JPH107568A - Aqueous composition of synthetic antimicrobial agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition capable of increasing solubility and directly obtaining an aqueous solution in a neutral area by adding calcium chloride, etc., to a specific pyrrolidone carboxylic acid. SOLUTION: This aqueous composition is obtained by adding (B) a calcium salt (e.g. calcium chloride) and (C) polyvinylpyrrolidone to (A) a pyrrolidone carboxylic acid of formula I or formula II [R1 is a 1-5C alkyl, a 3-6C cycloalkyl, 2,4-difluorophenyl, etc.; R2 is H, a halogen or an amino; R3 is an amino, a 1-5C aminoalkyl, an alkyalmino, alkyl, etc.; A is NCH, etc.; R4 is H or a 1-5C alkyl; B is O or S; X is H r a halogen] which is an amphoteric compound and has antimicrobial activity r its salt and controlling the mixture to pH6.0 to 8.5. Furthermore, e.g. (±)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthylidine-3-carboxylic acid paratoluenesulfonate hydrate is preferably used as the component A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an aqueous synthetic antibacterial agent composition containing a pyridonecarboxylic acid having an antibacterial activity and a salt thereof.

[0002] Pyridonecarboxylic acid is a compound having, as its partial skeleton, 1,4-dihydropyridine having a carboxyl group at the 3-position and an oxo group at the 4-position, and is represented by the following formula.

[0003]

Embedded image

Wherein, R _{1 is} an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, 2,4-difluorophenyl group or 2-fluoroethyl group, R _{2 is a} hydrogen atom, Halogen atom or amino group, R ₃ : amino group, aminoalkyl group having 1 to 5 carbon atoms, alkylamino group, alkyl group, 1-piperazinyl group, 3
-Methyl-1-piperazinyl group, 4-methyl-1-piperazinyl group, or 3-amino-1-pyrrolidinyl group, A: one in which hydrogen of N, CH or CH is substituted with a halogen atom, R ₄ : hydrogen An atom or an alkyl group having 1 to 5 carbon atoms, B: an oxygen atom or a sulfur atom, and X: a hydrogen atom or a halogen atom, respectively.

[0005]

2. Description of the Related Art Pyridonecarboxylic acids and salts thereof are widely known as extremely excellent antibacterial agents against not only Gram-positive bacteria but also Gram-negative bacteria.

[0006] In general, pyridonecarboxylic acids have poor solubility in the neutral region. For this reason, as the eye drops that require a neutral region, of the pyridonecarboxylic acid, ofloxacin is the only marketed product as far as the present inventors know.

[0007] This is because it is necessary to keep the pH in the neutral region as much as possible to reduce pain and irritation to the mucosal tissue of the eye.

Therefore, in Japanese Patent Application Laid-Open No. 2-119771, as a method for solubilizing quinolone carboxylic acid included in pyridone carboxylic acid, the quinolone carboxylic acid is reacted with at least an equimolar ratio of a water-soluble calcium compound in water, A method has been proposed in which the pH of the solution is adjusted to 6.5 to 7.5 to obtain an aqueous solution.

[0009]

However, in the case of the above-mentioned method, the solubility of pyridonecarboxylic acid or a salt thereof is not sufficient (see the upper right column on page 2 of JP-A-4-59726).

[0010] For this reason, the publication proposes a method in which a basic substance or a calcium salt is added to pyridonecarboxylic acid or a salt thereof for solubilization.

However, in the case of the above method, the preparation liquid (aqueous solution) shifts to the alkali side because a basic substance is used. In the publication, the calcium chloride solution has a pH of 6.5 to 6.7.
On the other hand, in this example, the pH is 9.0 to 9.3 (see Table 1).

[0012] Therefore, it cannot be used as it is as an eye drop or the like, and its solubility in the neutral region is not sufficient.

In view of the above, the present invention provides a synthetic antibacterial agent aqueous composition capable of increasing the solubility of pyridonecarboxylic acid or a salt thereof and capable of directly obtaining an aqueous solution in a neutral region. Aim.

[0014]

Means for Solving the Problems The aqueous composition of a synthetic antibacterial agent of the present invention solves the above problems by the following constitutions.

Pyridonecarboxylic acid or a salt thereof, which is an amphoteric compound, has antibacterial activity and is represented by the following general formula:
The pH is adjusted to 6.0 to 8.5 by adding calcium chloride and polyvinylpyrrolidone.

[0016]

[Detailed description of means]

(1) As the pyridone carboxylic acid, those represented by the above general formula can be used. Specific examples of the eye drops include the following.

Examples of the compound having a quinoline skeleton include 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (general name: norfloxacin) Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylate hydrochloride hydrate (generic name: ciprofloxacin hydrochloride) 5-amino-1- Cyclopropyl-7- (cis-3,5
-Dimethyl-1-piperazinyl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (general name: spafloxacin) Examples of those having a 1,8-naphthyridine skeleton include (±) -7- (3-Amino-1-pyrrolidinyl) -6
Fluoro-1- (2,4-difluorophenyl) -1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid paratoluenesulfonate hydrate (generic name: tosfloxacin tosylate) As the salt of pyridonecarboxylic acid, a salt of a known basic group such as an amino group or an acidic group such as a carboxyl group is usually used. Can be mentioned. As the salt in the basic group, for example, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid; acetic acid, lactic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, malonic acid or gluconic acid And salts with amino acids such as aspartic acid and glutamic acid, and salts with acidic groups such as salts with alkali metals such as sodium and potassium. (See the lower part of page 3 of JP-A-4-59726).

