WO2004058261A1

WO2004058261A1 - Antibacterial water-based preparation

Info

Publication number: WO2004058261A1
Application number: PCT/JP2003/016451
Authority: WO
Inventors: Yoshimine Fujii; Toshiaki Tomitsuka
Original assignee: Daiichi Pharmaceutical Co., Ltd.
Priority date: 2002-12-24
Filing date: 2003-12-22
Publication date: 2004-07-15
Also published as: TW200507845A; JP2006151808A; AU2003289478A1

Abstract

An antibacterial water-based preparation which contains the following ingredients (A) and (B): (A) a quinolonecarboxylic acid type antibacterial and (B) a sugar alcohol. The antibacterial water-based preparation has improved stability.

Description

Antibacterial aqueous formulation technical field

The present invention relates to a liquid preparation containing a quinolonecarboxylic acid-based antibacterial agent having improved stability, and a method for producing the same.

Light

Background art

Rice field

Quinolonecarboxylic acid derivatives are useful as pharmaceuticals because of their high antibacterial activity and safety, and various derivatives have been reported (JP-A-2-231475). Among them, sitafloxacin [In the present specification, names based on international common names (INN: International Nonproprietary Names) are used. Has a particularly strong antibacterial activity, but has the problem of reduced photostability in aqueous solutions. However, there is a known liquid formulation that solves this problem by coexisting sodium chloride in an aqueous solution of sitafloxacin. Have been. However, the coexistence of sodium chloride is not necessarily an effective method for all quinolone carboxylic acid antibacterial agents, and for quinolone carboxylic acid antibacterial agents other than sitafloxacin, the antimicrobial degradation of the quinolone carboxylic acid antibacterial agent is not affected. It is difficult to prevent (International Publication No. WO 01/80858). In addition, (1) -17-[(7S) -17_amino-5-azaspiro [2.4] heptane-15-yl] -16-fluoro 1-[(1R) , 2S) 12-Fluoro-1-cyclopropyl] 1-1,4-dihydro-1-methoxy-4-oxo-1-3-quinolinecarponic acid monohydrochloride monohydrate (International Publication No. 0 1/72738) Brochure) had problems with aqueous solutions such as decomposition by light and insoluble fine particles.

Therefore, the present invention provides an antibacterial aqueous preparation containing the quinolone carboxylic acid-based antibacterial agent, which improves the stability of the aqueous solution containing the antibacterial agent and is intended for parenteral use, and a method for producing the same. The purpose is to: 6451 DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies on an antibacterial aqueous preparation containing a quinolone carboxylic acid antibacterial agent and found that the addition of sugar alcohols to the quinolone carboxylic acid antibacterial agent significantly improved the stability. Heading, the present invention has been completed. Ie

The present invention provides the following components (A) and (B):

(A) Quinolonecarboxylic acid antibacterial agent

(B) Sugar alcohols

The present invention provides an antimicrobial aqueous preparation containing:

Further, the present invention provides a method for producing an antibacterial aqueous preparation, which comprises a step of preparing an aqueous solution in which a quinolone carboxylic acid antibacterial agent and a sugar alcohol are dissolved, and a step of adjusting the pH of the aqueous solution. It is.

Furthermore, the present invention provides a method for stabilizing an aqueous preparation containing a quinolonecarbonic acid-based antibacterial agent, which comprises adding a sugar alcohol, and an insoluble solution in an aqueous preparation, which comprises adding a sugar alcohol. It is intended to provide a method for suppressing the production of raw fine particles.

