JPH085779B2 - Fleroxacin eye drops - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention provides 6,8-difluoro-1-
(2-Fluoroethyl) -1,4-dihydro-7- (4-
The present invention relates to an ophthalmic solution containing methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid (hereinafter referred to as "fleroxacin" according to a general name) or a salt thereof.

[Problems to be Solved by Prior Art and Invention] Fleroxacin is a new quinolone antibacterial drug having a strong activity against broad-spectrum Gram-positive and Gram-negative bacteria (US Pat. No. 4,398,029). Among the new quinolone antibacterial agents, those which have been used for medical treatment as eye drops include norfloxacin, ofloxacin and the like (JP-A-60-123420). It is suggested that fleroxacin may also be effective as a new quinolone antibacterial agent against external eye infections, but its ophthalmic solution has not been proposed yet. The reason is that it is important for eye drops to keep the pH in the neutral range as much as possible in order to reduce pain and irritation to ocular mucosal tissues. Extremely low solubility,
This is because the known technique cannot be used to produce eye drops.

Generally, as a method of solubilizing a new quinolone antibacterial agent, a method of adding a metal compound having aluminum, magnesium or zinc as a constituent part has been proposed (JP-A-63-188626). The metal compound has a strong astringent action, and when used in a large amount, it is highly likely to cause side effects, and it is inconvenient to add a large amount as a component of an eye drop.

Commonly used solubilizing agents include, for example, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate, polyoxyethylene phenyl ether, nonionic surfactants such as lauromacrogol, sodium lauryl sulfate, sodium cholate. Anionic surfactants such as, dimethyl-β-cyclodextrin, cyclodextrins such as hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone,
Polymers such as carboxymethyl cellulose and hydroxypropyl cellulose, polyhydric alcohols, solvents such as glycerin and polyethylene glycol, and caffeine are known.

However, these components cannot dissolve fleroxacin more than 0.1 w / v% in the neutral region.

[Means for Solving the Problems] The present inventor has conducted extensive studies in order to achieve the above-mentioned object. As a result, freloxacin is added as an eye drop in the neutral range of pH 6 to 7 by adding calcium salts. Found to have a solubility that exerts effective activity,
The present invention has been completed based on such findings.

That is, the feature of the ophthalmic solution according to the present invention is that it contains 0.1-1.0 w / v% of fleroxacin as an active ingredient, and as a solubilizing agent, calcium chloride, calcium lactate, calcium carbonate, calcium pantothenate, calcium gluconate, etc. One or more of the calcium salts of
1 to 10 w / v% is contained.

In order to further increase the solubility of fleroxacin, a magnesium salt may be added in addition to the calcium salt to obtain a more excellent effect on the solubility.

In the fleroxacin ophthalmic solution of the present invention, as the above-mentioned calcium salts that can be used as a solubilizing agent which is an essential component, any calcium salt used for medicinal purposes can be used. The amount of addition depends on the type of calcium salt, but it is necessary to add it in the range of 0.1 to 10 w / v%. 1.0 w / v% of fleroxacin
To obtain a solution, use any of the above calcium salts
It does not require more than 10w / v%, and beyond this range,
The concentration of eye drops is too high, which may cause damage to the ocular mucosa. Further, unless at least 0.1 w / v% is added, it cannot be stored as a stable fleroxacin solution.

Regarding the solubility of fleroxacin, when the calcium salts described above are further used in combination with a magnesium salt such as magnesium nitrate, magnesium chloride or magnesium oxide, the solubility of fleroxacin is remarkably increased. When a solution is prepared by adding a metal compound such as magnesium, a calcium salt can be added to these to reduce the amount of the metal compound, which leads to a reduction in side effects.

The solubility of fleroxacin in the coexistence of the calcium salt and the magnesium salt is 1.2 times higher than that of each of them alone. Table 1 shows the results of the evaluation of the combined effect as INDEX. It can be seen from Table 1 that the combined use of calcium salt and magnesium salt act synergistically.

The present invention enables for the first time the preparation of an effective eye drop of fleroxacin.

