Otological liquid for preventing and / or treating otitis externa and / or otitis media

Abstract

Provided is an otological liquid or the like for preventing and / or treating otitis externa and / or otitis media, which contains, as an active ingredient, 10-20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate of the levofloxacin or the pharmaceutically acceptable salt in 1 ml.

Description

Technical Field

[0001] The present invention relates to an otological liquid for preventing and / or treating otitis externa and / or otitis media, containing levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof. In addition, the present invention relates to a method for preventing and / or treating otitis externa and / or otitis media, comprising administering a liquid preparation containing levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0002] Cross-references to related applications

[0003] This application claims the benefit of priority based on Japanese patent application No. 2022-080585 filed on May 17, 2022, the entire contents of which are incorporated into this specification by reference. Background Art

[0004] As the antibacterial drug with indications in the field of otolaryngology represented by otitis externa and otitis media, various medicaments such as penicillin antibiotics, cephem antibiotics, carbapenem antibiotics, quinolone antibiotics, macrolide antibiotics, tetracycline antibiotics, aminoglycoside antibiotics can be cited. However, even if such antibacterial drugs are administered systemically, since the tissue transferability of the drug to the middle ear cavity surrounded by bone tissue is poor compared with ordinary tissues, the blood drug concentration required for treatment will increase, and the influence on systemic tissues becomes a problem (non-patent literature 1). Therefore, for otitis externa and otitis media, in order to be able to administer high-concentration medicaments to the external auditory canal and the middle ear cavity while avoiding adverse effects on the whole body, local administration is often selected.

[0005] In Japan, ofloxacin, lomefloxacin hydrochloride, cefmenoxime hydrochloride, fosfomycin sodium, and chloramphenicol have been covered by insurance as topical therapeutic drugs for otitis externa and otitis media.

[0006] In the guidelines of the United States and Australia, etc., for the local application treatment of otitis media, quinolone antibiotics are recommended, which do not have the concerns about auditory organ toxicity that are problematic in aminoglycoside antibiotics (non-patent literature 2, 3). Ofloxacin is a kind of quinolone antibiotics. Since it shows a wide antibacterial spectrum and excellent antibacterial power, it is suitable for various bacterial infections. In Japan, 0.3% ofloxacin otologic solution has been used for the indications of otitis externa and otitis media. However, even with 0.3% ofloxacin otologic solution, otitis externa and otitis media sometimes cannot be cured in a short period of time, and long-term administration is required, and the emergence of drug-resistant bacteria caused by long-term administration is also a problem. Therefore, it is required to further improve the therapeutic effect and inhibit drug-resistant bacteria.

[0007] In addition, the ear liquid for the treatment of otitis externa and otitis media is repeatedly applied, so even if the front end of the ear liquid container is contaminated and bacteria invade when applying to the ear, the bacteria do not proliferate in the container, and a preservative is usually used. For example, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, etc. are used as preservatives, typically at a concentration of 0.001 to 1.0%. The above-mentioned 0.3% ofloxacin ear liquid also contains a preservative. However, there are also cases where patients have allergic reactions to preservatives. In addition, preservatives are mostly cytotoxic, and there are also cases where the patient's external ear and middle ear epithelium are damaged, so it is desirable to have an ear liquid without a preservative.

[0008] Prior art literature

[0009] Non-patent literature

[0010] Non-patent literature 1: Craig WA, Andes D, Pharmacokinetics and pharmacodynamics of antibiotics in otitis media, Pediatr Infect Dis J, 1996; 15(3): 255-9

[0011] Non-patent document 2: Rosenfeld RM, et al., Clinical practice guideline: acute otitis externa, Otolaryngol Head Neck Surg, 2014; 150(1Suppl): S1-S24

[0012] Non-patent literature 3: Coates H, Ear drops and ototoxicity, Aust Prescr, 2008; 31: 40-1 Summary of the invention

[0013] Problems to be solved by the invention

[0014] The present invention aims to provide an effective otological liquid preparation for the prevention and / or treatment of otitis externa and / or otitis media. Another object of the present invention is to provide a method for the prevention and / or treatment of otitis externa and / or otitis media, comprising administering such a prevention and / or treatment agent.

[0015] Means for solving problems

[0016] The inventors of the present application have found that otitis externa and otitis media can be cured in a short period of time by using an otologic solution containing levofloxacin, which is an optically active form of ofloxacin, at a high concentration as an active ingredient, and have completed the present invention.

[0017] That is, the gist of the present invention is as follows.

[0018] [1] An otologic solution for the prevention and / or treatment of otitis externa and / or otitis media, comprising 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient per ml.

[0019] [2] An otologic solution for the prevention and / or treatment of otitis externa and / or otitis media, comprising 12 to 18 mg, preferably 14 to 16 mg, and more preferably 15 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient per ml.

[0020] [3] The otologic solution as described in [1] or [2], which does not substantially contain a preservative or an ingredient having a preservative effect.

[0021] [4] The otologic solution according to [1] or [3], comprising at least one of a solubilizing agent, an isotonicity agent, and a pH adjuster.

[0022] [5] The otologic solution according to [1] or [3], wherein the levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof is a levofloxacin hydrate.

[0023] [6] The otologic solution according to [1] or [3], which is administered continuously for 5 to 14 days.

[0024] [7] The otologic solution according to [1] or [3], which is administered twice a day.

[0025] [8] The otologic solution according to [1] or [3], which is administered continuously for 5 to 14 days and is administered as ear drops twice a day.

[0026] [9] The otologic solution according to [1] or [3], which contains at least one of a solubilizing agent, an isotonicity agent, and a pH adjuster, and is administered continuously for 5 to 14 days.

[0027]

[10] The otologic solution according to [1] or [3], wherein the otitis externa and / or otitis media is bacterial otitis externa and / or otitis media.

[0028]

[11] The otologic solution according to [1] or [3], wherein the otitis externa and / or otitis media is chronic otitis media.

[0029]

[12] The otologic solution according to [1] or [3], wherein the otitis externa and / or otitis media is otitis externa and / or otitis media in a patient with a history of treatment with an antibiotic.

