WO2023224045A1 - Otological solution for preventing and/or treating otitis externa and/or otitis media - Google Patents

Abstract

Provided are an otological solution etc. for preventing and/or treating otitis externa and/or otitis media, said otological solution containing 10-20 mg/ml of levofloxacin, a pharmaceutically acceptable salt thereof or a solvate of the same as an active ingredient.

Description

Otological liquid for prevention and/or treatment of otitis externa and/or otitis media

The present invention relates to an otologic liquid for the prevention and/or treatment of otitis externa and/or otitis media, which contains levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof. Furthermore, the present invention relates to a method for preventing and/or treating otitis externa and/or otitis media, which comprises administering a solution containing levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Cross-reference to related applications

This application is based on Japanese Patent Application No. 2022-080585 filed on May 17, 2022, and claims the benefit of priority thereof, and all contents of the patent application are Incorporated herein by reference.

Antibiotics with indications in the field of otorhinolaryngology, including otitis externa and otitis media, include penicillin antibiotics, cephem antibiotics, carbapenem antibiotics, quinolone antibiotics, macrolide antibiotics, and tetracyclines. Various drugs include antibacterial agents and aminoglycoside antibacterial agents. However, even when these antibiotics are administered systemically, the drug does not migrate well into the middle ear cavity, which is surrounded by bone tissue, compared to normal tissues, so the blood concentration required for treatment is high. Therefore, the effect on the whole body tissue becomes a problem (Non-Patent Document 1). Therefore, local administration is often selected for otitis externa and otitis media in order to avoid adverse effects on the whole body while allowing high-concentration drugs to be administered to the external auditory canal and middle ear cavity.

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

Guidance from the United States and Australia recommends quinolone antibiotics, which are free from ototoxicity, which is a problem with aminoglycoside antibiotics, for topical treatment of otitis media (Non-Patent Documents 2, 3). Ofloxacin is a type of quinolone antibiotic and has been applied to various bacterial infections because it exhibits a broad antibacterial spectrum and excellent antibacterial activity. In Japan as well, ofloxacin otologic solution 0.3% has been used with the indication of otitis externa and otitis media. However, even with ofloxacin otologic solution 0.3%, otitis externa and otitis media may not be cured in a short period of time, and long-term administration may be necessary, and the emergence of resistant bacteria with long-term administration is also a problem. It became. Therefore, there is a need to further improve therapeutic effects and suppress resistant bacteria.

In addition, since otologic solutions used to treat otitis externa and otitis media are administered repeatedly, even if the tip of the otologic solution container becomes contaminated and bacteria enter the container when administering it to the ear, Preservatives are usually added to prevent the growth of bacteria. For example, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, etc. are used as preservatives, and typically 0.001~ It is used at a concentration of 1.0%. Ofloxacin otic solution 0.3% mentioned above also contains preservatives. However, patients may develop a hypersensitivity reaction to preservatives, and many preservatives are cytotoxic and may cause damage to the patient's outer ear and middle ear epithelium. No otologic fluid was desired.

Craig WA, Andes D, Pharmacokinetics and pharmacodynamics of antibiotics in otitis media, Pediatr Infect Dis J, 1996;15(3):255-9 Rosenfeld RM, et al., Clinical practice guideline: acute otitis externa, Otolaryngol Head Neck Surg, 2014;150(1 Suppl):S1-S24 Coates H, Ear drops and ototoxicity, Aust Prescr, 2008;31:40-1

An object of the present invention is to provide an otologic solution for effective prevention and/or treatment of otitis externa and/or otitis media. Another object of the present invention is to provide a method for preventing and/or treating otitis externa and/or otitis media, which includes administering such a preventive and/or therapeutic agent.

The present inventors have discovered that otitis externa and otitis media can be cured in a short period of time by using an otologic solution containing levofloxacin, an optically active form of ofloxacin, as an active ingredient at a high concentration. reached.

That is, the gist of the present invention is as follows.
[1] Otology for the prevention and/or treatment of otitis externa and/or otitis media, containing 10 to 20 mg per ml of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient Liquid for use.
[2] Otitis externa and/or containing 12 to 18 mg, preferably 14 to 16 mg, more preferably 15 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof per ml as an active ingredient. Otological liquid for prevention and/or treatment of otitis media.
[3] The otic liquid according to [1] or [2], which does not substantially contain a preservative or a component having a preservative effect.
[4] The otic liquid according to [1] or [3], which contains at least one of a solubilizing agent, an isotonizing agent, and a pH adjusting agent.
[5] The otic liquid according to [1] or [3], wherein levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof is levofloxacin hydrate.
[6] The otic liquid according to [1] or [3], which is continuously administered for 5 to 14 days.
[7] The otic liquid according to [1] or [3], which is administered twice a day.
[8] The otologic solution according to [1] or [3], which is administered by ear drop twice a day for 5 to 14 days.
[9] The otic liquid according to [1] or [3], which contains at least one of a solubilizing agent, an isotonic agent, and a pH adjusting agent, and is continuously administered for 5 to 14 days.
[10] The otologic liquid according to [1] or [3], wherein the otitis externa and/or otitis media is bacterial otitis externa and/or otitis media.
[11] The otologic liquid according to [1] or [3], wherein the otitis externa and/or otitis media is chronic otitis media.
[12] The otologic liquid according to [1] or [3], wherein the otitis externa and/or otitis media is otitis externa and/or otitis media of a patient who has a history of treatment with antibiotics.
[13] Otitis externa, which involves administering to a subject in need of administration a liquid preparation containing 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient per ml. and/or a method for preventing and/or treating otitis media.
[14] 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 said prevention and/or treatment Levofloxacin, its pharmaceutical composition, wherein a liquid preparation containing 10 to 20 mg per ml of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient is administered to the subject. Acceptable salts or solvates thereof.

