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 ophthalmic agent containing azithromycin. Specifically, the present invention provides an ophthalmic agent containing azithromycin for preventing or treating one or more of blepharitis, hordeolum, or dacryocystitis, or suppressing the progression of the disease, which is characterized by being administered at a specific dose and usage. Further, the present invention also provides an ophthalmic antibacterial agent for preventing or treating one or more of blepharitis, hordeolum, or dacryocystitis, or suppressing the progression of the disease, which is characterized by being administered at a specific dose and usage.

Background Art

[0002] The eye is susceptible to various infectious diseases, and various infectious diseases can occur in various eye tissues inside and outside the eye, that is, the eyelid, conjunctiva, cornea, and other eye accessory tissues (for example, the lacrimal sac).

[0003] For the treatment of eye infectious diseases, topical administration of antibiotics to the eye is performed. Macrolide antibiotics are known as effective antibiotics for the treatment of eye infectious diseases, and for example, azithromycin can be mentioned (Patent Documents 1 to 3).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0005] The present invention aims to provide an ophthalmic agent containing azithromycin and an ophthalmic antibacterial agent, which are administered at specific dosages and usage methods for specific indications.

Means for Solving the Problems

[0006] The inventors have found that an ophthalmic composition containing azithromycin, when administered at specific dosages and usage methods, is useful for treating one or more of the diseases such as blepharitis, hordeolum, or dacryocystitis. Further, the inventors have also found that an ophthalmic composition containing azithromycin, when administered at specific dosages and usage methods, is useful for suppressing the causative bacteria of one or more of the diseases such as blepharitis, hordeolum, or dacryocystitis.

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

[0008] (Ophthalmic Agent) [1] An ophthalmic agent containing azithromycin and an ophthalmically acceptable additive for preventing or treating one or more of the diseases such as blepharitis, hordeolum, or dacryocystitis in a patient, or suppressing the progression of the disease, wherein the ophthalmic agent is applied to the patient in an appropriate amount once, twice a day for 2 days, and then once a day for 12 days (hereinafter referred to as "the ophthalmic agent of the present invention" in this specification). [2] The ophthalmic agent according to [1], wherein the ophthalmic agent is eye drops or an eye ointment. [2-1] The ophthalmic agent according to [1], wherein the ophthalmic agent is eye drops. [3] The ophthalmic agent according to any one of [1] or [2], wherein at least polycarbophil is included as an additive. [4] The ophthalmic agent 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 agent according to any one of [1] to [4], wherein the concentration of the azithromycin is 0.1% (w / w) to 1.0% (w / w). The ophthalmic agent according to any one of [1] to [4], wherein the concentration of azithromycin is 1.0% (w / w). The ophthalmic agent according to any one of [1] to [5], wherein when the ophthalmic agent is eye drops, the appropriate amount per application is 1 drop per time. The ophthalmic agent according to any one of [1] to [6], which is used for suppressing one or more of the following symptoms: secretion at the root of the eyelashes, eyelid margin congestion / eyelid redness, conjunctival congestion, congestion / redness, eyelid swelling, reflux secretion, redness and swelling of the lacrimal sac, eye pain, pain, foreign body sensation, or tearing. The ophthalmic agent according to [7], wherein the symptoms are selected from the following (a) to (c): (a) When the patient has blepharitis, the symptoms are one or more of the following symptoms: secretion at the root of the eyelashes, eyelid margin congestion / eyelid redness, conjunctival congestion, foreign body sensation, or tearing; (b) When the patient has a hordeolum, the symptoms are one or more of the following symptoms: congestion / redness, eyelid swelling, eye pain, foreign body sensation, or tearing; (c) When the patient has dacryocystitis, the symptoms are one or more of the following symptoms: reflux secretion, redness and swelling of the lacrimal sac, pain, or tearing. The ophthalmic agent according to any one of [1] to [7], wherein the azithromycin is azithromycin anhydride or azithromycin hydrate. The ophthalmic agent according to any one of [1] to [7], wherein the azithromycin is azithromycin hydrate. The ophthalmic agent according to any one of [1] to [8], wherein the patient is of the yellow race. The ophthalmic agent according to any one of [1] to [8], wherein the patient is Japanese. The ophthalmic agent according to any one of [1] to [8], wherein the causative bacterium of the disease the patient has is a bacterium derived from Japan. The ophthalmic agent according to any one of [1] to [9], wherein the patient has blepharitis.