Still further, the present invention is characterized in that a sugar alcohol is compounded, a method for producing a stable aqueous formulation containing a quinoline carboxylic acid-based antibacterial agent, and sugar alcohols are compounded. An object of the present invention is to provide a method for producing an aqueous preparation in which generation of insoluble fine particles is suppressed. BEST MODE FOR CARRYING OUT THE INVENTION

The component (A) constituting the antibacterial aqueous preparation of the present invention includes the following general formula (1)

Or a salt thereof. One

In the formula (1), R ¹ represents an amino group, a methylamino group, a hydroxyl group, a thiol group or a hydrogen atom, and is preferably a hydrogen atom. R ² is the following substituent

(Wherein, R ^{1 2} and R ^{1 3} form a methylene chain jointly, 3 form a 6-membered ring.) At either ³ cyclopropane in 4-position carbon atoms of spiro-linked - human It indicates Dorokishi pyrrolidinyl group, the R ^2, a methylene chain forms a form jointly with R ^{1 2} and R ^{1 3} is, preferably forming a 3-6 membered ring, to form a three-membered ring Is particularly preferred.

A represents a C one X ³ or a nitrogen atom, C one X ³ are preferred. X ³ is a straight-chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, and cyclobutyl. C1-C6 alkoxy groups such as linear, branched or cyclic alkyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, A trifluoromethyl group or a hydrogen atom. Of these, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms is preferable, and an alkoxy group having 1 to 6 carbon atoms is more preferable. Methoxy groups are particularly preferred.

X ¹ and X ² each independently represent a halogen atom, and each is preferably a fluorine atom.

Z represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxyalkyl group having 1 to 6 carbon atoms in which the alkyl group having 1 to 6 carbon atoms is substituted with the alkoxy group having 1 to 6 carbon atoms ( For example, a methoxyalkyl group, a methoxyethyl group, an ethoxymethyl group, etc., a phenylalkyl group of an alkyl chain having 1 to 6 carbon atoms in which the alkyl group having 1 to 6 carbon atoms is substituted with a phenyl group (for example, a benzyl group) , Phenethyl group, etc.), phenyl group, acetomethyl group, bivaloyloxymethyl group, ethoxycalponyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group 5-substituted 1-2-oxo-1,3 —Dioxo ^ "Lou 4-ylmethyl And a 3-acetoxy-2-oxobutyl group, of which a hydrogen atom is preferable.

Salts of the compound represented by the formula (1) include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, hydrobromic acid and hydroiodic acid, p-toluenesulfonic acid, Salts of organic acids such as tansulfonic acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, maleic acid and fumaric acid, and ions of alkali metals such as sodium, potassium and lithium, and alkaline earth metals such as magnesium and calcium Can be mentioned. Further, the conjugate represented by the formula (1) can be used in the form of a solvate or a solvate of a salt thereof. Solvates include those formed by absorbing moisture in the air, in addition to solvates to which the solvent used for crystal crystallization has been added. Examples of the solvent include organic solvents such as methanol, ethanol, propanol, acetone and acetonitrile, and water. The quinolone carboxylic acid antibacterial agent used in the present invention includes the following formula (2):

(1) 17-[(7S) -7-Amino-5-azaspiro [2.4] heptane-5-yl]-6-fluoro-1-1 [(1R, 2S) -2-fluoro- [1-cyclopropyl] 1-1,4-dihydro-8-methoxy-14-oxo-3-quinolinecarboxylic acid, a salt thereof or a solvate thereof, preferably a hydrate of the salt Is more preferred. This compound is known as a synthetic antibacterial agent having a strong antibacterial activity (Japanese Patent No. 27145997 and Japanese Patent No. 2917010).

The aqueous preparation containing the quinoline carboxylic acid antibacterial agent of the present invention improves the stability and stability of the active ingredient quinoline carboxylic acid antibacterial agent by allowing sugar alcohols to coexist in the aqueous solution. Things. Examples of sugar alcohols include sonorebit 03 016451 Monolith, mannitol, xylitol, erythritol, manoletitone, inositol, etc., and sorbitol, mannitol or xylitol are more preferable, and sorbitol or mannitol is particularly preferable.

The content of the quinoline carboxylic acid antibacterial agent in the aqueous solution is not particularly limited, and should be set according to the purpose of use and the method of use within the range of the solubility of the quinoline carboxylic acid antibacterial agent in water. Can be. The content can be, for example, in the range of 0. ι to ιοοο mg / mL.

