JPH0558895A - Medicinal composition containing pyridone carboxylic acid or its salt and stabilization of solution of pyridone carboxylic acid or its salt - Google Patents

Abstract

PURPOSE:The subject composition containing a pyridone carboxylic acid (salt) exhibiting an antibacterial action, an Al-containing metal compound, borax and an alkali metal chloride, exhibiting a stable dissolution state, and useful as an antibacterial agent against gram-positive bacteria and gram-negative bacteria, etc. CONSTITUTION:A pyridone carboxylic acid (salt) represented by formula I [R<1> is (substituted)lower alkyl, aryl, etc.; R<2> is H, halogen, lower alkyl, etc.; R<3> is (substituted)cycloalkyl, vinyl, etc.; A is N, CX<1> (X<1> is H, halogen); B is N, CX<2> (X<2> is H, halogen), or B forms together with R<1> a group of formula II (R<4> is H, alkyl; D is O. S)], etc., and exhibiting an antibacterial action [e.g. 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthylidine -3-carboxylic acid] is compounded with a metal compound containing Al as a constituent (e.g. aluminum potassium sulfate), borax, and an alkali metal salt (e.g. sodium chloride) to stabilize the solution of the pyridone carboxylic acid (salt).

Description

Detailed Description of the Invention [0001] BACKGROUND OF THE INVENTION The present invention relates to a pigment having an antibacterial action.
Constitutes ridonecarboxylic acid or its salt, aluminum
Mineral compounds, borax and alkali metal chlorides
And a pyrido having an antibacterial effect
Provide a method for stabilizing a solution of a carboxylic acid or a salt thereof.
Especially. [0002] BACKGROUND OF THE INVENTION Pyridonecarboxylic acid or its salts are
Excellent not only for Lamb-positive bacteria but also for Gram-negative bacteria
It is widely known as an antibacterial agent. Pyridonecarboxylic acid
For solubilization of, for example, Al, Mg or Zn
A method of adding a metal compound having a component of [Patent Document 6]
No. 3-188626] is known. But got
Method for stably maintaining the dissolved state of an aqueous solution and antibacterial action
Pyridonecarboxylic acid or its salt
Metal compounds containing um, borax and alkali
Known about pharmaceutical compositions consisting of Li metal chloride
Not in. [0003] [Problems to be Solved by the Invention]
Solubilizes lidone carboxylic acid or its salts,
The stability of the dissolved state after adjusting the osmotic pressure to physiological conditions is
Still not enough, and maintain a stable dissolved state
Development of technology was desired. [0004] Means for Solving the Problems The present inventors
Pyridone carvone that exhibits antibacterial action
Metallization of aluminum with acid or its salt
To add compound, borax and alkali metal chloride
Therefore, pyridonecarboxylic acid that exerts antibacterial action or
It was found that the salt solution was stabilized, and the present invention was completed.
It came to be achieved. The present invention will be described in detail below. In the present invention
Pyridonecarboxylic acid or its antibacterial effect
The salt of is not particularly limited, but specifically, the salt of the general formula
[1] [Chemical 3] "In the formula, R¹Is an optionally substituted lower alkyl,
Lower alkenyl, cycloalkyl, aryl or hetero
A cyclic group; R²Is a hydrogen atom, halogen atom, lower
Killyl group, alkoxy group, optionally protected hydroxy group
Syl, amino or lower alkylamino group or di-
A lower alkylamino group; R³May be replaced
A cycloalkyl, vinyl or cyclic amino group; [Outside 13] Is [Outside 14] Or [Outside 15] To; [Outside 16] Is [Outside 17] Or [Outside 18] Or R¹Expression with [Formula 3] (R^FourIs a hydrogen atom or a lower alkyl group; D is an acid
Indicates an elementary atom or a sulfur atom. ) Represents a group represented by
Yes; X¹Is a hydrogen atom or a halogen atom; X²Is water
It means an elementary atom or a halogen atom, respectively. "so
Represented by pyridonecarboxylic acid or salts thereof
It Unless otherwise specified in this specification,
Halogen atom means, for example, a fluorine atom or a chlorine atom.
A child, a bromine atom or an iodine atom;
For example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl,
C such as ethyl, hexyl or octyl_1-10A
And the lower alkyl group is, for example, as described above.