The otologic liquid of the present invention is useful for the prevention and/or treatment of otitis externa and/or otitis media.

1 is a table showing the schedule of a clinical trial conducted in Example 1. FIG. 2 is a diagram showing the breakdown of subjects in the clinical trial conducted in Example 1. 2 is a graph showing the period until otorrhea stops as evaluated by the doctor in charge in the clinical test conducted in Example 1. 2 is a graph showing the period until otorrhea stops as evaluated by the efficacy and safety evaluation committee in the clinical trial conducted in Example 1.

The present invention will be described in more detail below with reference to preferred embodiments, but the present invention is not limited thereto.

In one embodiment, the present invention provides a method for preventing otitis externa and/or otitis media, which contains 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof per ml as an active ingredient. Relating to therapeutic otologic fluid.

In another aspect, the present invention provides levofloxacin, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient for the prevention and/or treatment of otitis externa and/or otitis media. Concerning an otological liquid containing ~20 mg.

In another aspect, the present invention provides for administering to a subject in need of administration a liquid preparation containing 10 to 20 mg per ml of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The present invention relates to a method for preventing and/or treating otitis externa and/or otitis media.

In yet another aspect, there is provided 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 said prevention And/or in treatment, a liquid preparation containing 10 to 20 mg of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient per ml is administered to the subject.

As used herein, the term "pharmacologically acceptable salts of levofloxacin" is not particularly limited as long as it is a pharmaceutically acceptable salt of levofloxacin, and examples include salts with inorganic acids such as hydrochloric acid and sulfuric acid, and maleic acid salts. Salts with acids and organic acids such as tartaric acid, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, salts with inorganic bases such as aluminum and ammonia, diethylamine and diethanolamine, etc. and salts with organic bases.

The solvate of levofloxacin or its pharmacologically acceptable salt is not particularly limited as long as it is a pharmaceutically acceptable solvate. hydrates, monohydrates, dihydrates, etc.), solvates with organic solvents, etc., but preferably hydrates (1/2 hydrates, monohydrates, dihydrates, etc.). and more preferably a hemihydrate.

In this specification, levofloxacin, its pharmacologically acceptable salts, or solvates thereof may be collectively referred to as "the compound of the present invention."

As the compound of the present invention, a hydrate of levofloxacin is preferable, and a hemihydrate of levofloxacin is more preferable.

The method for producing the compound of the present invention is known and can be produced using known compounds and reagents. For example, it may be manufactured by the method described in Japanese Patent Publication No. 3-27534 and Japanese Patent Publication No. 7-47592. Commercially available products may be used as the compounds of the present invention.

The otic solution of the present invention preferably contains the compound of the present invention in 1 ml of the solution in an amount of 10 to 20 mg, more preferably 12 to 18 mg, even more preferably 14 to 16 mg. For example, 15 mg of the compound of the present invention may be contained in 1 ml of the liquid preparation.

As used herein, "for prevention and/or treatment" means either for prevention, for treatment, or for both prevention and treatment.

The otologic liquid of the present invention is administered for otitis externa and/or otitis media. "Administered for otitis externa and/or otitis media" means administered for otitis externa, otitis media, or both otitis externa and otitis media. It means either. Otitis externa and otitis media may be acute or chronic. Otitis externa and/or otitis media may be bacterial or non-bacterial, but in some embodiments is bacterial. Examples of bacteria causing bacterial otitis externa and otitis media include Pseudomonas aeruginosa, MRSA, and the like. Regarding otitis media, it may be of the tympanic membrane perforation type or the tympanic membrane non-perforation type, but in one embodiment, it is the tympanic membrane perforation type. Otitis externa and/or otitis media may or may not have otorrhea, but in some embodiments there is otorrhea.

The otologic solution of the present invention may be administered to subjects with a history of antibiotic treatment (either local or systemic administration), or to subjects without a history of antibiotic treatment. However, in some embodiments, it is administered to subjects with a history of antibiotic treatment. The otologic solution of the present invention may be administered to a subject who has a history of treatment with steroid drugs (either local or systemic administration), or may be administered to a subject who has no history of treatment with steroid drugs. However, in some embodiments, it is administered to subjects with a history of steroid therapy. The otic fluid of the present invention may be administered to a subject with a history of surgical treatment, or may be administered to a subject without a history of surgical treatment.