The content of sugar alcohols in the aqueous solution is preferably in the range of 0.05 to 20% by weight, more preferably in the range of 1 to 20% by weight, and more preferably in the range of 1 to 15% by weight. More preferably, it is in the range of 1 to 10% by weight.

The antibacterial aqueous preparation of the present invention is produced from a step of preparing an aqueous solution in which a quinolone carboxylic acid antibacterial agent and sugar alcohols are dissolved, and a step of adjusting the pH of the aqueous solution with a pH adjusting agent. be able to. For example, it can be performed according to the following procedure. That is, the quinolone carboxylic acid antibacterial agent and the sugar alcohol are added to water for injection, dissolved by stirring, etc., adjusted to pH by adding a pH adjuster, and then added to water for injection. Adjust the solution volume to a predetermined volume, and adjust the pH as needed.

As the pH adjuster of the aqueous solution, an acid, a base, an aqueous solution thereof, or a combination thereof can be generally used. As the base or its aqueous solution, a dilute aqueous solution may be used, and an aqueous solution of about 1 mol 1 ZL can be used. Solid or powdered sodium hydroxide may be used in addition to the aqueous solution. The base is not limited to sodium hydroxide. The acid is not limited to hydrochloric acid, and a solid or powdered material other than an aqueous solution, such as citric acid, may be used.

The pH of the aqueous solution is preferably in the range of 2 to 7, more preferably in the range of 3 to 7, and particularly preferably in the range of 3.5 to 6.5.

The water used to produce the aqueous preparation is not particularly limited as long as it can be used for pharmaceuticals. Water for injection or water of the same standard can be used. The aqueous preparation of the present invention includes ampoules, vials, plastic containers, syringes and the like. Although it can be filled into various containers of TJP2003 / 016451, it is preferable to use non-glass containers such as plastic containers because glass components may be liberated in aqueous preparations. Materials for plastic containers include polyethylene resin, polypropylene resin, polystyrene resin, polyvinyl chloride resin, polyvinylidene chloride resin, fluorine resin, polyacrylonitrile resin, polyacrylamide resin, polyacrylic resin, and polymethacryl. Examples thereof include a methyl acid resin, a polyacetic acid butyl resin, and a cyclic olefin copolymer resin. Among these resins, a polyethylene resin, a polypropylene resin or a cyclic olefin copolymer resin is preferred. The aqueous preparation of the present invention produced as described above can be sterilized by a usual method such as filtration, heating and the like. The aqueous preparation of the present invention may further contain a solubilizing agent, a component as a buffer, and a stabilizer other than sugar alcohols. The aqueous formulation of the present invention is suitable for injections because of its high stability and stability, but it can be used not only for systemic administration such as injection and infusion, but also for local administration such as external solutions and sprays. it can. Example

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Examples of the quinolone carboxylic acid derivatives include (1) 17-[(7S) -17-amino-5-azaspiro [2.4] heptane-5-inole] -6-funolelol 11-((1R, 2S) — 2-Fluoro-1-cyclopropyl] — 1,4-dihydroxy 8-Methoxy 4-oxo-13-quinolinecarboxylic acid monohydrochloride monohydrate (hereinafter referred to as “compound a”) and hydrochloric acid For sodium hydroxide, sodium chloride, sodium salt, sorbitol, mannitol and glucose, reagents of special grade were used.

Example 1

(1) Preparation of compound a aqueous solution

According to the formulation shown in Table 1 below, Compound a and sorbitol (or mannitol) as an isotonic agent were dissolved in water for injection to make a total volume of 2 OmL. Here, 0. lmo, l ZL hydroxide Ihinatoriumu aqueous solution was添Ka卩was adjusted to _P H 5. 0, the following compounds a Of aqueous solutions A, B, C and D were prepared. To the aqueous solutions C and D, sodium chloride or glucose was added as a tonicity agent, respectively, for comparison. Each prepared aqueous solution was filled into a 20 nxL colorless glass sample and subjected to autoclaving.

table 1

(2) Stability evaluation (content)

