JP4850426B2 - Stable high concentration edaravone injection - Google Patents

Description

The present invention relates to a high-concentration injection solution containing edaravone as a main component. The present invention also relates to the highly concentrated edaravone injection filled in a plastic disposable container that is easy to use.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is used in the form of an infusion for infusion as an ameliorating agent for neurological symptoms and dysfunction in the acute phase of cerebral infarction. In order to administer 30 mg of edaravone, the clinical dose per patient of edaravone is 30 mg at a time, but edaravone is difficult to dissolve in water and it is difficult to prepare a high-concentration injection. It is necessary to administer a low-concentration injection solution in a large amount mixed with an infusion solution.

Actually, an injection solution containing 1.5 mg / mL of edaravone is marketed in a 20 mL large ampule (Japanese Patent Publication No. 7-121861), and this injection solution is diluted with physiological saline or the like. Instructed to infuse intravenously over 30 minutes.

However, the 20 mL ampoule of the commercially available edaravone preparation is larger than a general injection solution, and not only a large storage place is required in a medical institution or distribution channel, but also when the ampoule is opened compared to a small ampoule. There is a high risk of injury to the hands, and operations such as sucking a large amount of 20 mL of injection solution with a syringe and mixing it into an infusion solution are troublesome. Moreover, the ampule after use is bulky, and the volume as waste is large and disadvantageous.

In view of the above, it is desired to develop a preparation containing a high concentration of edaravone and having a small total volume, that is, an injection having a high concentration and a small volume.

As described above, edaravone is difficult to dissolve in water (2 mg / mL, 25 ° C.), and its chemical stability is lowered by increasing the concentration in an aqueous solution. Have. Therefore, it has been difficult to formulate an edaravone injection that is stable in the long term and contains an amount exceeding the saturation solubility in water.

In addition, regarding the development of a high-concentration small-volume edaravone injection, a preparation containing 3 to 60 mg / mL edaravone with respect to the total amount of the injection and using ethanol as a solubilizing agent has been disclosed (WO 2002/092028). Publication). However, the concentration of edaravone in the examples is 5 mg / mL, and there is no disclosure about higher concentration solutions.

Further, in this specification, it is described that when only ethanol is added, the solution is colored and there is a problem in stability. Therefore, ethylenediamine, calcium sodium edetate, or edetic acid 2 is used as a stabilizer. It is disclosed that the addition of a sodium chelating agent is necessary. Since these chelating agents chelate calcium or the like, which is an essential metal in the living body, there is a possibility that side effects may occur.

Therefore, there is a need to develop a high concentration edaravone injection with further improvements.
Japanese Examined Patent Publication No. 7-121861 WO2002 / 092028

An object of the present invention is to provide a stable high concentration edaravone injection. Another object of the present invention is to provide the high concentration and small volume edaravone injection filled in a plastic disposable container which is easy to use.

As described above, the development of a stable high-concentration edaravone injection is awaited. However, in the case of an injection, a small volume of 1 mL or less can not only ignore operational errors in clinical settings, Even small errors change the amount actually administered, which is not preferable. Considering the storage space and the volume of waste, etc., it is considered that the volume of the preparation is preferably 1 mL to 2 mL.

Considering the clinical dose of edaravone, it was judged that the above-mentioned problems could be solved by developing an injection solution containing edaravone at a concentration of 15 to 30 mg / mL.

Edaravone is hardly soluble in water, but easily soluble in ethanol (111 mg / mL, 25 ° C.). Therefore, preparation of a highly concentrated edaravone solution centering on ethanol, which has many precedents of use, was investigated as an additive for injectable preparations. As a result of examining the solubility of edaravone in ethanol / water at 4 ° C. and 25 ° C., the solubility curve shown in FIG. 1 was obtained, and the solubility of edaravone increased as the ethanol concentration increased.

Since it is assumed that the injection solution is stored at a low temperature, in order to prepare a high concentration edaravone injection solution of 15 to 30 mg / mL in consideration of the condition that crystals do not precipitate in such a case. An ethanol concentration in the range of 40 w / w% to 80 w / w% was considered necessary.

Although the solubility of edaravone can be ensured by increasing the ethanol concentration, the amount of ethanol increases, and it is not necessarily a highly safe pharmaceutical, so it is desirable that the dosage be small. It is said that when the blood ethanol concentration is higher than about 0.02% (0.2 mg / mL), the so-called sickness phenomenon appears.

The high-concentration edaravone injection solution of the present invention makes it possible to keep ethanol administered to 30 mg, which is a clinical dose of edaravone, to 1000 mg or less. Safe amount. In consideration of the fact that in actual use, it is diluted with a large amount of physiological saline or the like and intravenously administered, it is considered that there is no problem in safety.

That is, the present inventors set the ethanol concentration to 40 w / w% or more and 80 w / w% or less, and edaravone solution in which edaravone was dissolved in the range of about 1.5 w / w% to 3.5 w / w% was applied to the infusion. It has been found that it is suitable as an injection for use by mixing.

