JP2024061871A - Ophthalmic Composition - Google Patents

Abstract

[Problem] To provide a novel ophthalmic composition. [Solution] The ophthalmic composition is composed of (A) one or more members selected from the group consisting of epinastine and salts thereof, and (B) a terpenoid. [Selected Figures] None

Description

The present invention relates to an ophthalmic composition (or an ophthalmic agent).

Epinastine hydrochloride is known as an antihistamine, and there are also attempts to use epinastine hydrochloride for ophthalmic purposes.

For example, Patent Document 1 (JP Patent Publication 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 the active ingredient, and contains substantially no preservatives or ingredients with preservative properties.

Japanese Patent No. 6134853 (Claims, Examples)

The object of the present invention is to provide a novel ophthalmic composition.

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.

On the other hand, there is a demand for ophthalmic preparations containing menthol, etc. that reduce irritation and efficiently provide a cooling sensation.

In the midst of this, the inventors conducted extensive research to solve the above problems, and discovered that a novel ophthalmic composition can be obtained by combining epinastine or a salt thereof with a specific component (menthol, etc.), and that such a composition can solve or improve (suppress) problems such as white residue and cytotoxicity, reduce irritation, and efficiently exert a cooling sensation. After further research, the inventors have completed the present invention.

That is, the present invention relates to the following inventions, etc.
[1]
An ophthalmic composition comprising: (A) one or more members selected from the group consisting of epinastine and salts thereof; and (B) 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 ratio of the component (B) is 0.0002 to 100 parts by mass per 1 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), in which the proportion of the component (C) is 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 the component (A) is 0.01 to 0.1 w/v %,
The proportion of the (B) component is 0.0001 to 0.15 w/v%,
The proportion of the (C) component is 0.007 to 5 w/v%,
The ratio of the (B) component is 0.02 to 1 part by mass per 1 part by mass of the (A) component,
The ratio of the (C) component is 0.5 to 50 parts by mass per 1 part by mass of the (A) component,
The ophthalmic composition according to any one of [1] to [11], having 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 a portion 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, the method comprising 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 (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.
[21]
The method according to any one of [14] to [20], wherein the component (B) comprises one or more selected from the group consisting of menthol and camphor.
[22]
The method according to any one of [14] to [21], wherein the component (B) contains at least menthol and further contains a surfactant (C).

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

In another aspect of the ophthalmic composition of the present invention, the surface tension of the ophthalmic composition containing epinastine or a salt thereof may be reduced (or inhibited).

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).

In another aspect of the ophthalmic composition of the present invention, the filling property (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).

In another aspect of the ophthalmic composition of the present invention, the drainage of an ophthalmic composition containing epinastine or a salt thereof can be improved (or enhanced) (or dripping can be suppressed or prevented).

The above-mentioned properties are also useful from the viewpoint of formulating ophthalmic compositions. In addition, poor drainage can make it difficult to control the amount of eye drops administered, so they are also advantageous in terms of usability.

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 inventor's investigation, the cytotoxicity of an ophthalmic composition containing epinastine or a salt thereof appears to be relatively high. However, according to the present invention, it is possible to provide an ophthalmic composition that has low cytotoxicity (particularly, is substantially free of cytotoxicity) despite containing such epinastine or a salt thereof.

In another embodiment of the ophthalmic composition of the present invention, even if a terpene such as menthol is contained, the sense of 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 a sense of 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.

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.

As such, the composition of the present invention is extremely useful and highly practical.

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.

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

(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), and the like.

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

Epinastine and/or its salts may be used alone or in combination of two or more.

The content of 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%), even 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.

(B) Terpenoid (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.

Terpenoids include menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and lycopersicon gracilis. These may be in the d-, l-, or dl-form.

The composition may contain terpenoids in the form of essential oils. Examples of such essential oils include peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil.

Terpenoids (and essential oils) may be used alone or in combination of two or more types.