Of the alkyl groups, C_1-5An alkyl group; an alkoxy group
And, for example, an —O-alkyl group (an alkyl group is
Noted C_1-10Indicates an alkyl group. ); Lower alkyl
A mino group is, for example, methylamino or ethylamino.
Or C such as propylamino_1-5Alkylamino
And a di-lower alkylamino group is, for example,
Di-C such as tilamino_1-5Alkylamino group; low
Examples of the secondary alkenyl group include vinyl, allyl, 1-
C such as propenyl or 1-butenyl and the like_2-5Al
A alkenyl group; a cycloalkyl group means cyclopropyl,
Cyclobutyl, cyclopentyl or cyclohexyl
What C_3-6A cycloalkyl group; an aryl group
Is, for example, phenyl or naphthyl;
A xycarbonyl group is, for example, -COO-alkyl.
Group (the alkyl group is the above-mentioned C_1-10Indicates an alkyl group
You ) Is a hydroxy lower alkyl group, for example,
Hydroxymethyl, hydroxyethyl or hydroxy
Hydroxy-C such as propyl_1-5Alkyl group
And; an amino-lower alkyl group is, for example, aminomethyl
, Aminoethyl or aminopropyl etc.
Mino-C_1-5Alkyl group; lower alkyl amino lower
The alkyl group is, for example, methylaminomethyl, ethyl
C such as aminomethyl or ethylaminoethyl
_1-5Alkylamino-C_1-5Alkyl group; di-lower alkyl
For example, a lower alkylamino group is dimethylamino.
Di-C such as minomethyl or diethylaminomethyl
_1-5Alkylamino-C_{1 -Five}Alkyl group; cyclic amino group
And, for example, piperazinyl, pyrrolidinyl, morpho
Linyl or 1,4-diazabicyclo [3.2.1] o
A 4-10 membered cyclic amino group such as octyl;
A mino lower alkyl group is, for example, 1-piperazinyl
Methyl, 1-pyrrolidinylmethyl, 1-azetidinylme
4-6 such as tyl or 1-morpholinylmethyl and the like
Membered cyclic amino-C_1-5An alkyl group; an acylamino group
Is, for example, formylamino, acetylamino, pro
C such as pionylamino or butyrylamino
_1-4An acylamino group; an acyloxy group
For example, formyloxy, acetyloxy, propionylo.
C such as xy or butyryloxy_1-4Ashirou
A xy group; a trihalogeno-lower alkyl group
For example, trichloromethyl or trifluoromethyl
Trihalogeno-C_1-5An alkyl group; a heterocyclic group
Is selected from oxygen atom, nitrogen atom and sulfur atom
5-membered or 6-membered or containing one or more heteroatoms
Such a fused ring, for example, furyl, pyrrolyl, thienyl,
Oxazolyl, imidazolyl, thiazolyl, 1-pyrroli
Dinyl, benzofuryl, benzothiazolyl, pyridyl,
Such as quinolyl, pyrimidinyl or morpholinyl etc.
A group, respectively. Odor of the compound of the general formula [1] or a salt thereof
And R¹Each group of is a halogen atom, cyano group, protected
Optionally protected carboxyl group, optionally protected
Droxyl group, optionally protected amino group, alkyl group
Group, alkoxy group, alkoxycarbonyl group, aryl
Group, cycloalkyl group, acylamino group, acyloxy group
Si group, lower alkenyl group, trihalogeno-lower alkyl
Group, lower alkylamino group or di-lower alkylamino group
Substituted with one or more substituents selected from
May also be R³Each group of is a halogen atom or a lower
Alkyl group, optionally protected carboxyl group, protected
Optionally protected hydroxyl group, optionally protected
Amino group, optionally protected lower alkylamino
Group, optionally protected amino lower alkyl group, protected
Optionally lower alkylamino lower alkyl group,
Optionally protected hydroxy lower alkyl group, di-
Lower alkylamino group, di-lower alkylamino lower group
Selected from alkyl groups or cyclic amino lower alkyl groups, etc.
It may be substituted with one or more substituents. The carboxyl protecting group is, for example,
Such as an ester-forming group that is easily eliminated in vivo
Included are pharmaceutically acceptable carboxyl protecting groups. Further, an amino group, an amino lower alkyl group,
Lower alkylamino group and lower alkylamino lower group
Examples of the protecting group for the rukyl group include, for example, in vivo
Included are pharmaceutically acceptable amino protecting groups that are easily removed.