In addition to the above components, the eye drop of the present invention may appropriately contain other components as necessary.

For example, the eye drop of the present invention may contain a preservative, and as such a preservative, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride,
Paraoxybenzoic acid ester, benzyl alcohol, chlorobutanol, sodium dehydroacetate, phenylethyl alcohol, etc. are exemplified, and one kind or a mixture of two or more kinds of these is added at a concentration of 0.001 to 1.0 w / v%. be able to.

Further, an isotonicity agent can be added to the eye drop of the present invention for the purpose of alleviating irritation to the ocular mucosa. As the isotonicity agent, sodium chloride, glucose, fructose, sodium hydrogenphosphate, sodium dihydrogenphosphate, glycerin and the like are used, and these may be used alone or in combination of two or more. The amount to be added is determined by measuring the osmotic pressure of the solution and used as an isotonic solution.

In addition, a mucilage can be added to the fleroxacin eye drop of the present invention, if necessary. The mucilage imparts viscosity to the eye drop, prevents the liquid that has been applied to the eye from flowing out of the eye, and acts to prolong the residence time of the drug solution in the conjunctival sac. Due to the action, the sustainability of the drug effect and the intraocular transfer are enhanced, and the bioavailability of the drug can be enhanced.

In the fleroxacin eye drop of the present invention, examples of such mucilages that can be used are glycerin, polyhydric alcohols such as polyethylene glycol, sorbitol, sugars such as sucrose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, Cellulose such as hydroxyethyl cellulose and hydroxypropylmethyl cellulose, synthetic polymer compounds such as polyvinyl alcohol, polyvinylpyrrolidone and carboxyvinyl polymer, as well as chondroitin sulfate and sodium alginate can be used. When these are added, these can be used alone or in combination of two or more, and 0.01 to 10 w / v%
Is suitable to be added.

[Effects of the Invention] The fleroxacin eye drop according to the present invention has an effect that it can be clinically applied to various external ocular infections as an eye drop having a broad spectrum antibacterial spectrum which is a neutral solution and does not irritate the eye mucosa. .

[Reference example] After adjusting various salt solutions (10 mg / ml) shown in Table 1 below to about 0.1N sodium hydroxide test solution pH7, the solubility of fleroxacin at 25 ° was measured, and the results are shown in Table 1. .

[Examples] With respect to the fleroxacin eye drop according to the present invention,
This will be described in detail with reference to examples.

Example 1 100 ml of sterilized purified water was added to 3 g of fleroxacin and 40 g of calcium lactate, dissolved by heating and adjusted to pH 6.2 with a sodium hydroxide solution, and sterilized purified water was added to make 1000 ml. Next, after filtering with a 0.22 μm membrane filter, it was filled in an eye drop container, and it was possible to produce an eye drop solution of fleroxacin 0.3 w / v%.

Example 2 100 g of sterile purified water was added to 3 g of fleroxacin and 60 g of calcium pantothenate to dissolve, and sodium hydroxide solution was added to adjust the pH to 6.2, and then benzalkonium chloride 0.0
5 g was added and dissolved, and sterile purified water was added to make 1000 ml.
Next, after filtering with a 0.22 μm membrane filter,
It was possible to fill the eye drop container and prepare an eye drop solution of 0.3 w / v% fleroxacin.

Example 3 100 g of sterilized purified water was dissolved in 3 g of fleroxacin, 10 g of calcium chloride and 2 g of sodium chloride, and the pH was adjusted to 6.2 by adding a sodium hydroxide solution, and then 3 g of carboxymethyl cellulose was added to dissolve the sterilized purified water. In addition
It was set to 1000 ml. Next, after filtering with a 0.22 μm membrane filter, it was filled in an eye drop container and fleroxacin was added to 0.2.
It was possible to produce 3 w / v% eye drops. Osmotic pressure is 280mOs
m.

