Ophthalmic composition

Abstract

To provide a novel ophthalmic composition.SOLUTION: An ophthalmic composition comprises (A) at least one kind selected from a group consisting of epinastine and a salt thereof, and (B) terpenoid.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition (or ophthalmic agent). [Background technology]

[0002] Epinastine hydrochloride is known as an antihistamine, and attempts are being made to use epinastine hydrochloride for ophthalmic purposes.

[0003] For example, Patent Document 1 (Japanese Patent No. 6134853) discloses an eye drop solution that contains only epinastine or a salt thereof at a concentration of more than 0.075% (w / v) as an active ingredient, and is substantially free of preservatives and ingredients having preservative properties. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 6134853 (Claims, Examples) Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel ophthalmic composition. [Means for solving the problem]

[0006] As described above, epinastine or a salt thereof is used as an active ingredient, and ophthalmic preparations in combination with other ingredients have yet to be developed. The present inventors have found through their investigations that ophthalmic preparations containing epinastine or a salt thereof as an active ingredient have problems such as leaving a white residue after drying and being highly cytotoxic.

[0007] On the other hand, there has been a demand for ophthalmic preparations containing menthol or the like to reduce irritation and efficiently exert a cooling sensation.

[0008] Under these circumstances, the present inventors conducted intensive research to solve the above problems, and as a result, discovered that a novel ophthalmic composition can be obtained by combining epinastine or a salt thereof with a specific component (such as menthol), and that such a composition can solve or improve (suppress) problems such as white residue and cytotoxicity, and can reduce irritation and efficiently exert a cooling sensation. After further research, the present inventors completed the present invention.

[0009] That is, the present invention relates to the following inventions, etc. [1] (A) one or more members selected from the group consisting of epinastine and its salts, and (B) An ophthalmic composition containing a terpenoid. [2] The ophthalmic composition according to [1], wherein the component (B) contains one or more selected from the group consisting of menthol and camphor. [3] The ophthalmic composition according to [1] or [2], wherein the component (B) contains at least menthol. [4] The ophthalmic composition according to any one of [1] to [3], comprising 0.005 to 0.5 w / v % of component (A). [5] The ophthalmic composition according to any one of [1] to [4], comprising 0.0001 w / v % or more of the component (B). [6] The ophthalmic composition according to any one of [1] to [5], comprising component (B) in an amount of 0.05 w / v % or less. [7] The ophthalmic composition according to any one of [1] to [6], wherein the proportion of the component (B) is 0.0002 to 100 parts by mass per part by mass of the component (A). [8] The ophthalmic composition according to any one of [1] to [7], further comprising (C) a surfactant. [9] The ophthalmic composition according to any one of [1] to [8], further comprising a surfactant (C), the proportion of the component (C) being 0.02 to 500 parts by mass per part by mass of the component (A).

[10] The ophthalmic composition according to any one of [1] to [9], further comprising a surfactant (C), the proportion of the component (C) being 0.1 to 1000 parts by mass per part by mass of the component (B).

[11] The ophthalmic composition according to any one of [1] to

[10] , which has a pH of 4 to 9.

[12] Further, the composition contains a surfactant (C), The component (B) contains at least menthol, The proportion of component (A) is 0.01 to 0.1 w / v%, The proportion of the component (B) is 0.0001 to 0.15 w / v%, The proportion of component (C) is 0.007 to 5 w / v%, The ratio of the (B) component is 0.02 to 1 part by mass per part by mass of the (A) component, The ratio of the (C) component is 0.5 to 50 parts by mass per part by mass of the (A) component, The ophthalmic composition according to any one of [1] to

[11] , which has a pH of 5 to 8.

[13] The composition according to any one of [1] to

[12] , wherein the composition is contained in a container, and at least a part of the material of the container that comes into contact with the composition is polyethylene terephthalate.

[14] A method for reducing the surface tension of an ophthalmic composition containing (A) one or more members selected from the group consisting of epinastine and its salts, comprising comprising comprising (B) a terpene in the ophthalmic composition.

[15] A method for reducing white residue in an ophthalmic composition containing (A) one or more members selected from the group consisting of epinastine and its salts, comprising comprising comprising (B) a terpene in the ophthalmic composition.

[16] A method for improving the fillability of an ophthalmic composition containing (A) one or more members selected from the group consisting of epinastine and its salts into a container, comprising comprising comprising adding (B) a terpene to the ophthalmic composition.

[17] A method for improving drainage of an ophthalmic composition containing (A) one or more members selected from the group consisting of epinastine and its salts, comprising comprising comprising (B) a terpene in the ophthalmic composition.

[18] A method for reducing the cytotoxicity of an ophthalmic composition containing (A) one or more members selected from the group consisting of epinastine and its salts, comprising comprising comprising (B) a terpene in the ophthalmic composition.

[19] (B) A method for reducing (or suppressing) the irritation (irritation, irritation sensation) of an ophthalmic composition containing a terpene, comprising comprising comprising (A) one or more members selected from the group consisting of epinastine and its salts in the ophthalmic composition.

[20] (B) A method for enhancing (or improving) the cooling sensation of an ophthalmic composition containing a terpene, comprising comprising comprising the ophthalmic composition (A) containing one or more members selected from the group consisting of epinastine and its salts. [twenty one] The method according to any of

[14] to

[20] , wherein the component (B) comprises one or more selected from the group consisting of menthol and camphor. [twenty two] The method according to any one of

[14] to

[21] , wherein the component (B) contains at least menthol and further contains a surfactant (C). Effect of the Invention

[0010] The present invention provides a novel ophthalmic composition. Such an ophthalmic composition contains a terpenoid in addition to epinastine or a salt thereof, and is an unprecedented ophthalmic composition (a blended ophthalmic composition).

[0011] In another embodiment of the ophthalmic composition of the present invention, the surface tension of the ophthalmic composition comprising epinastine or a salt thereof may be reduced (or inhibited).

[0012] In another embodiment of the ophthalmic composition of the present invention, while containing epinastine or a salt thereof, the white residue after drying (whitening phenomenon or precipitation due to non-volatile matter) can be reduced (or inhibited or prevented).

[0013] In another aspect of the ophthalmic composition of the present invention, the filling properties (the ability to fill a container, the ease of filling a container) of an ophthalmic composition containing epinastine or a salt thereof can be improved (or enhanced).

[0014] In another embodiment of the ophthalmic composition of the present invention, the drainage of an ophthalmic composition containing epinastine or a salt thereof may be improved (or enhanced) (or dripping may be suppressed or prevented).

[0015] The above-mentioned properties are useful from the viewpoint of formulation of ophthalmic compositions, and are also advantageous from the viewpoint of usability, since poor drainage and the like can lead to difficulties in controlling the amount of eye drops administered.

[0016] In another aspect of the ophthalmic composition of the present invention, the cytotoxicity of an ophthalmic composition containing epinastine or a salt thereof can be reduced (and thus the safety can be improved or enhanced). According to the study by the present inventors, the cytotoxicity of an ophthalmic composition containing epinastine or a salt thereof seems to be relatively high. However, according to the present invention, an ophthalmic composition having low cytotoxicity (particularly substantially no cytotoxicity) can be provided, despite containing such epinastine or a salt thereof.

[0017] In another embodiment of the ophthalmic composition of the present invention, even if a terpene such as menthol is contained, the irritation can be reduced or suppressed. That is, while menthol and the like can function as a cooling agent or the like in the ophthalmic composition, they can also cause an irritation (stimulation) to the eyes. However, according to the present invention, unexpectedly, the presence of epinastine or a salt thereof can suppress such irritation (or can provide an ophthalmic composition with less irritation) even when the composition contains menthol or the like.

[0018] In another embodiment of the ophthalmic composition of the present invention, the cooling sensation can be improved (or efficiently exerted). That is, menthol and the like can impart a cooling sensation (function as a cooling agent) in an ophthalmic composition, but according to the present invention, unexpectedly, the presence of epinastine or a salt thereof can improve (or efficiently exert) such a cooling sensation.

[0019] Thus, the composition of the present invention is extremely useful and has high practical utility. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] In this specification, the unit of content "w / v%" is synonymous with "g / 100 mL." In addition, in this specification, unless otherwise specified, the abbreviation "POE" means polyoxyethylene, and "POP" means polyoxypropylene.

[0021] [1. Ophthalmic composition] The ophthalmic composition of the present invention contains at least (A) epinastine and / or a salt thereof, and (B) a terpenoid.

[0022] (A) Epinastine and / or its salt (Component (A)) Salts of epinastine are not particularly limited as long as they are pharma- ceutically or physiologically acceptable salts, and examples thereof include organic acid salts [e.g., monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylates (fumarate, maleate, succinate, malonate, etc.), oxycarboxylates (lactate, tartrate, citrate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate), etc.