Be done. Furthermore, hydroxyl groups and hydroxy groups
Examples of the protective group for a lower alkyl group include, for example, in vivo
A pharmaceutically acceptable hydroxyl that is easily eliminated at
Group protecting groups and the like. [0011] Pyridonecarboxylic acid having antibacterial activity is preferred.
Specific examples of preferable compounds include naphthyridine.
Is the 7-position of quinoline or benzoxazine or benzene
A compound in which a basic group is bonded to the 10-position of zotioxazine,
For example, the following compounds can be mentioned. -1-Ethyl-6-fluoro-1,4-dihydro-4
-Oxo-7- (1-piperazinyl) -1,8-naphthyl
Lysine-3-carboxylic acid * 7- (3-amino-1-pyrrolidinyl) -1-eth
Le-6-fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic acid * 7- (3-amino-1-pyrrolidinyl) -1-cycl
Ropropyl-6-fluoro-1,4-dihydro-4-o
Xo-1,8-naphthyridine-3-carboxylic acid * 7- (3-amino-4-methyl-1-pyrrolidini
) -1-Cyclopropyl-6-fluoro-1,4-di
Hydro-4-oxo-1,8-naphthyridine-3-cal
Boric acid * 1-cyclopropyl-6-fluoro-7- (3-me
Cylamino-1-pyrrolidinyl) -1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid 7- (3-amino-3-methyl-1-
Pyrrolidinyl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine
-3-carboxylic acid * 1-cyclopropyl-6-fluoro-7- (1-pi
Perazinyl) -1,4-dihydro-4-oxo-1,8
-Naphthyridine-3-carboxylic acid * 7- (cis-3-aminomethyl-4-chloro-1-
Pyrrolidinyl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine
-3-carboxylic acid * 7- (3-amino-1-pyrrolidinyl) -1-
(2,4-difluorophenyl) -6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid -1-Ethyl-6-fluoro-7- (1-piperazini
) -1,4-Dihydro-4-oxoquinoline-3-ca
Rubonic acid 1-ethyl-6,8-difluoro-7
-(3-Methyl-1-piperazinyl) -1,4-dihydride
Lo-4-oxoquinoline-3-carboxylic acid * 1- (2-fluoroethyl) -6,8-difluoro
-7- (4-Methyl-1-piperazinyl) -1,4-di
Hydro-4-oxoquinoline-3-carboxylic acid -5-amino-1-cyclopropyl-6,8-diflu
Oro-7- (3,5-dimethyl-1-piperazinyl)-
1,4-dihydro-4-oxoquinoline-3-carvone
acid * 7- (3-amino-1-pyrrolidinyl) -1-cycl
Ropropyl-6,8-difluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid * 7- (3-aminomethyl-1-morpholino) -1-
Cyclopropyl-6,8-difluoro-1,4-dihydride
Lo-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-6-fluoro-
7- (1-piperazinyl) -1,4-dihydro-4-o
Xoxoquinoline-3-carboxylic acid * 1-cyclopropyl-6-fluoro-5-methyl-
7- (3-methyl-1-piperazinyl) -1,4-dihi
Doro-4-oxoquinoline-3-carboxylic acid ・ 6-Fluoro-1- (2,4-difluorophenyl)
) -7- (3-Methyl-1-piperazinyl) -1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid -5-amino-1-cyclopropyl-7- (3-ethyl
Luaminomethyl-1-pyrrolidinyl) -6,8-diflu
Oro-1,4-dihydro-4-oxoquinoline-3-ca
Rubonic acid ・ 1-Cyclopropyl-7- (3-ethylaminomethyi
Ru-1-pyrrolidinyl) -5,6,8-trifluoro-
1,4-dihydro-4-oxoquinoline-3-carvone
acid 1-ethyl-6,8-difluoro-7
-(3-Methyl-1-piperazinyl) -1,4-dihydride
Lo-4-oxoquinoline-3-carboxylic acid * 1-ethyl-6-fluoro-7- (4-methyl-1
-Piperazinyl) -1,4-dihydro-4-oxoquino
Phosphorus-3-carboxylic acid -5-amino-1-cyclopropyl-6,8-diflu
Oro-7- (3,5-dimethyl-1-piperazinyl)-
1,4-dihydro-4-oxoquinoline-3-carvone
acid * 9-fluoro-3-methyl-10- (4-methyl-
1-piperazinyl) -7-oxo-2,3-dihydro-
7H-pyrido [1,2,3-de] [1,4] benzoo
Xazine-6-carboxylic acid * 10- (1-aminocyclopropyl) -9-fluor
Lo-3-methyl-7-oxo-2,3-dihydro-7H
-Pyrido [1,2,3-de] [1,4] benzoxa
Gin-6-carboxylic acid -(S) -9-Fluoro-3-methyl-10- (4-
Methyl-1-piperazinyl) -7-oxo-2,3-di
Hydro-7H-pyrido [1,2,3-de] [1,4]
Benzoxazine-6-carboxylic acid -(S) -10- (1-aminocyclopropyl) -9
-Fluoro-3-methyl-7-oxo-2,3-dihydride
Ro-7H-pyrido [1,2,3-de] [1,4] ben
Zoxazine-6-carboxylic acid Of the pyridonecarboxylic acid that exerts antibacterial activity
As salts, there is no salt such as hydrochloric acid, sulfuric acid or phosphoric acid.
