Ophthalmic components

Abstract

A first aspect of the present invention relates to an ophthalmic composition for suppressing the dryness of the eyes, the ophthalmic composition containing at least one component selected from the group consisting of chondroitin sulfate having a weight average molecular weight of 40,000 to 70,000 and salts thereof.　A second aspect of the present invention relates to an ophthalmic composition comprising at least one component selected from the group consisting of chondroitin sulfate having a weight average molecular weight of 40,000 to 70,000 and salts thereof and at least one component selected from the group consisting of an antihistaminic agent, a zinc salt, tetrahydrozoline and salts thereof, hydroxyethyl cellulose and salts thereof and a polyvinyl-based polymeric compound.　A third aspect of the present invention relates to an ophthalmic composition comprising at least one component selected from the group consisting of chondroitin sulfate having a weight average molecular weight of 40,000 to 70,000 and salts thereof and menthol.

Description

[Technical Field]

[0001] The first, second, and third aspects of the present invention will be described below in order. The first aspect of the present invention relates to an ophthalmic composition. [Background technology]

[0002] Dry eyes can be caused by factors such as dry air from air conditioning, reduced blinking due to prolonged computer work, and contact lens wear, and are accompanied by various unpleasant symptoms such as eye pain. While symptoms of dry eyes can be alleviated by frequently using artificial tears, there is little known about ophthalmic preparations that prevent dry eyes from occurring in the first place.

[0003] Chondroitin sulfate or its salts are a type of acidic mucopolysaccharide and are incorporated into ophthalmic preparations for purposes such as promoting energy metabolism, accelerating metabolism and cellular respiration to relieve eye fatigue, and replenishing tear fluid components (for example, Patent Document 1). [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2011-148791 [Overview of the project] [Problems that the invention aims to solve]

[0005] The first aspect of the present invention aims to provide an ophthalmic composition that can suppress dryness of the eyes. [Means for solving the problem]

[0006] The inventors have surprisingly found that sodium chondroitin sulfate having a specific weight-average molecular weight significantly suppresses corneal disorders caused by dry eyes, has a high affinity for contact lenses, and also suppresses the drying of contact lenses.

[0007] The first aspect of the present invention provides, for example, the following inventions. [1] An ophthalmic composition for suppressing dry eyes, containing at least one selected from the group consisting of chondroitin sulfate having a weight-average molecular weight of 40,000 to 70,000 and its salts. [2] An ophthalmic composition for suppressing drying of contact lenses, containing at least one selected from the group consisting of chondroitin sulfate having a weight-average molecular weight of 40,000 to 70,000 and its salts. [3] The ophthalmic composition according to [1] or [2], further containing at least one selected from the group consisting of anti-inflammatory agents, vitamin A compounds, vitamin B compounds, vitamin E compounds, aminoethylsulfonic acid and its salts, aspartic acid and its salts, neostigmine and its salts, and cellulose-based high molecular compounds.

[0008] The first aspect of the present invention also provides, for example, the following inventions. [2-1] An ophthalmic composition containing at least one selected from the group consisting of chondroitin sulfate having a weight-average molecular weight of 40,000 to 70,000 and its salts, and at least one selected from the group consisting of vitamin A compounds and aminoethylsulfonic acid and its salts. [2-2] An ophthalmic composition containing at least one selected from the group consisting of chondroitin sulfate having a weight-average molecular weight of 40,000 to 70,000 and its salts, and at least one selected from the group consisting of anti-inflammatory agents, vitamin A compounds, vitamin B compounds, vitamin E compounds, aminoethylsulfonic acid and its salts, aspartic acid and its salts, neostigmine and its salts, and cellulose-based high molecular compounds.

Advantages of the Invention

[0009] According to the first aspect of the present invention, an ophthalmic composition capable of suppressing dryness of the eyes can be provided. Furthermore, according to the first aspect of the present invention, an ophthalmic composition capable of suppressing dryness of contact lenses can be provided. [Brief explanation of the drawing]

[0010] [Figure 1] This graph shows the results of Test Example 1. [Modes for carrying out the invention]

[0011] The following describes in detail the first embodiment for carrying out the present invention. However, the first embodiment is not limited to the following embodiments.

[0012] In this specification, unless otherwise specified, the unit of content "%" means "w / v%" and is synonymous with "g / 100mL".

[0013] The ophthalmic composition according to this embodiment contains at least one selected from the group consisting of chondroitin sulfate and its salts, having a weight-average molecular weight of 40,000 to 70,000 (also simply referred to as "component (A)").

[0014] Chondroitin sulfate and its salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0015] Examples of chondroitin sulfate salts include alkali metal salts and alkaline earth metal salts. Examples of alkali metal salts include sodium salts and potassium salts. Examples of alkaline earth metal salts include magnesium salts and calcium salts.

[0016] Chondroitin sulfate and its salts are preferably chondroitin sulfate and alkali metal salts of chondroitin sulfate, more preferably chondroitin sulfate and sodium chondroitin sulfate, and even more preferably sodium chondroitin sulfate.

[0017] Chondroitin sulfate and its salts may be natural or synthetic products, but generally, chondroitin sulfate and its salts derived from animals (preferably mammals, fish, mollusks, etc.; more preferably cattle, sharks, squid, rays, etc.) which are natural products, are preferred, chondroitin sulfate and its salts derived from sharks and / or rays are more preferred, and chondroitin sulfate and its salts derived from sharks are even more preferred.

[0018] Commercially available chondroitin sulfate and its salts may also be used. Chondroitin sulfate and its salts may be used individually or in combination of two or more types. Furthermore, chondroitin sulfate and its salts with a weight-average molecular weight of 40,000 to 70,000 as defined herein may be used in combination with chondroitin sulfate and its salts having a weight-average molecular weight outside the range defined herein. For example, sodium chondroitin sulfate with a weight-average molecular weight of 56,000 and sodium chondroitin sulfate with a weight-average molecular weight of 25,000 may be used in combination. When using chondroitin sulfate and its salts with a weight-average molecular weight of 40,000 to 70,000 as defined herein in combination with chondroitin sulfate and its salts having a weight-average molecular weight outside the range defined herein, it is sufficient that chondroitin sulfate and its salts with a weight-average molecular weight of 40,000 to 70,000 are included as raw materials.

[0019] In this specification, "weight-average molecular weight" can be determined by using gel permeation chromatography with a multi-angle light scattering detector (MALS detector) and a differential refractive index detector (RI detector) connected online. Specifically, the following conditions are presented. <Standard Sample Preparation> 5 mg of chondroitin sulfate or its salt is added to 10 mL of 0.1 M sodium nitrate aqueous solution, gently stirred at room temperature, and completely dissolved. <Measurement conditions for weight-average molecular weight> Equipment: Gel permeation chromatograph - multi-angle light scattering meter Detector: Differential refractive index detector (Optilab rEX, manufactured by Wyatt Technology) Multi-angle light scattering detector (Wyatt Technology DAWN HELEOS) Column: Shodex OHpak SB-806M HQ, 2 pieces (φ7.8mm x 30cm, manufactured by Showa Denko) Solvent: 0.1M sodium nitrate aqueous solution Flow rate: 0.7mL / min Column temperature: 23℃ Detector temperature: 23℃ Injection volume: 0.2mL Data processing: Wyatt Technology data processing system (ASTRA) The weight-average molecular weight of chondroitin sulfate and its salts calculated using the method described above is not particularly limited as long as it is within the range of 40,000 to 70,000. Examples of lower limits for weight-average molecular weight include 41,000 or more, 42,000 or more, 43,000 or more, 44,000 or more, 45,000 or more, 46,000 or more, 47,000 or more, 48,000 or more, 49,000 or more, and 50,000 or more. Examples of upper limits for weight-average molecular weight include 69,000 or less, 68,000 or less, 67,000 or less, 66,000 or less, 65,000 or less, 64,000 or less, 63,000 or less, 62,000 or less, 61,000 or less, and 60,000 or less. Examples of weight-average molecular weight ranges include 41,000-69,000, 42,000-68,000, 43,000-67,000, 44,000-66,000, 45,000-65,000, 46,000-64,000, 47,000-63,000, 48,000-62,000, 49,000-61,000, and 50,000-60,000.

[0020] The content of component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set as appropriate depending on the type and content of other components, the use of the ophthalmic composition and the form of formulation. From the viewpoint of more significantly exhibiting the first effect of the present invention, the content of component (A) is, for example, usually 0.001 to 5 w / v%, preferably 0.005 to 5 w / v%, more preferably 0.008 to 4 w / v%, even more preferably 0.01 to 3 w / v%, even more preferably 0.05 to 2 w / v%, particularly preferably 0.1 to 1 w / v%, and most preferably 0.3 to 1 w / v%.

[0021] The ophthalmic composition according to this embodiment may further contain at least one selected from the group consisting of an anti-inflammatory agent, vitamins A, vitamins B, vitamins E, aminoethylsulfonic acid and its salts, aspartic acid and its salts, neostigmine and its salts, and cellulosic polymer compounds (also simply referred to as "component (B)"). The inclusion of component (B) in the ophthalmic composition makes the first effect according to the present invention more pronounced.

[0022] Furthermore, as confirmed in the test examples described later, the ophthalmic composition containing component (A) and component (B) according to this embodiment also has the following effects: it suppresses liquid residue in the piping when filling the container or dispensing the liquid, it enhances preservation effectiveness, it makes blinking easier regardless of the viscosity when the formulation is placed in the eye (even if it is a high-viscosity formulation), it suppresses discomfort when blinking regardless of the viscosity when the formulation is placed in the eye (even if it is a high-viscosity formulation), it suppresses viscosity changes due to daylight, it suppresses precipitation (white residue) of contained components, it suppresses discoloration of the formulation due to daylight, it suppresses discoloration of the formulation due to ultraviolet rays, it suppresses changes in appearance (transparency) due to heat, it enhances cell viability, it suppresses damage to eye cells due to external stimuli (blinking, irritation from contact lenses (when putting them in or taking them out, while wearing them), rubbing the eyes, and foreign matter contamination (pollen, air pollutants, eyelashes, eye makeup-related foreign matter, and other foreign matter), and it reduces liquid residue in the container after use.

[0023] [Anti-inflammatory drugs] Anti-inflammatory agents are compounds and salts thereof that have anti-inflammatory or soothing effects. Anti-inflammatory agents are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0024] Specific examples of anti-inflammatory agents include epsilon-aminocaproic acid, allantoin, berberine, azulenes (azulene, azulene sulfonic acid, chamazulene, guaiazulene, etc.), glycyrrhizic acid, zinc salts, lysozyme, lysozyme chloride, celecoxib, lofecoxib, indomethacin, diclofenac, bromfenac, piroxicam, meloxicam, methyl salicylate, glycol salicylate, tranexamic acid, ibuprofen, ibuprofen piconol, bufexamac, flufenamate butyl, bendazac, ketoprofen, felbinac, pranoprofen, and their salts. As anti-inflammatory agents, allantoin, glycyrrhizic acid and its salts, and zinc salts are preferred, and allantoin, glycyrrhizic acid and its salts are more preferred. As glycyrrhizic acid and its salts, alkali metal salts or ammonium salts of glycyrrhizic acid are preferred, dipotassium glycyrrhizinate and monoammonium glycyrrhizinate are more preferred, and dipotassium glycyrrhizinate is even more preferred. As zinc salts, zinc sulfate or zinc lactate are preferred, and zinc sulfate is more preferred. The zinc salt may also be a hydrate (for example, zinc sulfate heptahydrate).

[0025] Anti-inflammatory drugs can also be commercially available. Anti-inflammatory drugs may be used individually or in combination of two or more.

[0026] (B) When an anti-inflammatory agent is used as component, the content of the anti-inflammatory agent in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of anti-inflammatory agent, the types and content of other components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of more significantly exhibiting the first effect of the present invention, the total content of the anti-inflammatory agent is preferably 0.0001 to 10 w / v%, more preferably 0.001 to 5 w / v%, even more preferably 0.005 to 3 w / v%, even more preferably 0.01 to 1 w / v%, and particularly preferably 0.03 to 0.5 w / v%, based on the total amount of the ophthalmic composition. The total content of the anti-inflammatory agent may also be 0.25 w / v%.

[0027] When an anti-inflammatory agent is used as component (B), the ratio of the anti-inflammatory agent to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the anti-inflammatory agent, the type and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the first effect of the present invention, for example, the total content of the anti-inflammatory agent to component (A) is preferably 0.0002 to 1000 parts by mass, more preferably 0.001 to 500 parts by mass, even more preferably 0.01 to 100 parts by mass, even more preferably 0.05 to 50 parts by mass, even more preferably 0.05 to 30 parts by mass, and particularly preferably 0.1 to 10 parts by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0028] [Vitamin A] Vitamin A compounds are not particularly limited as long as they are medically, pharmacologically (pharmaceutically), or physiologically acceptable. Specific examples of vitamin A compounds include retinol, retinal, retinoic acid, and their derivatives, as well as their salts.

[0029] Examples of vitamin A derivatives include esters with monovalent carboxylic acids such as retinyl palmitate, retinyl acetate, retinyl butyrate, retinyl propionate, retinyl octylate, retinyl lauryl, retinyl oleate, and retinyl linolenate.

[0030] Examples of vitamin A salts include organic acid salts [e.g., monocarboxylic acid salts (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylic acid salts (fumarate, maleate, succinate, malonate, etc.), oxycarboxylic acid salts (lactate, tartrate, citrate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), and 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, etc.].

[0031] As for vitamin A derivatives, retinol derivatives are preferred, esters of retinol with monovalent carboxylic acids are more preferred, retinyl palmitate and retinyl acetate are even more preferred, and retinyl palmitate is even more preferred.

[0032] For vitamin A derivatives, synthetic compounds may be used, or extracts obtained from natural sources (e.g., vitamin A oil) may be used. Vitamin A oil refers to fatty oil obtained from animal tissues containing retinol, or its concentrate, or a mixture thereof to which vegetable oil is appropriately added. Commercially available vitamin A derivatives may also be used. Vitamin A derivatives may be used individually or in combination of two or more types.

[0033] In the ophthalmic composition according to this embodiment, the total vitamin A content is preferably 0.1 million to 300,000 IU / 100mL, more preferably 0.5 million to 300,000 IU / 100mL, even more preferably 10,000 to 100,000 IU / 100mL, even more preferably 30,000 to 55,000 IU / 100mL, even more preferably 35,000 to 55,000 IU / 100mL, and particularly preferably 45,000 to 55,000 IU / 100mL, based on the total amount of the ophthalmic composition.

[0034] "IU" refers to the International Unit determined by the method described in the 17th Revised Japanese Pharmacopoeia, Vitamin A Quantitative Determination Method, etc. For example, in the individual articles of the 17th Revised Japanese Pharmacopoeia, it is stated that retinol acetate contains 2.5 million units or more of vitamin A per gram, and retinyl palmitate contains 1.5 million units or more of vitamin A per gram.

[0035] When vitamin A compounds are used as component (B), the ratio of vitamin A compounds to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and vitamin A compounds, the type and content of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of further enhancing the first effect of the present invention, for example, the total content of vitamin A compounds to component (A) is preferably 0.1 million to 3 million IU / g, more preferably 10,000 to 1 million IU / g, even more preferably 35,000 to 550,000 IU / g, and even more preferably 45,000 to 550,000 IU / g per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0036] [Vitamin B group] Vitamin B compounds are not particularly restricted as long as they are medically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0037] Specific examples of B vitamins include flavin adenine dinucleotide and its salts (e.g., flavin adenine dinucleotide sodium), cobalamins (e.g., cyanocobalamin, methylcobalamin), pantothenic acid and its salts (e.g., sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), panthenol, pyridoxine or its salts (e.g., pyridoxine hydrochloride), and pyridoxal and its salts (e.g., pyridoxal phosphate). Panthenol, pyridoxine, or its salts are preferred as B vitamins.

[0038] You can also use commercially available B vitamins. B vitamins may be used individually or in combination of two or more.

[0039] (B) When vitamin B compounds are used as component (B), the amount of vitamin B compounds in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of vitamin B compounds, the type and amount of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of more significantly exhibiting the first effect of the present invention, the total amount of vitamin B compounds is preferably 0.0001 to 5 w / v%, more preferably 0.0005 to 1 w / v%, even more preferably 0.001 to 1 w / v%, even more preferably 0.005 to 0.5 w / v%, and particularly preferably 0.01 to 0.1 w / v%, based on the total amount of the ophthalmic composition.

