KR20160014987A - Instillations formulation for treating ocular infections comprising pyridin-2-one derivatives - Google Patents

Abstract

The present invention relates to an eye drop comprising 1-(3-amino-2-methyl-benzyl)-4-(2-thiophen-2-yl-ethoxy)-1H-pyridin-2-one. The non-stimulant eye drop causes no feeling of irritation when injecting the eye drop on an eyeball of a user, and has excellent solubility and stability, while having excellent effects in treating various ocular infectious diseases, thereby being suitable for an eye drop for being locally injected in the eyeball of the user. The eye drop for treating ocular infections comprises: (i) a compound represented by chemical formula 1 as an active ingredient or pharmaceutically acceptable salt thereof; (ii) a solubilizing agent; and (iii) an anti-precipitation agent.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to eye drops for the treatment of eye infections containing pyridin-

The present invention relates to eye drops for the treatment of ocular infections comprising 1- (3-amino-2-methylbenzyl) -4- (2-thiophen-2-yl-ethoxy) -1H-pyridin- .

Fatty acid synthase (FAS) is involved in the overall biosynthetic pathway of saturated fatty acids in all living organisms, but the structural organization of FAS is diverse among living organisms. The distinctive feature of FAS in vertebrates and yeast is that all enzyme activities are encoded in one or two polypeptide chains and that acyl carrier proteins (ACP) are present in a complex form. On the other hand, in the case of bacterial FAS, each synthesis step is catalyzed by a separate mono-functional enzyme, and ACP is a discrete protein apart. Therefore, it is possible to selectively inhibit the bacterial FAS by inhibiting one of the synthesis steps using an inhibitor.

The NADH-dependent enoyl-ACP reductase (Fab I) has been associated with the last step in four reaction steps associated with each cycle of bacterial fatty acid biosynthesis (Payne et al., Drug Discovery Today 6, 2001, 537-544 ). The first step, the condensation of malonyl-ACP with acetyl-CoA (Fab H) is catalyzed by the? -Ketoacyl-ACP synthase. The second step is keto ester reduction by NADPH-dependent [beta] -ketoacyl-ACP reductase (Fab G). Followed by dehydration by? -Hydroxyacyl-ACP dihydrate (Fab A or Fab Z) to trans-2-enoyl-ACP. Finally, in the fourth step, trans-2-enoyl-ACP is converted to acyl-ACP having two more carbon atoms by Fab I. This cycle is repeated, eventually resulting in palmitoyl-ACP (16C) and this cycle is stopped due to inhibition of Fab I by palmitoyl-ACP (Heath et al., J. Biol. Chem. 271, 1996, 1833-1836). Thus, Fab I is the biosynthetic enzyme of the overall synthetic pathway of bacterial fatty acid biosynthesis.

According to recent studies, Fab I has been reported to be a potent antioxidant, such as triclosan (McMurry et al., Nature, 1998, 394, 531-532) or diazaborin (Baldock et al., Science, 1996, 274, 2107-2110) Have been found to be targets for a broad spectrum of antibiotics. In addition, while diazaborin functions as an irreversible inhibitor of Fab I by forming a covalent bond with Fab I (Baldock et al., Biochem. Pham. 1998, 55, 1541-1549), triclosan is a reversible (Ward et al., Biochem., 38, 12514-12525).

Recently, 1- (3-amino-2-methylbenzyl) -4- (2-thiophen-2-yl-ethoxy) -1H-pyridin-2-one has been reported as a selective inhibitor for Fab I , It has been reported that the compound can alleviate or alleviate a disease caused by bacterial infection associated with bacterial fatty acid biosynthesis, and thus is useful for the treatment of urinary tract, respiratory or skin tissue infection, sepsis and the like (US Patent No. 7,973,060 215).

However, the pyridin-2-one derivative is an extremely low-solubility drug with low solubility in water, and thus has not yet been utilized in the field of eye drops for treating eye infections, which requires excellent solubility and stability and a small foreign body sensation in the eyeball .