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.

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.

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 (proportion) of the (B) component may be the terpenoid content (the content of the (B) component based on the terpenoid) (the same applies to the description of the content (proportion) below).

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, based on the total amount of the composition.

In particular, in the present invention, the (B) component may be used in a relatively small amount (low concentration). In such a case, the content of the (B) component 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.

The proportion of component (B) 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 component (A).

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, particularly 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.

Considering the viewpoint of achieving the effects of the present invention, the ratio 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, 0.15 parts by mass or more, 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 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.

[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 ensured in many cases. In addition, by containing other components, the effects of the present invention can be more effectively realized in some cases.

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

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) Examples of the polyethylene glycol monostearate include polyethylene glycol monostearate such as 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), polyethylene glycol monostearate (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 indicate the number of moles added.

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 stearate 40 being more preferred, with polysorbate 80 and POE hydrogenated castor oil 60 being even more preferred, and polysorbate 80 being particularly preferred.

Surfactants may be used alone or in combination of two or more.

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, based on the total amount of the composition.

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, based on the total amount of the composition.

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.

When the composition of the present invention contains a surfactant (particularly a nonionic surfactant), the proportion of 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 component (A).

When the composition of the present invention contains a surfactant (particularly a nonionic surfactant), the proportion of 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 component (B).

Amino Acids The compositions of the present invention may contain amino acids.
The amino acid includes, for example, an amino acid or a salt thereof, and an amino acid analogue, and also includes a compound having an amino group and a carboxyl group or a sulfone group in the molecule, or a derivative thereof.

Specific examples include amino acids or their salts, and mucopolysaccharides or their salts. Among amino acids, examples of amino acids or their salts include monoamino monocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid (epsilon aminocaproic acid, etc.); monoamino dicarboxylic acids such as aspartic acid and glutamic acid or their salts; diamino monocarboxylic acids such as arginine and lysine or their salts; and derivatives of aminoethylsulfonic acid (taurine) or their salts.

Among amino acids, mucopolysaccharides or their derivatives or salts thereof include, for example, acidic mucopolysaccharides such as chondroitin sulfate, hyaluronic acid, alginic acid, and the like, or their salts.

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.

Chondroitin sulfate is a sugar chain in which D-glucuronic acid and N-acetylglucosamine are repeated, and sulfate is ester-bonded to all or some of the hydroxyl groups. The bond positions and number of sulfate are diverse, and chondroitin sulfate also has derivatives (e.g., chondroitin sulfate 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.

The salts of amino acids or mucopolysaccharides include medicamentarily, pharmacologically, or physiologically acceptable salts. Examples of such salts include salts with organic acids [e.g., monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylates (fumarate, maleate, etc.), oxycarboxylates (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.)], salts with inorganic acids (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate), 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 alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.], and the salts are appropriately selected depending on the compound.

Specific salts include salts of aspartic acid (such as sodium aspartate, potassium aspartate, magnesium aspartate, and a mixture of magnesium and potassium aspartate), salts of glutamic acid (such as monosodium glutamate and magnesium glutamate), sodium chondroitin sulfate, and sodium hyaluronate.

The amino acids may be D-, L-, or DL-amino acids.

Preferred amino acids include aminoethylsulfonic acid (taurine) or its salts, sodium chondroitin sulfate, aspartates (e.g., potassium L-aspartate, magnesium potassium L-aspartate), epsilon aminocaproic acid or its salts, hyaluronic acid or its salts (sodium hyaluronate, etc.), and among these, hyaluronic acid or its salts (sodium hyaluronate, etc.), aminoethylsulfonic acid (taurine) and/or its salts, and sodium chondroitin sulfate are preferred.

Amino acids may be used alone or in combination of two or more.

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%)] based on the total amount of the composition.

Fat-Soluble Antioxidants The compositions of the present invention may contain a fat-soluble antioxidant.

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.