[0023] Preferred epinastine and / or its salts include epinastine hydrochloride (monohydrochloride).

[0024] Epinastine and / or a salt thereof may be used alone or in combination of two or more kinds.

[0025] The content of the component (A) in the composition may be, for example, about 0.0001 w / v% or more (e.g., 0.0003 to 5 w / v%), preferably 0.0005 w / v% or more (e.g., 0.001 to 1 w / v%), more preferably 0.003 w / v% or more (e.g., 0.005 to 0.5 w / v%), even more preferably 0.005 w / v% or more (e.g., 0.007 to 0.2 w / v%), still more preferably 0.008 w / v% or more (e.g., 0.01 to 0.1 w / v%), particularly preferably 0.02 w / v% or more (e.g., 0.03 to 0.1 w / v%), and most preferably 0.03 w / v% or more (e.g., 0.04 to 0.08 w / v%, 0.045 to 0.06 w / v%, etc.) relative to the total amount of the composition. Among these, 0.05 w / v%, 0.1 w / v%, 0.3 w / v%, etc. are preferred, with 0.05 w / v% being particularly preferred.

[0026] (B) Terpenoids (Component (B)) The composition of the present invention generally contains terpenoids (terpene, terpenes) in addition to epinastine and / or its salt. Such terpenoids are also used as cooling agents, and the composition of the present invention can efficiently exert the function of such cooling agents without impairing them.

[0027] Examples of terpenoids include menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, ryuno, etc. These may be in the d-, l- or dl-form.

[0028] The composition may contain terpenoids in the form of essential oils, such as, for example, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil.

[0029] The terpenoids (and essential oils) may be used alone or in combination of two or more.

[0030] In particular, the composition of the present invention preferably contains one or more selected from the group consisting of menthol, camphor and borneol, more preferably contains one or more selected from the group consisting of menthol and camphor, and even more preferably contains at least menthol.

[0031] When menthol is combined with other terpenoids, the ratio of menthol to the total terpenoids may be, for example, 10% by mass or more, 30% by mass or more, 50% by mass or more, 70% by mass or more, 90% by mass or more, etc.

[0032] The content of component (B) in the composition may be, for example, 0.00001 w / v% or more, 0.00005 w / v% or more, 0.0001 w / v% or more, 0.0003 w / v% or more, 0.0005 w / v% or more, 0.0007 w / v% or more, 0.0008 w / v% or more, 0.0009 w / v% or more, 0.001 w / v% or more, 0.002 w / v% or more, or 0.003 w / v% or more, relative to the total amount of the composition. The content (ratio) of the (B) component may be the terpenoid content (the content of the (B) component based on terpenoids) (the same applies hereinafter to the description of the content (ratio)).

[0033] In addition, the content of component (B) in the composition may be 5 w / v% or less, 3 w / v% or less, 2 w / v% or less, 1.5 w / v% or less, 1.2 w / v% or less, 1 w / v% or less, 0.9 w / v% or less, 0.8 w / v% or less, 0.7 w / v% or less, 0.6 w / v% or less, 0.5 w / v% or less, 0.4 w / v% or less, 0.3 w / v% or less, 0.2 w / v% or less, 0.15 w / v% or less, 0.1 w / v% or less, 0.08 w / v% or less, 0.07 w / v% or less, 0.06 w / v% or less, 0.05 w / v% or less, 0.04 w / v% or less, or 0.03 w / v% or less, relative to the total amount of the composition.

[0034] In particular, in the present invention, component (B) may be used in a relatively small amount (low concentration). In such a case, the content of the component (B) in the composition may be, for example, 0.5 w / v% or less (e.g., 0.00001 to 0.4 w / v%), preferably 0.3 w / v% or less (e.g., 0.00005 to 0.25 w / v% or less), more preferably 0.2 w / v% or less (e.g., 0.0001 to 0.15 w / v%), even more preferably 0.1 w / v% or less (e.g., 0.0005 to 0.08 w / v%), particularly preferably 0.07 w / v% or less (e.g., 0.001 to 0.06 w / v%), and most preferably 0.05 w / v% or less (e.g., 0.001 to 0.05 w / v%, 0.002 to 0.04 w / v%, 0.003 to 0.03 w / v%, etc.) relative to the total amount of the composition.

[0035] The proportion of the (B) component may be about 0.0002 to 100 parts by mass, preferably 0.001 to 20 parts by mass, more preferably 0.01 to 10 parts by mass, particularly preferably 0.02 to 5 parts by mass, and most preferably 0.05 to 1 part by mass, per part by mass of the (A) component.

[0036] In particular, when the (B) component is used in a relatively small amount (low concentration), the proportion of the (B) component may be, for example, about 0.0002 to 8 parts by mass, preferably 0.001 to 5 parts by mass, more preferably 0.01 to 2 parts by mass, even more preferably 0.02 to 2 parts by mass, particularly preferably 0.02 to 1 part by mass, especially more preferably 0.04 to 1 part by mass, and most preferably about 0.05 to 0.5 parts by mass, per part by mass of the (A) component.

[0037] In consideration of the viewpoint of achieving the effects of the present invention, the proportion of the (B) component, relative to 1 part by mass of the (A) component, may be, for example, 0.01 parts by mass or more, 0.02 parts by mass or more, 0.04 parts by mass or more, 0.06 parts by mass or more, 0.08 parts by mass or more, 0.1 parts by mass or more, or 0.15 parts by mass or more; or 2 parts by mass or less, 1.6 parts by mass or less, 1.2 parts by mass or less, 1.0 parts by mass or less, 0.9 parts by mass or less, 0.8 parts by mass or less, 0.6 parts by mass or less; or may be 0.01 to 2 parts by mass, preferably 0.02 to 1.6 parts by mass, more preferably 0.04 to 1.2 parts by mass, even more preferably 0.06 to 1.0 parts by mass, even more preferably 0.08 to 0.9 parts by mass, particularly preferably 0.1 to 0.8 parts by mass, and most preferably 0.15 to 0.6 parts by mass.

[0038] [Other ingredients] The composition of the present invention may or may not further contain other components. In the present invention, even if other components are contained, the effects of the present invention can be secured in many cases. In addition, by containing other components, the effects of the present invention can be more effectively realized in some cases.

[0039] (C) Surfactant (Component (C)) The composition of the present invention may contain a surfactant. Examples of the surfactant include nonionic surfactants. By including such a surfactant, various effects can be efficiently achieved. For example, by using the surfactant in combination with the (B) component, white residue and the like can be more efficiently improved.

[0040] Nonionic surfactants include polysorbates (POE sorbitan fatty acid esters) such as POE(20) sorbitan monolaurate (polysorbate 20), POE(20) sorbitan monopalmitate (polysorbate 40), POE(20) sorbitan monostearate (polysorbate 60), POE(20) sorbitan tristearate (polysorbate 65), and POE(20) sorbitan monooleate (polysorbate 80); poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 235 ... POE·POP glycols such as POE 403, Poloxamer 237, and Poloxamer 124; POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, and POE hydrogenated castor oil 80; POE castor oils such as POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, and POE castor oil 50; poly(monostearate) Ethylene glycol (2 E.O.), polyethylene glycol monostearate (4 E.O.), polyethylene glycol monostearate (9 E.O.), polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (23 E.O.), polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (32 E.O.), polyethylene glycol monostearate (40 E.O., Polyoxyl 40 stearate), poly Examples of the polyethylene glycol monostearate include ethylene glycol (45 E.O.), polyethylene glycol monostearate (55 E.O.), polyethylene glycol monostearate (75 E.O.), and polyethylene glycol monostearate (140 E.O.); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; and POE alkyl phenyl ethers such as POE (10) nonylphenyl ether.In the above compounds, POE stands for polyoxyethylene, POP stands for polyoxypropylene, and the numbers in parentheses stand for the number of moles added.

[0041] Among these, POE sorbitan fatty acid esters; POE·POP glycols; POE hydrogenated castor oil; POE castor oil; and polyethylene glycol monostearate are preferred, with polysorbate 80, poloxamer 407, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, POE castor oil 3, POE castor oil 10, POE castor oil 35, and polyoxyl 40 stearate being more preferred, with polysorbate 80 and POE hydrogenated castor oil 60 being even more preferred, and polysorbate 80 being particularly preferred.

[0042] The surfactants may be used alone or in combination of two or more kinds.

[0043] When the composition of the present invention contains a surfactant (particularly, a nonionic surfactant), the proportion of component (C) may be, for example, 0.001 w / v% or more, preferably 0.005 w / v% or more, more preferably 0.01 w / v% or more, and particularly preferably 0.05 w / v% or more, relative to the total amount of the composition.

[0044] When the composition of the present invention contains a surfactant (particularly a nonionic surfactant), the proportion of component (C) may be, for example, 10 w / v% or less, preferably 5 w / v% or less, more preferably 2 w / v% or less, and particularly preferably 1 w / v% or less, relative to the total amount of the composition.