Since the minimum inhibitory concentration (MIC) of the pyridin-2-one derivative was measured in the range of 0.2 to 128 μg / mL, specifically 0.2 to 1 μg / mL for the wild-type strain (see US Pat. No. 7,973,060 1). It is necessary to improve the solubility in water in order to exhibit a sustained and high drug efficacy over these MICs. The pyridin-2-one derivative can be dissolved in an acidic condition at a pH of 1.2 to 1,100 μg / mL. However, when such an acidic condition is directly applied to the eye, it may be fatal to the eye such as corneal damage. In general, when the eye drops are applied to the eye, the active ingredient is placed in a different concentration condition due to tears in the eye. If the concentration condition is changed, the active ingredient dissolved in the solubilizing agent may be precipitated, Ocular irritation due to impaired foreign body sensation may cause secondary infection. In addition, the drug may be released to the outside in the process of rubbing tears or eyes due to a foreign object, thereby reducing the efficacy of the drug.

US Patent Registration No. 7,973,060 (July 5, 2011)

 Payne et al., Drug Discovery Today 6, 2001, 537-544  Heath et al., J. Biol. Chem. 271, 1996, 1833-1836  McMurry et al., Nature, 1998, 394, 531-532  Baldock et al., Science, 1996, 274, 2107-2110  Baldock et al., Biochem. Pham. 1998, 55, 1541-1549  Ward et al., Biochem. 38, 12514-12525

Accordingly, it is an object of the present invention to provide a composition comprising 1- (3-amino-2-methylbenzyl) -4- (2-thiophen-2-yl-ethoxy) The present invention is to provide a novel eye drop formulation which can excellently attain various properties required as an eye drop while exhibiting an effect of treating infections.

According to the above object, the present invention provides an eyedrop for the treatment of eye infections, which comprises (i) a compound of the following general formula (1) or a pharmaceutically acceptable salt thereof, (ii) a solubilizing agent and (iii) do:

≪ Formula 1 >

The eyedrops according to the present invention are suitable for topical application to the eyeballs because they are excellent in the therapeutic effect of various eye infectious diseases, are excellent in solubility and stability,

1 is a graph showing the change of solubility of the compound of Chemical Formula 1 according to temperature and pH.
Fig. 2 is a graph showing changes in turbidity when diluting eye drops in Examples 1 to 6 and Comparative Example 2; Fig.
3 is a graph showing stability of the eye drops according to Examples 1 to 6 and Comparative Example 2 with respect to temperature changes.
4 is a graph showing the results of infecting mouse eyes with Staphylococcus aureus.
FIG. 5 is a graph showing the pharmacological effects of compounds of Example 6, Comparative Example 1, and a control group using a mouse eye infestation model.

Hereinafter, the present invention will be described in detail.

The eye drops according to the present invention contain the compound of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound of formula (I) can be obtained by reacting 1- (3-amino-2-methylbenzyl) -4- (2-thiophen- -2-methyl-benzyl) -4- (2-thiophen-2-yl-ethoxy) -1H-pyridin-2-one.

The compound of formula (1) exhibits selective inhibitory effect on Fab I, and thus is effective for the treatment of diseases caused by bacterial infection through topical ocular administration.

The compound of Formula 1 may be present in the eye drops in the form of amorphous, crystalline or a mixture thereof.

The compound of Formula 1 may be contained in the eye drop in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt may be an acid addition salt formed using an acid. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, oxalic acid, , Maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid.

The compound of Formula 1 or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.05 to 5% by weight, specifically 0.1 to 3% by weight, more preferably 0.2 To 1% by weight, more particularly 0.5% by weight.

The eye drops according to the present invention include pharmaceutically acceptable solubilizing agents and precipitation inhibitors in addition to the above-mentioned effective ingredients.

Accordingly, the eye drops can stably contain the poorly soluble active ingredient at a concentration of the solubility or higher, so that the pharmacological effect in the eye can be maintained.

The solubilizing agent is added in order to keep the active ingredient in a highly dissolved state.

Examples of the solubilizing agent include fatty acids, saccharides, glycerin, glycerides, polyethylene glycols or esters thereof, synthetic or semi-synthetic oils, polar aprotic solvents, or other pharmaceutically acceptable solubilizing agents.

Specific examples of the solubilizing agent include sorbitan stearate, polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene 40 stearate, polyethoxylated castor oil, cyclodextrin, triglycerides (e.g., medium chain triglycerides) triglyceride esters (eg triglycerides, PEG esters), Lavra Phil (Labrafil ^®), Lavra Phil M1944CS, Lavra Phil M2125CS, Lavra Phil M2130CS, Lavra Sol (Labrasol ^®), Lavra Park (Labrafac ^®), Capri ol (Capryol ^®) 90, Capri come PGMC, glycol as laurate (Lauroglycol ^®) glycol at 90, laurate (Lauroglycol ^®) FCC, fluorenyl roll (Plurol ^®) All Lake (Oleique) CC 497, dimethyl sulfoxide, glycerol, etc. .

