KR100213696B1 - Methods for the preparation of antibacterial solution with the good stability comprising quinolone carboxylic acids - Google Patents

Abstract

The present invention relates to a method for preparing a stable antibacterial aqueous solution of quinolone carboxylic acid having excellent storage stability. The preservative is added to distilled water, heated to 70-90 ° C., dissolved, and then cooled to 30-50 ° C. And dissolving aids are added to dissolve, the excess inorganic base is added and stirred to dissolve to pH 13-14, and then the quinolone carboxylic acid active compound of Formula 1 or Formula 2 is added to dissolve and stirred, and the pH is By adjusting the pH by adding acid to 10 to 11.5, an aqueous solution of an antibacterial agent of quinolone carboxylic acid having excellent storage stability is obtained. The production method according to the present invention can easily prepare an aqueous solution of quinolone carboxylic acid antibacterial agent excellent in high purity storage stability in a short time.

Description

Method for producing an antibacterial aqueous solution of quinolone carboxylic acid with excellent storage stability

The present invention relates to a method for preparing an antibacterial aqueous solution of quinolone carboxylic acid having excellent storage stability, and more particularly, to a method for preparing an antimicrobial composition in which an active compound which is poorly soluble in water is rapidly dissolved using a base. .

Quinolone carboxylic acids and their homologues which are used as active compounds in the antibacterial aqueous solution of the present invention are well known. They have a wide range of antimicrobial activities and are widely used as medicines and veterinary medicines.

However, since quinolone carboxylic acid is hardly soluble in water, it is difficult to prepare injectables, injectable solutions or aqueous solutions for oral administration. Since the quinolone carboxylic acid compound of the present invention is an amphoteric compound having both a basic group and an acidic group, the aqueous solution can be prepared when the quinolone carboxylic acid compound of the present invention is made of an acid or a base.

European Patent Publication No. 67,666 describes the salts of the compounds of formulas (I) and (II) and techniques for their preparation, and specific methods for preparing salts having high water solubility to formulate quinolone carboxylic acid compounds in medicine are described. It is described. In this European application, acid addition salts or base addition salts of known quinolone carboxylic acids are not suitable for parenteral formulations, and acid addition salts using certain acids, e.g., galacturonic acid, aspartic acid, glutamic acid and gluconic acid, may be used as pH and water. Although suitable in terms of formulation, formulations of basic salts having a pH above 8.0 are described as not suitable in terms of pH.

However, it is known that an aqueous acid addition salt solution of quinolone carboxylic acid as described above is not suitable for use as an injection because discoloration or precipitation occurs due to prolonged storage.

Therefore, a basic aqueous solution prepared by adding a base is more suitable for parenteral preparations such as injections or liquids, and a known aqueous solution of quinolone carboxylic acid having added a base is dissolved by adding an active compound to distilled water and slowly adding an excess of base. This method has been developed, but since the insoluble carboxylic acid compound is first added to distilled water and a base is added, it takes a considerable time to dissolve, and it is also a considerable force to adjust the pH to an appropriate pH for injection.

Accordingly, an object of the present invention is to provide a method for preparing an aqueous solution of quinolone carboxylic acid antibacterial agent having excellent storage stability in a high yield in a short time by using a suitable dissolution system in order to solve the above disadvantages.

According to the present invention, according to the present invention, depending on the distilled water, the preservative in distilled water, and dissolved by diluting at 70 ~ 90 ℃, and then cooled to 30 ~ 50 ℃, dissolved by adding an antioxidant and a dissolution aid, excess After adding the inorganic base and stirring to dissolve to pH 13 ~ 14, and then stirring to dissolve by adding the quinolone carboxylic acid active compound of the formula (I) or formula (2), acid was added so that the pH is 10 ~ 11.5 It is achieved by the manufacturing method of the quinolone carboxylic acid antibacterial aqueous solution excellent in the storage stability characterized by adjusting.

[Formula 1]

[Formula 2]

Wherein X is N, CH or CF, Z is 0 or CH ₂ , R ₁ is hydrogen, methyl, ethyl or β-hydroxyethyl and R ₂ is cyclopropyl, 2-fluoromethyl or ethyl R ₃ is hydrogen or methyl and R ₄ is hydrogen or methyl.