Organic acid; acetic acid, lactic acid, succinic acid, p-toluene sulfone
Acid, methanesulfonic acid, maleic acid, malonic acid or
Organic acids such as gluconic acid; and aspartic acid
Or an acid such as an amino acid such as glutamic acid
Acid addition salts formed from; or sodium salts or mosquitoes
Metal salts in the carboxyl group such as selenium salts
Be done. Next, the method of the present invention will be described in detail. Book
The method of the invention is, for example, a pyridone that exerts an antibacterial action.
Rubonic acid or its salt with aluminum as a constituent
After adding and dissolving the metal compound, add borax
Adjust the pH and add alkali metal chloride to this solution
Pyridone carbo
The dissolved state of the acid or its salt can be stably maintained. Alkali metal salts used in the present invention
Examples of the compound include sodium chloride or calcium chloride.
Examples thereof include sodium, but especially sodium chloride.
Um is preferred. As a preferred example of the method of the present invention, antibacterial
Pyridonecarboxylic acid or its salt that exerts its action in water
Suspend and add potassium aluminum sulfate to dissolve
After adjusting the pH, adjust the pH by adding borax, and then add sodium chloride.
Examples include a method of adding thorium to obtain an isotonic solution.
If the above solution is freeze-dried, the pharmaceutical composition of the present invention
It is possible to prepare an in-use dissolution type formulation which is a substance. Book
The formulation according to the invention has a pH at dissolution of 3.5-7.0, preferably
Adjust the pH to maintain the range of 4.0-6.5.
To be done. The aluminum used in the present invention is also
Examples of the metal compound having um as a constituent component include, for example,
Aluminum potassium sulfate (alum), aluminum chloride
Aluminum or aluminum sulphate and their hydrates
But especially aluminum potassium sulfate
(Alum) is preferred. Aluminum as a constituent
The amount of metal compound used usually exerts an antibacterial effect
0.1 to 5 for pyridonecarboxylic acid or its salt
The molar ratio is 0 times, preferably 0.1 to 30 times. The present invention is mainly for injection (solution or
Dissolving type), eye drops, nasal drops, ear drops, oral cavity or
It can be applied to oral formulations. When preparing the drug product
The pharmaceutically acceptable auxiliary agent may be further added.
As auxiliary agents, excipients, stabilizers, buffers, antioxidants
Agents, flavoring agents, soothing agents and the like. Also, throw
The method of administration, dose and frequency of administration depend on the age and weight of the patient.
It can be selected according to the patient's symptoms and symptoms
For oral or parenteral (eg injection, eye drop,
(Administration to ear, nose, rectum, etc.)
Converted to pyridonecarboxylic acid or its salt that exhibits fungal activity
Total 0.1 to 100 mg / kg / day divided into 1 to several times
And then administer. [0022] EXAMPLES Next, the present invention will be described with reference to Examples, Comparative Examples and Tests.
The present invention will be described with reference to examples, but the present invention is not limited to these.