[11] The ophthalmic preparation according to any one of [1] to [9], wherein the patient is a pre-surgical patient suffering from dacryocystitis.

[12] The ophthalmic preparation described in

[11] , wherein the patient is suffering from dacryocystitis and is a patient prior to surgery for dacryocystorhinostomy or relieving 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, an isotonicity 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 Antibacterial Agents)

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

[17] An ophthalmic antibiotic described in

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

[0010] The ophthalmic preparation containing azithromycin, characterized by the specific dosage and administration method of the present invention, is useful for safely and effectively preventing or treating any one or more of the following diseases: blepharitis, styes, or dacryocystitis, or inhibiting the progression of said diseases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] (Formulation) The ophthalmic agent or ophthalmic antibacterial agent of the present invention contains azithromycin and ophthalmically acceptable additives. The "azithromycin" contained as an active ingredient in the ophthalmic agent of the present invention is generally a 15-membered macrolide compound named N-methyl-11-aza-10-deoxo-10-dihydroerythromycin, which is described in Patent Documents 1 to 3 above. Azithromycin used in the present specification can take any form of its anhydride, hydrate, solvate and other forms, but for example, its hydrate form is preferred. The hydrate form may be a monohydrate form or a dihydrate form.

[0012] The formulation form of the ophthalmic agent or ophthalmic antibacterial agent of the present invention includes any formulation form applicable to the eye, specifically, eye drops, eye ointments, eye cream agents, Tenon's injection agents, and fundus injection agents, etc. Eye drops or eye ointments are preferred, and eye drops are more preferred. The form of the eye drops includes aqueous eye drops, aqueous suspension eye drops, viscous eye drops, non-aqueous eye drops, non-aqueous suspension eye drops or emulsion eye drops, etc. The ophthalmic agent or ophthalmic antibacterial agent of the present invention is more preferably a viscous eye drop. The viscous eye drop may have a viscosity of about 500 to about 5000 mPa·s. The viscosity can be measured by the second method described in the General Test Method 2.53 Viscosity Measurement Method of the 17th Revised Japanese Pharmacopoeia, specifically, it can be measured by a cone and plate viscometer.

[0013] The ophthalmic agent or ophthalmic antibacterial agent of the present invention contains a dose of azithromycin effective for treating, preventing or suppressing the progression of the target diseases described below intended by the present invention. Although the dose varies depending on the type or severity of the target disease, the age, weight, sex of the patient, dosage form, administration route, etc., examples of typical doses include that the amount of azithromycin contained in the ophthalmic agent or ophthalmic antibacterial agent of the present invention is usually 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 dosage form of the ophthalmic agent or ophthalmic antibacterial agent of the present invention is eye drops, an appropriate amount per application is 1 to 2 drops per application, preferably 1 drop per application, to reach an effective amount in the eye tissue. Here, the 1.0% (w / w) corresponds to 10.48 mg of azithromycin hydrate (equivalent to the 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 or prevention, etc., it can be administered locally into the eye, more specifically, by eye drops. Local administration to the eye can be performed by eye drop administration to the front side of the eye, under the upper eyelid, or above the lower eyelid, etc.

[0015] As the administration method of the ophthalmic agent or ophthalmic antibacterial agent of the present invention, the above-mentioned appropriate amount per application (for example, 1 drop per application) is administered 2 or more times a day (preferably 2 times) for 2 days, and then 1 or more times a day (preferably 1 time) for 12 days or more (preferably for example 12 days) for a total of 14 days or more (preferably for example 14 days). Here, in the administration twice a day, the timing of the second administration is at least 4 hours after the first administration, preferably at least 6 hours after, more preferably at least 12 hours after. Usually, the timing of the second administration is any time from 4 hours to 12 hours after the first administration, preferably any time from 6 hours to 12 hours after the first administration.

[0016] Generally, the administration of antibiotics requires a dosing schedule that consists of administering a specific dose of the antibiotic multiple times in a specific manner. Also, the dosing schedule can vary depending not only on the type of antibiotic, but also on the dose and method required by the causative bacterium and the target disease. In order to efficiently exhibit therapeutic efficacy, ophthalmic agents or ophthalmic antibacterial agents that are effective against a wide range of bacterial spectra and eye infections and can be administered in a dosing schedule with fewer administrations are useful.