Here, the preservatives include methyl paraoxybenzoate (methylparaben), propyl paraoxybenzoate (propyl paraben). Sodium benzoate and other nontoxic preservatives may be used alone or in combination. As the antioxidant, sodium bisulfite, sodium metabisulfide pipe, and the like may be used, and as a dissolution aid, lower alcohols such as ethanol, butanol, glycerol, benzyl alcohol, and propylene glycol may be used.

Moreover, potassium hydroxide, sodium hydroxide, calcium hydroxide, etc. are mentioned as said inorganic base, hydrochloric acid etc. are mentioned as said acid.

Preferred compounds of formula (I) or formula (II) are, for example, 1-cyclopropyl-7- (4-ethyl-1-piperazinyl) -6-fluoro-1, 4-dihydro-4-oxo-3- Quinolinecarboxylic acid, 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, or 6,7-dihydro-8- (1 -Piperazinyl) -9-fluoro-5-methyl-1-oxo-benzoquinoline-2-carboxylic acid, etc. are mentioned.

Hereinafter, the present invention will be described in detail.

A method for preparing a stable antimicrobial composition of quinolone carboxylic acid according to the present invention is first, such as methyl paraben, or propyl paraben, benzo paraphosphate, etc. in a predetermined amount (for example 70%) of distilled water corresponding to a part of the total amount in the reactor. Add the preservative, heat it to 70 ~ 90 ℃, completely dissolve the preservative in distilled water, cool the reactor to 30 ~ 50 ℃, antioxidants such as sodium bisulfide, sodium metabisulfide pipe and ethanol, methanol, benzyl alcohol or 1 Completely dissolved by adding a dissolution aid such as butanol, and then adding an excess of a base such as potassium hydroxide or sodium hydroxide to dissolve and stirring to make the pH 13-14, and finally the activity of Chemical Formula 1 or 2 Add compound to stir to dissolve, add acid to pH 10-11.5, and add distilled water until the desired concentration is added. Or to obtain a basic aqueous solution for liquid materials.

When explaining the dissolution mechanism of the method, the active compound of formula (1) or formula (2) is dissolved in water while the 3-carboxyl group is reacted with a base to form a basic salt in a solution containing distilled water and other auxiliary agents and inorganic bases. Since the active compound dissolves better when the basicity is strong, the active compound is dissolved quickly in a solution having a pH of 13 to 14 by adding an excess of base so that the compound dissolves quickly, thereby obtaining a highly pure and uniform component. The auxiliaries are also stirred and dissolved in a heated state, thereby reducing the overall process time.

In addition, when the pH is lowered with hydrochloric acid in the final step to be suitable as an injection, bactericidal hydrochloric acid further enhances the bactericidal effect of bacteria. Sodium bisulfide or the like used as an antioxidant is not changed even when the parasitic aqueous solution of the quinolone carboxylic acid according to the present invention is exposed to light, and thus it is possible to maintain a stable aqueous state without discoloration during storage.

, 바람직하게는 0.1 내지 5밀리당량/

이다.The concentration of the basic salt of the active compound in the basic aqueous solution according to the invention is 0.1 to 20%, more preferably 0.5 to 10%. The amount of inorganic salt added is 0.01-20 milliequivalents /

, Preferably 0.1 to 5 milliequivalents /

to be.

The time required to carry out the production process according to the invention is about 30 minutes to 2 hours, preferably about 40 minutes to 1 hour.

The basic aqueous solution prepared by the above method may be used as an injection, injection, oral solution for treating various bacterial infections due to the characteristics of the compound of Formula 1 or Formula 2 as an active compound, and may be used as a pharmaceutical or veterinary medicine. It has a use as.

The pH of the composition prepared by the method according to the invention is preferably about 10 to 11.5. Therefore, it is further necessary to add hydrochloric acid in the final step to lower the pH to an appropriate value.

Hereinafter, the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Example 1

Distilled water (about 70% of the total amount) was added to the reactor, and 0.72 g of methyl paraben and 0.08 g of propyl paraben were added thereto, and the mixture was heated to 80 ° C. or higher and then dissolved for 10 minutes while stirring.

Subsequently, cooling water was agglomerated in the reactor, cooled to 40 ° C., and 0.8 g of sodium bisulfide and 14.8 ml of 1-butanol were added and dissolved in stirring. 2.78 g of potassium hydroxide was added thereto, stirred, and completely dissolved. Then, a small amount of potassium hydroxide was added to adjust pH, and then the active compound 1-cyclopropyl-7- (4-ethyl-1 10.0 g of piperazinyl) -6-fluoro-1 and 4-dihydro-4-oxo-3-quinolonecarboxylic acid were slowly added to dissolve and distilled water until the total volume became 400 ml. In addition, basic aqueous solutions usable as injections were prepared and sterile filtered.

