Azithromycin-containing ophthalmic agent

Abstract

To provide an ophthalmic agent and an ophthalmic antibacterial agent that contain azithromycin and are administered in specific doses and dosage regimens for specific indications.SOLUTION: The present invention relates to an ophthalmic agent that contains azithromycin and ophthalmologically acceptable additives to prevent or treat one or more of a patient's blepharitis, hordeolum, and lacrimal pouchitis or to prevent the progression of the disease, the ophthalmic agent being applied to the patient twice daily for 2 days and then once daily for 12 days in an appropriate quantity once. The invention also relates to an ophthalmic antibacterial agent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides an azithromycin-containing ophthalmic preparation. Specifically, the present invention provides an azithromycin-containing ophthalmic preparation for preventing or treating one or more of blepharitis, hordeolum, and dacryocystitis, or inhibiting the progression of the disease, which is administered at a specific dose and by a specific administration method. The present invention also provides an ophthalmic antibacterial agent for preventing or treating one or more of blepharitis, hordeolum, and dacryocystitis, or inhibiting the progression of the disease, which is administered at a specific dose and by a specific administration method. [Background technology]

[0002] The eye is susceptible to a variety of infections, and various infections can occur in various internal and external ocular tissues, namely the eyelid, conjunctiva, cornea, and other ocular accessory tissues (eg, lacrimal sac).

[0003] Antibiotics are administered topically to the eye to treat eye infections. Macrolide antibiotics are known to be effective in treating eye infections, and examples thereof include azithromycin (Patent Documents 1 to 3). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 4,474,768 [Patent Document 2] U.S. Patent No. 4,517,359 [Patent Document 3] Special Publication No. 2002-540147 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide an ophthalmic preparation containing azithromycin, and an ophthalmic antibacterial agent, which are administered in specific doses and by specific administration methods for specific indications. [Means for solving the problem]

[0006] The present inventors have found that an ophthalmic composition containing azithromycin, when administered at a specific dose and by a specific method of administration, is useful for treating one or more of the diseases of blepharitis, hordeolum, and dacryocystitis. The present inventors have also found that an ophthalmic composition containing azithromycin, when administered at a specific dose and by a specific method of administration, is useful for inhibiting the causative bacteria of one or more of the diseases of blepharitis, hordeolum, and dacryocystitis.

[0007] That is, the present invention provides the following aspects, but is not limited to these.

[0008] (ophthalmic agent) [1] An ophthalmic preparation comprising azithromycin and an ophthalmologically acceptable excipient for preventing or treating any one or more of blepharitis, hordeolum, or dacryocystitis in a patient, or for inhibiting the progression of said disease, The ophthalmic preparation (hereinafter referred to as "the ophthalmic preparation of the present invention" in this specification) comprises applying an appropriate amount of the ophthalmic preparation to the patient twice a day for 2 days, and then once a day for 12 days. [2] The ophthalmic preparation according to [1], wherein the ophthalmic preparation is an eye drop or an eye ointment. [2-1] The ophthalmic preparation according to [1], wherein the ophthalmic preparation is an eye drop. [3] The ophthalmic preparation according to either [1] or [2], which contains at least polycarbophil as an additive. [4] The ophthalmic preparation according to any one of [1] to [3], wherein the concentration of the azithromycin is 0.01% (w / w) to 2.0% (w / w). [5] The ophthalmic preparation according to any one of [1] to [4], wherein the concentration of the azithromycin is 0.1% (w / w) to 1.0% (w / w). [5-1] The ophthalmic preparation according to any one of [1] to [4], wherein the concentration of the azithromycin is 1.0% (w / w). [6] The ophthalmic preparation according to any one of [1] to [5], wherein when the ophthalmic preparation is an eye drop, the appropriate amount for one application is one drop. [7] The ophthalmic preparation according to any one of [1] to [6], for suppressing one or more symptoms of secretions from the root of the eyelashes, eyelid margin congestion / eyelid redness, conjunctival congestion, congestion / redness, eyelid swelling, reflux secretions, redness and swelling of the lacrimal sac, eye pain, pain, foreign body sensation, or lacrimation. [7-1] The ophthalmic preparation according to [7], wherein the symptom is selected from the following (a) to (c): (a) If the patient has blepharitis, the symptoms include one or more of the following: discharge from the base of the eyelashes, redness of the eyelid margin, conjunctival hyperemia, foreign body sensation, or tearing; (b) if the patient has a stye, the symptom is one or more of the following: redness, eyelid swelling, eye pain, foreign body sensation, or tearing; (c) If the patient has dacryocystitis, the symptoms include one or more of reflux discharge, redness and swelling of the lacrimal sac, pain, or tearing. [8] The ophthalmic preparation according to any one of [1] to [7], wherein the azithromycin is anhydrous azithromycin or hydrate. [8-1] The ophthalmic preparation according to any one of [1] to [7], wherein the azithromycin is azithromycin hydrate. [9] The ophthalmic preparation according to any one of [1] to [8], wherein the patient is of Asian race. [9-1] The ophthalmic preparation according to any one of [1] to [8], wherein the patient is Japanese. [9-2] The ophthalmic preparation according to any one of [1] to [8], wherein the causative bacterium of the disease suffered by the patient is a bacterium originating from Japan.

