Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-18
1996-12-31
Spivack, Phyllis
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3144, A61K 31415
Patent
active
055894917
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP 93/00998 filed Jul. 15, 1993.
FIELD OF THE INVENTION
The present invention relates to an injection of a 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or a salt thereof having antiulcer activity, particularly sodium salt of omeprazole and to an injection kit thereof, which are used in clinical fields.
BACKGROUND OF THE INVENTION
The 2-[(2-pyridyl)methylsulfinyl]benzimidazole compounds such as omeprazole or lansoprazole are potent antiulcer agents, and are used as pharmaceutical compositions for oral administration. Further, the injections thereof have recently been developed.
As an injection of omeprazole, there has been known an injection prepared by dissolving sodium salt of omeprazole in sterilized water, filtering and lyophilizing the solution to give a lyophilized product, and then dissolving the lyophilized product in a mixture of polyethylene glycol 400 for injection, sodium dihydrogenphosphate and sterilized water (Japanese Patent Unexamined Publication No. 167587/1984).
Also, an injection prepared by dissolving a lyophilized product of an alkaline aqueous solution of a 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound having antiulcer activity such as lansoprazole in a mixture of (a) acid, and (b) at least one of ethanol, propylene glycol and polyethylene glycol (Japanese Patent Unexamined Publication No. 138213/1990).
In general, the pH of injection is preferably about 4-8, and a pH above 9 has a probability of causing hemolysis and local irritation.
In the case of the 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or a salt which may be hereinafter referred to as "benzimidazole compound or salt thereof" represented by sodium salt of omepazole, it shows a solubility of the level permitting formulation of the preparation, in water in an alkaline range of pH 9.5 or above, whereas it shows extremely low solubility in water at a pH of not more than 9, thus rendering formulation of the preparation very difficult.
While the benzimidazole compound or salt thereof is stable in the alkaline range, it poses a problem in that its stability decreases with the low ph values.
For this reason, the method employed in conventional injections of benzimidazole compound or salt thereof such as sodium salt of omeprazole has been to add an acid such as hydrochloric acid or sodium dihydrogenphosphate to the solution to keep the pH from neutral to weak basic, and to further add a nonaqueous solvent such as polyethylene glycol, ethanol or propylene glycol in order to obtain a certain level of solubility in such pH range.
Yet, these injections pose problems of local irritation and hemolysis caused by the nonaqueous solvent added to the solution for dissolution.
Accordingly, an object of the invention is to provide an injection of a benzimidazole compound or a salt thereof, particularly sodium salt of omeprazole causing less side-effects such as hemolysis, and less local irritation, which salt permits easy formulation.
SUMMARY OF THE INVENTION
As a result of the intensive study conducted by the inventors with the aim of achieving the aforementioned object, it has now been found that a product obtained by lyophilizing an alkaline aqueous solution of benzimidazole compound or salt thereof, and dissolving same in an aqueous solvent being devoid of nonaqueous solvent scarcely shows hemolytic property and local irritation, notwithstanding the high pH of from 9.5 to 11.5.
Accordingly, the present invention is: compound or a salt thereof having antiulcer activity and an aqueous solvent devoid of nonaqueous solvent, which has a pH of not less than 9.5 and not more than 11.5, (b) are adjusted such that the pH upon dissolution of (a) in (b) is not less than 9.5 and not more than 11.5; 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or a salt thereof having antiulcer activity
DETAILED DESCRIPTION
The 2-[(2-pyridyl)methylsulfinyl]benzimidazole compounds having antiulcer activity which are the element constituting the present invention include, for example, the compounds d
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patent: 4472409 (1984-09-01), Senn-Bilfinger
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patent: 4689333 (1987-08-01), Nohara et al.
patent: 4738974 (1988-04-01), Br andstr om
Higo Takashi
Nakanishi Shigeo
Shibata Toshiyuki
Tominaga Tetsuo
Yamanaka Iwao
Astra Aktiebolag
Spivack Phyllis
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