JPH0692853A - Parenteral injection and kit therefor - Google Patents

Abstract

PURPOSE:To obtain a parenteral injection of a benzimidazole-based compound or its salt, capable of being readily formulated into a pharmaceutical preparation, reduced in side effects such as hemolysis with hardly any local irritancy. CONSTITUTION:The objective parenteral injection at pH 9.5-11.5 is composed of a 2-[(2-pyridyl)methylsulfinyl]benzimidazole-based compound having antiulcer action (e.g. omeprazole) or its salt and an aqueous solvent without containing a nonaqueous solvent. This parental injection is prepared by dissolving the benzimidazole-based compound, preferably its salt, together with a strong alkaline substance, in water, etc., for the parenteral injection, regulating the pH to 10.5-12.5, preferably 11-12, preparing an alkaline aqueous solution, then filling the prepared aqueous solution in a vial, suitably replacing the atmosphere in the vial with nitrogen gas, subsequently freeze-drying the aqueous solution according to a well-known method and dissolving the freeze-dried substance in an aqueous solvent (e.g. a physiological saline solution of distilled water for the parenteral injection) without containing a nonaqueous solvent in use. The need for addition of the nonaqueous solvent for enhancing the solubility of the compound which is the active ingredient is eliminated to cancel side effects of the nonaqueous solvent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has an antiulcer effect.
The present invention relates to an injection and an injection kit of [[(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt thereof, particularly omeprazole sodium salt, and is used in the medical field.

[0002]

2. Description of the Related Art 2-[(2-pyridyl) methylsulfinyl] benzimidazole compounds such as omeprazole and lansoprazole are potent antiulcer agents, and in recent years, not only oral preparations but also injection preparations have been developed. As an injectable solution of omeprazole, a lyophilized product obtained by dissolving omeprazole sodium salt in sterile water, filtering and freeze-drying it, is prepared by injecting polyethylene glycol 40 for injection.
It is known that it is dissolved in a mixed solution of 0, sodium dihydrogen phosphate and sterilized water (JP-A-59-167587). On the other hand, a freeze-dried product of an alkaline aqueous solution of a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound having an anti-ulcer action such as lansoprazole is prepared by using (a) an acidic substance and (b) ethanol, propylene glycol and polyethylene glycol. An injection which is dissolved in a mixed solution with at least one of them is also known (JP-A-2-138213).

[0003]

Generally, the pH of an injection is
It is said that about 4 to 8 is preferable, and when the pH is higher than 9, hemolytic properties and local irritation may occur. However, a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound represented by omeprazole sodium salt or a salt thereof (hereinafter, also referred to as “benzimidazole compound or salt thereof”).
Generally shows solubility in water in an alkaline range of pH 9.5 or more to the extent that formulation is possible, but at pH 9 or less, the solubility in water is extremely small and formulation is difficult.

The benzimidazole compound or its salt is generally stable in the alkaline region, but p
There is also a problem that the stability decreases as H decreases. Therefore, in conventional injections of benzimidazole-based compounds such as omeprazole sodium salt or salts thereof, when dissolved, an acidic substance such as hydrochloric acid or sodium dihydrogen phosphate is added to the solution to keep the pH from neutral to weakly basic, Further, in order to obtain a certain solubility even at such pH, a non-aqueous solvent such as polyethylene glycol, ethanol or propylene glycol is further added to the solution and used.

However, these injections have problems of local irritation and hemolysis due to the non-aqueous solvent used in the solution. Therefore, an object of the present invention is to easily formulate, and side effects such as hemolytic properties are reduced, and the local stimulant benzimidazole compound or a salt thereof,
In particular, it is to provide an injection of omeprazole sodium salt.

[0006]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned object, the inventors of the present invention freeze-dried an alkaline aqueous solution of a benzimidazole compound or a salt thereof and added it with a non-aqueous solvent. It was found that a substance dissolved in an aqueous solvent that does not exhibit almost no hemolytic property or local irritation, despite the high pH of pH 9.5 to pH 11.5. Therefore, the injection of the present invention and the kit thereof have the following gist. (1) A 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt thereof having an anti-ulcer effect and an aqueous solvent containing no non-aqueous solvent, and having a pH of 9.5 or more and 11.5 or less An injectable preparation characterized by the following. (2) An injectable kit comprising the following components and having the pH adjusted to 9.5 or more and 11.5 or less when dissolved in the solvent. A freeze-dried product of an alkaline aqueous solution of a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound or its salt having an anti-ulcer effect. Aqueous solvent containing no non-aqueous solvent.

Examples of 2-[(2-pyridyl) methylsulfinyl] benzimidazole compounds having an anti-ulcer action, which is a constituent of the present invention, include, for example, JP-A-52-6.
2275, JP-A-54-141783, JP-A-57-53406, JP-A-58-13588.
1, JP-A-58-192880, JP-A-5
The compounds described in JP-A No. 9-181277, JP-A No. 61-50978 and the like are mentioned, and specific examples thereof include omeprazole [chemical name: 2- [2-
(3,5-Dimethyl-4-methoxy) -pyridylmethylsulfinyl]-(5-methoxy) benzimidazole], lansoprazole [chemical name: 2- {2- [3-methyl-4- (2,2,2- Trifluoroethoxy)]-
Pyridylmethylsulfinyl} benzimidazole] and the like. Examples of the salt of the benzimidazole compound include an alkali metal salt (for example, sodium salt, potassium salt, etc.), an alkaline earth metal salt (for example,
Calcium salts, magnesium salts, etc.) and the like. In the present invention, it is preferable to use a salt of a benzimidazole compound from the viewpoint of solubility.

