Preventive and / or therapeutic agent for dry eye

Abstract

The present invention provides a compound useful for preventing or treating dry eye, and a prophylactic and / or therapeutic agent for dry eye containing the compound, which does not substantially affect intraocular pressure.The present invention relates to a prophylactic and / or therapeutic agent for dry eye, which contains olodaterol or a salt thereof as an active ingredient.

Description

[Technical field]

[0001] The present invention relates to an agent for preventing and / or treating dry eye, which contains olodaterol or a salt thereof as an active ingredient. [Background technology]

[0002] Dry eye is a disease that causes dry eye symptoms such as eye discomfort or visual abnormality due to quantitative or qualitative abnormalities in tears, and may cause damage to the surface of the eye (cornea, etc.). Quantitative abnormalities mainly refer to a state in which the amount of tears secreted is low, and are an indicator of dry eye based on the amount of tears. On the other hand, qualitative abnormalities mainly refer to abnormalities in tear components, such as low levels of lipid or protein components in tears, which can reduce the stability of the tear film and cause dryness of the eye surface even when tears are secreted.

[0003] Meanwhile, clenbuterol and fenoterol are known as selective β2 adrenergic receptor agonists, and have been confirmed to have the effect of promoting the secretion of tears and tear proteins (Patent Document 1).

[0004] In addition, it has been confirmed that salbutamol, a β2 adrenergic receptor agonist, also has a lacrimal secretion promoting effect (Patent Document 2). On the other hand, it has been reported that salbutamol is not sufficiently effective in treating dry eye and increases intraocular pressure (Patent Document 3).

[0005] Patent Document 4 cites dry eye as one of many symptoms resulting from systemic lupus erythematosus (SLE), an autoimmune disease, and discloses the use of β2 adrenergic receptor agonists for the treatment of SLE. However, only some drugs have been verified in renal disease models, and the treatment of dry eye with β2 adrenergic receptor agonists has not been verified at all.

[0006] On the other hand, olodaterol (chemical name: 6-hydroxy-8-((1R)-1-hydroxy-2-{[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino}ethyl)-2H-1,4-benzoxazin-3-(4H)-one) is known as a selective β2 adrenergic receptor agonist and has the following formula: [ka] It is a compound represented by the formula: Since β2-adrenergic receptors are generally present in the bronchi or blood vessels, olodaterol hydrochloride is marketed in the form of a combination drug with tiotropium as a treatment for chronic obstructive pulmonary disease (COPD). However, the therapeutic effect of olodaterol on eye diseases, particularly dry eye, is not known at all.

[0007] Timolol, an antagonist of β2 adrenergic receptor, is used as a therapeutic agent for glaucoma and ocular hypertension and has an action of lowering intraocular pressure. In particular, it is desirable that a β2 adrenergic receptor agonist as a therapeutic agent for dry eye has substantially no effect on intraocular pressure, that is, does not cause an increase or decrease in intraocular pressure as a side effect. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. WO01 / 41806 [Patent Document 2] International Publication No. WO2011 / 068786 [Patent Document 3] International Publication No. WO2017 / 043612 [Patent Document 4] International Publication No. WO2019 / 020634 Summary of the Invention [Problem to be solved by the invention]

[0009] The problem to be solved by the present invention is to provide a compound useful for the prevention or treatment of dry eye, and a prophylactic and / or therapeutic agent for dry eye containing the compound, which does not substantially affect intraocular pressure. [Means for solving the problem]

[0010] Means for Solving the Problems The present inventors have conducted intensive research to solve the above problems and have surprisingly found that olodaterol or a salt thereof can stabilize the tear film, promote tear secretion, and / or increase tear volume, and can prevent and / or treat dry eye without substantially affecting intraocular pressure, thereby completing the present invention.

[0011] That is, in one embodiment, a preventive and / or therapeutic agent for dry eye containing olodaterol or a salt thereof as an active ingredient is provided. In another embodiment, a tear film stabilizer containing olodaterol or a salt thereof as an active ingredient is provided. In yet another embodiment, a tear secretion promoter and / or tear volume increaser containing olodaterol or a salt thereof as an active ingredient is provided. Effect of the Invention

[0012] Olodaterol or its salt can dose-dependently extend the tear film breakup time and stabilize the tear film, and is expected to be useful for preventing and / or treating dry eye. Olodaterol or its salt can also promote the secretion of tears and increase the tear volume, and can significantly increase the tear volume even at a low concentration compared to other selective β2 adrenergic receptor agonists, so that it can exert a preventive and / or therapeutic effect on dry eye with a small exposure amount. In addition, since it can exert a preventive and / or therapeutic effect with a small exposure amount, it can be expected to reduce the risk of systemic and / or local side effects. Furthermore, since it does not substantially increase or decrease intraocular pressure for a certain period after administration, it is possible to provide a preventive and / or therapeutic agent that is highly safe to the eyes. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 shows the effect of extending the tear film breakup time at each concentration and its change over time when 0.0001% (w / v), 0.001% (w / v), or 0.01% (w / v) olodaterol was administered once to cynomolgus monkeys. [Diagram 2] FIG. 1 shows the effect of extending the tear film breakup time and its change over time when 1% (w / v) fenoterol and 1% (w / v) clenbuterol ophthalmic solutions were instilled once in cynomolgus monkeys. [Diagram 3] FIG. 1 shows the effect of increasing tear volume at each concentration of 0.00001% (w / v), 0.0001% (w / v), 0.001% (w / v), or 0.01% (w / v) olodaterol when administered once to rats, and the change over time. [Figure 4] FIG. 1 shows the effect over time on intraocular pressure when 0.01% (w / v) or 0.1% (w / v) olodaterol ophthalmic solution was repeatedly instilled twice daily into cynomolgus monkeys. [Diagram 5] FIG. 1 shows the effect of extending the tear film breakup time at each concentration and its change over time when 0.00001% (w / v), 0.0001% (w / v), 0.001% (w / v), or 0.01% (w / v) olodaterol was instilled once into the eyes of SD rats. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Some specific embodiments are illustrated below. [Section 1] A preventive and / or therapeutic agent for dry eye, comprising olodaterol or a salt thereof as an active ingredient.

