Ophthalmic composition for inhibiting deterioration of soft contact lenses

Abstract

The present invention provides an ophthalmic composition containing only boric acid or a salt thereof, sodium chloride, a pH adjusting agent, and epinastine or a salt thereof, which has an effect of suppressing deterioration of a soft contact lens.

Description

[0001] The present application is a divisional application of an invention patent application with an application date of October 30, 2019, an application number of 201980071142.8 (PCT / JP2019 / 042590), and an invention name of “Ophthalmic composition for inhibiting deterioration of soft contact lenses”. Technical Field

[0002] The present invention relates to an ophthalmic composition for inhibiting deterioration of soft contact lenses, comprising boric acid or a salt thereof and epinastine or a salt thereof, and also relates to a pollen rupture inhibitor comprising boric acid or a salt thereof and epinastine or a salt thereof, wherein the concentration of the boric acid or a salt thereof is 0.01 to 2% (w / v). Background Art

[0003] For ophthalmic compositions that are envisioned to be reused and that contain solvents such as water, in order to prevent the reproduction of fungi, etc., antiseptic measures above a certain level are required. Therefore, such ophthalmic compositions are usually formulated with preservatives. For example, if it is an eye drop, in most cases, benzalkonium chloride is used as a preservative. Benzalkonium chloride is water-soluble, chemically stable, and has a high antiseptic effect compared to other preservatives. However, it is known that benzalkonium chloride has cytotoxicity and is also adsorbed on soft contact lenses. If benzalkonium chloride is adsorbed on soft contact lenses, it will not only cause discoloration and deformation of soft contact lenses, but also increase the possibility of causing corneal epithelial damage as the contact time with the cornea becomes longer. Therefore, eye drops containing preservatives are not used in the case of wearing soft contact lenses.

[0004] Non-patent document 1 describes Alesion, which is currently marketed in Japan as a therapeutic agent for allergic conjunctivitis and contains epinastine hydrochloride as an active ingredient. (注册商标) Eye drops 0.05%. It is known that this eye drop can be applied even when wearing soft contact lenses because it does not use benzalkonium chloride as a preservative and thus does not cause deterioration of the soft contact lenses.

[0005] It is not known that, depending on the type of active ingredient and additives contained in the ophthalmic composition and the combination of their contents, even an ophthalmic composition that does not contain a preservative such as benzalkonium chloride may affect the deterioration of a soft contact lens. In addition, it is not known that epinastine or its salt causes deterioration of a soft contact lens, and that boric acid or its salt has the effect of inhibiting deterioration of a soft contact lens caused by epinastine or its salt.

[0006] In addition, in recent years, various studies have been conducted on allergic diseases, and their pathogenesis has gradually become clear. For example, according to non-patent literature 2 and non-patent literature 3, it is believed that allergic conjunctivitis caused by fir pollen is due to the invasion of scattered pollen particles into the conjunctival sac, the pollen outer wall is broken by tears, the dissolved allergens are transferred to the conjunctival tissue, and bind to antibodies on mast cells, thereby causing the disease. The pollen outer wall is easily broken in tears, which teaches that the factors that affect the rupture of the pollen outer wall include, in addition to the physical and chemical effects such as pH and temperature, the influence of components in tears (lysozyme, protein, various decomposition enzymes, etc.). In addition, it is also taught that in various anti-allergic eye drops, depending on their different types, in addition to the previous pharmacological effects, they may also have an impact on the rupture of the pollen outer wall and the dissolution of allergens.

[0007] According to Non-Patent Document 4, it is taught that additives contained in eye drops may also affect the rupture of the pollen outer wall and the dissolution of allergens. For example, PBS (phosphate buffered saline) may promote the rupture of the pollen outer wall.

[0008] Prior art literature

[0009] Non-patent literature

[0010] Non-patent document 1: Alesion (registered trademark) eye drops 0.05% with instructions

[0011] Non-patent document 2: Allergy and Immunity 2010, Vol. 17, No. 2, 124-129

[0012] Non-patent document 3: Allergy and Immunity 2011, Vol. 18, No. 2, 82-87

[0013] Non-patent document 4: Allergy and Immunity 2016, Vol. 23, No. 2, 124-130 Summary of the invention

[0014] Problems to be solved by the invention

[0015] Therefore, it is a significant problem to provide an ophthalmic composition containing epinastine or a salt thereof which has the effect of inhibiting the deterioration of soft contact lenses and can be used safely even when wearing soft contact lenses. In addition, an object of the present invention is to provide a pollen rupture inhibitor containing boric acid or a salt thereof and epinastine or a salt thereof at a specific concentration.

[0016] Means for solving problems

[0017] The inventors of the present application have conducted intensive research on an ophthalmic composition containing epinastine or a salt thereof, and as a result, have found that epinastine or a salt thereof itself causes deterioration of soft contact lenses, and that deterioration of soft contact lenses can be suppressed by containing epinastine or a salt thereof and boric acid or a salt thereof. In addition, the inventors have found that by containing boric acid or a salt thereof and epinastine or a salt thereof at a specific concentration, the rupture of pollen can be suppressed, and the therapeutic effect of allergic diseases is excellent, thereby completing the present invention.

[0018] Specifically, the present invention provides the following solutions.

[0019] (1) An ophthalmic composition comprising boric acid or a salt thereof and inhibiting deterioration of a soft contact lens, the ophthalmic composition comprising epinastine or a salt thereof, wherein the soft contact lens can be worn for up to one month.

[0020] (2) The ophthalmic composition according to (1), wherein the concentration of epinastine or a salt thereof is 0.1% (w / v) or less.