[0017] As ophthalmically acceptable additives contained in the ophthalmic agent or ophthalmic antibacterial agent in the present invention, as long as the pharmacological effects and the like are not hindered, in addition to the active ingredient (for example, azithromycin), various drugs (including pharmacological active ingredients and physiologically active ingredients) and additives (for example, stabilizers, buffers, isotonic agents, thickeners, preservatives, solubilizing agents, pH adjusters, solvents, or bases) may be combined and contained according to various uses such as the target disease. These components can be appropriately formulated within a concentration range that poses no problem for ocular topical administration, and the types of components are not particularly limited.

[0018] Examples of stabilizers include any one or more compounds of sodium edetates (for example, sodium edetate hydrate), para-hydroxybenzoic acid esters (for example, methylparaben or propylparaben), alcohols (for example, chlorobutanol, benzyl alcohol, or phenylethyl alcohol), phenols (for example, phenol or cresol), thimerosal, acetic anhydride, or sorbic acid. However, a typical example of a stabilizer is sodium edetate hydrate.

[0019] Examples of buffers include any one or more compounds of phosphoric acid, phosphates (for example, sodium phosphate), citric acid (for example, citric acid hydrate), citrates (for example, sodium citrate hydrate), acetic acid, or ε-aminocaproic acid. However, typical examples of buffers include citric acid hydrate and sodium citrate hydrate, and combinations of citric acid hydrate and sodium citrate hydrate.

[0020] Examples of isotonic agents include any one or more compounds of glycerin, propylene glycol, sodium chloride, calcium chloride, sorbitol, or mannitol (e.g., D-mannitol). Typical examples of isotonic agents include sodium chloride and D-mannitol, and combinations of sodium chloride and D-mannitol are included.

[0021] Examples of thickeners include any one or more compounds of cellulose polymers (e.g., hydroxypropyl methylcellulose or hydroxypropyl cellulose), polyvinyl alcohol, polyvinyl pyrrolidone, or polycarbophil. A typical example of a thickener is polycarbophil.

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

[0023] Examples of solubilizers include any one or more compounds of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, or polyoxyethylene (196) polyoxypropylene (67) glycol. A typical example of a solubilizer is polyoxyethylene (196) polyoxypropylene (67) glycol.

[0024] Examples of pH adjusters include any one or more compounds such as hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, calcium hydroxide, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, or sodium bicarbonate. A typical example of a pH adjuster is sodium hydroxide. The pH of the eye drops may be within the range acceptable as an ophthalmic preparation, but is usually preferably adjusted to 4.0 to 8.5, more preferably 5.9 to 6.7.

[0025] Examples of solvents include, when the ophthalmic agent of the present invention is an eye drop, for example, sterilized purified water.

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

[0027] Examples of bases include, when the ophthalmic agent of the present invention is an ointment, for example, any one or more compounds such as liquid paraffin, white petrolatum, or plastibase.

[0028] Furthermore, the ophthalmic agent or ophthalmic antibacterial agent of the present invention may further contain one or more other agents for increasing their respective efficacies. Examples of such other agents include, but are not limited to, antiviral agents, antifungal agents (components other than azithromycin), anesthetics, anti-inflammatory agents, anti-allergy agents, steroids, analgesics, surfactants, chelating agents, or adjuvants, or combinations of two or more thereof, which are generally known as ophthalmic agents. Specific examples of such other 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 eye drops, it may contain, if necessary, a compound for increasing the efficacy within a range that does not cause eye pain. Examples include, but are not limited to, any one or more of anti-inflammatory agents (e.g., epsilon-aminocaproic acid or diclofenac sodium), vasoconstrictors (e.g., tetrahydrozoline hydrochloride or phenylephrine hydrochloride), anti-allergy agents (e.g., sodium cromoglycate or ketotifen fumarate), antihistamine agents (e.g., chlorpheniramine maleate or diphenhydramine hydrochloride), or vitamins (e.g., pyridoxine hydrochloride, riboflavin phosphate, cyanocobalamin, or panthenol).

[0030] According to one embodiment, the eye drops of the present invention can also be a preservative-free, sterile unit-dose type eye drops. Also, according to one embodiment, the eye drops of the present invention can be eye drops substantially free of benzalkonium chloride. The ophthalmic agent or ophthalmic antibacterial agent of the present invention is typically produced by adding any amount of the active ingredient, additives, and solvent in any order with stirring as necessary, and filling the resulting aqueous solution into an eye drop container.

