KR101435244B1 - Moxifloxacin formulation and method of preparing the same - Google Patents

Abstract

The present invention relates to a method for the preparation of a moxifloxacin aqueous formulation and to a moxifloxacin aqueous formulation prepared therefrom, and more particularly to a method for the preparation of a moxifloxacin aqueous formulation comprising dissolving moxifloxacin free base in an aqueous NaCl solution And a moxifloxacin aqueous formulation prepared therefrom.
According to the present invention, it is possible to provide a moxifloxacin male type formulation and a manufacturing method thereof, which are excellent in quality, content uniformity and accuracy, and simple in manufacturing process, because hygroscopicity is not a problem in the manufacturing process and storage .

Description

≪ Desc / Clms Page number 1 > MOXIFLOXACIN FORMULATION AND METHOD OF PREPARING THE SAME < RTI ID =

More particularly, the present invention relates to a water-in-oil liquid formulation for moxifloxacin and a method for producing the same. More specifically, the present invention relates to a water-in- And a method for producing the same.

Moxifloxacin hydrochloride represented by the following formula (1) is an antibiotic compound of the known 8-methoxyquinolonecarboxylic acid class, and an aqueous formulation containing it is commercially available as an intravenous infusion product developed by Bayer AG under the trade name Avelox .

[Chemical Formula 1]

Korean Patent No. 10-0735788 discloses an aqueous formulation comprising moxifloxacin hydrochloride and sodium chloride for preventing or treating bacterial infection in humans or animals, US Patent No. 6916484 is used as an injecting solution and stored There has been disclosed an aqueous formulation containing moxifloxacin hydrochloride having excellent stability and glucose, mannitol, iron of 10 ppb or less and the like. However, there is a problem that uniformity and accuracy of content are inferior due to hygroscopicity of moxifloxacin hydrochloride.

In addition, Korean Patent No. 10-0525146 discloses that moxifloxacin hydrochloride anhydride absorbs water when stored in the atmosphere or in the presence of water due to hygroscopicity and when the active ingredient is processed into a pharmaceutical form, Discloses a novel moxifloxacin hydrochloride monohydrate which can improve the storage stability at high humidity and can stably produce a pharmaceutical composition, and a method for producing the same. However, since the preparation process is difficult and the preparation step is too much, There is a problem that production is not easy.

Therefore, it is urgently required to develop a method for producing a moxifloxacin male type formulation which is excellent in uniformity and accuracy of content for prevention or treatment of bacterial infection in humans or animals, and is easy in mass production because of a simple manufacturing process.

In order to solve the problems of the prior art as described above, it is an object of the present invention to provide a moxifloxacin male type formulation suitable for mass production because it is excellent in quality, uniformity in content and accuracy, And a method for producing the same.

These and other objects of the present invention can be achieved by the present invention described below.

In order to achieve the above object, Which comprises dissolving a moxifloxacin free base, and a moxifloxacin aqueous formulation made therefrom.

The step of dissolving the moxifloxacin free base may be a step of dissolving moxifloxacin free base in an aqueous salt solution, an aqueous acid solution or a mixed solution thereof.

The aqueous salt solution may be an aqueous NaCl solution.

The NaCl aqueous solution is preferably an aqueous solution of 0.4 to 1.2% NaCl.

Preferably, the free radical scavenging base is 0.05 to 0.5 g based on 100 ml of the NaCl aqueous solution.

The moxifloxacin free base is prepared by dissolving moxifloxacin salt in water and then extracting moxifloxacin free base with an organic solvent which is not mixed with water or adding an organic solvent mixed with water to recrystallize the moxifloxacin organic base Step < / RTI >

The moxifloxacin free base may be prepared by further dissolving the moxifloxacin salt in water and then adding a base before extracting or recrystallizing the free moxifloxacin free base.

INDUSTRIAL APPLICABILITY As described above, according to the present invention, it is possible to provide a moxifloxacin male type formulation and a method for producing the same, which are excellent in quality, content uniformity and accuracy, and simple in manufacturing process, There is an effect to provide.

Hereinafter, the present invention will be described in detail.

The method of manufacturing the aqueous formulation of Moxifloxacin of the present invention is characterized by including the step of dissolving Moxifloxacin free base in an aqueous NaCl solution.

In the present specification, moxifloxacin free base, moxifloxacin hydrochloride and moxifloxacin hydrochloride monohydrate refer to the compounds shown in Tables 1 to 3, respectively.

[Chemical Formula 1] (free base)

[Chemical Formula 2] (hydrochloride salt)

[Chemical Formula 3] (hydrochloride monohydrate)

In the specification, aqueous formulation means that the formulation components are present in water, and% (w / v) means weight (g) per 100 ml of capacity, i.e. g / 100 ml.