[0021] (3) The ophthalmic composition according to (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.05% (w / v).

[0022] (4) The ophthalmic composition according to any one of (1) to (3), wherein the concentration of boric acid or a salt thereof is 0.01 to 2% (w / v).

[0023] (5) The ophthalmic composition according to any one of (1) to (4), which does not contain benzalkonium chloride.

[0024] (6) The ophthalmic composition according to any one of (1) to (5), further comprising a buffer.

[0025] (7) The ophthalmic composition according to any one of (1) to (6), further comprising an isotonicity agent.

[0026] (8) The ophthalmic composition according to any one of (1) to (7), further comprising a stabilizer.

[0027] (9) The ophthalmic composition according to (8), wherein the stabilizer is ethylenediaminetetraacetic acid or a salt thereof.

[0028] (10) The ophthalmic composition according to (9), wherein the concentration of ethylenediaminetetraacetic acid or a salt thereof is 0.005 to 0.1% (w / v).

[0029] (11) The ophthalmic composition according to any one of (1) to (10), which is an eye drop.

[0030] (12) The ophthalmic composition according to any one of (1) to (11), which is used by instillation into an eye wearing a soft contact lens.

[0031] (13) The ophthalmic composition according to any one of (1) to (11), which is used by instillation into an eye that does not wear a soft contact lens.

[0032] (14) The ophthalmic composition according to any one of (1) to (13), which is used by instilling 1 drop or 2 drops into each eye 2 to 4 times a day.

[0033] (15) The ophthalmic composition according to any one of (1) to (14), wherein the soft contact lens is a soft contact lens classified into any one of Group I, Group II, Group III, and Group IV.

[0034] (16) An ophthalmic composition for inhibiting deterioration of soft contact lenses, comprising boric acid or its salt at a concentration of 0.05 to 1% (w / v), ethylenediaminetetraacetic acid or its salt at a concentration of 0.01 to 0.05% (w / v), and an isotonic agent, wherein the ophthalmic composition further comprises epinastine or its salt at a concentration of 0.05 to 0.1 (w / v), wherein the soft contact lenses can be worn for up to one month.

[0035] (17) A method for inhibiting deterioration of a soft contact lens, comprising: applying an ophthalmic composition containing boric acid or a salt thereof, and epinastine or a salt thereof to an eye wearing the soft contact lens, thereby inhibiting deterioration of the soft contact lens.

[0036] (18) A pollen rupture inhibitor comprising boric acid or a salt thereof and epinastine or a salt thereof, wherein the concentration of the boric acid or the salt thereof is 0.01 to 2% (w / v).

[0037] (19) The pollen rupture inhibitor according to (18), wherein the concentration of epinastine or a salt thereof is 0.05% (w / v) or more.

[0038] (20) The pollen rupture inhibitor according to (18), wherein the concentration of epinastine or a salt thereof is 0.1% (w / v).

[0039] (21) The pollen rupture inhibitor according to any one of (18) to (20), which does not contain benzalkonium chloride.

[0040] (22) The pollen rupture inhibitor according to any one of (18) to (21), further comprising a buffer.

[0041] (23) The pollen rupture inhibitor according to any one of (18) to (22), further comprising an isotonic agent.

[0042] (24) The pollen rupture inhibitor according to any one of (18) to (23), further comprising a pH adjuster.

[0043] (25) The pollen rupture inhibitor according to any one of (18) to (24), further comprising a stabilizer.

[0044] (26) The pollen rupture inhibitor according to any one of (18) to (25), which is for use as an eye drop.

[0045] (27) The pollen rupture inhibitor according to any one of (18) to (26), which is used by instillation into an eye wearing a soft contact lens.

[0046] (28) The pollen rupture inhibitor according to any one of (18) to (26), which is used by instillation into an eye that does not wear a soft contact lens.

[0047] (29) The pollen rupture inhibitor according to any one of (18) to (28), which is used by instilling 1 or 2 drops into each eye 2 to 4 times a day.

[0048] (30) A pollen rupture inhibitor comprising boric acid or a salt thereof, epinastine or a salt thereof, and an isotonic agent, wherein the concentration of the boric acid or a salt thereof is 0.05 to 1% (w / v), and the concentration of the epinastine or a salt thereof is 0.05 to 0.1% (w / v).

[0049] (31) A method for inhibiting pollen rupture, characterized in that an ophthalmic composition containing epinastine or a salt thereof and boric acid or a salt thereof at a concentration of 0.01 to 2% (w / v) is brought into contact with pollen.

[0050] (32) An ophthalmic composition comprising boric acid or a salt thereof and epinastine or a salt thereof, wherein the concentration of epinastine or a salt thereof is 0.1% (w / v) or less, and the ophthalmic composition is used by instillation into an eye wearing a soft contact lens.

[0051] (33) The ophthalmic composition according to (32), wherein the concentration of epinastine or a salt thereof is 0.1% (w / v).

[0052] (34) The ophthalmic composition according to (32), wherein the concentration of epinastine or a salt thereof is 0.05% (w / v).

[0053] (35) The ophthalmic composition according to any one of (32) to (34), wherein the concentration of boric acid or a salt thereof is 0.01 to 2% (w / v).

[0054] (36) The ophthalmic composition according to any one of (32) to (35), which does not contain benzalkonium chloride.

[0055] (37) The ophthalmic composition according to any one of (32) to (36), further comprising a buffer.

[0056] (38) The ophthalmic composition according to any one of (32) to (37), further comprising an isotonic agent.

[0057] (39) The ophthalmic composition according to any one of (32) to (38), further comprising a stabilizer.