[10] The ophthalmic preparation according to any one of [1] to [9], wherein the patient is a patient suffering from blepharitis.

[11] The ophthalmic preparation according to any one of [1] to [9], wherein the patient is a patient suffering from dacryocystitis and is about to undergo surgery.

[12] The ophthalmic preparation according to

[11] , wherein the patient is suffering from dacryocystitis and is a patient who has not yet undergone dacryocystorhinostomy or surgery to relieve nasolacrimal duct obstruction.

[13] The ophthalmic preparation according to any one of [1] to

[12] , wherein the ophthalmologically acceptable additive is one or more of a stabilizer, a buffer, a tonicity agent, a viscosity agent, a preservative, a solubilizing agent, a pH adjuster, or a solvent.

[14] The ophthalmic preparation according to any one of [1] to

[13] , further comprising another drug.

[15] The ophthalmic preparation according to any one of [1] to

[14] , wherein the other drug is one or more of an antiviral drug, an antifungal drug, an anesthetic drug, an anti-inflammatory drug, or an antiallergic drug.

[0009] (ophthalmic antibiotic)

[16] An ophthalmic antibacterial agent comprising azithromycin and an ophthalmologically acceptable excipient for preventing or treating or inhibiting the progression of any one or more of blepharitis, hordeolum, or dacryocystitis in a patient, The ophthalmic antibacterial agent (hereinafter referred to in this specification as "the ophthalmic antibacterial agent of the present invention") comprises administering an appropriate amount of the ophthalmic antibacterial agent to the patient twice a day for two days, and then once a day for 12 days.

[17] An ophthalmic antibacterial agent according to

[16] , wherein the causative bacteria is one or more of Staphylococcus, Streptococcus, Pneumococcus, Corynebacterium, Haemophilus influenzae, or Propionibacterium acnes. [Effects of the Invention]

[0010] The ophthalmic preparation containing azithromycin, characterized by a specific dosage and administration method of the present invention, is useful for safely and effectively preventing or treating one or more of blepharitis, hordeolum, or dacryocystitis, or inhibiting the progression of the disease. DETAILED DESCRIPTION OF THE INVENTION

[0011] (formulation) The ophthalmic agent or ophthalmic antibacterial agent of the present invention comprises azithromycin and an ophthalmologically acceptable excipient. The "azithromycin" contained as an active ingredient in the ophthalmic preparation of the present invention is a 15-membered ring macrolide compound generally named N-methyl-11-aza-10-deoxo-10-dihydroerythromycin, and is described in the above-mentioned Patent Documents 1 to 3. Azithromycin used in this specification may be in any form, such as an anhydrate, a hydrate, a solvate, or any other form, but is preferably in the hydrate form, for example. The hydrate form may be a monohydrate or a dihydrate.

[0012] The formulation of the ophthalmic agent or ophthalmic antibacterial agent of the present invention may be any formulation applicable to the eyes, specifically, eye drops, eye ointment, eye cream, Tenon's injection, fundus injection, etc., with eye drops or eye ointment being preferred, and eye drops being more preferred. Examples of the form of eye drops include aqueous eye drops, aqueous suspension eye drops, viscous eye drops, non-aqueous eye drops, non-aqueous suspension eye drops, and emulsion eye drops. The ophthalmic agent or ophthalmic antibacterial agent of the present invention is more preferably a viscous eye drop. The viscous ophthalmic solution may have a viscosity of about 500 to about 5,000 mPa s. The viscosity may be measured by Method 2 described in Section 2.53, Viscosity Measurement, of the Japanese Pharmacopoeia, Seventeenth Edition, General Test Methods, specifically, by using a cone-and-plate viscometer.

[0013] The ophthalmic preparation or ophthalmic antibacterial agent of the present invention contains a dose of azithromycin effective for treating, preventing, or inhibiting the progression of the target diseases described below. The dose varies depending on the type or severity of the target disease, the patient's age, weight, and sex, the dosage form, and the route of administration. A typical example of a dose is that the amount of azithromycin contained in the ophthalmic preparation or ophthalmic antibacterial agent of the present invention is generally 0.01% (w / w) to 2.0% (w / w) in concentration units, preferably 0.1% (w / w) to 1.0% (w / w), and typically 1.0% (w / w). For example, when the ophthalmic preparation or ophthalmic antibacterial agent of the present invention is formulated as eye drops, an effective amount is achieved in ocular tissues by administering one to two drops at a time, preferably one drop at a time. Here, the above-mentioned 1.0% (w / w) corresponds to 10.48 mg of azithromycin hydrate (corresponding to a potency of 10 mg of azithromycin) in 1 g of the ophthalmic agent or ophthalmic antibacterial agent of the present invention.

[0014] When the ophthalmic agent or ophthalmic antibacterial agent of the present invention is used for treatment, prevention, etc., it can be administered locally into the eye, more specifically, by instillation. Topical administration to the eye can be by instillation into the anterior side of the eye, the lower side of the upper eyelid, or the upper side of the lower eyelid, etc.