The injection of the present invention has a pH of 9.5 or more and 1
It is 1.5 or less, preferably 10 or more and 11 or less. pH
When the value is less than 9.5, the benzimidazole compound or its salt cannot be sufficiently dissolved in an aqueous solvent and there is a problem in stability, and when it exceeds 11.5, hemolytic property and local irritation are caused. Become stronger.

In order to prepare an injectable preparation of the benzimidazole compound or its salt of the present invention, for example, first, a benzimidazole compound, preferably its salt, is added to sodium hydroxide, potassium hydroxide, sodium carbonate, L-arginine or the like. It is dissolved in water for injection or the like together with a strong alkaline substance to prepare an alkaline aqueous solution having a pH of 10.5 or more and 12.5 or less, preferably pH 11 or more and 12 or less. Mannitol, glycine, sorbitol, inositol and the like may be appropriately added to the alkaline aqueous solution in order to enhance the moldability of the freeze-dried product.

The concentration of the benzimidazole compound in the alkaline aqueous solution is 1 mg to 50 mg / ml, preferably 5 mg to 4 (calculated as a free form in the case of salt).
It is 0 mg / ml. Then, this alkaline aqueous solution is subjected to aseptic filtration, and 0.5 ml to 10 ml is filled in a vial,
After appropriately substituting nitrogen gas, it is freeze-dried by a method known per se. The lyophilized product is 2-[(2-pyridyl) having an antiulcer action in the injection kit of the present invention.
It corresponds to a lyophilized product of an alkaline aqueous solution of a methylsulfinyl] benzimidazole compound or a salt thereof.

In the injection of the present invention, the freeze-dried product thus obtained is dissolved in a non-aqueous solvent-free aqueous solvent such as physiological saline, 5% glucose solution, or distilled water for injection. Is obtained by The aqueous solvent corresponds to the aqueous solvent containing no non-aqueous solvent in the injection kit of the present invention.

The injectable composition of the present invention includes drip administration, intravenous injection,
It is used as intramuscular injection and subcutaneous injection. The concentration of the benzimidazole compound in the injection of the present invention varies depending on the administration route and the like, but in the case of a salt, it is usually 0.05 mg to 10 mg / ml, preferably 0.1 mg to 5 mg / ml in terms of a free form. Is. The benzimidazole-based compound in the injection of the present invention (in the case of a salt, converted into a free form) is administered in an amount of 10 mg to 100 mg per day in 1 to 3 divided doses depending on the patient's symptoms and the like.

[0013]

INDUSTRIAL APPLICABILITY The injectable preparation of the present invention, like the conventional injectable preparation, is lowered in pH to prevent hemolysis and local irritation, and is dissolved in an aqueous solvent as a solution in order to overcome the accompanying decrease in solubility. Since it is not necessary to add a non-aqueous solvent such as polyethylene glycol, there is no fear of irritation or hemolysis due to the non-aqueous solvent. Therefore, the injection of the present invention can secure sufficient solubility for formulation and safety for human body.

Test Example 1 (Test preparation) 1. Preparation obtained in Example 1 below

(Test method) 1. Hemolysis test Hemolysis was evaluated by the Akaishi method using whole rabbit blood. The results are shown in Table 1. 2. Local irritation test For local irritation, 1 ml of the test preparation was administered by intramuscular injection to 3 rabbits, and the muscle tissue necrosis area at the injection site after 2 days was adjusted to 1 ml of physiological saline and 1% of acetic acid solution 1
Each ml was compared to that given by intramuscular injection. The results are shown in Table 2. (Test results)

[0016]

[Table 1]

[0017]

[Table 2]

The formulation of the present invention is preferable as an injection because it has no hemolytic property at all even though the pH is high and has little local irritation.

[0019]

【Example】

Example 1 21.3 g of omeprazole sodium salt (20 g as omeprazole) and 2.3 ml of 1N sodium hydroxide
Is added and water for injection is added to adjust the pH to 11.5 to make the total amount 1 kg. After sterile filtration of this alkaline aqueous solution, 2 g each is filled in a 10 ml capacity vial, and a rubber stopper is half-capped to replace nitrogen. Then, freeze-drying is performed by a conventional method, and the obtained freeze-dried product is dissolved in 10 ml of physiological saline to obtain an omeprazole injection (concentration: 4 mg (free form) / ml).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Iwao Yamanaka 5-6-12 Kamiminami, Hirano-ku, Osaka (72) Inventor Takashi Higo 2-2-10 Midorigaoka, Ikeda-shi, Osaka (72) Inventor Shibata Shigeyuki 774-105, Higashihama, Nakatsu-shi, Oita Prefecture

Claims (5)

[Claims] 1. A method comprising a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound having antiulcer action or a salt thereof and an aqueous solvent containing no non-aqueous solvent and having a pH of 9.5 or more and 11.5. An injectable solution characterized by the following: 2. A freeze-dried product of an alkaline aqueous solution of a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound or its salt having an anti-ulcer effect is dissolved in an aqueous solvent containing no non-aqueous solvent. The injectable composition according to claim 1. 3. A component comprising the following and
When dissolved in a solvent of, the pH is 9.5 or more, 11.
An injectable drug kit, wherein and are adjusted so as to be 5 or less. A freeze-dried product of an alkaline aqueous solution of a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound or its salt having an anti-ulcer effect. Aqueous solvent containing no non-aqueous solvent. 4. The injection according to claim 1, wherein the 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt thereof is omeprazole sodium salt. 5. The injectable kit according to claim 3, wherein the 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt thereof is omeprazole sodium salt.