[0031] (Disease) The target diseases intended by the present invention include eye infections (e.g., anterior eye infections). Specific examples of eye infections include any one or more of blepharitis, hordeolum, or dacryocystitis. Regarding these diseases, for example, they are described in "Today's Guidelines for the Treatment of Eye Diseases, 3rd Edition" (edited by Masato Ohji, Hiroshi Goto, Masakazu Yamada, Toru Noda; publisher: Medical Book Publishing Co., Ltd., release date: October 15, 2016) or "Guidelines on the Clinical Evaluation Method of Antibacterial Eye Drops" (written by Seiji Asari et al., Journal of the Japanese Ophthalmological Society. 2015;119(4):273 - 86). Also, as the related findings and symptoms seen in these target diseases, for example, one or more of the symptoms such as secretions at 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 area, eye pain, pain, foreign body sensation, or tearing can be mentioned.

[0032] Blepharitis is an inflammatory disease centered on the eyelid margin. The eyelid is a skin tissue that covers the upper and lower parts of the eyeball and protects the cornea. The causes of blepharitis are roughly classified into infectious ones caused by bacteria and non - infectious ones that are combined with, for example, dermatological diseases. It can also be divided into anterior blepharitis occurring mainly at the root of the eyelashes, posterior blepharitis (meibomian adenitis) occurring mainly in the meibomian glands, and inner (outer) canthal blepharitis occurring at the inner (outer) canthus. As the cause of infectious blepharitis by bacteria, Staphylococcus is typical. The related findings and symptoms of blepharitis include, as objective findings, for example, any one or more of secretions at the root of the eyelashes, eyelid margin congestion / eyelid redness, or conjunctival congestion, and as subjective symptoms, any one or more of foreign body sensation or tearing.

[0033] A hordeolum is an acute suppurative inflammation of the sebaceous glands, sweat glands, or meibomian glands of the eyelid. Hordeolums are broadly classified into external hordeolums and internal hordeolums. In external hordeolums, acute suppurative inflammation occurs in the Zeis glands (sebaceous glands) or Moll glands (sweat glands) around the eyelashes, and in internal hordeolums, it occurs in the meibomian glands. The causative bacteria of hordeolums include coagulase-negative staphylococci (CNS), Propionibacterium acnes, Corynebacterium spp., and Staphylococcus spp. The related findings and symptoms of hordeolums include, as objective findings, for example, one or more of hyperemia / erythema or eyelid swelling, and, as subjective symptoms, one or more of eye pain, foreign body sensation, or tearing. When an abscess forms and spontaneous drainage is not observed, surgical treatment may be performed for incision and drainage.

[0034] Tears are produced by the lacrimal glands. After moistening the surface of the eyes, they are sucked in through the lacrimal puncta at the inner corners of the eyes, pass through the lacrimal ducts, and reach the lacrimal sac, a sac-like tissue located near the root of the nose. Then, they pass through the nasolacrimal duct below the lacrimal sac and flow into the nasal cavity. The path through which such tears pass is called the lacrimal passage. Dacryocystitis is an inflammatory disease in which bacteria infect the lacrimal sac due to an obstruction in the lacrimal passage. Acute dacryocystitis is a state in which acute suppurative inflammation spreads from the lacrimal sac to the surrounding tissues. The causative bacteria reported include Staphylococcus aureus, Corynebacterium spp., and Streptococcus pneumoniae. Chronic dacryocystitis is a state in which waste products and mucus accumulate in the lacrimal passage proximal to the stenotic / obstructed site of the lacrimal sac and nasolacrimal duct, and bacteria abnormally proliferate in the lacrimal passage, resulting in chronic inflammation. The related findings and symptoms of dacryocystitis include, as objective findings, for example, one or more of reflux secretions, erythema of the lacrimal sac area, or swelling, and, as subjective symptoms, one or more of pain or tearing.