[0015] The ophthalmic agent or ophthalmic antibacterial agent of the present invention can be administered in the aforementioned appropriate single dose (e.g., one drop at a time) at least twice a day (preferably twice) for two days, and then at least once a day (preferably once) for 12 days or more (preferably, for example, 12 days), for a total of 14 days or more (preferably, for example, 14 days). In the case of twice-daily administration, the second administration is preferably at least 4 hours, more preferably at least 6 hours, and even more preferably at least 12 hours after the first administration. Usually, the second administration is administered at any time between 4 and 12 hours after the first administration, and preferably at any time between 6 and 12 hours after the first administration.

[0016] Generally, antibiotics are administered in a regimen consisting of multiple administrations of a specific dose of antibiotic in a specific manner. Furthermore, the required dose and administration regimen may vary depending on the type of antibiotic, the causative bacteria, and the target disease. To efficiently exert therapeutic efficacy, an ophthalmic agent or ophthalmic antibacterial agent that is effective against a broad spectrum of bacteria and ocular infections and can be administered in a shorter administration regimen is useful.

[0017] The ophthalmologically acceptable additives contained in the ophthalmic agent or ophthalmic antibacterial agent of the present invention may include, in addition to the active ingredient (e.g., azithromycin), a combination of various drugs (including pharmacologically active ingredients and physiologically active ingredients) and additives (e.g., stabilizers, buffers, isotonicity agents, thickeners, preservatives, solubilizers, pH adjusters, solvents, or bases) depending on various uses such as the target disease, as long as they do not interfere with the pharmacological effect, etc. These components can be appropriately blended within a concentration range that does not cause problems when administered topically to the eye, and the types of components are not particularly limited.

[0018] Examples of stabilizers include one or more compounds selected from the group consisting of sodium edetates (e.g., sodium edetate hydrate), parahydroxybenzoates (e.g., methylparaben or propylparaben), alcohols (e.g., chlorobutanol, benzyl alcohol, or phenylethyl alcohol), phenols (e.g., phenol or cresol), thimerosal, acetic anhydride, and sorbic acid, and a typical example of the stabilizer is sodium edetate hydrate.

[0019] Examples of buffering agents include one or more compounds of phosphoric acid, phosphate salts (e.g., sodium phosphate), citric acid (e.g., citric acid hydrate), citrate salts (e.g., sodium citrate hydrate), acetic acid, or ε-aminocaproic acid, but typical examples of buffering agents include citric acid hydrate, sodium citrate hydrate, and a combination of citric acid hydrate and sodium citrate hydrate.

[0020] Examples of tonicity agents include one or more of glycerin, propylene glycol, sodium chloride, calcium chloride, sorbitol, or mannitol (e.g., D-mannitol), and typical examples of tonicity agents include sodium chloride, D-mannitol, and a combination of sodium chloride and D-mannitol.

[0021] Examples of thickening agents include one or more compounds of cellulose polymers (e.g., hydroxypropylmethylcellulose or hydroxypropylcellulose), polyvinyl alcohol, polyvinylpyrrolidone, or polycarbophil, and a typical example of a thickening agent is polycarbophil.

[0022] Examples of preservatives (antiseptics) include one or more compounds of sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and chlorobutanol, and a typical example of a preservative is benzalkonium chloride.

[0023] Examples of solubilizing agents include one or more compounds such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, and polyoxyethylene(196)polyoxypropylene(67)glycol, and a typical example of the solubilizing agent is polyoxyethylene(196)polyoxypropylene(67)glycol.

[0024] Examples of pH adjusters include one or more compounds selected from the group consisting of hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, calcium hydroxide, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, and sodium bicarbonate, and a typical example of a pH adjuster is sodium hydroxide. The pH of the eye drops may be within the range acceptable for ophthalmic preparations, and is generally adjusted to 4.0 to 8.5, preferably 5.9 to 6.7.

[0025] When the ophthalmic preparation of the present invention is an eye drop, an example of the solvent is sterilized purified water.

[0026] The ophthalmic agent or ophthalmic antibacterial agent of the present invention preferably contains azithromycin and one or more components selected from the group consisting of D-mannitol, citric acid hydrate, sodium citrate hydrate, polycarbophil, sodium edetate hydrate, polyoxyethylene (196) polyoxypropylene (67) glycol, benzalkonium chloride, an isotonicity agent, and a pH adjuster, and has a pH of 5.9 to 6.7. It is more preferred that the ophthalmic agent or ophthalmic antibacterial agent contains azithromycin and at least polycarbophil, and has a pH of 5.9 to 6.7. It is particularly preferred that the ophthalmic agent or ophthalmic antibacterial agent contains azithromycin hydrate, D-mannitol, citric acid hydrate, sodium citrate hydrate, polycarbophil, sodium edetate hydrate, polyoxyethylene (196) polyoxypropylene (67) glycol, benzalkonium chloride, an isotonicity agent, and a pH adjuster, and has a pH of 5.9 to 6.7.

[0027] When the ophthalmic preparation of the present invention is an ointment, examples of the base include one or more compounds such as liquid paraffin, white petrolatum, and plastibase.