[0030]

[13] A method for preventing and / or treating otitis externa and / or otitis media, comprising administering a liquid preparation containing 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient in 1 ml to a subject in need thereof.

[0031]

[14] Levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized in that it is levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof for use in the prevention and / or treatment of otitis externa and / or otitis media in a subject, wherein in the aforementioned prevention and / or treatment, a liquid preparation containing 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient in 1 ml is administered to the aforementioned subject.

[0032] Effects of the Invention

[0033] The otologic solution of the present invention is useful for the prevention and / or treatment of otitis externa and / or otitis media. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] [ Figure 1 ] is a table showing the plan of the clinical trial conducted in Example 1.

[0035] [ Figure 2 ] is a diagram showing the details of the subjects in the clinical trial conducted in Example 1.

[0036] [ Figure 3 ] is a graph showing the time until otorrhea stops as evaluated by the attending physician in the clinical trial conducted in Example 1.

[0037] [ Figure 4 ] is a graph showing the time until otorrhea stops as evaluated by the efficacy safety evaluation committee in the clinical trial conducted in Example 1. DETAILED DESCRIPTION

[0038] Hereinafter, the present invention will be described in further detail with reference to preferred embodiments, but the present invention is not limited thereto at all.

[0039] In one embodiment, the present invention relates to an otologic solution for preventing and / or treating otitis externa and / or otitis media, comprising 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient per ml.

[0040] In another embodiment, the present invention relates to an otologic solution for preventing and / or treating otitis externa and / or otitis media, which contains 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient per ml.

[0041] In another embodiment, the present invention relates to a method for preventing and / or treating otitis externa and / or otitis media, comprising administering a liquid preparation containing 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient in 1 ml to a subject in need thereof.

[0042] In another embodiment, levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof for preventing and / or treating otitis externa and / or otitis media in a subject is provided, wherein in the prevention and / or treatment, a liquid preparation containing 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient in 1 ml is administered to the subject.

[0043] In the present specification, the so-called "pharmacologically acceptable salt of levofloxacin" is not particularly limited as long as it is a salt of levofloxacin that is acceptable as a pharmaceutical, and examples thereof include salts formed with inorganic acids such as hydrochloric acid and sulfuric acid, salts formed with organic acids such as maleic acid and tartaric acid, salts formed with alkali metals such as sodium and potassium, salts formed with alkaline earth metals such as calcium and magnesium, salts formed with inorganic bases such as aluminum and ammonia, and salts formed with organic bases such as diethylamine and diethanolamine.

[0044] The solvate of levofloxacin or its pharmacologically acceptable salt is not particularly limited as long as it is a pharmaceutically acceptable solvate, and examples thereof include hydrates (1 / 2 hydrate, 1 hydrate, 2 hydrates, etc.) that are solvates formed with water, solvates formed with organic solvents, etc., preferably a hydrate (1 / 2 hydrate, 1 hydrate or 2 hydrate), and more preferably a 1 / 2 hydrate.

[0045] In the present specification, levofloxacin, a pharmacologically acceptable salt thereof, or a solvate thereof may be collectively referred to as "the compound of the present invention".

[0046] The compound of the present invention is preferably a hydrate of levofloxacin, and more preferably a 1 / 2 hydrate of levofloxacin.

[0047] The manufacturing method of the compound of the present invention is known, and known compounds and reagents can be used to manufacture. For example, the method described in Japanese Patent Publication No. 3-27534 and Japanese Patent Publication No. 7-47592 can be used to manufacture. As the compound of the present invention, commercial products can also be used.

[0048] The otologic solution of the present invention preferably contains 10 to 20 mg of the compound of the present invention per 1 ml of the liquid preparation, more preferably 12 to 18 mg of the compound of the present invention, and even more preferably 14 to 16 mg of the compound of the present invention. For example, 15 mg of the compound of the present invention may be contained in 1 ml of the liquid preparation.

[0049] In the present specification, the term "for prevention and / or treatment" means for prevention, for treatment, or for both prevention and treatment.

[0050] The otological solution of the present invention is applied to otitis externa and / or otitis media. The so-called "application to otitis externa and / or otitis media" refers to the case where it is applied to otitis externa, the case where it is applied to otitis media, or any one of the cases where it is applied to both otitis externa and otitis media. Otitis externa and otitis media can be acute or chronic. Otitis externa and / or otitis media can be bacterial or non-bacterial, and in a certain embodiment, they are bacterial. As inflammatory bacteria in bacterial otitis externa and otitis media, for example, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), etc. can be cited. Regarding otitis media, it can be a tympanic membrane perforation type or a non-tympanic membrane perforation type, and in a certain embodiment, it is a tympanic membrane perforation type. Otitis externa and / or otitis media can have otorrhea or no otorrhea, and in a certain embodiment, there is otorrhea.

[0051] The otologic solution of the present invention can be administered to a subject with a history of treatment based on antibiotics (which can be administered locally or systemically), or to a subject without a history of treatment based on antibiotics. In a certain embodiment, it is administered to a subject with a history of treatment based on antibiotics. The otologic solution of the present invention can be administered to a subject with a history of treatment based on steroids (which can be administered locally or systemically), or to a subject without a history of treatment based on steroids. In a certain embodiment, it is administered to a subject with a history of treatment based on steroids. The otologic solution of the present invention can be administered to a subject with a history of surgical treatment, or to a subject without a history of surgical treatment.

[0052] The otologic liquid of the present invention preferably contains substantially no preservatives and ingredients having a preservative effect. In the present specification, the term "substantially contains no preservatives and ingredients having a preservative effect" means that the otologic liquid preparation contains no "preservatives and ingredients having a preservative effect" at all, or contains "preservatives and ingredients having a preservative effect" alone to an extent that does not comply with the preservation effectiveness test method described in the 18th revised edition of the Japanese Pharmacopoeia.

[0053] The otologic solution of the present invention preferably contains at least one of a solubilizing agent, an isotonic agent, and a pH adjuster, more preferably contains at least two of the solubilizing agent, an isotonic agent, and a pH adjuster, and even more preferably contains a solubilizing agent, an isotonic agent, and a pH adjuster.