(2) Examples of the calcium salt include calcium chloride, calcium lactate, calcium pantothenate, calcium gluconate, calcium carbonate, calcium D-sugarate, calcium disodium edetate, and the like. And calcium chloride is particularly desirable. The amount of the calcium salt to be added is 0.5 to 4 times (preferably 1 to 3 times) the amount of the pyridonecarboxylic acid. If the amount is too small, the effect of the present invention (solubilization of pyridonecarboxylic acid) is hardly exhibited. If the amount is too large, side effects of ocular mucosal damage may occur when used as eye drops.

(3) As polyvinylpyrrolidone (PVP), “PVP K-25” (average molecular weight 25,000),
"PVP K-30" (average molecular weight 40,000), "PVP
K-90 "(average molecular weight: 360,000) and the like can be suitably used. The amount of PVP is 3 to 20 times (preferably 6 to 15 times) the amount of pyridonecarboxylic acid. If the amount is too small, the effect of the present invention (solubilization of pyridonecarboxylic acid) is hardly exhibited, and if the amount is too large, when used as eye drops, there is a possibility that refreshing feeling may be impaired.

(4) In the above, it is desirable to add glycerin or boric acid in order to further promote solubilization of the pyridonecarboxylic acid.

The amount of glycerin added is 3 to 10 times (preferably 4 to 7 times) the amount of pyridonecarboxylic acid.
And If the amount is too small, the effect of the present invention (promoting the solubilization of pyridonecarboxylic acid) is hard to be exhibited, and if the amount is too large, when used as eye drops, the exhilaration may be impaired due to an increase in osmotic pressure.

The amount of boric acid added is 1 to 5 times (preferably 2 to 4 times) the amount of pyridonecarboxylic acid. If the amount is too small, the effect of the present invention (promoting the solubilization of pyridonecarboxylic acid) is difficult to be exhibited. May come.

(5) A mixture obtained by adding calcium chloride, PVP, glycerin or boric acid, and if necessary, a preservative (bactericide) to the above-mentioned pyridonecarboxylic acid is heated and dissolved in sterilized purified water, and filtered with a filter. To prepare the aqueous composition of the present invention.

[0024]

The aqueous composition of the synthetic antibacterial agent of the present invention comprises a pyridonecarboxylic acid or a salt thereof to which a calcium salt and polyvinylpyrrolidone are added to adjust the pH to 6.0 to 8.5. The effect is as follows.

As supported by the test examples and examples described below,
The solubility of pyridonecarboxylic acid or a salt thereof can be increased, and an aqueous solution in a neutral region can be directly obtained.

Further, by adding glycerin and boric acid, the solubility of pyridonecarboxylic acid or a salt thereof can be further increased.

[0027]

[Examples and test examples]

(1) To a mixture having the composition shown in Table 1, 80 mL of sterilized purified water was added, dissolved by heating, and sterilized purified water was added to make 100 mL. Next, the mixture was filtered through a 0.22 μm membrane filter and filled in an eye dropper to prepare each ophthalmic solution of 0.3 W / V% of Compound A.

Table 1 shows the pH and osmotic pressure of each example.
From the results shown in Table 1, it can be seen that all the eye drops were in the neutral region.

(2) Norfloxacin was added to 20 mL of each sample solution until it was no longer soluble, heated at 60 ° C. for 30 minutes, then left at room temperature for 24 hours, and 4000 rpm, 30 rpm.
After centrifugation for 20 minutes, the supernatant was filtered through a 0.22 μm membrane filter, and the solubility of the filtrate was measured by high performance liquid chromatography (Waters 486).

Table 2 shows the test results and the solubility ratio (sample solution / water) calculated from the results.
In the P combination system, the solubility of pyridonecarboxylic acid is higher than that of each compound alone. Furthermore, when glycerin or boric acid is used together with them, it is found that the solubility is remarkably increased.

[0031]

[Table 1]

[0032]

[Table 2]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location A61K 31/54 A61K 31/54 31/55 31/55 47/02 47/02 G 47/10 47 / 10 G 47/32 47/32 G C07D 215/56 C07D 215/56 401/04 207 401/04 207 471/04 114 471/04 114Z 498/06 498/06 513/06 513/06 // (A61K 47/32 47:10) (A61K 47/32 47:02 47:10)

Claims (5)

[Claims] 1. An amphoteric compound having antibacterial activity and having a pH of 6.0 to 8.5 by adding a calcium salt and polyvinylpyrrolidone to pyridonecarboxylic acid or a salt thereof represented by the following general formula. An aqueous synthetic antibacterial agent composition characterized by being obtained. Embedded image However, in the formula, R ₁ : an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a 2,4-difluorophenyl group or a 2-fluoroethyl group, R ₂ : a hydrogen atom, a halogen atom or Amino group, R ₃ : amino group, aminoalkyl group having 1 to 5 carbon atoms, alkylamino group, alkyl group, 1-piperazinyl group, 3
-Methyl-1-piperazinyl group, 4-methyl-1-piperazinyl group, or 3-amino-1-pyrrolidinyl group, A: one in which hydrogen of N, CH or CH is substituted with a halogen atom, R ₄ : hydrogen An atom or an alkyl group having 1 to 5 carbon atoms, B: an oxygen atom or a sulfur atom, and X: a hydrogen atom or a halogen atom, respectively. 2. The synthetic antibacterial agent aqueous composition according to claim 1, wherein the pyridonecarboxylic acid has a 1,8-naphthyridine skeleton. 3. The synthetic antibacterial agent aqueous composition according to claim 1, wherein the pyridonecarboxylic acid has a quinoline skeleton. 4. The synthetic antibacterial agent aqueous composition according to claim 1, further comprising glycerin. 5. The synthetic antibacterial agent aqueous composition according to claim 1, further comprising boric acid.