[0028] Furthermore, the ophthalmic preparation or ophthalmic antibacterial agent of the present invention may further contain one or more additional agents to enhance their efficacy. Examples of such additional agents include, but are not limited to, commonly known ophthalmic agents, such as antiviral agents, antifungal agents (components other than azithromycin), anesthetics, anti-inflammatory agents, antiallergic agents, steroids, analgesics, surfactants, chelating agents, or adjuvants, or combinations of two or more thereof. Specific examples of such additional agents in the case of eye drops include, but are not limited to, a vitamin C source, a vitamin E source, a vitamin A source, beta-carotene, a zinc source, or a copper source, or combinations of two or more thereof.

[0029] When used as an eye drop, if necessary, a compound for increasing the efficacy without causing eye pain may be contained, and examples thereof include, but are not limited to, one or more compounds selected from the group consisting of anti-inflammatory drugs (e.g., epsilon aminocaproic acid or diclofenac sodium), vasoconstrictors (e.g., tetrahydrozoline hydrochloride or phenylephrine hydrochloride), antiallergic drugs (e.g., sodium cromoglycate or ketotifen fumarate), antihistamines (e.g., chlorpheniramine maleate or diphenhydramine hydrochloride), and vitamins (e.g., pyridoxine hydrochloride, riboflavin phosphate, cyanocobalamin, or panthenol).

[0030] According to one embodiment, the eye drops of the present invention may be a sterile unit-dose eye drop containing no preservatives, or may be substantially free of benzalniconium chloride. The ophthalmic agent or ophthalmic antibacterial agent of the present invention is typically produced by adding any amounts of active ingredient, additive, and solvent in any order, optionally with stirring, and filling the resulting aqueous solution into an eye dropper container.

[0031] (disease) Target diseases contemplated by the present invention include ocular infections (e.g., anterior ocular infections). Specific examples of ocular infections include one or more of blepharitis, hordeolum, and dacryocystitis. These diseases are described, for example, in "Today's Guide to the Treatment of Ocular Diseases, Third Edition" (edited by Masato Oji, Hiroshi Goto, Masakazu Yamada, and Toru Noda; published by Igaku-Shoin Co., Ltd., published October 15, 2016) or "Guidelines for Clinical Evaluation of Antibacterial Eye Drops" (by Seiji Asari et al., Journal of the Japanese Ophthalmological Society, 2015; 119(4):273-86). Additionally, associated findings and symptoms of these target diseases include, for example, one or more of the following symptoms: discharge from the base of the eyelashes, eyelid margin hyperemia / eyelid redness, conjunctival hyperemia, hyperemia / redness, eyelid swelling, reflux discharge, redness and swelling of the lacrimal sac, eye pain, pain, foreign body sensation, or tearing.

[0032] Blepharitis is an inflammatory disease affecting the eyelid margin. The eyelid is the skin tissue that covers the upper and lower parts of the eyeball and protects the cornea. Blepharitis can be broadly divided into infectious bacterial causes and non-infectious causes, such as those associated with dermatological conditions. It can also be divided into anterior blepharitis, which occurs mainly at the base of the eyelashes; posterior blepharitis (meibomianitis), which occurs mainly at the meibomian glands; and medial and lateral canthitis, which occurs at the medial and lateral canthi. Staphylococcus is a typical cause of infectious bacterial blepharitis. Associated findings and symptoms of blepharitis include one or more of the following objective findings: discharge from the base of the eyelashes, eyelid margin hyperemia, eyelid redness, or conjunctival hyperemia. Subjective symptoms include one or more of the following: foreign body sensation or lacrimation.

[0033] A hordeolum is an acute suppurative inflammation of the sebaceous, sweat, or meibomian glands of the eyelid. Hordeolum is broadly divided into external and internal. External hordeolum is an acute suppurative inflammation of the Zeis glands (sebaceous glands) or Mol glands (sweat glands) around the eyelashes, while internal hordeolum is an acute suppurative inflammation of the meibomian glands. Reported causative bacteria of hordeolum include coagulase-negative Staphylococcus (CNS), Propionibacterium acnes, Corynebacterium, and Staphylococcus. Signs and symptoms associated with hordeolum include one or more of the following objective findings: hyperemia, redness, or eyelid swelling. Subjective symptoms include one or more of the following: eye pain, foreign body sensation, or tearing. If an abscess forms and does not drain naturally, surgical treatment may be required to incise and drain the pus.

[0034] Tears are produced in the lacrimal gland and moisten the surface of the eye. They are then absorbed through the lacrimal puncta at the inner corner of the eye, passing through the lacrimal canaliculi and into the lacrimal sac, a sac-like structure at the base of the nose. They then pass through the nasolacrimal duct below the lacrimal sac and into the nasal cavity. This pathway is called the lacrimal duct. Dacryocystitis is an inflammatory disease caused by bacterial infection within the lacrimal sac due to lacrimal duct obstruction. Acute dacryocystitis is a condition in which acute purulent inflammation spreads from the lacrimal sac to surrounding tissues. Reported causative bacteria include Staphylococcus aureus, Corynebacterium, and Streptococcus pneumoniae. Chronic dacryocystitis is a condition in which waste products and mucus accumulate in the lacrimal duct proximal to the site of stenosis or obstruction of the lacrimal sac or nasolacrimal duct, leading to bacterial overgrowth and chronic inflammation. Associated findings and symptoms of dacryocystitis include objective findings such as reflux secretions, redness, or swelling of the lacrimal sac, and subjective symptoms such as pain or tearing.