[0015] [Section 2] Item 2. The preventive and / or therapeutic agent according to Item 1, wherein the dry eye is caused by corneal and / or conjunctival epithelial disorder resulting from at least one selected from the group consisting of superficial punctate keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbic keratoconjunctivitis, filamentous keratoconjunctivitis, non-infectious keratitis, and non-infectious conjunctivitis.

[0016] [Section 3] Item 2. The preventive and / or therapeutic agent according to Item 1, wherein the dry eye is a disease caused by at least one selected from the group consisting of decreased stability of the tear film, aqueous lacrimation, dry eye, hypolacrimation, keratoconjunctivitis sicca, lacrimal gland dysfunction, meibomian gland dysfunction, VDT (Visual Display Terminal) work, contact lens wear, tear abnormality, and keratoconjunctivitis.

[0017] [Section 4] Item 4. The prophylactic and / or therapeutic agent according to any one of Items 1 to 3, wherein olodaterol or a salt thereof is contained at a concentration of 0.1% (w / v) or less.

[0018] [Section 5] Item 4. The preventive and / or therapeutic agent according to any one of Items 1 to 3, wherein olodaterol or a salt thereof is contained at a concentration of 0.01% (w / v) or less.

[0019] [Section 6] Item 4. The preventive and / or therapeutic agent according to any one of Items 1 to 3, wherein olodaterol or a salt thereof is contained at a concentration of 0.00001 to 0.1% (w / v).

[0020] [Section 7] Item 4. The preventive and / or therapeutic agent according to any one of Items 1 to 3, wherein olodaterol or a salt thereof is contained at a concentration of 0.00001 to 0.01% (w / v).

[0021] [Section 8] Item 4. The preventive and / or therapeutic agent according to any one of Items 1 to 3, wherein olodaterol or a salt thereof is contained at a concentration of 0.00001 to 0.005% (w / v).

[0022] [Section 9] Item 4. The preventive and / or therapeutic agent according to any one of Items 1 to 3, wherein olodaterol or a salt thereof is contained at a concentration of 0.00001 to 0.001% (w / v).

[0023] [Section 10] Item 10. The preventive and / or therapeutic agent according to any one of Items 1 to 9, which is in the form of eye drops.

[0024] [Section 11] Item 11. The preventive and / or therapeutic agent according to any one of items 1 to 10, which has substantially no intraocular pressure increasing effect and / or no intraocular pressure decreasing effect.

[0025] [Section 12] Item 12. The preventive and / or therapeutic agent according to any one of items 1 to 11, wherein olodaterol or a salt thereof is olodaterol hydrochloride.

[0026] [Section 13] A tear film stabilizer containing olodaterol or a salt thereof as an active ingredient.

[0027] [Section 14] A tear secretion promoter and / or tear volume increaser containing olodaterol or a salt thereof as an active ingredient.

[0028] [Section 15] A method for preventing and / or treating dry eye, comprising administering a therapeutically effective amount of olodaterol or a salt thereof to a subject.

[0029] [Section 16] Item 16. The method for preventing and / or treating dry eye according to Item 15, wherein the dry eye is caused by corneal and / or conjunctival epithelial disorder resulting from at least one selected from the group consisting of superficial punctate keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbic keratoconjunctivitis, filamentous keratoconjunctivitis, non-infectious keratitis, and non-infectious conjunctivitis.

[0030] [Section 17] Item 16. The method for preventing and / or treating dry eye according to Item 15, wherein the dry eye is a disease caused by at least one selected from the group consisting of decreased stability of the tear film, aqueous lacrimation, dry eye, hypolacrimation, keratoconjunctivitis sicca, lacrimal gland dysfunction, meibomian gland dysfunction, VDT (Visual Display Terminal) work, contact lens wear, tear abnormality, and keratoconjunctivitis.

[0031] [Section 18] Item 18. The method for prevention and / or treatment according to any one of Items 15 to 17, wherein the concentration of olodaterol or a salt thereof is 0.1% (w / v) or less.

[0032] [Section 19] Item 18. The method for prevention and / or treatment according to any one of Items 15 to 17, wherein the concentration of olodaterol or a salt thereof is 0.01% (w / v) or less.

[0033] [Section 20] Item 18. The method for prevention and / or treatment according to any one of Items 15 to 17, wherein the concentration of olodaterol or a salt thereof is 0.00001 to 0.1% (w / v).

[0034] [Section 21] Item 18. The method for prevention and / or treatment according to any one of Items 15 to 17, wherein the concentration of olodaterol or a salt thereof is 0.00001 to 0.01% (w / v).

[0035] [Section 22] Item 18. The method for prevention and / or treatment according to any one of Items 15 to 17, wherein the concentration of olodaterol or a salt thereof is 0.00001 to 0.005% (w / v).

[0036] [Section 23] Item 18. The method for prevention and / or treatment according to any one of Items 15 to 17, wherein the concentration of olodaterol or a salt thereof is 0.00001 to 0.001% (w / v).

[0037] [Section 24] Item 24. The method for prevention and / or treatment according to any one of Items 15 to 23, wherein olodaterol or a salt thereof is administered in the form of eye drops.

[0038] [Section 25] 25. The method for prevention and / or treatment according to any one of items 15 to 24, which does not substantially have an effect of increasing intraocular pressure and / or decreasing intraocular pressure.

[0039] [Section 26] 26. The method for prevention and / or treatment according to any one of items 15 to 25, wherein olodaterol or a salt thereof is olodaterol hydrochloride.