[0058] (40) The ophthalmic composition according to (39), wherein the stabilizer is ethylenediaminetetraacetic acid or a salt thereof.

[0059] (41) The ophthalmic composition according to (40), wherein the concentration of ethylenediaminetetraacetic acid or a salt thereof is 0.005 to 0.1% (w / v).

[0060] (42) The ophthalmic composition according to any one of (32) to (41), which is an eye drop.

[0061] (43) The ophthalmic composition according to any one of (32) to (42), wherein the soft contact lens is a soft contact lens that can be worn for up to one month.

[0062] (44) An ophthalmic composition comprising boric acid or a salt thereof, and epinastine or a salt thereof, wherein the concentration of epinastine or a salt thereof is 0.1% (w / v) or less.

[0063] (45) The ophthalmic composition according to (44), wherein the concentration of epinastine or a salt thereof is 0.1% (w / v).

[0064] (46) The ophthalmic composition according to (44), wherein the concentration of epinastine or a salt thereof is 0.05% (w / v).

[0065] (47) The ophthalmic composition according to any one of (44) to (46), wherein the concentration of boric acid or a salt thereof is 0.01 to 2% (w / v).

[0066] (48) The ophthalmic composition according to any one of (44) to (47), which does not contain benzalkonium chloride.

[0067] (49) The ophthalmic composition according to any one of (44) to (48), further comprising a buffer.

[0068] (50) The ophthalmic composition according to any one of (44) to (49), further comprising an isotonic agent.

[0069] (51) The ophthalmic composition according to any one of (44) to (50), further comprising a stabilizer.

[0070] (52) The ophthalmic composition according to (51), wherein the stabilizer is ethylenediaminetetraacetic acid or a salt thereof.

[0071] (53) The ophthalmic composition according to (52), wherein the concentration of ethylenediaminetetraacetic acid or a salt thereof is 0.005 to 0.1% (w / v).

[0072] (54) The ophthalmic composition according to any one of (44) to (53), which is an eye drop.

[0073] (55) An ophthalmic composition comprising boric acid or a salt thereof and epinastine or a salt thereof, wherein the concentration of epinastine or a salt thereof is 0.1% (w / v).

[0074] (56) The ophthalmic composition according to (55), wherein the concentration of boric acid or a salt thereof is 0.01 to 2% (w / v).

[0075] (57) The ophthalmic composition according to (55) or (56), comprising boric acid or a salt thereof as a buffer.

[0076] (58) The ophthalmic composition according to any one of (55) to (57), comprising only boric acid or a salt thereof as a buffer.

[0077] (59) The ophthalmic composition according to any one of (55) to (58), which does not contain benzalkonium chloride.

[0078] (60) The ophthalmic composition according to any one of (55) to (59), which does not contain phosphoric acid or a salt thereof.

[0079] (61) The ophthalmic composition according to any one of (55) to (60), which is an eye drop.

[0080] (62) The ophthalmic composition according to any one of (55) to (61), which is used for treating allergic conjunctivitis.

[0081] (63) The ophthalmic composition according to any one of (55) to (62), wherein the composition is administered to each eye twice a day, with one or two drops each time.

[0082] It should be noted that two or more of the above-mentioned structures (1) to (63) may be arbitrarily selected and combined.

[0083] In addition, the present invention also provides the following solutions.

[0084] (64) A method for treating and / or preventing an allergic disease, characterized in that a therapeutically effective amount of the pollen rupture inhibitor according to any one of (18) to (30) is administered to a patient in need of treatment.

[0085] (65) The pollen rupture inhibitor according to any one of (18) to (30), which is used for the treatment and / or prevention of an allergic disease.

[0086] (66) Use of the pollen rupture inhibitor according to any one of (18) to (30) for the manufacture of a medicament for treating and / or preventing allergic diseases.

[0087] (67) The method according to (64), the pollen rupture inhibitor according to (65), or the use according to (66), wherein the allergic disease is allergic conjunctivitis.

[0088] (68) A method for treating and / or preventing an allergic disease, characterized in that a therapeutically effective amount of the ophthalmic composition according to any one of (1) to (16) and (32) to (61) is administered to a patient in need of treatment.

[0089] (69) The ophthalmic composition according to any one of (1) to (16) and (32) to (61), which is used for the treatment and / or prevention of an allergic disease.

[0090] (70) Use of the ophthalmic composition according to any one of (1) to (16) and (32) to (61) for the manufacture of a medicament for treating and / or preventing an allergic disease.

[0091] (71) The method according to (68), the ophthalmic composition according to (69), or the use according to (70), wherein the allergic disease is allergic conjunctivitis.

[0092] (72) The method according to (68), the ophthalmic composition according to (69) or the use according to (70), characterized in that the ophthalmic composition is administered to each eye twice a day, with 1 or 2 drops each time.

[0093] Effects of the Invention

[0094] The present invention can provide an ophthalmic composition containing epinastine or a salt thereof, which has the effect of inhibiting the deterioration of soft contact lenses and can be used safely even when wearing soft contact lenses. In addition, by containing boric acid or a salt thereof and epinastine or a salt thereof at a specific concentration, a pollen rupture inhibitor can be obtained. DETAILED DESCRIPTION

[0095] Hereinafter, the present invention will be described in detail. It should be noted that in the present specification, the "ophthalmic composition" may be replaced with a "pollen rupture inhibitor".

[0096] In the ophthalmic composition of the present invention, "epinastin" refers to a compound represented by the chemical name (±)-3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine, and is a compound represented by the following formula:

[0097] [Chemical formula 1]

[0098]

[0099] Epinastine contained in the ophthalmic composition of the present invention may be a racemic form or an optical isomer.

