JP3535537B2 - Intravenous injection - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stable, intravenous injection preparation containing glucose or maltose and ritodrine hydrochloride.

[0002]

BACKGROUND ART ritodrine hydrochloride is exchange feeling nervous beta ₂ - receptor-stimulating agent, yet act selectively to the uterine muscle, because it exhibits a strong myometrial contractions suppressed, important as a therapeutic agent for preterm labor It is used as a drug.

Conventionally, an injection of ritodrine hydrochloride is sold as a small volume (5 ml to 10 ml) ampoule or a vial formulation (Yutopar ^R , manufactured by Astra, USA).
It is a Pre-par ^R manufactured by ECDuphar Co., and a Utemerin injection R manufactured by Nippon Kissei Co., Ltd.). Since this drug has a strong action and its blood concentration rapidly decreases after administration, a large amount of ordinary glucose or a substance diluted with maltose solution is slowly and continuously administered to a patient by intravenous drip infusion.

Incidentally, the above-mentioned small volume of ritodrine hydrochloride preparation (simple) has a pH of 4.7 to 5.5, and the pH when blended with glucose or maltose solution is 4.5 to.
It is 6.0.

[0005]

In the conventional preparations, it is essential to perform an operation of mixing and diluting ritodrine hydrochloride with glucose or maltose solution each time it is administered to a patient. During this mixing and diluting operation, strict control is required because there is a possibility of contamination of foreign substances such as glass pieces and microbial contamination, and in an emergency, the mixing and diluting operation is complicated. Inconvenience in use is an unavoidable drawback.

[0006] Therefore, it is possible to solve such problems and inconveniences by providing a preparation in which ritodrine hydrochloride and glucose or maltose solution are mixed in advance. However, ritodrine hydrochloride and glucose or maltose solution are mixed in advance and heat sterilized. Then, by heating 4-hydroxybenzaldehyde, which is an oxidative decomposition product of ritodrine hydrochloride, and an adduct of bisulfite ion and ritodrine hydrochloride, which are stabilizers, are formed, and the stability required as a pharmaceutical cannot be maintained, Such a formulation has not yet been developed.

[0007]

[Means for Solving the Problems] Therefore, the inventors of the present invention have conducted intensive studies on a formulation in which ritodrine hydrochloride and glucose or maltose have been preliminarily blended, and as a result, have identified the blending amount and pH of sulfite as a stabilizer. It was clarified that the above-mentioned problems can be solved by setting the above range and reached the present invention.

The present invention isotonic or hypertonic glucose or maltose, ritodrine hydrochloride 0.05-2 mg /
It is a stable intravenous injection obtained by adjusting pH of an aqueous solution in which 0.02 to 0.3 mg / ml of sulfites is dissolved to 3.0 to 4.0 and sterilizing by heating.

Glucose or maltose is blended in isotonic to hypertonic concentrations, preferably in concentrations of 5-10%.
Ritodrine hydrochloride is preferably used at a concentration of 0.05-2 mg / ml, and sulfites are preferably used at a concentration of 0.02-0.3 mg / ml (see Test Example 1).

As the sulfites, for example, alkali metal sulfites such as sodium hydrogen sulfite, sodium pyrosulfite and sodium sulfite are preferably used.

The pH is adjusted to 3.0-4.0, but p
As the H-adjusting agent, a mineral acid or an organic acid generally used for infusion can be used, but hydrochloric acid is preferable,
Citric acid or acetic acid.

The injectable composition of the present invention is suitable for heat sterilization.
-Production of S ₁ and S ₂ which are adducts of hydroxybenzaldehyde or bisulfite ion and ritodrine hydrochloride is suppressed, and stability as a drug can be maintained (see Test Example 2).

Further, after the solution is dispensed into the container and the air in the container is replaced with nitrogen gas, the stability is remarkably improved.

The injection of the present invention can be administered intravenously by the drip method, and the unit volume in that case is preferably 100 to 1,000 ml for the convenience of clinical use. 200-500 is preferred
ml.

[0015]

The present invention will be further described with reference to the following test examples and examples.