It is preferable that the otologic liquid of the present invention does not substantially contain a preservative or a component having a preservative effect. As used herein, the term "substantially free of preservatives and components with antiseptic action" means that the otologic solution does not contain "preservatives and components with antiseptic action" at all, or "preservatives and components with antiseptic action" are not included in the otologic solution. This means that "component having preservative effect" alone is contained to an extent that does not meet the preservative efficacy test method described in the 18th edition of the Japanese Pharmacopoeia.

The otic solution of the present invention preferably contains at least one of a solubilizing agent, an isotonic agent, and a pH adjusting agent, and preferably contains at least two of a solubilizing agent, an isotonic agent, and a pH adjusting agent. It is even more preferable to contain a solubilizing agent, a tonicity agent, and a pH adjusting agent.

The solubilizing agent is not particularly limited as long as it has the effect of improving the solubility of the compound of the present invention in water, but for example, surfactants or cosolvents may be used as the solubilizing agent. can do. Such cosolvents include polysorbate 20 (polyoxyethylene sorbitan monolaurate), polysorbate 60 (polyoxyethylene sorbitan monostearate), polysorbate 65 (polyoxyethylene sorbitan tristearate), and polysorbate 80 (polyoxyethylene sorbitan oleate). Sorbitan fatty acid esters such as ethylene sorbitan); polyoxyethylene/polyoxypropylene block copolymer surfactants (eg, Pluronic (registered trademark) F-68 and Tetronic (registered trademark) 1304); cyclodextrin, and the like. When these are used as solubilizing agents, for example, 0.01 to 2% by weight, preferably 0.05 to 1.5% by weight, more preferably 0.07 to 1.5% by weight, based on the total weight of the liquid preparation. It can be used in a range of 2% by weight.

Alternatively, a polyhydric alcohol (dihydric or trihydric alcohol) may be used as a solubilizing agent. Examples of polyhydric alcohols include diols (water-soluble polypropylene glycols such as ethylene glycol, diethylene glycol, polyethylene glycol (PEG), propylene glycol, and dipropylene glycol), trivalent or higher polyhydric alcohols such as glycerin, and polyglycerin. can be mentioned. Further, as a solubilizing agent, medium chain fatty acid triglyceride, castor oil, macrogol, isopropyl myristate, etc. can also be used. Among these solubilizing agents, glycerin, propylene glycol, a combination thereof, etc. are preferably used. When these are used as solubilizing agents, they can be used in an amount of, for example, 5 to 50% by weight, preferably 10 to 40% by weight, and more preferably 15 to 30% by weight based on the total weight of the liquid. .

The pH regulator may be one that does not adversely affect the biological functions of the subject to be administered or the activity of the compound of the present invention, and is not particularly limited, but includes hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide, citric acid and its salts such as triethanolamine, diisopropanolamine sodium citrate, potassium citrate, calcium citrate, lithium citrate; tartaric acid and its salts such as sodium tartrate, potassium tartrate, calcium tartrate, lithium tartrate; Phosphoric acid and its salts such as sodium dihydrogen phosphate, sodium monohydrogen phosphate, lithium phosphate, potassium phosphate, calcium phosphate, carbonic acid and its salts such as sodium carbonate, sodium bicarbonate, sodium lactate, potassium lactate, Lactic acid and its salts such as calcium lactate, acetic acid and its salts such as sodium acetate, potassium acetate, calcium acetate, sulfuric acid and its salts such as sodium sulfate and potassium sulfate, boric acid and its salts such as sodium borate , maleic acid and its salts, such as lithium maleate, sodium maleate, potassium maleate, calcium maleate; succinic acid and its salts, such as lithium succinate, sodium succinate, potassium succinate, calcium succinate; can be selected from the group consisting of mixtures of.

The pH of the otic solution of the present invention may be within the range acceptable for otolaryngological preparations, but is usually preferably within the range of pH 5 to 8, more preferably pH 6 to 7.

The otic solution of the present invention can be produced using the above-mentioned components by conventional means such as mixing, dissolving, and sterilization (for example, sterile filtration).

The otologic liquid of the present invention can be administered, for example, by dropping into the external auditory canal (ear drops) or spraying, or by applying to the external ear using a cotton swab or the like. The otic liquid of the present invention may be filled into a multiple-dose container (multi-dose container) or a single-dose container (unit-dose container). If a single-dose container is filled, a new container is opened each time the drug is administered, and the possibility of contamination from outside the container with microorganisms, body secretions, etc. can be easily avoided.

The otic solution of the present invention can be administered one to three times a day, but preferably twice a day. The administration period depends on the symptoms of otitis externa and/or otitis media of the subject to be administered, but is usually 5 to 14 days. The administration period is preferably 6 days or more, more preferably 7 days or more, and even more preferably 8 days or more. The administration period is preferably 13 days or less, more preferably 12 days or less, and even more preferably 11 days or less. The administration period was 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 -13 days, 7-12 days, 7-11 days, 7-10 days, 7-9 days, and 7-8 days. The administration period is preferably 6 to 13 days, more preferably 7 to 12 days, even more preferably 8 to 11 days.