[0035] The representative causative bacteria of the target eye diseases intended by the present invention are as described above, but are not limited thereto. The causative bacteria of each target eye disease differ in the distribution of bacterial species in different regions (e.g., Japan and the United States). Also, for the same bacterial species, the susceptibility to drugs may differ between Japan and the United States. The causative bacteria intended by the present invention are not limited to the following, but include, for example, bacteria of the genus Staphylococcus (including coagulase-negative Staphylococcus (CNS) such as Staphylococcus aureus and Staphylococcus epidermidis), bacteria of the genus Streptococcus (including Streptococcus pneumoniae and Streptococcus pyogenes), bacteria of the genus Neisseria (including Neisseria gonorrhoeae), bacteria of the genus Moraxella (including Moraxella catarrhalis and Moraxella lacunata), bacteria of the genus Corynebacterium, bacteria of the genus Haemophilus (including Haemophilus influenza), bacteria of the genus Enterococcus, bacteria of the genus Bacillus, the genus Pseudomonas, Serratia marcescens, Escherichia coli, or bacteria of the genus Propionibacterium (including Propionibacterium acnes). Preferably, one or more of the bacteria of the genus Staphylococcus, the genus Streptococcus, Streptococcus pneumoniae, the genus Corynebacterium, Haemophilus influenza, and Propionibacterium acnes are included.

[0036] As used herein, "treating" a disease to be treated includes (1) eliminating any one or more of the above diseases, blepharitis, hordeolum, or dacryocystitis, and one or more associated symptoms; or (2) reducing or minimizing the severity of any one or more of the above diseases, blepharitis, hordeolum, or dacryocystitis, and one or more associated symptoms; "inhibiting progression" includes (1) delaying the progression or onset of any one or more of the above diseases, blepharitis, hordeolum, or dacryocystitis, and one or more associated symptoms; and "preventing" includes (1) delaying the onset of any one or more of the above diseases, blepharitis, hordeolum, or dacryocystitis, and one or more associated symptoms; or (2) reducing, minimizing, or eliminating the occurrence or frequency of any one or more of the above 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 applied may be a patient before a surgical operation. 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 applied may be a patient before a dacryocystonasostomy or a surgery to release a blockage of the nasolacrimal duct. As described above, dacryocystitis is a disease caused by the narrowing or blockage of the nasolacrimal duct, which causes tears or secretions from the lacrimal duct to accumulate proximal to the blockage, and then bacterial infection occurs. For adult dacryocystitis, antibacterial eye drops are administered to control bacterial infection as a treatment until a radical surgical treatment (dacryocystonasostomy, release of a blockage of the nasolacrimal duct) is performed. The ophthalmic agent or ophthalmic antibacterial agent of the present invention is also useful as a treatment until a surgical treatment of dacryocystitis.

[0038] As used herein, the "subject (patient)" for the purpose of treatment or the like is a mammal, including humans and non-human animals, with humans being preferred. The subject may be an adult. Also, from the perspective of the target disease and causative bacteria, the subject is preferably a human who has developed blepharitis, hordeolum, or dacryocystitis in Japan. For example, the yellow race may be mentioned, preferably the Japanese, but the causative bacteria of the disease are bacteria derived from Japan or equivalent bacteria. Alternatively, the subject may be a human who resides in Japan and has been diagnosed with blepharitis, hordeolum, or dacryocystitis.

Examples

[0039] The present invention will be described in more detail below with reference to test examples and examples, but the present invention is not limited to these test examples and examples. The compounds, animals (e.g., rabbits), and bacterial species used in the test examples and examples were obtained commercially or produced according to known methods.

[0040] (Test Example 1) Confirmation of the transferability of azithromycin to eye tissues The transferability of azithromycin, which is the active ingredient of the present invention, to eye tissues such as the eyelid was confirmed. As comparative compounds, the following levofloxacin and ofloxacin were selected for a comparative test. This experiment was carried out with the approval of the Animal Experiment Ethics Committee based on the Law Concerning the Humane Treatment and Management of Animals (Law No. 105 of October 1, 1973, last amended: Law No. 38 of June 12, 2013), etc.

[0041] (1) Test method (Specimen) As the preparation of the present invention, 1% azithromycin eye drops were used, and as comparative preparations, 1.5% levofloxacin eye drops (Clavivid (trademark) eye drops 1.5%) (manufacturer: Santen Pharmaceutical Co., Ltd.) and 0.3% ofloxacin eye ointment (Tarivid (trademark) eye ointment 0.3%) (manufacturer: Santen Pharmaceutical Co., Ltd.) were used. 1% Azithromycin Eye Drops were prepared by mixing azithromycin hydrate as the active ingredient, and 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 as additives by a conventional method. 1% Azithromycin Eye Drops contain 10.48 mg of azithromycin hydrate (10 mg (titer) as azithromycin) per 1 g of the eye drops.