[0040] When vitamin B compounds are used as component (B), the ratio of vitamin B compounds to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the types of component (A) and vitamin B compounds, the types and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the first effect of the present invention, for example, the total content of vitamin B compounds to component (A) is preferably 0.00002 to 1000 parts by mass, more preferably 0.0001 to 500 parts by mass, more preferably 0.001 to 100 parts by mass, even more preferably 0.005 to 50 parts by mass, even more preferably 0.01 to 30 parts by mass, and particularly preferably 0.05 to 1 part by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0041] [Vitamin E derivatives] Vitamin E derivatives are not particularly limited as long as they are medically, pharmacologically (pharmaceutically), or physiologically acceptable. Specific examples of vitamin E derivatives include, for example, tocopherol, tocotrienol and their derivatives, and their salts. Tocopherol and tocotrienol may be α-, β-, γ-, or δ-, and may be either d-isomers or dl-isomers.

[0042] Examples of vitamin E derivatives include esters with organic acids such as tocopherol acetate, tocopherol succinate, tocopherol nicotinate, and tocopherol linolenic acid.

[0043] Examples of vitamin E salts include organic acid salts (lactate, acetate, butyrate, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate, malonate, methanesulfonate, toluenesulfonate, tosylate, palmitate, stearate, etc.), inorganic acid salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, amino acids, tripyridine, picoline, etc.), and salts with inorganic bases (e.g., salts with ammonium salts, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and metals such as aluminum, etc.).

[0044] Preferred vitamin E derivatives include d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E acetate (e.g., tocopherol acetate), vitamin E nicotinate, vitamin E succinate, and vitamin E linolenic acid, with tocopherol acetate (e.g., d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.) being more preferred.

[0045] Vitamin E derivatives may be either natural or synthetic. Commercially available vitamin E derivatives can also be used. Vitamin E derivatives may be used individually or in combination of two or more types.

[0046] In the ophthalmic composition according to this embodiment, the total content of vitamin E is preferably 0.0001 to 0.5 w / v%, more preferably 0.001 to 0.1 w / v%, even more preferably 0.005 to 0.05 w / v%, and even more preferably 0.01 to 0.05 w / v%, based on the total amount of the ophthalmic composition.

[0047] When vitamin E compounds are used as component (B), the ratio of vitamin E compounds to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the types of component (A) and vitamin E compounds, the types and amounts of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of further enhancing the first effect of the present invention, for example, the total content of vitamin E compounds to component (A) is preferably 0.0001 to 50 parts by mass, more preferably 0.001 to 20 parts by mass, even more preferably 0.005 to 10 parts by mass, even more preferably 0.01 to 5 parts by mass, and particularly preferably 0.01 to 0.5 parts by mass, per 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment.

[0048] [Aminoethylsulfonic acid and its salts] Aminoethylsulfonic acid (taurine) and its salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0049] Examples of aminoethylsulfonic acid salts include salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, and picoline), and salts with inorganic bases (e.g., ammonium salts, salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), and metals such as aluminum).

[0050] Among aminoethylsulfonic acid and its salts, aminoethylsulfonic acid is preferred.

[0051] Aminoethylsulfonic acid and its salts can also be commercially available. Aminoethylsulfonic acid and its salts may be used individually or in combination of two or more types.

[0052] In the ophthalmic composition according to this embodiment, the total content of aminoethylsulfonic acid and its salts is preferably 0.001 to 10 w / v%, more preferably 0.01 to 5 w / v%, even more preferably 0.05 to 3 w / v%, and even more preferably 0.1 to 2 w / v%, based on the total amount of the ophthalmic composition.

[0053] When aminoethylsulfonic acid and its salts are used as component (B), the content ratio of aminoethylsulfonic acid and its salts to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and aminoethylsulfonic acid and its salts, the type and content of other components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of further enhancing the first effect of the present invention, for example, the content ratio of aminoethylsulfonic acid and its salts to component (A) is preferably 0.001 to 1000 parts by mass, more preferably 0.01 to 200 parts by mass, even more preferably 0.05 to 100 parts by mass, even more preferably 0.1 to 20 parts by mass, and particularly preferably 0.1 to 10 parts by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0054] [Aspartic acid and its salts] Aspartic acid, also known as 2-aminobutanediic acid, is a well-known acidic amino acid. Aspartic acid and its salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable. Aspartic acid may be the L-isomer, D-isomer, or DL-isomer, but the L-isomer is preferred.

[0055] Examples of aspartic acid salts include salts with inorganic bases (e.g., ammonium salts; salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.), and salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, and picoline). As for aspartic acid and its salts, salts of aspartic acid with inorganic bases are preferred, alkali metal salts and alkaline earth metal salts of aspartic acid are more preferred, and potassium aspartate, magnesium aspartate, and magnesium-potassium aspartate are even more preferred.

[0056] Aspartic acid and its salts can be commercially available. Aspartic acid and its salts may be used individually or in combination of two or more types.

[0057] The content of aspartic acid and its salts in the ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the type and content of other components, the form of formulation, etc. As for the content of aspartic acid or its salts, for example, based on the total amount of the ophthalmic composition, the total content of aspartic acid or its salts is preferably 0.001 to 10 w / v%, more preferably 0.01 to 5 w / v%, even more preferably 0.05 to 3 w / v%, and even more preferably 0.1 to 2 w / v%.

[0058] When aspartic acid and its salts are used as component (B), the content ratio of aspartic acid and its salts to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and aspartic acid and its salts, the type and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the first effect of the present invention, for example, the content ratio of aspartic acid and its salts to component (A) is preferably 0.001 to 1000 parts by mass, more preferably 0.01 to 300 parts by mass, even more preferably 0.05 to 200 parts by mass, even more preferably 0.1 to 50 parts by mass, and particularly preferably 0.1 to 20 parts by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0059] [Neostigmine and its salts] Neostigmine and its salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of neostigmine salts include neostigmine methylsulfate. Neostigmine methylsulfate is preferred as the neostigmine and its salts.

[0060] Neostigmine and its salts can be commercially available. Neostigmine and its salts may be used individually or in combination of two or more types.

[0061] In the ophthalmic composition according to this embodiment, the total content of neostigmine and its salts is preferably 0.0001 to 0.05 w / v%, more preferably 0.0005 to 0.01 w / v%, even more preferably 0.0008 to 0.008 w / v%, and still more preferably 0.001 to 0.005 w / v%, based on the total amount of the ophthalmic composition.

[0062] When neostigmine and its salts are used as component (B), the content ratio of neostigmine and its salts to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and neostigmine and its salts, the type and content of other components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of further enhancing the first effect of the present invention, for example, the content ratio of neostigmine and its salts to component (A) is preferably 0.0001 to 5 parts by mass, more preferably 0.0001 to 1 part by mass, even more preferably 0.0005 to 0.8 parts by mass, even more preferably 0.001 to 0.5 parts by mass, and particularly preferably 0.001 to 0.05 parts by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0063] [Cellulose-based polymer compounds] Cellulosic polymer compounds are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0064] Examples of cellulosic polymer compounds include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), carboxymethylcellulose, carboxyethylcellulose, and their salts. Hydroxyethylcellulose, hydroxypropylmethylcellulose, and their salts are preferred as cellulosic polymer compounds, and hydroxypropylmethylcellulose and its salts are more preferred. Examples of such salts include salts with organic bases (amine salts, basic ammonium salts such as arginine, etc.) and salts with inorganic bases (ammonium salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, etc.), with sodium salts, potassium salts, and calcium salts being more preferred, and sodium salts being particularly preferred.

[0065] As the cellulose polymer compound, commercially available products can also be used. The cellulose polymer compound may be used alone or in combination of two or more types.

[0066] (B) When a cellulose polymer compound is used as component, the content of the cellulose polymer compound in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of cellulose polymer compound, the types and content of other components, the use of the ophthalmic composition and the formulation form. From the viewpoint of more significantly exhibiting the first effect of the present invention, the total content of the cellulose polymer compound is preferably 0.0001 to 10 w / v%, more preferably 0.001 to 5 w / v%, even more preferably 0.005 to 3 w / v%, and even more preferably 0.01 to 2 w / v%, based on the total amount of the ophthalmic composition.

[0067] When a cellulose polymer compound is used as component (B), the content ratio of the cellulose polymer compound to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the cellulose polymer compound, the type and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the first effect of the present invention, for example, the content ratio of the cellulose polymer compound to component (A) is preferably 0.0001 to 500 parts by mass, more preferably 0.001 to 100 parts by mass, even more preferably 0.005 to 50 parts by mass, and even more preferably 0.01 to 30 parts by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0068] The ophthalmic composition according to this embodiment may further contain (C) a surfactant (also referred to as "component (C)"). The further inclusion of component (C) in the ophthalmic composition makes the first effect according to the present invention more pronounced. The surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and may be any of nonionic surfactants, amphoteric surfactants, anionic surfactants, or cationic surfactants.

[0069] Examples of nonionic surfactants include POE(20) sorbitan fatty acid esters such as POE(20) 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); POE hydrogenated castor oils such as POE(40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40) and POE(60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); and POE(3) hydrogenated castor oil (poly Examples include POE castor oils such as polyoxyethylene castor oil3), POE(10) castor oil (polyoxyethylene castor oil 10), and POE(35) castor oil (polyoxyethylene castor oil 35); POE alkyl ethers such as POE(9) lauryl ether; POE-POP alkyl ethers such as POE(20) POP(4) cetyl ether; polyoxyethylene-polyoxypropylene block copolymers such as POE(196) POP(67) glycol (poloxamer 407, Pluronic F127) and POE(200) POP(70) glycol; and polyethylene glycol monostearate such as polyoxyl stearate 40. In the compounds exemplified above, POE represents polyoxyethylene, POP represents polyoxypropylene, and the numbers in parentheses indicate the number of moles added.

[0070] Examples of amphoteric surfactants include alkyldiaminoethylglycine or its salts (e.g., hydrochloride salts).

[0071] Examples of anionic surfactants include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, and α-olefin sulfonic acid.

[0072] Examples of cationic surfactants include cetylpyridinium chloride, benzalkonium chloride, and benzethonium chloride.

[0073] Among these surfactants, nonionic surfactants are preferred, and POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE castor oil, and POE-POP block copolymers are more preferred. Commercially available surfactants can also be used. One surfactant may be used alone, or two or more may be used in combination.

[0074] The content of component (C) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (C), the use of the ophthalmic composition, and the formulation form. As for the content of component (C), from the viewpoint of more significantly exhibiting the first effect of the present invention, for example, the total content of component (C) is preferably 0.001 to 3 w / v%, more preferably 0.005 to 2 w / v%, even more preferably 0.01 to 1 w / v%, and particularly preferably 0.05 to 1 w / v%, based on the total amount of the ophthalmic composition.

[0075] In the ophthalmic composition according to this embodiment, the content ratio of component (C) to component (A) is not particularly limited and is set appropriately depending on the types of component (A) and component (C), the types and content of other components, the use of the ophthalmic composition and the form of formulation, etc. As for the content ratio of component (C) to component (A), from the viewpoint of further enhancing the first effect of the present invention, for example, the total content of component (C) in the ophthalmic composition according to this embodiment is more preferably 0.001 to 30 parts by mass, more preferably 0.005 to 20 parts by mass, even more preferably 0.01 to 10 parts by mass, and particularly preferably 0.01 to 2 parts by mass, per 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment.

[0076] The ophthalmic composition according to this embodiment preferably further contains (D) a buffering agent (also referred to as "component (D)"). The further inclusion of component (D) in the ophthalmic composition makes the first effect of the present invention more pronounced. The buffering agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of buffering agents include inorganic buffering agents, which are buffering agents derived from inorganic acids, and organic buffering agents, which are buffering agents derived from organic acids or organic bases.

[0077] Examples of inorganic buffers include borate buffers, phosphate buffers, and carbonate buffers. Examples of borate buffers include boric acid or its salts (alkali metal borate, alkaline earth metal borate, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphate, alkaline earth metal phosphate, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonate, alkaline earth metal carbonate, etc.). In addition, hydrates of borates, phosphates, or carbonates may be used as borate buffers, phosphate buffers, or carbonate buffers. More specific examples include boric acid buffers such as boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphoric acid buffers such as phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffers such as carbonate or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.).

[0078] Examples of organic buffers include citrate buffers, acetate buffers, lactic acid buffers, succinate buffers, Tris buffers, and AMPD buffers. Examples of citrate buffers include citric acid or its salts (alkali metal citrate, alkaline earth metal citrate, etc.). Examples of acetate buffers include acetic acid or its salts (alkali metal acetate, alkaline earth metal acetate, etc.). Examples of lactic acid buffers include lactic acid or its salts (alkali metal lactate, alkaline earth metal lactate, etc.). Examples of succinate buffers include succinic acid or its salts (alkali metal succinate, etc.). In addition, citrate, acetate, lactate, or succinate hydrates may be used as citrate buffers, acetate buffers, lactic acid buffers, or succinate buffers. More specific examples include citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) as citrate buffers; acetic acid or its salts (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.) as acetic acid buffers; lactic acid or its salts (sodium lactate, potassium lactate, calcium lactate, etc.) as lactic acid buffers; and succinic acid or its salts (monosodium succinate, disodium succinate, etc.) as succinic acid buffers. Examples of Tris buffers include trometamol or its salts (trometamol hydrochloride, etc.). Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol or its salts.

[0079] Preferred buffering agents include boric acid buffers (e.g., a combination of boric acid and borax), phosphate buffers (e.g., a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), and Tris buffers (e.g., trometamol). Boric acid buffers are more preferred, boric acid and its salts are even more preferred, and a combination of boric acid and borax is even more preferred.

[0080] You may use commercially available cushioning material. You may use one type of cushioning material alone, or you may use two or more types in combination.

[0081] The content of component (D) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (D), the types and content of other components, the use of the ophthalmic composition and the form of formulation. As for the content of component (D), from the viewpoint of more significantly exhibiting the first effect of the present invention, for example, the total content of component (D) is preferably 0.01 to 10 w / v%, more preferably 0.05 to 5 w / v%, and even more preferably 0.1 to 3 w / v%, based on the total amount of the ophthalmic composition.

[0082] In the ophthalmic composition according to this embodiment, the content ratio of component (D) to component (A) is not particularly limited and is set appropriately depending on the types of component (A) and component (D), the types and content of other components, the use of the ophthalmic composition and the form of formulation, etc. As for the content ratio of component (D) to component (A), from the viewpoint of further enhancing the first effect of the present invention, for example, the total content of component (D) in the ophthalmic composition according to this embodiment is preferably 0.01 to 100 parts by mass, more preferably 0.05 to 50 parts by mass, and even more preferably 0.1 to 30 parts by mass, per 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment.

[0083] The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, even more preferably 4.5 to 8.5, even more preferably 5.0 to 8.5, particularly preferably 5.0 to 8.0, even more particularly preferably 5.3 to 7.5, and most preferably 5.3 to 7.0.

[0084] The ophthalmic composition according to this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the body, as needed. An appropriate osmotic pressure ratio can be set as appropriate depending on the use, formulation form, and method of use of the ophthalmic composition, but for example, it can be 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and even more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 17th edition of the Japanese Pharmacopoeia, and the osmotic pressure is measured by referring to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, then 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 by using a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

[0085] The viscosity of the ophthalmic composition according to this embodiment is not particularly limited, as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The viscosity of the ophthalmic composition according to this embodiment is preferably 1 to 10,000 mPa·s, more preferably 1 to 8,000 mPa·s, even more preferably 1 to 1,000 mPa·s, even more preferably 1 to 100 mPa·s, particularly preferably 1 to 20 mPa·s, and most preferably 1.5 to 10 mPa·s, as measured at 20°C with a rotational viscometer (TV-20 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' × R24).

[0086] The ophthalmic composition according to this embodiment may contain, in addition to the above-mentioned components, an appropriate amount of components selected from various pharmacologically active components and physiologically active components, provided that the effects of the first aspect of the present invention are not impaired. The components are not particularly limited, and examples include the active ingredients in ophthalmic drugs listed in the 2017 edition of the Standards for Approval of Manufacturing and Marketing of Prescription-Only and Over-the-Counter Drugs (supervised by the Regulatory Science Society of Japan). Specifically, examples of components used in ophthalmic drugs include the following: Antiallergic agents: For example, sodium cromoglycate, tranilast, pemirolast potassium, acitazanol, anlexanox, ibudilast, etc. Antihistamines: for example, diphenhydramine or its salt (e.g., diphenhydramine hydrochloride), iproheptine or its salt (e.g., iproheptine hydrochloride), chlorpheniramine or its salt (e.g., chlorpheniramine maleate), levocabastine or its salt (e.g., levocabastine hydrochloride), ketotifen or its salt (e.g., ketotifen fumarate), pemirolast potassium, olopatadine or its salt (e.g., olopatadine hydrochloride), etc. Steroids: For example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc. Decongestants: For example, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc. Ocular muscle modulating agents: For example, cholinesterase inhibitors that have an active site similar to acetylcholine, specifically tropicamide, helenien, atropine sulfate, pilocarpine hydrochloride, etc. Vitamins: For example, ascorbic acid, sodium ascorbate, etc. Amino acids: For example, L-arginine, glutamic acid, glycine, alanine, lysine, gamma-aminobutyric acid, gamma-aminovaleric acid, trimethylglycine, and their salts. Astringent agents: For example, zinc oxide. Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and their salts.