[0035] Representative causative bacteria of the target ocular diseases intended by the present invention are as described above, but are not limited to these. The distribution of causative bacteria of each target ocular disease varies depending on the region (e.g., Japan and the United States). Furthermore, even for the same bacterial species, the susceptibility to drugs may differ between Japan and the United States. The causative bacteria contemplated by the present invention include, but are not limited to, Staphylococcus (including coagulase-negative Staphylococcus (CNS) such as Staphylococcus aureus and Staphylococcus epidermidis), Streptococcus (including Streptococcus pneumoniae and Streptococcus pyogenes), Neisseria (including Neisseria ganorrhoeae), Moraxella (including Moraxella catarrhalis and Moraxella lacunae), and the like. lacunae), Corynebacterium, Haemophilus (including Haemophilus influenzae), Enterococcus, Bacillus, Pseudomonas, Serratia marcescens, Escherichia coli, or Propionibacterium (including Propionibacterium acnes). Preferably, the bacteria include one or more of Staphylococcus, Streptococcus, Pneumococcus, Corynebacterium, Haemophilus influenzae, and Propionibacterium acnes.

[0036] As used herein, "treating" a disease to be treated includes (1) eliminating one or more of the above-mentioned diseases, blepharitis, hordeolum, or dacryocystitis, and one or more associated symptoms; or (2) reducing or minimizing the severity of one or more of the above-mentioned diseases, blepharitis, hordeolum, or dacryocystitis, and one or more associated symptoms; "inhibiting the progression" includes (1) delaying the progression or onset of one or more of the above-mentioned diseases, blepharitis, hordeolum, or dacryocystitis, and one or more associated symptoms; and "preventing" includes (1) delaying the onset of one or more of the above-mentioned diseases, blepharitis, hordeolum, or dacryocystitis, and one or more associated symptoms; or (2) reducing, minimizing, or eliminating the occurrence or frequency of one or more of the above-mentioned diseases, blepharitis, hordeolum, or dacryocystitis, and one or more associated symptoms.

[0037] When the disease to be treated is dacryocystitis, the patient to whom the ophthalmic agent or ophthalmic antibacterial agent of the present invention is to be administered may be a patient who has not yet undergone surgical treatment. Preferably, when the disease to be treated is dacryocystitis, the patient to whom the ophthalmic agent or ophthalmic antibacterial agent of the present invention is to be administered is a patient who has not yet undergone dacryocystorhinostomy or surgery to relieve nasolacrimal duct obstruction. As described above, dacryocystitis is a disease caused by the accumulation of tears and secretions from the lacrimal duct proximal to the obstruction due to stenosis or obstruction of the nasolacrimal duct, which then develops as a result of bacterial infection. For adult dacryocystitis, antibacterial eye drops are administered to control bacterial infection until definitive surgical treatment (dacryocystorhinostomy or relief of nasolacrimal duct obstruction) is performed. The ophthalmic agent or ophthalmic antibacterial agent of the present invention is also useful as a treatment for dacryocystitis until surgical treatment.

[0038] As used herein, the term "subject (patient)" intended for treatment or the like refers to a mammal, including humans and non-human animals, with humans being preferred. Examples of subjects include adults. Furthermore, in terms of the target disease and causative bacteria, the subject is preferably a human in Japan who has developed blepharitis, hordeolum, or dacryocystitis. For example, the subject may be a person of Asian descent, preferably Japanese, in whom the causative bacteria of the disease are bacteria originating in Japan or equivalent bacteria. Alternatively, the subject may be a human residing in Japan who has been diagnosed with blepharitis, hordeolum, or dacryocystitis. [Example]

[0039] The present invention will be explained in more detail below by way of test examples and examples, but the present invention is not limited to these test examples and examples. The compounds, animals (eg, rabbits) and bacterial species used in the Test Examples and Examples were either commercially available or prepared according to known methods.

[0040] (Test Example 1) Confirmation of penetration of azithromycin into ocular tissues The transfer of azithromycin, the active ingredient of the present invention, to ocular tissues such as the eyelids was confirmed. Levofloxacin and ofloxacin, listed below, were selected as comparative compounds for comparison. This experiment was conducted with the approval of the Ethics Committee for Animal Experiments based on the Act on the Welfare and Management of Animals (Act No. 105 of October 1, 1973, last revised: Act No. 38 of June 12, 2013).