Preferably, as the solubilizing agent, a polar aprotic solvent such as dimethylsulfoxide, dimethylacetamide, dimethylformamide, N-alkylpyrrolidine and the like may be used, and more preferably, dimethylsulfoxide is used as the solubilizing agent Can be used.

The solubilizing agent may be used alone or in combination of two or more, and may be contained in the eyedrops (100% by weight) in an amount of 0.5 to 25% by weight.

The precipitation inhibitor (crystallization inhibitor) is added in order to keep the active ingredient in a high-concentration dissolved state.

Examples of the precipitation inhibitor include polyhydric alcohols such as propylene glycol, polyethylene glycol, dipropylene glycol, diethylene glycol, diethylene glycol monoethyl ether, and glycerol; Surfactants such as Tween 80, Cremophor ( ^R ), Transcutol ( ^R ) and the like can be used.

Preferably, the trans kyutol (Transcutol ^®, Gattefosse), as the precipitation preventing agent may be used. The transcutol can be composed mainly of diethylene glycol monoethyl ether of high purity.

The precipitation inhibitor may be used alone or in admixture of two or more, and may be contained in an amount of 0.5 to 10% by weight in the eye drop (100% by weight).

In addition to the solubilizing agent and the precipitation inhibitor, the eyedrops according to the present invention further include other pharmaceutically acceptable additives. Specifically, the eyedrops may further include at least one member selected from the group consisting of stabilizers, preservatives, viscosity regulators, adsorption inhibitors, and isotonic agents. In addition, the eyedrops may further contain a pH adjusting agent, a buffer, and the like. Accordingly, conditions similar to those of artificial tears can be provided, so that non-magnetic properties and foreign objects can be significantly reduced in an eye drop.

The stabilizer may be sodium edetate hydrate, but is not limited thereto.

The preservative may be, but is not limited to, chlorohexidine gluconate.

The viscosity modifier may be sodium carboxymethylcellulose, hydroxyethylcellulose, or a mixture thereof, but is not limited thereto.

The adsorption inhibitor may be polysorbate 80, but is not limited thereto.

The isotonic agents may be selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and mixtures thereof. In addition, the eye drops may contain pharmaceutically acceptable auxiliaries, pH adjusters, buffers, antioxidants, tonicity adjusting agents, preservatives, thickeners, and the like.

Examples of the pH adjuster include organic acids such as acetic acid, citric acid, lactic acid, maleic acid, adipic acid, tartaric acid and benzoic acid; Hydrochloric acid; Phosphoric acid; Carbonic acid; And cyanic acid, but are not limited thereto.

Such buffers include organic acid buffers such as acetic acid, citric acid, lactic acid, maleic acid, adipic acid, tartaric acid and benzoic acid; Phosphate buffer; And a carbonic acid buffer solution. However, the present invention is not limited thereto.

As an example of a specific composition containing these additives, dimethylsulfoxide as a solubilizing agent; Transcuttol as a precipitation inhibitor; Sodium edetate hydrate as a stabilizer; Chlorohexidine gluconate as preservative; A mixture of sodium carboxymethylcellulose and hydroxyethylcellulose as viscosity modifiers; Polysorbate 80 as an adsorption inhibitor; And eyedrops containing a mixture of sodium chloride and potassium chloride as isotonic agents.

Preferably, the eye drops contain 10 to 20,000 parts by weight of the solubilizing agent, 10 to 20,000 parts by weight of the precipitation inhibitor, 0.1 to 100 parts by weight of the stabilizer, 0.0005 to 0.05 part by weight of the preservative, 1 to 1,000 parts by weight of the viscosity modifier, 0.001 to 100 parts by weight of the adsorption inhibitor and 1 to 1,000 parts by weight of the isotonic agent.