[0040] [Section 27] A method for stabilizing the tear film, comprising administering a therapeutically effective amount of olodaterol or a salt thereof to a subject.

[0041] [Section 28] A method for promoting tear secretion and / or increasing tear volume, comprising administering a therapeutically effective amount of olodaterol or a salt thereof to a subject.

[0042] [Section 29] 1. Olodaterol or a salt thereof for use in the prevention and / or treatment of dry eye.

[0043] [Section 30] Item 30. Olodaterol or a salt thereof according to item 29, wherein the dry eye is caused by corneal and conjunctival epithelial disorder resulting from at least one selected from the group consisting of superficial punctate keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbic keratoconjunctivitis, filamentous keratoconjunctivitis, non-infectious keratitis, and non-infectious conjunctivitis.

[0044] [Section 31] Item 30. Olodaterol or a salt thereof according to item 29, wherein the dry eye is a disease caused by at least one selected from the group consisting of decreased stability of the tear film, aqueous lacrimation, dry eye, hypolacrimation, keratoconjunctivitis sicca, lacrimal gland dysfunction, meibomian gland dysfunction, VDT (Visual Display Terminal) work, contact lens wear, tear abnormality, and keratoconjunctivitis.

[0045] [Section 32] Item 32. Olodaterol or a salt thereof according to any one of items 29 to 31, having a concentration of 0.1% (w / v) or less.

[0046] [Section 33] Item 32. Olodaterol or a salt thereof according to any one of items 29 to 31, having a concentration of 0.01% (w / v) or less.

[0047] [Section 34] Item 32. Olodaterol or a salt thereof according to any one of items 29 to 31, having a concentration of 0.00001 to 0.1% (w / v).

[0048] [Section 35] Item 32. Olodaterol or a salt thereof according to any one of items 29 to 31, having a concentration of 0.00001 to 0.01% (w / v).

[0049] [Section 36] Item 32. The olodaterol or a salt thereof according to any one of items 29 to 31, having a concentration of 0.00001 to 0.005% (w / v).

[0050] [Section 37] Item 32. Olodaterol or a salt thereof according to any one of items 29 to 31, having a concentration of 0.00001 to 0.001% (w / v).

[0051] [Section 38] Item 38. The olodaterol or a salt thereof according to any one of items 29 to 37, which is in the form of an eye drop.

[0052] [Section 39] Item 39. Olodaterol or a salt thereof according to any one of Items 29 to 38, which has substantially no intraocular pressure increasing effect and / or intraocular pressure decreasing effect.

[0053] [Section 40] Item 40. Olodaterol or a salt thereof according to any one of items 29 to 39, wherein the olodaterol or a salt thereof is olodaterol hydrochloride.

[0054] [Section 41] Olodaterol or a salt thereof for use in stabilizing the tear film.

[0055] [Section 42] Olodaterol or a salt thereof for use in promoting tear secretion and / or increasing tear volume.

[0056] [Section 43] Use of olodaterol or a salt thereof in the manufacture of a medicament for preventing and / or treating dry eye.

[0057] [Section 44] Item 44. The use according to item 43, wherein the dry eye is accompanied by a corneal and conjunctival epithelial disorder caused by at least one selected from the group consisting of superficial punctate keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbic keratoconjunctivitis, filamentary keratoconjunctivitis, non-infectious keratitis, and non-infectious conjunctivitis.

[0058] [Section 45] Item 44. The use according to item 43, wherein the dry eye is a disease caused by at least one selected from the group consisting of decreased stability of the tear film, aqueous lacrimation, dry eye, hypolacrimation, keratoconjunctivitis sicca, lacrimal gland dysfunction, meibomian gland dysfunction, VDT (Visual Display Terminal) work, contact lens wear, tear abnormality, and keratoconjunctivitis.

[0059] [Section 46] Item 46. The use according to any one of items 43 to 45, wherein the concentration of olodaterol or a salt thereof is 0.1% (w / v) or less.

[0060] [Section 47] Item 46. The use according to any one of items 43 to 45, wherein the concentration of olodaterol or a salt thereof is 0.01% (w / v) or less.

[0061] [Section 48] Item 46. The use according to any one of items 43 to 45, wherein the concentration of olodaterol or a salt thereof is 0.00001 to 0.1% (w / v).

[0062] [Section 49] Item 46. The use according to any one of items 43 to 45, wherein the concentration of olodaterol or a salt thereof is 0.00001 to 0.01% (w / v).

[0063] [Section 50] Item 46. The use according to any one of items 43 to 45, wherein the concentration of olodaterol or a salt thereof is 0.00001 to 0.005% (w / v).

[0064] [Section 51] Item 46. The use according to any one of items 43 to 45, wherein the concentration of olodaterol or a salt thereof is 0.00001 to 0.001% (w / v).

[0065] [Section 52] Item 52. The use according to any one of items 43 to 51, wherein the medicament is in the form of eye drops.

[0066] [Section 53] Item 53. The use according to any one of Items 43 to 52, wherein the medicament has substantially no intraocular pressure increasing and / or intraocular pressure decreasing effect.

[0067] [Section 54] Item 54. The use according to any one of items 43 to 53, wherein olodaterol or a salt thereof is olodaterol hydrochloride.

[0068] [Section 55] Use of olodaterol or a salt thereof in the manufacture of a medicament for stabilizing the tear film.

[0069] [Section 56] Use of olodaterol or a salt thereof in the manufacture of a medicine for promoting tear secretion and / or increasing tear volume.

[0070] Olodaterol is a selective agonist for the human β2 adrenergic receptor, represented by the following general formula, and has high β2 selectivity, exhibiting weak intrinsic activity at the β1 adrenergic receptor while exhibiting almost complete intrinsic activity at the β2 adrenergic receptor.