Of these, dibutylhydroxytoluene is preferred.

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

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 about 0.0045 to 0.006 w/v%, based on the total amount of the composition.

Water-Soluble Antioxidants The compositions of the present invention may contain a water-soluble antioxidant.

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

Of these, edetic acid or its salts (disodium edetate, tetrasodium edetate, etc.) are preferred.

Water-soluble antioxidants may be used alone or in combination of two or more.

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.

Antiallergic Agent The composition of the present invention may contain an antiallergic agent.

Examples of antiallergic agents include tranilast, cromoglycate, ibudilast, azalast, tazanolast, suplatast, pemirolast, levocabastine, olopatadine, ketotifen, amlexanox, oxatomide, and salts thereof.

Examples of 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, sulfate, etc.), and organic acid salts (e.g., tosylate, fumarate, etc.).

The composition of the present invention may not contain ashitazanolast, etc., from the viewpoint of the stability of the composition, etc.

Antiallergic agents may be used alone or in combination of two or more.

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 about 0.9 to 1.2 w/v%, based on the total amount of the composition.

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.

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

Specific examples of salts include diphenhydramine hydrochloride, iproheptine hydrochloride, and chlorpheniramine maleate.

Antihistamines may be used alone or in combination of two or more.

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%, even 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%), based on the total amount of the composition, and may usually be about 0.01 to 0.05 w/v%.

Anti-inflammatory Agents The compositions of the present invention may comprise 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.

Examples of salts 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.

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.

Anti-inflammatory agents may be used alone or in combination of two or more.

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 about 0.2 to 0.3 w/v% (e.g., 0.25 w/v%) relative to the total amount of the composition.

The composition of the present invention may contain various ingredients (e.g., ingredients that do not belong to the categories of the above-mentioned ingredients). Examples of such ingredients (additives) include preservatives, buffers, pH adjusters, isotonicity agents, thickeners or viscosifiers, stabilizers, oils, sugars, polymeric compounds, polyhydric alcohols, inorganic salts, non-fat-soluble antioxidants (or water-soluble antioxidants), etc.

The additives can be used alone or in combination of two or more. In addition, each additive can be used alone or in combination of two or more.

Specific examples of additives are given below.

Preservatives The compositions of the present invention may 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).

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.

When the composition contains a preservative, the proportion of the preservative in the composition, relative to the total amount of the composition, can be, 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. Also, the total amount of the preservative relative to the total amount of the composition can be, 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.

Buffering Agents The compositions of the present invention may comprise a buffering agent.
Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer and the like.

The components of borate buffers include boric acid and borate salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.). The borate salts may be hydrated.

Phosphate buffer components include phosphoric acid and phosphate salts (such as disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, and calcium dihydrogen phosphate). Phosphates may be hydrates.

The components of the carbonate buffer include carbonic acid and carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, etc.). The carbonates may be hydrated.

Components of citrate buffer include citric acid and citrate salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.). Citrate salts may be in the form of hydrates.

Components of acetate buffers include acetic acid and acetate salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). Acetate salts may be hydrates.

Among these, boric acid buffers are preferred from the viewpoint of preservative effectiveness and more prominent effects of the present invention, phosphate buffers are preferred from the viewpoint of low cytotoxicity, and boric acid buffers are more preferred. As boric acid buffers, 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.

When the buffer is composed of multiple components, the ratio may be appropriately selected depending on the range in which the buffer function can be exhibited. For example, when boric acid is combined with a borate (such as borax), 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 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 per 100 parts by mass of boric acid.

Even if the composition of the present invention contains such a buffer (borate buffer), it can still efficiently exhibit functions such as reducing white residue. In addition, by using a borate buffer (or boric acid) or a phosphate buffer, the various properties of the composition may be more efficiently exhibited.

