JPH03109326A - Fleroxacin eye drop - Google Patents

Abstract

PURPOSE:To provide the title eye drops having such a fleroxacin solubility as to give effective activity in the neutral region, incorporated with calcium salt(s) as dissolution aid. CONSTITUTION:The objective eye drops containing, as active ingredient, 0.1-1.0w/v% of 6,8-difluoro-1-(2-fluoroethyl)-1,1-dihydro-7-(4-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid or its salt and, as dissolution aid, 0.1-1.0w/v% of calcium salt (s) selected from calcium chloride, calcium lactate, calcium pantothenate, calcium gluconate and calcium carbonate. Furthermore, if magnesium salt(s) selected from magnesium nitrate, magnesium chloride and magnesium oxide is incorporated in the present eye drops at the ratio Mg<2+>/Ca<2+>=2-0.2, the solubility of fleroxacin will be dramatically increased. The present eye drops can be further incorporated, where appropriate, with preservative, isotonicity-affording agent and/or thickening agent.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention uses 6,8-difluoro-1-(
2-fluoroethyl)-1,4-dihydro-7-(4-
The present invention relates to an eye drop containing methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (hereinafter referred to as fleroxacln J according to its common name) or a salt thereof.

[Prior art and problems to be solved by the invention] Fleroxacin is a new quinolone antibiotic that has strong activity against a broad spectrum of Durham-positive and Durham-negative bacteria (US Pat. No. 4,398,029). . Among the new quinolone antibacterial drugs, those used medically as eye drops include norfloxacin and ofloxacin (Japanese Unexamined Patent Publication No. 123420/1980). It has been suggested that fleroxacin may also be effective against external ocular infections as a new quinolone antibiotic, but an ophthalmic solution for it has not yet been proposed. It is important to maintain it in the neutral range as much as possible in order to reduce pain and irritation to the ocular mucosal tissue, but due to its nature, fleroxacin has extremely low solubility in the acidic and neutral ranges, so it cannot be used with eye drops using known techniques. This is because it cannot be produced as a liquid.

Generally, as a method for solubilizing new quinolone antibacterial drugs, a method of adding a metal compound containing aluminum, magnesium, or zinc as a constituent has been proposed (Japanese Patent Application Laid-open No. 188626/1983); Metal compounds have a strong astringent effect and are likely to cause side effects when used in large amounts, making them inconvenient to be added in large amounts as components of eye drops.

Commonly used solubilizing agents include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate, polyoxyethylene phenyl ether, nonionic surfactants such as lauromacrogol, sodium lauryl sulfate, and sodium cholate. anionic surfactants such as dimethyl-β-cyclodextrin, sifrobukis such as hydroxypropyl-β-cyclodextrin], phosphorus, polyvinylpyrrolidone,
Polymers such as carboxymethyl cellulose and hydroxypropyl cellulose, polyvalents, solvents such as alcohol, glycerin, and polyethylene glycol, and caffeine are known.

However, these components cannot dissolve fleroxacin at a concentration of 0.1 w/vk or more in the neutral region.

[Means for Solving the Problems] In order to achieve the above object, the present inventor has made extensive studies and found that fleroxacin can be used as an ophthalmic solution in the neutral range of p) 16 to 7 by adding calcium salts. The inventors have discovered that the compound has a solubility that exhibits effective activity as a compound, and based on this knowledge, the present invention has been completed.

That is, the eye drops of the present invention are characterized by containing 0.1 to 1.0 w/vk of fleroxacin as an active ingredient, and calcium chloride, calcium lactate, calcium carbonate, calcium pantothenate, and gluconic acid as solubilizing agents. It contains one or more calcium salts such as calcium in an amount of 0.1 to 10 stomachs/v9g.

To further increase the solubility of fleroxacin, by adding magnesium salt in addition to calcium salt,
Even better effects on solubility can be obtained.

In the fleroxacin ophthalmic solution of the present invention, any of the calcium salts used for pharmaceutical purposes can be used as the above-mentioned calcium salts that can be used as a solubilizing agent which is an essential component. The amount added varies depending on the type of calcium salt, but it is necessary to add it in the range of 0.1 to 10 calcium salts/square. fleroxacin 1,
In order to obtain a 0 w/vt solution, it is not necessary to use any of the above calcium salts in a concentration of 10 g/v96 or more, and if this range is exceeded, the concentration is too high for eye drops and may be harmful to the ocular mucosa. It is feared. Also, at least 0.1 w
/v96 or more cannot be stored as a stable fleroxacin solution.