Not of. As compound A, 7- (3-amino
-1-Pyrrolidinyl) -1- (2,4-difluorofe
Nyl) -6-fluoro-1,4-dihydro-4-oxo
P-Toluene of -1,8-naphthyridine-3-carboxylic acid
Sulfonate as compound B (S) -10
-(1-Aminocyclopropyl) -9-fluoro-3-
Methyl-2,3-dihydro-7H-pyrido [1,2,3
-De] [1,4] benzoxazine-6-carboxylic acid
As aluminum potassium sulfate,
The dihydrate was used respectively. Example 1 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, add borax.
Adjust the pH of the solution to 5.3. Then, Na chloride
0.9 g of thorium was added, and the total amount was 100 with distilled water.
Set to ml. Add this solution to a membrane filter (0.2
(2μm) after aseptic filtration, fill 5 ml each into eye drop bottles
Then, an eye drop having an osmotic pressure ratio of 1.1 is obtained. Example 2 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, add borax.
Adjust the pH of the solution to 5.4. Then, Na chloride
Thorium 0.54g was added, and the total amount was 10 with distilled water.
Make up to 0 ml. Add this solution to a membrane filter (0.
22 μm), and then aseptically filter and fill 5 ml each into an eye drop bottle.
Then, an ophthalmic solution having an osmotic pressure ratio of 0.7 is obtained. Example 3 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, add borax.
Adjust the pH of the solution to 5.3. Then, Na chloride
Thorium 1.1g was added, and the total amount was 100 with distilled water.
Set to ml. Add this solution to a membrane filter (0.2
(2μm) after aseptic filtration, fill 5 ml each into eye drop bottles
Then, an ophthalmic solution having an osmotic pressure ratio of 1.3 is obtained. Example 4 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, add borax.
Adjust the pH of the solution to 5.3. Then, Na chloride
Thorium 1.6g was added, and the total amount was 100 with distilled water.
Set to ml. Add this solution to a membrane filter (0.2
(2μm) after aseptic filtration, fill 5 ml each into eye drop bottles
Then, an eye drop having an osmotic pressure ratio of 1.9 is obtained. Example 5 Compound B (0.3 g) was suspended in distilled water (90 ml).
To the suspension, add 163 mg of potassium aluminum sulfate and
Compound B is dissolved. Then add borax and add
Adjust the pH to 6.1. Furthermore, sodium chloride 0.8
5 g is added and the total volume is made up to 100 ml with distilled water.
Sterilize this solution with a membrane filter (0.22 μm)
After filtration, fill 5 ml each into an eye dropper and adjust the osmotic pressure ratio to 1.
0 eye drops are obtained. Example 6 Compound B (0.3 g) was suspended in distilled water (90 ml).
To the suspension, add 167 mg of potassium aluminum sulfate and
Compound B is dissolved. Then add borax and add
Adjust the pH to 6.1. Furthermore, sodium chloride 0.8
5 g is added and the total volume is made up to 100 ml with distilled water.
Sterilize this solution with a membrane filter (0.22 μm)
After filtration, fill 5 ml each into an eye dropper and adjust the osmotic pressure ratio to 1.
0 eye drops are obtained. Example 7 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, add borax.
Adjust the pH of the solution to 6.5. Then, Na chloride
0.9 g of thorium was added, and the total amount was 100 with distilled water.
Set to ml. Add this solution to a membrane filter (0.2
(2μm) after aseptic filtration, fill 5 ml each into eye drop bottles
Then, an ophthalmic solution having an osmotic pressure ratio of 1.1 is obtained. Example 8 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, add borax.
Adjust the pH of the solution to 6.5. Then, chloride
Add 1.0 g of helium, and add 100 m of distilled water.
Let l. This solution is a membrane filter (0.22
After aseptic filtration with 5 μm), fill each 5 ml in an eye drop bottle,
An ophthalmic solution with an osmotic pressure ratio of 1.0 is obtained. Comparative Example 1 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, sodium hydroxide
Adjust the pH of the solution to 5.3 by adding an aqueous solution of lithium.
It Then add 0.9 g of sodium chloride, and
Make up to 100 ml with distilled water. Membrane this solution
After sterile filtration with a filter (0.22 μm), 5 ml without
Then, the solution is filled in an eye dropper to obtain an eye drop having an osmotic pressure ratio of 1.1. Comparative Example 2 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, add borax.
Adjust the pH of the solution to 5.4. Then isotonic
Add 3.0 g of D-mannitol as an agent and steam
Make up to 100 ml with distilled water. This solution is a membrane
After sterile filtration with a filter (0.22 μm), 5 ml each
Fill an eye drop bottle to obtain an eye drop having an osmotic pressure ratio of 0.7. Comparative Example 3 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, add borax.