Example 2

Distilled water (about 70% of the total amount) was added to the reactor, and 0.72 g of methyl paraben and 0.08 g of propyl paraben were added thereto, and the mixture was heated to 80 ° C. or higher and then dissolved for 10 minutes while stirring.

Subsequently, after cooling water was passed through the reactor to 40 ° C., 0.8 g of sodium bisulfide pipe and 14.8 ml of 1-butanol were added and dissolved in stirring. To this, 4.6 g of potassium hydroxide was added and stirred to dissolve completely, and then a small amount of hydrochloric acid was added to form a pH, followed by 1-cyclopropyl-7- (4-ethyl-1-piperazinyl) as an active compound. 20.0 g of -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was slowly added to the solution, dissolved by stirring, and further distilled water was added until the total volume became 400 ml A basic aqueous solution usable was prepared and sterile filtered.

Example 3

Distilled water (about 70% of the total amount) was added to the reactor, and 0.72 g of methyl paraben and 0.08 g of propyl paraben were added thereto, and the mixture was heated to 80 ° C. or higher and then dissolved for 10 minutes while stirring.

Subsequently, after cooling water was passed through the reactor to 40 ° C., 0.6 g of sodium bisulfide pipe and 14.8 ml of 1-butanol were added and dissolved in stirring. 8.24 g of potassium hydroxide was added thereto, stirred to completely dissolve it, and then a small amount of hydrochloric acid was added to form pH, followed by active compound 1-cyclopropyl-7- (4-ethyl-1-piperazinyl). 40.0 g of -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added slowly to dissolve and dissolved, and further distilled water was added until the total volume became 400 ml. A basic aqueous solution usable was prepared and sterile filtered.

Example 4

Distilled water (about 70% of the total amount) was added to the reactor, and 0.54 g of methyl paraben and 0.06 g of propyl paraben were added thereto, and the mixture was heated to 80 ° C. or more and completely dissolved while stirring for 10 minutes.

Subsequently, after cooling water was passed through the reactor to 40 ° C., 0.6 g of sodium bisulfide pipe and 6 g of benzyl alcohol were added and stirred and dissolved. To this, 6.5 g of potassium hydroxide was added, stirred, and completely dissolved. Then, a small amount of potassium hydroxide was added to form a pH, and then the active compound 1-cyclopropyl-7- (4-ethyl-1- 30.0 g of piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is slowly added to the solution, stirred and dissolved, and further distilled water is added until the total volume is 300 ml. In addition, a basic aqueous solution usable as a liquid was prepared and sterile filtered.

[Test Examples 1 to 4]

The properties, pH, titer and reaction time of the active compounds obtained in the above examples were measured by conventional methods, and the results are shown in Table 1. As can be seen from Table 1, it was found that the basic aqueous solution prepared by the method according to the present invention has a pH and titer suitable for use as an injection or a liquid.

As described above, by using the preparation method according to the present invention, by rapidly dissolving the quinolone carboxylic acid active compound in an aqueous solution of high pH, the reaction time is shortened, a uniform aqueous solution of high purity is obtained, manufacturing cost This is reduced.

Claims (2)

Put the preservative in distilled water, dissolve it by heating to 70 ~ 90 ℃, cool to 30 ~ 50 ℃, and add antioxidant and dissolution aid to dissolve, add excess inorganic base and stir to dissolve to pH 13 ~ 14 Then, the quinolone carboxylic acid active compound of the following formula (1) or (2) is added to dissolve and agitate, and the pH is adjusted by adding an acid so that the pH is 10 to 11.5. Method for producing an antibacterial aqueous solution of acid. [Formula 1]

[Formula 2]

The method of claim 1, wherein the preservative is at least one selected from the group consisting of methyl paraben, propyl paraben and sodium benzoate, the antioxidant is sodium bisulfide or sodium metabisulfite, the dissolution aid is ethanol, butanol, At least one member selected from the group consisting of glycerol, benzyl alcohol and propylene glycol, wherein the inorganic base is potassium hydroxide, sodium hydroxide or calcium hydroxide, and the acid is hydrochloric acid. Method of Preparation of the Composition.