[0087] The ophthalmic composition according to this embodiment may contain, in accordance with conventional methods, various additives selected appropriately and used in combination in appropriate amounts, one or more types, depending on its use and formulation, as long as the effects of the first aspect of the present invention are not impaired. Examples of such additives include the various additives listed in the 2016 Dictionary of Pharmaceutical Additives (edited by the Japan Pharmaceutical Additives Association). The following are examples of typical additives. Carrier: For example, an aqueous solvent such as water or aqueous ethanol. Chelating agents: For example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc. Base: For example, octyldodecanol, titanium dioxide, potassium bromide, Plastibase, etc. pH adjusters: For example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, etc. Fragrances or cooling agents: For example, menthol, menthone, camphor, borneol, geraniol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymene, terpineol, pinene, camphene, isoborneol, fencienne, nerol, myrcene, myrcenol, linalool acetate, lavandulol, eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil, etc. These may be d-isomers, l-isomers, or dl-isomers. Thickeners: For example, polyvinyl polymer compounds such as polyvinylpyrrolidone and polyvinyl alcohol; carboxyvinyl polymers; guar gum; hydroxypropyl guar gum; gum arabic; karaya gum; xanthan gum; agar; alginic acid and its salts (sodium salt, etc.); mucopolysaccharides such as heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and its salts (sodium salt, etc.); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan; monosaccharides such as glucose, etc. Stabilizers: For example, EDTA, EDTA salts (disodium EDTA, disodium calcium EDTA, trisodium EDTA, tetrasodium EDTA), sodium formaldehyde sulfoxylate (Longalit), aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, sodium bisulfite, sodium pyrosulfite, etc. Preservatives: For example, alkyl polyaminoethylglycine quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, polydronium chloride, zinc chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), alexidine, etc.), Glokill (a trade name of Rhodia Corporation), etc. Isotonic agents: For example, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, sodium bisulfite, sodium sulfite, etc. Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin, etc. These may be in d-isomer, l-isomer, or dl-isomer. Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil, and olive oil; animal oils such as squalane; mineral oils such as liquid paraffin and petrolatum.

[0088] From the viewpoint of significantly achieving the first effect of the present invention, the ophthalmic composition according to this embodiment preferably does not contain at least one selected from the group consisting of geraniol, linalyl acetate, limonene, citral, and linalool in an amount of 0.01% or more, and more preferably does not contain it at all.

[0089] If the ophthalmic composition according to this embodiment contains water, from the viewpoint of more significantly exhibiting the first effect of the present invention, the water content is preferably 80 w / v% or more and less than 100 w / v%, more preferably 85 w / v% or more and 99.5 w / v%, and even more preferably 90 w / v% or more and 99.2 w / v%, based on the total amount of the ophthalmic composition.

[0090] The water used in the ophthalmic composition according to this embodiment may be any water that is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable. Examples of such water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection. Their definitions are based on the 17th edition of the Japanese Pharmacopoeia.

[0091] The ophthalmic composition according to this embodiment can be prepared by adding and mixing a desired amount of component (A) and, if necessary, other components such as component (B) to the desired concentration. For example, it can be prepared by dissolving or dispersing these components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like.

[0092] The ophthalmic composition according to this embodiment can take various formulation forms depending on the purpose. Examples of formulation forms include liquids, gels, and semi-solid preparations (such as ointments).

[0093] The ophthalmic compositions according to this embodiment can be used, for example, as eye drops (also called eye solutions or eye medicines; eye drops include eye drops that can be used while wearing contact lenses), artificial tears, eye washes (also called eye wash solutions or eye medicines; eye washes include eye washes that can be used while wearing contact lenses), and contact lens compositions [contact lens insertion solutions, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaning agents, contact lens cleaning and preservation agents), contact lens packaging solutions, etc.]. Note that "contact lenses" include hard contact lenses and soft contact lenses (including both ionic and nonionic types, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0094] The ophthalmic composition according to this embodiment exhibits an effect of suppressing dryness of the eyes, and is therefore suitably used as an ophthalmic composition for suppressing dryness of the eyes. Accordingly, as a first embodiment of the present invention, an ophthalmic composition for suppressing dryness of the eyes is provided, which contains at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000. It should be noted that the "effect of suppressing dryness of the eyes" as described herein is not due to a tear secretion promoting effect, but rather is considered to be due to an effect of reducing eye cell damage caused by dryness, an effect of improving affinity to contact lenses, etc.

[0095] Furthermore, as a first embodiment of the present invention, a method for suppressing dry eyes is provided, which uses at least one selected from the group consisting of chondroitin sulfate and salts thereof having a weight-average molecular weight of 40,000 to 70,000. Furthermore, as a first embodiment of the present invention, the use of at least one selected from the group consisting of chondroitin sulfate and salts thereof having a weight-average molecular weight of 40,000 to 70,000 is provided for the production of an ophthalmic composition for suppressing dry eyes.

[0096] The ophthalmic composition according to this embodiment can suppress dryness of the eyes and contact lenses. Therefore, it can improve various symptoms caused by these symptoms. Specifically, by suppressing dryness of the eyes and contact lenses, the ophthalmic composition according to this embodiment can alleviate symptoms such as friction during blinking, watery eyes, eye fatigue, redness, blurred vision, decreased visual function, inflammation, itching, gritty feeling in the eyes, foreign body sensation, pain, photophobia, eye discomfort (for example, discomfort when wearing hard or soft contact lenses), damage to the eye surface due to dryness stress, damage to the eye surface due to light or other light rays, a dull feeling in the eyelids (heavy eyelids), and inability to concentrate on looking for extended periods.

[0097] The ophthalmic composition according to this embodiment has high affinity for contact lenses and exhibits an effect of suppressing the drying of contact lenses, and therefore can be suitably used as an ophthalmic composition for suppressing the drying of contact lenses. In this embodiment, from the viewpoint of more significantly exhibiting the first effect according to the present invention, the contact lens is preferably a soft contact lens, and more preferably a silicone hydrogel contact lens.

[0098] Furthermore, as a first embodiment of the present invention, a method for suppressing the drying of contact lenses is provided, which uses at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000. Furthermore, as a first embodiment of the present invention, the use of at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000 is provided for the manufacture of an ophthalmic composition for suppressing the drying of contact lenses.

[0099] The ophthalmic composition according to this embodiment is preferably an eye drop (including eye drops that can be instilled while wearing contact lenses) because it can more clearly exhibit the effects of the first embodiment of the present invention. When the ophthalmic composition according to this embodiment is an eye drop, the method of use and dosage are not particularly limited as long as they are effective and have few side effects, but for example, for adults (15 years of age or older) and children 7 years of age or older, examples include instilling 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops at a time, 2 to 4 times or 5 to 6 times a day.

[0100] The ophthalmic composition according to this embodiment is provided in any container. The container for containing the ophthalmic composition according to this embodiment is not particularly limited and may be made of glass or plastic, for example. Plastic is preferred. Examples of plastics include polyethylene terephthalate (PET), polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide and copolymers of monomers constituting these, and mixtures of two or more of these. From the viewpoint of further enhancing the effects of the first aspect of the present invention, polyethylene terephthalate is preferred as the container for containing the ophthalmic composition. Furthermore, the container for containing the ophthalmic composition according to this embodiment may be a transparent container that allows visibility of the inside of the container, or an opaque container that makes it difficult to see inside the container. A transparent container is preferred. Here, "transparent container" includes both colorless transparent containers and colored transparent containers.

[0101] A nozzle may be attached to the container for containing the ophthalmic composition according to this embodiment. The material of the nozzle is not particularly limited and may be made of glass or plastic, for example. Plastic is preferred. Examples of plastics include polybutylene terephthalate, polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate and copolymers of monomers constituting these, and mixtures of two or more of these. From the viewpoint of further enhancing the first effect of the present invention, polypropylene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate are preferred as the material of the nozzle, and polyethylene is more preferred.

[0102] The container for containing the ophthalmic composition according to this embodiment may be a multi-dose type that contains multiple doses, or a unit-dose type that contains a single dose.

[0103] The ophthalmic composition according to this embodiment is preferably filled in a container with an internal volume of 4 to 30 mL, more preferably in a container with an internal volume of 5 to 20 mL, even more preferably in a container with an internal volume of 6 to 16 mL, and even more preferably in a container with an internal volume of 10 to 15 mL. It may also be filled in a container with an internal volume of 0.1 to 3 mL, or in a container with an internal volume of 0.2 to 1 mL. [Examples]

[0104] The first aspect of the present invention will be specifically described below based on test examples, but the first aspect of the present invention is not limited to these. Furthermore, the chondroitin sulfate sodium used in the following test examples is as follows, and the chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 is derived from sharks. Chondroitin Sodium Sulfate Weight-average molecular weight approximately 56,000: Seikagaku Corporation; Grade NK Weight-average molecular weight approximately 28,000: Seikagaku Corporation; Grade ND-K Weight-average molecular weight approximately 25,000: Maruha Nichiro Corporation; Non-pharmaceutical standard chondroitin sulfate sodium

[0105] [Test Example 1: Desiccation Stress Test Using Rabbits] Each test substance was prepared by dissolving either chondroitin sulfate sodium with a weight-average molecular weight of approximately 25,000 (Maruha Nichiro Corporation; non-pharmaceutical grade chondroitin sulfate sodium) or chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 (Seikagaku Corporation; grade NK) in physiological saline (Otsuka Pharmaceutical Factory Co., Ltd.) to a concentration of 0.5 w / v% or 3 w / v%. Following the method of Nagano et al. (New Ophthalmology, 13(2), 267-270, 1996), five groups (n=5) of rabbits (Japanese white rabbits (Kitayama Labes)) were administered general anesthesia. Rings made from the finger portions of gloves were then attached to the eyeballs of both rabbits to forcibly open their eyelids. Immediately after eyelid opening, 100 μL of the test substance was instilled into both eyes of each group of rabbits, and they were left with their eyelids open for 3 hours. 50 μL of 1% methylene blue solution was dropped onto the ocular surface for staining, and the surface was washed with physiological saline. After excising the cornea from the ocular surface, the methylene blue dye was extracted, and the absorbance at 660 nm was measured using a microplate reader Multiskan GO (Thermo Fisher Scientific Co., Ltd.). The results are shown in Figure 1. Furthermore, since dry eyes can lead to corneal damage and an increase in the amount of pigment adhering to the corneal surface, a higher absorbance value indicates drier eyes.

[0106] As shown in Figure 1, chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 exhibited significantly lower absorbance compared to chondroitin sulfate sodium with a weight-average molecular weight of approximately 25,000 (**p<0.01, Tukey multiple comparison test), confirming its ability to suppress corneal damage caused by dry eyes.

[0107] [Test Example 2: Wettability Test of Contact Lenses] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 1, and these were used as test solutions. The units for each component in Table 1 are w / v%. In Test Example 2 and the following test examples, chondroitin sulfate sodium with a weight-average molecular weight of approximately 28,000 (Seikagaku Corporation; Grade ND-K) and approximately 56,000 (Seikagaku Corporation; Grade NK) was used. Four milliliters of phosphate-buffered saline (0.60% sodium chloride, 0.60% sodium hydrogen phosphate (dodecahydrate), 0.05% sodium dihydrogen phosphate (dihydrate), pH 7.4 ± 0.1) were dispensed into each well of a 12-well plate (BD Falcon, No. 35-3043). One contact lens (Acuvue Oasys (Johnson & Johnson Co., Ltd.)) was immersed in each well and left to stand at room temperature for at least 4 hours. Four milliliters of phosphate-buffered saline and each test solution were dispensed into the 12-well plate. The moisture from the contact lenses was lightly wiped off with lint-free paper and immersed, and left to stand for 15 minutes. 100 milliliters of phosphate-buffered saline were dispensed into a beaker. The immersed contact lenses were lightly rinsed with phosphate-buffered saline and the moisture was removed using lint-free paper. A contact lens was placed on a glass slide, and the contact angle was measured 0.10 seconds after dropping 3 μl of phosphate-buffered saline solution using a contact angle measuring device (Solid-Liquid Interface Analysis System DropMaster500 (Kyowa Interface Science Co., Ltd.)). The results are shown in Table 1. A lower contact angle indicates better wettability of the contact lens and higher affinity to the contact lens.

[0108] [Table 1]

[0109] Test solution 2, containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 28,000, showed a contact angle almost the same as test solution 1, which did not contain chondroitin sulfate sodium. On the other hand, test solution 3, containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000, showed a significantly smaller contact angle compared to test solution 2, indicating significantly improved wettability and higher affinity to contact lenses.

[0110] Furthermore, when the contact angle (°) was measured in the same manner as in Test Example 2 for Test Solution 3-1, which had the same composition as Test Solution 3 except that the content of sodium chondroitin sulfate (weight-average molecular weight approximately 56,000) in Test Solution 3 was set to 1 w / v%, and for Test Solution 3-2, which contained 50,000 units / 100 mL of retinyl palmitate, 0.35 w / v% of polyoxyethylene hydrogenated castor oil 60, and 0.2 w / v% of polyoxyethylene castor oil 10 in addition to Test Solution 3-1, the results were 67.4° for Test Solution 3-1 and 44.2° for Test Solution 3-2.

[0111] [Test Example 3: Contact Lens Dryness Test] Four mL of phosphate-buffered saline (0.60% sodium chloride, 0.60% sodium hydrogen phosphate (dodecahydrate), 0.05% sodium dihydrogen phosphate (dihydrate), pH 7.4 ± 0.1) was dispensed into each well of a 12-well plate (BD Falcon, No. 35-3043). Two contact lenses (Acuvue Oasys (Johnson & Johnson Co., Ltd.)) were immersed in each well and left to stand at room temperature for at least 4 hours. After lightly wiping the moisture off the contact lenses with lint-free paper, the contact lenses were immersed in 12-well plates containing four mL each of phosphate-buffered saline and each of the test solutions listed in Table 1 above, and left to stand at room temperature for 24 hours. The moisture from the contact lenses was lightly wiped off with lint-free paper, and the lenses were immersed in 12-well plates containing 2 mL each of a color comparison stock solution of cobalt(II) chloride (Wako Pure Chemical Industries, Ltd., distributor code: 031-19041). The plates were shaken for 5 minutes at room temperature and 200 rpm. The moisture from the contact lenses was lightly wiped off with lint-free paper, and the discoloration of the soft contact lenses was observed immediately after placing them on the coverslip (0 minutes), and at 5, 15, and 30 minutes after placement. In this test, the contact lenses turned blue when they dried. The results of evaluating the presence or absence of discoloration according to the following criteria are shown in Table 2. A: No coloring B: Slightly colored (less than 30% of the entire contact lens surface) C: Clearly discolored (more than 30% of the entire contact lens surface)

[0112] [Table 2]

[0113] In test solution 1, which did not contain sodium chondroitin sulfate, and in test solution 2, which contained sodium chondroitin sulfate with a weight-average molecular weight of approximately 28,000, slight discoloration was observed after 15 minutes. In contrast, in test solution 3, which contained sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000, no discoloration was observed after 15 minutes, and slight discoloration was observed after 30 minutes. Therefore, it was confirmed that sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000 suppresses contact lens drying more effectively than sodium chondroitin sulfate with a weight-average molecular weight of approximately 28,000.

[0114] [Test Example 4: Wettability Test of Contact Lenses] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 3, and used as a test solution. Unless otherwise specified in the table, the units for each component in Table 3 are w / v%. In Test Example 4 and the following test examples, retinyl palmitate with a concentration of 1,740,000 IU / g was used. After thoroughly wiping the surface of a contact lens (Acuvue Advance (Johnson & Johnson Co., Ltd.)) immersed in 2 mL of physiological saline for at least 4 hours with lint-free paper, a droplet (approximately 1 μL) of each prepared ophthalmic composition was dropped onto the lens. The contact angle (static contact angle) to the contact lens 0.1 seconds after dropping was measured using an automated contact angle meter (Solid-Liquid Interface Analysis System Drop Master, DM-A501 (Kyowa Interface Science Co., Ltd.)). The contact angle was measured three times for each ophthalmic composition, and the average value was calculated as the contact angle for each ophthalmic composition. The results are shown in Table 3. A lower contact angle indicates better wettability of the contact lens and higher affinity to the contact lens.