When the moxifloxacin free base is dissolved in the aqueous solution of NaCl, the operation is not affected by humidity and there is no change in the content, and the dissolving speed is fast and the working time is greatly shortened.

When the moxifloxacin free base is used, the content accuracy is excellent compared to when moxifloxacin hydrochloride is used, the content uniformity and quality are excellent in mass production, and compared with the case of using moxifloxacin hydrochloride monohydrate, And thus it has an economical effect.

Due to its hygroscopicity, the hydrolyzate of moxifloxacin hydrochloride requires strict handling conditions, and the dissolution rate is slow, which requires a long working time.

The NaCl aqueous solution may be an aqueous solution of 0.4 to 1.2% NaCl, preferably an aqueous solution of 0.6 to 1.0% NaCl, more preferably an aqueous solution of 0.7 to 0.9% NaCl. Within this range, the solubility of moxifloxacin free base is excellent The working time is greatly shortened and the osmotic pressure can be easily adjusted to the physiological condition.

The aqueous NaCl solution may be, for example, a solution prepared by dissolving sodium chloride in water or a solution prepared by diluting a physiological saline solution.

The moxifloxacin may be contained in an amount of 0.05 to 0.5 g based on 100 ml of the NaCl aqueous solution, preferably 0.08 to 0.32 g, more preferably 0.1 to 0.2 g, most preferably 0.0 > g. ≪ / RTI >

The process for preparing the moxifloxacin aqueous formulation comprises i) dissolving moxifloxacin free base in an aqueous NaCl solution; And ii) adjusting the pH by adding an acid.

In addition, the method for preparing the aqueous flocasin formulation of the present invention comprises the steps of: i) acidifying an aqueous NaCl solution by adding an acid thereto; And ii) dissolving the moxifloxacin free base in the acidified NaCl aqueous solution.

The acid is preferably HCl.

The HCl is preferably a 10 to 35% aqueous HCl solution, more preferably a 10 to 25% aqueous HCl solution, most preferably a 10 to 15% aqueous HCl solution.

The acidification may be adjusted to a pH of 1.0 to 6.0, preferably 3.0 to 5.0, more preferably 3.5 to 5.0, and most preferably 4.0 to 4.6.

The method of the present invention may further comprise the step of adjusting the concentration of NaCl and Moxifloxacin by adding a diluent as necessary.

The diluent may be water.

The method for preparing the aqueous flocosaccharide formulation of the present invention comprises dissolving moxifloxacin salt in water and then extracting moxifloxacin free base with an organic solvent (organic layer) which is not mixed with water or adding an organic solvent to be mixed with water, And recrystallizing the germanium organic base.

It may be preferable to dissolve the moxifloxacin salt in water and then add the base before extracting or recrystallizing the moxifloxacin free base.

The moxifloxacin salt is preferably moxifloxacin hydrochloride anhydride.

The base is preferably a NaOH aqueous solution.

The base may be added in such an amount that the pH of the aqueous solution of moxifloxacin is 6.0 to 9.0, preferably 7.0 to 9.0, more preferably 7.5 to 8.5, and most preferably 8.0 to 8.5. In the amount of.

The moxifloxacin aqueous formulation of the present invention is characterized in that it is prepared by the method of manufacturing the moxifloxacin aqueous formulation.

The moxifloxacin aqueous formulation may contain moxifloxacin in an amount of 0.08 to 0.32% (w / v), preferably 0.1 to 0.2%, more preferably 0.14 to 0.18%, and most preferably 0.16 % (For example, 400 mg / 250 ml).

The moxifloxacin aqueous formulation may contain 0.4 to 0.9% (w / v) NaCl, preferably 0.5 to 0.9%, more preferably 0.7 to 0.9%, and most preferably 0.8% Within this range, the osmotic pressure of 270 to 350 mOsmol / kg, which is suitable for physiological conditions, is effective to avoid the damage of red blood cells and irritation of tissues due to hypotonic or hyperosmotic conditions.

Preferably, the aqueous ophthalmic suspension formulation has an osmolality of 270 to 350 mOsmol / kg.

The moxifloxacin aqueous formulation may further comprise a pH adjusting agent conventionally used in the parenteral dosage form.

The pH adjusting agent may be HCl, NaOH or the like.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention. Such variations and modifications are intended to be within the scope of the appended claims.