The solubility of fleroxacin in the above calcium salts is
Surprisingly, when a magnesium salt such as magnesium nitrate, magnesium chloride or magnesium oxide is added and used in combination, the solubility of fleroxacin is dramatically increased. When a solution is prepared by adding a metal compound such as magnesium, a calcium salt can be added to the solution to reduce the amount of the metal compound, which in turn leads to a reduction in side effects.

The solubility of fleroxacin in the coexistence of calcium salt and magnesium salt is 1.2 times higher than that of each alone.INDEX
The results obtained are shown in Table 1. From Table 1, it can be seen that the combination of calcium salt and magnesium salt acts synergistically.

The present invention has made it possible for the first time to prepare effective eye drops of fleroxacin.

In addition to the above-mentioned components, the eye drops of the present invention may contain other components as appropriate.

For example, the eye drops of the present invention can contain preservatives, such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, paraoxybenzoic acid ester, benzyl alcohol, chlorobutanol, dehydrogen Examples include sodium acetate and phenylethyl alcohol, among which 1f!
! Or by mixing two or more types, 0.001 to 1.0 w/v
It can be added at a concentration of X.

Furthermore, an isotonic agent may be added to the eye drops of the present invention for the purpose of alleviating irritation to the ocular mucosa. As the tonicity agent, sodium chloride, glucose, fructose, sodium hydrogen phosphate, sodium dihydrogen phosphate, glycerin, etc. are used, and these can be used alone or in combination of two or more. The amount added is determined by measuring the osmotic pressure of the solution, and the solution is made isotonic.

In addition, a seminal plasma agent can be added to the fleroxacin ophthalmic solution of the present invention, if necessary.

Seminal plasma gives the eye drops viscosity, prevents the instilled liquid from flowing out of the eye, and has the effect of prolonging the residence time of the drug solution in the conjunctival capsule. Due to this action, the persistence of drug efficacy and intraocular distribution are enhanced, and the bioavailability of the drug can be increased.

In the fleroxacin ophthalmic solution of the present invention, glycerin,
Synthesis of polyhydric alcohols such as polyethylene glycol, sugars such as sorbitol and sucrose, celluloses such as methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and carboxyvinyl polymers. In addition to polymer compounds, chondroitin sulfate, sodium alginate, etc. can be used. When adding these, these lfi or 2
It is possible to use a mixture of more than 0 species, 0, O1 to 10w
/v% is suitable.

[Effects of the Invention] The fleroxacin ophthalmic solution of the present invention has the effect that it can be clinically applied to various external ocular infections as an ophthalmic solution that is a neutral solution and has a broad antibacterial spectrum without irritating ocular mucous membranes. .

[Reference Example] Various salt solutions (10 mg/ml) shown in Table 1 below were mixed with 0,
After adjusting the solubility of IN sodium hydroxide test solution p) to around 17, the solubility of fleroxacin at 25° was measured, and the results are shown in Table 1.

Table 1 Solubility IN of fleroxacin in saline solution
DEX > 1: Synergistic action, -1: Additive action, Ku1:
Antagonism [Example] The fleroxacin ophthalmic solution according to the present invention will be explained in detail below using Examples.

Example 1 Add sterilized purified water 10011 to 3 g of fleroxacin and 40 g of calcium lactate, dissolve by heating, and adjust the pH to 6.2 by adding sodium hydroxide solution. Next, the mixture was filtered through a 0.22 pm membrane filter and then filled into an eye drop container to prepare an eye drop containing fleroxacin at 0.3 w/vk.

Example 2 Fleloxacin 3g and calcium pantothenate 60g
Add 100alffi of sterile purified water to dissolve, add sodium hydroxide solution to adjust fJH to 6.2, add and dissolve 0.05 g of benzalkonium chloride, and add sterile purified water to make 1000IIlffi. 0th order, 0
．． After passing through a 22 fLm membrane filter, it was filled into an eye drop container to prepare an eye drop containing 0.3 w/vX fleroxacin.

Example 3 3 g of fleroxacin, 10 g of calcium chloride and 2 g of sodium chloride were dissolved by adding 100 m of sterile purified water,
After adjusting the pH to 6.2 by adding sodium hydroxide solution,
3 g of carboxymethyl cellulose was added and dissolved, and sterile purified water was added to make 100 hffi. Next, 0.22
After filtering through a .mu.m membrane filter, it was filled into an eye drop container to prepare an eye drop containing 0.3 vt/v9 g of fleroxacin. Osmotic pressure was 280 moss.