The subject to whom the prophylactic and/or therapeutic agent of the present invention is administered or the subject of the prophylactic and/or therapeutic method of the present invention is not limited to animals, but preferably mammals (e.g., humans, dogs, cats, monkeys, cows). , horses, pigs, mice, rats, etc.), more preferably humans.

The prophylactic and/or therapeutic agent of the present invention may be administered alone, but may be administered in combination with other drugs as long as the effects of the prophylactic and/or therapeutic agent of the present invention are not thereby inhibited. For example, it may be administered in combination with an antihistamine, a chemical mediator release inhibitor, an anti-leukotriene drug, an anti-prostaglandin _D2 /thromboxane drug, a TRP (transient receptor potential) channel agonist, a steroid drug, and the like.

Hereinafter, the present invention will be explained in more detail based on Examples, but the present invention is not limited to these Examples.

[Example 1] Test to evaluate the effect on otitis media A randomized, parallel-group comparative clinical trial using placebo as a control was conducted to evaluate the high-concentration levofloxacin otitis media of the present invention for patients with otitis media who have persistent or protracted purulent otorrhea. The clinical effects, bacteriological effects, safety, pharmacokinetics (PK), etc. of the solution were investigated.

(Test design)
Subjects who provided written informed consent underwent background investigation and screening tests within 14 days before administration of the study drug. Group to which 1.5wt/vol% otologic solution of levofloxacin hemihydrate (hereinafter referred to as "levofloxacin test otologic solution") is administered (hereinafter referred to as "levofloxacin group") and placebo otologic solution Targeting 100 subjects in each group (total of 200 subjects) in the group to be administered the oral solution (hereinafter referred to as the "placebo group"), subjects whose eligibility was confirmed were enrolled and randomized to receive either the levofloxacin group or the ``placebo group.'' They were randomly assigned to one of the placebo groups in a 1:1 ratio. The subjects to be evaluated for PK were those with only one affected ear, and the target was 10 subjects in each group (20 subjects in total) for the levofloxacin group and the placebo group.

The criteria for selecting subjects were patients who met the following criteria:
(1) Patients who are 15 years of age or older at the time of obtaining consent.
(2) Patients diagnosed with acute otitis media or perforated chronic otitis media due to infection.
(3) Patients with clinically persistent purulent otorrhea.
(4) Patients with any of the following pathological conditions.
(i) Patients who underwent transtympanic ventilation tube insertion and have persistent otorrhea after surgery.
(ii) Patients who have persistent otorrhea due to granulation formation around the tube after placement of a transtympanic ventilation tube.
(iii) Patients with perforated chronic otitis media who have persistent otorrhea from the erosive surface or granulation. However, patients with persistent otorrhea from residual granulation lesions after surgery for chronic otitis media may also be enrolled.
(5) Patients who have provided written consent to participate in this clinical trial. For patients aged 15 to under 20, written consent was obtained from their parents and ascent documentation was obtained from the patient.

The test was conducted according to the schedule shown in Figure 1. 6 to 10 drops of levofloxacin test otologic solution or placebo otologic solution were instilled into the affected ears of the subjects twice a day, in the morning and evening, and a 10-minute ear bath was performed after the instillation. However, for subjects evaluating PK, the number of drops at the first administration was 10 drops. Administration was terminated when healing was confirmed and the attending physician determined that continued treatment was unnecessary, and continued for a maximum of 10 days. If the administration is completed at Visit 2 or Visit 3 in Figure 1, a final examination, etc. will be conducted on the day of the visit, and an examination at the time of cure determination (Visit 5) will be conducted from the 5th day to the 10th day after the end of the administration. I did it. In addition, in the case of administration for 10 days, tests for determining cure were conducted from the 19th day to the 24th day after the start of administration.

The composition of the investigational drug levofloxacin test otologic solution and the composition of the placebo otologic solution are shown in Table 1. The placebo otic fluid was visually indistinguishable from the levofloxacin test otic fluid.

During the trial period, only suction was allowed for ear treatment, and cleaning of the tympanic cavity was prohibited. Otology-related surgeries (excluding transtympanic ventilation tube insertion and myringotomy) were also prohibited. It was decided not to perform suction before completing the imaging of the tympanic membrane and tympanic cavity findings during digital endoscopy. Additionally, during the trial period, ear drops other than the investigational drug were prohibited, and systemic administration of antibacterial agents (antibiotics) and corticosteroids (steroids) other than the investigational drug was also prohibited.

Subjects were asked about the quality and amount of otorrhea, hearing ability (difficulty hearing), other ear-related symptoms (tinnitus, dizziness, discomfort in the ears, etc.), adverse events (concerns; health conditions such as physical condition), etc. During the administration period, the situation before the start of administration was to be recorded in the patient diary twice a day. After the 11th day of administration, the status of the day, excluding the study drug administration status, was to be recorded once a day until Visit 4. If administration was terminated or discontinued before Visit 4, entries in the patient diary were not required after the completion or discontinuation examination was completed. The attending physician checked the patient's diary prior to examinations and surveys at each visit of the subject, and confirmed the subject's otorrhea, hearing ability, ear-related symptoms, adverse events, and study drug use status.