[0115] [Table 3]

[0116] Test solutions 6-10 and 13-15 showed significantly smaller contact angles and significantly improved wettability compared to test solution 4. Similarly, test solutions 11 and 12 showed significantly smaller contact angles and significantly improved wettability compared to test solution 5. In other words, compared to a test solution containing only chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000, test solutions containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 along with neostigmine methylsulfate, allantoin, dipotassium glycyrrhizate, pyridoxine hydrochloride, panthenol, d-α-tocopherol acetate, retinyl palmitate, potassium L-aspartate, taurine, or hydroxypropyl methylcellulose, respectively, showed significantly smaller contact angles, significantly improved wettability, and demonstrated high affinity for contact lenses.

[0117] [Test Example 5: Measurement of Contact Angle in Stainless Steel Pipes] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 4, and used as a test solution. The units for each component in Table 4 are w / v%. Droplets (approximately 1 μL) of each prepared ophthalmic composition were dropped onto a stainless steel metal plate (ferrule cap TypeCLF-B), and the contact angle with the metal (static contact angle) 0.1 seconds after dropping was measured using an automatic contact angle meter (solid-liquid interface analysis system Drop Master, DM-A501 (Kyowa Interface Science Co., Ltd.)). The contact angle was measured three times for each ophthalmic composition, and the average value was calculated to determine the contact angle of each ophthalmic composition. The results are shown in Table 4.

[0118] [Table 4]

[0119] Test solution 15 showed a significantly increased contact angle compared to test solution 4. In other words, it was confirmed that the test solution containing chondroitin sulfate sodium (with a weight-average molecular weight of approximately 56,000) and hydroxypropyl methylcellulose had significantly lower affinity to stainless steel tubes compared to the test solution containing only chondroitin sulfate sodium (with a weight-average molecular weight of approximately 56,000). Since the filling tubes in the manufacturing line are made of metal such as stainless steel, it is possible to reduce the amount of liquid droplets adhering to the end of the filling tube when filling containers with ophthalmic compositions, making it easier to achieve uniformity in the filling amount.

[0120] [Test Example 6: Test on Preservative Efficacy] Each ophthalmic composition was prepared according to standard procedures using the compositions shown in Table 5, and used as test solutions. Unless otherwise specified in the table, the units for each component in Table 5 are w / v%. Staphylococcus aureus (ATCC6538) was inoculated onto the surface of soybean casein digest slant agar and cultured at 33°C for 24 hours. The cultured cells were aseptically collected using a platinum loop and suspended in an appropriate amount of sterile physiological saline, resulting in approximately 1 × 10⁶ cells. 7 A bacterial suspension containing viable bacteria at a CFU / mL concentration was prepared. The number of viable bacteria in the suspension was measured separately by culturing. Next, 10 mL of each prepared ophthalmic composition was filled into 15 mL conical tubes (CORNING) made of PET material. Each of these ophthalmic compositions was then filled with bacteria with a viable bacterial count (final concentration) of approximately 10. 5 A sample was prepared by inoculating a Staphylococcus aureus bacterial suspension (suspended in physiological saline) to a concentration of CFU / mL and thoroughly mixing it. The sample containing the bacteria was stored at 23°C under light protection for 3 days. After that, the sample containing the bacteria was adjusted to a concentration suitable for counting and prepared as a 3M solution. TM Petrifilm TM1 mL of the culture solution was inoculated onto a rapid viable cell count plate (RAC plate), incubated at 33°C for 2 days, and the number of colonies observed was counted to determine the viable cell count. The viable cell count immediately after inoculation was compared with the viable cell count in the sample after 3 days of storage, and the decrease in the bacterial count was calculated as Log Reduction. Furthermore, the calculated Log Reduction was evaluated according to the following criteria to determine whether the preservation effect was sufficient. The bacterial culture for initial counting was performed at 33°C for 2 days. The results are shown in Table 5. Evaluation Criteria Log Reduction < 0.7:D 0.7 ≤ Log Reduction < 0.8:C 0.8 ≤ Log Reduction < 0.9: B 0.9 ≤ Log Reduction: A

[0121] [Table 5]

[0122] Compared to test solutions 16 and 17, which contain sodium chondroitin sulfate with a weight-average molecular weight of approximately 28,000, test solutions 7, 8, 12, and 14, which contain sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000 along with allantoin, dipotassium glycyrrhizate, retinyl palmitate, or taurine, respectively, were found to exhibit improved preservative efficacy. Furthermore, for test solution 12, a similar improvement in preservative efficacy could be obtained when conducting the same test with the same formulation as test solution 12, except that the concentration of retinyl palmitate was 50,000 units / 100 mL.

[0123] [Test Example 7: Viscosity Measurement] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 6, and used as a test solution. Unless otherwise specified in the table, the units for each component in Table 6 are w / v%. The viscosity of each prepared ophthalmic composition (600 μL) was measured at 34°C against shear rate using a rheometer (MCR302 (Anton Paar)) with a cone-plate measuring jig (CP50-1, d: 0.102 mm). For viscosity (mPa·s) at a shear rate of 10000 (1 / s), the viscosity reduction rate of test solution 12 or 13 relative to test solution 4 or 5 (a formulation containing sodium chondroitin sulfate alone) was calculated according to the following formula. Note that a decrease in viscosity indicates a decrease in viscosity when stress is applied, and the shear rate of 10000 (1 / s) is assumed to be the blink speed. Measuring viscosity at a shear rate of 10000 (1 / s) allows for evaluation of the viscosity change of the formulation within the eye during blinking. A decrease in viscosity during blinking indicates that blinking is easier and less uncomfortable. (Formula) Viscosity reduction rate (%) = (1 - viscosity of test solution 12 or 13 / viscosity of corresponding test solution) × 100 The corresponding test solutions are test solution 5 for test solution 12 and test solution 4 for test solution 13. The results are shown in Table 6.

[0124] [Table 6]

[0125] Compared to test solutions 5 and 4, test solutions 12 and 13 containing retinol palmitate or potassium L-aspartate showed a significant decrease in viscosity. Here, the inventors confirmed that the viscosity measured by a rotational viscometer after preparation of test solution 4, which used sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000, was higher than that of test solutions with the same composition, except that sodium chondroitin sulfate with a weight-average molecular weight of approximately 28,000 was used instead of sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000 in test solution 4. When an ophthalmic composition has high viscosity when instilled, problems such as difficulty blinking and discomfort may occur. Therefore, it can be said that if the viscosity at high shear rates is low, blinking will be easier and discomfort will be less likely after instillation. Therefore, it was confirmed that ophthalmic compositions containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 and retinol palmitate or potassium L-aspartate made blinking easier and caused less discomfort after instillation compared to ophthalmic compositions containing only chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000.

[0126] [Test Example 8: Viscosity Stability Test by Light Irradiation] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 7, and used as a test solution. Unless otherwise specified in the table, the units for each component in Table 7 are w / v%. 10 mL of each ophthalmic composition was filled into 10 mL glass headspace vials (GL Sciences Co., Ltd.), and irradiated using a D65 fluorescent lamp as the light source at room temperature (25°C) with an illuminance of 4000 lx / h until an integrated illuminance of 1,200,000 lx was reached. The viscosity of each ophthalmic composition (600 μL) before and after irradiation was measured using a rheometer (MCR302 (Anton Paar Co., Ltd.)) with a cone-plate type measuring jig (CP50-1, d:0.102 mm) for shear rates (1~10000 (1 / s)) at 34°C. Then, using the viscosity (mPa·s) at a shear rate of 1000 (1 / s), the viscosity stability before and after the test was evaluated according to the following formula. The results are shown in Table 7. Note that a smaller viscosity change rate indicates less viscosity change due to light, and that the ophthalmic composition is maintained in the same physical properties. (Formula) Viscosity change rate (%) = {(Viscosity of each ophthalmic composition before light irradiation - Viscosity of each ophthalmic composition after light irradiation) / Viscosity of each ophthalmic composition before light irradiation} × 100

[0127] [Table 7]

[0128] In test solutions 16 and 17, which contain sodium chondroitin sulfate with a weight-average molecular weight of approximately 28,000, no viscosity change occurred upon light irradiation. However, in test solutions 4 and 5, which contain sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000, a viscosity change occurred upon light irradiation. However, in test solutions 6 and 11-14, which contain sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000 and neostigmine methyl sulfate, d-α-tocopherol acetate, retinyl palmitate, potassium L-aspartate, or taurine, respectively, the viscosity change rate decreased significantly, confirming improved stability of the ophthalmic composition upon light irradiation. A similar trend was observed when viscosity was measured at a shear rate of 100 (1 / s). Furthermore, when the same test was performed with the same formulation as test solution 12, except for the concentration of retinyl palmitate at 50,000 units / 100 mL, the same effect of improving the stability of the ophthalmic composition upon light irradiation was obtained.

[0129] [Test Example 9: Precipitation Inhibition Test] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 8, and used as a test solution. The units for each component in Table 8 are w / v%. One mL of each ophthalmic composition was added to a 24-well plate (Corning), and the plate was stored in a dry heat dryer (Ikeda Rika Co., Ltd.) at 60°C for two days. The precipitation in each well of the plate was then visually observed, and the occurrence of precipitates was evaluated according to the following evaluation criteria. The results are shown in Table 8. <Evaluation Criteria for Precipitation Formation> Clearly identifiable precipitates are present at the bottom of the well, and the precipitates occupy more than half of the bottom surface area:+++ There is clearly visible precipitate at the bottom of the well, and the precipitate occupies between 1 / 3 and 1 / 2 of the bottom surface:++ There is clearly visible precipitate at the bottom of the well, and the precipitate occupies less than 1 / 3 of the bottom surface. No precipitates present:

[0130] [Table 8]

[0131] Compared with test solution 18 containing sodium chondroitin sulfate with a weight average molecular weight of about 28,000 and potassium aspartate, the occurrence of precipitation was significantly suppressed in test solution 13 containing sodium chondroitin sulfate with a weight average molecular weight of about 56,000 and potassium aspartate.

[0132] [Test Example 10: Test for suppressing change in appearance (color) by light irradiation] Each ophthalmic composition was prepared according to a conventional method with the composition shown in Table 9 and used as a test solution. The unit of each component in Table 9 is w / v% except as specified in the table. Each ophthalmic composition was filled in a 10 mL glass headspace vial in an amount of 10 mL each, and irradiated with a D65 fluorescent lamp as a light source in a light stability test apparatus (LT-120A-WCD, manufactured by Nagano Science Co., Ltd.) at room temperature of 25 °C until the integrated illuminance reached 1.2 million lx at an illuminance of 4000 lx / h. After the test, for each ophthalmic composition before and after light irradiation, the color difference change (b * value) was measured, and according to the following formula 1, the change in appearance (color) of the ophthalmic composition before and after light irradiation (color difference change degree; Δb<^ * value) was calculated, and further, according to the following formula 2, the color difference change reduction rate was calculated. The results are shown in Table 9. Note that the smaller the Δb * value, the more the change in appearance (color) of the ophthalmic composition (coloring) is suppressed. (Formula 1) Δb<^ * = b value of each ophthalmic composition before light irradiation - b value of each ophthalmic composition after light irradiation * value - b value of each ophthalmic composition after light irradiation * value (Formula 2) Color difference change reduction rate (%) = {1 - (Δb of test solution 12 * / Δb of test solution 19 * )} × 100

[0133]

Table 9

[0134] Compared to test solution 19 containing chondroitin sulfate sodium and retinyl palmitate with a weight-average molecular weight of approximately 28,000, test solution 12 containing chondroitin sulfate sodium and retinyl palmitate with a weight-average molecular weight of approximately 56,000 showed a greater degree of color difference change (Δb) upon light irradiation. * The amount of coloration was small, and it was confirmed that discoloration due to light irradiation was suppressed. Furthermore, a difference in the degree of discoloration was observed visually between test solution 19 before and after light irradiation, and between test solution 19 after light irradiation and test solution 12.

[0135] [Test Example 11: Test to suppress changes in appearance (color) due to ultraviolet irradiation] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 10, and used as a test solution. Unless otherwise specified in the table, the units for each component in Table 10 are w / v%. Each ophthalmic composition was filled into a 10 mL glass bottle and tested at 35°C using a SUNTESTER XLS+ (manufactured by Toyo Seiki Co., Ltd., 1700 W xenon air-cooled lamp light source) with an ultraviolet light irradiance of 765 (W / m²). 2 ), and irradiated for 96 hours. After that, each ophthalmic composition was allowed to remain at a constant temperature of 25°C, and the color difference change of each ophthalmic composition before and after UV irradiation (b * The value is measured, and the change in appearance (color) of the ophthalmic composition before and after UV irradiation (color difference change; Δb) is calculated according to Formula 1 below. * The value was calculated, and the color difference change reduction rate was further calculated according to Equation 2 below. The results are shown in Table 9. Note that Δb * A smaller value indicates that the change in the appearance (color) (staining) of the ophthalmic composition is suppressed. (Formula 1)Δb * = b before UV irradiation * Value - b after UV irradiation * value (Equation 2) Color difference change reduction rate (%) = {1 - (Δb of test solution 9 or 12) * / Δb of the corresponding test solution * )} × 100 The corresponding test solutions are test solution 20 for test solution 9 and test solution 19 for test solution 12.

[0136] [Table 10]

[0137] Compared to test solutions 20 and 19 containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 28,000 and pyridoxine hydrochloride or retinol palmitate, test solutions 9 and 12 containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 and pyridoxine hydrochloride or retinol palmitate showed a greater degree of color difference change (Δb) upon UV irradiation. * It was confirmed that the ) was small and discoloration caused by UV irradiation was suppressed.

[0138] [Test Example 12: Test to suppress changes in appearance (transparency) due to heat] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 11, and used as a test solution. Unless otherwise specified in the table, the units for each component in Table 11 are w / v%. 10 mL of each ophthalmic composition was filled into 10 mL glass headspace vials and stored statically in a 60°C incubator for 3 weeks (thermal acceleration test). Subsequently, each ophthalmic composition was allowed to reach a constant temperature of 25°C, and the color difference change (L) of each ophthalmic composition before and after the thermal acceleration test was measured using a spectrophotometer (CM3500d: Konica Minolta). * The value is measured, and the change in appearance (transparency) of the ophthalmic composition before and after the thermal acceleration test (ΔL) is calculated according to Formula 1 below. * The following formula was used to calculate the percentage of the change in transparency difference. The results are shown in Table 11. Note that L * The value is used as an indicator of transparency. Therefore, ΔL * A smaller value indicates that the change in the appearance (transparency) of the formulation is suppressed. (Formula 1)ΔL * =L before thermal acceleration test * Value - L after thermal acceleration test * value (Equation 2) Transparency change reduction rate (%) = {1 - (ΔL of test solution 11 or 12) * / ΔL of the corresponding test solution * )} × 100 The corresponding test solutions are test solution 21 for test solution 11 and test solution 19 for test solution 12.

[0139] [Table 11]

[0140] Compared to test solutions 21 and 19 containing sodium chondroitin sulfate with a weight-average molecular weight of approximately 28,000 and d-α-tocopherol acetate or retinyl palmitate, test solutions 11 and 12 containing sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000 and d-α-tocopherol acetate or retinyl palmitate showed significantly smaller changes in transparency due to heat, confirming that changes in appearance (transparency) due to heat were suppressed.

[0141] [Test Example 13: Cell Drying Test] Each ophthalmic composition was prepared according to standard procedures using the compositions shown in Table 12, and used as the test solution. Unless otherwise specified in the table, the units for each component in Table 12 are w / v%. Human corneal epithelial cell line HCE-T cells were seeded at a concentration of 1 × 10⁵ cells / mL in 100 μL per well of a 96-well plate (Corning), and cultured in a CO₂ incubator set to 37°C, 90% humidity, and 5% CO₂ until confluence. The growth medium used was DMEM / F12 (ThermoFisher) with 5% FCS (DS Pharma), 0.5% DMSO (Wako Pure Chemical Industries), 10 ng / mL recombinant human EGF (R&D), and 5 μg / mL insulin solution human (SIGMA). After 2-4 days, when the cells reached confluence, the growth medium was aspirated and removed from each well. 50 μL of each ophthalmic composition was added to each well, and the cells were incubated at 37°C and 5% CO2 for 15 minutes. After aspirating and removing each ophthalmic composition from each well, the cells were subjected to drying stress by being left in a clean bench for 20 minutes, and then the number of viable cells was evaluated. The number of viable cells was evaluated by adding 10 μL of Cellcountingkit-8 (Dojin Chemical Co., Ltd.) per 100 μL of culture medium to each well, culturing at 37°C, 5% CO2, and 90% humidity for 2-3 hours, and then measuring the absorbance at 450 nm using a spectrophotometer (MOLECULAR DEVICES). A higher absorbance value indicates a higher number of viable cells. The results are shown in Table 12.