[0100] Epinastine contained in the ophthalmic composition of the present invention may be in the form of a salt, and is not particularly limited as long as it is a salt acceptable as a pharmaceutical. Examples of the salt include salts with inorganic acids and salts with organic acids.

[0101] Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[0102] Examples of the salt with an organic acid include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid.

[0103] As the salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferred.

[0104] Epinastine or a salt thereof contained in the ophthalmic composition of the present invention may be in the form of a hydrate or a solvate.

[0105] In the ophthalmic composition of the present invention, the content of epinastine or its salt as an active ingredient is preferably less than 0.15% (w / v), and more preferably 0.1% (w / v) or less. For example, the content is 0.1% (w / v). In addition, when the content of epinastine or its salt as an active ingredient is low, in order to obtain a sufficient pharmacological effect, the amount of eye drops and the number of eye drops must be increased, so the lower limit is preferably 0.05% (w / v), and more preferably 0.05% (w / v) or more.

[0106] It should be noted that, in the present invention, "% (w / v)" refers to the mass (g) of the target component contained in 100 mL of the ophthalmic composition of the present invention. In the present invention, when a salt of epinastine is contained, the value is the content of the salt of epinastine. In addition, in the present invention, when epinastine or its salt is formulated in the form of a hydrate or a solvate, the value is the content of epinastine or its salt, the hydrate or the solvate. The same shall apply unless otherwise specified below.

[0107] In the ophthalmic composition of the present invention, boric acid or its salt contributes to inhibiting the deterioration of soft contact lenses, and also has a role as an additive to pharmaceuticals, such as a buffer, preservative, stabilizer, pH adjuster, etc. Therefore, boric acid or its salt can be used as an additive to pharmaceuticals. In addition, in the present invention, the ophthalmic composition containing epinastine or its salt contains boric acid or its salt, thereby improving the pharmacological effect.

[0108] Examples of the boric acid or a salt thereof include boric acid, sodium borate, potassium borate, and the like. These may be hydrates thereof, and boric acid is preferred.

[0109] In the ophthalmic composition of the present invention, the content of boric acid or its salt can be appropriately adjusted and can be 0.001 to 5% (w / v), preferably 0.01 to 2% (w / v), more preferably 0.05 to 1% (w / v), and even more preferably 0.1 to 0.5% (w / v). In addition, 0.1% (w / v), 0.2% (w / v), 0.3% (w / v), 0.4% (w / v), and 0.5% (w / v) are further preferred.

[0110] The ophthalmic composition of the present invention may further contain pharmaceutical additives as needed. Specifically, a buffer, an isotonic agent, a thickener, a surfactant, a stabilizer, an antioxidant, a preservative, a pH adjuster, etc. may be added. These may be used alone or in combination of two or more, and may be mixed in appropriate amounts.

[0111] When a buffer is added to the ophthalmic composition of the present invention, a buffer that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the buffer include trishydroxymethylaminomethane, phosphoric acid or its salt, carbonic acid or its salt, or organic acid or its salt, and may be hydrates or solvates thereof.

[0112] Examples of the phosphoric acid or its salt include phosphoric acid, trisodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate (disodium hydrogen phosphate), tripotassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate, and hydrates thereof may be used.

[0113] Examples of the carbonic acid or its salt include sodium carbonate and sodium hydrogen carbonate, and these may be hydrates.

[0114] Examples of the organic acid or its salt include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acids, and sodium salts and potassium salts thereof, and hydrates thereof may be used.

[0115] When a buffer is added to the ophthalmic composition of the present invention, phosphoric acid or a salt thereof is more preferred, and sodium dihydrogen phosphate and sodium hydrogen phosphate are particularly preferred.

[0116] When a buffer is added to the ophthalmic composition of the present invention, two or more buffers may be used in combination.

[0117] When a buffer is added to the ophthalmic composition of the present invention, the content of the buffer can be appropriately adjusted depending on the type of the buffer, etc., and is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), further preferably 0.1 to 5% (w / v), and particularly preferably 0.1 to 1% (w / v).

[0118] When the isotonic agent is added to the ophthalmic composition of the present invention, an isotonic agent that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the isotonic agent include ionic isotonic agents and nonionic isotonic agents.

[0119] Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

[0120] Examples of the nonionic isotonic agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, and xylitol.

[0121] When the isotonic agent is added to the ophthalmic composition of the present invention, an ionic isotonic agent is more preferred, and sodium chloride is particularly preferred.

[0122] When an isotonic agent is added to the ophthalmic composition of the present invention, two or more isotonic agents may be used in combination.

[0123] The content of the isotonic agent when it is added to the ophthalmic composition of the present invention can be appropriately adjusted depending on the type of the isotonic agent, etc., and is preferably 0.001 to 10% (w / v), more preferably 0.01% to 5% (w / v), further preferably 0.1 to 3% (w / v), and particularly preferably 0.5 to 2% (w / v).

[0124] When a thickener is added to the ophthalmic composition of the present invention, a thickener that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the thickener include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate, and the like.

[0125] When a thickener is added to the ophthalmic composition of the present invention, two or more thickeners may be used in combination.

[0126] When a thickener is added to the ophthalmic composition of the present invention, the content of the thickener can be appropriately adjusted depending on the type of the thickener, etc., and is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and even more preferably 0.1 to 2% (w / v).

[0127] When a surfactant is added to the ophthalmic composition of the present invention, a surfactant that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the surfactant include cationic surfactants, anionic surfactants, and nonionic surfactants.