When a buffering agent is blended into the composition of the present invention, the blending amount of the buffering agent varies depending on the type of buffering agent and the types and amounts of other blended ingredients, and cannot be uniformly specified. However, examples of the amount of the buffering agent relative to the total amount of the composition include a total amount of 0.001 w/v% or more, preferably 0.01 w/v% or more, preferably 0.05 w/v% or more, and preferably 0.1 w/v% or more. Also, examples of the total amount of the buffering agent relative to the total amount of the composition include a total amount of 10 w/v% or less, preferably 5 w/v% or less, preferably 3 w/v% or less, preferably 2.5 w/v% or less, and preferably 2 w/v% or less.

In particular, when a boric acid buffer (total amount of boric acid and borate salts) 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.

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.

Isotonicity Agents Examples of isotonicity 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.

Viscosity or Thickening Agents The ophthalmic compositions of the present invention may include a viscosity or thickening agent.

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 the polyacrylic acid include tallow, polyvinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salts, potassium salts, etc.), amine salts of polyacrylic acid (monoethanolamine salts, diethanolamine salts, triethanolamine salts, etc.), casein, gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (sodium salts, etc.), alginate esters (propylene glycol esters, etc.), powdered tragacanth, and triisopropanolamine.
The thickening or viscosifying agents may be used alone or in combination of two or more.

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.

Oils 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.

Sugars Examples of sugars include monosaccharides and oligosaccharides (such as disaccharides), and specific examples include glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, and mannitol.

Polyhydric Alcohols Examples of polyhydric alcohols include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, and polyvinyl alcohol.

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.

The composition of the present invention may further contain ingredients that have pharmacological or physiological activity.

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

Examples of such pharmacologically active ingredients and physiologically active ingredients include the active ingredients in various pharmaceuticals 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 given below.

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 hydrogen tartrate, etc. These may be in any of the d-, l- or dl-forms.

To elaborate on the imidazoline vasoconstrictor, the salt of the imidazoline vasoconstrictor may be any pharma- ceutically or physiologically acceptable salt, and examples of such salts include organic acid salts such as maleates and fumarates; inorganic acid salts such as hydrochlorides and sulfates; and metal salts. Among the salts, inorganic acid salts are preferred, with hydrochlorides or nitrates being more preferred, and hydrochlorides (e.g., tetrahydrozoline hydrochloride) being particularly preferred.

Among decongestants (vasoconstrictors), imidazoline vasoconstrictors are preferred, with tetrahydrozoline, naphazoline, or salts thereof being more preferred, and tetrahydrozoline or salts thereof being even more preferred.

Ocular muscle regulating agents Examples of ocular muscle regulating agents include cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, and atropine sulfate.

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.

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.

Antibacterial or Bactericidal Agents 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.

Local anesthetic components Examples of local anesthetic components include procaine hydrochloride and lidocaine hydrochloride.

Base or Carrier The composition of the present invention may comprise 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, for example, by a conventional method described in the 17th edition of the Japanese Pharmacopoeia. The composition may be appropriately heated during preparation.

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.

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

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. Also includes those that are 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).

As described above, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier), an oil-based composition (mainly containing an oil-based or hydrophobic base or carrier), or in particular an aqueous composition.

In the case of an aqueous composition, the water content 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.

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).

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.

The pH of the composition of the present invention may be, for example, 4 to 9, preferably 4.5 to 8.5, 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.

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. Also, it is preferably 5 or less, more preferably 3 or less, and even more preferably 2 or less.

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) according to the 17th Revised Japanese Pharmacopoeia. 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 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, allowing it to cool in a desiccator (silica gel), accurately weighing 0.900 g of it, dissolving it in purified water to make exactly 100 mL, or use a commercially available standard solution for measuring osmotic pressure ratio (0.9 w/v% sodium chloride aqueous solution).

Dosage form The dosage form (dosage 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, packaged solutions), preservatives for excised eye tissues such as corneas for transplantation, irrigation solutions for surgery, etc. Eye drops, eye washes, and eye ointments also include those used when wearing contact lenses.