Test Example 1 Glucose (50 g) was added to and dissolved in 800 ml of water for injection, 200 mg of ritodrine hydrochloride was further added and dissolved therein, and then water for injection was added to bring the total amount to 900 ml. Take 90 ml of this liquid and add sodium bisulfite to 0, 1, 2, 5, 1
After adding 0, 20, 30, 40 and 50 mg and adjusting the pH of each solution to 3.7 with citric acid, water for injection was added to each to make the total volume 100 ml. Dispense 20 ml of each sodium bisulfite concentration solution into ampoules,
It was heat sterilized at 115 ° C. for 10 minutes.

[0017]

[Table 1]

* S ₁ : threo-1- (4-hydroxyphenyl) -2- [2- (4-hydroxyphenyl) ethylamino] -1-propanesulfonic acid S ₂ : erythro-1- (4-hydroxyphenyl) ) -2
-[2- (4-hydroxyphenyl) ethylamino]-
1-propanesulfonic acid

From the results shown in Table 1, the amount of sulfite added was 0.
Although the decomposition product of 4-hydroxybenzaldehyde is significantly suppressed at 02 mg / ml or more, the production amount of the adducts S ₁ and S ₂ rapidly increases at 0.3 mg / ml or more, and therefore 0.02 to 0. It turns out that the range of 3 mg / ml is good.

Test Example 2 Glucose (50 g) was added and dissolved in water for injection (800 ml), and sodium bisulfite (200 mg) and ritodrine hydrochloride (300 mg) were added and dissolved therein. Then, water for injection was added to bring the total amount to 900 ml. 90 ml of this solution was taken, and the pH of each solution was adjusted to 5.0, 4.5, 4.0, 3.8, 3.
After adjusting to 6, 3.4, 3.2 and 3.0, water for injection was added to each solution to make the total volume 100 ml.
Dispense 20 ml of each pH solution into ampoules, and
It was sterilized by heating at ℃ for 10 minutes.

[0021]

[Table 2]

As is clear from Table 2, pH of 3.0-4.
In the range of 0, preferably 3.2 to 3.8, the formation of the adduct due to heat sterilization is remarkably suppressed, but when the pH exceeds 4, the adduct rapidly increases.

[0023]

Example 1 50 g of glucose was added and dissolved in 900 ml of water for injection, and sodium pyrosulfite 1 was added as a stabilizer.
Add 00 mg and dissolve. Next, ritodrine hydrochloride 600m
After adding and dissolving g, the pH is adjusted to 3.7 with a citric acid solution, and then water for injection is added to make the total volume 1000 ml. This solution is filtered by a membrane filter according to a conventional method and dispensed into a 200 ml drip intravenous vial,
After the space is replaced with nitrogen gas, it is sterilized by heating at 110 ° C. for 15 minutes to give an intravenous drip infusion containing ritodrine hydrochloride 0.6 mg / ml.

[0024]

Example 2 50 g of glucose was added and dissolved in 900 ml of water for injection, and sodium pyrosulfite 4 was added as a stabilizer.
Add 0 mg to dissolve. Next 200 mg of ritodrine hydrochloride
Was added and dissolved, the pH was adjusted to 3.5 with a hydrochloric acid solution,
Next, water for injection is added to make the total volume 1000 ml. This liquid is filtered by a membrane filter according to a conventional method,
The solution is dispensed into a 250 ml vial for intravenous infusion, the space is replaced with nitrogen gas, and sterilized by heating at 115 ° C. for 10 minutes to give an intravenous infusion containing 0.2 mg / ml of ritodrine hydrochloride.

[0025]

[Example 3] 100 g of maltose in 900 ml of water for injection
Is added and dissolved, and 200 mg of sodium hydrogen sulfite is added and dissolved as a stabilizer. Next, ritodrine hydrochloride 50
After adding and dissolving mg, adjust the pH to 3.7 with a citric acid solution, and then add water for injection to make the total volume 1000 ml. This solution is filtered by a membrane filter according to a conventional method and dispensed into a 500 ml intravenous infusion vial,
After substituting the space with nitrogen gas, it is heat-sterilized at 115 ° C. for 10 minutes to give an intravenous drip infusion containing ritodrine hydrochloride 0.05 mg / ml.

