KR100840125B1 - High concentration water-solution composition including antibiotic compound - Google Patents

Abstract

The present invention relates to a quinolone carboxylic acid-based antimicrobial compound as 5-oxotetrahydrofuran-2-carboxylic acid (or 2-hydroxy glutaric acid which can be converted therefrom), glutaric acid, glutonic acid, aspartic acid. Or it relates to an aqueous solution composition containing a high concentration of the antimicrobial compound by dissolving with a dissolution aid selected from the group consisting of a mixture of two or more of these. Aqueous solutions of the quinolone carboxylic acid-based antimicrobial compounds may be used for injection, infusion or liquid oral preparations.

Quinolone carboxylic acid-based antibacterial compound, 5-oxotetrahydrofuran-2-carboxylic acid, dissolution aid, glutaric acid, gluconic acid, aspartic acid

Description

High concentration water-solution composition including antibiotic compound

The present invention relates to a high concentration aqueous solution composition of the antimicrobial compound. More specifically, the present invention is an antimicrobial compound of the quinolone carboxylic acid-based antibacterial compound represented by the formula (1) 5-oxotetrahydrofuran-2-carboxylic acid (or 2-hydroxy glutaric acid which can be converted therefrom) The present invention relates to an aqueous solution composition containing a high concentration of an antimicrobial compound by dissolving with a dissolution aid selected from the group consisting of glutaric acid, glutonic acid, aspartic acid or a mixture of two or more thereof. Aqueous solutions of the quinolone carboxylic acid-based antimicrobial compounds may be used for injection, infusion or liquid oral preparations.

In the above formula, R represents (±) -methyl or S-(-)-methyl.                         

The antimicrobial compound of Chemical Formula 1 is (±) -9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [ 1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid or S-(-)-9-fluoro-2,3-dihydro-3-methyl-10- (4 -Methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid, to gram positive and gram negative bacteria It is known to have a broad and strong antimicrobial effect and is a known compound widely used for the treatment of bacterial infections (Antimicrobacterial Agents and Chemotheraphy, 1986, pp 163-164). The antimicrobial compound of Formula 1 has excellent antimicrobial effects as oral and parenteral administration, but has a disadvantage in that it is difficult to make a high concentration aqueous solution formulation because of poor solubility in water of about 0.5%.

Korean Patent Publication No. 87-1958 describes hydrochloric acid, methanesulfonic acid, acetic acid, propionic acid, succinic acid, fumaric acid, lactic acid, etc. as suitable acids generally used in formulating aqueous solutions of low solubility quinolone antimicrobial agents. In addition, Korean Patent Publication No. 94-26654 mentions glucuronic acid, glutamic acid, gluconic acid, galacturonic acid, hydrochloric acid, and the like as a dissolution aid of a quinolone antibacterial agent. In addition, Korean Patent Publication No. 89-2240 describes a method of making an aqueous solution of a quinolone compound using a base such as sodium hydroxide, potassium hydroxide, ethanolamine, lysine, N-methylglutamine, arginine, and the like.

Like the quinolone antimicrobials, the antimicrobial compound of Formula 1 also has low solubility in water, making it difficult to prepare an aqueous solution for injection or infusion, or a liquid oral preparation. In Korean Patent Publication No. 95-15062, reference is made to aqueous pharmaceutical compositions by the incorporation of various additives of the compounds. Additives include hydrochloric acid, sodium hydroxide, sodium chloride, lactic acid, tartaric acid, succinic acid, mannitol, glycerol, etc., but the above additives were not easy to make the antimicrobial compound of Formula 1 to a concentration of about 10% or more, and once the solution Even if it is made as a poor stability in the solution, pH is too low or high, it can be said that the composition has a lot of pharmaceutical problems for use in humans and animals due to inadequate smell.

It is an object of the present invention to provide a pharmaceutical composition containing an organic acid salt of the antimicrobial compound of Formula 1, wherein the solubility in water is improved compared to the salts of acids or bases mentioned above.

The high concentration aqueous solution composition of the antimicrobial compound according to the present invention is a 5-oxotetrahydrofuran-2-carboxylic acid (or a 2-hydroxy glycol which can be converted therefrom) to the quinolone carboxylic acid-based antimicrobial compound represented by Formula 1 below. Solubility is markedly improved over other known salts of organic acids with dissolution aids selected from the group consisting of rutaric acid), glutaric acid, gluconic acid, galacturonic acid, aspartic acid or mixtures of two or more thereof. Solubility, stability of solution, etc. are remarkably improved at pH 4-6, which is suitable for human administration, thereby preparing a highly concentrated solution for injection, injection, or oral administration of a quinolone carboxylic acid-based antimicrobial compound represented by the following formula (1). It is characterized by providing a composition that can be used in humans and animals.                     