[0071] [ka]

[0072] In this specification, the term "olodaterol or its salt" includes olodaterol and its salt with inorganic or organic acid. Examples of the salt of olodaterol include hydrochloride, sulfate, acetate, trifluoroacetate, hydrobromide, hydroiodide, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate, more preferably olodaterol hydrochloride. The salt can be produced according to a conventional method in the field of organic synthetic chemistry or the production method described in International Publication WO2004 / 045618, US Patent Publication No. 2007 / 0027148, and the like.

[0073] Olodaterol or its salt may also exist as a hydrate or solvate. The solvate may include, for example, an ethanol solvate. The hydrate and solvate may be prepared according to a conventional method in the field of organic synthetic chemistry, or may be commercially available.

[0074] When olodaterol or a salt thereof has a crystal polymorphism and a crystal polymorphism group (i.e., a crystal polymorphism system), the crystal polymorphism and the crystal polymorphism group (i.e., a crystal polymorphism system) are also included in the scope of the present invention. Here, the crystal polymorphism group (i.e., a crystal polymorphism system) means not only individual crystal forms obtained at each stage when the crystal form changes depending on the conditions and states of the production, crystallization, storage, etc. of the crystals, but also a mixture of crystal forms obtained at two or more stages.

[0075] In the present specification, the concentration of olodaterol or its salt in the prophylactic and / or therapeutic agent is not particularly limited, but is preferably 0.1% (w / v) or less, more preferably 0.01% (w / v) or less, and even more preferably 0.005% (w / v) or less. The upper limit of the concentration includes 0.1% (w / v), 0.05% (w / v), 0.03% (w / v), 0.01% (w / v), 0.005% (w / v), 0.003% (w / v), and 0.001% (w / v). The lower limit of the concentration includes 0.0000001% (w / v), 0.000001% (w / v), 0.000003% (w / v), 0.000005% (w / v), 0.00001% (w / v), 0.00003% (w / v), 0.00005% (w / v), 0.0001% (w / v), 0.0003% (w / v), and 0.0005% (w / v). The concentration ranges are 0.0000001-0.1% (w / v), 0.0000001-0.05% (w / v), 0.0000001-0.03% (w / v), 0.0000001-0.01% (w / v), 0.0000001-0.005% (w / v), 0.0000001-0.003% (w / v), 0.000000 1~0.001%(w / v), 0.000001~0.1%(w / v), 0.000001~0.05%(w / v), 0.000001~0.03%(w / v), 0. 000001~0.01%(w / v), 0.000001~0.005%(w / v), 0.000001~0.003%(w / v), 0.000001~0.001% (w / v), 0.000003~0.1%(w / v), 0.000003~0.05%(w / v), 0.000003~0.03%(w / v), 0.000003~0 .01%(w / v), 0.000003~0.005%(w / v), 0.000003~0.003%(w / v), 0.000003~0.001%(w / v), 0. 000005~0.1%(w / v), 0.000005~0.05%(w / v), 0.000005~0.03%(w / v), 0.000005~0.01%(w / v) ), 0.000005~0.005%(w / v), 0.000005~0.003%(w / v), 0.000005~0.001%(w / v), 0.00001~0.1% (w / v), 0.00001 - 0.05% (w / v), 0.00001 - 0.03% (w / v), 0.00001 - 0.01% (w / v), 0.00001 - 0.005% (w / v), 0.00001 - 0.003% (w / v), 0.00001 - 0.001% (w / v), 0.00003 - 0.1% (w / v), 0.00003 - 0.05% (w / v), 0.00003 - 0.03% (w / v), 0.00003 - 0.01% (w / v), 0.00003 - 0.005% (w / v), 0.00003 - 0.003% (w / v), 0.00003 - 0.001% (w / v), 0.00005 - 0.1% (w / v), 0.00005 - 0.05% (w / v), 0.00005 - 0.03% (w / v), 0.00005 - 0.01% (w / v), 0.00005 - 0.005% (w / v), 0.00005 - 0.003% (w / v), 0.00005 - 0.001% (w / v), 0.0001 - 0.1% (w / v), 0.0001 - 0.05% (w / v), 0.0001 - 0.03% (w / v), 0.0001 - 0.01% (w / v), 0.0001 - 0.005% (w / v), 0.0001 - 0.003% (w / v), 0.0001 - 0.001% (w / v), 0.0003 - 0.1% (w / v), 0.0003 - 0.05% (w / v), 0.0003 - 0.03% (w / v), 0.0003 - 0.01% (w / v), 0.0003 - 0.005% (w / v), 0.0003 - 0.003% (w / v), 0.0003 - 0.001% (w / v), 0.0005 - 0.1% (w / v), 0.0005 - 0.05% (w / v), 0.0005 - 0.03% (w / v), 0.0005 - 0.01% (w / v), 0.0005 - 0.005% (w / v), 0.0005 - 0.003% (w / v), and 0.0005 - 0.001% (w / v) are included.

[0076] It is known that β2 adrenergic receptor agonists can cause systemic side effects such as cardiovascular side effects (e.g., increased heart rate, arrhythmia, etc.) when they also act on the β1 subtype that is abundant in the heart (Patent Document 1), but olodaterol or a salt thereof does not substantially exhibit systemic and / or local side effects at concentrations below and / or below the above-mentioned concentrations, and is expected to be a preventive and / or therapeutic agent that is well tolerated.

[0077] Olodaterol or a salt thereof can be administered in the form of a preventive and / or therapeutic agent containing it as an active ingredient. Examples of the administration form include parenteral administration, preferably eye drop administration. Examples of the dosage form include an ophthalmic composition. Here, the ophthalmic composition may be a medicine having a preventive or therapeutic effect on an ophthalmic disease or symptom of a subject or patient, that is, an effect of alleviating, improving, relieving, inhibiting progression, preventing, or delaying the disease, and examples of the medicine include eye drops and eye ointments, and preferably eye drops, more preferably aqueous eye drops. The ophthalmic composition may be a medicine prescribed by a doctor or a medicine (artificial tears, lubricants, etc.) commercially available at a pharmacy or the like.