[0026]

Example 4 25 g of glucose was added and dissolved in 450 ml of water for injection, and sodium pyrosulfite 2 was added as a stabilizer.
Add 5 mg and dissolve. Next, ritodrine hydrochloride 100mg
Was added and dissolved, pH was adjusted to 3.3 with acetic acid, and then water for injection was added to bring the total volume to 500 ml. This solution was filtered through a membrane filter according to a conventional method to obtain 200
The solution is dispensed into a vial for intravenous drip infusion, the space is replaced with nitrogen gas, and sterilized by heating at 110 ° C. for 15 minutes to give an intravenous drip infusion containing ritodrine hydrochloride 0.2 mg / ml.

[0027]

Example 5 Maltose (50 g) was added and dissolved in water for injection (450 ml), and further sodium bisulfite (150 mg) was added and dissolved as a stabilizer. Next ritodrine hydrochloride 750
After adding and dissolving mg, the pH was adjusted to 3.7 with acetic acid,
Next, water for injection is added to bring the total volume to 500 ml. This solution was filtered through a membrane filter according to a conventional method, and 2
Dispense into a 00 ml vial for intravenous infusion, replace the space with nitrogen gas, and sterilize by heating at 115 ° C. for 10 minutes to give an intravenous infusion containing 1.5 mg / ml of ritodrine hydrochloride.

Test Example 3 0.2 m ritodrine hydrochloride prepared according to Example 2.
A formulation containing g / ml and a formulation containing ritodrine hydrochloride 0.6 mg / ml prepared according to Example 3 and a commercially available ritodrine hydrochloride formulation (containing 50 mg of the active ingredient in a 5 ml ampoule) were used in an amount of 500 ml of 5
% Ritodrine Hydrochloride diluted with% glucose solution
The preparation containing mg / ml was heat sterilized at 115 ° C. for 10 minutes (hereinafter, referred to as a control product), and 4-hydroxybenzaldehyde and bisulfite ion were adducted with ritodrine hydrochloride (S ₁ , S ₂ ) were compared. . As a result, as shown in Table 3, the amounts of S ₁ and S ₂ produced were 0.01% for both 0.2 and 0.6 mg / ml formulations of ritodrine hydrochloride prepared according to the examples. It was 0.09% when the commercially available preparation was dissolved at the time of use and then heat sterilized. Also, 4-
The amount of hydroxybenzaldehyde produced was determined in Examples 2 and 3
Both were 0.01%, but 0.02 for the control product.
%Met.

[Table 3]

Test Example 4 0.2 m ritodrine hydrochloride prepared according to Example 2.
Formulation containing g / ml and a commercial littoral as a control
Of a pharmaceutical preparation (single, containing 50 mg in a 5 ml ampoule)
Add 2 pulls to 500 ml of 5% glucose solution to prepare
Prepared ritodrine hydrochloride containing about 0.2 mg / ml
The intravenous solution was heated at 115 ° C. for 10 minutes to give 4-hydrogen.
Xybenzaldehyde and bisulfite ion and hydrochloric acid
To compare the production of todrine adducts (S ₁ , S ₂ )
It was As shown in Table 4, 4-hydroxybenzaldehyde
And the amounts of S ₁ and S ₂ are the same as those of the intravenous infusion preparation of Example 2.
Both were 0.01%, but 0.1% and 0.12% in the control product.
Was 0.03%.

[Table 4]

[0030]

EFFECTS OF THE INVENTION The intravenous injection of the present invention is stable and can be administered as it is by using an ordinary drip device without being mixed with a glucose solution or the like at the time of use. Therefore, administration does not require any complicated mixing / diluting operation. In addition, there is no problem such as contamination due to the mixing operation, and it can be used immediately in an emergency and is medically useful.

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Claims (3)

(57) [Claims] 1. A pH of an aqueous solution in which isotonic or hypertonic concentration glucose or maltose, ritodrine hydrochloride 0.05-2 mg / ml and sulfites 0.02-0.3 mg / ml is 3.0-4.0. A stable intravenous injection prepared by adjusting the temperature to 1 and sterilized by heating. 2. The intravenous injection according to claim 1, which is for intravenous administration. 3. A glucose or maltose concentration of 5
The intravenous injection according to claim 1 or 2, which is -10%.