(Evaluation method)
A. Clinical efficacy The clinical efficacy of the high-concentration levofloxacin otic solution of the present invention was evaluated based on the time taken for the inflammation of the middle ear and tympanic membrane to subside and for the otorrhea to stop.

A-1. Elimination of inflammation of the middle ear and tympanic membrane: Elimination of inflammation of the middle ear and tympanic membrane, resolution of purulent otorrhea, resolution of congestion (redness) of the middle ear mucosa and tympanic membrane, and resolution of granulation of the middle ear mucosa and tympanic membrane. The clinical efficacy of the investigational drug was evaluated by the attending physician and the efficacy and safety evaluation committee as evaluation indicators.

Based on the screening and findings of the tympanic membrane and tympanic cavity (digital endoscopy) at each visit (including the time of discontinuation), the attending physician determines resolution of purulent otorrhea, middle ear mucosa, and tympanic membrane for each affected ear based on the criteria shown in Table 2. The disappearance of hyperemia (redness) and the disappearance of granulation of the middle ear mucosa and tympanic membrane were evaluated and judged, and based on the results, the disappearance of inflammation of the middle ear and tympanic membrane (clinical effect) was judged according to the criteria in Table 3. The Efficacy and Safety Evaluation Committee blindly evaluated each affected ear using the same evaluation indicators and criteria from digital endoscopic images of the tympanic membrane and tympanic cavity taken during screening and each visit (including the time of discontinuation). - Judgment was made (central judgment). However, if the findings of the middle ear mucosa and tympanic membrane cannot be confirmed or photographed using digital endoscopy due to a large amount of otorrhea, etc., the case is classified as "indeterminate."

Regarding purulent otorrhea, it was determined that it had resolved if the symptoms improved after the start of administration and the purulent otorrhea improved to "none" or "non-purulent otorrhea."

Regarding hyperemia (redness) of the middle ear mucosa and tympanic membrane, if there are no symptoms at screening and Visit 1, and if it is confirmed that no new symptoms have developed in the evaluation of symptoms after the start of administration, it will be considered "no symptoms". If the symptoms were found to be "partial" or "all" at screening or Visit 1, and the symptoms were evaluated after the start of administration, and the hyperemia (redness) improved to "none", it was considered "resolved". Furthermore, if the symptoms at Screening and Visit 1 cannot be determined due to a large amount of otorrhea, etc., and when it becomes possible to determine the symptoms due to the disappearance of the otorrhea during the evaluation of symptoms after the start of administration, if the symptoms are "none", It was marked as “disappeared.”

Regarding granulation of the middle ear mucosa and tympanic membrane, if there is no granulation in screening and Visit 1, and if it is confirmed that no new granulation has developed in the evaluation of symptoms after the start of administration, it will be treated as "no symptoms" and screening will be performed. Or, if there is "granulation without purulent exudate" in Visit 1, and the symptom evaluation after the start of administration shows that "granulation without purulent exudate" remains and there is no increase in the granulation lesion, " If there was no granulation, it was classified as "removed". If there is "granulation with purulent exudate" at screening or Visit 1, and the symptom evaluation after the start of administration shows "granulation without purulent exudate" and there is no increase in the granulation lesion, it is considered "improved". If there was no granulation, it was considered to have disappeared. Furthermore, if the symptoms at Screening and Visit 1 were undiagnosable due to a large amount of otorrhea, etc., and when it became possible to determine granulation due to disappearance of otorrhea during symptom evaluation after the start of administration, it was determined that there was no purulent exudate. If there was no granulation or granulation, it was considered to have disappeared.

When all of the resolution criteria for each index shown in Table 3 were met, it was determined that the inflammation of the middle ear and tympanic membrane had "resolved" as a comprehensive evaluation. If both sides were affected, if all the resolution criteria for each index were met on both sides, the overall evaluation was determined as "resolution" of the inflammation of the middle ear and tympanic membrane.

A-2. Period until otorrhea stops The period until otorrhea stops was calculated from the start date of administration. Based on the tympanic membrane and tympanic cavity findings (digital endoscopy) on the patient's most recent hospital visit (each visit) on the day when purulent otorrhea stopped in the patient's diary (aural symptoms), the doctor in charge determined that purulent otorrhea was detected. If it was confirmed that there was no otorrhea, the date when the otorrhea stopped was set as an event. If bilateral disease was present, the event was the day on which purulent otorrhea stopped on both sides. In addition, if the patient's diary does not show that the purulent otorrhea has stopped, and the doctor in charge confirms that there is no purulent otorrhea based on the findings of the tympanic membrane and tympanic cavity (digital endoscopy) on the day of the patient's visit, The date of visit was defined as the date when otorrhea stopped. In cases where the efficacy and safety evaluation committee determined in a blinded manner that there was no purulent otorrhea based on digital endoscopic image findings of the tympanic membrane and tympanic cavity, the period until otorrhea stopped was similarly evaluated.