[Example]

Production Example 1

≪ Preparation of Moxifloxacin free base >

100 g of Moxifloxacin hydrochloride and 1500 g of water were added and stirred. To this mixture was added 1500 mL of dichloromethane and the mixture was stirred vigorously. After adjusting the pH of the mixed solution to 8.0 with 1N aqueous NaOH solution and vigorously stirring, the solution was allowed to stand to extract (separate) the dichloromethane layer (organic layer). 1000 mL of dichloromethane was added to the water layer, and the mixture was vigorously stirred for 5 minutes. After standing for 5 minutes, the dichloromethane (organic layer) was extracted and the dichloromethane (organic layer) was combined with the previously extracted dichloromethane (organic layer). 1000 g of tertiary purified water was added to the combined dichloromethane, stirred vigorously for 5 minutes, and then allowed to stand to extract dichloromethane. 10 g of magnesium sulfate was added to the extracted dichloromethane, stirred for 10 minutes, and then filtered to obtain a filtrate. The filtrate was concentrated at 45 캜 to obtain a concentrate. 1000 mL of ethanol was added to the obtained concentrate, and the mixture was agitated for 1 hour to agitate (crystallize) the solid. The crystallized solid was filtered and the filtered solid was dried at 70 ° C for 16 hours to finally yield 77.9 g of light yellow crystalline Moxifloxacin free base.

Production Example 2

100 g of Moxifloxacin hydrochloride and 1000 g of water were added and stirred. 10% NaOH aqueous solution was added to the mixed solution to adjust the pH to 8.1, and the mixture was further stirred for 1 hour. 1000 mL of dimethylsulfoxide was slowly added dropwise to this mixed solution to precipitate a solid. The mixture in which the solid was precipitated was stirred for 2 hours at 25 DEG C to agitate (crystallize) the solid. The crystallized solid was filtered and the filtered solid was dried at 70 ° C for 16 hours to finally yield 82.5 g of pale yellow crystalline moxifloxacin free base.

Example 1

0.4 g of Moxifloxacin free base prepared in Preparation Example 1 or 2 was dissolved in 0.8% NaCl aqueous solution and 15% hydrochloric acid aqueous solution was added thereto to prepare a moxifloxacin mixed solution having pH adjusted to 4.26.

The prepared moxifloxacin mixed solution was filtered through a 0.2 μm sterilizing filter, each was injected into a 250 ml glass bottle, sealed, and then sterilized in an autoclave at 120 ° C. for 20 minutes to prepare a moxifloxacin aqueous formulation.

Example 2

The pH was adjusted to 4.5 by adding a 10% hydrochloric acid aqueous solution to a 0.8% NaCl aqueous solution. Then, 0.4 g of Moxifloxacin free base prepared in Preparation Example 1 or 2 was cooled to room temperature and then immediately added and dissolved. Flocassin mixture was prepared.

The prepared moxifloxacin mixed solution was filtered through a 0.2 μm sterilizing filter, each was injected into a 250 ml glass bottle, sealed, and then sterilized in an autoclave at 120 ° C. for 20 minutes to prepare a moxifloxacin aqueous formulation.

Consequently, the moxifloxacin aqueous formulations (Examples 1 and 2) according to the present invention are much easier to work and significantly shorten the manufacturing time compared to the method of making moxifloxacin aqueous formulations using flocosaccharide hydrochloride , Content uniformity, accuracy and storage stability were all excellent.

[Test Example]

The solubilities of the moxifloxacin free base and moxifloxacin hydrochloride are shown in Table 1 below.

division Solubility (mg / ml, 25 캜) 0.9% NaCl solution 0.9% NaCl solution, pH = 4.1 to 4.6 Moxifloxacin glass base 23 3 Moxifloxacin hydrochloride 3 3

As shown in Table 1, the solubility of Moxifloxacin free base was about 8 times higher in NaCl aqueous solution than the solubility of Moxifloxacin hydrochloride in aqueous NaCl solution, and it was confirmed that the pH was controlled in the NaCl aqueous solution.

Claims (12)

And dissolving moxifloxacin free base in water in the presence of NaCl. ≪ RTI ID = 0.0 > 11. < / RTI > The method according to claim 1,
Wherein the step of dissolving the moxifloxacin free base is a step of dissolving moxifloxacin free base in a NaCl aqueous solution or a mixed solution of an aqueous NaCl solution and an aqueous acid solution. delete 3. The method of claim 2,
Wherein the aqueous NaCl solution is a 0.4 to 1.2% (w / v) aqueous NaCl solution. 3. The method of claim 2,
Wherein the moxifloxacin free base is 0.05 to 0.5 g based on 100 ml of the NaCl aqueous solution. The method according to claim 1,
The moxifloxacin free base is prepared by dissolving moxifloxacin salt in water and then extracting moxifloxacin free base with an organic solvent which is not mixed with water or adding an organic solvent to be mixed with water to recrystallize moxifloxacin organic base ≪ RTI ID = 0.0 > 1, < / RTI > The method according to claim 6,
Wherein the moxifloxacin free base is prepared by further dissolving the moxifloxacin salt in water and then adding a base before extracting or recrystallizing the free moxifloxacin free base. ≪ / RTI >
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