[0142] [Table 12]

[0143] Compared to test solution 4, which contains sodium chondroitin sulfate, test solutions 8, 13, and 14, which contain sodium chondroitin sulfate and dipotassium glycyrrhizinate, magnesium aspartate, or taurine, respectively, showed a significant increase in the number of viable cells, confirming that cell death due to drought stress was significantly suppressed. Furthermore, compared to test solution 5, which contains sodium chondroitin sulfate, test solutions 11 and 12, which contain d-α-tocopherol acetate or retinol palmitate, also showed a significant increase in the number of viable cells, confirming that cell death due to drought stress was significantly suppressed. In addition, from the results for test solutions 4 and 22, it was confirmed that sodium chondroitin sulfate, with a weight-average molecular weight of approximately 56,000, significantly increases the number of viable cells at a concentration of 1%. Furthermore, regarding test solution 12, a similar inhibitory effect on cell death due to drought stress can be obtained when the same formulation as test solution 12 is used in the same test, except that the concentration of retinol palmitate is 50,000 units / 100 mL.

[0144] [Test Example 14: Cell Damage Test] Each ophthalmic composition was prepared according to a standard method with the composition shown in Table 13, and used as a test solution. The units for each component in Table 13 are w / v%. Human corneal epithelial cell line HCE-T cells were placed in a 24-well plate (Corning) at a rate of 1 × 10⁶ 5500 μL of cells were seeded into each well at a concentration of cells / mL and cultured in a CO2 incubator set to 37°C and 5% CO2. The growth medium used was DMEM / F12 (ThermoFisher) with 5% FCS (DS Pharma), 0.5% DMSO (Wako Pure Chemical Industries), 10 ng / mL recombinant human EGF (R&D), and 5 μg / mL of insulin solution human (SIGMA). After 2-4 days, when the cells reached confluence, the growth medium was aspirated and removed from each well. 50 μL of each ophthalmic composition was added to each well, and the mixture was incubated at 37°C and 5% CO2 for 15 minutes. Three or four glass beads (AS ONE) were placed in each well, and the mixture was shaken at 450 rpm for 1 minute using a microplate shaker (Heidlph Instruments GmbH & Co. KG). After removing the supernatant and glass beads, 500 μL of a culture medium containing Cellcountingkit-8 (Dojin Chemical Co., Ltd.) and culture medium in a 1:10 ratio was added. The cells were incubated in a CO2 incubator for 2 hours, and the absorbance at 450 nm was measured using a spectrophotometer (MOLECULAR DEVICES). Cell viability was calculated using the following formula. (Formula) Cell viability (%) = (Absorbance in each formulation / Absorbance of the control) × 100 The results are shown in Table 13.

[0145] [Table 13]

[0146] Compared to test solution 16 containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 28,000, test solution 4 containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 was found to have a higher cell viability rate. Furthermore, compared to test solution 4, test solutions 4, 7, and 8-10 containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000, along with allantoin, dipotassium glycyrrhizate, pyridoxine hydrochloride, or panthenol, were found to have significantly higher cell viability rates. Therefore, it is expected that even when the eye is subjected to external stimuli (for example, rubbing the eyes with hands, blinking, inserting or removing contact lenses, friction with contact lenses, or foreign matter contamination (pollen, air pollutants, eyelashes, eye makeup, or other foreign matter)) after instilling an ophthalmic composition containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000, along with allantoin, dipotassium glycyrrhizate, pyridoxine hydrochloride, or panthenol), damage to eye cells is suppressed.

[0147] [Test Example 15: Measurement of residual liquid volume in eye drop bottle] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 14, and used as a test solution. The units for each component in Table 14 are w / v%. The tare weight of 10 mL PET eye drop bottles was measured, and 5 mL of each ophthalmic composition was filled into each bottle. Next, the weight of each eye drop bottle after the filled ophthalmic composition had been dispensed was measured, and the residual volume (g) and the improvement rate (%) of the residual volume relative to the residual volume of test solution 22 were calculated according to formulas 1 and 2 below. (Formula 1) Residual volume (g) = Weight of the eye drop bottle after all ophthalmic composition has been dispensed - Weight of the eye drop bottle (tare) (Equation 2) Improvement rate of residual liquid volume (%) = {1 - (residual liquid volume of each test solution / residual liquid volume of test solution 22)} × 100

[0148] [Table 14]

[0149] Compared to test solution 22, which does not contain sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000, test solutions 4 and 5, which contain sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000, showed increased viscosity but reduced residual volume. Furthermore, in test solutions 6 and 14, which contained neostigmine methyl sulfate or taurine in test solution 4, and in test solutions 11 and 12, which contained d-α-tocopherol acetate or retinol palmitate in test solution 5, respectively, the residual volume was significantly reduced, confirming that the ophthalmic composition in the eye drop bottle could be used up more easily.

[0150] [Examples of formulations] The eye drops are prepared by conventional methods according to the prescriptions listed in Tables 15-19 below. Note that the units for the amounts of each ingredient in Tables 15-19 are w / v%, unless otherwise specified in the table.

[0151] [Table 15]

[0152] [Table 16]

[0153] [Table 17]

[0154] [Table 18]

[0155] [Table 19]

[0156] This concludes the first description of the present invention, and next, the second description of the present invention will be given.

[0157] The second aspect of the present invention relates to ophthalmic compositions.

[0158] [Background technology] Chondroitin sulfate or its salts are a type of acidic mucopolysaccharide and are incorporated into ophthalmic preparations for purposes such as promoting energy metabolism, relieving eye fatigue by promoting metabolism and cellular respiration, and replenishing tear fluid components (for example, Patent Document 2-1).

[0159] [Prior art document] [Patent] [Patent Document 2-1] Japanese Unexamined Patent Publication No. 2011-148791

[0160] [Summary of the second aspect of the present invention] [Second problem that the present invention aims to solve] The present inventors have discovered a new problem with ophthalmic compositions containing chondroitin sulfate or its salts having a specific weight-average molecular weight: when exposed to light, the viscosity decreases and stability declines. The second aspect of the present invention aims to provide a stable ophthalmic composition that contains chondroitin sulfate or its salts having a specific weight-average molecular weight while suppressing viscosity changes due to light.

[0161] [Second means for solving the problems of the present invention] The inventors have discovered that an ophthalmic composition containing sodium chondroitin sulfate, which has a weight-average molecular weight of 40,000 to 70,000, and a specific component, unexpectedly suppresses viscosity changes caused by light.

[0162] The second invention provides, for example, the following inventions: [1] An ophthalmic composition comprising at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000, and at least one selected from the group consisting of an antihistamine, a zinc salt, a decongestant, hydroxyethylcellulose and its salts, and a polyvinyl polymer compound. [2] The ophthalmic composition according to [1], wherein the antihistamine is at least one selected from the group consisting of chlorpheniramine and its salts, the decongestant is at least one selected from the group consisting of tetrahydrozoline and its salts, and the polyvinyl polymer compound is polyvinylpyrrolidone.

[0163] [Second effect of the present invention] According to the second aspect of the present invention, it is possible to provide a stable ophthalmic composition that contains chondroitin sulfate or a salt thereof having a specific weight-average molecular weight, while suppressing viscosity changes due to light.

[0164] [A second embodiment for carrying out the present invention] The following describes in detail a second embodiment for carrying out the present invention. However, the second embodiment is not limited to the following embodiments.

[0165] In this specification, unless otherwise specified, the unit of content "%" means "w / v%" and is synonymous with "g / 100mL".

[0166] The ophthalmic composition according to this embodiment contains at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000 (also simply referred to as "component (A)") and at least one selected from the group consisting of antihistamines, zinc salts, decongestants, hydroxyethylcellulose and its salts, and polyvinyl polymer compounds (also simply referred to as "component (B)").

[0167] As confirmed in the test examples described later, the ophthalmic composition according to this embodiment has the effect of suppressing viscosity changes due to light, as well as the effect of suppressing liquid residue in piping when filling containers or when dispensing liquid, the effect of improving preservation effectiveness, the effect of making blinking easier regardless of the viscosity when the formulation is placed in the eye (even if it is a high viscosity formulation), the effect of suppressing discomfort when blinking regardless of the viscosity when the formulation is placed in the eye (even if it is a high viscosity formulation), the effect of suppressing discoloration of the formulation due to ultraviolet light, the effect of increasing cell viability, and the effect of suppressing damage to eye cells caused by external stimuli (blinking, irritation from contact lenses (when putting them in or taking them out, while wearing them), rubbing the eyes, and contamination by foreign matter (pollen, air pollutants, eyelashes, foreign matter related to eye makeup, and other foreign matter).

[0168] [Chondroitin sulfate and its salts] Chondroitin sulfate and its salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0169] Examples of chondroitin sulfate salts include alkali metal salts and alkaline earth metal salts. Examples of alkali metal salts include sodium salts and potassium salts. Examples of alkaline earth metal salts include magnesium salts and calcium salts.

[0170] Chondroitin sulfate and its salts are preferably chondroitin sulfate and alkali metal salts of chondroitin sulfate, more preferably chondroitin sulfate and sodium chondroitin sulfate, and even more preferably sodium chondroitin sulfate.

[0171] Chondroitin sulfate and its salts may be natural or synthetic products, but generally, chondroitin sulfate and its salts derived from animals (preferably mammals, fish, mollusks, etc.; more preferably cattle, sharks, squid, rays, etc.) which are natural products, are preferred, chondroitin sulfate and its salts derived from sharks and / or rays are more preferred, and chondroitin sulfate and its salts derived from sharks are even more preferred.

[0172] Commercially available chondroitin sulfate and its salts may also be used. Chondroitin sulfate and its salts may be used individually or in combination of two or more types. Furthermore, chondroitin sulfate and its salts with a weight-average molecular weight of 40,000 to 70,000 as defined herein may be used in combination with chondroitin sulfate and its salts having a weight-average molecular weight outside the range defined herein. For example, sodium chondroitin sulfate with a weight-average molecular weight of 56,000 and sodium chondroitin sulfate with a weight-average molecular weight of 25,000 may be used in combination. When using chondroitin sulfate and its salts with a weight-average molecular weight of 40,000 to 70,000 as defined herein in combination with chondroitin sulfate and its salts having a weight-average molecular weight outside the range defined herein, it is sufficient that chondroitin sulfate and its salts with a weight-average molecular weight of 40,000 to 70,000 are included as raw materials.

[0173] In this specification, "weight-average molecular weight" can be determined by using gel permeation chromatography with a multi-angle light scattering detector (MALS detector) and a differential refractive index detector (RI detector) connected online. Specifically, the following conditions are presented. <Standard Sample Preparation> 5 mg of chondroitin sulfate or its salt is added to 10 mL of 0.1 M sodium nitrate aqueous solution, gently stirred at room temperature, and completely dissolved. <Measurement conditions for weight-average molecular weight> Equipment: Gel permeation chromatograph - multi-angle light scattering meter Detector: Differential refractive index detector (Optilab rEX, manufactured by Wyatt Technology) Multi-angle light scattering detector (Wyatt Technology DAWN HELEOS) Column: Shodex OHpak SB-806M HQ, 2 pieces (φ7.8mm x 30cm, manufactured by Showa Denko) Solvent: 0.1M sodium nitrate aqueous solution Flow rate: 0.7mL / min Column temperature: 23℃ Detector temperature: 23℃ Injection volume: 0.2mL Data processing: Wyatt Technology data processing system (ASTRA) The weight-average molecular weight of chondroitin sulfate and its salts calculated using the method described above is not particularly limited as long as it is within the range of 40,000 to 70,000. Examples of lower limits for weight-average molecular weight include 41,000 or more, 42,000 or more, 43,000 or more, 44,000 or more, 45,000 or more, 46,000 or more, 47,000 or more, 48,000 or more, 49,000 or more, and 50,000 or more. Examples of upper limits for weight-average molecular weight include 69,000 or less, 68,000 or less, 67,000 or less, 66,000 or less, 65,000 or less, 64,000 or less, 63,000 or less, 62,000 or less, 61,000 or less, and 60,000 or less. Examples of weight-average molecular weight ranges include 41,000-69,000, 42,000-68,000, 43,000-67,000, 44,000-66,000, 45,000-65,000, 46,000-64,000, 47,000-63,000, 48,000-62,000, 49,000-61,000, and 50,000-60,000.

[0174] The content of component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set as appropriate depending on the type and content of other components, the use of the ophthalmic composition and the form of formulation. From the viewpoint of more significantly exhibiting the second effect of the present invention, the content of component (A) is, for example, usually 0.001 to 5 w / v%, preferably 0.005 to 5 w / v%, more preferably 0.008 to 4 w / v%, even more preferably 0.01 to 3 w / v%, even more preferably 0.05 to 2 w / v%, particularly preferably 0.1 to 1 w / v%, and preferably 0.3 to 1 w / v%, based on the total amount of the ophthalmic composition.

[0175] [Antihistamines] Antihistamines are compounds that have antihistamine activity, and their salts. Antihistamines are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0176] Specific examples of antihistamines include chlorpheniramine, iproheptine, diphenhydramine, ketotifen, olopatadine, levocabastine, and their salts. As antihistamines, chlorpheniramine and its salts are preferred, and chlorpheniramine maleate is more preferred.

[0177] Antihistamines can also be used commercially available. Antihistamines may be used individually or in combination of two or more types.

[0178] (B) When an antihistamine is used as component, the content of the antihistamine in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of antihistamine, the types and content of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of more significantly exhibiting the second effect of the present invention, the total content of the antihistamine is preferably 0.001 to 1 w / v%, more preferably 0.003 to 0.5 w / v%, even more preferably 0.005 to 0.1 w / v%, even more preferably 0.01 to 0.05 w / v%, and particularly preferably 0.02 to 0.04 w / v% (for example, 0.03 w / v%), based on the total amount of the ophthalmic composition.

[0179] When an antihistamine is used as component (B), the ratio of the antihistamine to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the antihistamine, the type and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the second effect of the present invention, for example, the total content of the antihistamine to component (A) is preferably 0.0002 to 20 parts by mass, more preferably 0.001 to 10 parts by mass, and even more preferably 0.01 to 1 part by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0180] [Zinc salts] The zinc salt is not particularly limited as long as it is medically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0181] Preferred zinc salts include zinc sulfate, zinc lactate, or zinc chloride, with zinc sulfate being more preferred. The zinc salt may also be a hydrate (for example, zinc sulfate heptahydrate).

[0182] Zinc salts can also be commercially available. Zinc salts may be used individually or in combination of two or more types.

[0183] (B) When a zinc salt is used as component, the zinc salt content in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of zinc salt, the types and content of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of more significantly exhibiting the second effect of the present invention, the total zinc salt content is usually 0.00001 to 10 w / v%, preferably 0.0001 to 10 w / v%, more preferably 0.001 to 5 w / v%, even more preferably 0.005 to 3 w / v%, even more preferably 0.01 to 1 w / v%, and particularly preferably 0.03 to 0.5 w / v%, based on the total amount of the ophthalmic composition. The total zinc salt content may also be 0.25 w / v%.

[0184] When a zinc salt is used as component (B), the ratio of zinc salt to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and zinc salt, the type and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the second effect of the present invention, for example, the total content of zinc salt to component (A) is preferably 0.0002 to 1000 parts by mass, more preferably 0.001 to 500 parts by mass, even more preferably 0.01 to 100 parts by mass, even more preferably 0.05 to 50 parts by mass, even more preferably 0.05 to 30 parts by mass, and particularly preferably 0.1 to 1 part by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0185] [Decongestant]

[0186] An anticonjunctival agent is a compound that has the effect of reducing redness of the eye, and its salts. An anticonjunctival agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0187] Specific examples of decongestants include imidazoline compounds such as tetrahydrozoline, naphazoline, and oxymetazoline, and their salts (e.g., hydrochloride, nitrate); epinephrine, ephedrine, methylephedrine, phenylephrine, and their salts (e.g., hydrochloride). Imidazolin compounds and their salts are preferred as decongestants, tetrahydrozoline, naphazoline, and their salts are more preferred, tetrahydrozoline and its salts are even more preferred, and tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride) is particularly preferred.

[0188] Commercially available decongestants can also be used. One type of decongestant may be used alone, or two or more types may be used in combination.