Example 4 100 g of sterile purified water was dissolved in 3 g of fleroxacin, 2 g of calcium chloride, 2 g of magnesium nitrate and 40 g of glucose, and sodium hydroxide solution was added to adjust the pH to 6.2,
Sterile purified water was added to make 1000 ml. Next, after filtering with a 0.22 μm membrane filter, it was filled in an eye drop container, and it was possible to produce an eye drop solution of fleroxacin 0.3 w / v%.

Example 5 100 g of sterile purified water was added to and dissolved in 3 g of fleroxacin, 2 g of calcium chloride, 2 g of magnesium chloride and 7 g of sodium chloride, and sodium hydroxide solution was added to adjust the pH to 6.2, and then sterile purified water was added to 1000 ml. did. Next, 0.22μ
After filtering with a membrane filter of m, the solution was filled in an eye drop container, and an eye drop solution of fleroxacin 0.3 w / v% could be prepared.

Example 6 20 g of calcium pantothenate and 30 g of glucose were added to and dissolved in 3 g of fleroxacin, the pH was adjusted to 6.2 by adding sodium hydroxide solution, and sterilized purified water was added to make 1000 ml. Next, after filtering with a 0.22 μm membrane filter, it was filled in an eye drop container, and it was possible to produce an eye drop solution of fleroxacin 0.3 w / v%.

Example 7 To 3 g of fleroxacin, 30 g of calcium gluconate was added and dissolved, and a sodium hydroxide solution was added to adjust the pH to 6.2, and then sterile purified water was added to make 1000 ml. Next, 0.22μ
After filtering with a membrane filter of m, the solution was filled in an eye drop container, and an eye drop solution of fleroxacin 0.3 w / v% could be prepared.

Example 8 To 1 g of fleroxacin and 15 g of calcium lactate, 100 ml of sterilized purified water was added, dissolved by heating, and 0.5 ml of sodium chloride was added thereto.
g was dissolved and sterile purified water was added to make 800 ml. Next, a sodium hydroxide solution was added to adjust the pH to 6.5, and sterilized purified water was added to make 1000 ml. This solution was filtered through a 0.22 μm membrane filter and then filled in an eye drop container, whereby an eye drop solution of fleroxacin 0.1 w / v% could be prepared.

Example 9 200 g of sterilized purified water was added to 10 g of fleroxacin, 2.5 g of calcium chloride and 3 g of sodium chloride to dissolve, and the pH was adjusted to 6.5 by adding a sodium hydroxide solution, and sterilized purified water was added to make 1000 ml. Next, after filtering with a 0.22 μm membrane filter, it was filled in an eye drop container, and it was possible to produce an eye drop solution of fleroxacin 0.3 w / v%.

Example 10 To 3 g of fleroxacin and 40 g of calcium lactate, 100 ml of sterilized purified water was added, dissolved by heating, and a sodium hydroxide solution was added to adjust the pH to 6.5. To this solution, 3 g of methyl cellulose and 0.05 g of benzalkonium chloride were added and dissolved,
Sterile purified water was added to make a total volume of 1000 ml. Next, 0.22 μm
After filtering with a membrane filter of No. 3, it was filled in an eye drop container, and it was possible to prepare an eye drop solution of 0.3% w / v of fleroxacin.

Claims (4)

[Claims] 1. An active ingredient, 6,8-difluoro-1-
(2-Fluoroethyl) -1,4-dihydro-7- (4-
Methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid or a salt thereof is contained in an amount of 0.1 to 1.0 w / v% and a calcium salt as a solubilizing agent. 2. The calcium salt as a solubilizing agent according to claim 1, which is one or more selected from calcium chloride, calcium lactate, calcium pantothenate, calcium gluconate and calcium carbonate.
Fleroxacin ophthalmic solution containing 0.1 to 10 w / v%. 3. The one or two selected from magnesium nitrate, magnesium chloride or magnesium oxide together with a calcium salt as a solubilizing agent according to claim 1 or 2.
Fleroxacin ophthalmic solution containing at least one magnesium salt and having a magnesium ion / calcium ion ratio of 2 to 0.2. 4. An ophthalmic solution of fleroxacin, which contains at least one of a preservative, an isotonicity agent, and a mucilage agent according to any one of claims 1 to 3.