[0078] In the present specification, the preventive and / or therapeutic agent can be produced by formulating an active ingredient together with a pharma- ceutically acceptable carrier. Examples of such pharma- ceutically acceptable carriers include buffers, isotonicity agents, pH regulators, preservatives, stabilizers, bases, etc. The amount of these carriers contained in the preventive and / or therapeutic agent is not particularly limited, and may be any amount commonly used in the art.

[0079] The dosage of the preventive and / or therapeutic agent in this specification (also referred to as "therapeutically effective amount" in this specification) is not particularly limited as long as it has the desired efficacy and is tolerable. For example, in the case of eye drops, it is preferable to instill 1 to 3 drops per eye, more preferably 1 or 2 drops per eye, and even more preferably 1 drop per eye. In addition, it is preferable to instill 1 to 6 times per day per eye, more preferably 1 to 3 times per day, even more preferably 1 or 2 times per day, and particularly preferably 1 drop per day. In addition, it is preferable to instill 1 drop per eye, 1 or 2 times per day, and more preferably 1 drop per eye, 1 time, and 1 time.

[0080] As used herein, the term "dry eye" refers to a disease that causes dry eye symptoms such as eye discomfort or decreased or abnormal visual function due to quantitative or qualitative abnormalities in tears, and may cause damage to the surface of the eye (cornea, etc.). Dry eye symptoms include, for example, tired eyes, itchy eyes, sore eyes, watery eyes, eye discharge, dry eyes, blurred vision, bloodshot eyes, eye irritation, foreign body sensation (gritty or tingling sensation), discomfort when wearing soft or hard contact lenses, and burning, inflammation, and discomfort in the eyes, including exposure to wind and sun. The dry eye may be associated with and / or caused by at least one selected from the group consisting of superficial punctate keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbal keratoconjunctivitis, filamentous keratoconjunctivitis, non-infectious keratitis and non-infectious conjunctivitis, corneal epithelial disorder caused by at least one selected from the group consisting of keratoconjunctivitis sicca, superior limbal keratoconjunctivitis, filamentous keratoconjunctivitis, non-infectious keratitis and non-infectious conjunctivitis, decreased stability of the tear film, aqueous hypolacrimia, dry eye, hypolacrimia, Sjogren's syndrome, keratoconjunctivitis sicca, Stevens-Johnson syndrome, Graves' disease, lacrimal gland dysfunction, meibomian gland dysfunction, diabetes, graft-versus-host disease, VDT (Visual Display Terminal) work, surgery, medication, trauma, contact lens wear, tear abnormality, and keratoconjunctivitis. Preferably, the dry eye may be associated with and / or caused by at least one selected from the group consisting of superficial punctate keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbal keratoconjunctivitis, filamentous keratoconjunctivitis, non-infectious keratitis and non-infectious conjunctivitis, keratoconjunctivitis with reduced stability of the tear film, aqueous lacrimation, dry eye, hypolacrimation, keratoconjunctivitis sicca, lacrimal gland dysfunction, meibomian gland dysfunction, VDT (Visual Display Terminal) work, contact lens wearing, tear abnormality and keratoconjunctivitis.

[0081] In the present specification, the tear film stabilizing effect refers to the effect of prolonging the tear film break-up time (also referred to as "TBUT" in the present specification), which is mainly related to qualitative abnormality of the tear film and is an index of the stability of the tear film covering the corneal surface, and can be evaluated by measuring the TBUT. Specifically, the time until the tear film covering the cornea is disturbed without blinking after opening the eyes is measured, and in humans, if the time is 10 seconds or more, it is normal, and if it is 5 seconds or less, it may be diagnosed as dry eye. TBUT is usually measured using a staining solution such as fluorescein, but is not limited thereto. More specifically, it can be evaluated under the conditions of, for example, Test Example 1 described later. When dry eye is related to a decrease in the stability of the tear film, the dry eye may be a tear film break-up time-shortened dry eye. The preventive and / or therapeutic agent in the present specification can prolong TBUT, for example, 15 minutes, preferably 30 minutes, and more preferably 60 minutes after administration. The prolonging effect may be dependent on the dose of the active ingredient. As described below in Test Example 2, other selective β2 adrenergic receptor agonists had no TBUT prolonging effect, whereas olodaterol showed a sustained TBUT prolonging effect even at low concentrations as shown in Test Example 1. Therefore, the tear film stabilizing effect of olodaterol is considered to be a different effect from that of other β2 adrenergic receptor agonists.

[0082] In this specification, the effect of increasing the amount of tear refers to the effect of improving quantitative and / or qualitative abnormality of tear, and refers to the action of promoting the secretion of tear and / or tear protein. The effect of increasing the amount of tear can be evaluated by measuring the amount of tear secretion, for example, by Schirmer's test. Specifically, it can be evaluated under the conditions of Test Example 3 described later. When dry eye is associated with a decrease in the amount of tear secretion, the dry eye may be a dry eye with reduced tear secretion, or may be associated with Sjogren's syndrome or the like. When dry eye is associated with qualitative abnormality of tear, the dry eye may be a dry eye with increased tear evaporation, or may be associated with meibomian gland dysfunction or the like. The effect of increasing the amount of tear may also be brought about by a low concentration of olodaterol, for example, at a concentration of 0.1% (w / v) or less, 0.01% (w / v) or less, 0.001% (w / v) or less, and 0.0001% (w / v) or less. The effect of increasing tear volume may also be sustained, for example, for 0.5 hours or more, 2 hours or more, 8 hours or more, or 16 hours or more after instillation.

