JPH051075A - Aqueous solution stably containing carbapenem compound - Google Patents

Abstract

PURPOSE:To obtain the subject clinically useful aqueous solution causing no decline in its potency over several hours at room temperature, excellent in stability by adjusting a specific compound within a specified range of pH values. CONSTITUTION:The objective aqueous solution containing (1R,5S,6S)-2-(6,7- dihydro-5H-pyrazolo[1,2-a] [1,2,4]-triazolium-6-yl)thio-6-[(R)--1-hydroxyethyl]-1- methyl-carbapenem-3-carboxylate of the formula, in a stably dissolved state at pH4-8 in, e.g. a 0.1M phosphoric acid buffer solution.

Description

Detailed Description of the Invention

The present invention relates to an aqueous solution containing a carbapenem compound in a stable manner, more specifically, the following formula:

[0002]

[Chemical 2]

(1R, 5S, 6S) -2-
(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio-6-
An aqueous solution having a pH of 4 to 8 containing [(R) -1-hydroxyethyl] -1-methyl-carbapenem-3-carboxylate in a stable dissolved state is provided.

The compound of the formula (I) contained in the aqueous solution provided by the present invention in a stable dissolved state is a carbapenem compound having a broad antibacterial spectrum and a strong bactericidal activity (Japanese Patent Laid-Open No. 64-25,779). No.), a compound currently under clinical development, which is expected to be an excellent drug.
In actual clinical use of the compound of formula (I),
The compound is dissolved in distilled water for injection or an infusion solution such as physiological saline and administered by injection.

In the case of administering a pharmaceutically active substance as an injectable solution, the pharmacologically active compound is dissolved in distilled water for injection or an infusion solution such as physiological saline to prepare an aqueous solution for injection, and the solution is administered. It is common. Further, the prepared aqueous solution for injection is not intended to be completely administered immediately after preparation, but for example, in the case of intravenous administration, administration is performed over a certain period of time after preparation.

However, distilled water for injection and infusion solutions used for such purposes are often acidic or weakly acidic because of isotonicity with body fluids. Therefore, when the pharmacologically active compound is administered as an injection, it is preferable that the pharmacologically active compound is stably dissolved without being degraded in an acidic or weakly acidic aqueous solution without causing decomposition or the like. ..

The compound represented by the above formula (I) is also used for treating or preventing a bacterial infection, wherein the compound of the formula (I) is used alone or together with other pharmaceuticals in an aqueous solution. It will be dissolved in the solution and administered by infusion, or used for washing the infected site. Therefore, it is necessary that the compound of formula (I) intended for administration is contained in the above acidic aqueous solution in a stable dissolved state, and no decrease in titer is observed over several hours at room temperature.

The compound represented by the above formula (I) has a characteristic quaternary ammonium substituent at the 2-position of the carbapenem skeleton, and is present in the form of an inner salt with the carboxyl anion at the 3-position. .. Therefore, even when the compound of formula (I) is dissolved in an aqueous solution for injection, it is desired that the compound be stably present in the solution in the form of an inner salt.

As a result of intensive studies on the above points, the present inventors have found that the compound of formula (I) is in a very stable dissolved state in an aqueous solution of pH 4-8. That is, the present inventors have prepared an aqueous solution obtained by dissolving a compound represented by the formula (I) in injectable distilled water, or an infusion solution such as physiological saline, and having a pH in the range of 4 to 8. Is
Completed the present invention by finding that it is an aqueous solution of antibiotics, which shows extremely low titer over a few hours at room temperature, is extremely stable, and is extremely useful clinically when washing the infected site or performing drip administration. It was made.

That is, the present invention provides an aqueous solution having a pH of 4 to 8 containing a compound represented by the formula (I) in a stable dissolved state.

The aqueous solution of the present invention can be prepared by dissolving the compound represented by the formula (I) in distilled water for injection or an infusion solution.