[0189] (B) When a decongestant is used as component, the amount of the decongestant in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of decongestant, the types and amounts of other components, the use of the ophthalmic composition and the form of formulation. From the viewpoint of more significantly exhibiting the second effect of the present invention, the total amount of the decongestant is preferably 0.0001 to 1 w / v%, more preferably 0.0005 to 0.5 w / v%, even more preferably 0.001 to 0.1 w / v%, and even more preferably 0.002 to 0.1 w / v%, based on the total amount of the ophthalmic composition.

[0190] When a decongestant is used as component (B), the ratio of the decongestant to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the decongestant, the type and content of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of further enhancing the second effect of the present invention, for example, the total content of the decongestant to component (A) is preferably 0.0001 to 50 parts by mass, more preferably 0.0005 to 20 parts by mass, even more preferably 0.001 to 10 parts by mass, and even more preferably 0.003 to 5 parts by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0191] [Hydroxyethylcellulose and its salts] Hydroxyethylcellulose and its salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0192] Examples of hydroxyethylcellulose salts include salts with organic bases (amine salts, basic ammonium salts such as arginine, etc.) and salts with inorganic bases (ammonium salts, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, etc.). Among these, sodium salt, potassium salt, and calcium salt are more preferred, with sodium salt being particularly preferred.

[0193] Commercially available hydroxyethylcellulose and its salts can also be used. Hydroxyethylcellulose and its salts may be used individually or in combination of two or more types.

[0194] (B) When hydroxyethylcellulose and its salts are used as component, the content of hydroxyethylcellulose and its salts in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of hydroxyethylcellulose and its salts, the types and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of more significantly exhibiting the second effect of the present invention, the total content of hydroxyethylcellulose and its salts is preferably 0.0001 to 10 w / v%, more preferably 0.001 to 5 w / v%, even more preferably 0.005 to 3 w / v%, and even more preferably 0.01 to 1 w / v%, based on the total amount of the ophthalmic composition.

[0195] When hydroxyethylcellulose and its salts are used as component (B), the content ratio of hydroxyethylcellulose and its salts to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and hydroxyethylcellulose and its salts, the type and content of other components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of further enhancing the second effect of the present invention, for example, the content ratio of hydroxyethylcellulose and its salts to component (A) is preferably 0.0001 to 500 parts by mass, more preferably 0.001 to 100 parts by mass, even more preferably 0.005 to 50 parts by mass, and even more preferably 0.01 to 30 parts by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0196] [Polyvinyl polymer compounds]

[0197] Polyvinyl polymer compounds are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0198] Examples of polyvinyl polymer compounds include polyvinyl alcohol (complete or partially saponified), polyvinylpyrrolidone, and carboxyvinyl polymer. The polyvinyl polymer that can be used in the second aspect of the present invention is not limited by its molecular weight, but for example, a weight-average molecular weight of 0.5 million to 5 million, preferably 10,000 to 3 million, and more preferably 10,000 to 1 million can be used. The K value (viscosity characteristic value) of polyvinylpyrrolidone is not particularly limited, but a value of 10 to 150 can be preferably used. Among these, from the viewpoint of further enhancing the effects of the second aspect of the present invention, polyvinylpyrrolidone is preferred, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, and polyvinylpyrrolidone K90 are more preferred, and polyvinylpyrrolidone K30 and polyvinylpyrrolidone K90 are even more preferred.

[0199] Commercially available polyvinyl polymer compounds can also be used. These polyvinyl polymer compounds may be used individually or in combination of two or more types.

[0200] (B) When a polyvinyl polymer compound is used as component, the content of the polyvinyl polymer compound in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of polyvinyl polymer compound, the types and content of other components, the use of the ophthalmic composition and the formulation form. From the viewpoint of more significantly exhibiting the second effect of the present invention, the total content of the polyvinyl polymer compound is preferably 0.0001 to 10 w / v%, more preferably 0.001 to 8 w / v%, even more preferably 0.005 to 5 w / v%, even more preferably 0.01 to 3 w / v%, and particularly preferably 0.01 to 2 w / v%, based on the total amount of the ophthalmic composition.

[0201] When a polyvinyl polymer compound is used as component (B), the content ratio of the polyvinyl polymer compound to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the polyvinyl polymer compound, the type and content of other blending components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the second effect of the present invention, for example, the content ratio of the polyvinyl polymer compound to component (A) is preferably 0.0001 to 1000 parts by mass, more preferably 0.001 to 500 parts by mass, even more preferably 0.005 to 100 parts by mass, and even more preferably 0.01 to 50 parts by mass, per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0202] The ophthalmic composition according to this embodiment may further contain (C) a surfactant (also referred to as "component (C)"). The further inclusion of component (C) in the ophthalmic composition makes the second effect according to the present invention more pronounced. The surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and may be any of nonionic surfactants, amphoteric surfactants, anionic surfactants, or cationic surfactants.

[0203] Examples of nonionic surfactants include 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); POE hydrogenated castor oils such as POE(40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40) and POE(60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE castor oils such as POE(3) hydrogenated castor oil (polyoxyethylene castor oil 3), POE(10) castor oil (polyoxyethylene castor oil 10), and POE(35) castor oil (polyoxyethylene castor oil 35); POE alkyl ethers such as POE(9) lauryl ether; POE-POP alkyl ethers such as POE(20)POP(4) cetyl ether; polyoxyethylene-polyoxypropylene block copolymers such as POE(196)POP(67) glycol (poloxamer 407, pluronic F127) and POE(200)POP(70) glycol; and polyethylene glycol monostearates such as polyoxyl 40 stearate. In the compounds exemplified above, POE represents polyoxyethylene, POP represents polyoxypropylene, and the numbers in parentheses indicate the number of added moles respectively.

[0204] Examples of amphoteric surfactants include alkyl diaminoethyl glycine or its salts (such as hydrochloride, etc.).

[0205] Examples of anionic surfactants include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, α-olefin sulfonic acids, etc.

[0206] Examples of cationic surfactants include cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, etc.

[0207] Among these surfactants, nonionic surfactants are preferred, and POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE castor oil, and POE·POP block copolymers are more preferred. Commercially available surfactants can also be used. The surfactant may be used alone or in combination of two or more.

[0208] The content of component (C) in the ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the type of component (C), the use of the ophthalmic composition, the dosage form, etc. From the viewpoint of more significantly exhibiting the effects according to the second invention, the total content of component (C) is preferably 0.001 to 3 w / v%, more preferably 0.005 to 2 w / v%, still more preferably 0.01 to 1 w / v%, and particularly preferably 0.05 to 1 w / v% based on the total amount of the ophthalmic composition.

[0209] The content ratio of component (C) to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the types of components (A) and (C), the types and contents of other compounding components, the use of the ophthalmic composition, the dosage form, etc. From the viewpoint of further enhancing the effects according to the second invention, for example, based on 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment, the total content of component (C) is more preferably 0.001 to 30 parts by mass, more preferably 0.005 to 20 parts by mass, still more preferably 0.01 to 10 parts by mass, and particularly preferably 0.01 to 2 parts by mass.

[0210] The ophthalmic composition according to this embodiment preferably further contains (D) a buffering agent (also referred to as "component (D)"). The further inclusion of component (D) in the ophthalmic composition makes the second effect of the present invention more pronounced. The buffering agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of buffering agents include inorganic buffering agents, which are buffering agents derived from inorganic acids, and organic buffering agents, which are buffering agents derived from organic acids or organic bases.

[0211] Examples of inorganic buffers include borate buffers, phosphate buffers, and carbonate buffers. Examples of borate buffers include boric acid or its salts (alkali metal borate, alkaline earth metal borate, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphate, alkaline earth metal phosphate, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonate, alkaline earth metal carbonate, etc.). In addition, hydrates of borates, phosphates, or carbonates may be used as borate buffers, phosphate buffers, or carbonate buffers. More specific examples include boric acid buffers such as boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphoric acid buffers such as phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffers such as carbonate or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.).

[0212] Examples of organic buffers include citrate buffers, acetate buffers, lactic acid buffers, succinate buffers, Tris buffers, and AMPD buffers. Examples of citrate buffers include citric acid or its salts (alkali metal citrate, alkaline earth metal citrate, etc.). Examples of acetate buffers include acetic acid or its salts (alkali metal acetate, alkaline earth metal acetate, etc.). Examples of lactic acid buffers include lactic acid or its salts (alkali metal lactate, alkaline earth metal lactate, etc.). Examples of succinate buffers include succinic acid or its salts (alkali metal succinate, etc.). In addition, citrate, acetate, lactate, or succinate hydrates may be used as citrate buffers, acetate buffers, lactic acid buffers, or succinate buffers. More specific examples include citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) as citrate buffers; acetic acid or its salts (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.) as acetic acid buffers; lactic acid or its salts (sodium lactate, potassium lactate, calcium lactate, etc.) as lactic acid buffers; and succinic acid or its salts (monosodium succinate, disodium succinate, etc.) as succinic acid buffers. Examples of Tris buffers include trometamol or its salts (trometamol hydrochloride, etc.). Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol or its salts.

[0213] Preferred buffering agents include boric acid buffers (e.g., a combination of boric acid and borax), phosphate buffers (e.g., a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), and Tris buffers (e.g., trometamol). Boric acid buffers are more preferred, boric acid and its salts are even more preferred, and a combination of boric acid and borax is even more preferred.

[0214] You may use commercially available cushioning material. You may use one type of cushioning material alone, or you may use two or more types in combination.

[0215] The content of component (D) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (D), the types and content of other components, the use of the ophthalmic composition and the form of formulation, etc. As for the content of component (D), from the viewpoint of more significantly exhibiting the second effect of the present invention, for example, the total content of component (D) is preferably 0.01 to 10 w / v%, more preferably 0.05 to 5 w / v%, and even more preferably 0.1 to 3 w / v%, based on the total amount of the ophthalmic composition.

[0216] In the ophthalmic composition according to this embodiment, the content ratio of component (D) to component (A) is not particularly limited and is set appropriately depending on the types of component (A) and component (D), the types and content of other components, the use of the ophthalmic composition and the form of formulation, etc. As for the content ratio of component (D) to component (A), from the viewpoint of further enhancing the second effect of the present invention, for example, the total content of component (D) in the ophthalmic composition according to this embodiment is preferably 0.01 to 100 parts by mass, more preferably 0.05 to 50 parts by mass, and even more preferably 0.1 to 30 parts by mass, per 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment.

[0217] The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, even more preferably 4.5 to 8.5, even more preferably 5.0 to 8.5, particularly preferably 5.0 to 8.0, even more particularly preferably 5.3 to 7.5, and most preferably 5.3 to 7.0.

[0218] The ophthalmic composition according to this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the body, as needed. An appropriate osmotic pressure ratio can be set as appropriate depending on the use, formulation form, and method of use of the ophthalmic composition, but for example, it can be 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and even more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 17th edition of the Japanese Pharmacopoeia, and the osmotic pressure is measured by referring to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, then 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 by using a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

[0219] The viscosity of the ophthalmic composition according to this embodiment is not particularly limited, as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The viscosity of the ophthalmic composition according to this embodiment is preferably 1 to 10,000 mPa·s, more preferably 1 to 8,000 mPa·s, even more preferably 1 to 1,000 mPa·s, even more preferably 1 to 100 mPa·s, particularly preferably 1 to 20 mPa·s, and most preferably 1.5 to 10 mPa·s, as measured at 20°C with a rotational viscometer (TV-20 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' × R24).

[0220] The ophthalmic composition according to this embodiment may contain, in addition to the above-mentioned components, a combination of components selected from various pharmacologically active and physiologically active components in appropriate amounts, as long as the second effect of the present invention is not impaired. The components are not particularly limited, and examples include the active ingredients in ophthalmic drugs listed in the 2017 edition of the Standards for Approval of Manufacturing and Marketing of Prescription-Only and Over-the-Counter Drugs (supervised by the Regulatory Science Society of Japan). Specifically, examples of components used in ophthalmic drugs include the following components. Antiallergic agents: For example, sodium cromoglycate, tranilast, pemirolast potassium, acitazanol, anlexanox, ibudilast, etc. Steroids: For example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc. Ocular muscle modulating agents: For example, cholinesterase inhibitors that have an active site similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, atropine sulfate, pilocarpine hydrochloride, etc. Anti-inflammatory agents: For example, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, flufenamate butyl, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, sodium azulene sulfonate, glycyrrhizic acid or its salts (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), etc. Vitamins: For example, retinyl acetate, retinyl palmitate, tocopherol acetate, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, ascorbic acid, sodium ascorbate, etc. Amino acids: For example, L-arginine, glutamic acid, glycine, alanine, lysine, gamma-aminobutyric acid, gamma-aminovaleric acid, trimethylglycine, taurine, aspartic acid, and their salts. Astringent agents: For example, zinc oxide. Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and their salts.

[0221] The ophthalmic composition according to this embodiment may contain, in accordance with conventional methods, various additives selected appropriately and used in combination in appropriate amounts, one or more types, depending on its use and formulation, as long as the second effect of the present invention is not impaired. Examples of such additives include the various additives listed in the 2016 Dictionary of Pharmaceutical Additives (edited by the Japan Pharmaceutical Additives Association). The following are some typical additives. Carrier: For example, an aqueous solvent such as water or aqueous ethanol. Chelating agents: For example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc. Base: For example, octyldodecanol, titanium dioxide, potassium bromide, Plastibase, etc. pH adjusters: For example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, etc. Fragrances or cooling agents: For example, menthol, menthone, camphor, borneol, geraniol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymene, terpineol, pinene, camphene, isoborneol, fencienne, nerol, myrcene, myrcenol, linalool acetate, lavandulol, eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil, etc. These may be d-isomers, l-isomers, or dl-isomers. Thickeners: For example, cellulosic polymer compounds such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; guar gum; hydroxypropyl guar gum; gum arabic; karaya gum; xanthan gum; agar; alginic acid and its salts (sodium salt, etc.); mucopolysaccharides such as heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and its salts (sodium salt, etc.); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan; monosaccharides such as glucose, etc. Stabilizers: For example, EDTA, EDTA salts (disodium EDTA, disodium calcium EDTA, trisodium EDTA, tetrasodium EDTA), sodium formaldehyde sulfoxylate (Longalit), aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, sodium bisulfite, sodium pyrosulfite, etc. Preservatives: For example, alkyl polyaminoethylglycine quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, polydronium chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), alexidine, etc.), Glokill (a trade name of Rhodia Corporation), etc. Isotonic agents: For example, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, sodium bisulfite, sodium sulfite, etc. Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin, etc. These may be in d-isomer, l-isomer, or dl-isomer. Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil, olive oil, etc.; animal oils such as squalane; mineral oils such as liquid paraffin, petrolatum, etc.

[0222] From the perspective that the ophthalmic composition according to this embodiment can remarkably exhibit the effects of the second invention, it is preferably not to contain at least one selected from the group consisting of geraniol, linalyl acetate, limonene, citral, and linalool, and more preferably not to contain any of them.

[0223] When the ophthalmic composition according to this embodiment contains water, from the perspective of more remarkably exhibiting the effects according to the second invention, for example, based on the total amount of the ophthalmic composition, the water content is preferably 80 w / v% or more and less than 100 w / v%, more preferably 85 w / v% or more and 99.5 w / v% or less, and still more preferably 90 w / v% or more and 99.2 w / v% or less.

[0224] The water used in the ophthalmic composition according to this embodiment may be pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such water include distilled water, tap water, purified water, sterilized purified water, water for injection, and distilled water for injection, etc. Their definitions are based on the seventeenth revised Japanese Pharmacopoeia.

[0225] The ophthalmic composition according to this embodiment can be prepared by adding and mixing a desired amount of component (A), component (B), and optionally other components to a desired concentration. For example, it can be prepared by dissolving or dispersing these components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like.

[0226] The ophthalmic composition according to this embodiment can take various dosage forms according to the purpose. Examples of dosage forms include solutions, gels, semi-solid agents (such as ointments), etc.

[0227] The ophthalmic composition according to this embodiment can be used, for example, as eye drops (also called eye solutions or eye medicines; eye drops include eye drops that can be instilled while wearing contact lenses), artificial tears, eye washes (also called eye wash solutions or eye medicines; eye washes include eye washes that can be used while wearing contact lenses), and contact lens compositions [contact lens insertion solutions, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaning agents, contact lens cleaning and preservation agents), contact lens packaging solutions, etc.]. Note that "contact lenses" include hard contact lenses and soft contact lenses (including both ionic and nonionic lenses, and including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses). From the viewpoint of more significantly exhibiting the second effect of the present invention, an ophthalmic composition for silicone hydrogel contact lenses is preferred, and an eye drop that can be instilled while wearing silicone hydrogel lenses is more preferred.