[0054] The cosolvent is not particularly limited as long as it has the effect of improving the solubility of the compound of the present invention in water. For example, a surfactant or a cosolvent can be used as a cosolvent. Examples of such cosolvents include sorbitan fatty acid esters such as polysorbate 20 (polyoxyethylene sorbitan monolaurate), polysorbate 60 (polyoxyethylene sorbitan monostearate), polysorbate 65 (polyoxyethylene sorbitan tristearate), and polysorbate 80 (polyoxyethylene sorbitan oleate); polyoxyethylene / polyoxypropylene block copolymer surfactants (e.g., Pluronic (registered trademark) F-68 and Tetronic (registered trademark) 1304); cyclodextrin, etc. When these are used as cosolvents, for example, they can be used in an amount of 0.01 to 2% by weight, preferably 0.05 to 1.5% by weight, and more preferably 0.07 to 1.2% by weight, relative to the total weight of the liquid preparation.

[0055] Alternatively, as a solubilizing agent, a polyol (a divalent or trivalent polyol) can be used. As a polyol, for example, glycols (water-soluble polypropylene glycols such as ethylene glycol, diethylene glycol, polyethylene glycol (PEG), propylene glycol, dipropylene glycol, etc.), glycerol, polyglycerol and other trivalent or higher polyols can be cited. In addition, as a solubilizing agent, medium-chain fatty acid triglycerides, castor oil, polyethylene glycol or isopropyl myristate can also be used. Among these solubilizing agents, glycerol, propylene glycol or a combination thereof can be preferably used. When using them as solubilizing agents, for example, they can be used in the range of 5 to 50% by weight, preferably 10 to 40% by weight, and more preferably 15 to 30% by weight relative to the total weight of the liquid preparation.

[0056] The pH adjuster is not particularly limited as long as it does not adversely affect the biological function of the subject to be administered or the activity of the compound of the present invention, and can be selected from the group consisting of hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine, citric acid and salts thereof such as sodium citrate, potassium citrate, calcium citrate, and lithium citrate, tartaric acid and salts thereof such as sodium tartrate, potassium tartrate, calcium tartrate, and lithium tartrate, phosphoric acid and salts thereof such as sodium dihydrogen phosphate, sodium monohydrogen phosphate, lithium phosphate, potassium phosphate, and calcium phosphate, carbonate and salts thereof such as sodium carbonate and sodium hydrogen carbonate, lactic acid and salts thereof such as sodium lactate, potassium lactate, and calcium lactate, acetic acid and salts thereof such as sodium acetate, potassium acetate, and calcium acetate, sulfuric acid and salts thereof such as sodium sulfate and potassium sulfate, boric acid and salts thereof such as sodium borate, maleic acid and salts thereof such as lithium maleate, sodium maleate, potassium maleate, and calcium maleate, succinic acid and salts thereof such as lithium succinate, sodium succinate, potassium succinate, and calcium succinate, or mixtures thereof.

[0057] The pH of the otologic solution of the present invention may be within the acceptable range for otologic preparations, and is usually preferably within the range of pH 5 to 8, and more preferably pH 6 to 7.

[0058] The otologic solution of the present invention can be produced using the above-mentioned components by conventional means such as mixing, dissolving, and sterilizing (eg, sterile filtration).

[0059] The otologic solution of the present invention can be administered, for example, by dripping (ear drops) or spraying into the external auditory canal, or by applying to the external ear using a cotton swab, etc. The otologic solution of the present invention can be filled in a multiple administration container (multiple dose container) or in a single administration container (unit dose container). If filled in a single administration container, since a new container must be opened each time administration is performed, the possibility of contamination from outside the container caused by microorganisms, body secretions, etc. can be easily avoided.

[0060] The otologic solution of the present invention can be administered 1 to 3 times a day, preferably 2 times a day. The administration time depends on the symptoms of otitis externa and / or otitis media of the subject, but is usually 5 to 14 days. The administration time is preferably 6 days or more, more preferably 7 days or more, and more preferably 8 days or more. The administration time is preferably 13 days or less, more preferably 12 days or less, and more preferably 11 days or less. The administration time can be 6 to 14 days, 6 to 13 days, 6 to 12 days, 6 to 11 days, 6 to 10 days, 6 to 9 days, 6 to 8 days, 6 to 7 days, 7 to 14 days, 7 to 13 days, 7 to 12 days, 7 to 11 days, 7 to 10 days, 7 to 9 days, 7 to 8 days. The administration time is preferably 6 to 13 days, more preferably 7 to 12 days, and more preferably 8 to 11 days.

[0061] The subject of administration of the preventive and / or therapeutic agent of the present invention or the subject of the preventive and / or therapeutic method of the present invention is not limited as long as it is an animal, but is preferably a mammal (e.g., human, dog, cat, monkey, cow, horse, pig, mouse, rat, etc.), more preferably human.

[0062] The preventive and / or therapeutic agent of the present invention can be administered alone, or in combination with other agents as long as the effect of the preventive and / or therapeutic agent of the present invention is not hindered thereby. For example, it can be administered in combination with antihistamines, chemical mediator release inhibitors, anti-leukotrienes, anti-prostaglandin D2·thromboxane drugs, TRP (transient receptor potential) channel agonists, steroid drugs, etc.

[0063] Hereinafter, the present invention will be described in further detail based on Examples, but the present invention is not limited to these Examples.

[0064] Example

[0065] [Example 1] Research test on the effect on otitis media

[0066] A randomized parallel group comparative clinical trial with a placebo as a control was conducted to study the clinical effect, bacteriological effect, safety, pharmacokinetics (PK), etc. of the high-concentration levofloxacin otologic solution of the present invention on patients with otitis media with persistent or prolonged purulent otorrhea.