[0045] When the composition of the present invention contains a surfactant (particularly a nonionic surfactant), the proportion of component (C) may typically be, for example, 0.001 to 10 w / v%, preferably 0.007 to 5 w / v%, more preferably 0.03 to 2 w / v%, and particularly preferably 0.1 to 1 w / v%, relative to the total amount of the composition.

[0046] When the composition of the present invention contains a surfactant (particularly, a nonionic surfactant), the proportion of the component (C) may be, for example, 0.02 to 500 parts by mass, preferably 0.1 to 100 parts by mass, more preferably 0.5 to 50 parts by mass, and particularly preferably 1 to 20 parts by mass, per part by mass of the component (A).

[0047] When the composition of the present invention contains a surfactant (particularly, a nonionic surfactant), the proportion of the component (C) may be, for example, 0.02 to 10,000 parts by mass, preferably 0.1 to 5,000 parts by mass, more preferably 0.6 to 2,000 parts by mass, and particularly preferably 2 to 1,000 parts by mass, per part by mass of the component (B).

[0048] Amino acids The composition of the present invention may contain amino acids. Amino acids include, for example, amino acids or their salts, and amino acid analogs, including compounds having an amino group and a carboxyl group or a sulfone group in the molecule, or derivatives thereof.

[0049] Specific examples include amino acids or their salts, and mucopolysaccharides or their salts. Among amino acids, examples of amino acids or their salts include monoaminomonocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid (epsilon aminocaproic acid, etc.), monoaminodicarboxylic acids such as aspartic acid and glutamic acid, and their salts, diaminomonocarboxylic acids such as arginine and lysine, and their salts, and derivatives of aminoethylsulfonic acid (taurine), and their salts.

[0050] Among the amino acids, examples of mucopolysaccharides or derivatives or salts thereof include acidic mucopolysaccharides such as derivatives of chondroitin sulfate, hyaluronic acid, alginic acid, and the like, or salts thereof.

[0051] Specific examples of amino acids and mucopolysaccharides include, preferably, glycine, alanine, γ-aminobutyric acid, γ-aminovaleric acid, epsilon aminocaproic acid, aspartic acid, glutamic acid, arginine, aminoethylsulfonic acid, chondroitin sulfate, hyaluronic acid, alginic acid, and salts thereof.

[0052] Chondroitin sulfate is a sugar chain in which D-glucuronic acid and N-acetylglucosamine are repeated, and sulfate is ester-linked to all or some of the hydroxyl groups. The positions and number of sulfate bonds vary, and chondroitin sulfate also has derivatives (e.g., those in which all or some of the N-acetylglucosamine is replaced with iduronic acid). Such chondroitin sulfate may have any structure. Examples include chondroitin 4-sulfate (chondroitin sulfate A), chondroitin 6-sulfate (chondroitin sulfate C), and chondroitin sulfate E in which the 4- and 6-positions of N-acetylglucosamine are sulfated. Chondroitin sulfate may also be extracted from animals.

[0053] The salt of an amino acid or the salt of a mucopolysaccharide includes a medicamentously, pharmacologically or physiologically acceptable salt. Examples of such salts include salts with organic acids [e.g., monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polycarboxylates (fumarates, maleates, etc.), oxycarboxylates (lactates, tartrates, citrates, succinates, malonates, etc.), organic sulfonates (methanesulfonates, toluenesulfonates, tosylates, etc.)], salts with inorganic acids (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [e.g., ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), and aluminum], and the like, and the salts are appropriately selected depending on the compound.

[0054] Specific salts include salts of aspartic acid (sodium aspartate, potassium aspartate, magnesium aspartate, magnesium-potassium aspartate mixture, etc.), salts of glutamic acid (sodium glutamate, magnesium glutamate, etc.), sodium chondroitin sulfate, and sodium hyaluronate.

[0055] The amino acids may be of the D-, L- or DL-form.

[0056] Preferred amino acids include aminoethylsulfonic acid (taurine) or a salt thereof, sodium chondroitin sulfate, aspartates (e.g., potassium L-aspartate, magnesium potassium L-aspartate), epsilon-aminocaproic acid or a salt thereof, hyaluronic acid or a salt thereof (such as sodium hyaluronate), and among these, hyaluronic acid or a salt thereof (such as sodium hyaluronate), aminoethylsulfonic acid (taurine) and / or a salt thereof, and sodium chondroitin sulfate are preferred.

[0057] The amino acids may be used alone or in combination of two or more kinds.

[0058] When the composition contains amino acids, the content of the amino acids in the composition may be, for example, about 0.001 w / v%, preferably 0.01 to 20 w / v%, more preferably 0.03 to 10 w / v%, even more preferably 0.05 to 5 w / v%, even more preferably 0.1 to 3 w / v%, and particularly preferably about 0.15 to 2 w / v%, and may usually be 0.001 to 10 w / v% [for example, 0.005 to 10 w / v%, preferably 0.01 to 5 w / v%, and even more preferably 0.05 to 3 w / v% (for example, 0.1 to 1 w / v%)] relative to the total amount of the composition.

[0059] Fat-soluble antioxidants The compositions of the present invention may also include a fat-soluble antioxidant.

[0060] Examples of fat-soluble antioxidants include butyl-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbic acid esters such as ascorbyl palmitate, ascorbyl stearate, aminopropyl ascorbyl phosphate, tocopherol ascorbyl phosphate, ascorbyl triphosphate, and ascorbyl phosphate palmitate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2-one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechin, tannin, and curcumin; and CoQ10.

[0061] Of these, dibutylhydroxytoluene is preferred.

[0062] The fat-soluble antioxidants may be used alone or in combination of two or more kinds.

[0063] When the composition contains a fat-soluble antioxidant, the content of the fat-soluble antioxidant in the composition may be, for example, about 0.0001 to 0.1 w / v%, preferably 0.0005 to 0.01 w / v%, more preferably 0.0007 to 0.009 w / v%, even more preferably 0.001 to 0.008 w / v%, even more preferably 0.003 to 0.007 w / v%, and most preferably 0.0045 to 0.006 w / v%, relative to the total amount of the composition.

[0064] Water-soluble antioxidants The compositions of the present invention may also include a water-soluble antioxidant.

[0065] Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (such as disodium ascorbic acid 2-sulfate, sodium ascorbate, magnesium ascorbyl 2-phosphate, and sodium ascorbyl 2-phosphate), sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetic acid, or a salt thereof (such as disodium edetate and tetrasodium edetate).

[0066] Of these, edetic acid or a salt thereof (disodium edetate, tetrasodium edetate, etc.) is preferred.

[0067] The water-soluble antioxidants may be used alone or in combination of two or more kinds.

[0068] When the composition contains a water-soluble antioxidant, the content of the water-soluble antioxidant in the composition may be, for example, about 0.0001 to 1 w / v%, preferably 0.0005 to 0.5 w / v%, more preferably 0.0007 to 0.1 w / v%, even more preferably 0.001 to 0.008 w / v%, even more preferably 0.003 to 0.007 w / v%, and most preferably about 0.00455 to 0.0065 w / v%, relative to the total amount of the composition.

[0069] Antiallergic The composition of the present invention may contain an anti-allergic agent.

[0070] Examples of antiallergic agents include tranilast, cromoglycic acid, ibudilast, ashitazanolast, tazanolast, suplatast, pemirolast, levocabastine, olopatadine, ketotifen, amlexanox, oxatomide, and salts thereof.

[0071] Examples of the salts include the salts exemplified above, such as alkali metal or alkaline earth metal salts (sodium cromoglycate, potassium cromoglycate, magnesium cromoglycate, calcium cromoglycate, etc.), inorganic acid salts (e.g., hydrochloride salts, sulfate salts, etc.), and organic acid salts (e.g., tosylate salts, fumarate salts, etc.).

[0072] From the viewpoint of the stability of the composition, the composition of the present invention may not contain ashitazanolast or the like.

[0073] The antiallergic agents may be used alone or in combination of two or more kinds.

[0074] When the composition contains an antiallergic agent, the content of the antiallergic agent in the composition may be, for example, about 0.1 to 10 w / v%, preferably 0.2 to 8 w / v%, more preferably 0.3 to 5 w / v%, even more preferably 0.5 to 3 w / v%, particularly preferably 0.7 to 2 w / v%, even more particularly preferably 0.8 to 1.5 w / v%, and most preferably 0.9 to 1.2 w / v%, relative to the total amount of the composition.

[0075] Antihistamines The compositions of the present invention may also include an antihistamine. The antihistamine (antihistamine other than epinastine and its salts) is not particularly limited as long as it is a substance having an antihistamine effect, and examples thereof include chlorpheniramine, diphenhydramine, ketotifen, olopatadine, levocabastine, iproheptine, and salts thereof.