[0042] (Animal Experiment) 1) Rabbits, Japanese white strain, male (source: Kitayama Labes), body weight: 2.0 - 2.5 kg were used in the test system. The temperature and relative humidity of the breeding environment were 22°C ± 3°C, 55% ± 10%, lights on at 8:00, lights off at 20:00, 1 rabbit / cage, fed with feed (100 g / day), and water was supplied by an automatic water supply device. 2) After confirming that there was no disorder in the anterior eye part of the animals, any of the above eye drops was administered by single-drop instillation to both eyes using a micropipette. After administration, the animals were forced to blink twice. The number of eyes in each group was 4. 1% Azithromycin Eye Drops: Dosage 30 μL, administration site: near the upper bulbar conjunctiva; 1.5% Levofloxacin Eye Drops: Dosage 30 μL, administration site: near the upper bulbar conjunctiva; 0.3% Ofloxacin Ophthalmic Ointment: Dosage 46 μL (about 40 mg), administration site: into the lower conjunctival sac 3) At 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, eye tissues were collected according to the following procedure. Somnopentyl (trademark) Anesthetic Injection (manufacturer: Kyoritsu Pharmaceutical Co., Ltd.) was administered intravenously into the ear vein, and it was confirmed by palpation that the heartbeat had stopped. Next, the eye surface and the conjunctival sac were washed with more than 40 mL of physiological saline. Then, aqueous humor, conjunctiva, eyelid, and cornea were collected. Each tissue was cryopreserved in a deep freezer until use.

[0043] (Analysis) 1) Standard Substance Azithromycin dihydrate (manufacturer: Tokyo Chemical Industry Co., Ltd.) (purity: 98.2%) was used as a reference substance for azithromycin concentration analysis, and ofloxacin (manufacturer: Tokyo Chemical Industry Co., Ltd.) (purity: 99.7%) was used as a reference substance for ofloxacin and levofloxacin concentration analysis. In addition, phenytoin (manufacturer: Fujifilm Wako Pure Chemical Corporation) (specification: Wako special grade) was used as an internal standard substance (IS).

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

[0045] 3) Conditions for liquid chromatography tandem mass spectrometer The pretreated actual sample was injected into a liquid chromatography tandem mass spectrometer for measurement. The liquid chromatography conditions are as follows. Column: ACQUITY UPLC (trademark) HSS T3 1.8 μm 2.1 × 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 Calibration curves were created using Analyst software (version 1.6.2, manufactured by AB SCIEX Pte. Ltd.), and the tissue concentration was calculated from the calibration curves and the peak area ratios of each sample. Non-compartmental analysis was performed using Phoenix WinNonlin Build 8.1.0 software (manufactured by Certara, Princeton, NJ, USA), and the area under the drug concentration-time curve (AUC 0-24 ) from 0 to 24 hours after administration was calculated for each tissue and specimen.

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

Table 1

[0048] (Example 1)(Example 1) Confirmation of the therapeutic effect of various eye diseases by instillation of 1% azithromycin eye drops (Objective) For patients with bacterial blepharitis, hordeolum, or dacryocystitis, 1% azithromycin eye drops prepared in the same manner as in Test Example 1 were instilled once a drop, twice a day for 2 days, and then once a drop, once a day for 12 days, and the effectiveness of the eye drops as an ophthalmic agent of the present invention was examined.

[0049] (Subjects) Patients were those diagnosed with any of the diseases of bacterial blepharitis, hordeolum, or dacryocystitis, and who had a score of 1 or more on any of the objective findings of the eye receiving eye drops. The main exclusion criteria were as follows. i) Those in whom eye infections other than the target disease could not be ruled out based on the clinical findings of either eye; ii) Those with corneal epithelial defects in the eye receiving eye drops (excluding superficial punctate keratitis), especially those with corneal ulcers. A total of 32 cases were included in the analysis of effectiveness, including 10 cases of blepharitis, 10 cases of dacryocystitis, and 12 cases of hordeolum.

[0050] (Evaluation criteria) The judgment criteria for the findings and symptom scores shown in the guidelines for antibacterial eye drops (written by Makoto Asari et al., Guidelines on the Clinical Evaluation Method of Antibacterial Eye Drops, Journal of the Japanese Ophthalmological Society. 2015;119(4):273 - 86) were used (Tables 2, 3, and 4 below). For the findings and symptom scores of blepharitis, as objective findings, secretions at the root of the eyelashes, eyelid margin congestion / eyelid redness, and conjunctival congestion were evaluated in 5 grades, and as subjective symptoms, foreign body sensation and tearing were evaluated in 5 grades respectively. For the findings and symptom scores of hordeolum, as objective findings, congestion / redness and eyelid swelling were evaluated in 5 grades, and as subjective symptoms, eye pain, foreign body sensation, and tearing were evaluated in 5 grades respectively. For the findings and symptom scores of dacryocystitis, as objective findings, reflux secretions, redness and swelling of the lacrimal sac area were evaluated in 5 grades, and as subjective symptoms, pain and tearing were evaluated in 5 grades respectively.