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).

Preferred dosage forms of the composition of the present invention include eye drops, eye washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens wearing solutions, contact lens solutions (cleaning solutions, storage solutions, disinfectants, multipurpose solutions, packaging solutions), etc., more preferred are eye drops, eye washes, contact lens wearing solutions, contact lens solutions (cleaning solutions, storage solutions, disinfectants, multipurpose solutions), etc., even more preferred are eye drops and eye washes, and particularly preferred are eye drops.

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

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.

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

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

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.).

Examples of styrene-based resins include polystyrene and acrylonitrile-containing styrene-based resins (e.g., acrylonitrile-styrene copolymer (AS resin), acrylonitrile-butadiene-styrene copolymer (ABS resin), etc.).

Examples of acrylic resins include resins whose polymerization components include acrylic acid esters such as methyl acrylate, and methacrylic acid esters such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate.

Examples of polyester resins include aromatic polyester resins [e.g., resins having alkylene terephthalate units (alkylene terephthalate 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.)], etc.

Fluorine resins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluorine resins, tetrafluoroethylene-hexafluoropropylene copolymer, ethylene-tetrafluoroethylene copolymer, ethylene-chlorotrifluoroethylene copolymer, etc.

Polyacetal resins include those that are composed only of oxymethylene units, as well as those that contain some oxyethylene units.

Examples of modified polyphenylene ethers include polystyrene-modified polyphenylene ethers.

Examples of polyarylates include amorphous polyarylates.

Examples of polyimide resins include aromatic polyimides, such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

The container is preferably made of glass, plastic, or the like. Therefore, at least a portion of the container (or the container's material) may be made of glass, plastic, or the like.

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, with polypropylene, polyethylene terephthalate, and polystyrene being even more preferred, and polyethylene terephthalate being even more preferred.

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.

The container material may be a polymer blend with a polymer other than the above polymer. When the container material for storing the ophthalmic composition of the present invention is a polymer blend with the above polymer, the mixing ratio of the above polymer to the polymer other than the above polymer is not particularly limited as long as the effects of the present invention are achieved, but the total weight of the polymers relative to the total amount of the entire constituent materials 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.

At least a portion of the container (contact surface) that comes into contact with the composition of the present invention 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 achieving a significant effect of the present invention, it is preferable that the container itself is molded from the above material.

In addition, the parts constituting the container (container body, part of the container including the 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 layers constituting the container body are not made of the above materials).

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, eye itching, eye pain, 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.

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.

In this specification, "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.

In particular, the composition of the present invention is suitable for alleviating, improving, suppressing, or treating allergic symptoms (eye allergy symptoms).

Allergens causing allergic symptoms are not particularly limited, but may include pollen (e.g., cedar pollen, cypress pollen), house dust, etc.

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

Method of Use The method of use (mode of use) of the composition of the present invention can be appropriately selected depending on its properties, etc.

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 administration varies depending on the symptoms to be treated, but can be, for example, one or more times, two or more times, three or more times, four or more times, five or more times, or six or more times per day. It can also be nine or less times, eight or less times, seven or less times, six or less times, five or less times, or four or less times per day. Administration four times per day is particularly preferred.

When the composition of the present invention is an eye drop, for example, 1 to 3 drops may be instilled at one time, or 1 to 2 drops or 2 to 3 drops may be instilled. Preferably, 1 to 2 drops may be instilled. It is also possible to instill 1 drop. The amount of one drop instilled may preferably be 30 to 50 μL.

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.

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.

When the composition of the present invention is a contact lens wearing 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.

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

Therefore, as one embodiment of the present invention, the following method is provided:

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

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

In addition, as one embodiment of the present invention, the following agent is provided:

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

[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).