[0076] The salt may be any pharmacy or physiologically acceptable salt, and examples thereof include the above-mentioned exemplified salts such as organic acid salts [e.g., maleate salts, fumarate salts (ketotifen fumarate, etc.)], inorganic acid salts (e.g., olopatadine hydrochloride, etc.), and metal salts.

[0077] Specific salts include, for example, diphenhydramine hydrochloride, iproheptine hydrochloride, chlorpheniramine maleate, and the like.

[0078] The antihistamines may be used alone or in combination of two or more.

[0079] When the composition contains an antihistamine, the content of the antihistamine in the composition may be, for example, about 0.0001 w / v%, preferably 0.001 to 10 w / v%, more preferably 0.003 to 5 w / v%, even more preferably 0.005 to 1 w / v%, still more preferably 0.01 to 0.5 w / v%, particularly preferably about 0.015 to 0.3 w / v% (e.g., 0.02 to 0.1 w / v%), and most preferably about 0.025 to 0.05 w / v% (e.g., 0.03 w / v%), and typically about 0.01 to 0.05 w / v%, relative to the total amount of the composition.

[0080] Anti-inflammatory agents The compositions of the present invention may also include an anti-inflammatory agent. The anti-inflammatory agent is not particularly limited as long as it is a substance having an anti-inflammatory effect, and examples thereof include pranoprofen, indomethacin, allantoin, berberine, azulene sulfonic acid, diclofenac, bromfenac, glycyrrhizic acid, epsilon aminocaproic acid, zinc, silver, tranexamic acid, lysozyme, and salts thereof.

[0081] Examples of the salt include the above-mentioned exemplified salts such as salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases, and examples thereof include sulfate salts, lactate salts, hydrochloride salts, chloride salts, sodium salts, and potassium salts.

[0082] Specific salts include berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, sodium azulene sulfonate, diclofenac sodium, bromfenac sodium, zinc sulfate, zinc lactate, silver nitrate, and lysozyme chloride.

[0083] The anti-inflammatory agents may be used alone or in combination of two or more kinds.

[0084] When the composition contains an anti-inflammatory agent, the content of the anti-inflammatory agent in the composition may be, for example, about 0.001 w / v%, preferably 0.005 to 5 w / v%, more preferably 0.01 to 1 w / v%, even more preferably 0.1 to 0.5 w / v% (e.g., 0.3 w / v%), and particularly preferably 0.2 to 0.3 w / v% (e.g., 0.25 w / v%) relative to the total amount of the composition.

[0085] The composition of the present invention may contain various components (for example, components not belonging to the categories of the above-mentioned components). Examples of such components (additives) include preservatives, buffers, pH regulators, isotonicity agents, thickeners or viscosifiers, stabilizers, oils, sugars, polymeric compounds, polyhydric alcohols, inorganic salts, non-fat-soluble antioxidants (or water-soluble antioxidants), etc.

[0086] The additives may be used alone or in combination of two or more thereof. Furthermore, each additive may be used alone or in combination of two or more thereof.

[0087] Specific examples of the additives are given below.

[0088] Preservatives The compositions of the present invention may also contain a preservative. Examples of preservatives include polydonium chloride, alkyl polyaminoethyl glycines (e.g., alkyl diaminoethyl glycine hydrochloride, etc.), sodium benzoate, ethanol, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, alexidine, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoic acid esters (e.g., methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (e.g., polyhexanide hydrochloride, etc.), and Gloquil (manufactured by Rhodia).

[0089] Among these, alkyl polyaminoethyl glycines (e.g., alkyl diaminoethyl glycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoic acid esters, and biguanide compounds are preferred, with quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds being more preferred, and benzalkonium chloride and polyhexanide hydrochloride being even more preferred.

[0090] When the composition contains a preservative, the proportion of the preservative in the composition is, for example, 0.000001 w / v% or more, particularly 0.00001 w / v% or more, particularly 0.00005 w / v% or more, particularly 0.001 w / v% or more, particularly 0.005 w / v% or more, relative to the total amount of the composition. The total amount of the preservative is, for example, 1 w / v% or less, particularly 0.1 w / v% or less, particularly 0.05 w / v% or less, particularly 0.03 w / v% or less, particularly 0.025 w / v% or less, relative to the total amount of the composition.

[0091] Buffer The compositions of the present invention may also include a buffering agent. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer and the like.

[0092] Components of the borate buffer include boric acid, borate salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.), etc. The borate salts may be hydrates.

[0093] Ingredients of the phosphate buffer include phosphoric acid, phosphate salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.), etc. The phosphate salts may be hydrates.

[0094] Components of the carbonate buffer include carbonic acid, carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, etc.), etc. The carbonates may be hydrates.

[0095] Components of the citrate buffer include citric acid, citrate salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.), etc. The citrate salts may be in the form of a hydrate.

[0096] Components of the acetate buffer include acetic acid, acetate salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.), etc. The acetate salts may be hydrates.

[0097] Among them, boric acid buffers are preferred from the viewpoint of preservative effectiveness and more prominently exhibiting the effects of the present invention, and phosphate buffers are more preferred from the viewpoint of low cytotoxicity, etc., and boric acid buffers are more preferred. As the boric acid buffer, a combination of boric acid and its salts is preferred, a combination of boric acid and an alkali metal salt and / or an alkaline earth metal salt of boric acid is more preferred, a combination of boric acid and an alkali metal salt of boric acid is even more preferred, and a combination of boric acid and borax is even more preferred.

[0098] When the buffer is composed of a plurality of components, the ratio may be appropriately selected depending on the range in which the buffer function can be exhibited, etc. For example, when boric acid and a borate (such as borax) are combined, the ratio may be about 0.1 to 100 parts by mass, preferably 0.5 to 80 parts by mass, more preferably 1 to 50 parts by mass, and particularly preferably 2 to 40 parts by mass (e.g., 3 to 30 parts by mass, 5 to 25 parts by mass, 7 to 22 parts by mass, 10 to 20 parts by mass) of the borate relative to 100 parts by mass of boric acid.

[0099] In the composition of the present invention, even if such a buffer (borate buffer) is contained, the function of reducing white residue can be efficiently exhibited. In addition, by using a borate buffer (or boric acid) or a phosphate buffer, etc., various properties of the composition may be more efficiently exhibited in some cases.

[0100] When a buffer is added to the composition of the present invention, the amount of the buffer varies depending on the type of buffer, the type and amount of other ingredients, etc., and cannot be uniformly specified, but examples of the buffer amount include 0.001 w / v% or more, particularly 0.01 w / v% or more, particularly 0.05 w / v% or more, particularly 0.1 w / v% or more, based on the total amount of the composition. Also, the buffer amount includes 10 w / v% or less, particularly 5 w / v% or less, particularly 3 w / v% or less, particularly 2.5 w / v% or less, particularly 2 w / v% or less, based on the total amount of the composition.

[0101] In particular, when a boric acid buffer (total amount of boric acid and borate) is used, the proportion of the buffer in the composition may be about 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 4 w / v%, and even more preferably 0.2 to 3 w / v% (e.g., 0.2 to 2.5 w / v%, 0.3 to 2 w / v%, 0.3 to 1.5 w / v%, 0.4 to 1 w / v%, etc.) relative to the entire composition.

[0102] pH Adjustment Agent Examples of pH adjusters include hydrochloric acid, sulfuric acid, polyphosphoric acid, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, and diisopropanolamine. The pH adjusters may be used alone or in combination of two or more kinds.

[0103] Isotonic agent Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol. The isotonicity agents may be used alone or in combination of two or more kinds.

[0104] Thickeners or Viscosifiers The ophthalmic compositions of the present invention may include a viscosity increasing or thickening agent.

[0105] Examples of thickening agents or viscosifying agents include guar gum, hydroxypropyl guar gum, cellulose-based polymer compounds (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), gum arabic, karaya gum, xanthan gum, agar, alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (e.g., heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid, hyaluronate (sodium salt, etc.), etc.), starch, chitin and derivatives thereof, chitosan and derivatives thereof, carrageenan, sorbitol ... Examples of suitable alginate salts include tallow, polyvinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salt, potassium salt, etc.), amine salts of polyacrylic acid (monoethanolamine salt, diethanolamine salt, triethanolamine salt, etc.), casein, gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (sodium salt, etc.), alginate esters (propylene glycol ester, etc.), powdered tragacanth, and triisopropanolamine. The thickening or viscosifying agents may be used alone or in combination of two or more.

[0106] Stabilizers Stabilizers include, for example, hydroxyalkylamines (or aminoalkanols or alkanolamines, such as monoethanolamine, diethanolamine, triethanolamine, trometamol, etc.), sodium formaldehyde sulfoxylate (Rongalit), aluminum monostearate, and glyceryl monostearate. The stabilizers may be used alone or in combination of two or more kinds.

