Stabilized pharmaceutical composition

Details Stabilized pharmaceutical composition Stabilized pharmaceutical composition

2002-12-31

2004-06-15

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S495000, C424S683000, C424S686000, C424S692000, C514S394000, C514S395000, C514S951000

Reexamination Certificate

active

06749864

ABSTRACT:

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 the derivatives 2-[[3-methyl-4-(2,2,2-trifluoromethoxy)-2-pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole, or a pharmaceutically acceptable salt thereof, which 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 can 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 H
2
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 described in Japanese Unexamined Patent laid open Nos. 62275/77, 141783/79, 33406/82, 135881/83, 192880/83 and 181277/84, corresponding to U.S. Pat. No. 4,045,563, U.S. Pat. No. 4,275,431, European Patent Publication No. 45,200, U.S. Pat. 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 stability 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 compared 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 compounds. Furthermore, in the case of coated tablets and coated granules among the above dosage forms, enteric coating bases such as cellulose acetate phthalate, hydroxy-propylmethylcellulose acetate succinate and Eudragit (methacrylic 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 difficulties are inevitably encountered in dosage form manufacture.
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 investigations in an attempt to stabilize pharmaceutical preparations containing benzimidazole compounds and, as a result, have completed the present invention.
Thus, this invention relates to
(1) A pharmaceutical composition which comprises 2-[(2-pyridyl)methylsulfinyl]benzimidazole or a derivative thereof, which has an antiulcer activity, and a basic inorganic salt of magnesium and/or a basic inorganic salt of calcium, and
(2) A method of producing a stabilized pharmaceutical composition which comprises incorporating a basic inorganic salt of magnesium and/or a basic inorganic salt of calcium in a pharmaceutical composition containing 2-[(2-pyridyl-methylsulfinyl]benzimidazole or a derivative thereof, which has an antiulcer activity.
The benzimidazole compounds having an antiulcer activity which are to be used in the practice of the invention are those compounds which are described in the above-cited laid-open patent specifications, for instance and are represented by the formula
wherein R
1
is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl, R
2
is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl, R
3
and R
5
are the same or different and each is hydrogen, alkyl, alkoxy or alkoxyalkoxy, R
4
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 substituents in those compounds which have the formula (I) and are already known.
Referring to R
1
in the above formula, C
1-7
alkyls may be mentioned as the alkyl represented by R
1
; C
1-4
alkoxys as the alkoxy moiety of the carboalkoxy; C
1-4
alkoxys as the alkoxy moiety of the carboalkoxyalkyl and C
1-4
alkyls as the alkyl moiety; C
1-4
alkyls as the alkyl moiety of the carbamoylalkyl; C
1-5
alkoxys as the alkoxy; C
1-7
alkyls as the alkyl moiety of the hydroxyalkyl; C
1-4
alkanoyls as the acyl; phenyl as the aryl; phenyl as the aryl moiety of the aryloxy; C
1-6
alkyls as the alkyl moiety of the alkylthio; and C
1-6
alkyls as the alkyl moiety of the alkylsulfinyl.
Referring to R
2
, C
1-5
alkyls may be mentioned as the alkyl represented by R
2
; C
1-4
alkanoyls as the acyl; C
1-4
alkoxys as the alkoxy moiety of the carboalkoxy; C
1-4
alkyls as the alkyl moiety of the alkylcarbamoyl; C
1-4
alkyls as each of the alkyl moieties of the dialkylcarbamoyl; C
1-4
alkyls as the alkyl moiety of the alkylcarbonylmethyl; C
1-4
alkoxys as the alkoxy moiety of the alkoxycarbonylmethyl; and C
1-4
alkyls as the alkyl moiety of the alkylsulfonyl.
Referrring to R
3
, R
4
and R
5
, C
1-4
alkyls may be mentioned as the alkyl represented by any of them; C
1-8
alkoxys as the alkoxy; and C
1-4
alkoxys as each of the alkoxy moieties of the alkoxyalkoxy.
Referring to R
4
, C
1-8
alkoxys may be mentioned as the alkoxy, which may optionally be fluorinated.
Among those compounds of the above formula (I), (1) the compounds of which R
1
is hydrogen, methoxy or trifluoromethyl, R
2
is hydrogen, R
3
and R
5
are the same or different and each is hydrogen or methyl, R
4
is fluorinated C
2-5
alkoxy and m is 1, (2) the compounds of which R
1
is hydrogen, fluorine, methoxy or trifluoromethyl, R
2
is hydrogen, R
3
is hydrogen or methyl, R
4
is C
3-8
alkoxy, R
5
is hydrogen and m is 1, and (3) the compounds of which R
1
is hydrogen, fluorine, methoxy or trifluoromethyl. R
2
is hydrogen, R
3
is C
1-8
alkoxy, R
4
is C
1-8
alkoxy which may be fluorinated, R
5
is hydrogen and m is 1.
Detailed mention is now made of the substituents in such novel compounds.
Referring to R
3
, the lower alkyl represented thereby is preferably C
1-8
lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy and more preferably C
1-4
lower alkoxy.
Referring to R
4
, C
1-8
lower alkoxy

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