Adjust the pH of the solution to 5.3. Then isotonic
6.1 g of D-mannitol was added as an agent, and steam was added.
Make up to 100 ml with distilled water. This solution is a membrane
After sterile filtration with a filter (0.22 μm), 5 ml each
Fill an eye drop bottle to obtain an eye drop having an osmotic pressure ratio of 1.3. Comparative Example 4 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, add borax.
Adjust the pH of the solution to 5.3. Then isotonic
9.1 g of D-mannitol was added as an agent, and steam was added.
Make up to 100 ml with distilled water. This solution is a membrane
After sterile filtration with a filter (0.22 μm), 5 ml each
Fill an eye drop bottle to obtain an eye drop having an osmotic pressure ratio of 1.9. Comparative Example 5 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, sodium hydroxide
Adjust the pH of the lysate to 6.5 by adding lymium. Just
Then, add 0.9 g of sodium chloride as a tonicity agent,
In addition, the total volume is 100 ml with distilled water. This solution is
After sterile filtration with a blanc filter (0.22 μm), 5
Fill the eye dropper with each ml to obtain an eye drop with an osmotic pressure ratio of 1.1.
It Comparative Example 6 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling,
Thorium is added to adjust the pH of the solution to 6.5. One
Add 0.9 g of sodium chloride, and add distilled water.
Adjust the total volume to 100 ml. Membrane fill this solution
After sterile filtration with a filter (0.22 μm), instill 5 ml each
Fill the bottle to obtain an eye drop having an osmotic pressure ratio of 1.1. Comparative Example 7 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, Natri carbonate
Um is added to adjust the pH of the solution to 6.5. Just
Then, add 0.9 g of sodium chloride, and further with distilled water.
The total volume is 100 ml. This solution is a membrane filter
(0.22 μm) after sterile filtration
To obtain an eye drop having an osmotic pressure ratio of 1.1. Comparative Example 8 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, with isotonicity agent
Then, add 2.7 g of xylitol, and then add borax.
Adjust the pH of the solution to 6.5. In addition, distilled water
Adjust the total volume to 100 ml. Membrane fill this solution
After sterile filtration with a filter (0.22 μm), instill 5 ml each
Fill the bottle to obtain an eye drop having an osmotic pressure ratio of 1.0. Comparative Example 9 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, with isotonicity agent
Then add 3.1 g of glucose, and then add borax
Adjust the pH of the lysate to 6.5. In addition, use distilled water to
The volume is 100 ml. This solution is a membrane filter
After aseptic filtration (0.22 μm), add 5 ml to each eye drop bottle.
After filling, an ophthalmic solution having an osmotic pressure ratio of 1.0 is obtained. Comparative Example 10 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, with isotonicity agent
Then, 3.1 g of D-mannitol was added, and then borax
Is added to adjust the pH of the solution to 6.5. In addition, steam
Make up to 100 ml with distilled water. This solution is a membrane
After sterile filtration with a filter (0.22 μm), 5 ml each
Fill an eye drop bottle to obtain an eye drop having an osmotic pressure ratio of 1.0. Comparative Example 11 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, with isotonicity agent
Then add 2.0 g of glycerin, then add borax
Adjust the pH of the lysate to 6.5. In addition, with distilled water
The total volume is 100 ml. This solution is a membrane filter
(0.22 μm) after sterile filtration
To obtain an eye drop having an osmotic pressure ratio of 1.0. Comparative Example 12 0.3 g of compound A was suspended in 90 ml of distilled water and
120 mg of potassium aluminum sulfate was added to the suspension, and 5
Compound A is dissolved at 0 ° C. After cooling, with isotonicity agent
Then add 1.4 g of propylene glycol, then
Adjust the pH of the solution to 6.5 by adding sand. Furthermore
Then, the total volume is made up to 100 ml with distilled water. Membrane this solution
5m after aseptic filtration with a run filter (0.22μm)
Fill the eye drops one by one to obtain an eye drop with an osmotic pressure ratio of 1.0.
It Test Example 1 The eye drops of Examples 1 to 4 and Comparative Examples 1 to 4 were respectively prepared.
Stored in a thermostatic layer at 50 ° C for 5 months and observed the appearance.