[0107] Oil Examples of oils include animal oils such as squalane and refined lanolin, mineral oils such as liquid paraffin and petrolatum (white petrolatum, etc.), and vegetable oils such as castor oil and sesame oil. From the viewpoint of the stability of the composition, petrolatum (white petrolatum, etc.) may not be contained.

[0108] Sugars Examples of sugars include monosaccharides and oligosaccharides (disaccharides, etc.), and specific examples include glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, and mannitol.

[0109] Polyhydric alcohol Examples of the polyhydric alcohol include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, and polyvinyl alcohol.

[0110] Inorganic salts Examples of inorganic salts include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, sodium carbonate (including dry sodium carbonate), potassium bicarbonate, potassium carbonate, magnesium sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium acetate, sodium acetate, and sodium thiosulfate. Among these, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate are preferred, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferred, and potassium chloride and sodium chloride are even more preferred.

[0111] The composition of the present invention may further contain a component having pharmacological activity or physiological activity.

[0112] The pharmacologically active ingredients or physiologically active ingredients can be used alone or in combination of two or more kinds.

[0113] Examples of such pharmacologically active ingredients and physiologically active ingredients include the active ingredients in various medicines listed in the 2017 edition of the Guide to Manufacturing and Marketing Approval Standards and Application Practices for Prescription and Non-prescription Drugs (supervised by the Japan Society of Regulatory Science). Examples include decongestants, eye muscle regulating agents, astringents, vitamins, amino acids, antibacterial or disinfectant agents, local anesthetic ingredients, analgesics, and sulfa drugs. Specific examples of these drugs are listed below.

[0114] Decongestants (vasoconstrictors) Decongestants include, for example, α-adrenergic agonists, specifically imidazoline decongestants such as oxymetazoline, tetrahydrozoline, naphazoline, or salts thereof such as hydrochlorides and nitrates, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine bitartrate, etc. These may be in any of the d-, l- or dl-forms.

[0115] To explain the imidazoline vasoconstrictor in detail, the salt of the imidazoline vasoconstrictor may be any salt that is pharma- ceutically or physiologically acceptable, and examples of such salts include organic acid salts such as maleate and fumarate, inorganic acid salts such as hydrochloride and sulfate, metal salts, etc. Among the salts, inorganic acid salts are preferred, hydrochloride or nitrate are more preferred, and hydrochloride (e.g., tetrahydrozoline hydrochloride) is particularly preferred.

[0116] Among decongestants (vasoconstrictors), imidazoline vasoconstrictors are preferred, tetrahydrozoline, naphazoline, or a salt thereof is more preferred, and tetrahydrozoline or a salt thereof is even more preferred.

[0117] Eye muscle regulator Examples of eye muscle adjusting agents include cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, and atropine sulfate.

[0118] Vitamins Examples of vitamins include flavin adenine dinucleotide or a salt thereof (e.g., sodium flavin adenine dinucleotide), cobalamin or a salt thereof (e.g., cyanocobalamin, methylcobalamin), retinol, a salt thereof or a derivative thereof (e.g., retinol acetate, retinol palmitate), pyridoxine or a salt thereof (e.g., pyridoxine hydrochloride), panthenol, pantothenic acid or a salt thereof (e.g., sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol, a salt thereof or a derivative thereof (e.g., tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or a salt thereof (e.g., pyridoxal phosphate), ascorbic acid or a salt thereof (e.g., sodium ascorbate, calcium ascorbate), and the like.

[0119] Among these, flavin adenine dinucleotide or a salt thereof (particularly sodium flavin adenine dinucleotide), cobalamin or a salt thereof (particularly cyanocobalamin), retinol, a salt thereof or a derivative thereof (particularly retinol acetate and retinol palmitate), pyridoxine or a salt thereof (particularly pyridoxine hydrochloride), panthenol, pantothenic acid or a salt thereof (particularly sodium pantothenate and calcium pantothenate), tocopherol, a salt thereof or a derivative thereof (particularly tocopherol acetate) are preferred, with pyridoxine hydrochloride and tocopherol acetate being more preferred. The composition of the present invention may not contain pyridoxine or a salt thereof.

[0120] Antibacterial or disinfectant Examples of antibacterial or bactericidal agents include sulfa drugs such as sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomazole sodium, and sulfisomidine sodium, alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride.

[0121] Local anesthetic ingredients Examples of local anesthetic ingredients include procaine hydrochloride and lidocaine hydrochloride.

[0122] Base or Carrier The compositions of the present invention may include a base or carrier. The composition containing such a base or carrier can be prepared, for example, by mixing the above-mentioned components with a pharma- ceutically acceptable base or carrier, according to a conventional method described in the 17th Edition of the Japanese Pharmacopoeia. The composition may be appropriately heated during preparation.

[0123] Examples of the base or carrier include water, polar solvents (particularly water-soluble solvents) such as ethanol, oily bases, etc. The base or carrier may be used alone or in combination of two or more. In such a composition (particularly an aqueous composition), each component may usually be dissolved.

[0124] In particular, the composition of the present invention may be an aqueous composition (eg, a composition containing water or a mixture of water and a water-soluble solvent).

[0125] Properties The properties of the composition of the present invention are not particularly limited, and may be any of liquid, fluid, gel, or semi-solid.In addition, it also includes those that become liquid, fluid, gel, or semi-solid by preparation at the time of use.Semi-solid refers to a property that has plasticity that can be deformed by applying force, such as an ointment.The preferred property of the composition is liquid (liquid).

[0126] Furthermore, as described above, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier), an oily composition (mainly containing an oily or hydrophobic base or carrier), or in particular an aqueous composition.

[0127] In the case of an aqueous composition, the content of water is preferably 50% by mass or more, more preferably 75% by mass or more, and even more preferably 90% by mass or more, based on the total amount of the composition (or preparation). It may also be 95% by mass or more, or 98% by mass or more. The base or carrier may consist of only water.

[0128] In the case of an oil-based composition, the water content is preferably less than 50% by mass, more preferably 30% by mass or less, and even more preferably 20% by mass or less, based on the total amount of the composition (or preparation).

[0129] pH The pH of the composition of the present invention is preferably 3 or more (e.g., 4 or more), more preferably 5 or more (e.g., 5.5 or more), and even more preferably 6 or more. Also, the pH is preferably 10 or less, more preferably 9 or less, and even more preferably 8.5 or less.

[0130] The pH of the composition of the present invention may be, for example, 4 to 9, preferably 4.5 to 8.5, and more preferably 5 to 8, or may be 5.5 to 8, 6 to 8, 6 to 7.5, or 6.5 to 7.5. In the present invention, even at the above pH level, the effects of reducing white residue and cytotoxicity can be efficiently achieved.

[0131] Osmolarity The osmotic pressure ratio of the composition of the present invention is, for example, preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more, and is preferably 5 or less, more preferably 3 or less, and even more preferably 2 or less.

[0132] The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 17th revised Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, cooling it in a desiccator (silica gel), accurately weighing 0.900 g of it, dissolving it in purified water to make exactly 100 mL, or by using a commercially available standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution).

[0133] Dosage form The dosage form (form, shape, structure) of the composition of the present invention is not particularly limited, and examples thereof include eye drops (also called eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), eye washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens wetting solutions, intraocular injections (e.g., intravitreal injections), contact lens solutions (cleaning solutions, storage solutions, disinfectants, multipurpose solutions, package solutions), preservatives for excised eye tissues such as corneas for transplantation, and irrigation solutions for surgery. Eye drops, eye washes, and eye ointments also include those used when wearing contact lenses.

[0134] It should be noted that the term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0135] Preferred dosage forms of the composition of the present invention include eye drops, eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens wearing solution, contact lens solution (cleaning solution, storage solution, disinfectant, multi-purpose solution, packaging solution), etc., more preferred are eye drops, eye wash, contact lens wearing solution, contact lens solution (cleaning solution, storage solution, disinfectant, multi-purpose solution), etc., even more preferred are eye drops and eye wash, and particularly preferred are eye drops.

[0136] The composition of the present invention may be in the form of a single-use unit dose or a multi-dose that can be used repeatedly, and may be contained and used in a multi-dose form.

[0137] container The composition of the present invention may be contained (filled, injected, sealed) in a container. The container may be any packaging material having a part (surface) that comes into contact with the composition (formulation), and may be composed of, for example, a container body that contains the composition (e.g., a liquid composition), a part that includes the container's extraction port (nozzle, inner plug), a suction tube, a cap, etc.

