example, 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoro-propoxy, l-~trifluoromethyl)-2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,4,4,4-heptafluorobutoxy and 2,2,3,3,4,4,5,5-octafluoropentoxy, and fluorinated C2 4 lower alkoxys are preferred.
The position of Rl is position 4 or position 5, preferably position 5.
Some methods of producing the above novel compounds [hereinafter referred to as "compounds of formula (I')"]
are described below.
Said compounds can be produced by subjecting a com-pound of the formula . R~

(R~ 1 ~ N ~ S - C~z ~ ~) R' wherein Rl-R5 are as defined above, to oxidation.
The oxidizing agent to be used is, for example, meta-chloroperbenzoic acid, peracetic acid, trifluoroper-acetic acid, permaleic acid or the like peracid, sodium bromite or sodium hypochlorite. Examples of the solvent to be used in carrying out the reaction are halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as tetrahydrofuran and dioxane, amides such as di-methylformamide, and water. These solvents may be used either singly or in admixture. Said oxidizing agent is used preferably in an amount approximately equivalent or slightly excessive relative to the compound tII). Thus, said agent is used in an amount of about 1-3 equivalents, more preferably about l to 1.5 equivalents. The reaction is carried out at a temperature from about 0C (ice cool-ing) to around the boiling point of the solvent used, generally at a temperature from about 0C (ice cooling) to room temperature, preferably at a temperature of about 0C to 10C. The reaction time is generally about 0.1 to 24 hours, preferably about 0.1 to 4 hours.
The desired novel compounds (I') produced by the above reaction can be isolated and purified by conven-tional means such as recrystallization, chromatography and so on.
Said compounds may be converted to pharmacologically acceptable salts by conventional means. As such salts, there may be mentioned hydrochloride, hydrobromide, hydro-iodide, phosphate, nitrate, sulfate, acetate and citrate, 2~12U5- 71 ~LD
.

among others.
The novel compounds (II) can be produced by reacting a starting compound of the formula S ( )m (~XJLSH ( m ) wherein Rl and R2 are as defined above, with a starting compound of the formula R~

R 3~JR ~ ( ~r wherein R3-R5 are as defined above and X is a halogen atom.

The halogen atom represented by X is, for example, chlorine, bromine or iodine.

The reaction is carried out advantageously in the presence of a base. As said base, there may be mentioned alkali metal hydrides such as-sodium hydride and potassium hydride, alkali metals such as metallic sodium, sodium alcoholates such as sodium methoxide and sodium ethoxide, alkali metal carbonates such as potassium carbonate and sodium carbonate, and organic amines such as triethylamine, among others. As the solvent to be used in carrying out the reaction, there may be mentioned, for example, alcohols such as methanol and ethanol, and dimethylformamide. The -base is used generally in an amount slightly excessive relative to the equivalent amount but may also be used in large excess. Thus, it is used in an amount of about 2-10 equivalents, preferably about 2-4 equivalents. The above reaction is carried out generally at a temperature of about 0C to around the boiling point of the solvent used, preferably at about 20C to 80C, for a period of about 0.2-24 hours, preferably about 0.5-2 hours.
Some methods of producing the starting compounds (IV) are described below.
Among the compounds (IV), those compounds ~herein R3 and R5 are the same or different and each is hyd~gen or methyl and R4 is fluorinated C2 5 alkoxy or C3 8 alkoxy can be produced by the ollowing process:
Process 1) R3 ~ ~ Rs R4 OH ('.'1) R3 ~ ,R5 CH3 ~ CH3 O O