It was The results of the change in appearance (presence or absence of precipitates) are shown in Table 1.
You [0044] [Table 1] Test Example 2 The eye drops of Examples 5 and 6 were treated at 5 ° C and 40 ° C, respectively.
Or store in a constant temperature layer at 50 ℃ for 6 months and observe the appearance.
did. The results of the appearance change (presence or absence of precipitates) are shown in Table 2.
Show. [0046] [Table 2]Test Example 3 The eye drops of Examples 7 and 8 and Comparative Examples 5 to 12 were prepared as
Stored in a constant temperature layer at 25 ℃ or 40 ℃ for 1 month each
Then, the appearance was observed. Of its appearance change (presence or absence of deposits)
The results are shown in Table 3, Table 4 and Table 5. [0048] [Table 3] [0049] [Table 4][0050] [Table 5][0051] From the above results, the present invention can be applied.
Pyridonecarboxylic acid that exerts antibacterial activity by or
To significantly improve the stability of the dissolved state of its salt solution
You can Therefore, pyridone that exhibits antibacterial activity
If rubonic acid or its salt is administered orally only as a medicine,
Not applicable to parenteral administration, especially eye drops and injection administration.
It can be understood that and becomes easier.

Claims (1)

Claims: (1) A pharmaceutical composition comprising pyridonecarboxylic acid or a salt thereof exhibiting an antibacterial action, a metal compound containing aluminum as a constituent, borax and an alkali metal chloride. (2) A pyridonecarboxylic acid exhibiting an antibacterial action is represented by the general formula: “In the formula, R ¹ is optionally substituted lower alkyl,
Lower alkenyl, cycloalkyl, aryl or heterocyclic group; R ² represents hydrogen atom, halogen atom, lower alkyl group, alkoxy group, optionally protected hydroxyl, amino or lower alkylamino group or di-
A lower alkylamino group; R ³ represents an optionally substituted cycloalkyl, vinyl or cyclic amino group; Is [outside 2] Or [outside 3] [Outside 4] Is [outside 5] Or [outside 6] Or means together with R ¹ the formula (R ⁴ represents a hydrogen atom or a lower alkyl group; D represents an oxygen atom or a sulfur atom); X ¹ represents a hydrogen atom or a halogen atom; X ² represents a hydrogen atom or Each means a halogen atom. The pharmaceutical composition according to claim 1, which is represented by: 3. The pharmaceutical composition according to claim 1 or 2, wherein (3) the metal compound containing aluminum as a constituent is potassium aluminum sulfate (alum). 4. The pharmaceutical composition according to claim 1, wherein the alkali metal chloride (4) is sodium chloride. 5. A pyridone exhibiting antibacterial activity, which is characterized by adding a metal compound having aluminum as a constituent, borax and an alkali metal chloride to pyridonecarboxylic acid or a salt thereof exhibiting an antibacterial effect. A method for stabilizing a solution of a carboxylic acid or a salt thereof. (6) The pyridonecarboxylic acid exhibiting an antibacterial action is represented by the general formula: “In the formula, R ¹ is optionally substituted lower alkyl,
Lower alkenyl, cycloalkyl, aryl or heterocyclic group; R ² represents hydrogen atom, halogen atom, lower alkyl group, alkoxy group, optionally protected hydroxyl, amino or lower alkylamino group or di-
A lower alkylamino group; R ³ represents an optionally substituted cycloalkyl, vinyl or cyclic amino group; Is outside [8] Or [outside 9] A; [outside 10] Is [outside 11] Or [outside 12] Or means together with R ¹ the formula [Formula 2] (R ⁴ represents a hydrogen atom or a lower alkyl group; D represents an oxygen atom or a sulfur atom); X ¹ represents a hydrogen atom or a halogen atom; X ² represents a hydrogen atom or Each means a halogen atom. A method for stabilizing a solution of a pyridonecarboxylic acid or a salt thereof exhibiting an antibacterial action according to claim 5. 7. A solution of a pyridonecarboxylic acid or a salt thereof exhibiting an antibacterial action according to claim 5 or 6, wherein (7) the metal compound containing aluminum as a constituent is potassium aluminum sulfate (alum). Stabilization method. (8) The method for stabilizing a solution of pyridonecarboxylic acid or a salt thereof exhibiting an antibacterial action according to (5) or (6), wherein the alkali metal chloride is sodium chloride.