[0138] The material constituting the container can be selected from a wide range of materials, and examples thereof include a material in which at least a part or all of the portion in contact with the composition is plastic (e.g., olefin-based resins, styrene-based resins, acrylic-based resins, polyester-based resins, polycarbonate-based resins, fluororesins, chlorine-based resins (polyvinyl chloride, etc.), polyamide-based resins, polyacetal-based resins, polyphenylene ether-based resins (modified polyphenylene ether, etc.), polyarylates, polysulfones, polyimide-based resins, cellulose-based resins (cellulose acetate, etc.), hydrocarbon-based resins which may be substituted with halogen atoms, etc.), glass, metals (aluminum, etc.), and the like.

[0139] The container may be made of a single material or two or more materials.

[0140] Examples of olefin-based resins include ethylene-based resins [e.g., polyethylene (including high-density polyethylene, low-density polyethylene, very low-density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene, etc.), ethylene-propylene copolymers, etc.], propylene-based resins [e.g., polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymers, etc.], and methylpentene-based resins (e.g., polymethylpentene, etc.).

[0141] Examples of styrene-based resins include polystyrene and acrylonitrile-containing styrene-based resins (such as acrylonitrile-styrene copolymers (AS resins), acrylonitrile-butadiene-styrene copolymers (ABS resins)).

[0142] Examples of acrylic resins include resins containing, as a polymerization component, an acrylic acid ester such as methyl acrylate, or a methacrylic acid ester such as methyl methacrylate, cyclohexyl methacrylate, or t-butylcyclohexyl methacrylate.

[0143] Examples of polyester-based resins include aromatic polyester-based resins [e.g., resins having alkylene terephthalate units (alkylene terephthalate-based resins: e.g., polyethylene terephthalate (PET), polytrimethylene terephthalate, polybutylene terephthalate (PBT)), etc.), resins having alkylene naphthalate units (e.g., polyethylene naphthalate (PEN), polybutylene naphthalate, etc.)].

[0144] Examples of fluororesin include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene-hexafluoropropylene copolymer, ethylene-tetrafluoroethylene copolymer, and ethylene-chlorotrifluoroethylene copolymer.

[0145] The polyacetal resin may be one consisting only of oxymethylene units, or one partially containing oxyethylene units.

[0146] The modified polyphenylene ether may, for example, be polystyrene-modified polyphenylene ether.

[0147] The polyarylate may be, for example, amorphous polyarylate.

[0148] The polyimide resin may be an aromatic polyimide, for example, a polymer of pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

[0149] Examples of the cellulose acetate include cellulose diacetate and cellulose triacetate.

[0150] The material of the container is preferably glass, plastic, etc. Therefore, at least a part of the container (or the material of the container) may be made of glass, plastic, etc.

[0151] In particular, plastics (i.e., plastic containers) such as olefin-based resins, styrene-based resins, and polyester-based resins are preferred, with ethylene-based resins, propylene-based resins, alkylene terephthalate-based resins, and polystyrene being more preferred, polypropylene, polyethylene terephthalate, and polystyrene being even more preferred, and polyethylene terephthalate being even more preferred.

[0152] The composition of the present invention can achieve the effects of the present invention in a relatively wide variety of containers (or their materials, such as glass, plastic, and particularly plastic such as PET). In particular, the composition of the present invention can efficiently achieve the effects of the present invention (e.g., excellent filling properties) in containers made of plastic such as PET.

[0153] The container may be made of a material that is a polymer blend with a polymer other than the polymer. When the container material for storing the ophthalmic composition of the present invention is a polymer blend with the polymer, the mixing ratio of the polymer to the polymer other than the polymer is not particularly limited as long as the effects of the present invention are achieved, but the total weight of the polymers is preferably 30 w / w% or more, more preferably 50 w / w% or more, even more preferably 65 w / w% or more, and particularly preferably 80 w / w% or more, based on the total weight of the entire constituent materials.

[0154] At least a part of the container that comes into contact with the composition of the present invention (contact surface) may be made of the above material. For example, a layer or film made of the above material may be formed on the inner surface of the container, or the container itself may be molded from the above material. From the viewpoint of significantly achieving the effects of the present invention, it is preferable that the container itself is molded from the above material.

[0155] Furthermore, the parts constituting the container (the container body, the part including the container's extraction port (nozzle, inner plug), suction tube, cap, etc.) may be made of the above materials, or the entire container may be made of the above materials. In particular, from the viewpoint of significantly achieving the effects of the present invention, it is preferable that the container body is made of the above materials, and it is more preferable that the entire container body is made of the above materials (a state in which some of the layers constituting the container body are not made of the above materials).

[0156] Target disease (use) The target disease (use) of the composition of the present invention is not particularly limited, so long as it is for ophthalmic use. For example, the composition is useful for alleviating, improving, suppressing, or treating allergic symptoms, itchy eyes, sore eyes, eye inflammation, blepharitis, blurred vision, hyperemia, foreign body sensation (gritty feeling, etc.), corneal damage, corneal injury, watery eyes (epiphora), palpebral conjunctival follicles, ocular discharge (eye discharge), etc., as well as for enhancing, normalizing, and protecting the cornea barrier function.

[0157] Watery eyes are a symptom that occurs when the tear drainage pathway from the lacrimal puncta to the lacrimal canaliculus, lacrimal sac, and nasolacrimal duct becomes blocked by eye discharge or when excessive tears are produced due to irritation.

[0158] As used herein, "alleviation" includes alleviation of symptoms and inhibition of progression of symptoms, and "improvement," "inhibition," and "treatment" include alleviation of symptoms, inhibition of progression of symptoms, cure, or complete recovery.

[0159] In particular, the composition of the present invention is suitable for use in alleviating, improving, suppressing, or treating allergic symptoms (eye allergic symptoms).

[0160] Allergens causing allergic symptoms are not particularly limited, but may be pollen (such as cedar pollen and cypress pollen), house dust (indoor dust), and the like.

[0161] In another embodiment, the composition of the present invention is suitable for relieving, improving, suppressing, or treating symptoms such as itchy eyes, eye pain, eye inflammation, blepharitis, blurred vision, bloodshot eyes, watery eyes, foreign body sensation, corneal damage, corneal injury, watery eyes (epiphora), palpebral conjunctival follicles, eye discharge, etc. These symptoms may or may not be caused by allergic symptoms.

[0162] How to use The method of use (mode of use) of the composition of the present invention can be appropriately selected depending on its properties, etc.

[0163] For example, when the composition of the present invention is a preparation to be applied to the eyes, such as eye drops, eye washes, or eye ointments, the method of use varies depending on the symptoms to be treated, and may be, for example, once or more, twice or more, three or more, four or more, five or more, or six or more times per day. It may also be 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, or 4 or less times per day. It is particularly preferred to administer the composition four times per day.

[0164] When the composition of the present invention is an eye drop, for example, 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops may be administered each time. Preferably, 1 to 2 drops are administered. One drop may also be administered. The amount of one drop administered may preferably be 30 to 50 μL.

[0165] When the composition of the present invention is an eyewash, for example, 1 to 30 mL, preferably 1 to 20 mL, and more preferably 4 to 6 mL may be used for each eyewash.

[0166] When the composition of the present invention is an eye ointment, for example, 0.001 to 5 g may be applied to the eye each time.

[0167] When the composition of the present invention is a contact lens wetting solution, when putting on or taking off a contact lens, for example, 1 to 3 drops, preferably 1 to 2 drops, may be dropped onto one and / or both sides of the contact lens each time to wet the lens before wearing, and it is preferable to wet both sides of the contact lens before wearing.

[0168] 2. Reduction of surface tension The ophthalmic composition according to this embodiment can reduce (or suppress) the surface tension in the ophthalmic composition.

[0169] Thus, as one embodiment of the present invention, the following method is provided.

[0170] A method for reducing the surface tension of an ophthalmic composition by combining (or containing in combination) (A) one or more members selected from the group consisting of epinastine and its salts, (B) a terpenoid, and (C) a surfactant.

[0171] A method for reducing the surface tension of an ophthalmic composition comprising (A) one or more members selected from the group consisting of epinastine and its salts, comprising comprising incorporating (B) a terpenoid (and (C) a surfactant) into the ophthalmic composition.

[0172] Furthermore, as one embodiment of the present invention, the following agent is provided.

[0173] An agent for reducing the surface tension of an ophthalmic composition comprising (A) one or more members selected from the group consisting of epinastine and its salts, and comprising (B) a terpenoid (and (C) a surfactant).

[0174] 3. Reducing white residue The ophthalmic composition according to this embodiment can reduce (or suppress) white residue in the ophthalmic composition (the ophthalmic composition after drying).

[0175] Thus, as one embodiment of the present invention, the following method is provided.

[0176] A method for reducing white residue in an ophthalmic composition by combining (or containing in combination) (A) one or more members selected from the group consisting of epinastine and its salts, (B) a terpenoid, and (C) a surfactant.