Therefore, as one embodiment of the present invention, the following method is provided:

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

(A) A method for reducing white residue in an ophthalmic composition containing one or more selected from the group consisting of epinastine and its salts, comprising the step of adding (B) a terpenoid (and (C) a surfactant) to the ophthalmic composition.

In addition, as one embodiment of the present invention, the following agent is provided:

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

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

Therefore, as one embodiment of the present invention, the following method is provided:

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

(A) A method for improving the fillability of an ophthalmic composition containing one or more 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.

In addition, as one embodiment of the present invention, the following agent is provided:

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

[5. Improvement of liquid cutting (suppression 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.

Therefore, as one embodiment of the present invention, the following method is provided:

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

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

In addition, as one embodiment of the present invention, the following agent is provided:

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 (A) epinastine and its salts, and containing (B) a terpenoid (and (C) a surfactant).

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

Therefore, as one embodiment of the present invention, the following method is provided:

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

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

In addition, as one embodiment of the present invention, the following agent is provided:

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

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.

Therefore, as one embodiment of the present invention, the following method is provided:

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

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

In addition, as one embodiment of the present invention, the following agent is provided:

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

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

Therefore, as one embodiment of the present invention, the following method is provided:

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

(B) A method for improving the cooling sensation of an ophthalmic composition containing a terpenoid, comprising adding (A) one or more selected from the group consisting of epinastine and its salts (and (C) a surfactant) to the ophthalmic composition.

In addition, as one embodiment of the present invention, the following agent is provided:

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

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

In addition, two or more of the above embodiments may be combined. For example, when 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.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples, and many modifications are possible within the technical concept of the present invention by those with ordinary skill in the art.

Test Example 1 Surface Tension and Other Properties Aqueous ophthalmic compositions (eye drops) having the compositions shown in the table below were prepared, and the surface tension was measured (average value of N=3).

Surface tension was measured using the SURFAVE TENSIONMETER CBVP-A3 manufactured by Kyowa Interface Science Co., Ltd.

Then, from the measured surface tension, the surface tension improvement rate of each composition (Test Examples 1B to 1F) was calculated, as defined by the following formula:

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

The results are shown in the table below. Note that in the aqueous ophthalmic compositions in the table below, the units for each component are (w/v%). The same applies to the following tables.

As is clear from the results in the table above, the surface tension could be reduced by combining epinastine hydrochloride with terpenoids.

And this surface tension reduction effect could be made even more pronounced by combining terpenoids with surfactants.

Furthermore, unexpectedly, this effect of reducing surface tension was greater when the amount of terpenoid was smaller (Test Examples 1B and 1C).

Furthermore, among the terpenoids, menthol showed a greater effect of reducing surface tension than camphor (Test Examples 1E and 1F).

The properties of these compositions were further investigated.

First, each of these compositions was dropped onto a colorless and transparent PE (polyethylene) film, and the water was allowed to evaporate. 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.

Next, each of the compositions of these other test examples was filled into an eye drop container (made of PET, 6 mm in diameter). All of the compositions could be filled without any problems and had excellent filling properties. In this way, it was confirmed that all of the obtained compositions can be efficiently formulated.

In addition, when each composition was dropped from an eye dropper, all of the compositions were easily drained. Therefore, it was found that all of the obtained compositions were compositions that were unlikely to drip.

[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.

Using Medium 199 (HEPES), the cell concentration was adjusted to 5.0 x 10 ⁵ cells/ml using SIRC cells. 100 μL of cell solution was dispensed into a 96-well plate (Corning) (5.0 x 10 ⁴ cells/well). After adding the formulation of the test example diluted with Medium 199 (HEPES) to a concentration of 25% to each well, the cells were 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 only with Medium 199 (HEPES).

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 reduction rate (%) =
(mortality rate of Test Example 2A-mortality rate of Test Example 2B or 2C)/mortality rate of Test Example 2A x 100

The results are shown in the table below.