More preferably, the eye drops contain 100 to 10,000 parts by weight of the solubilizing agent, 100 to 6,000 parts by weight of the precipitation inhibitor, 1 to 50 parts by weight of the stabilizer, 0.001 to 0.05% by weight of the preservative, 10 to 500 parts by weight of the viscosity modifier, 0.01 to 0.1 parts by weight of the adsorption inhibitor and 10 to 500 parts by weight of the isotonic agent.

The eyedrops according to the present invention described above can be administered in a dose-free manner for ocular administration with a limited total dose, for example, 20 times or more, and more preferably 40 times or more times the solubility of the compound of formula It is possible not only to maintain a stable state even when administered at a high concentration, but also to exhibit improved instability by non-irritation.

The eye drops according to the present invention can be used for the treatment of eye infectious diseases of Gram-positive bacteria such as MRSA (methicillin resistant staphylococcus aureus), or various other ocular infectious diseases.

Examples of the Gram-positive bacteria include staphylococcus such as staphylococcus aureus and staphylococcus epidermidis; Streptococcus pneumoniae, streptococcus pyrogenes, group C / F / G streptococci of the C, F and G groups and viridans group of the Viridans group Streptococcus such as streptococci.

Specific examples of eye infections to be treated with the eye drops include corneal ulcers, surface or inner keratitis, surface or inner conjunctivitis, conjunctivitis, eyelid conjunctiva, conjunctival septaemia, acute or chronic septicemia, aciduria, dacryocystitis, But are not limited to, eye drops, trachoma, endophthalmitis, infectious uveitis, and the like.

The eye drops can be administered to the patient in an appropriate manner and dosage, depending on the indication, condition or condition of the patient.

The eye drops may be administered to a patient at a daily dose of 0.1 to 100 mg / kg body weight.

The eye drops may be administered 1 to 5 drops once, and may be administered by various schedules such as 1 to 4 times a day, but are not limited thereto.

Hereinafter, the present invention will be described by way of more specific examples. It should be understood, however, that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Preparation Example 1: Preparation of 1- (3-amino-2-methylbenzyl) -4- (2-thiophen-2-yl-ethoxy) -1H-pyridin-

The compound of formula (1) was prepared in the same manner as described in example 215 of U.S. Patent No. 7,973,060. Specifically, a solution of 4-benzyloxy-1H-pyridone (300 mg, 1.49 mmol) and NaH (60 mg, 1.49 mmol) in DMF solvent was stirred for 30 min and 2-methyl-3-nitro- benzyl chloride (277 mg, 1.49 mmol) was added thereto, followed by further stirring at room temperature for 30 minutes. The resulting solution was treated with water and dichloromethane and purified via column chromatography (ethyl acetate / hexanes, 1: 1) to give the nitro compound (370 mg, 67%). The resulting nitro compound (370 mg, 0.999 mmol) was added to a mixed solution (10 mL) of methanol / dichloromethane (10: 1) and thereto was added hydrochloric chloride hexahydrate (10.8 mg, 0.04 mmol) and hydrazine monohydrate mmol) were added and the mixture was heated and stirred for 4 hours. After stirring, the reaction solution was filtered with celite, and the filtrate was concentrated, diluted with dichloromethane and washed twice with water. The organic layer was separated, dried over magnesium sulfate, and filtered to obtain an organic solution, which was then concentrated. The concentrated organics were separated by column chromatography on silica gel to give the desired compound (299 mg, 88%).

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 2.01 (s, 3H), 3.28 (t, 2H), 3.65 (br s, 2H), 4.14 (t, 2H), 5.04 (s, 2H), 5.84 (dd (D, 1H), 5.95 (d, 1H), 6.57 (d, 1H), 6.70 (d, 1H), 6.88-7.02 (m, 4H), 7.16

Example 1: Preparation of eyedrops

Trans kyutol (Transcutol ^® HP) then a solution of 300mg, which was stirred for 10 minutes, here the 1- (3-amino-2-methylbenzyl) obtained in Preparation Example 1 as dimethylsulfoxide 500mg and precipitation agent as a solubilizer - 5 mg of 4- (2-thiophen-2-yl-ethoxy) -1H-pyridin-2-one was added as an active ingredient and stirred for 20 minutes until completely dissolved. After dissolution was completed, water for injection was added and stirred for 30 minutes to prepare eye drops.

Then, the eye drops were aseptically filtered with a 0.22 mu m filter, and then filled in 5 ml of the eye drop container for later use.