Formula 1

In the above formula, R represents (±) -methyl or S-(-)-methyl.

The high concentration aqueous solution composition of the antimicrobial compound according to the present invention is 5-oxotetrahydrofuran-2-carboxylic acid (or the like) which does not cause precipitation other than the quinolone carboxylic acid-based antibacterial compound of the general formula (1) and a conventional additive as an active compound. It further contains an organic acid, such as 2-hydroxy glutaric acid which can be converted into, to significantly enhance the solubility of the antimicrobial compound in water.

The present inventors prepared an aqueous solution using lactic acid, a dissolution aid, in the antibacterial compound of Formula 1 as a conventional molar ratio (antibacterial compound: molar ratio of acid 1: 1.1 to 1.2) as an antimicrobial compound. Was found not to dissolve more than 20% and tended to precipitate easily during storage in saturated solutions.

 A method for preparing a high concentration aqueous solution of the antimicrobial compound of Chemical Formula 1 using other organic acids such as glutaric acid and glucuronic acid is shown in the following examples.

In general, when a large amount of the organic acid is added to a predetermined amount of the antimicrobial compound of Chemical Formula 1, the solubility tends to increase. Therefore, according to the composition of the present invention, it is possible to make the antibacterial compound at a high concentration even without using an organic acid far exceeding the usual molar ratio. In addition, according to the method of the present invention, an aqueous pharmaceutical composition of a high concentration of antimicrobial compound of more than 200 mg / ml can be prepared in the vicinity of pH 4.0 to 6.0, which is good for living organisms.

The inventors of the present invention, 5-oxotetrahydrofuran-2-carboxylic acid (or convertible 2-hydroxygluta), which is an organic acid other than lactic acid, which is most commonly used in preparing a high concentration solution of the antimicrobial compound of Formula 1 It was found that a solution of more than 100 mg / ml, especially a solution of more than 200 mg / ml, can be prepared using lyric acid) and found that this solution is very stable even after long-term storage. This can be said to be very important in terms of providing a pharmaceutical means of choice. Because the aqueous solution of the antimicrobial compound of Chemical Formula 1 can be made in a small volume, it is convenient to transport and store, and can be used as it is in ampoules, vials, bottles, plastic bags, etc. It is also suitable for making products in the form of administration. The composition of the present invention may use water, antibacterial compounds, organic acids and other suitable additives, if necessary. However, in general, the compositions of the present invention can produce a stable high concentration solution with only minimal components of water, antibacterial compounds, and organic acids, which means that the process can be simplified as much as possible from an industrial point of view.

For example, the method for preparing the solution of the present invention will be briefly described as follows. First, the antimicrobial compound represented by Chemical Formula 1 is mixed at a ratio of 1.1 moles of organic acid per mole, and stirred at room temperature for about 16 hours by adding water to make a supersaturated solution, followed by centrifugation to obtain only a supernatant. Taken and quantified by high performance liquid chromatography (HPLC), the pH was measured. The remaining aqueous solution was stored at room temperature for about 7 days to determine whether or not it could be used as an aqueous solution formulation with or without precipitates and the color of the solution.

According to the present invention, the aqueous solution prepared by using 5-oxotetrahydrofuran-2-carboxylic acid in the antimicrobial compound of Formula 1 has surprising advantages in the following points compared to the aqueous solution prepared by using the conventional organic acid. Can be. First, coloring and precipitation did not occur even after long-term storage for more than 2 months in 1,000Lux room light, and there was no decrease in content. Second, there was no pigmentation and precipitation at high temperature and high pressure by sterilization used in general injection preparation. Third, the composition according to the present invention maintained a pH that can be directly administered to the human body without using a suitable pH additive, and significant pH changes were observed even in long-term harsh conditions (40 ℃, -4 ℃, more than 2 months) It wasn't.

Although the following embodiments are illustrated, the following embodiments are only a part of the present invention as an example, which does not limit the scope of the present invention.