[0177] A method for reducing white residue in an ophthalmic composition containing (A) one or more members selected from the group consisting of epinastine and its salts, comprising comprising incorporating (B) a terpenoid (and (C) a surfactant) into the ophthalmic composition.

[0178] Furthermore, as one embodiment of the present invention, the following agent is provided.

[0179] An agent for reducing white residue in an ophthalmic composition comprising (A) one or more members selected from the group consisting of epinastine and its salts, and comprising (B) a terpenoid (and (C) a surfactant).

[0180] [4. Improved filling properties] The ophthalmic composition according to this embodiment can improve (or enhance) the fillability of the ophthalmic composition in a container.

[0181] Thus, as one embodiment of the present invention, the following method is provided.

[0182] A method for improving the fillability of an ophthalmic composition into a container by combining (or containing in combination) (A) one or more members selected from the group consisting of epinastine and its salts, (B) a terpenoid, and (C) a surfactant.

[0183] A method for improving the fillability of an ophthalmic composition containing (A) one or more members selected from the group consisting of epinastine and its salts into a container, comprising the step of incorporating (B) a terpenoid (and (C) a surfactant) into the ophthalmic composition.

[0184] Furthermore, as one embodiment of the present invention, the following agent is provided.

[0185] An agent for improving the filling property of an ophthalmic composition containing one or more members selected from the group consisting of (A) epinastine and its salts into a container, the agent comprising (B) a terpenoid (and (C) a surfactant).

[0186] [5. Improved liquid cutting (prevention of dripping)] The ophthalmic composition according to the present embodiment can improve (or enhance) the drainage of the ophthalmic composition. In addition, the ophthalmic composition according to the present embodiment can suppress (or reduce or prevent) dripping of the ophthalmic composition.

[0187] Thus, as one embodiment of the present invention, the following method is provided.

[0188] A method for improving (or enhancing) the drainage of an ophthalmic composition (or suppressing dripping) by combining (or containing in combination) (A) one or more types selected from the group consisting of epinastine and its salts, (B) a terpenoid, and (C) a surfactant.

[0189] A method for improving (or enhancing) the drainage (or suppressing dripping) of an ophthalmic composition containing (A) one or more members selected from the group consisting of epinastine and its salts, comprising comprising incorporating (B) a terpenoid (and (C) a surfactant) into the ophthalmic composition.

[0190] Furthermore, as one embodiment of the present invention, the following agent is provided.

[0191] (A) An agent for improving (or enhancing) the drainage (or suppressing dripping) of an ophthalmic composition containing one or more members selected from the group consisting of epinastine and its salts, and (B) an agent containing a terpenoid (and (C) a surfactant).

[0192] 6. Reduction of cytotoxicity The ophthalmic composition according to this embodiment can reduce (or suppress) the cytotoxicity in the ophthalmic composition.

[0193] Thus, as one embodiment of the present invention, the following method is provided.

[0194] A method for reducing the cytotoxicity of an ophthalmic composition by combining (or containing in combination) (A) one or more members selected from the group consisting of epinastine and its salts, (B) a terpenoid, and (C) a surfactant.

[0195] A method for reducing the cytotoxicity of an ophthalmic composition containing (A) one or more members selected from the group consisting of epinastine and its salts, comprising comprising incorporating (B) a terpenoid (and (C) a surfactant) into the ophthalmic composition.

[0196] Furthermore, as one embodiment of the present invention, the following agent is provided.

[0197] An agent for reducing the cytotoxicity of an ophthalmic composition comprising (A) one or more members selected from the group consisting of epinastine and its salts, the agent comprising (B) a terpenoid (and (C) a surfactant).

[0198] 7. Reduction of irritation The ophthalmic composition according to this embodiment can reduce (or suppress) irritation (irritation to the eyes) caused by the ophthalmic composition.

[0199] Thus, as one embodiment of the present invention, the following method is provided.

[0200] A method for reducing irritation (stinging sensation, irritability) of an ophthalmic composition by combining (or containing in combination) (A) one or more types selected from the group consisting of epinastine and its salts, (B) a terpenoid, and (C) a surfactant.

[0201] (B) A method for reducing the irritation (stinging sensation, irritability) of an ophthalmic composition containing a terpenoid, comprising comprising (A) one or more members selected from the group consisting of epinastine and its salts (and (C) a surfactant) contained in the ophthalmic composition.

[0202] Furthermore, as one embodiment of the present invention, the following agent is provided.

[0203] (B) An agent for reducing the irritation (stinging sensation, irritability) of an ophthalmic composition containing a terpenoid, the agent comprising (A) one or more types selected from the group consisting of epinastine and its salts (and (C) a surfactant).

[0204] [8. Improved cooling sensation] The ophthalmic composition according to this embodiment can enhance (or improve) the cooling sensation in the ophthalmic composition.

[0205] Thus, as one embodiment of the present invention, the following method is provided.

[0206] A method for improving the cooling sensation of an ophthalmic composition by combining (or containing in combination) (A) one or more members selected from the group consisting of epinastine and its salts, (B) a terpenoid, and (C) a surfactant.

[0207] (B) A method for improving the cooling sensation of an ophthalmic composition containing a terpenoid, comprising comprising: (A) one or more members selected from the group consisting of epinastine and its salts (and (C) a surfactant) contained in the ophthalmic composition.

[0208] Furthermore, as one embodiment of the present invention, the following agent is provided.

[0209] (B) An agent for improving the cooling sensation of an ophthalmic composition containing a terpenoid, the agent comprising (A) one or more members selected from the group consisting of epinastine and its salts (and (C) a surfactant).

[0210] In each of the above embodiments, the types and contents of the (A) to (B) components (and further the (C) component), the types and contents of other components, the formulation form and use of the ophthalmic composition, etc. are as described in [1. Ophthalmic Composition].

[0211] In addition, each of the above embodiments may be combined in two or more forms. For example, when the embodiments [2] and [3] are combined, the embodiment includes a method of reducing the surface tension of an ophthalmic composition and reducing white residue by combining (or containing in combination) one or more selected from the group consisting of (A) epinastine and its salts with (B) a terpenoid. EXAMPLES

[0212] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to these examples, and many modifications can be made by those skilled in the art within the technical spirit of the present invention.

[0213] [Test Example 1] Surface tension and various properties Aqueous ophthalmic compositions (eye drops) having the compositions shown in the following table were prepared, and the surface tensions were measured (average values ​​of N=3).

[0214] The surface tension was measured using a SURFAVE TENSIONMETER CBVP-A3 manufactured by Kyowa Interface Science Co., Ltd.

[0215] From the measured surface tension, the surface tension improvement rate of each composition (Test Examples 1B to 1F) defined by the following formula was calculated.

[0216] Surface tension improvement rate (%) = [(surface tension of Test Example 1A - surface tension of each test example) / (surface tension of Test Example 1A)] x 100

[0217] The results are shown in the following table. Note that in the aqueous ophthalmic compositions in the following table, the unit of each component is (w / v%). The same applies to the following tables.

[0218] [Table 1]

[0219] As is clear from the results in the above table, the surface tension could be reduced by combining epinastine hydrochloride with a terpenoid.

[0220] Furthermore, this surface tension reducing effect could be made even more pronounced by combining a terpenoid with a surfactant.

[0221] Moreover, unexpectedly, the effect of reducing the surface tension was greater when the amount of terpenoid was smaller (Test Examples 1B and 1C).

[0222] Furthermore, among the terpenoids, menthol exhibited a higher surface tension reducing effect than camphor (Test Examples 1E and 1F).

[0223] The properties of these compositions were further examined.

[0224] First, each of these compositions was dropped onto a colorless and transparent PE (polyethylene) film, and the water was evaporated. When the state after evaporation was visually confirmed, the composition of Test Example 1A left a white residue (whitening phenomenon or precipitation due to non-volatile content), but the compositions of Test Examples 1B, 1C, 1E, and 1F did not leave (or hardly left) such a white residue or could reduce the white residue. In other words, it was found that the white residue caused by an aqueous composition containing epinastine hydrochloride can be suppressed or prevented by combining terpenoids.

[0225] Next, when each of the compositions of the other test examples was filled into an eye drop container (made of PET, 6 mm in diameter), all of them could be filled without any problems and had excellent filling properties. Thus, it was confirmed that all of the obtained compositions were compositions that could be efficiently formulated.

[0226] Furthermore, when each composition was dropped from an eye dropper, all of the compositions were easily drained, indicating that all of the compositions obtained were compositions that were unlikely to drip.

[0227] [Test Example 2] Cytotoxicity test 1 (with or without terpenoids) The compositions shown in the table below were dissolved in purified water to prepare the compositions, and the cytotoxicity of the resulting compositions was evaluated as follows.