Examples 2 to 5: Preparation of Eye Drops

The procedure of Example 1 was repeated except that lavasol, capriol, lavarax or glycerin described in the following Table 1 was used instead of dimethylsulfoxide as a solubilizing agent to prepare eye drops.

Example 6: Preparation of eyedrops

In the same manner as in Example 1, the compound of Chemical Formula 1 was completely dissolved in dimethylsulfoxide and transcutol. Thereafter, 195 mL of artificial tears, in which sodium carboxymethyl cellulose (CMC), sodium chloride, sodium chloride, sodium edetate hydrate, chlorohexidine gluconic acid salt solution, hydroxyethyl cellulose and polysorbate 80 were dissolved in water for injection, . The artificial tears were mixed with a solution of the compound of formula (I) dissolved therein to prepare eye drops.

Comparative Example 1: Preparation of eyedrops

Except that the active ingredient 1- (3-amino-2-methylbenzyl) -4- (2-thiophen-2-yl-ethoxy) -1H-pyridin- The procedure of Example 1 was followed to prepare eye drops.

Comparative Example 2: Preparation of eyedrops

The same procedure as in Example 1 was repeated to prepare eye drops, except that no solubilizing agent was added and the amount of water for injection was added instead.

The compositions of the eye drops of Examples 1 to 6 and Comparative Examples 1 and 2 are summarized in Table 1 below.

Experimental Example  1: Evaluation of solubility in water

The solubility of the compound of Chemical Formula 1 obtained in Preparation Example 1 in water according to temperature and pH was measured and shown in FIG.

As shown in FIG. 1, the compound of formula (1) had little effect on the temperature, but showed a tendency that the solubility was inversely proportional to pH, and the solubility in water was very low overall, indicating that it was an extremely poorly soluble drug.

In addition, the solubility of the compound of Formula 1 and the eyedrops of Example 6 in water was measured at the same pH and temperature conditions and compared in Table 2 below.

As shown in Table 2, the solubility in water of the compound of formula (1) itself is as low as 119 μg / mL, but the solubility of the compound of formula (1) in water of 5,000 μg / And thus it was confirmed that the drug was stable and did not precipitate.

Experimental Example 2: Evaluation of turbidity by dilution

The turbidity of the eye drops of Examples 1 to 6 and Comparative Example 2 was measured. As a result, the eyedrops of Examples 1 to 6 using the solubilizer were measured to be colorless transparent at 0% of turbidity and Comparative Example 2 The turbidity of the eye drops was very high.

Thereafter, the eyedrops of Examples 1 to 6 and Comparative Example 2 were diluted 4-fold and 8-fold with a pH 7.4 solution showing the same acidity as that of human tears, respectively, and the concentrations of the compounds of Formula 1 in the eyedrops were respectively 1250 占 퐂 / mL And 625 占 퐂 / mL.

Relative turbidity of the eye drops of Examples 1 to 6 when the turbidity of the eye drops of Comparative Example 2 was set to 100% with respect to the diluted eye drops was measured and is shown in Fig.

As shown in Fig. 2, the eyedrops of Examples 1 to 5, in which the turbidity was very low before dilution, showed that the turbidity increased after dilution. However, the eyedrops of Example 6 did not show much increase in turbidity even after dilution.

Experimental Example 3: Evaluation of precipitation with temperature change

The eyedrops of Examples 1 to 6 and Comparative Example 2 were refrigerated for 24 hours, and their turbidity was measured to determine whether or not there was a compound to be precipitated. The turbidity measurement is shown in Fig. 3 as the relative turbidity of the eyedrops of Examples 1 to 6 when the turbidity of the eyedrops of Comparative Example 2 was taken as 100%.

As shown in FIG. 3, the turbidity of the eye drops of Examples 4 and 5 using lavagepar or glycerin as a solubilizing agent significantly increased after refrigerated storage. On the other hand, the eyedrops of Examples 1 to 3 and 6 using dimethylsulfoxide, labrasol, or caprylol as a solubilizer did not precipitate even after refrigerated storage, and maintained a very clear solution state and had excellent stability .

In particular, when the results of Experimental Examples 1 to 3 are summarized, the eyedrops of Example 6 using dimethyl sulfoxide as the solubilizing agent and artificial tears containing carboxymethylcellulose were found to have the best solubilization and the most stable Eye drops, and as a result, it is anticipated that it will be possible to show non-irritating and high drug efficacy at the eye spot.