[0041] (1) Test method (Specimen) As the formulation of the present invention, 1% azithromycin eye drops were used, and as comparative formulations, 1.5% levofloxacin eye drops (Cravit™ eye drops 1.5%) (manufacturer: Santen Pharmaceutical Co., Ltd.) and 0.3% ofloxacin eye ointment (Tarivid™ eye ointment 0.3%) (manufacturer: Santen Pharmaceutical Co., Ltd.) were used. The 1% azithromycin ophthalmic solution was prepared by mixing azithromycin hydrate as the active ingredient with the additives D-mannitol, citric acid hydrate, sodium citrate hydrate, polycarbophil, sodium edetate hydrate, polyoxyethylene (196) polyoxypropylene (67) glycol, benzalkonium chloride, an isotonic agent, and a pH adjuster in a conventional manner. 1% azithromycin ophthalmic solution contained 10.48 mg of azithromycin hydrate (10 mg potency as azithromycin) per 1 g of the solution.

[0042] (Animal experiments) 1) The test system used was male Japanese white rabbits (obtained from Kitayama Labes) weighing 2.0-2.5 kg. The temperature and relative humidity of the rearing environment were 22°C ± 3°C, 55% ± 10%, lights on at 8:00, lights off at 20:00, one rabbit per cage, and they were fed 100 g of food per day and provided with water via an automatic watering system. 2) After confirming that the anterior segment of the eye was not damaged, one of the above eye drops was administered to both eyes using a micropipette. After administration, the animals were forced to blink twice. Each group consisted of four eyes. 1% azithromycin ophthalmic solution: Dose: 30 μL, Administration site: near the upper bulbar conjunctiva; 1.5% levofloxacin ophthalmic solution: Dose: 30 μL, Administration site: near the upper bulbar conjunctiva; 0.3% ofloxacin ophthalmic ointment: Dose: 46 μL (approximately 40 mg), Administration site: In the lower conjunctival sac 3) Ocular tissues were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration using the following procedure. Somnopentyl™ anesthetic injection (manufacturer: Kyoritsu Pharmaceutical Co., Ltd.) was administered intravenously through the ear vein, and the absence of cardiac activity was confirmed by palpation. Next, the ocular surface and conjunctival sac were washed with at least 40 mL of saline. The aqueous humor, conjunctiva, eyelid, and cornea were then collected. Each tissue was frozen and stored in a deep freezer until use.

[0043] (analysis) 1) Standard material Azithromycin dihydrate (manufacturer: Tokyo Chemical Industry Co., Ltd.) (purity: 98.2%) was used as the standard substance for azithromycin concentration analysis, and ofloxacin (manufacturer: Tokyo Chemical Industry Co., Ltd.) (purity: 99.7%) was used as the standard substance for ofloxacin and levofloxacin concentration analysis. Phenytoin (manufacturer: Fujifilm Wako Pure Chemical Industries Co., Ltd.) (standard: Wako special grade) was used as the internal standard (IS).

[0044] 2) Preparation of analytical samples If necessary, aqueous humor samples were prepared by diluting the aqueous humor with water and mixing it with acetonitrile, IS solution, and 1 mmol / L ammonium formate solution / formic acid (1000:1, v / v) for pretreatment. In addition, ocular tissue (eyelid, cornea, or conjunctiva) and water were added to a tube containing zirconia beads, and the ocular tissue was disrupted using a bead homogenizer to prepare ocular tissue homogenates. The ocular tissue homogenates were added to a 1 mmol / L ammonium formate / formic acid solution (1000:1, v / v), and then acetonitrile and IS solution were added and mixed. After pretreatment using an Oasis™ HLB μElution Plate (manufacturer: Waters Corp.), eyelid, corneal, and conjunctival samples were prepared.

[0045] 3) Liquid chromatography tandem mass spectrometry conditions The pretreated sample was injected into a liquid chromatography tandem mass spectrometer and measured. The liquid chromatography conditions were as follows: Column: ACQUITY UPLC™ HSS T3 1.8 μm 2.1 x 50 mm column Mobile phase A: 1 mmol / L ammonium formate solution / formic acid (1000:1, v / v) Mobile phase B: acetonitrile / formic acid (1000:1, v / v)

[0046] 4) Calculation of quantitative values A calibration curve was prepared using Analyst software (version 1.6.2, manufactured by AB SCIEX Pte. Ltd.), and tissue concentrations were calculated from the calibration curve and the peak area ratio of each sample. Noncompartmental analysis was performed using Phoenix WinNonlin Build 8.1.0 software (manufacturer: Certara, Princeton, NJ, USA), and the area under the drug concentration-time curve (AUC) from 0 to 24 hours after administration was calculated for each tissue and specimen. 0-24 ) was calculated.

[0047] (result) AUC 0-24 The results are shown in Table 1 below.

[0048] [Table 1]

[0049] Levofloxacin eyelid AUC 0-24 is the AUC of aqueous humor 0-24 The efficacy was approximately 7.5 times higher for ofloxacin, approximately 270 times higher for ofloxacin, and approximately 850 times higher for azithromycin. Therefore, it was found that azithromycin penetrates more easily into the eyelids than into the aqueous humor. It was also found that azithromycin penetrates more easily into the eyelids than other drugs.

[0050] Example 1 Confirmation of the therapeutic effect of 1% azithromycin ophthalmic solution on various eye diseases (the purpose) The efficacy of the eye drops of the present invention as an ophthalmic agent was investigated in patients with bacterial blepharitis, hordeolum, or dacryocystitis by administering one drop of 1% azithromycin ophthalmic solution, prepared in the same manner as in Test Example 1, twice a day for two days, and then one drop once a day for 12 days.