The infusion solution used herein includes, for example, physiological saline solution; sugar solution such as glucose solution or fructose solution; Ringer solution; sugar alcohol solution such as D-sorbitol solution or xylitol solution; and one or more amino acids. Amino acid aqueous solution and the like,
These infusion solutions may be those having a pH within the range of 4 to 8 when the compound represented by the formula (I) is dissolved.

The aqueous solution provided by the present invention is prepared by dissolving the compound represented by the above formula (I) in these infusion solutions. In this case, the concentration of the compound represented by the formula (I) is not particularly limited. Instead, it may be an effective amount required depending on the intended use of the aqueous solution. Also, if necessary,
Other antibiotics or other pharmaceuticals can also be included.

The aqueous solution of the present invention thus prepared contains the compound of the formula (I) stably in the form of an intramolecular salt, and the strength of the compound of the formula (I) contained therein. It was found to be extremely useful for administration such as intravenous drip infusion, as it does not cause a decrease in valency.

Hereinafter, the usefulness of the aqueous solution of the present invention will be described in more detail with reference to Examples and stability tests thereof. The present invention is not limited to these descriptions.

[0016]

【Example】

Example 1: Stability of compounds of formula (I) in various pH ranges
Test The stability of the compound of formula (I) in the aqueous solution of each pH of the present invention was confirmed. The stability was evaluated by measuring the residual titer of the compound of formula (I) in each solution over time.

The test solution contains the compound of formula (I) at pH 4,
It was adjusted to a concentration of 1 mg / ml and 5.2 mg / ml by using 5, 6, 7 and 8 of 0.1 M phosphate buffer. After the preparation, the test solution was stored at each temperature of 4 ° C. and 25 ° C., and the residual titer (%) with respect to the titer immediately after preparation was calculated from the titer after 1, 2, 3 and 6 hours. High-performance liquid chromatographic method (apparatus; HITACHI)
655A-11).

The results are shown in Table 1.

As is clear from the table, in the test liquid stored at 4 ° C., in any case of pH 4 to 8,
Almost no decrease in titer was observed after 6 hours.
Similarly, the pH of the test solution stored at 25 ° C was 4
In any case of ~ 8, almost no decrease in titer was observed until after 3 hours. In addition, no change in appearance was observed in any of the test solutions.

[0020]

[Table 1]

Example 2: Various aqueous solutions of the present invention 300 mg of the compound of formula (I) was added to a physiological saline solution (0.9%).
Dissolve in 15 ml of sodium chloride, pH 6.29),
An aqueous solution (pH 4.89) of the present invention was obtained.

Next, the above aqueous solution was diluted with various infusion solutions shown in Table 2 (shown later) to prepare the aqueous solutions of the present invention (Nos. 1 to 12).
Got

Example 3: Compound of formula (I) in various aqueous solutions
Stability test of compound of the aqueous solution (No. 1 to 12) obtained in Example 2 above,
The stability of the compound of formula (I) at 25 ° C was confirmed.

The stability was evaluated according to the method described in Example 1 above.

The results are shown in Table 2.

In all the aqueous solutions, almost no decrease in the titer was observed until 6 hours after the preparation.

No change in appearance was observed in any of the aqueous solutions.

[0028]

[Table 2]

The stability of the compound of formula (I) in the aqueous solution of the present invention is due to the specific structure of the compound of formula (I). That is, the compound of formula (I) forms an intramolecular salt with the ammonium cation of the 2-position substituent and the carboxyl anion of the 3-position substituent, and the intramolecular salt is stably dissolved in an aqueous solution of pH 4-8. Is in a state. Therefore, the aqueous solution provided by the present invention has extremely high stability,
It is highly useful in clinical use.

Claims (1)

Claims: 1. The following formula: (1R, 5S, 6S) -2- (6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio-6-[(R ) -1-Hydroxyethyl] -1-methyl-carbapenem-3-carboxylate in a stable dissolved state at pH 4-8.