After heat treatment of compound a aqueous solution A to C after high-pressure steam sterilization (heating for 2 weeks at 60 ° C) or light irradiation treatment (using a D65 lamp for 1.2 million LxZ hours), the content of compound a was reduced. It was measured by high performance liquid mouth chromatography. The aqueous solution immediately after autoclaving was used as a sample of Initial for evaluating the stability. Operating conditions; column: Symmetry C18, detection wavelength: 295 nm, mobile phase: 0.05 M phosphate buffer (pH 2.4): methanol: acetonitrile = 28: 7: 2. Table 2 shows the results. Table 2

Content

Aqueous solution storage conditions

(% Of display amount)

initial 99.5

A

60 ° C, 2W 99.9

(Sorbitol)

1.2 million Lxhr 96.5

initial 99.7

B

.

(Mannitol) 60C, 2W 99.9

1.2 million Lxhr 96.1

initial 98.7

C

60. C, 2W 99.4

(Sodium chloride)

1.2 million Lxhr 93.6 As a result, in the heat treatment, no decrease in the content of the compound a in the aqueous solution was observed when any of sorbitol, mannitol and sodium chloride was used as the tonicity agent. On the other hand, in the light irradiation treatment, a decrease in the content of compound a was observed when sodium salt was used, as compared with the case where sorbitol and mannitol were used.

(3) Stability evaluation (insoluble fine particles)

After heat treatment at 60 ° C. for 2 weeks with respect to the aqueous solutions A to D of the compound a after the high-pressure steam sterilization, insoluble fine particles in each aqueous solution were evaluated. Table 3 shows the results. The evaluation is based on the insoluble particle test method 2 for injections (microscopic method) specified in the Japanese Pharmacopoeia. In the case of injections, the limit of insoluble fine particles in Japan is that when converted to the number in lmL, the number of particles with a length of 10 m or more is 20 or less, and the number of particles with a length of 25 m or more is 2 or less. It is defined in the pharmacopeia.

As a result, in the Shiridani sodium formulation, a remarkable increase in the number of insoluble fine particles was observed, while in the glucose prescription, many insoluble fine particles were observed with the naked eye immediately after high-pressure steam sterilization. It could not be measured because it was too long. Table 3

Example 2

In accordance with the formulation shown in Table 4 below, the aqueous solutions E to G were prepared and filled into a 20 mL colorless glass ampoule. After high-pressure steam sterilization and heat treatment at 60 ° C for 2 weeks, insoluble fine particles were evaluated. Table 5 shows the results. Table 4

Table 5

In the aqueous formulation with ρΗ6, insoluble fine particles were already observed immediately after autoclaving, and a significant increase in insoluble fine particles was observed after heat treatment.

Example 3

According to the formulation shown in Table 6 below, an aqueous solution (pH 4) of the compound 1 was prepared, and each of the colorless glass sample and the plastic bottle was filled with 10 OmL. After high-pressure steam sterilization and heat treatment at 60 ° C for 2 weeks, the content of insoluble fine particles was evaluated. Table 7 shows the results.

¾ 6

Purpose of use Component Amount

Active ingredient Compound a (free form) 225mg (200rag)

Isotonizing agent Sorbitol 5000rag

Hydrochloric acid, Nato hydroxide

pH adjuster qs (pH4)

Dream

Solvent Water for injection lOOmL JP2003 / 016451 Table 7

In the case of the compound a preparation filled with 100 mL of glass vial, an increase in insoluble fine particles was observed after the heat treatment, but no increase was observed in the case of filling in a plastic bottle. Industrial applicability

The antibacterial aqueous preparation containing the quinoline carboxylic acid antibacterial agent and the sugar alcohol of the present invention has high stability and is particularly useful for parenteral use.

Claims

The scope of the claims

1. The following components (A) and (B):

(A) Quinolonecarboxylic acid antibacterial agent

(B) Sugar alcohols

An antibacterial aqueous preparation containing:

2. Component (A) has the following general formula (1)

[Wherein, R ¹ represents an amino group, a methylamino group, a hydroxyl group, a thiol group or a hydrogen atom; R ² represents a substituent described below.