B. Bacteriological effect Bacterial eradication rate was evaluated for each affected ear based on the presence or absence of pathogenic bacteria detected from middle ear secretions (otorrhea) collected at the time of screening and at the end or discontinuation of administration. If healing was confirmed at the end of administration or discontinuation, and there was no middle ear fluid (otorrhea) that could be collected, it was assumed that the bacteria had disappeared. Middle ear secretions (otorrhea) were aseptically collected directly from the middle ear cavity. In addition, if there is a perforation of the tympanic membrane and middle ear secretions (otorrhea) are flowing out into the external auditory canal, after cleaning the middle ear secretions (otorrhea) by suction or swabbing, remove the newly drained middle ear secretions. (otorrhea) was collected aseptically. A designated swab was used for collection.

Drug susceptibility to levofloxacin was evaluated by MIC for all pathogenic bacteria (isolated bacteria) that could be detected from middle ear secretions (otorrhea) collected at the time of screening and at the end or discontinuation of administration. The MIC was measured according to the microbroth dilution method, which is the standard method of the Japanese Society of Chemotherapy. The antimicrobial susceptibility rate of each bacterial species was calculated according to the MIC breakpoint defined by the Clinical Laboratory Standards Institute (CLSI).

C. Safety Hearing tests (measured in 5 dB steps at frequencies of 125, 250, 500, 1000, 2000, 4000, and 8000 Hz) were performed at screening, at the end of administration or discontinuation, and at the time of determination of cure. Furthermore, balance function tests (evaluated by gaze nystagmus test and spontaneous nystagmus test (frontal sitting test under Frenzel glasses)) were conducted at screening and at the end of administration or discontinuation.

Interviews were conducted at the times shown in the "Test Schedule" in Figure 1, and if any abnormalities were found in the physical findings, additional tests (auscultation, visual inspection, palpation, etc.) were conducted. In addition, height and weight were measured at the time of screening. Hematological tests (red blood cell count, hemoglobin level, hematocrit value, platelet count, white blood cell count, white blood cell differential (neutrophils, lymphocytes, basophils, eosinophils, blood biochemical tests (total bilirubin, direct bilirubin, total protein, albumin, ALP, LDH, AST, ALT, gamma-GT (γ-GTP), CPK, BUN, creatinine, Na, K, Cl, Ca , CRP).

An unfavorable medical event that occurs to a subject is considered an adverse event, and the attending physician determines the severity of the adverse event as mild (the subject notices the event or symptom and does not interfere with daily life), moderate. (Those with obvious symptoms (discomfort) that interfere with or diminish the subject's daily life) or severe (Those who are unable to carry out daily life or are life-threatening). In addition, the attending physician will determine whether there is a relationship between the study drug and the adverse event, whether it is unrelated (a causal relationship is probably unrelated or can be clearly ruled out, and other causes are most plausible), or relevant (a causal relationship is not likely or can be clearly ruled out, and other causes are most plausible). Clinically/biologically relevant and there is an explainable time relationship between the administration of the study drug and the onset of the adverse event).

D. Pharmacokinetics Blood was collected at the time indicated in the "Test schedule" in Figure 1, and the maximum plasma concentration (C _max ) of levofloxacin and the area under the plasma concentration curve (AUC) from 0 to time t after administration were measured. _0-t : area under the plasma concentration-time curve from time 0 to after administration), area under the plasma concentration curve from 0 to infinity after administration (AUC _0-inf : area under the plasma concentration-time curve from time 0 to infinity after administration), etc. were calculated.

(Test results)
A. Breakdown of subjects and administration period Figure 2 shows the breakdown of subjects, and Table 4 shows the administration period (number of administration days) for each group.

B. Clinical effect B-1. Elimination of inflammation in the middle ear and tympanic membrane Table 5 shows the percentage of subjects whose inflammation in the middle ear and tympanic membrane disappeared (improvement rate) as determined by the attending physician at the time of completion or discontinuation of administration. The analysis target population was FAS (full analysis set: a group excluding subjects who did not meet the selection criteria, subjects who were clearly never administered the investigational drug, subjects with no efficacy data to analyze, 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 (95% confidence interval (CI)) between the levofloxacin group and the placebo group, adjusted using the Mantel-Haenszel method using the affected ear as a stratification factor, was 38.0 (24.5 to 49.6)%. , a statistically significant difference was observed (p<0.001).

Table 6 shows the three evaluation indicators regarding the resolution of inflammation in the middle ear and tympanic membrane (purulent otorrhea, hyperemia (redness) of the middle ear mucosa and tympanic membrane, and swelling of the middle ear mucosa and tympanic membrane) as judged by the attending physician at the time of completion or discontinuation of administration. It shows the percentage of subjects whose granulation (granulation) disappeared (improvement rate).

Table 7 shows the percentage of subjects whose middle ear and eardrum inflammation disappeared (improvement rate) as determined by the efficacy and safety evaluation committee at the time of completion or discontinuation of administration. The analysis target population was FAS. As shown in the table, the improvement rate was 46.5% (46/99 cases) in the levofloxacin group and 23.5% (24/102 cases) in the placebo group. In addition, the difference in improvement rate (levofloxacin group - placebo group) and its two-sided 95% CI (Newcombe score) were calculated. The difference in improvement rate between the levofloxacin group and the placebo group (95% CI) was 22.0 (8.7 to 34.2), using the affected ear (one ear, both ears) as a stratification factor and adjusting using the Mantel-Haenszel method. %, and a statistically significant difference was observed by Cochran-Mantel-Haenszel test (p=0.001).