[0067] (Design of the experiment)

[0068] For subjects who have obtained written consent, background investigation and screening examination were performed within 14 days before the administration of the test drug. With the goal of administering 1.5wt / vol% otological solution of levofloxacin 1 / 2 hydrate (hereinafter referred to as "levofloxacin test otological solution") (hereinafter referred to as "levofloxacin group") and the group administered with placebo otological solution (hereinafter referred to as "placebo group"), 100 cases in each group (a total of 200 cases) were registered, and the subjects who had been confirmed to be eligible were randomized and randomly assigned to either the levofloxacin group or the placebo group at a ratio of 1:1. The subjects for evaluating PK were set as subjects with only one ear disease, and with respect to the levofloxacin group and the placebo group, 10 cases in each group (a total of 20 cases) were targeted.

[0069] The selection criteria for subjects were patients who met the following conditions.

[0070] (1) Patients who are 15 years of age or older at the time of consent.

[0071] (2) Patients diagnosed with acute otitis media caused by infection or chronic otitis media with perforation.

[0072] (3) Patients with clinically persistent purulent otorrhea.

[0073] (4) Patients with any of the following conditions.

[0074] (i) Patients who underwent tympanostomy tube placement and had persistent postoperative otorrhea.

[0075] (ii) Patients with persistent otorrhea after tympanostomy tube placement with granulation around the tube.

[0076] (iii) Patients with perforating chronic otitis media and persistent otorrhea from erosions or granulation lesions. Among them, patients with persistent otorrhea from residual granulation lesions after surgery for chronic otitis media can also be registered.

[0077] (5) Patients who have obtained written consent to participate in this trial. For patients aged 15 years and above but less than 20 years old, in addition to obtaining written consent from their guardians, their own child informed consent form must also be obtained.

[0078] according to Figure 1 The experiment was conducted according to the plan shown. The test otologic solution of levofloxacin or the placebo otologic solution was instilled into the affected ear of the subject twice a day (once in the morning and once in the evening), 6 to 10 drops each time, and the ear was bathed for 10 minutes after the ear was instilled. However, for subjects evaluating PK, the number of drops at the time of initial administration was set to 10 drops per time. The administration was terminated at the time when the cure was confirmed and the attending physician judged that no further treatment was necessary, and the maximum duration was 10 days. Figure 1 If the administration is completed at the second or third visit, the end-of-treatment examination is performed on the day of the consultation, and the examination for determination of cure (fifth visit) is performed from the fifth day to the tenth day after the administration is completed. In addition, if the administration is performed for 10 days, the examination for determination of cure is performed from the 19th day to the 24th day after the administration is started.

[0079] The composition of the experimental levofloxacin otic solution and the placebo otic solution as the experimental drug are shown in Table 1. The placebo otic solution was indistinguishable from the levofloxacin otic solution in appearance.

[0080] [Table 1]

[0081] Table 1 Composition and properties of the experimental drugs

[0082]

[0083] During the trial, only suction is allowed for ear treatment, and cleaning of the tympanic cavity is prohibited. Otological surgery (except for tympanic tube placement and myringotomy) is also prohibited. Suction is not performed before the tympanic membrane and tympanic cavity are photographed using a digital endoscope. In addition, during the trial, the concomitant use of ear drops other than the trial drug is prohibited, and systemic administration of antibacterial drugs (antibiotic preparations) and adrenocortical hormones (steroid drugs) other than the trial drug is also prohibited.

[0084] During the administration period, the subjects recorded the conditions before the start of the administration in the patient diary twice a day, including the nature and amount of otorrhea, hearing (difficulty in listening), other ear-related symptoms (tinnitus, dizziness, ear discomfort, etc.), adverse phenomena (things to be concerned about; health conditions such as physical condition), etc. After the 11th day of administration, the conditions of the day other than the administration of the trial drug were recorded once a day until the fourth visit. If the administration has been completed or terminated before the fourth visit, there is no need to record the patient diary after the examination is completed at the end or termination. The attending physician confirms the patient diary before the examination and investigation of each visit of the subject to confirm the subject's otorrhea, hearing, ear-related symptoms, adverse phenomena, and trial drug use.

[0085] (Evaluation method)

[0086] A. Clinical Effect

[0087] The clinical effectiveness of the high-concentration levofloxacin otologic solution of the present invention was evaluated by the resolution of inflammation of the middle ear and tympanic membrane and the time until otorrhea stopped.

[0088] A-1. Relief of inflammation of the middle ear and eardrum

[0089] Regarding the disappearance of inflammation of the middle ear and tympanic membrane, the disappearance of purulent otorrhea, the disappearance of congestion (redness) of the middle ear mucosa and tympanic membrane, and the disappearance of granulation tissue of the middle ear mucosa and tympanic membrane were used as evaluation indicators. The attending physician and the efficacy and safety evaluation committee evaluated them separately to determine the clinical efficacy of the test drug.

[0090] The attending physician evaluated and determined the disappearance of purulent otorrhea, the disappearance of congestion (redness) of the middle ear mucosa and tympanic membrane, and the disappearance of granulation tissue of the middle ear mucosa and tympanic membrane for each affected ear according to the criteria shown in Table 2 based on the findings of the tympanic membrane and tympanic cavity (digital endoscopy) at screening and each visit (including discontinuation). Based on the results, the disappearance of inflammation of the middle ear and tympanic membrane was determined according to the criteria of Table 3 (clinical effect). The Effect Safety Evaluation Committee evaluated and determined each affected ear under blind inspection (central review) based on the digital endoscopy images of the tympanic membrane and tympanic cavity taken at screening and each visit (including discontinuation) according to the same evaluation indicators and criteria. However, in the case where the findings of the middle ear mucosa and tympanic membrane cannot be confirmed due to a large amount of otorrhea, etc., and it is impossible to take pictures using digital endoscopy, it is set as "unable to determine".

[0091] [Table 2]

[0092] Table 2 Evaluation criteria for purulent otorrhea and findings on the middle ear mucosa and tympanic membrane

[0093]

[0094] [Table 3]

[0095] Table 3 Comprehensive evaluation criteria for inflammation of the middle ear and tympanic membrane

[0096]

[0097] Purulent otorrhea was judged as “resolved” when purulent otorrhea was “absent” or improved to “non-purulent otorrhea” in the symptom evaluation after the start of administration.