(Wherein, R ¹² and R ¹³ together form a methylene chain to form a 3- to 6-membered ring) or 3-hydroxypyrrolidinyl in which cyclopropane is spiro-bonded to the carbon atom at position 4. A represents C—X ³ or a nitrogen atom; X ¹ and X ² each independently represent a halogen atom; X ³ represents an alkyl group having 1 to 6 carbon atoms and 1 carbon atom. Z represents an alkoxy group, trifluoromethyl group or a hydrogen atom; Z is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, an alkyl chain having 1 to 6 carbon atoms Phenylalkyl, phenyl, acetomethyl, bivaloyloxymethyl, ethoxycarboxy, choline, dimethylaminoethyl, 5-indanyl, phthalidinyl, 5-substituted 1-2- Kiso 1, 3—Dioxol Indicates a 4-ylmethyl group or a 3-acetoxy-2-oxobutyl group. The compound according to claim 1, which is a compound represented by the formula: Antibacterial aqueous preparation.

3. Ingredient (A) Force (1-) 17-[(7S) 17-amino-5-azaspiro [2.4] heptane-5-yl] 1-6-fluoro-11- [(1 R, 2 S 3.) The antimicrobial aqueous preparation according to claim 1, which is a 2-fluoro-1- [1-cyclopropyl] -1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid or a salt thereof.

4. The antibacterial aqueous preparation according to any one of claims 1 to 3, wherein the pH of the aqueous solution is in the range of 2 to 7.

5. The antibacterial aqueous preparation according to any one of claims 1 to 4, wherein the ingredient (B) is sorbitol or mannitol.

6. The content of component (B) is in the range of 0.05 to 20% by weight. The antibacterial aqueous preparation according to any one of claims 1 to 5.

7. The antibacterial aqueous preparation according to claim 1, which is filled in a plastic container.

8. The antibacterial aqueous preparation according to claim 7, wherein the plastic container is made of a polyethylene resin, a polypropylene resin or a cyclic olefin copolymer resin.

9. A method for producing an aqueous antibacterial preparation, comprising a step of preparing an aqueous solution in which a quinoline carboxylic acid antibacterial agent and a sugar alcohol are dissolved, and a step of adjusting the pH of the aqueous solution.

10. A method for stabilizing an aqueous preparation containing a quinolone carboxylic acid antibacterial agent, which comprises adding a sugar alcohol.

1 1. A method for suppressing the formation of insoluble fine particles in an aqueous preparation, which comprises adding a sugar alcohol.

12. The method for suppressing generation of insoluble fine particles in an aqueous preparation according to claim 11, wherein the aqueous preparation contains a quinolone carboxylic acid antibacterial agent.

13. The method according to claim 10 or 11, wherein the sugar alcohol is sorbitol or mannitol.

14. The quinolone carboxylic acid is (1-) 17-[(7S) 17-amino-5- Zaspiro [2.4] heptane-5-yl] -1-6-fluoro-11-[(1R, 2S) 1-2-fluoro-1-1-cyclopropyl] —1,4 dihydro 8-—methoxy-4-1-oxo-3— The method according to claim 10 or 12, which is quinoline carboxylic acid or a salt thereof.

15. A method for producing a stabilized aqueous preparation containing a quinoline carboxylic acid antibacterial agent, which comprises adding a sugar alcohol.

16. A method for producing an aqueous preparation in which formation of insoluble fine particles is suppressed, characterized by incorporating a sugar alcohol.

17. The production method according to claim 16, wherein the aqueous preparation contains a quinoline carboxylic acid antibacterial agent.

18. The production method according to claim 15, wherein the sugar alcohol is sorbitol or mannitol.

19. Quinolonecarboxylic acid is (1-) 17-[(7S) 17-amino-5-azaspiro [2.4] heptane-5-yl] 16-fluoro-11- [(1 R, 2 S) 12-Funoleolone 1-cyclopropinole] The production method according to claim 15 or 17, which is 11,4-dihydro-18-methoxy-4-oxo-13-quinolinecarboxylic acid or a salt thereof.