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

[Test Example 3] Cytotoxicity Test 2 (amount and type of terpenoid)
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 cell density was changed from 5.0 × ¹⁰⁴ cells/well to 2.5 × ¹⁰⁴ cells/well and the incubation time after addition of the formulation of the Test Example was changed from 4 hours to 1 hour. The cell viability of the composition of Test Example 3A was set to 100, and the comparative cell viability ratio of each composition (cell viability of each composition/cell viability of the composition of Test Example 3A × 100) was calculated.

The results are shown in the table below.

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

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

The irritation sensation of the prepared eye drops was evaluated as follows.
The VAS value for the irritation sensation immediately after instillation was measured for each subject, and the average value (average VAS value) was used as the value (intensity value) of the irritation sensation. 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.

As is clear from the results in the table above, it was found that irritation can be reduced by adding epinastine hydrochloride to a composition containing menthol.

[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 (strength value) of the cooling sensation. 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.

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).

[Test Example 6] Sensory Test The stimulating sensation and cooling sensation confirmed 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).

As is clear from the results in the table above, we were able to confirm that various different formulations reduced irritation and improved cooling sensation.

[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 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, TRPA1 activity, which may be helpful in evaluating the sensation of stimulation at the cellular level, was measured as follows.

<Cells used>
Preparation of T-REx-293 cell line carrying hTRPA1 gene hTRPA1 mRNA was extracted from human WI38 cells. T-REx-293 cells stably expressing hTRPA1 were prepared 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 gene expression vector for mammalian cells, and then introduced into T-REx-293 cells using Lipofectamin 2000 reagent, a gene introduction reagent from Invitrogen. Zeocin was incorporated into pcDNA4/TO, and a plasmid (blasticidin resistance gene) for maintaining the T-Rex system was maintained in T-REx-293 cells. Using the antibiotics Zeocin 500 μg/mL and blasticidin 10 μg/mL, a T-REx-293 cell line stably carrying the hTRPA1 gene was established.

<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 subcultures was 50 or less.
Specifically, T-REx-293 cells were cultured in a 60 mm dish to become semi-confluent as a preculture, and then washed with PBS(-). The cells were detached from the dish by 1x Trypsin/EDTA treatment, and DMEM medium was added. Then, the cells were transferred to a 15 mL tube and centrifuged at room temperature at 800 rpm for 4 minutes. Only the DMEM medium was aspirated and removed, the cells were loosened by tapping, and fresh DMEM medium was added to prepare a cell suspension in which the cell number was adjusted to about 40x10 ⁴ to 50x10 ⁴ cells/mL. At this time, tetracycline was added for receptor expression. The prepared cell suspension was dispensed into a 96-well plate, incubated overnight at 37°C in a 5% CO ₂ incubator, and used for the test.

<Experiment>
A Ca2 ⁺ concentration indicator (Fluo-8 (AAT Bioquest, Inc.)) was used to observe whether TRP activity changed. The ^Ca2+ 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 following protocol was followed. The 96-well plate that had been prepared the day before (cell culture 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 KH ₂ PO ₄ , 137 mM NaCl, 0.34 mM Na ₂ HPO ₄ , 5.56 mM D-glucose, 20 mM HEPES, 1 mM CaCl ₂ , 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 then the plate was treated for 1 hour in a 37° C., 5% CO ₂ incubator. 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 was added, and measurement was started using a Flexstation III (registered trademark) microplate reader (Molecular Devices, Sunnyvale, Calif., USA).
Thirty seconds after the start of measurement with the microplate reader, 20 μL/well of each sample (test sample and reference sample) was added, and the maximum fluorescence intensity was measured from 5 to 120 seconds after addition, and this value was taken as the fluorescence intensity.

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)×100

The results are shown in the table below along with the composition of the samples used.

As is clear from the results in the above table, 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.

[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 units of each component are (w/v %).

The present invention provides an ophthalmic composition that is useful as an eye drop, etc.

Claims (1)

The invention described in this specification.