Table 8 shows the three evaluation indicators regarding the resolution of inflammation in the middle ear and tympanic membrane (purulent otorrhea, hyperemia (redness) of the middle ear mucosa and tympanic membrane, It shows the percentage of subjects whose ear mucosa and tympanic membrane granulation disappeared (improvement rate).

B-2. Period until otorrhea stops Figure 3 and Table 9 show the period until otorrhea stops as evaluated by the attending physician. The period until otorrhea stopped was evaluated by ITT (intention-to-treat: all subjects assigned regardless of whether they received the study drug). The median time to otorrhea cessation (95% CI) estimated by the Kaplan-Meier method was 7.0 (6.0-7.0) days in the levofloxacin group and 20.0 (12.0-7.0) days in the placebo group. (not estimable) days, which was shorter in the levofloxacin group than in the placebo group, and a statistically significant difference was observed in a stratified log-rank test stratified by affected ears (p<0.001). The hazard ratio (95% CI) estimated using the Fine-Gray model with discontinuation of the trial as a competing risk was 3.257 (2.358 to 4.499), and the Gray test showed that there was no statistical difference between the two groups. A significant difference was observed (p<0.001).

Figure 4 and Table 10 show the period until otorrhea stops as evaluated by the Efficacy and Safety Evaluation Committee. Median time to otorrhea cessation (95% CI) was 7.0 (7.0-8.0) days in the levofloxacin group and 22.0 (14.0-not estimable) days in the placebo group; Similar to the evaluation by the attending physician, the duration was shorter in the levofloxacin group than in the placebo group, and a statistically significant difference was observed (p<0.001).

C. Bacteriological effect Table 11 shows the eradication rate of pathogenic bacteria detected from otorrhea collected at the time of screening and at the end or discontinuation of administration. The bacterial eradication rate was 93.9% (77/82 cases) in the levofloxacin group and 12.5% (11/88 cases) in the placebo group. ) was 81.4 (70.1 to 87.8)%, and the bacterial eradication rate in the levofloxacin group was high, and a statistically significant difference was observed (p<0.001).

Table 12 shows the bacterial species that showed drug sensitivity to levofloxacin. Levofloxacin was effective against all pathogenic bacteria detected during screening.

D. Safety Hearing tests were conducted at the end of administration or discontinuation and at the time of determination of cure, using the screening time as the baseline for the average hearing according to the quarter-average hearing level of the affected ear and the hearing at 125 to 8000 Hz (air conduction/bone conduction). As a result, in both the levofloxacin group and the placebo group, there were no significant changes between the baseline and the measured values at the end of administration, at the time of discontinuation, and at the time of determination of cure. Regarding the balance function test findings by gaze nystagmus test and spontaneous nystagmus test, gaze nystagmus and spontaneous nystagmus were abnormal and clinically problematic in both the levofloxacin group and the placebo group at baseline and at the end of treatment. There were no cases in which this was determined to be the case.

In this clinical trial, there were no serious adverse events or side effects in either the levofloxacin group or the placebo group, and no adverse events related to laboratory test values were observed.

E. Table 13 shows various parameters calculated by a model-independent method regarding the plasma levofloxacin concentration of each subject in the analysis population regarding pharmacokinetics PK. The mean ± standard deviation of the plasma levofloxacin concentration increased to 9.7767 ± 14.4944 ng/ml 30 minutes after the completion of the 10-minute ear bath after administration of the study drug, and then gradually decreased. Four out of six subjects showed C _max after 30 minutes. In addition, the plasma levofloxacin concentration was less than 10 ng/ml except for one case. The average values ± standard deviation of various parameters are: C _max is 9.9008 ± 14.4606 ng/ml, AUC _0-t is 40.2175 ± 59.3665 ng・h/ml, and AUC _0-inf is 98.6797 ± 125. It was .5012 ng·h/ml.

F. Analysis of clinical effects on subpopulations Tables 14 and 15 show the results of the judgment by the attending physician regarding resolution of middle ear and tympanic membrane inflammation at the end or discontinuation of administration in subjects with a history of antibiotic treatment. Among subjects with no history of antibiotic treatment, the rate of improvement in inflammation was 62.9% in the levofloxacin group and 31.8% in the placebo group, a statistically significant difference. (p=0.009). Among subjects with a history of antibiotic treatment, the rate of improvement in inflammation was 61.7% in the levofloxacin group and 19.0% in the placebo group, a statistically significant difference. (p<0.001).

[Example 2] Study to evaluate the effect on otitis externa Of the 201 patients with otitis media (99 patients in the levofloxacin group, 102 patients in the placebo group) who were the subjects of the study in Example 1, 161 patients who had otitis externa ( The efficacy of levofloxacin test otic solution for otitis externa was investigated in 82 patients in the levofloxacin group and 79 patients in the placebo group.

(Test design)
Targeted subjects whose image evaluation committee determined that there was any evidence of swelling, erosion, or redness in the ear canal in the digital endoscopic images of the eardrum and tympanic cavity obtained at the time of screening obtained in the clinical trial of Example 1. did.