[0098] Congestion (redness) of the middle ear mucosa and eardrum was determined as “asymptomatic” if there were no symptoms at screening and the first visit, and no new symptoms were confirmed in the symptom evaluation after the start of administration. It was determined as “resolved” if there were symptoms “partially” or “entirely” at screening or the first visit, and the congestion (redness) improved to “none” in the symptom evaluation after the start of administration. In addition, if the symptoms at screening and the first visit could not be determined due to a large amount of otorrhea, etc., and the symptoms were determined as “none” in the symptom evaluation after the start of administration due to the disappearance of otorrhea, etc., it was determined as “resolved”.

[0099] Regarding the granulation of the middle ear mucosa and the tympanic membrane, if there were no granulation at the time of screening and the first visit, and no new granulation was confirmed in the symptom evaluation after the start of administration, it was judged as "asymptomatic", if there were "granulation without purulent exudate" at the time of screening or the first visit, and if it remained "granulation without purulent exudate" in the symptom evaluation after the start of administration and there was no increase in granulation lesions, it was judged as "unchanged", and if there was "no granulation", it was judged as "resolved". If there were "granulation with purulent exudate" at the time of screening or the first visit, and if it became "granulation without purulent exudate" in the symptom evaluation after the start of administration and there was no increase in granulation lesions, it was judged as "improved", and if there was "no granulation", it was judged as "resolved". In addition, when the symptoms at screening and the first visit could not be determined due to heavy otorrhea, etc., and when granulation could be determined due to the disappearance of otorrhea, etc. in the symptom evaluation after the start of administration, the condition was judged as "granulation without purulent exudate" or "absent".

[0100] When the regression criteria of each index shown in Table 3 are met, the inflammation of the middle ear and the eardrum is determined as "regressed" as a comprehensive evaluation. When both sides are affected, when the regression criteria of each index are met on both sides, the inflammation of the middle ear and the eardrum is determined as "regressed" as a comprehensive evaluation.

[0101] A-2. Time until otorrhea stops

[0102] The time until otorrhea stops is calculated from the day of administration start. When the attending physician determines that there is no purulent otorrhea based on the tympanic membrane and tympanic cavity findings (digital endoscopy) of the patient's visit day (each visit) that is considered to be the day of cessation of purulent otorrhea in the patient's diary (subjective ear symptoms), the day on which otorrhea stops is regarded as an event. In the case of bilateral disease, the date on which purulent otorrhea on both sides stops is regarded as an event. In addition, when the cessation of purulent otorrhea is not recorded in the patient's diary, when the attending physician confirms that there is no purulent otorrhea based on the tympanic membrane and tympanic cavity findings (digital endoscopy) on the patient's visit day, the visit day is regarded as the day on which otorrhea stops. For cases where the efficacy safety evaluation committee determines that there is no purulent otorrhea based on the digital endoscopy images of the tympanic membrane and tympanic cavity under blind inspection, the time until otorrhea stops is evaluated in the same way.

[0103] B. Bacteriological Effects

[0104] The bacterial clearance rate is evaluated for each affected ear by the presence or absence of inflammatory bacteria detected in the middle ear secretions (otorrhea) collected at the time of screening and at the end or termination of administration. When the cure is confirmed at the end or termination of administration and there is no middle ear effusion (otorrhea) that can be collected, it is judged as "bacterial clearance". Middle ear secretions (otorrhea) are collected directly from the middle ear cavity under sterile conditions. In addition, in the case of a perforated tympanic membrane and the outflow of middle ear secretions (otorrhea) into the external auditory canal, the middle ear secretions (otorrhea) are cleaned by suction or wiping, and the newly outflowing middle ear secretions (otorrhea) are collected under sterile conditions. A designated swab is used for collection.

[0105] For all inflammatory bacteria (isolated bacteria) detected in the middle ear secretions (otorrhea) collected at the time of screening and at the end of administration or at the time of suspension, the drug sensitivity to levofloxacin was evaluated by MIC. The determination method of MIC followed the micro-liquid dilution method as the standard method of the Japanese Chemotherapy Society. The antimicrobial drug sensitivity rate of each strain was calculated according to the MIC breakpoint specified by the Clinical Laboratory Standards Committee (CLSI).

[0106] C. Security

[0107] At screening, at the end or suspension of administration, and at the time of cure determination, an audiometry test was performed (measured by the 5 dB step up method at frequencies of 125, 250, 500, 1000, 2000, 4000, and 8000 Hz). In addition, at screening and at the end or suspension of administration, a balance function test was performed (evaluated by gaze nystagmus test and spontaneous nystagmus test (frontal examination in sitting position under Frenzel glasses)).

[0108] exist Figure 1 The patient will be interviewed at the time indicated in the "Test Plan". If any abnormality is found in the physical findings, additional examinations (auscultation, inspection, palpation, etc.) will be carried out. In addition, height and weight will be measured at screening. Hematological examinations (red blood cell count, hemoglobin level, hematocrit value, platelet count, white blood cell count, white blood cell differential count (neutrophils, lymphocytes, basophils, eosinophils, monocytes) and blood biochemistry examinations (total bilirubin, direct bilirubin, total protein, albumin, ALP, LDH, AST, ALT, gamma-GT (γ-GTP), CPK, BUN, creatinine, Na, K, Cl, Ca, CRP) will be performed at screening and at the end or discontinuation of administration.

[0109] Adverse medical events that occur to subjects are considered adverse phenomena, and the attending physician determines the severity of the adverse phenomenon as mild (the subject can perceive the phenomenon or symptoms, but it does not affect daily life), moderate (there are obvious symptoms (discomfort) that affect or weaken the subject's daily life), and severe (inability to live a daily life or life-threatening). In addition, the attending physician determines the correlation between the test drug and the adverse phenomenon as no correlation (the causal relationship may be irrelevant or can be clearly denied, and other causes are the most reasonable) or related (the causal relationship is clinically / biologically reasonable, and there is an explainable time relationship between the administration of the test drug and the occurrence of the adverse phenomenon).