[0128] Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, 1-hydroxyethyl-2-alkylimidazolines, etc. However, although benzalkonium chloride has the properties of a cationic surfactant, it is not included.

[0129] Examples of the anionic surfactant include phospholipids such as lecithin.

[0130] Examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; castor oil polyoxyl 5, castor oil polyoxyl 6. 9. Castor oil polyoxyl esters such as castor oil polyoxyl 15, castor oil polyoxyl 35, and castor oil polyoxyl 40; polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid esters such as sucrose stearate; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), etc.

[0131] When a surfactant is added to the ophthalmic composition of the present invention, two or more surfactants may be used in combination.

[0132] When a surfactant is added to the ophthalmic composition of the present invention, the content of the surfactant can be appropriately adjusted depending on the type of the surfactant, etc., but is preferably 0.01 to 1%.

[0133] The content of the organic solvent in the aqueous solution is preferably 0.05% to 0.5% (w / v), more preferably 0.05% to 0.2% (w / v).

[0134] When a stabilizer is added to the ophthalmic composition of the present invention, a stabilizer that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the stabilizer include ethylenediaminetetraacetic acid or a salt thereof.

[0135] Examples of ethylenediaminetetraacetic acid or a salt thereof include ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate.

[0136] When a stabilizer is added to the ophthalmic composition of the present invention, two or more stabilizers may be used in combination.

[0137] The content of the stabilizer when the stabilizer is added to the ophthalmic composition of the present invention can be appropriately adjusted according to the type of the stabilizer, and is preferably 0.001 to 1% (w / v), more preferably 0.005 to 0.1% (w / v), and even more preferably 0.01 to 0.05% (w / v). In addition, 0.01% (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), and 0.05% (w / v) are even more preferred.

[0138] When an antioxidant is added to the ophthalmic composition of the present invention, an antioxidant that can be used as an additive for pharmaceuticals may be appropriately added. Examples of the antioxidant include ascorbic acid, tocopherol, butylated hydroxytoluene, sodium sulfite, and the like.

[0139] When an antioxidant is added to the ophthalmic composition of the present invention, two or more antioxidants may be used in combination.

[0140] When an antioxidant is added to the ophthalmic composition of the present invention, the content of the antioxidant can be appropriately adjusted depending on the type of the antioxidant, etc., and is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and even more preferably 0.1 to 2% (w / v).

[0141] When a preservative is added to the ophthalmic composition of the present invention, a preservative that can be used as an additive for pharmaceuticals can be appropriately added.

[0142] In the present invention, examples of the preservative include inverse soaps, parabens, alcohols, and organic acids or salts thereof.

[0143] Examples of the inverse soaps include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzethonium bromide, chlorhexidine gluconate, and chlorhexidine hydrochloride.

[0144] Examples of the parabens include methyl paraben, ethyl paraben, propyl paraben and butyl paraben.

[0145] As the alcohol, for example, there is chlorobutanol.

[0146] Examples of the organic acid or its salt include sorbic acid or its salt and sodium dehydroacetate. Examples of the sorbic acid or its salt include sodium sorbate and potassium sorbate.

[0147] The content of the preservative when the ophthalmic composition of the present invention is combined with the preservative can be appropriately adjusted according to the type of the preservative, etc. The content of the preservative is as long as it is an amount that does not adversely affect safety, and its upper limit is, for example, 1% (w / v), preferably 1% (w / v) or less, more preferably 0.5% (w / v) or less, further preferably 0.1% (w / v) or less, and further preferably 0.01% (w / v) or less. In addition, as long as it is an amount that can play an antiseptic role, its lower limit is, for example, 0.0001% (w / v), preferably 0.0001% (w / v) or more, and more preferably 0.001% (w / v) or more. As the content of the preservative, it is preferably 0.0001 to 1% (w / v), more preferably 0.001 to 0.5% (w / v), and more preferably 0.001 to 0.1% (w / v).

[0148] Generally, preservatives affect the deterioration of soft contact lenses. Therefore, the ophthalmic composition of the present invention may contain a preservative as long as the soft contact lenses do not deteriorate, but preferably contains no preservative, and particularly preferably contains no benzalkonium chloride.

[0149] In addition, the ophthalmic composition of the present invention contains boric acid or a salt thereof in order to suppress deterioration of soft contact lenses. Since boric acid or a salt thereof also functions as an antiseptic, the above-mentioned antiseptic may not be contained.

[0150] When a pH adjuster is added to the ophthalmic composition of the present invention, the pH adjuster can be appropriately added as a pH adjuster that can be used as an additive to pharmaceuticals, for example, an acid or a base. Examples of the acid include hydrochloric acid, phosphoric acid, citric acid, and acetic acid, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0151] The pH of the ophthalmic composition of the present invention may be within a range acceptable as a pharmaceutical, for example, within a range of 4.0 to 8.5 or 4.0 to 8.0, preferably 6.0 to 8.0, more preferably 6.5 to 7.5. A particularly preferred pH is 6.7 to 7.3, and even more preferably 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, or 7.3.

[0152] The osmotic pressure ratio of the ophthalmic composition of the present invention may be within a range acceptable as a pharmaceutical, and is, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, and further preferably 0.9 to 1.2.

[0153] The ophthalmic composition of the present invention can be used for eyes not wearing contact lenses, and can also be used when wearing hard contact lenses or soft contact lenses.