[0083] In the present specification, the term "has substantially no intraocular pressure increasing and / or intraocular pressure decreasing effect" means that even when the active ingredient is administered once or continuously to a subject, there is no significant difference between the intraocular pressure of the control and that of the subject for a predetermined period of time. In one embodiment, the term "has substantially no intraocular pressure increasing and / or intraocular pressure decreasing effect" means that even when the active ingredient is administered once a day or continuously 2 to 6 times a day to a subject at 0.1% (w / v) or less, there is no significant difference between the intraocular pressure of the control and that of the subject immediately after administration, 2 hours, 4 hours, 2 days, 7 days, or 14 days after administration, for example, and the intraocular pressure can be evaluated, for example, under the conditions of Test Example 5 described below.

[0084] As used herein, the term "prevention" includes prevention or delay of the onset of dry eye symptoms. Olodaterol or a salt thereof is expected to be useful in preventing dry eye because it can stabilize the tear film and increase tear volume.

[0085] As used herein, the term "treatment" includes alleviating, improving, ameliorating, or inhibiting, preventing or slowing the progression of dry eye symptoms. EXAMPLES

[0086] The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited thereto. Furthermore, unless otherwise specified, concentrations refer to mass to volume percentages (w / v (g / 100 mL)%).

[0087] [Test Example 1] Effect of extending tear film breakup time We investigated the effect of olodaterol ophthalmic solution in extending the tear film breakup time.

[0088] (Sample Preparation) As an olodaterol ophthalmic solution, ophthalmic solution 1 below was prepared and used in the test.

[0089] Eye drops 1: Olodaterol hydrochloride (0.0001 g), a buffering agent, and an isotonic agent were dissolved in water to make 100 mL, and a pH adjuster was added to prepare an olodaterol ophthalmic solution with a concentration of 0.0001% (w / v). Furthermore, by changing the amount of olodaterol hydrochloride added, olodaterol ophthalmic solutions with concentrations of 0.001 and 0.01% (w / v) were also prepared. In addition, as a control for the olodaterol ophthalmic solution group, an ophthalmic solution (base) not containing olodaterol was prepared and used as the control group.

[0090] (Test Method) A TBUT measurement test was conducted on 10 normal male cynomolgus monkeys, 5 monkeys per group, using a partial crossover method. The experimental animals were given general anesthesia by intramuscular injection of ketamine hydrochloride injection (Ketalar 500 mg for intramuscular injection (registered trademark), Daiichi Sankyo) and then their eyes were intentionally closed. Next, TBUT was measured before and 15, 30, and 60 minutes after instillation of the vehicle or each eye drop (20 μL / eye) into the right eye. Specifically, 1% fluorescein solution (2 μL / eye) was instilled, and the time from immediately after opening the eyelids to destruction of the fluorescein film (tear film) on the cornea was measured three times using a slit lamp, and the average value was calculated. (N=5 eyes)

[0091] (result) The test results are shown in Figure 1. In Figure 1, ΔTBUT means the difference in the mean TBUT between the olodaterol ophthalmic solution group of each concentration and the olodaterol-free ophthalmic solution (base) group (also referred to as the "control group").

[0092] (Consideration) As is clear from Figure 1, when olodaterol was instilled, a concentration-dependent TBUT prolongation effect was observed, whereas when the vehicle was instilled, no TBUT prolongation was observed. From the above, it was suggested that olodaterol has an excellent tear film stabilizing effect and is useful as a preventive and / or therapeutic agent for dry eye, especially for tear film breakup time-shortening dry eye.

[0093] [Test Example 2] Effect of extending tear film breakup time We investigated the effect of fenoterol and clenbuterol eye drops on extending the tear film breakup time.

[0094] (Sample Preparation) As fenoterol eye drops and clenbuterol eye drops, eye drops 2 and 3 were prepared and used in the test.

[0095] Eye drops 2: (1%) Fenoterol hydrobromide (1 mg) was dissolved in physiological saline and water to make a volume of 100 μL, and a pH adjuster was added to prepare a fenoterol ophthalmic solution with a concentration of 1% (w / v).

[0096] Eye drops 3: (1%) Clenbuterol hydrochloride (1 mg) was dissolved in physiological saline and water to make a volume of 100 μL, and a pH adjuster was added to prepare a clenbuterol ophthalmic solution with a concentration of 1% (w / v).

[0097] (Test Method) TBUT was measured in the same manner as in Test Example 1 (N=4 or 5 eyes).

[0098] (result) The test results are shown in Figure 2. In addition, ΔTBUT in Figure 2 means the difference in the average value of TBUT between the fenoterol ophthalmic solution group or clenbuterol ophthalmic solution group and the physiological saline group containing neither fenoterol nor clenbuterol.

[0099] (Consideration) As is clear from Figure 2, fenoterol eye drops and clenbuterol eye drops did not extend TBUT and did not show any tear film stabilizing effect. On the other hand, as is clear from Figure 1, olodaterol, which is also a selective β2 adrenergic receptor agonist, showed tear film stabilizing effect at a low concentration of 0.0001%. Therefore, it was suggested that the tear film stabilizing effect of olodaterol is not a common effect of selective β2 adrenergic receptor agonists, but is a characteristic effect of olodaterol. From the above, olodaterol has a unique and excellent tear film stabilizing effect and is expected to be useful as a preventive and / or therapeutic agent for dry eye, particularly for dry eye that shortens the tear film breakup time.

[0100] [Test Example 3] Effect of increasing tear volume We investigated the effect of olodaterol ophthalmic solution on increasing tear volume.

[0101] (Sample Preparation) As an olodaterol ophthalmic solution, the following ophthalmic solution 4 was prepared and used in the test.