(V) (~) R3 ~ ~ Rs R3 ~ , (~) 2sCH3COCH2 ~' HOCH2 N
(~ ) (IX) A nitro compound of the formula (V), wherein R3 and RS are as defined above, is reacted with an alcohol de-rivative of the formula R OH (VI) wherein R is fluori-nated C2 5 alkyl or C3 8 alkyl, in the presence of a base to S give an alkoxy derivative of the formula (VII) wherein R3, R4 and R5 are as defined above. The base to be used in carrying out the reaction includes, among others, al-kali metals such as lithium, sodium and potassium, alka-li metal hydrides such as sodium hydride and potassium 1~ hydride, alcoholates such as potassium t-butoxide and sodium propoxide, alkali metal carbonates and hydrogen carbonates such as potassium carbonate, lithium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The alcohol derivative to be submitted to the reaction includes, among others, propanol, isopropanol, butanol, pentanol, hexanol, 2,2,2-trifluoroethanol, 2,2,3,3,3-pentafluoropropanol, 2,2,3,3-tetrafluoropropanol, 1-(trifluoromethyl)-2,2,2-trifluoroethanol, 2,2,3,3,4,4,4-heptafluorobutanol and 2,2,3,3,4,4,5,5-octafluoropentanol. While R4 OH itself may be used as a solvent in carrying out the reaction, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethyl-formamide and he~thylphosphoric acid triamide, for instance, may also be used as solvents. An appropriate reaction tem-1 33~3~

perature may be selected within the range of about 0C(ice cooling) to around the boiling point of the solvent used. The reaction time is about 1-48 hours.
Heating (about 80-120C) of the thus-obtained com-pound (VII) with acetic anhydride alone or in the presenceof an inorganic acid such as sulfuric acid or perchloric acid gives an 2-acetoxymethylpyridine derivative of the formula (VIII) wherein R3, R4 and R5 are as defined above. The reaction period is generally about 0.1-10 hours.
The subsequent alkaline hydrolysis of the compound (VIII) gives a 2-hydroxymethylpyridine derivative of the formula (IX). Sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate, for instance, are usable as alkalis, and methanol, ethanol and water, among others, are usable as solvents. The reaction is generally conducted at about 20-60C for about 0.1-2 hours.
The compound (IX) is further halogenated with a chlorinating agent such as thionyl chloride to give a 2-halomethylpyridine derivative of the formula (IV) wherein R3, R4 and R5 are as defined above and X is chlorine, bromine or iodine. Usable as solvents are, for example, chloroform, dichloromethane and tetrachloro-ethane. The reaction is generally carried out at about20-80C for about 0.1-2 hours.
The compound (IV) thus produced occurs in the form -13- . 1 338377 of a salt of hydrohalogenic acid corresponding to the halogenating agent used and it is generally preferable to subject said compound to reaction with the compound (III) immediately.
S Among the compounds (V), those compounds wherein R3 is Cl 8 lower aLkoxy, R4 is alkoxy which may optionally be fluorinated, and R5 is hydrogen can be produced by the following process:
Process 2) ~,,/1[' C H 3 ~/ ~ C H 3 ~N~ C H
(~c) (~) / (~) ~I
15 R~ / X
~, R ~/ R4~oH