[0154] According to the Medical and Pharmaceutical Approval No. 645 of March 31, 1999, "Regarding the handling of information to be attached when applying for a license to manufacture (import) soft contact lenses and disinfectants for soft contact lenses (Regarding the handling of information to be attached when applying for a license to manufacture (import) soft contact lenses and disinfectants for soft contact lenses)", soft contact lenses are divided into four categories. That is, they are classified into Group I (substances with a water content of less than 50% and non-ionic), Group II (substances with a water content of 50% or more and non-ionic), Group III (substances with a water content of less than 50% and ionic), and Group IV (substances with a water content of 50% or more and ionic), and substances having an anionic monomer content of 1% or more in the constituent monomers of the raw material polymer are ionic, and substances having an anionic monomer content of less than 1% are non-ionic. In addition, as soft contact lenses, for example, soft contact lenses having 2-hydroxyethyl methacrylate (HEMA), (polyethylene glycol) monomethacrylate (PEGMA), glyceryl methacrylate (GMA), N,N-dimethylacrylamide (DMA), vinyl alcohol (VA), N-vinyl pyrrolidone (NVP or VP), methacrylic acid (MAA), fluorine-containing methacrylate compounds, silicon-containing methacrylate compounds, silicone hydrogels, cycloalkyl methacrylates, etc. as main components can be cited.

[0155] The soft contact lens in the present invention may be made of any of the above-mentioned materials, and may also be classified into any of the four types of soft contact lenses, regardless of whether they are ionic or non-ionic, and whether they contain water or not.

[0156] Soft contact lenses are divided into glasses that are worn all day (worn on the eyes when getting up in the morning and removed before going to bed) and glasses that are worn continuously (worn during sleep within a specified period of time) according to their wearing method. The soft contact lenses in the present invention can be glasses of any of the above categories.

[0157] Soft contact lenses are classified into conventional glasses, disposable (disposable after use) glasses, frequently replaced glasses, and regularly replaced glasses according to their replacement cycle. Disposable glasses are contact lenses that are no longer worn once they are removed from the eyes, and there are daily disposable glasses, weekly disposable glasses, etc. Frequently replaced glasses are glasses that are taken care of and stored every day when the glasses are removed, and can be worn again within a specified period, and the replacement period is usually 1 week or 2 weeks. Regularly replaced glasses are glasses that can be worn again by performing lens care in the same way as frequently replaced glasses, and the replacement period is usually 1 month or 3 months. The soft contact lenses in the present invention can be any of the above-mentioned classifications. Since the ophthalmic composition of the present invention inhibits the deterioration of soft contact lenses, it is also preferably used for instillation into eyes wearing daily disposable glasses, but it is more preferably used for instillation into eyes wearing disposable glasses that can be worn for more than 2 days, frequently replaced glasses, or regularly replaced glasses. In addition, it is more preferably used for instillation into eyes wearing soft contact lenses that can be worn for more than 1 week, more than 2 weeks, or 1 month.

[0158] In the present invention, "deterioration of soft contact lenses" refers to deformation, discoloration, etc. of soft contact lenses. Examples of causes of contact lens deterioration include adsorption of active ingredients such as epinastine or its salts, and additives such as benzalkonium chloride on the surface of soft contact lenses.

[0159] As a method for confirming whether a soft contact lens is deteriorated by the ophthalmic composition of the present invention, for example, a method of directly dropping the composition onto the soft contact lens, a method of dipping the composition onto the soft contact lens, etc. can be cited. From the viewpoint of the contact time between the ophthalmic composition of the present invention and the soft contact lens, the method of dipping the composition onto the soft contact lens causes the soft contact lens to deteriorate more than the method of directly dropping the composition onto the soft contact lens. When the soft contact lens is dipped, the dipping time is, for example, 5 minutes or 10 minutes, and the longer the time, the easier it is for the soft contact lens to deteriorate.

[0160] In the ophthalmic composition of the present invention, all of the components may be dissolved or part of them may be suspended, and it is more preferably in the form of a liquid in which all of the components are dissolved.

[0161] Unless otherwise specified, the ophthalmic composition of the present invention may contain active ingredients used in eye drops other than epinastine or a salt thereof.

[0162] Since the ophthalmic composition of the present invention contains epinastine or a salt thereof, it can be used for all treatments (e.g., improvement, alleviation, inhibition of aggravation, etc.) and prevention of allergic conjunctivitis and its symptoms, and can be used for both eyes wearing soft contact lenses and eyes not wearing soft contact lenses.

[0163] The ophthalmic composition of the present invention can be used as an ophthalmic preparation, and its dosage form is not particularly limited as long as it can be used as a pharmaceutical. As dosage forms, for example, eye drops, ointments, creams, gels, percutaneous absorption preparations, patches, injections, etc. are mentioned. Eye drops are particularly preferred.

[0164] The ophthalmic composition of the present invention is preferably administered in an appropriate amount 2 to 4 times a day. In particular, when the ophthalmic composition is an eye drop, it is preferably administered 2 to 4 times a day, 1 drop or 2 drops per eye, and it is further preferred to administer 2 to 4 times a day, 1 drop per eye. It should be noted that when the ophthalmic composition of the present invention is administered 2 to 4 times a day, the interval between eye drops can be at least 1 hour, preferably 2 hours, and more preferably 3 hours. 1 drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, more preferably about 0.02 to about 0.05 mL, and particularly preferably about 0.03 mL.