[0102] Eye drops 4: Olodaterol hydrochloride (0.00001 g), a buffering agent, and an isotonicity agent were dissolved in water to make 100 mL, and a pH adjuster was added to prepare an olodaterol ophthalmic solution with a concentration of 0.00001% (w / v). Furthermore, by changing the amount of olodaterol hydrochloride added, olodaterol ophthalmic solutions with concentrations of 0.0001, 0.001 and 0.01% (w / v) were also prepared. In addition, as a control for the olodaterol ophthalmic solution group, an ophthalmic solution (base) not containing olodaterol was prepared and used as the control group.

[0103] (Test Method) -How to prepare the dry eye model Normal male SD (Sprague-Dawley) rats were given general anesthesia by intraperitoneally administering 2.5mL / kg of Somnopentyl injection solution diluted 5-fold with physiological saline, and the anesthesia state was maintained by inhalation of approximately 1-3% isoflurane. Next, the skin of both cheeks was incised, and the extraorbital lacrimal glands were removed and sutured with Micher sutures. In this study, animals that showed a decrease in tear volume 13 weeks after removal of the extraorbital lacrimal glands were included as experimental animals.

[0104] -Measurement of tear volume The tear volume was measured using Schirmer's test paper before and at a specified time after the start of instillation of the vehicle or each eye drop. Specifically, pentobarbital was administered intraperitoneally immediately (0 hour), 1.5 hours, 7.5 hours, and 15.5 hours after the vehicle or each eye drop was instilled into both eyes (5 μL / eye). 0.5 hours after general anesthesia, a Schirmer's test paper (1 mm × 17 mm) was inserted into the conjunctival sac of the rat's lower eyelid, and the wet area of ​​the Schirmer's test paper was read in 0.5 mm increments 1 minute later. (N=14 or 16 eyes).

[0105] (result) The test results are shown in Figure 3.

[0106] (Consideration) As is clear from Figure 3, in the olodaterol instillation group, a lacrimal secretion promoting effect was observed, and in the 0.0001-0.01% olodaterol instillation group, a high lacrimal secretion promoting effect was observed even 8 hours after instillation. Furthermore, in the high concentration 0.001 and 0.01% olodaterol instillation groups, an increase in tear volume was observed even 16 hours after instillation, and a long-lasting lacrimal secretion promoting effect was confirmed. From the above, it can be expected that olodaterol is useful as a preventive and / or therapeutic agent for dry eye, and is particularly useful as a preventive and / or therapeutic agent for aqueous tear deficient dry eye.

[0107] [Test Example 4] Effect of increasing tear volume We investigated the tear volume-increasing effects of fenoterol and clenbuterol eye drops.

[0108] (Sample Preparation) As fenoterol eye drops and clenbuterol eye drops, eye drops 5 and 6 were prepared and used in the test.

[0109] Eye drops 5: Fenoterol hydrobromide (0.0001 g), a buffering agent, and an isotonic agent were dissolved in water to make 100 mL, and a pH adjusting agent was added to prepare a fenoterol ophthalmic solution with a concentration of 0.001% (w / v). Furthermore, fenoterol ophthalmic solutions with concentrations of 0.01, 0.1 and 1% (w / v) were also prepared by changing the amount of fenoterol hydrobromide added.

[0110] Eye drops 6: Clenbuterol hydrochloride (0.0001 g), a buffering agent, and an isotonic agent were dissolved in water to make 100 mL, and a pH adjusting agent was added to prepare a clenbuterol ophthalmic solution with a concentration of 0.001% (w / v). Furthermore, by varying the amount of clenbuterol hydrochloride added, clenbuterol ophthalmic solutions with concentrations of 0.01, 0.1 and 1% (w / v) were also prepared.

[0111] In addition, as a control for the fenoterol and clenbuterol eye drop group, an eye drop (base) not containing fenoterol or clenbuterol was prepared and used as a control group.

[0112] (Test Method) The tear volume was measured in the same manner as in Test Example 3 (N=10 eyes).

[0113] (result) Based on the results of Test Examples 3 and 4, the Schirmer increase differentials (mm / min) at 0.5 hours and 8 hours after instillation for the vehicle group and each ophthalmic solution group are shown in the following Tables 1 and 2, respectively. In Tables 1 and 2, "-" means not measured.

[0114] [Table 1] [Table 2]

[0115] (Consideration) From the results in Table 1 above, it was found that olodaterol had a lacrimal secretion promoting effect at a much lower concentration than fenoterol and clenbuterol. Also, as is clear from the results in Table 2, it was revealed that olodaterol also has excellent sustained action even at low concentrations. Therefore, olodaterol has an excellent lacrimal secretion promoting effect and is useful as a preventive and / or therapeutic agent for dry eye, and is expected to be particularly useful as a preventive and / or therapeutic agent for aqueous tear-deficient dry eye.

[0116] [Test Example 5] Intraocular pressure test We investigated the effect of olodaterol ophthalmic solution on intraocular pressure.

[0117] (Sample Preparation) Olodaterol eye drops were prepared and used in the test as eye drops 1 (0.01% and 0.1%) in the same manner as in Test Example 1. In addition, as a control for the olodaterol eye drop group, an eye drop (base) not containing olodaterol was prepared to set up a control group.

[0118] (Test Method) Nine normal male cynomolgus monkeys were used in a partial crossover intraocular pressure measurement test with three monkeys per group. The vehicle or each eye drop (20 μL / eye) was instilled into the right eye of the experimental animals twice a day, and intraocular pressure was measured immediately before and 2 hours after instillation on the first, seventh, and 14th days, and also 4 hours after instillation on the first day. Specifically, one drop of 0.4% oxybuprocaine hydrochloride eye drop (trade name: Benoxil (registered trademark) eye drop 0.4%) was instilled into the right eye to administer topical anesthesia, and intraocular pressure was measured three times using a Mentor tonometer (applanation type) and the average value was calculated (N=6 eyes).

