JP3424038B2 - Synthetic antimicrobial agent aqueous composition - Google Patents

Description

Detailed Description of the Invention

[0001]

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

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

[0003]

[Chemical 7]

However, in the formula, R _{1 is} 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 is a} hydrogen atom, halogen atom or an amino group, R _3: an amino group, an aminoalkyl group, an alkylamino group, an alkyl group having 1 to 5 carbon atoms, 1-piperazinyl group, 3
- methyl-1-piperazinyl, 4-methyl-1-piperazinyl group, or 3-amino-1-pyrrolidinyl group, A: what N, is hydrogen CH or CH substituted by 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, X: a hydrogen atom or a halogen atom, respectively.

[0005]

BACKGROUND OF THE INVENTION Pyridonecarboxylic acid and its salts are widely known as extremely excellent antibacterial agents against not only Gram-positive bacteria but also Gram-negative bacteria.

Generally, pyridonecarboxylic acid has poor solubility in the neutral range. Therefore, of the pyridonecarboxylic acids, ofloxacin is the only commercially available eye drop that requires a neutral range, as far as the present inventors know.

This is because it is necessary for eye drops to maintain the pH in the neutral range as much as possible to reduce pain and irritation to ocular mucosal tissues.

Therefore, in Japanese Patent Application Laid-Open No. 2-121971, a method for solubilizing a quinolonecarboxylic acid included in pyridonecarboxylic acid is to react with a water-soluble calcium compound in water at least at an equimolar ratio, and then It has been proposed to adjust the pH of the solution to a value between 6.5 and 7.5 to obtain an aqueous solution.

[0009]

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

Therefore, in this publication, a method of solubilizing a pyridonecarboxylic acid or its salt by adding a basic substance or a calcium salt is proposed.

However, in the case of the above method, since the basic substance is used, the preparation liquid (aqueous solution) shifts to the alkaline side. 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).

Therefore, it cannot be used as an eye drop as it is, and the solubility in the neutral range was 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 directly obtaining an aqueous solution in a neutral range. To aim.

[0014]

The synthetic antibacterial agent aqueous composition of the present invention solves the above problems by the following constitution.

An amphoteric compound, which has an antibacterial activity and is represented by the following general formula, pyridonecarboxylic acid or a salt thereof,
It is characterized in that the pH is adjusted to 6.0 to 8.5 by adding calcium chloride and polyvinyl pyrrolidone.

[0016]

[Detailed description of means]

(1) As the pyridonecarboxylic acid, those represented by the above general formula can be used, and specifically for the eye drops, the following can be exemplified.

As those having a quinoline skeleton, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (general name: norfloxacin) 1- Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid 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 (generic name: spafloxacin) As having a 1,8-naphthyridine skeleton, (±) -7- (3-amino-1-pyrrolidinyl) -6-
Fluoro-1- (2,4-difluorophenyl) -1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid paratoluene sulfonate hydrate (generic name: tosfloxacin tosylate) As a salt of pyridonecarboxylic acid, a salt in a known basic group such as amino group or an acidic group such as carboxyl group is usually used. Can be mentioned. Examples of the salt in the basic group include salts with inorganic acids 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. With an organic acid, or a salt with an amino acid such as aspartic acid or glutamic acid, and examples of the salt in the acidic group include salts with an alkali metal such as sodium or potassium (the above-mentioned. JP-A-4-59726, page 3, lower part).

(2) Examples of calcium salts include calcium chloride, calcium lactate, calcium pantothenate, calcium gluconate, calcium carbonate, calcium D-sugarate, and disodium calcium edetate. Therefore, calcium chloride is particularly desirable. The amount of calcium salt added is 0.5 to 4 times (preferably 1 to 3 times) the amount of pyridonecarboxylic acid. When the amount is too small, the effect of the present invention (solubilization of pyridonecarboxylic acid) is difficult to be achieved, and when the amount is too large, it may cause a side effect of ocular mucosal damage when used as an eye drop.

(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 preferably used. The amount of PVP added 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 difficult to be exhibited, and if the amount is too large, the viscosity is increased and the refreshing feeling may be hindered when used as an eye drop.

(4) In the above, in order to further promote the solubilization of pyridonecarboxylic acid, it is desirable to add glycerin or boric 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 solubilization of pyridonecarboxylic acid) is difficult to be exhibited, and if the amount is too large, when used as an eye drop, there is a possibility that the refreshing feeling may be hindered 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 solubilization of pyridonecarboxylic acid) is difficult to be exerted, and if too much, when used as an eye drop, it may inhibit refreshing feeling due to increase in osmotic pressure, and hypersensitivity symptoms appear There is a possibility of coming.