[0228] The ophthalmic composition according to this embodiment is preferably an eye drop (including eye drops that can be instilled while wearing contact lenses) because it can more clearly exhibit the second effect of the present invention. When the ophthalmic composition according to this embodiment is an eye drop, the method of use and dosage are not particularly limited as long as they are effective and have few side effects, but for example, for adults (15 years of age or older) and children 7 years of age or older, examples include instilling 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops at a time, 2 to 4 times or 5 to 6 times a day.

[0229] The ophthalmic composition according to this embodiment is provided in any container. The container for containing the ophthalmic composition according to this embodiment is not particularly limited and may be made of glass or plastic, for example. Plastic is preferred. Examples of plastics include polyethylene terephthalate (PET), polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide and copolymers of monomers constituting these, and mixtures of two or more of these. Polyethylene terephthalate is preferred. The container for containing the ophthalmic composition according to this embodiment may be a transparent container that allows visibility of the inside of the container, or an opaque container that makes it difficult to see inside the container. A transparent container is preferred. Here, "transparent container" includes both colorless transparent containers and colored transparent containers.

[0230] A nozzle may be attached to the container for containing the ophthalmic composition according to this embodiment. The material of the nozzle is not particularly limited and may be made of glass or plastic, for example. Plastic is preferred. Examples of plastics include polybutylene terephthalate, polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate and copolymers of monomers constituting these, and mixtures of two or more of these. As for the material of the nozzle, from the viewpoint of further enhancing the second effect of the present invention, polypropylene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate are preferred, and polyethylene is more preferred.

[0231] The container for containing the ophthalmic composition according to this embodiment may be a multi-dose type that contains multiple doses, or a unit-dose type that contains a single dose.

[0232] The ophthalmic composition according to this embodiment is preferably filled in a container with an internal volume of 4 to 30 mL, more preferably in a container with an internal volume of 5 to 20 mL, even more preferably in a container with an internal volume of 6 to 16 mL, and even more preferably in a container with an internal volume of 10 to 15 mL. It may also be filled in a container with an internal volume of 0.1 to 3 mL, or in a container with an internal volume of 0.2 to 1 mL.

[0233] [Second embodiment of the present invention] The second aspect of the present invention will be specifically described below based on test examples, but the second aspect of the present invention is not limited to these. Furthermore, the chondroitin sulfate sodium used in the following test examples is as follows, and the chondroitin sulfate sodium with a weight-average molecular weight of 56,000 is derived from sharks. Chondroitin Sodium Sulfate Weight-average molecular weight approximately 56,000: Seikagaku Corporation; Grade NK Weight-average molecular weight approximately 28,000: Seikagaku Corporation; Grade ND-K Weight-average molecular weight approximately 25,000: Maruha Nichiro Corporation; Non-pharmaceutical standard chondroitin sulfate sodium

[0234] [Test Example 1: Viscosity Stability Test by Light Irradiation] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 20, and used as a test solution. The units for each component in Table 20 are w / v%. 10 mL of each ophthalmic composition was filled into 10 mL glass headspace vials (GL Sciences Co., Ltd.), and irradiated using a D65 fluorescent lamp as the light source at room temperature of 25°C with an illuminance of 4000 lx / h until the cumulative illuminance reached 1,200,000 lx. The viscosity of each ophthalmic composition (600 μL) before and after irradiation was measured using a rheometer (MCR302 (Anton Paar Co., Ltd.)) with a cone-plate type measuring jig (CP50-1, d:0.102 mm) for shear rates (1 to 10000 (1 / s)) at 34°C. Then, using the viscosity (mPa·s) at a shear rate of 1000 (1 / s), the viscosity stability before and after the test was evaluated according to the following formula. The results are shown in Table 20. Note that a smaller viscosity change rate indicates less viscosity change due to light, and that the ophthalmic composition is maintained in the same physical properties. (Formula) Viscosity change rate (%) = {(Viscosity of each ophthalmic composition before light irradiation - Viscosity of each ophthalmic composition after light irradiation) / Viscosity of each ophthalmic composition before light irradiation} × 100

[0235] [Table 20]

[0236] In Reference Example 1, which contained sodium chondroitin sulfate with a weight-average molecular weight of approximately 28,000, no viscosity change occurred upon light irradiation. However, in Reference Example 2, which contained sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000, a viscosity change was observed upon light irradiation. However, in Examples 1 to 6, which contained sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000, along with tetrahydrozoline hydrochloride, zinc sulfate hydrate, chlorpheniramine maleate, hydroxyethylcellulose, and polyvinylpyrrolidone K30 or polyvinylpyrrolidone K90, respectively, the viscosity change rate decreased significantly, confirming improved stability of the ophthalmic composition upon light irradiation. A similar trend was observed when viscosity was measured at a shear rate of 100 (1 / s).

[0237] [Test Example 2: Measurement of Contact Angle in Stainless Steel Pipes] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 21, and used as a test solution. The units for each component in Table 21 are w / v%. Droplets (approximately 1 μL) of each prepared ophthalmic composition were dropped onto a stainless steel metal plate (ferrule cap TypeCLF-B), and the contact angle with the metal (static contact angle) 0.1 seconds after dropping was measured using an automatic contact angle meter (solid-liquid interface analysis system Drop Master, DM-A501 (Kyowa Interface Science Co., Ltd.)). The contact angle was measured three times for each ophthalmic composition, and the average value was calculated to determine the contact angle of each ophthalmic composition. The results are shown in Table 21.

[0238] [Table 21]

[0239] The test solutions of Examples 4 and 5 showed a significantly increased contact angle compared to the test solution of Reference Example 2. Specifically, it was confirmed that the test solutions containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 and hydroxyethylcellulose or polyvinylpyrrolidone had significantly lower affinity to stainless steel tubes compared to the test solution containing only chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000. Since the filling tubes in the manufacturing line are made of metal such as stainless steel, it is possible to reduce the amount of liquid droplets adhering to the end of the filling tube when filling containers with ophthalmic compositions, making it easier to achieve uniformity in the filling amount.

[0240] [Test Example 3: Test on Preservative Efficacy] Each ophthalmic composition was prepared according to a standard method with the composition shown in Table 22, and used as a test solution. The units for each component in Table 22 are w / v%. Staphylococcus aureus (ATCC6538) was inoculated onto the surface of soybean casein digest slant medium and cultured at 33°C for 24 hours. The cultured cells were aseptically collected using a platinum loop and suspended in an appropriate amount of sterile physiological saline, resulting in approximately 1 × 10⁶ cells. 7A bacterial suspension containing viable bacteria at a CFU / mL concentration was prepared. The number of viable bacteria in the suspension was measured separately by culturing. Next, 10 mL of each prepared ophthalmic composition was filled into 15 mL conical tubes (CORNING) made of PET material. Each of these ophthalmic compositions was then filled with bacteria with a viable bacterial count (final concentration) of approximately 10. 5 A sample was prepared by inoculating a Staphylococcus aureus bacterial suspension (suspended in physiological saline) to a concentration of CFU / mL and thoroughly mixing it. The sample containing the bacteria was stored at 23°C under light protection for 3 days. After that, the sample containing the bacteria was adjusted to a concentration suitable for counting and prepared as a 3M solution. TM Petrifilm TM 1 mL of the culture solution was inoculated onto a rapid viable cell count plate (RAC plate), incubated at 33°C for 2 days, and the number of colonies observed was counted to determine the viable cell count. The viable cell count immediately after inoculation was compared with the viable cell count in the sample after 3 days of storage, and the decrease in the bacterial count was calculated as Log Reduction. Furthermore, the calculated Log Reduction was evaluated according to the following criteria to determine whether the preservation efficacy was sufficient. The bacterial culture for initial counting was performed at 33°C for 2 days. The results are shown in Table 22. Evaluation Criteria Log Reduction < 0.7:D 0.7 ≤ Log Reduction < 0.8:C 0.8 ≤ Log Reduction < 0.9: B 0.9 ≤ Log Reduction: A

[0241] [Table 22]

[0242] Reference Example 1 showed low preservative efficacy, while Examples 2 and 6 showed improved preservative efficacy. Specifically, compared to the test solution of Reference Example 1, which contained sodium chondroitin sulfate with a weight-average molecular weight of approximately 28,000, the test solutions of Examples 2 and 6, which contained sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000 and zinc sulfate hydrate or polyvinylpyrrolidone, showed improved preservative efficacy.

[0243] [Test Example 4: Measurement of Viscosity] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 23, and used as a test solution. The units for each component in Table 21 are w / v%. The viscosity of each prepared ophthalmic composition (600 μL) was measured at 34°C against shear rate using a rheometer (MCR302 (Anton Paar)) with a cone-plate measuring jig (CP50-1, d: 0.102 mm). For the viscosity (mPa·s) at a shear rate of 10000 (1 / s), the viscosity reduction rate of Example 2 compared to Reference Example 2 (a formulation containing sodium chondroitin sulfate alone) was calculated according to the following formula. Note that a decrease in viscosity indicates that the viscosity decreases when stress is applied, and the viscosity change during blinking can be evaluated. Therefore, a decrease in viscosity during blinking indicates that blinking is easier and less discomfort is felt during blinking. (Formula) Viscosity reduction rate (%) = (1 - Viscosity of Example 2 / Viscosity of Reference Example 2) × 100 The results are shown in Table 23.

[0244] [Table 23]

[0245] Compared to Reference Example 2, Example 2, which contains zinc sulfate hydrate, showed a significantly lower viscosity. Here, the inventors confirmed that the viscosity measured using a rotational viscometer after preparation of Reference Example 2, which uses chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000, was higher than the viscosity of the test solution with the same composition, except that in Reference Example 2, chondroitin sulfate sodium with a weight-average molecular weight of approximately 28,000 was used instead of chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000. When an ophthalmic composition has high viscosity when instilled, problems such as difficulty blinking and discomfort may occur. Therefore, it can be said that if the viscosity at high shear rates is low, blinking will be easier and discomfort will be less likely after instillation. Thus, it was confirmed that the ophthalmic composition containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 and zinc sulfate hydrate makes blinking easier and discomfort is less likely to occur after instillation compared to the ophthalmic composition containing only chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000.

[0246] [Test Example 5: Test to suppress changes in appearance (color) due to ultraviolet irradiation] Each ophthalmic composition was prepared according to a standard method using the compositions shown in Table 24, and used as a test solution. The units for each component in Table 24 are w / v%. 10 mL of each ophthalmic composition was filled into a glass bottle (10 mL), and tested at 35°C using a SUNTESTER XLS+ (manufactured by Toyo Seiki Co., Ltd., 1700 W xenon air-cooled lamp light source) with an ultraviolet light irradiance of 765 (W / m²). 2 ), and irradiated for 96 hours. After that, each ophthalmic composition was allowed to remain at a constant temperature of 25°C, and the color difference change of each ophthalmic composition before and after UV irradiation (b * The value is measured, and the change in appearance of the ophthalmic composition before and after UV irradiation (degree of color difference; Δb) is calculated according to Formula 1 below. * The value was calculated, and the color difference change reduction rate was further calculated according to Equation 2 below. The results are shown in Table 24. Note that Δb * A smaller value indicates that the change in the appearance (color) (staining) of the ophthalmic composition is suppressed. (Formula 1)Δb * = b before UV irradiation *Value - b after UV irradiation * value (Equation 2) Color difference change reduction rate (%) = {1 - (Δb of Example 1) * / Δb in Comparative Example 1 * )} × 100

[0247] [Table 24]

[0248] Compared to Comparative Example 1, which contained chondroitin sulfate sodium and tetrahydrozoline hydrochloride with a weight-average molecular weight of approximately 28,000, Example 1, which contained chondroitin sulfate sodium and tetrahydrozoline hydrochloride with a weight-average molecular weight of approximately 56,000, showed a greater degree of color difference change (Δb) upon UV irradiation. * It was confirmed that the ) was small and that discoloration of the formulation due to ultraviolet irradiation was suppressed.

[0249] [Test Example 6: Cell Damage Test] Each ophthalmic composition was prepared according to a standard method with the composition shown in Table 25, and used as a test solution. The units for each component in Table 25 are w / v%. Human corneal epithelial cell line HCE-T cells were placed in a 24-well plate (Corning) at a rate of 1 × 10⁶ 5500 μL of cells were seeded into each well at a concentration of cells / mL and cultured in a CO2 incubator set to 37°C and 5% CO2. The growth medium used was DMEM / F12 (ThermoFisher) with 5% FCS (DS Pharma), 0.5% DMSO (Wako Pure Chemical Industries), 10 ng / mL recombinant human EGF (R&D), and 5 μg / mL of insulin solution human (SIGMA). After 2-4 days, when the cells reached confluence, the growth medium was aspirated and removed from each well. 50 μL of each ophthalmic composition was added to each well, and the mixture was incubated at 37°C and 5% CO2 for 15 minutes. Three or four glass beads (AS ONE) were placed in each well, and the mixture was shaken at 450 rpm for 1 minute using a microplate shaker (Heidlph Instruments GmbH & Co. KG). After removing the supernatant and glass beads, 500 μL of a culture medium containing Cellcountingkit-8 (Dojin Chemical Co., Ltd.) and culture medium in a 1:10 ratio was added. The cells were incubated in a CO2 incubator for 2 hours, and the absorbance at 450 nm was measured using a spectrophotometer (MOLECULAR DEVICES). Cell viability was calculated using the following formula. (Formula) Cell viability (%) = (Absorbance in each formulation / Absorbance of the control) × 100 The results are shown in Table 25.

[0250] [Table 25]

[0251] Compared to Reference Example 1, which contained chondroitin sulfate sodium with a weight-average molecular weight of approximately 28,000, Example 4, which contained chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 and hydroxyethylcellulose, was found to have a significantly higher cell viability rate. Therefore, it is expected that even when the eye is subjected to external stimuli (for example, rubbing the eyes with hands, blinking, inserting or removing contact lenses, friction with contact lenses, or foreign matter contamination (pollen, air pollutants, eyelashes, eye makeup-related foreign matter, and other foreign matter)) after instilling an ophthalmic composition containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 and hydroxyethylcellulose) into the eye, damage to eye cells will be suppressed.

[0252] [Examples of formulations] The eye drops are prepared by conventional methods according to the prescriptions listed in Tables 26-29 below. Note that the units for the amounts of each ingredient in Tables 26-29 are w / v%, unless otherwise specified in the table.

[0253] [Table 26]

[0254] [Table 27]

[0255] [Table 28]

[0256] [Table 29]

[0257] This concludes the explanation of the second part of the present invention, and next, we will explain the third part of the present invention.

[0258] The third aspect of the present invention relates to an ophthalmic composition.

[0259] [Background technology] Chondroitin sulfate or its salts are a type of acidic mucopolysaccharide and are incorporated into ophthalmic preparations for purposes such as promoting energy metabolism, relieving eye fatigue by promoting metabolism and cellular respiration, and replenishing tear fluid components (for example, Patent Document 3-1).

[0260] [Prior art document] [Patent] [Patent Document 3-1] Japanese Unexamined Patent Publication No. 2011-148791

[0261] [Summary of the third aspect of the present invention] [Third problem that the present invention aims to solve] The third aspect of the present invention aims to provide a novel ophthalmic composition containing chondroitin sulfate or a salt thereof.

[0262] [Third means for solving the problems of the present invention] The inventors have found that while ophthalmic compositions containing menthol can sometimes cause unpleasant irritation or burning sensations in the eyes, these symptoms are surprisingly significantly suppressed in an ophthalmic composition containing menthol in chondroitin sulfate sodium, which has a weight-average molecular weight of approximately 56,000.

[0263] The third invention provides, for example, the following inventions: [1] An ophthalmic composition containing at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000, and menthol. [2] The ophthalmic composition according to [1], further comprising at least one selected from the group consisting of boric acid and salts thereof. [3] The ophthalmic composition according to [1] or [2], further comprising chlorobutanol. [4] The ophthalmic composition according to [1] or [2], further comprising at least one selected from the group consisting of a decongestant, an ocular muscle stabilizer, an anti-inflammatory agent, an antihistamine, vitamins A, B, and E, amino acids and their salts, and cellulosic polymer compounds.

[0264] [Third effect of the present invention] According to the third aspect of the present invention, it is possible to provide an ophthalmic composition that contains menthol while suppressing unpleasant irritation.

[0265] [A third embodiment for carrying out the present invention] The following describes in detail a third embodiment for carrying out the present invention. However, the third embodiment is not limited to the following embodiments.

[0266] In this specification, unless otherwise specified, the unit of content "%" means "w / v%" and is synonymous with "g / 100mL".

[0267] The ophthalmic composition according to this embodiment contains at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000 (also simply referred to as "component (A)") and menthol (also simply referred to as "component (B)").