[0051] In addition, the efficacy evaluation was determined in 5 grades of marked efficacy, effective, ineffective, deteriorated, and undetermined according to the clinical efficacy judgment criteria shown in the above guidelines for antibacterial eye drops (Table 5).

[0052] The methods of bacterial examination and symptom observation were carried out according to the following methods. 1) Bacterial examination Samples were collected from the congested and swollen local area of the eye receiving the drug or the pus discharged from it and cultured. Using the collected samples, bacteria were isolated and identified. 2) Symptom observation The doctor determined each objective finding and subjective symptom of the eye instilled with the eye drops according to the tables (Table 2, Table 3, Table 4) of the Guidelines for the Clinical Evaluation Method of Antibacterial Eye Drops (the above: by Makoto Asari et al., Guidelines for the Clinical Evaluation Method of Antibacterial Eye Drops. 273 - 86), and the score of each symptom was entered into the case report form. In the observation on the administration start date, the finding with the highest symptom score among the objective findings in the above table was taken as the main symptom. The examination was carried out before the bacterial examination.

[0053]

Table 2

[0054]

Table 3

[0055]

Table 4

[0056]

Table 5

[0057] (Statistical method) 1) Clinical efficacy (main evaluation item) For the entire population of subjects or by disease of interest, the effective rate (the ratio of marked efficacy and efficacy) and 95% confidence interval of the clinical efficacy based on the clinical efficacy judgment criteria (Table 5) were obtained. 2) Number of days until the disappearance of the bacteria detected at the first visit (secondary evaluation item) For the clinical isolates detected by bacterial examination at the first visit (administration start date) for the entire population of subjects or by disease of interest, the number of days from the administration start date until the bacteria disappeared for each bacterial species was calculated and taken as the number of days until the disappearance of the bacteria detected at the first visit. 3) Number of days until the disappearance of the main symptom (secondary evaluation item) For the entire population of subjects or by disease of interest, the number of days from the administration start date until the main symptom score became 0 was calculated. 4) Number of days for the symptom score to reach 1 / n (secondary evaluation item) For the entire population or by target disease, the number of days from the start date of administration until the total symptom score reached 1 / 2, 1 / 3, or 1 / 4 compared to the initial diagnosis (start date of administration) was calculated respectively. The total symptom score is the sum of the scores of objective findings and subjective symptoms (Tables 2 to 4). It may also be referred to as the "symptom score" hereinafter.

[0058] (Results) Based on the clinical efficacy criteria, cure, effectiveness, ineffectiveness, and deterioration were determined from the disappearance of detected bacteria (Table 7), disappearance of main symptoms (Table 8), and total symptom score (Table 9), and the effective rate of clinical efficacy (the proportion of cases determined to be cured or effective) was shown in Table 6. Regarding the clinical efficacy, the combined effective rate of cure and effectiveness was 70.0% for blepharitis, 90.0% for hordeolum, 50.0% for dacryocystitis, and 68.8% overall.

[0059]

Table 6

[0060] The number of days until the disappearance of detected bacteria at the initial diagnosis was shown in Table 7. For blepharitis, it was 70.0% on the 3rd day, 80.0% on the 7th day, and 100.0% on the 14th day; for hordeolum, it was 60.0% on the 3rd day, 100.0% on the 7th day, and 100.0% on the 14th day; for dacryocystitis, it was 75.0% on the 3rd day, 91.7% on the 7th and 14th days. Overall, it was 68.8% on the 3rd day, 90.6% on the 7th day, and 96.9% on the 14th day. The disappearance of detected bacteria at the initial diagnosis was observed on the 14th day in all subjects except for one case of dacryocystitis.