(xm) ~ R~ (.~lV) ~R3 R4 Il CH3 ~' ~,R3 ( X V ) N CH 20COCH3 R ~

~N ~ CH OH
(X ~ ) Thus, maltol (X) is reacted with a alkyl halide of the formula R X in the presence of silver oxide, for instance, to give a compound of the formula (XI). Reaction of (XI) with aqueous ammonia gives a pyridone derivative of ~e fonm~a (XII). Direct alkylation of the compound (XII) with an alkyl halide, or halogenation of (XII) with a halogenating agent such as phosphorus oxychloride follow-ed by reaction of the resultant halo derivative (XIV) with a lower alcohol of the formula R4 OH in the presence of a base gives a compound of the formula (XIII). The com-pound (XIII) can be converted to the compound (IV) by direct halogenation with N-bromosuccinimide or chlorine, for instance. The compound (XIII) may also be converted to the compound (IV) by oxidizing the same with an oxi-dizing agent such as m-chloroperbenzoic acid, reacting the resulting compound (XV) with acetic anhydride, hydro-lyzing the resulting comppund (XVI) and halogenating the resulting compound (XVII) with a halogenating agent such as thionyl chloride.
The alkyl halide to be used in the production of the compound (XI) includes, among others, methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, pentyl iodide and hexyl iodide, and the alkyl halide to be used in the production of the compound (XIII) further includes, in addition to those mentioned above for use in the production of the compounds (XI), 2,2,2-trifluoroethyl iodide, 2,2,3,3,3-pentafluoropropyl iodide, 2,2,3,3-tetrafluoropropyl iodide, l-(trifluoro-methyl)-2,2,2-trifluoroethyl iodide, 2,2,3,3,4,4,4-hepta-fluorobutyl iodide and 2,2,3,3,4,4,5,5-octafluoropentyl iodide, for instance. Such alkyl iodides are used in an amount of about 1-10 equivalents. Silver oxide, potas-sium carbonate, sodium carbonate or the like is used as a deacidifying agent and dimethylformamide, dimethylacet-amide or the like is used as a solvent. The reaction is generally carried out at room temperature.
The halogenating agent to be used in the production of the compound (XIV) includes, among others, phosphorus oxychloride, phosphorus pentoxide and phosphorus tribro-mide and is used in an amount of 1 equivalent to a large excess. The reaction is carried out at a temperature of about 50-150C. The alcohol to be used for the conver-sion of compound (XIV) to compound (XIII) includes metha-nol and ethanol and further those alcohol derivaitves mentioned for use in process 1) and is used in an amount of 1 equivalent to a large excess, and the base includes those sodium alcoholates and potassium alcoholates which correspong to the respective alcohols as well as potas-sium t-butoxide, sodium hydride and so forth. An appro-priate reaction temperature may be selected within the range of room temperature to the boiling point of the solvent used.
For direct bromination of the compound (XIII) with N-bromosuccinimide, the reaction is preferably carried out under light irradiation, and carbon tetrachloride, chloroform, tetrachloroethane or the like is used as a solvent.
The oxidizing agent to be used for the conversion of compound (XIII) to compound (XV) includes, among others, peracids such as meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid and permaleic acid as well as hydrogen peroxide. Usable as solvents for the reaction are halogenated hydrocarbons such as chloroform and di-chloromethane, ethers such as tetrahydrofuran and dioxane,amides such as dimethylformamide, acetic acid and water, for instance,.and these can be used either singly or in admixture. Said oxidizing agent is preferably used in an amount of about 1 equivalent to an excess relative to the compound (XIII), more preferably about 1-10 equivalents.
The reaction is carried out at a temperature of about 0C
(ice cooling) to around the boiling point of the solvent used generally for a period of about 0.1-24 hours, prefer-ably for about 0.1-4 hours.
The conversion of compound (XV) to compound (XVI) is effected by heating (at about 80-120C) the compound (XV) with acetic anhydride alone or in the presence of an in-organic acid such as sulfuric acid ~r perchloric acid and so on.
The reaction period is generally 0.1-10 hours.
The alkali to be used in the alkaline hydrolysis of compound (XVI) to compound (XVII) includes, among others, sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate. Methanol, ethanol and water, for instance, may be mentioned as usable solvents. The re-action is generally carried out at a temperature of about 20-60C for a period of about 0.1-2 hours.
For the production of compound (IV) from compound ~XVII), a chlorinating agent such as thionyl chloride or an organic sulfonic or organic phosphoric acid chloride such as methanesulfonyl chloride, p-toluenesulfonyl chloride or diphenylphosphoryl chloride is used. When a chlorinating agent such as thionyl chloride is used, it is used in an amount of 1 equivalent to a large excess relative to the compound (XVII) and a solvent such as chloroform, dichloromethane or tetrachloroethane is used, and the reaction is generally carried out at a temperature lS Of about 20-80C for a period of about 0.1-2 hours. When an organic sulfonic or organic phosphoric acid chloride is used, it is used in an amount of 1 equivalent to a slight excess relative to the compound (XVII) and the re-action is generally carried out in the presence of a base.
As usable bases, there may be mentioned organic bases such as triethylamine and tributylamine and inorganic bases such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate. The base is used in an amount of 1 equivalent to a slight excess. As usable solvents, there may be mentioned, for example, chloroform, dichloro-methane, carbon tetrachloride and acetonitrile. An appro-priate reaction temperature and an appropriate reaction can be selected within the ranges of about 0C (ice cooling) to around the boiling point and several minutes to several hours, respectively.
The above-mentioned novel benzimidazole compounds have excellent gastric antisecretory activity, gastric mucosa-protecting activity and antiulcer activity but have low toxicity, so that they can be used in the treatment of digestive ulcers in mammals (e.g. mouse, rat, rabbit, dog, cat, human).
The basic inorganic stabilizing agents which are to be used in accordance with the invention, are now described.
Especially useful basic inorganic salt stabilizing agents are basic inorganic salts of magnesium and calcium.
Those basic inorganic magnesium compounds include, among others, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6A12(OH)16 CO3 4H2O] and aluminum magnesium hydroxide [2.5MgO A12O3-xH2O] and those basic inorganic calcium compounds include among others, (precipitated) calcium carbonate and calcium hydroxide. Other baslc inorganic salts useful as stabilizing agents include sodium and potassium salts such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, as well as alnm;nllm basic salts such as aluminum silicate. It is only required of such basic inorganic salts to show basicity (pH of not less than 7) when they are in the form of a 1% aqueous solution or suspension.
Those basic inorganic compounds may be used either singly or in combination of two or more species in an amount which may vary depending on the kinds thereof but generally lies within the range of about 0.3-20 parts by weight, preferably about 0.6-7 parts by weight, per part by~weight of the benzimidazole compounds.
The composition of the invention may further contain such additives as vehicles (e.g. lactose, corn starch, light silicic anhydride, microcrystalline cellulose, sucrose), binders (e.g. ~-form starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl-pyrrolidone), disintegrating agents (e.g. carboxymethylcellulose calcium, starch, low substituted hydroxypropylcellulose), surfactants [e.g. Tween 80 (Kao-Atlas: polyoxyethylene sorbitan *