(5) A mixture prepared by adding calcium chloride salt, PVP, glycerin or boric acid, and optionally a preservative (bactericide) to the above pyridonecarboxylic acid is dissolved by heating with sterilized purified water and filtered with a filter. To prepare the aqueous composition of the present invention.

[0024]

EFFECTS OF THE INVENTION The synthetic antibacterial agent aqueous composition of the present invention contains pyridonecarboxylic acid or a salt thereof , in addition to calcium salt , polyvinylpyrrolidone , glycerin and / or borate.
By adding an acid, the following effects can be achieved by the constitution in which the pH is adjusted to 6.0 to 8.5.

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

[0026]

[0027]

[Examples and test examples]

(1) To the 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 solution was filtered through a 0.22 μm membrane filter and then filled in an eye drop container to prepare each eye drop solution of Compound A 0.3 W / V%.

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 are in the neutral range.

(2) Norfloxacin was added to 20 mL of each sample solution until it became insoluble, heated at 60 ° for 30 minutes, and then allowed to stand at room temperature for 24 hours, 4000 rpm, 30
After centrifuging, the supernatant was filtered with a 0.22 μm membrane filter and the solubility of the filtrate was measured by high performance liquid chromatography (Waters 486).

The test results and the solubility ratios (sample solution / water) calculated from them are shown in Table 2.
The P combination system has a higher solubility of pyridonecarboxylic acid than each compound alone. Furthermore, it can be seen that the solubility is remarkably increased when glycerin or boric acid is used in combination with them.

[0031]

[Table 1]

[0032]

[Table 2]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61K 47/32 A61K 47/32 A61P 27/02 A61P 27/02 31/04 31/04 C07D 215/56 C07D 215/56 401 / 04 401/04 471/04 114 471/04 114Z 498/06 498/06 513/06 513/06 (56) Reference JP-A-2-121917 (JP, A) JP-A-63-264418 (JP, A ) JP-A-63-174930 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/47 A61K 9/08 A61K 31/435 A61K 31/495 A61K 31/535 A61K 31 / 54 A61K 31/55 A61K 47/02 A61K 47/10 A61K 47/32 A61P 31/04 A61P 27/02 C07D 215/56 C07D 401/04 C07D 471/04 C07D 498/06 C07D 513/06 CAPLUS (STN) REGISTRY (STN) MEDLINE (STN) EMBASE (STN)

Claims (6)