(Test results)
Table 16 shows that in digital endoscopic images at the end or discontinuation of study drug administration, the "swelling" and "erosion/redness" in the ear canal had disappeared, and the purulent otorrhea had disappeared, according to the Efficacy and Safety Evaluation Committee. It shows the percentage of subjects judged by (improvement rate). For cases in which both sides were affected, the condition was considered improved if it was confirmed that swelling and erosion/redness in the ear canal and purulent otorrhea had disappeared on both sides. The improvement rate was 47.6% (39/82 cases) in the levofloxacin group and 20.3% (16/79 cases) in the placebo group, and there was a statistically significant difference in the improvement rate between the two groups. (p<0.001;Fisher's exact test).

Table 17 shows the percentage of subjects for whom the efficacy and safety evaluation committee determined that the "swelling" and "erosion/redness" in the external auditory canal had disappeared in digital endoscopic images at the end or discontinuation of study drug administration ( improvement rate). For cases in which both sides were affected, the condition was considered improved if swelling and erosion/redness in the external auditory canal were confirmed to have disappeared on both sides. The improvement rate was 54.9% (45/82 cases) in the levofloxacin group and 35.4% (28/79 cases) in the placebo group, and there was a statistically significant difference in the improvement rate between the two groups. (p<0.017; Fisher's exact test).

[Example 3] Study of the effect of ofloxacin otologic solution on otitis media Commercially available ofloxacin otologic solution 0.3% (Ceolia Pharma Co., Ltd.) was administered to patients with otitis media with persistent purulent otorrhea. The drug was administered twice a day in the morning and evening for 10 days using the same method as in Example 1, and the clinical efficacy and bacteriological evaluation were performed by the attending physician in the same manner as in Example 1. The target patients were a 78-year-old man (case 1), a 73-year-old man (case 2), and a 68-year-old man (case 3), all of whom had perforated chronic otitis media.

Table 18 shows the results of the judgment of clinical efficacy by the attending physician based on the resolution of inflammation in the middle ear and eardrum on each patient's visit day. As is clear from the table, there were no cases in which inflammation was determined to have disappeared in the comprehensive evaluation. In addition, in case 1, otorrhea other than purulent developed during the course of treatment, and in case 2, otorrhea other than purulent developed during the course of treatment, and although the purulent otorrhea disappeared once, it recurred during the administration period. Therefore, it was not determined that the purulent otorrhea had stopped.

Table 19 shows the results of bacteriological examination of middle ear secretions (otorrhea) collected at screening and at the end of administration (Visit 4). In case 1, S. maltophilia and MRSA were detected, and S. Maltophilia was not detected, but MRSA was detected. In case 2, a bacterial test was not performed on the purulent otorrhea at the end of administration, and in case 3, no pathogenic bacteria was detected before or at the end of administration. The disappearance rate could not be evaluated.

[Example 4] Preparation of levofloxacin otic solution

The entire amount of a solution obtained by dissolving 840 g of sodium chloride and 100 g of polysorbate 80 in 1 L of purified water and 1500 g of levofloxacin hemihydrate were added and mixed to the purified water to obtain a total amount of 96 kg of a levofloxacin aqueous solution. The pH of the obtained levofloxacin aqueous solution was adjusted to 6.5 with a 2 mol/L hydrochloric acid solution or a 2 mol/L sodium hydroxide solution, and purified water was added to bring the total amount to 101.1 kg. It was sterile filtered using an ethersulfone filter to obtain a levofloxacin otic solution. The obtained levofloxacin otic solution was filled into a 5 ml container made of sterilized polyethylene.

The otologic liquid of the present invention can be useful for the prevention and treatment of otitis externa and/or otitis media.

Claims (11)

An otologic liquid for the prevention and/or treatment of otitis externa and/or otitis media, containing 10 to 20 mg per ml of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The otic liquid according to claim 1, which does not substantially contain a preservative or a component having a preservative effect. The otic liquid according to claim 1 or 2, which contains at least one of a solubilizing agent, an isotonizing agent, and a pH adjusting agent. The otic liquid according to claim 1 or 2, wherein levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof is levofloxacin hydrate. The otic liquid according to claim 1 or 2, which is continuously administered for 5 to 14 days. The otic liquid according to claim 1 or 2, which is administered twice a day. The otic fluid according to claim 1 or 2, which is administered twice a day for 5 to 14 consecutive days. The otic fluid according to claim 1 or 2, which contains at least one of a solubilizing agent, an isotonizing agent, and a pH adjusting agent, and is administered continuously for 5 to 14 days. The otologic liquid according to claim 1 or 2, wherein the otitis externa and/or otitis media is otitis externa and/or otitis media of a patient who has a history of treatment with antibiotics. Otitis externa and/or comprising administering a liquid preparation containing 10 to 20 mg per ml of levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient to a subject in need of administration. A method for preventing and/or treating otitis media. 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 prevention and/or treatment, levofloxacin Levofloxacin, a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized in that a liquid preparation containing 10 to 20 mg per ml as an active ingredient is administered to the subject. salts or solvates thereof.

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