fatty acid ester), Pluronic F68 (Asahi Denka: polyoxyethylene-polyoxypropylene block copolymer], antioxidants (e.g. L-cysteine, sodium sulfite, sodium ascorbate), lubricants (e.g. magnesium stearate, talc), etc.
The composition of the invention is prepared by homo-geneously admixing the above benzimidazole compound, the basic inorganic stabilizing agent, and the above additives.
The particle sizes of the benzimidazole compound and the inorganic compound are not especially critical in a condition that they can be homogeneously admixed. For example, preferable particle size is about less than 100 ~m, more preferable one is about less than 20 ~m.
The moisture amount in the composition is preferably about 6 - 60%, more preferably about 20 - 40% as equilibrium Trade-mark ~~ - 20 -relative humidity (E.R.H.).
The method of admixing is not critical as far as the benzimidazole compound can finally be made in even contact with the basic inorganic stabilizing agent. Thus, for example, the additives may be admixed with a mixture of the benzimidazole compound and the basic inorganic stabilizing agent as prepared by preliminary admixing, or the basic inorganic stabilizing agent may be added to a mixture of the benzimidazole compound and the additives as prepared by preliminary admixing.
The mixture can be made up into dosage forms suited for oral administration, such as tablets, capsules, powders, granules and fine granules, by per se known means.
Tablets, granules and fine granules are then coated by a E~ se known method for the purpose of providing enteric property, optionally as well as for the purpose of masking the taste or providing sustained release property. Usable as coating agents are, for example, hydroxypropylmethylcellulose, ethyl-cellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, polyoxyethylene sorbitan fatty acid ester (e.g. Tween 80), polyoxyethylene-polyoxypropylene block copolymer (e.g. Pluronic F68), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate and methacrylic acid-acrylic acid copolymer (e.g. Eudragit (Rohm, West Germany)). Pigments such as titanium oxide and ferric oxide may be employed together.

Trade-mark Tablets, granules, powders, fine granules and capsules can be produced by a conventional method (e.g. the method described in the 10th edition of the Japanese Pharmacopeia under General Rules for Preparations). Thus, for example, tablets are produced by adding the basic inorganic stabilizing agent-to a mixture of the benz;imidazole compound, vehicle and disintegrant, mixing, adding a binder, granulating the mixture, adding a lubricant etc. and tableting the resultant granular composition. Granules are produced by extrusion in approximately the same manner as in the production of tablets or by coating nonpareils, which contain sucrose and corn starch, with a mixture of benzimidazole compound, a basic inorganic stabilizing agent, and additives (e.g. sucrose, corn starch~, crystalline, cellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, polyvinylpyrrolidone).