[0165] The container for storing the ophthalmic composition of the present invention can be any of a multi-dose container, a single-dose container for one-time use, or a PFMD (preservative-free multi-dose) container. It should be noted that the raw material of the container is not particularly limited, as long as it is a general container for eye drops, preferably a resin container, for example, polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic acid, polystyrene, polycyclic olefin copolymer, etc. can be used. In addition, when the material of the resin container is polyethylene, polyethylene is classified according to its density, and containers such as low-density polyethylene (LDPE), medium-density polyethylene (MDPE), and high-density polyethylene (HDPE) can be used.

[0166] The ophthalmic composition of the present invention can be prepared by a general method, for example, by dissolving or suspending each component in distilled water, adjusting the osmotic pressure, pH, etc. to within a predetermined range, and performing filtration sterilization or heat sterilization.

[0167] The ophthalmic composition of the present invention has the effect of inhibiting the rupture of pollen present on the mucous membrane and effectively inhibiting the occurrence of allergic symptoms caused by pollen, and can therefore be used as a pollen rupture inhibitor. When the ophthalmic composition of the present invention is used as a pollen rupture inhibitor, the ophthalmic composition of the present invention is useful as a therapeutic agent for allergic diseases, particularly allergic conjunctivitis.

[0168] In the present invention, "allergic disease" refers to a disease or its symptoms caused by an immune response to an antigen from the outside due to the rupture of the pollen outer wall. As an example of an allergic disease, allergic conjunctivitis can be cited, but it is not limited to this. In the present invention, the treatment of an allergic disease refers to all treatments (e.g., cure, improvement, alleviation, inhibition of aggravation, etc.) of an allergic disease or its symptoms and its prevention. In addition, it also includes preventing the recurrence of an allergic disease.

[0169] In the present invention, the so-called "patient" is not limited to humans, but also refers to other animals, such as dogs, cats, horses, etc. The patient is preferably a mammal, more preferably a human. In the present invention, "therapeutically effective amount" means: an amount that brings about a therapeutic effect on a disease and its symptoms, or an amount that brings about a delay in the aggravation of a disease and its symptoms, etc., compared with an untreated subject.

[0170] Example

[0171] Preparation examples and test examples are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

[0172] Preparation Examples

[0173] Representative formulation examples of the present invention are shown below. In the following formulation examples, the amount of each component is the content in 100 mL of the formulation.

[0174] Preparation Example 1

[0175]

[0176] Preparation Example 2

[0177]

[0178] Preparation Example 3

[0179]

[0180] Preparation Example 4

[0181]

[0182] Test example

[0183] 1. Deformation test of soft contact lens (SCL) based on drop addition

[0184] (1) Preparation of test preparation

[0185] Epinastine hydrochloride, phosphate, and sodium chloride were dissolved in water so that the concentration of epinastine hydrochloride contained was 0.1% (w / v), and a pH adjuster (hydrochloric acid and / or sodium hydroxide) and water were added to make a total of 10 mL, and the mixture was sterilized by filtration to prepare a test preparation (pH 7.0) of composition 1. In addition, a test preparation (pH 7.0) of composition 2 was prepared by the same method as the test preparation of composition 1, except that the concentration of epinastine hydrochloride was 0.15% (w / v). It should be noted that the amounts of phosphate and sodium chloride contained in the test preparation of composition 2 were the same as those of the test preparation of composition 1.

[0186] (2) Test methods

[0187] Add 1 drop of each test preparation to the convex surface of the soft contact lens so that it spreads all over the soft contact lens. Shake off the excess and rinse with saline after 4 minutes. Repeat 7 cycles as 1 cycle. Measure the diameter and base curve of the soft contact lens, and set the diameter deformation and base curve deformation in the range of -0.20 to +0.20 as suitable. It should be noted that the soft contact lens used is 2Week Acuvue, which is classified as Group IV. (注册商标) (Johnson & Johnson Co., Ltd.).

[0188] The diameter deformation amount and the base arc deformation amount are calculated using the following calculation formula.

[0189] Diameter deformation (mm) = (diameter after 7 cycles) - (diameter before use) Base arc deformation (mm) = (base arc after 7 cycles) - (base arc before use)

[0190] (3) Experimental results and discussion

[0191] Table 1 shows the test results.

[0192] [Table 1]

[0193] Test preparation Composition 1 Composition 2 Diameter deformation (mm) 0.09 0.28 Base arc deformation (mm) 0.07 -0.04 determination Suitable Not suitable

[0194] As shown in Table 1, even when Composition 1 was repeatedly dropped onto the soft contact lens, deformation of the soft contact lens was not observed, but with Composition 2, deformation of the soft contact lens due to repeated dropping was observed.

[0195] 2. Deformation test of soft contact lens (SCL) based on immersion

[0196] (1) Preparation of test preparation

[0197] The test preparations of compositions 3 to 8 were prepared by the same method as the preparation method of composition 1. The concentrations of the components contained in the test preparations are shown in Table 2. It should be noted that the amounts of phosphate and sodium chloride contained in the test preparations did not differ between the test preparations and were contained in the same amounts.

[0198] [Table 2]

[0199]

[0200] (2) Test methods

[0201] The soft contact lenses were immersed in each test preparation at room temperature for 10 minutes and then taken out. The diameter and base curve of the soft contact lenses were measured, and the diameter deformation and base curve deformation were set to be suitable within the range of -0.20 to +0.20. It should be noted that the soft contact lenses used were 2Week Acuvue, which is classified as Group IV. (注册商标) (Johnson & Johnson Co., Ltd.).

[0202] The diameter deformation amount and the base arc deformation amount are calculated using the following calculation formula.

[0203] Diameter deformation (mm) = (diameter after immersion) - (diameter before immersion)

[0204] Base arc deformation (mm) = (base arc after dipping) - (base arc before dipping)

[0205] (3) Experimental results and discussion

[0206] The test results are shown in Table 3.