[0051] (subject) Patients were diagnosed with bacterial blepharitis, hordeolum, or dacryocystitis, and had a score of 1 or higher for any of the objective findings in the eye treated with the eye drops. The main exclusion criteria were as follows: i) those for whom clinical findings in any eye could not rule out ocular infection other than the target disease; ii) those with corneal epithelial defects (excluding superficial punctate keratopathy), especially corneal ulcers, in the eye treated with the eye drops. The efficacy analysis population consisted of 32 cases overall, 10 cases of blepharitis, 10 cases of dacryocystitis, and 12 cases of hordeolum.

[0052] (Evaluation criteria) The criteria for scoring findings and symptoms shown in the Guidelines for Antibacterial Eye Drops (Guidelines for Clinical Evaluation of Antibacterial Eye Drops, by Asari Seishi et al., Journal of the Japanese Ophthalmological Association. 2015; 119(4): 273-86) were used (Tables 2, 3, and 4 below). The findings and symptoms of blepharitis were scored on a 5-point scale, with objective findings including discharge from the base of the eyelashes, eyelid margin congestion, eyelid redness, and conjunctival congestion, and subjective symptoms including foreign body sensation and lacrimation. The findings and symptoms of styes were scored on a 5-point scale, with objective findings of redness, congestion, and swelling of the eyelid, and subjective symptoms of eye pain, foreign body sensation, and lacrimation. The findings and symptoms of dacryocystitis were scored using a 5-point scale, with objective findings including reflux secretions, redness and swelling of the lacrimal sac, and subjective symptoms including pain and tearing.

[0053] In addition, efficacy was evaluated according to the clinical efficacy evaluation criteria set forth in the guidelines for antibacterial eye drops, and clinical efficacy was assessed on a five-point scale: markedly effective, effective, ineffective, worsening, and indeterminable (Table 5).

[0054] The bacterial tests and symptom observations were carried out according to the following methods. 1) Bacteriological testing The reddened, swollen area of the eye or the pus that came out of it was collected in a culture medium. The collected samples were used for bacterial isolation and identification. 2) Symptom observation The doctor assessed the objective findings and subjective symptoms of the eye administered with eye drops according to the tables (Tables 2, 3, and 4 below) in the Guidelines for Clinical Evaluation of Antibacterial Eye Drops (see above: Guidelines for Clinical Evaluation of Antibacterial Eye Drops, by Asari Seishi et al., 273-86), and the score for each symptom was entered into the case report form. The objective findings with the highest symptom scores in the above tables on the day of administration were considered to be the main symptom. The examination was performed before the bacterial test.

[0055] [Table 2]

[0056] [Table 3]

[0057] [Table 4]

[0058] [Table 5]

[0059] (Statistical method) 1) Clinical efficacy (primary endpoint) The clinical efficacy rate (proportion of markedly effective and effective) and 95% confidence interval were calculated for all subjects or for each target disease based on the clinical efficacy criteria (Table 5). 2) Number of days until bacteria detected at the first visit disappears (secondary endpoint) For clinical isolates detected by bacterial testing at the first visit (start date of administration) for all subjects or for each target disease, the number of days from the start date of administration until the bacteria disappeared for each bacterial species was calculated, and this was taken as the number of days until the bacteria detected at the first visit disappeared. 3) Number of days until the main symptoms disappear (secondary endpoint) The number of days from the start of administration until the main symptom score reached 0 was calculated for all subjects or for each target disease. 4) Symptom score 1 / n days (secondary endpoint) For all subjects or for each target disease, the number of days from the start of administration until the total symptom score reached 1 / 2, 1 / 3, or 1 / 4 of the score at the first visit (start of administration) was calculated. The total symptom score is the sum of the scores for objective findings and subjective symptoms (Tables 2 to 4). Hereinafter, this will also be referred to as the "symptom score."

[0060] (result) Based on the clinical efficacy evaluation criteria, the disappearance of detected bacteria (Table 7), disappearance of main symptoms (Table 8), and total symptom score (Table 9) were used to determine whether the treatment was markedly effective, effective, ineffective, or worsening, and the clinical efficacy rates (the percentage of cases judged to be markedly effective or effective) are shown in Table 6. The combined efficacy rates for markedly effective and effective clinical efficacy were 70.0% for blepharitis, 90.0% for hordeolum, and 50.0% for dacryocystitis, for an overall efficacy of 68.8%.

[0061] [Table 6]

[0062] The number of days until the bacteria detected at the initial visit had disappeared is shown in Table 7. In the case of blepharitis, the disappearance rates were 70.0% on day 3, 80.0% on day 7, and 100.0% on day 14. In the case of hordeolum, the disappearance rates were 60.0% on day 3, 100.0% on day 7, and 100.0% on day 14. In the case of dacryocystitis, the disappearance rates were 75.0% on day 3, and 91.7% on days 7 and 14. Overall, the disappearance rates were 68.8% on day 3, 90.6% on day 7, and 96.9% on day 14. All subjects except one with dacryocystitis had disappeared from the bacteria detected at the initial visit by day 14.