_ 22 ~ 1 338377 Capsules are produced by mere mixing and filling. The dosage forms thus obtained show excellent stability with slight changes in appearance and little decreases in con-tent even after storage for a long period of time.
The pharmaceutical composition of the pres-ent invention as obtained in the above manner exhibits excellent gastric antisecretory, gastric mucosa-protecting and antiulcer activities and has low toxicity and there-fore can be used in the treatment of digestive ulcers in mammals te.g. mouse, rat, rabbit, dog, cat, pig, human).
The pharmaceutical composition of the in-vention can be orally administered for the treatment of digestive ulcers in mammals in admixture with pharma-cologically acceptable carriers, vehicles, diluents andso forth and in the form of capsules, tablets, granules and some other dosage forms, as mentioned hereinabove.
The dose as the benzimidazole compound lies within the range of about 0.01 mg to 30 mg/kg/day, preferably about 0.1 mg to 3 mg/kg/day.

The following reference examples and working examples as well as the experimental examples described later herein illus-trate the present invention in more detail but are by no 25 means limitative of the present invention.
Reference Example 1 A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 gl, methyl ethyl ketone (30 ml), 2,2,3,3,3-penta-fluoropropanol (3.05 ml), anhydrous potassium carbonate (3.~9 g) and he ~ ethylphosplloric acid ~iamide (2.07 g) was hea~d at 70-80C with stirring for 4.5 days. Then, the insol-uble matter was filtered off and the filtrate was concen-trated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract layer was dried over magnesium sulfate, then the solvent was distil-led off, and the residue was applied to a silica gel col-umn (50 g). Elution with chloroform-methanol (10:1) and recrystallization from ethyl acetate-hexane gave 2.4 g of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as colorless needles. Melting point 148-149~C.
The following compounds (VII) were produced from the corresponding compounds (V) in the same manner as above.
Compounds (VII) R3 R5 R4 Melting point (C) CH3 H OCH2CF3 131.0-131.5 20 Note 1) H H OCH2CH2CH3 Oil Note 2) CH3 H OCH2CH2CH3 Oil Note 1): NMR spectrum (CDC13) ~: 1.01 (3H, t, J =
7 Hz), 1.81 (2H, m), 2.50 (3H, s), 3.93 (2H, t, J = 7 Hz), 6.50-6.80 (2H, m), 8.10 (lH, d, J = 7 Hz) Note 2): NMR spectrum (CDC13) ~: 1.07 (3H, t, J =
7.5 Hz), 1.65-2.02 (2H, m), 2.21 (3H, s), 2.52 (3H, s), 3.99 (2H, t, J = 6 Hz), 6.68 (lH, d, J =