[0207] [Table 3]

[0208]

[0209] As shown in Table 3, for composition 7 not containing boric acid and composition 8 not containing boric acid but containing benzalkonium chloride, deformation of the soft contact lens due to immersion in the test preparation was confirmed. On the other hand, for compositions 3 to 6 containing boric acid, deformation of the soft contact lens was not observed even when immersed in the test preparation.

[0210] The above results indicate that a composition containing epinastine or a salt thereof and boric acid or a salt thereof has an effect of suppressing deformation of soft contact lenses.

[0211] 3. Pollen outer wall rupture inhibition test (1)

[0212] (1) Preparation of test preparation

[0213] As the test preparations, the test preparations of compositions 5 to 7 used in the above-mentioned "2. Soft contact lens (SCL) deformation test by immersion" were used.

[0214] (2) Test methods

[0215] Each time, about 3 μL of cedar pollen particles were collected and inoculated into a 96-well microplate. Then, 50 μL of the test preparation was dripped into each well, and the total pollen count was immediately measured under an optical microscope using a hemocytometer. In addition, the number of pollen particles that broke after 5 minutes and 10 minutes of dripping was also measured under a microscope.

[0216] The pollen rupture rate was calculated by the following formula.

[0217] Pollen rupture rate (%) = (number of pollens ruptured 5 minutes or 10 minutes after dropwise addition) / (total number of pollens immediately after dropwise addition of the test preparation) × 100

[0218] (3) Experimental results and discussion

[0219] Table 4 shows the test results.

[0220] [Table 4]

[0221] Test preparation Composition 5 Composition 6 Composition 7 Pollen rupture rate after 5 minutes 21％ 20％ 28％ Pollen rupture rate after 10 minutes 36％ 41％ 66％

[0222] As shown in Table 4, compositions 5 and 6 containing boric acid showed an effect of inhibiting pollen outer wall rupture compared to composition 7 not containing boric acid. Therefore, it is taught that the pharmacological effect of epinastine or its salt is enhanced by incorporating boric acid or its salt into epinastine or its salt.

[0223] 4. Pollen outer wall rupture inhibition test (2)

[0224] (1) Preparation of test preparation

[0225] The test preparations of compositions 9 to 14 were prepared by the same method as the preparation method of composition 1. The concentrations of the components contained in each test preparation are shown in Table 5. It should be noted that the amounts of phosphate and sodium chloride contained in each test preparation did not differ between the test preparations and were contained in the same amounts.

[0226] [Table 5]

[0227]

[0228] (2) Test methods

[0229] The pollen rupture rate was calculated by the same method as in the above-mentioned "3. Pollen outer wall rupture inhibition test (1)".

[0230] (3) Experimental results and discussion

[0231] The test results are shown in Table 6.

[0232] [Table 6]

[0233]

[0234] As shown in Table 6, the composition containing epinastine or a salt thereof and boric acid or a salt thereof at a concentration of 0.1% (w / v) showed an effect of suppressing the rupture of the pollen outer wall.

[0235] In addition, as shown in Tables 4 and 6, the composition containing epinastine or its salt and boric acid or its salt at a concentration of 0.1% (w / v) further inhibits the rupture of the pollen outer wall compared to the composition containing epinastine or its salt and boric acid or its salt at a concentration of 0.05% (w / v).

[0236] Industrial Applicability

[0237] The present invention provides an ophthalmic composition for inhibiting the deterioration of soft contact lenses, comprising boric acid or a salt thereof and epinastine or a salt thereof. In addition, a pollen rupture inhibitor is provided, comprising boric acid or a salt thereof and epinastine or a salt thereof, wherein the concentration of the boric acid or a salt thereof is 0.01 to 2% (w / v).

Claims

1. An ophthalmic composition comprising only boric acid or a salt thereof, sodium chloride, a pH adjuster, and epinastine or a salt thereof, wherein the boric acid or a salt thereof is at least one selected from the group consisting of boric acid, sodium borate, and potassium borate, and the pH value of the ophthalmic composition is 6.5 to 7.

5.

2. The ophthalmic composition according to claim 1, wherein Boric acid or its salt is boric acid and sodium borate.

3. The ophthalmic composition according to claim 1, wherein The pH adjuster is dilute hydrochloric acid and / or sodium hydroxide.

4. The ophthalmic composition according to claim 1, wherein The pH value of the ophthalmic composition is 6.7 to 7.

3.

5. The ophthalmic composition according to claim 1, wherein The pH value of the ophthalmic composition was 7.

0.

6. The ophthalmic composition according to claim 1, wherein The concentration of epinastine or its salt is 0.1% (w / v).

7. The ophthalmic composition according to claim 1, wherein Epinastine or its salt is epinastine hydrochloride.

8. The ophthalmic composition according to claim 1, wherein 0.01 to 2% (w / v) of boric acid is added.

9. The ophthalmic composition according to claim 1, wherein 0.01-2% (w / v) sodium borate is added.

10. The ophthalmic composition according to claim 1, which is an eye drop.

11. The ophthalmic composition according to claim 1, wherein Use 1 or 2 drops in each eye twice a day. 12 . The ophthalmic composition according to claim 1 , which is used by instillation into an eye wearing a soft contact lens.

13. The ophthalmic composition according to claim 1, which is used for suppressing deterioration of soft contact lenses.

14. The ophthalmic composition according to claim 1, which is used for treating allergic conjunctivitis.

15. The ophthalmic composition according to claim 1, which is used for inhibiting the rupture of the outer wall of pollen.

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