[0110] D. Pharmacokinetics

[0111] exist Figure 1 Blood was collected at the time indicated in the “Test Plan” and the maximum plasma concentration of levofloxacin (C max :maximum plasma concentration) and the area under the plasma concentration curve (AUC 0-t area under the plasma concentration-time curve from time 0 to t after administration (AUC 0-inf : area under the plasma concentration-time curve from time 0 to infinity after administration), etc.

[0112] (Test results)

[0113] A. Details of subjects and administration time

[0114] Figure 2 The details of the subjects are shown, and Table 4 shows the administration time (administration days) of each group.

[0115] [Table 4]

[0116] Table 4 Administration time (administration days)

[0117]

[0118] Days in which ear drops were administered to the affected ear twice a day were counted as one day.

[0119] B. Clinical Effect

[0120] B-1. Inflammation of the middle ear and eardrum subsides

[0121] Table 5 shows the proportion of subjects whose inflammation of the middle ear and tympanic membrane subsided (improvement rate) based on the judgment of the attending physician at the end or discontinuation of administration. The analysis subject population was FAS (full analysis set: a population after excluding subjects who did not meet the selection criteria, subjects who had never been administered with the test drug, subjects with no efficacy data available for analysis, etc.). The improvement rate was 62.6% (62 / 99 cases) in the levofloxacin group and 24.5% (25 / 102 cases) in the placebo group. The difference in improvement rate between the levofloxacin group and the placebo group (95% confidence interval (CI)) adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor was 38.0 (24.5-49.6)%, which was statistically significant (p<0.001).

[0122] [Table 5]

[0123] Table 5 Clinical effect based on the resolution of inflammation of the middle ear and tympanic membrane (attending physician) (FAS)

[0124]

[0125] a) Wilson score

[0126]

[0127] b) Levofloxacin group-placebo group

[0128] c) Newcombe score

[0129] d) Levofloxacin group vs placebo group, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor

[0130] e) Newcombe score, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor

[0131] f) Cochran-Mantel-Haenszel test with the affected ear as the stratification factor

[0132] Table 6 shows the proportion of subjects (improvement rate) whose three evaluation indicators related to the disappearance of inflammation of the middle ear and tympanic membrane (purulent otorrhea, congestion (redness) of the middle ear mucosa and tympanic membrane, and granulation of the middle ear mucosa and tympanic membrane) disappeared based on the judgment of the attending physician at the end or termination of administration.

[0133] [Table 6]

[0134] Table 6 Reduction of each index of clinical effect (attending physician) (FAS)

[0135]

[0136] a) Wilson score

[0137]

[0138] b) Levofloxacin group-placebo group

[0139] c) Newcombe score

[0140] d) Levofloxacin group vs placebo group, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor

[0141] e) Newcombe score, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor

[0142] f) Cochran-Mantel-Haenszel test with the affected ear as the stratification factor

[0143] Table 7 shows the proportion of subjects whose inflammation of the middle ear and tympanic membrane subsided (improvement rate) based on the judgment of the effect safety evaluation committee when the administration is completed or stopped. The analysis subject population is FAS. As shown in the table, in terms of improvement rate, the levofloxacin group is 46.5% (46 / 99 cases), and the placebo group is 23.5% (24 / 102 cases). In addition, the difference in improvement rate (levofloxacin group-placebo group) and its bilateral 95% CI (Newcombe score) are calculated. With the affected ear (monaural, bilateral) as the stratification factor, the difference in improvement rate (95% CI) between the levofloxacin group and the placebo group adjusted by the Mantel-Haenszel method is 22.0 (8.7-34.2)%, and there is a statistically significant difference (p=0.001) by the Cochran-Mantel-Haenszel test.

[0144] [Table 7]

[0145] Table 7 Clinical effect based on the reduction of inflammation of the middle ear and tympanic membrane (Function Safety Evaluation Committee) (FAS)

[0146]

[0147] a) Wilson score

[0148]

[0149] b) Levofloxacin group-placebo group

[0150] c) Newcombe score

[0151] d) Levofloxacin group vs placebo group, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor

[0152] e) Newcombe score, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor

[0153] f) Cochran-Mantel-Haenszel test with the affected ear as the stratification factor

[0154] Table 8 shows the proportion of subjects (improvement rate) whose three evaluation indicators related to the disappearance of inflammation of the middle ear and tympanic membrane (purulent otorrhea, congestion (redness) of the middle ear mucosa and tympanic membrane, and granulation of the middle ear mucosa and tympanic membrane) disappeared based on the judgment of the efficacy safety evaluation committee at the end or discontinuation of administration.

[0155] [Table 8]

[0156] Table 8 Reduction of each index of clinical effect (Effect Safety Evaluation Committee) (FAS)

[0157]

[0158] a) Wilson score

[0159]

[0160] b) Levofloxacin group-placebo group

[0161] c) Newcombe score

[0162] d) Levofloxacin group-placebo group, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor e) Newcombe score, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor f) Cochran-Mantel-Haenszel test with the affected ear as the stratification factor

[0163] B-2. Time until otorrhea stops

[0164] Figure 3Table 9 shows the time until otorrhea stops based on the evaluation of the attending physician. The time until otorrhea stops was evaluated using ITT (intention-to-treat: all assigned subjects, regardless of whether the trial drug was administered). The median (95% CI) of the time until otorrhea stops estimated by the Kaplan-Meier method was 7.0 (6.0-7.0) days in the levofloxacin group and 20.0 (12.0-unable to estimate) days in the placebo group. The levofloxacin group was shorter than the placebo group, and there was a statistically significant difference in the stratified Log-rank test with the affected ear as the stratum (p<0.001). The hazard ratio (95% CI) estimated using the Fine-Gray model with trial discontinuation as a competing risk was 3.257 (2.358-4.499), and there was a statistically significant difference between the two groups by the Gray test (p<0.001).