6 Hz), 8.15 (lH, d, J = 6 Hz) Reference Example 2 Concentrated sulfuric acid (2 drops) was added to a solution of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine-l-oxide (2.5 g) in acetic anhydride (8 ml) and the mixture was stirred at 110C for 2 hours and then con-centrated. The residue was dissolved in methanol (30 ml), 2 N aqueous sodium hydroxide (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. After concentration, water was added to the residue and the mix-ture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was then distil-led off, and the residue was applied to a silica gel (50 g) column. Elution with chloroform-methanol (10:1) and re-crystallization from isopropyl ether gave 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine as a brown oil.
NMR spectrum (CDCl3) o: 2.07 (3H, s), 4.28 (lH, brs), 4.49 (2H, t, J = 12 Hz), 4.67 (2H, s), 6.69 (lH, d, J = 5 Hz), 8.34 (lH, d, J = 5 Hz) The following compounds (IX) were produced from the corresponding compounds (VII) in the same manner as men-tioned a~ove.
Compounds (IX) R3 R5 R4 Melting point (C) CH3 H OCH2CF3 93.5-94.0 Note 1) H H OCH2CH2CH3 Oil Note 2) CH3 H OCH2CH2CH3 Oil Note 1) NMR spectrum (CDC13) ~: 1.0 (3H, t, J = 7.5 Hz), 1.79 (2H, m), 3.92 (2H, t, J = 6 Hz), 4.51-4.90 (lH, br), 4.68 (2H, s), 6.68 (lH, dd, J = 2 and 6 Hz), 6.80 (lH, d, J = 2 Hz), 8.28 (lH, d, J = 6 Hz) Note 2) NMR spectrum (CDC13) ~: 1.03 (3H, t, J = 7.5 Hz), 1.82 (2H, m), 2.02 (3H, s), 3.95 (2H, t, J =
6 Hz), 4.62 (2H, s), 5.20 (lH, brd, s), 6.68 (lH, d, J = 6 Hz), 8.25 (lH, d, J = 6 Hz) Reference Example 3 Thionyl chloride (0.2 ml) was added to a solution of 2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine (350 mg) in chloroform (10 ml) and the mixture was refluxed for 30 minutes and then concentrated. The residue was dissolved in methanol (5 ml) and the solution was added to a mixture of 2-mercaptobenzimidazole (200 mg), 28% sodium methoxide solution (1 ml) and methanol (6 ml).
The resultant mixture was refluxed for 30 minutes. The methanol was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with dilute sodium hydroxide solution and dried over magnesium sulfate. The solvent was then distilled off, and the residue was applied to a silica gel (20 g) column. Elution with ethyl acetate-hexane (2:1) and recrystallization from ethyl acetate-hexane gave 370 mg of 2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl~--methylthio]benzimidazole hemihydrate as colorless plates. Melting point 145-146C.
The following compounds (II~ were produced by react-ing the compound (III) with the corresponding compound (IV) in the same manner as mentioned above.
Compounds (II) Rl R2 R4 Melting point (C) Note) H H CH3 H OCH2CH2CH3 Oil Note) NMR spectrum (CDC13) o: 0.98 (3H, t, J = 7.5 Hz), 1.54-1.92 (2H, m), 2.15 (3H, s), 3.80 (2H, t, J = 6 Hz), 4.43 (2H, s), 6.55 (lH, d, J = 6 15 Hz), 7.09 (2H, m), 7.50 (2H, m), 8.21 (lH, d, J =
6 Hz) Reference Example 4 A solution of m-chloroperbenzoic acid (1.3 g) in chloroform (15 ml) was added dropwise to a solution of 2-[[3-methyl-4-(2~2~3~3~3-pentafuloropropoxy)-2-pyridyl~-methylthio]benzimidazole(2.2 g) in chloroform (20 ml) with ice cooling over 30 minutes and, then, the reaction mix-ture was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and con-centrated. The concentrate was applied to a silica gel (50 g) column. Elution with ethyl acetate and recrystal-lization from acetone-isopropyl ether gave 1.78 g of 2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methyl-sulfinyl]benzimidazole [hereinafter sometimes referred to as compound (A)] as pale yellow prisms. Melting point 161-163C (decomposition).
The following compounds (I) [hereinafter sometimes referred to as compound (B), compound (C) and compound (D), respectively] were produced in the same manner from the corresponding compounds (II).
Compounds (I) Rl R2 R3 R5 R4 Melting point (C) (B) H H CH3 H OCH2CF3 178-182 (decomp.) (C) H H H H OCH2CH2CH3 123-125 (decomp.) (D) H H CH3 H OCH2CH2CH3 81-83 15 - Example 1 Of the components given below, the compound (A), magnesium hydroxide, L-cysteine, corn starch and lactose were mixed together, then microcrystalline cellulose, light silicic anhydride and magnesium stearate, each in half the intended amount, were added. After sufficient admixing, the mixture was compression-molded on a dry granulator (roller compactor; Freund, Japan. The compressed mass was ground in a mortar, the resultant granular mass was passed through a round sieve (16 mesh). The remain-ing portions of microcrystalline cellulose, light silicicanhydride and magnesium stearate were added to the sieved mass and, after admixing, the whole mixture was made up into tablets each weighing 250 mg on a rotary tableting machine (Kikusui Seisakusho, Japan).
Composition per tablet:
Compound (A) 50 mg Magnesium hydroxide 30 mg L-Cysteine 20 mg Corn starch 20 mg Lactose 65.2 mg Microcrystalline cellulose 60 mg Light silicic anhydride 1.8 mg Magnesium stearate 3.0 mg Total 250.0 mg Example 2 Tablets were produced in the same manner as in Ex-ample l except that omeprazole (Note) was used instead of the compound (A).
Note: 5-Methoxy-2-[(4-methqxy-3/5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole Example 3 Of the components given below, the compound (B), precipitated calcium carbonate, corn starch, lactose and hydroxypropylcellulose were mixed together, water was added, and the mixture was kneaded, then dried in vacuum at 40C for 16 hours, ground in a mortar and passed through a 16-mesh sieve to give granules. To this was added magnesium stearate and the resultant mixture was made up into tablets each weighing 200 mg on a rotary tableting machine (Kikusui Seisakusho,Japan).