[0063] [Table 7]

[0064] The results of the number of days until the main symptoms disappeared are shown in Table 8. For blepharitis, the numbers were 10.0% on day 7 and 70.0% on day 14; for hordeolum, the numbers were 10.0% on day 7 and 60.0% on day 14; for dacryocystitis, the numbers were 8.3% on days 3 and 7 and 16.7% on day 14. Overall, the numbers were 3.1% on day 3, 9.4% on day 7 and 46.9% on day 14, meaning that the main symptoms disappeared in approximately half of the subjects by day 14.

[0065] [Table 8]

[0066] The symptom score 1 / n days for each target disease are shown in Table 9. For blepharitis, the symptom score 1 / n days on day 14 was 90.0% for 1 / 2 day, 90.0% for 1 / 3 day, and 90.0% for 1 / 4 day; for styes, it was 90.0% for 1 / 2 day, 90.0% for 1 / 3 day, and 80.0% for 1 / 4 day; and for dacryocystitis, it was 58.3% for 1 / 2 day, 33.3% for 1 / 3 day, and 16.7% for 1 / 4 day.

[0067] [Table 9]

[0068] From the results of the above test examples and examples, it was found that administering the ophthalmic preparation of the present invention (e.g., eye drops) one drop at a time, twice a day for two days, and then one drop at a time, once a day for 12 days, can suppress the number of viable bacteria in intraocular tissues (e.g., corneal tissue), and can prevent or treat blepharitis, hordeolum, and dacryocystitis, or suppress the progression of these diseases. [Industrial Applicability]

[0069] The azithromycin-containing ophthalmic preparation of the present invention is useful as a medicine for preventing or treating eye infections (e.g., one or more of blepharitis, hordeolum, and dacryocystitis) or suppressing the progression of such diseases.

Claims

1. An ophthalmic preparation for preventing or treating any one or more of blepharitis, hordeolum, or dacryocystitis in a patient, or for inhibiting the progression of said disease, comprising azithromycin and an ophthalmologically acceptable excipient, applying the ophthalmic preparation to the patient in a single dose twice a day for two days, and then once a day for 12 days.

2. The ophthalmic preparation according to claim 1 , wherein the ophthalmic preparation is an eye drop.

3. 3. The ophthalmic preparation according to claim 1, which comprises at least polycarbophil as an additive.

4. The ophthalmic preparation according to any one of claims 1 to 3, wherein the concentration of the azithromycin is 0.01% (w / w) to 2.0% (w / w).

5. The ophthalmic preparation according to any one of claims 1 to 4, wherein the concentration of the azithromycin is 0.1% (w / w) to 1.0% (w / w).

6. The ophthalmic preparation according to any one of claims 1 to 5, wherein the ophthalmic preparation is an eye drop, and the appropriate amount for one administration is one drop.

7. The ophthalmic preparation according to any one of claims 1 to 6, for suppressing one or more symptoms of secretions from the roots of eyelashes, eyelid margin congestion / eyelid redness, conjunctival congestion, congestion / redness, eyelid swelling, reflux secretions, redness and swelling of the lacrimal sac, eye pain, pain, foreign body sensation, or lacrimation.

8. The ophthalmic agent according to any one of claims 1 to 7, wherein the azithromycin is anhydrous azithromycin or hydrate.

9. The ophthalmic preparation according to any one of claims 1 to 8, wherein the patient is Japanese.

10. The ophthalmic agent according to any one of claims 1 to 9, wherein the patient is a patient suffering from blepharitis.

11. The ophthalmic agent according to any one of claims 1 to 9, wherein the patient is a patient suffering from dacryocystitis and is undergoing preoperative surgery.

12. The ophthalmic agent according to claim 11, wherein the patient is suffering from dacryocystitis and is a patient who has not yet undergone dacryocystorhinostomy or nasolacrimal duct obstruction relief surgery.

13. The ophthalmic preparation according to any one of claims 1 to 12, wherein the ophthalmologically acceptable additive is one or more of a stabilizer, a buffering agent, a tonicity adjusting agent, a viscosity agent, a preservative, a solubilizing agent, a pH adjusting agent, or a solvent.

14. The ophthalmic preparation according to any one of claims 1 to 13, further comprising another drug.

15. The ophthalmic agent according to any one of claims 1 to 14, wherein the additional drug is one or more of an antiviral drug, an antifungal drug, an anesthetic drug, an anti-inflammatory drug, or an antiallergic drug.

16. An ophthalmic antibacterial agent for preventing or treating or inhibiting the progression of any one or more of blepharitis, hordeolum, or dacryocystitis in a patient, comprising azithromycin and an ophthalmologically acceptable excipient, applying the ophthalmic antibacterial agent to the patient in a single appropriate dose twice daily for two days, followed by once daily for 12 days.

17. The ophthalmic antibacterial agent according to claim 16, wherein the causative bacteria is one or more of the following bacteria: Staphylococcus, Streptococcus, Pneumococcus, Corynebacterium, Haemophilus influenzae, and Propionibacterium acnes.

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