[0165] [Table 9]

[0166] Table 9 Time until otorrhea stops (attending physician) (ITT)

[0167]

[0168] a) Using the affected ear as the layer

[0169] b) Fine-Gray model for levofloxacin group / placebo group with trial discontinuation as competing risk

[0170] Figure 4 The time until otorrhea stopped based on the evaluation of the efficacy safety evaluation committee is shown in Table 10. The median time until otorrhea stopped was 7.0 (7.0-8.0) days in the levofloxacin group and 22.0 (14.0-unable to estimate) days in the placebo group, and similarly to the evaluation based on the attending physician, the levofloxacin group was shorter than the placebo group, with a statistically significant difference (p<0.001).

[0171] [Table 10]

[0172] Table 10 Time until otorrhea stops (Effect Safety Evaluation Committee) (ITT)

[0173]

[0174] a) Using the affected ear as the layer

[0175] b) Fine-Gray model for levofloxacin group / placebo group with trial discontinuation as competing risk

[0176] C. Bacteriological effects

[0177] The bacterial clearance rates of inflammatory bacteria detected from otorrhea collected at the time of screening and at the end or discontinuation of administration are shown in Table 11. The bacterial clearance rates were 93.9% (77 / 82 cases) in the levofloxacin group and 12.5% ​​(11 / 88 cases) in the placebo group, and the difference (95% CI) in bacterial clearance rates between the levofloxacin group and the placebo group was 81.4 (70.1-87.8)%, indicating that the bacterial clearance rate in the levofloxacin group was high, with a statistically significant difference (p<0.001).

[0178] [Table 11]

[0179] Table 11 Bacterial clearance rate (mFAS)

[0180]

[0181] a) Wilson score

[0182]

[0183] b) Levofloxacin group-placebo group

[0184] c) Newcombc score

[0185] d) Chi-square test

[0186] Table 12 shows bacterial species that show drug sensitivity to levofloxacin. Levofloxacin showed effects on all inflammatory bacteria detected during screening.

[0187] [Table 12]

[0188] Table 12 Bacterial species showing drug sensitivity to levofloxacin

[0189]

[0190] D. Security

[0191] The average hearing of the affected ear based on the four-point average hearing level and the hearing of 125-8000 Hz (air conduction and bone conduction) were tested at the screening time point as the baseline, at the end or discontinuation of administration, and at the time of cure. The results showed that there was no significant change between the baseline and the measured values ​​at the end or discontinuation of administration and at the time of cure in both the levofloxacin group and the placebo group. Regarding the findings of the balance function test based on the gaze nystagmus test and the spontaneous nystagmus test, there were no cases judged to be abnormal in gaze nystagmus or spontaneous nystagmus and clinically problematic at the baseline and at the end of administration in both the levofloxacin group and the placebo group.

[0192] In this trial, no serious adverse events or side effects occurred in either the levofloxacin group or the placebo group, and no adverse events related to clinical examination values ​​were confirmed.

[0193] E. Pharmacokinetics

[0194] Table 13 shows various parameters calculated using a model-independent method for the plasma levofloxacin concentration of each subject in the PK analysis target group. The mean ± standard deviation of the plasma levofloxacin concentration increased to 9.7767 ± 14.4944 ng / ml 30 minutes after the end of the 10-minute ear bath after the test drug administration, and then slowly decreased. Four of the six subjects showed C after 30 minutes. max In addition, the plasma levofloxacin concentration was less than 10 ng / ml except for one case. max 9.9008±14.4606ng / ml, AUC 0-t 40.2175±59.3665ng·h / ml, AUC 0-inf It is 98.6797±125.5012ng·h / ml.

[0195] [Table 13]

[0196] Table 13 PK parameters (analysis subject population involving PK)

[0197]

[0198] F. Analysis of clinical effects on some groups

[0199] Tables 14 and 15 show the results of the attending physician's assessment of the resolution of inflammation in the middle ear and tympanic membrane at the end or discontinuation of administration in subjects with a history of antibiotic treatment. The proportion of subjects with no history of antibiotic treatment who were judged to have resolved inflammation (improvement rate) was 62.9% in the levofloxacin group and 31.8% in the placebo group, with a statistically significant difference (p = 0.009). The proportion of subjects with a history of antibiotic treatment who were judged to have resolved inflammation (improvement rate) was 61.7% in the levofloxacin group and 19.0% in the placebo group, with a statistically significant difference (p < 0.001).

[0200] [Table 14]

[0201] Table 14 Partial group analysis: Clinical effect based on the resolution of inflammation of the middle ear and tympanic membrane (attending physician) (FAS) (1 / 2)

[0202]

[0203] a) Wilson score

[0204] [Table 15]

[0205] Table 15 Partial group analysis: Clinical effect based on the resolution of inflammation of the middle ear and tympanic membrane (attending physician) (FAS) (2 / 2)

[0206]

[0207] b) Levofloxacin group-placebo group

[0208] c) Newcombe score

[0209] d) Levofloxacin group vs placebo group, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor

[0210] e) Newcombe score, adjusted by the Mantel-Haenszel method with the affected ear as the stratification factor

[0211] f) Cochran-Mantel-Haenszel test with the affected ear as the stratification factor

[0212] [Example 2] Study on the effect on otitis externa

[0213] The effectiveness of the levofloxacin experimental otologic solution on otitis externa was studied for 161 patients (82 in the levofloxacin group and 79 in the placebo group) with concurrent otitis externa among the 201 patients (99 in the levofloxacin group and 102 in the placebo group) of otitis media who were the test subjects of Example 1.

[0214] (Design of the experiment)

[0215] The subjects were those who were judged by the image judgment committee to have swelling or erosion / redness in the external auditory canal in the digital endoscopic images of the tympanic membrane and tympanic cavity at the time of screening obtained in the clinical trial of Example 1.

[0216] (Test results)

[0217] Table 16 shows the proportion of subjects (improvement rate) who were judged by the Effect Safety Evaluation Committee to have subsided "swelling" and "erosion and redness" of the external auditory canal and subsided purulent otorrhea in the digital endoscopic images at the end or termination of the test drug administration. For cases with bilateral disease, the situation in which both sides can confirm that the "swelling" and "erosion and redness" of the external auditory canal have subsided, as well as the subsided purulent otorrhea, was evaluated as improvement. In terms of improvement rate, the levofloxacin group was 47.6% (39 / 82 cases), and the placebo group was 20.3% (16 / 79 cases), and there was a statistically significant difference in the improvement rate between the two groups (p < 0.001; Fisher's exact probability test).