- 29 - l 338377 Composition per tablet:
Compound (B) 30 mg Precipitated calcium carbonate 50 mg Corn starch 40 mg Lactose 73.4 mg Hydroxypropylcellulose 6 mg Magnesium stearate 0.6 mg Water (0.05 ml) Total 200.0 mg Example 4 Tablets were produced in the same manner as in Ex-ample 3 except that timoprazole (Note) was used instead of the compound (B).
Note: 2-[(2-Pyridyl)methylsulfinyl]benzimidazole Example 5 The ingredients given below were mixed well in the porportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui SeisaKusho;screen size l.0 mm ~). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder~s Marumerizer, Japan; l,000 rpm). The spherical granules were then dried under vacuum at 40C for 16 hours and passed through round sieves to give 12- to 42-mesh granules.
Composition per 200 mg of granules Compound (~) 30 mg Heavy magnesium carbonate 20 mg - 30 ~ 1 338377 Corn starch 80 mg Microcrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg Example 6 Granules were produced in the same manner as in Example 5 except that the compound (D) was used instead of the compound (B).
Example 7 Enteric granules were produced by coating the gran-ules obtained in Example 3 with an enteric coating com-position specified below using a fluidized bed granulator (Okawara, Japan) under conditions such that the inlet air temperature was 50C and the granule temperature was 40C.
No. 1 hard capsules were filled with the enteric granules thus obtained in an amount of 260 mg per capsule using a capsule filling machine (Parke-Davis, U.S.A.).
Enteric coating composition:
Eudragit L-30D 138 mg (solids 41.4 mg) Talc 4.1 mg Polyethylene glycol 6000 12.4 mg Tween 80 2.1 mg Water 276 ~1 Composition of enteric granules:
Granules of Example 5 200 mg Enteric coat 60 mg Total 260 mg 5 Composition per capsule:
Enteric granules 260 mg No. 1 hard capsule 76 mg Total 336 mg Example 8 Of the components given below, the compound (B), magunesium carbonate, socrose, corn starch and crystalline cellulose were thoroughly mixed together to obtain dusting powder.
Nonpareils were put on a centrifugal fluidized coating-granulatar (CF-360 Freund, Japan) and then coated with the dusting powder as described above, while spraying hydroxypropylcellulose solution [4% (w/w)], to give spherical granules. The spherical granules were dried in vacuum at 40C for 16 hours and then passed through round sieves to give 12 to 32-mesh granules.
Composition per 190 mg of granules:
Nonpareil 75 mg Compound (B) 15 mg Magnesium carbonate 15 mg Sucrose 29 mg Corn starch 27 mg Crystalline cellulose27 mg - 32 _ 1 338377 Hydroxypropylcellulose 2 mg [Hydroxypropoxy group content: 53.4-77.5%]
Water (0.05 ml) Total 190 mg Example 9 Enteric granules were produced by coating the granules obtained in Example 8 with an enteric coatig composition specified below usig a fluidized bed granulator (Okawara, Japan) under conditions such that inlet air temperature was 50C and the granule temperature was 40C. No. 2 hard capsules were filled with the enteric granules thus obtained in an amount of 240mg per capsule using a capsule filling machine (Parke-Davis, USA).
Enteric coating composition:
Eudragit L-30D 104.7 mg (solids 31.4 mg) Talc 9.6 mg Polyethylene glycol 6000 3.2 mg Tween 80 1.6 mg Titanium oxide 4.2 mg Water (220 ~1) Composition of enteric granules:
Granules of Example 8190 mg Enteric coat 50 mg Total 240 mg Composition per capsule;
Enteric granules240 mg No. 2 hard capsule65 mg Total 305 m~

~ 24205-714D

Experimental Example 1 Granules were produced by the method of Example 5 and, after storage at 50C and 75% RH for 1 week, were observed for changes in appearance. Granules were also produced in the same manner except that lactose was used instead of heavy magnesium carbonate or that one of other additives specificed below in Table 1.
Table 1 Changes in apperance Additive after 1 week at 50C
and 75% RH

Heavy magnesium carbonate Magnesium oxide Magnesium metasilicate aluminate Synthetic hydrotalcite Aluminum magnesium hydroxide Magnesium silicate Precipitated calcium carbonate ~ . 24205-714D

