JPH05262650A - Stable composition for injection - Google Patents

Abstract

PURPOSE:To provide the stable amrinone injection preparation. CONSTITUTION:The content of a monocarboxylic acid for dissolving the amrinone is controlled to <=0.3V/V% to obtain the stable aqueous solution containing the produced monocarboxylic acid adduct in an amount of <=0.1W/W% and the amrinone in an amount of 0.1-5W/V%.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an injectable composition excellent in stability of amrinone having a cardiotonic action.

[0002]

BACKGROUND OF THE INVENTION Amrinone is a highly safe therapeutic drug for acute heart failure, which has an action of enhancing cardiac contractile force and a vasodilator action. Amrinone is almost insoluble in water, but since it is a weakly basic substance, it can be dissolved in a concentration that can be used as an injection by adding an appropriate acidic substance to adjust the pH to 5 or less.

Generally, hydrochloric acid or the like is used as an acidic substance, but since amrinone is a weakly basic substance, it is difficult to adjust the pH with hydrochloric acid having a strong acid, and when chloride is contained, the solubility decreases due to the common ionic effect. Therefore, it is necessary to use a weak acid such as acetic acid or lactic acid in order to obtain a sufficient concentration. Amrinone in the United States
It is already commercially available under the trade name of R, and lactic acid is used as an additive as an acid for dissolving.

[0004]

However, it has been found that coexisting with lactic acid, amrinone binds to lactic acid and gradually changes to a new compound with a small amount over time. Although the detailed action of this compound is unknown, it is needless to say that it is necessary to reduce the amount of such a compound as much as possible considering that it is directly administered to the body as an injection. Although the limit of such impurity content should not be clearly specified, Uchiyama "I would like to request a standard value of 0.1% or less for those with concern about toxicity" (February 21, 1989) Held daily, the Pharmaceutical Affairs Seminar "Problems concerning new drugs"), which is a target value as one standard value.

[0005]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventor diligently studied the concentration of amrinone and monocarboxylic acid in consideration of the solubility and pH of amrinone, and as a result, maintained an injectable pH range. However, it is essential to keep the concentration of monocarboxylic acid to 0.3 V / V% or less in order to make the amount of the compound estimated to be the monocarboxylic acid adduct of amrinone to be an allowable amount (0.1% or less). The present invention has been completed and the present invention has been completed. The monocarboxylic acid used in the present invention is not limited to acetic acid, lactic acid, any pharmaceutically acceptable monocarboxylic acid, or a mixture thereof.

On the other hand, the upper limit of the concentration of amrinone is limited to 0.5 W / V% because of its physical properties, but the lower limit is not limited because of its physical properties. However, in the case of congestive heart failure, which is a target disease of amrinone, it is often necessary to avoid administration of a large amount of water, so the lower limit for obtaining a therapeutically sufficient dose of 100 to 200 mg is recommended. Is preferably set to 0.1 W / V%.
In addition, a pharmaceutically acceptable pH adjusting agent, an antioxidant, a surfactant, a buffering agent, a preservative or the like may be added to the composition of the present invention to prepare an injection according to a usual method. ..

[0007]

EXAMPLES Next, the present invention will be described in more detail by way of examples.
To do. Example 1 Lactic acid 2.5ml, 15m in 3.5L water for injection
1 and 25 ml are added and the solution is aerated with nitrogen. Next
Add 5 g of amrinone while dissolving little by little. A
After dissolution of murinone, 0.1N hydrochloric acid solution or 1N hydroxide
After adjusting the pH to 4 with thorium solution,
Add 1.25 g of Um. Add water for injection to make the total volume 5 L
Then, a preparation liquid was prepared. 200 ml of the prepared liquid is added to a glass via
And replace the headspace with nitrogen.
Stopper and aluminum stopper, and autoclave sterilize (121 ℃, 20
Min) to obtain a preparation for injection.

Example 2 Lactic acid 2.5 ml and 15 m in 3.5 L of water for injection, respectively.
1 and 25 ml are added and the solution is bubbled with nitrogen for 15 minutes. Next, 25 g of amrinone is dissolved or suspended little by little, the pH is adjusted to 4 with a 1N sodium hydroxide solution or a 1N hydrochloric acid solution, if necessary, and further 1.25 g of sodium pyrosulfite is added. Add water for injection to bring the total volume to 5
It was designated as L to prepare a preparation liquid. 20 ml of the prepared liquid was dispensed into a glass vial, the head space was replaced with nitrogen, and then a rubber stopper and an aluminum stopper were applied, followed by autoclave sterilization (121 ° C,
For 20 minutes) to obtain a preparation for injection.

Example 3 Using the injectable preparations (formulations shown in Table 1) prepared in Examples 1 and 2, changes in appearance, amrinone content and lactic acid adduct content after the manufacturing process and storage at 80 ° C. for 1 week. Was measured. The measuring method was carried out by visually observing the change in appearance, and the amrinone content and the lactic acid adduct content were measured by the HPLC method.

As a result of the measurement, the appearance change and the amrinone content were not particularly changed in each sample, but the lactic acid adduct content was not observed before sterilization, but all samples were stored at 80 ° C. for 1 week. Detected from. The ratio (%) to the amrinone content was calculated based on the content of lactic acid adduct obtained by the HPLC method, and shown in Table 2 (average of n = 3).

[0011]

[Table 1] Table 1 Sample No. per 1 ml of injection solution Amrinone content Lactic acid content Lactic acid content,% 1-1 1 mg 0.5 μl 0.05% 1-2 1-2 mg 3 μl 0.3% 1-3 1 mg 5 μl 0.5% 5-1 5 mg 0.5 μl 0.05% 5-2 5mg 3 μl 0.3% 5-3 5mg 5 μl 0.5%

[0012]

[Table 2] Table 2 Content of lactic acid adduct (% of amrinone content) 80 ° C Sample No Before sterilization, stored for 1 week after sterilization 1-1 Not detected Not detected 1-2 Trace not detected Not detected Not detected 0.05 1-3 Not detected Not detected 0.11 5-1 Not detected Not detected 0.01 5-2 Not detected 0.06 5-3 Not detected 0.01 0.14

Almost no lactic acid adduct was detected before and after sterilization, but the monocarboxylic acid adduct after 1 week at 80 ° C. seems to be approximately the estimated warranty period considering the distribution process and storage in medical institutions. It was shown that the lactic acid concentration should be 0.3% or less regardless of the amrinone concentration in order to keep the product at 0.1% or less of the content of the main drug, which is considered to be safe.

[0014]

INDUSTRIAL APPLICABILITY The present invention provides a stable amrinone injectable preparation.

Claims (1)

[Claims] 1. A monocarboxylic acid of 0.3 V / V% to obtain an aqueous solution containing 0.1 to 0.5 W / V of amrinone.
Stable injectable composition characterized by obtaining a stable injectable solution by dissolving below