The edaravone solution prepared in the above ethanol concentration range shows no change in color when heated at 121 ° C. for 20 minutes for sterilization, and no generation of impurities is observed even in analysis by high performance liquid chromatography. It was. However, after heat treatment, when stored at 80 ° C. for 3 months, it was colored yellowish brown, suggesting that impurities were generated.

Therefore, various stabilizers were studied for the purpose of being stable even when stored under severe conditions, and the results shown in Table 1 were obtained. As a specific examination method, edaravone is dissolved in an aqueous ethanol solution of 65 w / w% or more to 3.0 w / w%, a stabilizer is further added, and the mixture is heated at 121 ° C. for 180 minutes, and its color tone Changes and analysis of related substances by high performance liquid chromatography were studied as indicators. At the same time, the stabilizing effects of ascorbic acid, citric acid and citrate, and chelating agents were investigated.

As shown in Table 1, it was found that sodium bisulfite and sodium pyrosulfite have a stabilizing effect at 0.025 w / w% or more. It was also found that when sodium hydrogen sulfite and sodium pyrosulfite were mixed, a better effect was obtained than when they were used individually. When the concentration to be added exceeds 1.0 w / w%, since precipitation of sodium bisulfite and sodium pyrosulfite is observed particularly at 4 ° C., it is desirable that the addition concentration does not exceed 1.0 w / w%.

In addition, when the effect of disodium edetate exemplified as a stabilizer in the literature (WO2002 / 092028) disclosing the ethanol-containing high-concentration edaravone injection described above was examined, 0.1 w / w No stabilizing effect was observed at a concentration of%.

Considering the above requirements, edaravone concentration is 1.5 w / w% to 3.5 w / w%, ethanol concentration is 40 w / w% or more and 80 w / w% or less as a solubilizer, sodium bisulfite and pyrosulfite It has been found that a high-concentration edaravone injection solution containing one or more selected from sodium is a preparation with good storage stability.

Furthermore, while a commercially available edaravone aqueous solution is adjusted at pH 3.0 to 4.5, the high concentration edaravone injection of the present invention is stable at pH 4.6 to 6.0, and is more neutral. A formulation close to can be provided.

The high concentration edaravone injection solution of the present invention makes it possible to use a small container having a capacity of 1 mL to 2 mL when injecting the same amount of edaravone as before. Adopting small containers even when using containers such as so-called prefilled syringes that pre-fill medicines into syringes for injection or plastic resins as well as ampoules by reducing the volume in this way Is possible. Thereby, when mixing with an infusion solution, it becomes possible to inject the medicine directly from the container into the infusion bag, and the usability is greatly improved. The inventor has intensively studied and found that 1 mL to 5 mL of a plastic disposable small container can be filled with 1 mL to 2 mL of high-concentration edaravone injection according to the present invention.

For adjusting the pH of the injection, a pharmaceutically acceptable buffer such as citric acid or a salt thereof, phosphoric acid or a salt thereof, acetic acid or a salt thereof can be used as an injection. . In addition, the present injection can be prepared using a pharmaceutically acceptable isotonic agent, preservative and the like, if necessary.

The present invention makes it possible to increase the concentration of edaravone injection, and in the case of injecting a clinical dose of edaravone, instead of a 20 mL large ampoule provided at a low concentration, the use of a small container of 1 mL to 5 mL capacity It becomes possible to fill edaravone injection solution of 1 mL to 2 mL capacity.

In this way, small containers can be used not only for ampoules, but also when using containers such as so-called prefilled syringes that are pre-filled with drugs in injection syringes or plastic resin containers. It becomes possible. In particular, in preparations filled in syringes or plastic resin containers with injection needles, it is possible to inject drugs directly from the container into the infusion bag when mixed with the infusion, and there is a risk of injury to the hand when the ampoule is opened. Usability is drastically improved, such as eliminating the need for suctioning a large amount of injection solution with a syringe and mixing it into an infusion solution.

Furthermore, the use of a small container eliminates the need for a wide storage place in a medical institution or distribution channel, reduces the bulk of the ampoule after use and the volume of waste, and can be expected to reduce the cost of disposal.

Examples will be described in detail below, but the present invention is not limited to these examples as long as it does not exceed the gist thereof. In addition, 99.5% ethanol was used for ethanol in this specification.

In a 50 mL glass centrifuge tube with a stopper, which weighed 300 mg of edaravone, 6.50 g of ethanol and 3.30 g of water for injection in which 25 mg of sodium bisulfite had been previously dissolved were added, and heated to 60 ° C. in a hot water bath and stirred. Was dissolved. 0.98 g of this solution was taken out and filled in a 1 mL colorless glass ampoule and sterilized by heating at 121 ° C. for 30 minutes. (Edaravone concentration: 3.0 w / w%, ethanol concentration: 66 w / w%)

Comparative Example 1

The same composition as in Example 1 except that only sodium bisulfite was removed was prepared in the same manner.