Experimental Example 4: Evaluation of adverse reaction

The eyelashes of Examples 1, 2, and 6 were repeatedly administered at a maximum of 12 times at 20 minute intervals in 2 쨉 l of one eye. Thereafter, adverse reactions occurring in the rat's eye were observed and summarized in Table 3 below.

As shown in Table 3, the adverse reaction of the compound of Example 1 using dimethylsulfoxide as a solubilizing agent compared to the eye drop of Example 2 using the solubilizing agent La Labrosol was remarkably decreased, and other abnormal symptoms No response was seen. In particular, the eyedrops of Example 6 using the artificial tears composition are expected to be excellent in terms of non-irritation and convenience of medication because no adverse reactions occur at all.

Experimental Example 5: Evaluation of Eye Infection Model

The in vivo antimicrobial activity was evaluated by inducing ocular infections by administering a bacterial solution to the eyeballs of rats, administering the drug to the infected eyeballs, and confirming the number of viable cells in the mouse eyeballs.

This experiment was carried out at the Department of Bioscience and Biotechnology, Handong National University (Address: No. 3, Hwanghae-eup, Namsongri, Buk-Gu, Gyeongsangbuk-do). The detailed experimental conditions are shown in Table 4 below.

Experimental procedures were as follows: 1) incubation of Staphylococcus aureus at 37 ° C for 18 hours; 2) dilution of the bacterial culture with 0.9% sterile physiological saline to produce a final bacterial concentration of 2 × 10 ¹⁰ cfu / 3) induction of infection by administering 10 μl of mycobacterial solution to the right eye of anesthetized rats; 4) vancomycin for 3 hours at intervals of 30 minutes 4 hours after induction of infection, eye drops of Comparative Examples 1 and 6 for 7 times And 5) After 1 hour after the administration of the drug, the eyeballs of the rats were extracted and the number of viable bacteria per eye was measured.

FIG. 4 shows the results of experiments showing that eye infections of S. aureus were successfully induced in rats. The control group was the result of left eye examination of rats not inducing bacterial infection. After 24 hours, the number of viable cells was not detected in the left eye tissue of rats and no staphylococcal infection was observed in only the right eye tissue Respectively. Based on the results of this experiment, ICR mice were selected as suitable mice for eye infections.

As a control group, a group (control) in which no drug was administered after infection induction, a group in which the eye drops of Comparative Example 1 were administered as a vehicle, a group in which vancomycin 5 mg / mL or vancomycin 20 mg / mL was administered as a conventional drug, For the group administered with the eye drop (5 mg / mL) of Example 6, the number of bacteria survived in the eye of the rats after the administration of the drug was measured and shown in FIG.

As shown in FIG. 5, the eye drops of Example 6 according to the present invention exhibited better antibacterial activity at the same concentration than vancomycin, which is a conventional drug.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (7)

(i) an eye drop for the treatment of eye infections, which comprises, as an active ingredient, a compound of the formula (1) or a pharmaceutically acceptable salt thereof, (ii) a solubilizing agent and (iii)
≪ Formula 1 >

The method according to claim 1,
An eye drop for the treatment of eye infections, characterized in that the solubilizer is a polar aprotic solvent.
3. The method of claim 2,
The eye drop for the treatment of eye infections, wherein the solubilizing agent is dimethylsulfoxide.
The method according to claim 1,
The eye drop for the treatment of eye infections, wherein the precipitation inhibitor is transcutoyl.
The method according to claim 1,
Wherein the solubilizing agent is dimethylsulfoxide, and the precipitation inhibitor is transcutoyl.
The method according to claim 1,
The eye drop for treating eye infections according to claim 1, wherein the eyedrops further comprise at least one selected from the group consisting of stabilizers, preservatives, viscosity regulators, anti-adsorption agents and isotonic agents.
The method according to claim 1,
Wherein the ocular infection is selected from the group consisting of a corneal ulcer, a superficial layer or an inner keratitis, a superficial layer or an inner conjunctivitis, a conjunctivitis, a blepharitis, a conjunctival septalitis, an acute or chronic septicemia, an aciduria, a dacryocystitis, a pinealitis, a neonatalitis, a trachoma, Wherein the ophthalmic solution is an ophthalmic solution.

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