[0218] [Table 16]

[0219] Table 16 Inflammatory findings in the external auditory canal and resolution of otorrhea

[0220]

[0221] a) Wilson score

[0222]

[0223] b) Levofloxacin group-placebo group

[0224] c) Newcombe score

[0225] d) Fisher's exact probability test

[0226] Table 17 shows the proportion of subjects (improvement rate) who were judged by the Effect Safety Evaluation Committee to have subsided "swelling" and "erosion and redness" of the external auditory canal in the digital endoscopic images at the end or termination of the test drug administration. For cases with bilateral disease, the situation in which the "swelling" and "erosion and redness" of the external auditory canal can be confirmed to have subsided on both sides was judged to be improved. In terms of improvement rate, the levofloxacin group was 54.9% (45 / 82 cases) and the placebo group was 35.4% (28 / 79 cases). There was a statistically significant difference in the improvement rate between the two groups (p<0.017; Fisher's exact probability test).

[0227] [Table 17]

[0228] Table 17 Relief of inflammation of the external auditory canal

[0229]

[0230] a) Wilson score

[0231]

[0232] b) Levofloxacin group-placebo group

[0233] c) Newcombe score

[0234] d) Fisher's exact probability test

[0235] [Example 3] Research test on the effect of ofloxacin otologic solution on otitis media

[0236] For patients with otitis media with persistent purulent otorrhea, commercially available 0.3% ofloxacin otologic solution (CeoliaPharma Co., Ltd.) was administered twice a day (morning and evening) for 10 days using the same administration method as in Example 1, and the attending physician performed clinical effect determination and bacteriological evaluation using the same method as in Example 1. The subject patients were 3 cases of a 78-year-old male (Case 1), a 73-year-old male (Case 2), and a 68-year-old male (Case 3), all of whom had perforating chronic otitis media.

[0237] Table 18 shows the results of clinical effects determined by the attending physician based on the inflammation regression of the middle ear and tympanic membrane on each patient's visit day. As can be seen from the table, in the comprehensive evaluation, there was no case determined to have resolved inflammation. It should be noted that in case 1, otorrhea other than purulent otorrhea temporarily occurred during the treatment, and in case 2, otorrhea other than purulent otorrhea temporarily disappeared during the treatment, but since both recurred during the administration period, purulent otorrhea was not determined to have stopped.

[0238] [Table 18]

[0239] Table 18 Effect of ofloxacin otologic solution (0.3%) on chronic otitis media

[0240]

[0241] Table 19 shows the results of bacteriological examination of the middle ear secretion (otorrhea) collected at the time of screening and at the end of administration (4th visit). In case 1, S. maltophilia and MRSA were detected before the start of administration, and S. maltophilia was not detected after the end of administration, but MRSA was detected. In case 2, bacterial examination from purulent otorrhea at the end of administration was not performed, and in case 3, inflammatory bacteria were not detected before the start of administration and at the end of administration, so the clearance rate of inflammatory bacteria could not be evaluated for these two cases.

[0242] [Table 19]

[0243] Table 19 Bacteriological examination results of otorrhea

[0244]

[0245] *R indicates resistance to levofloxacin, and S indicates sensitivity to levofloxacin.

[0246] * In case 3, Corynebacterium was detected before and after the administration, but it is a bacterium constituting normal flora, and inflammatory bacteria were not detected.

[0247] [Example 4] Preparation of Levofloxacin Otological Solution

[0248] The sodium chloride of 840g and the polysorbate 80 of 100g are dissolved in the purified water of 1L, the total amount of solution obtained and levofloxacin 1 / 2 hydrate 1500g are added to the purified water and mixed, and the total amount is 96kg of the levofloxacin aqueous solution. The pH regulator of the levofloxacin aqueous solution obtained with 2mol / L hydrochloric acid solution or 2mol / L sodium hydroxide solution is 6.5, and further adding purified water makes the total amount 101.1kg, and then using a pore size of 0.2 μm polyethersulfone filter to carry out aseptic filtration, make levofloxacin otology liquid. The levofloxacin otology liquid obtained is filled in a 5ml container of sterilized polyethylene.

[0249] Industrial Applicability

[0250] The otological solution of the present invention can contribute to the prevention and treatment of otitis externa and / or otitis media.

Claims

1. An otologic solution for the prevention and / or treatment of otitis externa and / or otitis media, comprising 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient per ml.

2. The otologic solution according to claim 1, which is substantially free of preservatives and ingredients having preservative effects.

3. The otologic solution according to claim 1 or 2, comprising at least one of a solubilizing agent, an isotonic agent, and a pH adjuster.

4. The otologic solution according to claim 1 or 2, wherein: Levofloxacin, its pharmaceutically acceptable salt or their solvate is levofloxacin hydrate.

5. The otologic solution according to claim 1 or 2, which is administered continuously for 5 to 14 days.

6. The otologic solution according to claim 1 or 2, which is administered twice a day.

7. The otologic solution according to claim 1 or 2, which is administered continuously for 5 to 14 days and twice a day.

8. The otologic solution according to claim 1 or 2, comprising at least one of a solubilizing agent, an isotonic agent, and a pH adjuster, and is administered continuously for 5 to 14 days.

9. The otologic solution according to claim 1 or 2, wherein: Otitis externa and / or otitis media refers to otitis externa and / or otitis media in patients with a history of treatment with antibiotics.

10. A method for preventing and / or treating otitis externa and / or otitis media, comprising administering a liquid preparation containing 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient in 1 ml to a subject in need thereof.

11. Levofloxacin, its pharmaceutically acceptable salt or their solvate, characterized in that Levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof for preventing and / or treating otitis externa and / or otitis media in a subject, wherein in the prevention and / or treatment, a liquid preparation containing 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient in 1 ml is administered to the subject.

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