In a 50 mL glass centrifuge tube with a stopper, 6.75 g of ethanol and 6.75 g of water for injection in which 70 mg of sodium bisulfite has been dissolved in advance are mixed, 300 mg of edaravone is added, and then heated to 60 ° C. in a hot water bath and stirred. Edaravone was dissolved. Each 1.39 g of the resulting solution was filled into a 2 mL colorless glass ampoule under a stream of nitrogen gas and heat sterilized at 121 ° C. for 20 minutes. (Edaravone concentration: 2.2 w / w%, ethanol concentration: 50 w / w%)

Comparative Example 2

The same composition as in Example 2 except that only sodium hydrogen sulfite was removed was prepared.

In a glass centrifuge tube with 50 mL stoppered stopper, 7.0 g of ethanol and 3.0 g of water for injection in which 2.5 mg of sodium hydrogen sulfite and 2.5 mg of sodium pyrosulfite were previously dissolved were mixed. After adding 300 mg of edaravone, The edaravone was dissolved by heating to 60 ° C. and stirring. The obtained solution was filled into a 2 mL white ampule every 1.0 g, and then heat sterilized at 121 ° C. for 30 minutes. (Edaravone concentration: 3.0 w / w%, ethanol concentration: 70 w / w%)

Comparative Example 3

What added 5 mg of phosphoric acid instead of the sodium hydrogen sulfite and sodium pyrosulfite of Example 3 was prepared similarly.

Comparative Example 4

Example 2 was prepared in the same manner as Example 2 except for sodium bisulfite and sodium pyrosulfite.

The edaravone solutions of Formulas A to G in Table 2 below were prepared. Specifically, edaravone was dissolved in 20.0 g of ethanol in a glass flask with a 100 mL stoppered stopper, and then 25.0 g of water for injection in which sodium bisulfite and / or sodium pyrosulfite was dissolved in advance or water for injection that did not dissolve them was added. The mixture was heated to 60 ° C. and stirred in a hot water bath to obtain an edaravone solution. The obtained solution was filled into a 5 mL colorless glass ampoule every 1.9 g and heat sterilized at 121 ° C. for 30 minutes. (Edaravone concentration: 1.6 w / w%, ethanol concentration: 44 w / w%)

Stability of Formulations A to G Formulations A to G were examined for changes in appearance when stored at 60C for 2 months. The observation results are as shown in Table 3. The stabilizing effect of sodium bisulfite and sodium pyrosulfite was observed.

In a 50 mL glass centrifuge tube with a stopper, mix 21.0 g of ethanol with 9.0 g of water for injection containing 150 mg of sodium pyrosulfite, add 900 mg of edaravone, and then heat and stir at 60 ° C in a hot water bath. Thus, edaravone was dissolved and heat sterilized at 121 ° C. for 30 minutes. Thereafter, the solution was filtered through a 0.2 μm filter, and six 1 mL polyethylene injection containers were filled every 1.03 g. (Edaravone concentration: 3.0 w / w%, ethanol concentration: 70 w / w%)

Comparative Example 5

Example 5 except that only sodium pyrosulfite of Example 5 was prepared.

In a glass flask with a 200 mL stopper, 3.0 g of edaravone was dissolved in 70.0 g of ethanol, and then 30.0 g of water for injection in which 300 mg of sodium bisulfite had been dissolved in advance was mixed and heated to 60 ° C. in a hot water bath. By stirring, an edaravone solution was obtained. Further, sterilization filtration was performed, and the resulting solution was placed in a clean bench every 1.0 g in a 2 mL-volume low-density polyethylene injection container with a needle (made by Nippon Becton Dickinson, trade name: Uniject), and a nitrogen gas stream Filled below and closed with a heat sealer. (Edaravone concentration: 3.0 w / w%, ethanol concentration: 70 w / w%)

Formulation stability The stability of each prepared formulation was investigated and the results shown in Table 4 were obtained.

From these results, it was clarified that the chemical stability can be obtained by adding sodium hydrogen sulfite and / or sodium pyrosulfite, although a preparation which is stable at room temperature can be obtained only by adding ethanol.

FIG. 5 is a solubility curve showing the solubility of edaravone in ethanol / water at 4 ° C. and 25 ° C. FIG.

Claims (4)

It contains edaravone as an active ingredient at a concentration in the range of 1.5 w / w% to 3.5 w / w%, ethanol as a solubilizer, and 0.025 w sodium bisulfite or sodium pyrosulfate as a stabilizer. Edaravone injection, characterized by containing / w% to 1.0w / w% .   The edaravone injection solution according to claim 1, wherein the ethanol concentration is in the range of 40 w / w% to 80 w / w%.   The edaravone injection solution according to claim 1 or 2, wherein the pH is 4.6 to 6.0.   The edaravone injection solution according to any one of claims 1 to 3, wherein a plastic disposable container having a capacity of 1 mL to 5 mL is filled with a volume of 1 mL to 2 mL.

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