Example 1

1g antibacterial compound

0.4 g of 5-oxotetrahydrofuran-2-carboxylic acid

3.3ml of distilled water                     

pH 4.5

Solubility 30% or more

1.0 g of the antimicrobial compound of Formula 1 was weighed, 0.4 g of 5-oxotetrahydrofuran-2-carboxylic acid was weighed and mixed at a ratio of 1: 1.1, and 3.3 ml of distilled water was added thereto, followed by stirring slowly at room temperature. Dissolved over time. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, it was proved to be a very stable solution when 5-oxotetrahydrofuran-2-carboxylic acid was added to the antimicrobial compound of Chemical Formula 1. In this example, only up to 30% aqueous solution was shown, but more than 30% aqueous solution preparation was possible under the same experimental conditions.

Example 2

Antibacterial Compound 10g

4.0 g of 5-oxotetrahydrofuran-2-carboxylic acid

30ml of distilled water

pH 5.0

Solubility 30% or more

Example 3

Antibacterial Compound 30g

12 g of 5-oxotetrahydrofuran-2-carboxylic acid                     

90ml of distilled water

pH 5.1

Solubility 30% or more

Example 4

Antibacterial Compound 1.0g

0.4 g glutaric acid

3.3ml of distilled water

pH 5.0

Solubility 30% or more

1.0 g of the antimicrobial compound of Chemical Formula 1 was weighed, 0.4 g of glutaric acid was weighed and mixed in a molar ratio of 1: 1.1, and 3.3 ml of distilled water was added thereto, and the mixture was slowly stirred at room temperature for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when glutaric acid was added to the antimicrobial compound of Formula 1, all were dissolved and showed 30% or more solubility.

Example 5

Antibacterial Compound 1.0g

0.4 g of L-aspartic acid

3.3ml of distilled water

pH 5.0                     

Solubility 30% or more

1.0 g of the antimicrobial compound of Formula 1 was weighed, 0.4 g of L-aspartic acid was weighed and mixed in a 1: 1.1 molar ratio, and 3.3 ml of distilled water was added thereto, and the mixture was slowly stirred at room temperature and dissolved for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when L-aspartic acid was added to the antimicrobial compound of Formula 1, all of them were dissolved and showed more than 30% solubility, but after about 8 hours, L-aspartic acid was denatured and the color of the solution turned dark brown. .

Comparative Example 1

Antibacterial Compound 1.0g

0.27 g of lactic acid

3.3ml of distilled water

pH 5.5

Solubility 18%

1.0 g of the antimicrobial compound of Chemical Formula 1 was weighed, 0.27 g of lactic acid was weighed and mixed at a molar ratio of 1: 1.1, and 3.3 ml of distilled water was added thereto, and the mixture was slowly stirred at room temperature for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when lactic acid was added to the antimicrobial compound of Chemical Formula 1, it became a supersaturated solution. The solution was centrifuged (10,000 rpm, 2 minutes), the supernatant was taken, and quantified by high performance liquid chromatography. However, in lactic acid salt, when the gastric supernatant was stored at room temperature, precipitation of the antimicrobial compound of Chemical Formula 1 occurred in 24 hours. The precipitate solution was recentrifuged to separate the supernatant, but the precipitate formed again after 24 hours.

Comparative Example 2

Antibacterial Compound 1.0g

3.3 ml of 2N lactic acid

pH 3.0

Solubility 30% or more

1.0 g of the antimicrobial compound of Chemical Formula 1 was weighed, and 3.3 ml of 2N lactic acid was added thereto (this results in a 30% (w / v) aqueous solution), and the solution was slowly stirred at room temperature for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when 2N lactic acid was added to the antimicrobial compound of Formula 1, it showed a solubility of 30% or more, but the pH of the solution was about 3.0, which was not suitable for injection.

Comparative Example 3

Antibacterial Compound 1.0g

3.3 ml of 1.1N hydrochloric acid

pH 1.0

Solubility 8.1%

1.0 g of the antimicrobial compound of Chemical Formula 1 was weighed, and 3.3 ml of 1.1 N hydrochloric acid was added thereto, and the resulting mixture was slowly stirred at room temperature for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when hydrochloric acid was added to the antimicrobial compound of Chemical Formula 1, it became a supersaturated solution. The solution was centrifuged (10,000 rpm, 2 minutes), the supernatant was taken, and quantified by high performance liquid chromatography.

Comparative Example 4

Antibacterial Compound 1.0g

0.56 g of glucuronic acid

3.3ml of distilled water

pH 3.5

Solubility 4.9%

1.0 g of the antimicrobial compound of Chemical Formula 1 was weighed, 0.56 g of glucuronic acid was weighed and mixed in a 1: 1.1 molar ratio, and 3.3 ml of distilled water was added thereto, and the mixture was slowly stirred at room temperature and dissolved for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when glucuronic acid was added to the antimicrobial compound of Formula 1, it became a supersaturated solution. The solution was centrifuged (10,000 rpm, 2 minutes), the supernatant was taken, and quantified by high performance liquid chromatography.