Magnesium hydroxide Sodium carbonate + (to yellow) Potassium carbonate + (to yellow) Sodium hydrogen carbonate+ (to yellow) Magnesium chloride ++ (to violet) Magnesium sulfate ++ (to violet) Calcium chloride ++ (to violet) Aluminum silicate + (to violet) No additive (lactose) ++ (to violet) Notes: - : No changes in + : Moderately ++ : Severely As a result, no substantial changes in appearance were noted for the compositions supplemented with the additives of the invention.
Experimental Example 2 Granules were produced in the same manner as in Example 5 except that the compound (A), the compound (C), the com-pound (D), omeprazole or timoprazole was used instead ofthe compound (B). After storage at 50C and 75% RH for 1 week, they were observed for changes in appearance. As a control to each composition, granules were also produced in the same manner except that lactose was used instead of heavy magnesium carbonate and stored under the same condi-tions.

_ 35 _ 1 3 3 8 3 7 7 Changes in appear-Compound Additive ance after 1 week at 50C and 75% RH

Compound (A) Invention: Heavy magnesium carbonate Control: Lactose ++

Omeprazole Invention: Heavy magnesium carbonate Control: Lactose ++

Timoprazole Invention: Heavy magnesium carbonate Control: Lactose ++

Compound (C) Invention: Heavy magnesium carbonate Control: Lactose ++

Compound (D) Invention: Heavy magnesium carbonate Control: Lactose ++

Notes: - : No changes ++ : Severely As is evident from the above results, the pharma-ceutical compositions of the invention were all stable whether the active ingredient was the compound (A), omeprazole, timoprazole, the compound (C) or the compound (D).
Experimental Example 3 Pharmaceutical compositions were produced in the same manner as in Examples 3 and 5 except that different basic inorganic Mg or Ca salts were used or that lactose was used as a cont~l, and Example 6. After strage at 50C and 75% RH for 1 week or at 40C for 6 months, the compositions were observed for changes in appearance and for active in-gredient content (residual percentage).

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The above results clearly indicate that the composi-tions of the invention show no changes in appear-ance at all and are stable in terms of the active ingredi-ent content.

Claims (10)

1. A stabilized pharmaceutical composition for the inhibition of gastric acid secretion, comprising:
an effective amount of 2-[(2-pyridyl)methylsulfinyl]-benzimidazole derivative selected from the group consisting of

2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methylsulfinyl]benzimidazole, or a pharmaceutically acceptable salt thereof;
a basic inorganic salt stabilizing agent which is selected from the group consisting of potassium, sodium and aluminum salts and which is present in an amount effective to stabilize the composition; and an enteric coating for the composition.

2. A composition as claimed in claim 1, wherein the basic inorganic salt stabilizing salt is a basic inorganic salt of potassium which is effective to stabilize the composition.

3. Composition as claimed in claim 2, wherein the basic inorganic salt of potassium is potassium carbonate.

4. A composition as claimed in claim 1, wherein the basic inorganic salt stabilizing salt is a basic inorganic salt of sodium which is effective to stabilize the composition.

5. A composition as claimed in claim 4, wherein the basic inorganic salt of sodium is a member selected from the group consisting of sodium carbonate and sodium hydrogen carbonate.

6. A composition as claimed in any one of claims 1 to 5, wherein the amount of the basic inorganic salt stabilizing salt is 0.3 to 20 parts by weight per part of the 2-[(2-pyridyl)-methylsulfinyl]benzimidazole compound or its pharmaceutically acceptable salt.

7. A composition as claimed in claim 6, which further comprises a pharmaceutically acceptable carrier.

8. A composition as claimed in claim 7, which comprises, as the carrier, at least one member selected from the group consisting of a vehicle, a binder, a disintegrating agent, a surfactant, an antioxidant and a lubricant.

9. A composition as claimed in any one of claims 1 to 5, which comprises a plurality of enteric coated granules, each of the granules containing therein the 2-[(2-pyridyl)-methylsulfinyl]benzimidazole compound or its pharmaceutically acceptable salt and the basic inorganic salt stabilizing agent.

10. A composition as claimed in any one of claims 1 to 5, which has a moisture content of 6-60% as equilibrium relative humidity.