(57) [Claims] 1. A pyridonecarboxylic acid represented by the following general formula or a salt thereof which is an amphoteric compound and has antibacterial activity.
On the other hand, calcium salts , polyvinylpyrrolidone and glycerin were added as solubilization promoters to increase pH.
A synthetic antibacterial agent aqueous composition characterized by being adjusted to 6.0 to 8.5. [Chemical 1] 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: an amino group, an aminoalkyl group, an alkylamino group having 1 to 5 carbon atoms, an alkyl group, 1-piperazinyl group, 3
- methyl-1-piperazinyl, 4-methyl-1-piperazinyl group, or 3-amino-1-pyrrolidinyl group, A: what N, is hydrogen CH or CH substituted by 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, X: a hydrogen atom or a halogen atom, respectively. 2. An amphoteric compound, which has antibacterial activity
The pyridonecarboxylic acid represented by the general formula or its salt
On the other hand, calcium salt: 0.5 to 4 times amount, polyvinylpyrrole
Loridone: 3 to 20 times amount and glycerin: 3 to 10 times amount
Is added to adjust the pH to 6.0-8.5.
A synthetic antibacterial agent aqueous composition comprising: [Chemical 2] However, in the formula, R _{1 is} an alkyl group having 1 to 5 carbon atoms,
3-6 cycloalkyl groups, 2,4-difluorophenyl
Le group or a 2-fluoroethyl group, R _2: a hydrogen atom, a halogen atom or an amino group, R _3: an amino group, an aminoalkyl group, A 1 to 5 carbon atoms
Rukylamino group, alkyl group, 1-piperazinyl group, 3
-Methyl-1-piperazinyl group, 4-methyl-1-pipet
Razinyl group or 3-amino-1-pyrrolidinyl
Group, A: hydrogen of N, CH or CH is replaced by a halogen atom.
And R _{4 is a} hydrogen atom or an alkyl group having 1 to 5 carbon atoms, B is an oxygen atom or a sulfur atom, and X is a hydrogen atom or a halogen atom. 3. An amphoteric compound having antibacterial activity
The pyridonecarboxylic acid represented by the general formula or its salt
On the other hand, calcium salts and
Rivinylpyrrolidone and boric acid were added to give a pH of 6.
Synthetic antibacterial characterized by being adjusted to 0 to 8.5
Aqueous composition. [Chemical 3] However, in the formula, R _{1 is} an alkyl group having 1 to 5 carbon atoms,
3-6 cycloalkyl groups, 2,4-difluorophenyl
Le group or a 2-fluoroethyl group, R _2: a hydrogen atom, a halogen atom or an amino group, R _3: an amino group, an aminoalkyl group, A 1 to 5 carbon atoms
Rukylamino group, alkyl group, 1-piperazinyl group, 3
-Methyl-1-piperazinyl group, 4-methyl-1-pipet
Razinyl group or 3-amino-1-pyrrolidinyl
Basis. A: N, CH or CH hydrogen is replaced by a halogen atom.
And R _{4 is a} hydrogen atom or an alkyl group having 1 to 5 carbon atoms, B is an oxygen atom or a sulfur atom, and X is a hydrogen atom or a halogen atom. 4. An amphoteric compound having antibacterial activity
The pyridonecarboxylic acid represented by the general formula or its salt
On the other hand, calcium salt: 0.5 to 4 times amount, polyvinylpyrrole
Loridone: 3 to 20 times amount and boric acid: 1 to 5 times amount added
The pH is adjusted to 6.0-8.5.
A synthetic antibacterial agent aqueous composition. [Chemical 4] However, in the formula, R _{1 is} an alkyl group having 1 to 5 carbon atoms,
3-6 cycloalkyl groups, 2,4-difluorophenyl
Le group or a 2-fluoroethyl group, R _2: a hydrogen atom, a halogen atom or an amino group, R _3: an amino group, an aminoalkyl group, A 1 to 5 carbon atoms
Rukylamino group, alkyl group, 1-piperazinyl group, 3
-Methyl-1-piperazinyl group, 4-methyl-1-pipet
Razinyl group or 3-amino-1-pyrrolidinyl
Basis. A: N, CH or CH hydrogen is replaced by a halogen atom.
And R _{4 is a} hydrogen atom or an alkyl group having 1 to 5 carbon atoms, B is an oxygen atom or a sulfur atom, and X is a hydrogen atom or a halogen atom. 5. An amphoteric compound having an antibacterial activity
The pyridonecarboxylic acid represented by the general formula or its salt
On the other hand, calcium salts and
Rivinylpyrrolidone, glycerin and boric acid are added
And pH is adjusted to 6.0 to 8.5.
A synthetic antibacterial agent aqueous composition. [Chemical 5] However, in the formula, R _{1 is} an alkyl group having 1 to 5 carbon atoms,
3-6 cycloalkyl groups, 2,4-difluorophenyl
Le group or a 2-fluoroethyl group, R _2: a hydrogen atom, a halogen atom or an amino group, R _3: an amino group, an aminoalkyl group, A 1 to 5 carbon atoms
Rukylamino group, alkyl group, 1-piperazinyl group, 3
-Methyl-1-piperazinyl group, 4-methyl-1-pipet
Razinyl group or 3-amino-1-pyrrolidinyl
Group, A: hydrogen of N, CH or CH is replaced by a halogen atom.
And R _{4 is a} hydrogen atom or an alkyl group having 1 to 5 carbon atoms, B is an oxygen atom or a sulfur atom, and X is a hydrogen atom or a halogen atom. 6. An amphoteric compound having antibacterial activity
The pyridonecarboxylic acid represented by the general formula or its salt
On the other hand, calcium salt: 0.5 to 4 times amount, polyvinylpyrrole
Loridone: 3 to 20 times amount, glycerin: 3 to 10 times amount
Biboric acid: 1 to 5 times the amount of boric acid is added to give a pH of 6.0 to 8.
Synthetic antibacterial agent aqueous set characterized by being adjusted to 5
A product. [Chemical 6] However, in the formula, R _{1 is} an alkyl group having 1 to 5 carbon atoms,
3-6 cycloalkyl groups, 2,4-difluorophenyl
Le group or a 2-fluoroethyl group, R _2: a hydrogen atom, a halogen atom or an amino group, R _3: an amino group, an aminoalkyl group, A 1 to 5 carbon atoms
Rukylamino group, alkyl group, 1-piperazinyl group, 3
-Methyl-1-piperazinyl group, 4-methyl-1-pipet
Razinyl group or 3-amino-1-pyrrolidinyl
Group, A: hydrogen of N, CH or CH is replaced by a halogen atom.
And R _{4 is a} hydrogen atom or an alkyl group having 1 to 5 carbon atoms, B is an oxygen atom or a sulfur atom, and X is a hydrogen atom or a halogen atom.