Comparative Example 5

Antibacterial Compound 1.0g                     

0.56 g of citric acid

3.3ml of distilled water

pH 3.3

Solubility 1.3%

1.0 g of the antimicrobial compound of Formula 1 was weighed, 0.56 g of citric acid was weighed and mixed at a ratio of 1: 1.1, and 3.3 ml of distilled water was added thereto, and the mixture was slowly stirred at room temperature for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when citric acid was added to the antimicrobial compound of Formula 1, it became a supersaturated solution. The solution was centrifuged (10,000 rpm, 2 minutes), the supernatant was taken, and quantified by high performance liquid chromatography.

Comparative Example 6

Antibacterial Compound 1.0g

Fumaric acid 0.33 g

3.3ml of distilled water

pH 3.0

Solubility 4.9%

1.0 g of the antimicrobial compound of Chemical Formula 1 was weighed, 0.33 g of fumaric acid was weighed and mixed in a molar ratio of 1: 1.1, and 3.3 ml of distilled water was added thereto, and the mixture was slowly stirred at room temperature for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when fumaric acid was added to the antimicrobial compound of Chemical Formula 1, it became a supersaturated solution. The solution was centrifuged (10,000 rpm, 2 minutes), the supernatant was taken, and quantified by high performance liquid chromatography.

Comparative Example 7

Antibacterial Compound 1.0g

Malic acid 0.4g

3.3ml of distilled water

pH 4.0

Solubility 10.6%

1.0 g of the antimicrobial compound of Formula 1 was weighed, 0.4 g of malic acid was weighed and mixed at a molar ratio of 1: 1.1, and 3.3 ml of distilled water was added thereto, and the mixture was slowly stirred at room temperature for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when the maleic acid was added to the antimicrobial compound of Formula 1, it became a supersaturated solution. The solution was centrifuged (10,000 rpm, 2 minutes), the supernatant was taken, and quantified by high performance liquid chromatography.

Comparative Example 8

Antibacterial Compound 1.0g

Maleic Acid 0.33g                     

3.3ml of distilled water

pH 2.0

Solubility 2.6%

1.0 g of the antimicrobial compound of Chemical Formula 1 was weighed, 0.33 g of maleic acid was weighed and mixed at a molar ratio of 1: 1.1, and 3.3 ml of distilled water was added thereto, and the mixture was slowly stirred at room temperature for about 10 hours. The pH of this solution was measured and left at room temperature for 7 days to observe color change, precipitation, pH change, and the like. In this case, when maleic acid was added to the antimicrobial compound of Chemical Formula 1, it became a supersaturated solution. The solution was centrifuged (10,000 rpm, 2 minutes), the supernatant was taken, and quantified by high performance liquid chromatography.

As described above, according to the present invention, as a dissolution aid, 5-oxotetrahydrofuran-2-carboxylic acid (or 2-hydroxy glutaric acid which can be converted therefrom), glutaric acid, gluconic acid, aspartic acid or these It is effective to provide an aqueous solution composition containing a high concentration of the antimicrobial compound by dissolving with a dissolution aid selected from the group consisting of a mixture of two or more. The high concentration aqueous solution composition of the antimicrobial compound is a quinolone carboxylic acid-based aqueous solution of the antimicrobial compound can be used as an injection, infusion or liquid oral preparation, and because it can be made in a small volume, it is convenient to transport and store, ampoules, vials, bottles In addition, it may be used as it is in a plastic bag, or when used, it is also suitable for making a product in a form in which it is diluted to a necessary concentration upon administration to a human or an animal.

Claims (2)

As an antimicrobial compound, a quinolone carboxylic acid-based antimicrobial compound represented by the following formula (1) is 5-oxotetrahydrofuran-2-carboxylic acid, 2-hydroxy glutaric acid, glutaric acid, gluconic acid, aspartic acid or An aqueous solution composition comprising an antimicrobial compound, characterized in that it is dissolved with a dissolution aid selected from the group consisting of two or more mixtures. (Formula 1)

In the above formula, R represents (±) -methyl or S-(-)-methyl. The method of claim 1, An aqueous solution composition comprising an antimicrobial compound, characterized in that the molar ratio of the dissolution aid to the antimicrobial compound is 1: 1.0 to 2.0 times.