[0119] (result) The test results are shown in Figure 4.

[0120] (Consideration) As is clear from Figure 4, no increase and / or decrease in intraocular pressure was observed with 0.01% and 0.1% olodaterol ophthalmic solutions. Therefore, olodaterol is expected to be a preventive and / or therapeutic agent that does not cause side effects that affect intraocular pressure.

[0121] [Test Example 6] Effect of extending tear film breakup time The effect of olodaterol ophthalmic solution on extending the tear film breakup time was examined in a rat model of dry eye following extraorbital lacrimal gland removal.

[0122] (Sample Preparation) As an olodaterol ophthalmic solution, the following ophthalmic solution 7 was prepared and used in the test.

[0123] Eye drops 7: Olodaterol hydrochloride (0.00001 g), a buffering agent, and an isotonicity agent were dissolved in water to make 100 mL, and a pH adjuster was added to prepare an olodaterol ophthalmic solution with a concentration of 0.00001% (w / v). Furthermore, by changing the amount of olodaterol hydrochloride added, olodaterol ophthalmic solutions with concentrations of 0.0001, 0.001 and 0.01% (w / v) were also prepared. In addition, as a control for the olodaterol ophthalmic solution group, an ophthalmic solution (base) not containing olodaterol was prepared and used as the control group.

[0124] (Creation of a rat model of dry eye caused by extraorbital lacrimal gland removal) Male SD rats were given general anesthesia, and under general anesthesia, the skin on both ear-side cheeks was incised and the extraorbital lacrimal glands were removed to create an extraorbital lacrimal gland-removed dry eye model rat.

[0125] (Test Method) The no-instillation group consisted of untreated normal rats, while the vehicle instillation group and each ophthalmic solution group consisted of dry eye model rats with extraorbital lacrimal gland removal, each group consisting of 6 rats, and a TBUT measurement test was performed. When measuring TBUT, the vehicle or each eye drop (5 μL / eye) was instilled into both eyes, and TBUT was measured 0.5 and 2 hours later. Specifically, 0.5 hours after general anesthesia, Flawless eye examination test paper was inserted into the conjunctival sac of both eyes of the experimental animals to stain the ocular surface, and the time from immediately after opening the eyelids to the destruction of the fluorescein film (tear film) on the cornea was measured three times using a slit lamp, and the average value was calculated. (N=12 eyes)

[0126] (result) The test results are shown in Figure 5. In Figure 5, TBUT shows the average value of the measured values ​​for the olodaterol ophthalmic solution groups of each concentration, the olodaterol-free ophthalmic solution (base) group (also called the "control group"), and the non-administered group.

[0127] (Consideration) As is clear from FIG. 5, a TBUT prolonging effect was observed at concentrations of 0.00001% or more 0.5 and 2 hours after instillation. From the above, it was suggested that olodaterol has an excellent and long-lasting tear film stabilizing effect and is useful as a preventive and / or therapeutic agent for dry eye, especially for tear film breakup time-shortening dry eye. [Industrial Applicability]

[0128] Olodaterol or a salt thereof stabilizes the tear film and continuously increases tear volume even at low concentrations, and is therefore expected to be useful in the prevention and / or treatment of dry eye.

Claims

1. An ophthalmic composition containing olodaterol or a salt thereof as an active ingredient.

2. An ophthalmic composition as described in claim 1 for preventing and / or treating dry eye.

3. The ophthalmic composition according to claim 2, wherein the dry eye is caused by corneal and conjunctival epithelial disorder resulting from at least one selected from the group consisting of superficial punctate keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbic keratoconjunctivitis, filamentous keratoconjunctivitis, non-infectious keratitis, and non-infectious conjunctivitis.

4. 3. The ophthalmic composition according to claim 2, wherein the dry eye is a disease caused by at least one selected from the group consisting of decreased stability of the tear film, aqueous lacrimation, dry eye, hypolacrimation, keratoconjunctivitis sicca, lacrimal gland dysfunction, meibomian gland dysfunction, VDT (Visual Display Terminal) work, contact lens wear, tear abnormalities, and keratoconjunctivitis.

5. The ophthalmic composition according to any one of claims 1 to 4, wherein olodaterol or a salt thereof is contained at a concentration of 0.1% (w / v) or less.

6. The ophthalmic composition according to any one of claims 1 to 4, wherein olodaterol or a salt thereof is contained at a concentration of 0.01% (w / v) or less.

7. The ophthalmic composition according to any one of claims 1 to 4, wherein olodaterol or a salt thereof is contained at a concentration of 0.00001 to 0.1% (w / v).

8. The ophthalmic composition according to any one of claims 1 to 4, wherein olodaterol or a salt thereof is contained at a concentration of 0.00001 to 0.01% (w / v).

9. The ophthalmic composition according to any one of claims 1 to 4, wherein olodaterol or a salt thereof is contained at a concentration of 0.00001 to 0.005% (w / v).

10. The ophthalmic composition according to any one of claims 1 to 4, wherein olodaterol or a salt thereof is contained at a concentration of 0.00001 to 0.001% (w / v).

11. An ophthalmic composition described in any one of claims 1 to 4, containing olodaterol or its salt at a concentration of 0.0001 to 0.001% (w / v).

12. The ophthalmic composition according to any one of claims 1 to 11, which is in the form of eye drops.

13. The ophthalmic composition according to any one of claims 1 to 12, which has substantially no intraocular pressure increasing and / or intraocular pressure decreasing effect.

14. The ophthalmic composition according to any one of claims 1 to 13, wherein the olodaterol or a salt thereof is olodaterol hydrochloride.

15. An ophthalmic composition for stabilizing the tear film, comprising olodaterol or a salt thereof as an active ingredient.

16. An ophthalmic composition for promoting tear secretion and / or increasing tear volume, comprising olodaterol or a salt thereof as an active ingredient.

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