[0228] Using Medium 199 (HEPES), SIRC cells were cultured at a cell concentration of 5.0 × 10 5 The cell suspension was dispensed in 100 μL portions (5.0 × 10 4 (cells / well). The formulation of the test example diluted with Medium 199 (HEPES) to a concentration of 25% was added to each well and then cultured for 4 hours. Using Cell Counting Kit-8 (wst-8) REF:343-07623, the cell viability (%) was calculated by comparing with the absorbance when cultured in Medium 199 (HEPES) alone.

[0229] Then, the mortality reduction rate relative to Test Example 2A (without menthol) was calculated as shown in the following formula. Mortality rate (%) = 100 - survival rate (%) Mortality rate reduction rate (%) = (mortality rate of Test Example 2A - mortality rate of Test Example 2B or 2C) / mortality rate of Test Example 2A x 100

[0230] The results are shown in the table below.

[0231] [Table 2]

[0232] As is clear from the results in the above table, menthol was able to reduce cytotoxicity. Moreover, unexpectedly, the effect of reducing cytotoxicity was greater when the amount of menthol was smaller.

[0233] [Test Example 3] Cytotoxicity Test 2 (amount and type of terpenoid) 5.0×10 4 2.5 x 10 cells / well 4 The cell viability of each composition was measured as described below in the same manner as in Test Example 2 (Cytotoxicity Test 1), except that the incubation time after addition of the formulation of the Test Example to the cells / well was changed from 4 hours to 1 hour. The comparative cell viability of each composition was calculated (cell viability of each composition / cell viability of the composition of Test Example 3A×100), assuming that the cell viability of the composition of Test Example 3A was 100.

[0234] The results are shown in the table below.

[0235] [Table 3]

[0236] As is clear from the results in the above table, it was confirmed that the smaller the amount of menthol, the greater the effect of reducing cytotoxicity, and that among terpenoids, menthol has a greater effect of reducing cytotoxicity than camphor.

[0237] [Test Example 4] Sensory test Aqueous ophthalmic compositions (eye drops) having the compositions shown in the following table were prepared.

[0238] [Table 4]

[0239] The irritation sensation of the prepared eye drops was evaluated as follows. The VAS value for the sensation of irritation immediately after instillation was measured for each subject, and the average value (average VAS value) was used as the value (intensity) of the sensation of irritation. The VAS scale had a maximum scale of 20, and the subjects were five healthy subjects (with naked eyes) who participated in this study of their own free will. The results are shown in the table below.

[0240] [Table 5]

[0241] As is clear from the results in the above table, it was found that irritation can be reduced by blending epinastine hydrochloride with a composition containing menthol.

[0242] [Test Example 5] Sensory test The cooling sensation of the eye drops prepared in Test Example 4 was evaluated as follows. The VAS value for the cooling sensation immediately after instillation was measured for each subject, and the average value (average VAS value) was used as the value (intensity) of the cooling sensation. The VAS scale had a maximum scale of 20, and the subjects were five healthy subjects (without glasses) who participated in this study of their own free will. The results are shown in the table below.

[0243] [Table 6]

[0244] As is clear from the results in the above table, a cooling sensation can be exerted even when epinastine hydrochloride is added to a composition containing menthol, and it has been found that the cooling sensation can actually be improved. Combining this result with the result of Test Example 4, it was found that it was possible to achieve both a refreshing sensation and a reduced irritating sensation (in particular, it was possible to reduce the irritating sensation while improving the refreshing sensation).

[0245] [Test Example 6] Sensory test The stimulating sensation and cooling sensation observed in Test Examples 4 and 5 were similarly evaluated for the formulations (concentrations) having different compositions shown in the table below. The results are shown in the table below together with the composition of the eye drops (aqueous ophthalmic composition).

[0246] [Table 7]

[0247] [Table 8]

[0248] [Table 9]

[0249] As is clear from the results in the above table, it was possible to confirm a reduction in the sensation of irritation and an improvement in the sensation of coolness in various different formulations.

[0250] [Test Example 7] Evaluation of TRPA1 activity As described above, it was confirmed that the irritation sensation could be reduced in the eye drops of the various test examples. On the other hand, it has been reported that the pathway by which such stimuli (pain) are evoked is related to the cell sensor TRPA1 (activation of TRPA1) (e.g., Curr. Ophthalmol. Rep. (2015), 3: 111-121). From this perspective, we measured TRPA1 activity, which can help evaluate the sensation of stimulation at the cellular level, as follows.

[0251] <Cells used> Preparation of T-REx-293 cell line harboring the hTRPA1 gene hTRPA1 mRNA was extracted from human WI38 cells. T-REx-293 cells stably expressing hTRPA1 were created using Invitrogen's tetracycline-controlled T-REx expression system. hTRPA1 cDNA, amplified by RT-PCR using hTRPA1 mRNA as a template, was incorporated into pcDNA4 / TO (Invitrogen), a mammalian cell gene expression vector, and then introduced into T-REx-293 cells using Lipofectamin 2000 reagent, an Invitrogen gene introduction reagent. Zeocin was incorporated into pcDNA4 / TO, which holds a plasmid (blasticidin resistance gene) for maintaining the T-Rex system in T-REx-293 cells. A T-REx-293 cell line stably holding the hTRPA1 gene was established using the antibiotics Zeocin 500 μg / mL and blasticidin 10 μg / mL.

[0252] <Cell culture> T-REx-293 cells carrying hTRPA1 were cultured in the presence of 5% carbon dioxide using DMEM medium containing 10% FBS, 100 unit / mL penicillin, 100 mg / mL streptomysin, and 250 ng / mL amphotericin B. During subculture, 200 μg / mL Zeocin and 5 μg / mL blasticidin were added, and the maximum number of passages was 50 or less. Specifically, T-REx-293 cells were cultured in a 60 mm dish as a preculture until they became semi-confluent, and then washed with PBS(-). The cells were detached from the dish by 1x Trypsin / EDTA treatment, and DMEM medium was added. The cells were then transferred to a 15 mL tube and centrifuged at 800 rpm at room temperature for 4 minutes. The DMEM medium was removed by suction, and the cells were loosened by tapping, after which fresh DMEM medium was added and approximately 40 x 10 4 ~50×10 4A cell suspension was prepared by adjusting the cell number to 100 cells / mL. Tetracycline was added to the suspension to express the receptor. The cell suspension was dispensed into a 96-well plate and incubated overnight at 37°C in a 5% CO2 incubator before use in the test.

[0253] <Experiment> Ca 2+ The change in TRP activity was observed using a concentration indicator (Fluo-8 (AAT Bioquest, Inc.)). 2+ The concentration indicator was first incorporated into T-REx-293 cells carrying hTRPA1, and the amount of fluorescence was measured using a microplate reader. Specifically, the experiment was carried out according to the following protocol. The 96-well plate that had been prepared the day before (cell culture as described above) was removed from the incubator, and the DMEM medium was removed by decantation. The plate was gently washed with 100 μL / well of LB buffer (pH 7.4, 5.37 mM KCl, 0.44 mM KH2PO4, 137 mM NaCl, 0.34 mM Na2HPO4, 5.56 mM D-glucose, 20 mM HEPES, 1 mM CaCl2, 0.1% bovine serum albumin, 2.5 mM probenecid, remaining purified water), and 50 μL of the above buffer dissolved with 1.5 μM Fluo-8 was added to each well, and the plate was then treated in a 37°C, 5% CO2 incubator for 1 hour. After incubation, the above buffer containing Fluo-8 was removed by decantation, and the plate was gently washed with 100 μL / well of the above buffer. Further, 180 μL / well of the same buffer solution was added, and measurement was started using a Flexstation III (registered trademark) microplate reader (Molecular Devices, Sunnyvale, Calif., USA). Thirty seconds after starting the measurement with the microplate reader, samples (test sample and reference sample) were added at 20 μL / well each, and the maximum fluorescence intensity was measured 5 to 120 seconds after addition, and this value was taken as the fluorescence intensity.

[0254] The TRP activity (%) was calculated based on the following formula. TRP activity (%)= (Fluorescence amount when test sample is administered / Fluorescence amount when reference sample is administered) x 100

[0255] The results are shown in the table below, together with the composition of the samples used.

[0256] [Table 10] As is clear from the results in the table above, it was confirmed that TRPA1 activity is suppressed by combining epinastine hydrochloride with menthol, and that this tendency is more pronounced when boric acid is included.

[0257] [Formulation example] According to the formulations shown in the following tables, ophthalmic compositions were prepared and filled into containers [PET containers (Formulation Examples 1 to 9 and 19 to 25) or PE (polyethylene) containers (Formulation Examples 10 to 18 and 26 to 31)]. In the following tables, the unit of each component is (w / v%).

[0258] [Table 11]

[0259] [Table 12]

[0260] [Table 13]

[0261] [Table 14] [Industrial Applicability]

[0262] The present invention can provide an ophthalmic composition useful as an eye drop or the like.

Claims

[Claim 1] The invention described herein.

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