[0061]

Table 7

[0062] The number of days until the main symptoms disappeared was shown in Table 8. In the case of blepharitis, it was 10.0% on the 7th day and 70.0% on the 14th day. In the case of hordeolum, it was 10.0% on the 7th day and 60.0% on the 14th day. In the case of dacryocystitis, it was 8.3% on the 3rd and 7th days and 16.7% on the 14th day. Also, overall, it was 3.1% on the 3rd day, 9.4% on the 7th day, and 46.9% on the 14th day, and the main symptoms disappeared in about half of the subjects on the 14th day.

[0063]

Table 8

[0064] The symptom score 1 / n days by target disease was shown in Table 9. The symptom score 1 / n days on the 14th day was 90.0% for 1 / 2 days, 90.0% for 1 / 3 days, and 90.0% for 1 / 4 days in the case of blepharitis; 90.0% for 1 / 2 days, 90.0% for 1 / 3 days, and 80.0% for 1 / 4 days in the case of hordeolum; and 58.3% for 1 / 2 days, 33.3% for 1 / 3 days, and 16.7% for 1 / 4 days in the case of dacryocystitis.

[0065]

Table 9

[0066] From the results of the above test examples and examples, by administering the ophthalmic agent (for example, eye drops) of the present invention once a drop, twice a day for 2 days, and then once a drop, once a day for 12 days, the viable bacteria count in the intraocular tissue (for example, corneal tissue) can be suppressed, and blepharitis, hordeolum, and dacryocystitis can be prevented or treated, or the progression of the disease can be suppressed.

Industrial Applicability

[0067] The azithromycin-containing ophthalmic agent of the present invention is useful as a medicament for preventing or treating eye infectious diseases (for example, one or more diseases among blepharitis, hordeolum, and dacryocystitis) or suppressing the progression of the disease.

Claims

1. An ophthalmic preparation for preventing or treating dacryocystitis or inhibiting the progression of dacryocystitis in a patient, comprising azithromycin and an ophthalmically acceptable excipient, The additive comprises a thickening agent, and the thickening agent consists solely of polycarbophil; applying said ophthalmic preparation to said patient in a single dose twice a day for two days, followed by once a day for twelve 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, wherein the concentration of azithromycin is 0.01% (w / w) to 2.0% (w / w).

4. The ophthalmic preparation according to any one of claims 1 to 3, wherein the concentration of azithromycin is 0.1% (w / w) to 1.0% (w / w).

5. The ophthalmic preparation according to any one of claims 1 to 4, wherein when the ophthalmic preparation is an eye drop, the appropriate amount for one application is one drop.

6. The ophthalmic preparation according to any one of claims 1 to 5, for suppressing one or more symptoms of reflux secretion, redness and swelling of the lacrimal sac, pain, or tearing.

7. The ophthalmic preparation according to any one of claims 1 to 6, wherein the azithromycin is anhydrous azithromycin or hydrate.

8. The ophthalmic preparation according to any one of claims 1 to 7, wherein the patient is Japanese.

9. The ophthalmic preparation according to any one of claims 1 to 8, wherein the patient is a pre-surgical patient suffering from dacryocystitis.

10. The ophthalmic preparation according to claim 9 , wherein the patient is a patient suffering from dacryocystitis and is prior to surgery for dacryocystorhinostomy or relief of nasolacrimal duct obstruction.

11. The ophthalmic agent according to any one of claims 1 to 10, wherein the ophthalmically acceptable additive further comprises any one or more of a stabilizer, a buffer, an isotonic agent, a preservative, a solubilizing agent, a pH adjuster, or a solvent.

12. The ophthalmic agent according to any one of claims 1 to 11, further comprising another drug.

13. The ophthalmic agent according to any one of claims 1 to 12, wherein the other drug is any one or more of an antiviral drug, an antifungal drug, an anesthetic drug, an anti-inflammatory drug, or an anti-allergy drug.

14. An ophthalmic antibacterial agent comprising azithromycin and an ophthalmically acceptable additive for preventing or treating a patient's dacryocystitis or suppressing the progression of dacryocystitis, wherein the additive comprises a thickening agent, and the thickening agent consists only of polycarbophil, The ophthalmic antibacterial agent, comprising applying the ophthalmic antibacterial agent to the patient in an appropriate amount once a day, twice a day for 2 days, and then once a day for 12 days.

15. The ophthalmic antibacterial agent according to claim 14, wherein the causative bacterium is any one or more of Staphylococcus spp., Streptococcus spp., Streptococcus pneumoniae, Corynebacterium spp., Haemophilus influenzae, or Propionibacterium acnes.

Images