Example 4 3 g of fleuroxacin 2 g of lucium chloride 2 g of magnesium nitrate and 40 g of glucose with 10 oz of sterile purified water
Add fi to dissolve, add sodium hydroxide solution to p
After adjusting H to 6.2, add sterile purified water and heat to 10100o.
And so. Next, after passing through a 0.22μI membrane filter, it was filled into an eye drop container, and fleroxacin 0.
3 w/v! An eye drop of Ii could be prepared.

Example 5 100% sterile purified water to 3g fleroxacin, 2g calcium chloride, 2g magnesium chloride and 7g sodium chloride
Add mN to dissolve, add sodium hydroxide solution to p
After adjusting H to 6.2, add sterilized purified water and boil for 1000 m.
First, it was filtered with a 0.221 membrane filter, filled into an eye drop container, and fleroxacin 0.
3 w/v turtle eye drops could be prepared.

Example 6 20 g of calcium pantothenate and 930 g of grapes were added and dissolved in 3 g of fleroxacin, and sodium hydroxide solution was added to adjust p)I to 6.2, and sterile purified water was added to make it 100,100 O. After filtering with a 0.22#Lm membrane filter, fill it into an eye drop container.
It was possible to prepare eye drops containing 0.3 caps/vX of fleroxacin.

Example 7 30 g of calcium gluconate was added and dissolved in 3 g of fleroxacin, and a sodium hydroxide solution was added to adjust the pH to 6.
After adjusting to 2, sterilized purified water was added to make it 1000 d. Next, after filtering with a 0.22 μm membrane filter, it was filled into an eye drop container, and fleroxacin 0.3 w/v was added.
We were able to produce eye drops of K.

Example 8 Add 100 ml of sterile silk water to 1 g of fleroxacin and 15 g of calcium lactate, dissolve by heating, dissolve 0.5 g of sodium chloride, and add sterile purified water to make 800 ml.
Next, sodium hydroxide solution was added to adjust the pH to 6.
．． After adjusting the temperature to 5, sterilized purified water was added to bring the temperature to 10,100O. After filtering this solution with a 0.22 μm membrane filter, it was filled into an eye drop container and fleroxacin 0.1
It was possible to produce eye drops with a w/v ratio of zero.

Example 9 10 g of fleroxacin, 2.5 g of calcium chloride, and 3 g of sodium chloride were dissolved in 200 mL of sterile purified water, and sodium hydroxide solution was added to adjust p)l to 6.5, and then sterile purified water was added to give a solution of 100,100 O. And so. Next, after filtration with a 0.22 μm membrane filter, the eye dropper was filled with fleroxacin at 1.0 stomach/v9.
It was possible to prepare eye drops of g.

Example 10 100 ml of sterile purified water was added to 3 g of fleroxacin and 40 g of calcium lactate, dissolved by heating, and the pH was adjusted to 6.5 by adding sodium hydroxide solution. Add 3 g of methylcellulose and 0.05 g of benzalkonium chloride to this liquid.
Add and dissolve, and add sterile purified water to make a total volume of 10,100O
And so. Next, after filtration with a 0.22μI membrane filter, it was filled into an eye dropper, and fleroxacin 0.
3 w/v96 eye drops could be produced.

4 others

Claims (1)

[Claims] 1. 6,8-difluoro-1-(2-
0.1 to 1.0 w/v% of fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid or its salt, and a solubilizing agent. A fleroxacin ophthalmic solution characterized by containing a calcium salt. 2. In claim 1, the calcium salt as a solubilizing agent is one or more selected from calcium chloride, calcium lactate, calcium pantothenate, calcium gluconate, and calcium carbonate, and 0.1 ~
A fleroxacin ophthalmic solution containing 10 w/v%. 3. In claim 1 or 2, the dissolution aid contains one or more magnesium salts selected from magnesium nitrate, magnesium chloride, or magnesium oxide together with calcium salt, and the magnesium ion/calcium ion ratio is A fleroxacin ophthalmic solution characterized in that it has a molecular weight of 2 to 0.2. 4. A fleroxacin ophthalmic solution according to any one of claims 1 to 3, which contains at least one of a preservative, an isotonic agent, and a mucilage agent.