[0268] [Chondroitin sulfate and its salts] Chondroitin sulfate and its salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0269] Examples of chondroitin sulfate salts include alkali metal salts and alkaline earth metal salts. Examples of alkali metal salts include sodium salts and potassium salts. Examples of alkaline earth metal salts include magnesium salts and calcium salts.

[0270] Chondroitin sulfate and its salts are preferably chondroitin sulfate and alkali metal salts of chondroitin sulfate, more preferably chondroitin sulfate and sodium chondroitin sulfate, and even more preferably sodium chondroitin sulfate.

[0271] Chondroitin sulfate and its salts may be natural or synthetic products, but generally, chondroitin sulfate and its salts derived from animals (preferably mammals, fish, mollusks, etc.; more preferably cattle, sharks, squid, rays, etc.) which are natural products, are preferred, chondroitin sulfate and its salts derived from sharks and / or rays are more preferred, and chondroitin sulfate and its salts derived from sharks are even more preferred.

[0272] Commercially available chondroitin sulfate and its salts may also be used. Chondroitin sulfate and its salts may be used individually or in combination of two or more types. Furthermore, chondroitin sulfate and its salts with a weight-average molecular weight of 40,000 to 70,000 as defined herein may be used in combination with chondroitin sulfate and its salts having a weight-average molecular weight outside the range defined herein. For example, sodium chondroitin sulfate with a weight-average molecular weight of 56,000 and sodium chondroitin sulfate with a weight-average molecular weight of 25,000 may be used in combination. When using chondroitin sulfate and its salts with a weight-average molecular weight of 40,000 to 70,000 as defined herein in combination with chondroitin sulfate and its salts having a weight-average molecular weight outside the range defined herein, it is sufficient that chondroitin sulfate and its salts with a weight-average molecular weight of 40,000 to 70,000 are included as raw materials.

[0273] In this specification, "weight-average molecular weight" can be determined by using gel permeation chromatography with a multi-angle light scattering detector (MALS detector) and a differential refractive index detector (RI detector) connected online. Specifically, the following conditions are presented. <Standard Sample Preparation> 5 mg of chondroitin sulfate or its salt is added to 10 mL of 0.1 M sodium nitrate aqueous solution, gently stirred at room temperature, and completely dissolved. <Measurement conditions for weight-average molecular weight> Equipment: Gel permeation chromatograph - multi-angle light scattering meter Detector: Differential refractive index detector (Optilab rEX, manufactured by Wyatt Technology) Multi-angle light scattering detector (Wyatt Technology DAWN HELEOS) Column: Shodex OHpak SB-806M HQ, 2 pieces (φ7.8mm x 30cm, manufactured by Showa Denko) Solvent: 0.1M sodium nitrate aqueous solution Flow rate: 0.7mL / min Column temperature: 23℃ Detector temperature: 23℃ Injection volume: 0.2mL Data processing: Wyatt Technology data processing system (ASTRA) The weight-average molecular weight of chondroitin sulfate and its salts calculated using the method described above is not particularly limited as long as it is within the range of 40,000 to 70,000. Examples of lower limits for weight-average molecular weight include 41,000 or more, 42,000 or more, 43,000 or more, 44,000 or more, 45,000 or more, 46,000 or more, 47,000 or more, 48,000 or more, 49,000 or more, and 50,000 or more. Examples of upper limits for weight-average molecular weight include 69,000 or less, 68,000 or less, 67,000 or less, 66,000 or less, 65,000 or less, 64,000 or less, 63,000 or less, 62,000 or less, 61,000 or less, and 60,000 or less. Examples of weight-average molecular weight ranges include 41,000-69,000, 42,000-68,000, 43,000-67,000, 44,000-66,000, 45,000-65,000, 46,000-64,000, 47,000-63,000, 48,000-62,000, 49,000-61,000, and 50,000-60,000.

[0274] The content of component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set as appropriate depending on the type and content of other components, the use of the ophthalmic composition and the form of formulation. From the viewpoint of more significantly exhibiting the third effect of the present invention, the content of component (A) may be, for example, 0.001 to 5 w / v%, 0.005 to 5 w / v%, 0.008 to 4 w / v%, 0.01 to 3 w / v%, 0.05 to 2 w / v%, 0.1 to 1 w / v%, or 0.3 to 1 w / v%, based on the total amount of the ophthalmic composition.

[0275] 〔menthol〕 Menthol is not particularly limited as long as it is medically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0276] The menthol may be in the d-, l-, or dl-form, with l-menthol, d-menthol, and dl-menthol being examples. Furthermore, an essential oil containing menthol may be used as component (B). Examples of such essential oils include peppermint oil, cool mint oil, spearmint oil, and peppermint oil.

[0277] The content of component (B) in the ophthalmic composition according to this embodiment is not particularly limited and is set as appropriate depending on the type and content of other components, the use of the ophthalmic composition and the formulation form. From the viewpoint of more significantly exhibiting the third effect of the present invention, the menthol content may be 0.00001 to 0.5 w / v%, 0.0001 to 0.1 w / v%, or 0.001 to 0.05 w / v%, based on the total amount of the ophthalmic composition. When using an essential oil containing menthol as component (B), the blending ratio of the essential oil is set so that the menthol content in the blended essential oil satisfies the above blending ratio.

[0278] In the ophthalmic composition according to this embodiment, the content ratio of component (B) to component (A) is not particularly limited and is set appropriately depending on the type of component (A), the types and content of other components, the use of the ophthalmic composition and the formulation form. From the viewpoint of further enhancing the third effect of the present invention, the content ratio of component (B) to component (A) may be, for example, 0.00001 to 10 parts by mass, 0.0001 to 1 part by mass, or 0.001 to 0.1 parts by mass of component (B) per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0279] The ophthalmic composition according to this embodiment may further contain, in addition to components (A) and (B), at least one selected from the group consisting of boric acid and its salts (also simply referred to as "component (C)"). The further inclusion of component (C) in the ophthalmic composition makes the third effect of the present invention more pronounced. Component (C) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0280] Specific examples of boric acid and its salts include boric acid, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. A combination of boric acid and borax is preferred as the boric acid and its salts.

[0281] The content of component (C) in the ophthalmic composition according to this embodiment is not particularly limited and is set as appropriate depending on the type and content of other components, the use of the ophthalmic composition and the formulation form. From the viewpoint of more significantly exhibiting the third effect of the present invention, the content of component (C) may be 0.01 to 5 w / v%, 0.05 to 3 w / v%, or 0.1 to 2 w / v%, based on the total amount of the ophthalmic composition.

[0282] In the ophthalmic composition according to this embodiment, the content ratio of component (C) to component (A) is not particularly limited and is set appropriately depending on the type of component (A), the types and content of other components, the use of the ophthalmic composition and the formulation form. From the viewpoint of further enhancing the third effect of the present invention, for example, the total content of component (C) in the ophthalmic composition according to this embodiment may be 0.001 to 50 parts by mass, 0.01 to 10 parts by mass, or 0.1 to 5 parts by mass per 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment.

[0283] The ophthalmic composition according to this embodiment may further contain chlorobutanol (also simply referred to as "component (D)") in addition to component (A), component (B), and optionally component (C). The further inclusion of component (D) in the ophthalmic composition further enhances the third effect of the present invention. Component (D) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0284] The content of component (D) in the ophthalmic composition according to this embodiment is not particularly limited and is set as appropriate depending on the type and content of other components, the use of the ophthalmic composition, and the form of formulation. From the viewpoint of more significantly suppressing the unpleasant irritation and burning sensation caused by menthol, the content of component (D) may be 0.0005 to 1 w / v%, 0.001 to 0.5 w / v%, 0.005 to 0.3 w / v%, or 0.01 to 0.1 w / v%, based on the total amount of the ophthalmic composition.

[0285] In the ophthalmic composition according to this embodiment, the content ratio of component (D) to component (A) is not particularly limited and is set appropriately depending on the type of component (A), the types and content of other components, the use of the ophthalmic composition and the formulation form. From the viewpoint of further enhancing the third effect of the present invention, the content ratio of component (D) to component (A) may be, for example, 0.0001 to 5 parts by mass, 0.001 to 1 part by mass, or 0.01 to 0.5 parts by mass of component (D) per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0286] A third embodiment of the ophthalmic composition according to the present invention may further contain, in addition to components (A) and (B), at least one selected from the group consisting of decongestants, ocular muscle regulators, anti-inflammatory agents, antihistamines, water-soluble vitamins, and amino acids (also simply referred to as "component (E)"). The further inclusion of component (E) in the ophthalmic composition provides the effects of reducing liquid residue in the container after use, making blinking easier regardless of the viscosity of the formulation when placed in the eye (even in the case of a high-viscosity formulation), suppressing viscosity changes due to ultraviolet light, and / or suppressing discomfort during blinking, as confirmed in the test examples described later.

[0287] [Decongestant] An anticonjunctival agent is a compound that has the effect of reducing redness of the eye, and its salts. An anticonjunctival agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0288] Specific examples of decongestants include imidazoline compounds such as tetrahydrozoline, naphazoline, and oxymetazoline, and their salts (e.g., hydrochloride, nitrate); epinephrine, ephedrine, methylephedrine, phenylephrine, and their salts (e.g., hydrochloride). Imidazolin compounds and their salts are preferred as decongestants, tetrahydrozoline, naphazoline, and their salts are more preferred, tetrahydrozoline and its salts are even more preferred, and tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride) is particularly preferred.

[0289] Commercially available decongestants can also be used. One type of decongestant may be used alone, or two or more types may be used in combination.

[0290] (E) When a decongestant is used as component, the amount of the decongestant in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of decongestant, the types and amounts of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of more significantly exhibiting the third effect of the present invention, the amount of the decongestant may be 0.0001 to 0.5 w / v%, 0.0006 to 0.1 w / v%, or 0.0015 to 0.05 w / v%, based on the total amount of the ophthalmic composition.

[0291] When tetrahydrozoline and its salts are used as component (E), the content of component (E) may be, for example, 0.01 to 0.05 w / v% or 0.025 to 0.05 w / v% based on the total amount of the ophthalmic composition.

[0292] When an anticongestive agent is used as component (E), the ratio of the anticongestive agent to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the anticongestive agent, the type and content of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of further enhancing the third effect of the present invention, the ratio of the anticongestive agent to component (A) may be, for example, 0.0005 to 1 part by mass, 0.0015 to 0.5 parts by mass, or 0.025 to 0.25 parts by mass of the total content of component (A) in the ophthalmic composition according to this embodiment, per 1 part by mass of the total content of component (A).

[0293] [Ocular muscle regulators] Ocular muscle regulators are compounds and salts thereof that have the effect of adjusting focus by tensing or relaxing the extraocular muscles (ciliary muscles). Ocular muscle regulators are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0294] Specific examples of ocular muscle modulators include cholinesterase inhibitors having an active site similar to acetylcholine, and more specifically, neostigmine, tropicamide, helenien, atropine, and their salts (e.g., sulfates, methylsulfates). Neostigmine and its salts are preferred as ocular muscle modulators, and neostigmine methylsulfate is more preferred.

[0295] Over-the-counter eye muscle regulators can also be used. Eye muscle regulators may be used individually or in combination of two or more types.

[0296] (E) When an ophthalmic muscle regulator is used as component, the content of the ophthalmic muscle regulator in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of ophthalmic muscle regulator, the types and content of other components, the use of the ophthalmic composition and the form of formulation, etc. The content of the ophthalmic muscle regulator may be 0.0001 to 0.05 w / v%, 0.0005 to 0.01 w / v%, or 0.001 to 0.005 w / v%, based on the total amount of the ophthalmic composition.

[0297] When an ophthalmic muscle regulator is used as component (E), the ratio of the ophthalmic muscle regulator to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the ophthalmic muscle regulator, the type and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the third effect of the present invention, the ratio of the ophthalmic muscle regulator to component (A) may be, for example, 0.0001 to 0.5 parts by mass, 0.0005 to 0.1 parts by mass, or 0.001 to 0.05 parts by mass of the total content of component (A) in the ophthalmic composition according to this embodiment, per 1 part by mass of the total content of component (A).

[0298] [Anti-inflammatory drugs] Anti-inflammatory agents are compounds and salts thereof that have anti-inflammatory or soothing effects. Anti-inflammatory agents are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0299] Specific examples of anti-inflammatory agents include epsilon-aminocaproic acid, allantoin, berberine, azulenes (azulene, azulene sulfonic acid, chamazulene, guaiazulene, etc.), glycyrrhizic acid, zinc salts, lysozyme, celecoxib, lofecoxib, indomethacin, diclofenac, bromfenac, piroxicam, meloxicam, methyl salicylate, ibuprofen, ibuprofen piconol, bufexamac, flufenamate butyl, bendazac, ketoprofen, felbinac, pranoprofen, and salts thereof. As anti-inflammatory agents, allantoin, glycyrrhizic acid and its salts, and zinc salts are preferred. As for glycyrrhizic acid and its salts, alkali metal salts or ammonium salts of glycyrrhizic acid are preferred, dipotassium glycyrrhizinate and monoammonium glycyrrhizinate are more preferred, and dipotassium glycyrrhizinate is even more preferred. As the zinc salt, zinc sulfate or zinc lactate is preferred, and zinc sulfate is more preferred. The zinc salt may also be a hydrate (for example, zinc sulfate heptahydrate).

[0300] Anti-inflammatory drugs can also be commercially available. Anti-inflammatory drugs may be used individually or in combination of two or more.

[0301] (E) When an anti-inflammatory agent is used as component, the content of the anti-inflammatory agent in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of anti-inflammatory agent, the types and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of more significantly exhibiting the third effect of the present invention, the content of the anti-inflammatory agent may be 0.001 to 1 w / v%, 0.005 to 0.6 w / v%, or 0.05 to 0.3 w / v%, based on the total amount of the ophthalmic composition.

[0302] When an anti-inflammatory agent is used as component (E), the ratio of the anti-inflammatory agent to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the anti-inflammatory agent, the type and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the third effect of the present invention, the ratio of the anti-inflammatory agent to component (A) may be, for example, 0.001 to 10 parts by mass, 0.005 to 6 parts by mass, or 0.05 to 3 parts by mass of the total content of component (A) in the ophthalmic composition according to this embodiment, per 1 part by mass of the total content of component (A).

[0303] [Antihistamines] Antihistamines are compounds that have antihistamine activity, and their salts. Antihistamines are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0304] Specific examples of antihistamines include chlorpheniramine, iproheptine, diphenhydramine, ketotifen, olopatadine, levocabastine, and their salts. As antihistamines, chlorpheniramine and its salts are preferred, and chlorpheniramine maleate is more preferred.

[0305] Antihistamines can also be used commercially available. Antihistamines may be used individually or in combination of two or more types.

[0306] (E) When an antihistamine is used as component, the content of the antihistamine in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of antihistamine, the types and content of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of more significantly exhibiting the third effect of the present invention, the content of the antihistamine may be 0.0001 to 0.05 w / v%, 0.0006 to 0.05 w / v%, 0.006 to 0.04 w / v%, or 0.015 to 0.03 w / v%, based on the total amount of the ophthalmic composition.

[0307] When an antihistamine is used as component (E), the ratio of the antihistamine to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the antihistamine, the type and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the third effect of the present invention, the ratio of the antihistamine to component (A) may be, for example, 0.0001 to 0.5 parts by mass, 0.0006 to 0.5 parts by mass, 0.006 to 0.4 parts by mass, or 0.015 to 0.3 parts by mass of the total content of component (A) in the ophthalmic composition according to this embodiment, per 1 part by mass of the total content of component (A).

[0308] [Vitamin A] Vitamin A compounds are not particularly limited as long as they are medically, pharmacologically (pharmaceutically), or physiologically acceptable. Specific examples of vitamin A compounds include retinol, retinal, retinoic acid, and their derivatives, as well as their salts.

[0309] Examples of vitamin A derivatives include esters with monovalent carboxylic acids such as retinyl palmitate, retinyl acetate, retinyl butyrate, retinyl propionate, retinyl octylate, retinyl lauryl, retinyl oleate, and retinyl linolenate.

[0310] Examples of vitamin A salts include organic acid salts [e.g., monocarboxylic acid salts (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylic acid salts (fumarate, maleate, succinate, malonate, etc.), oxycarboxylic acid salts (lactate, tartrate, citrate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), and 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, etc.].

[0311] As for vitamin A derivatives, retinol derivatives are preferred, esters of retinol with monovalent carboxylic acids are more preferred, retinyl palmitate and retinyl acetate are even more preferred, and retinyl palmitate is even more preferred.

[0312] For vitamin A derivatives, synthetic compounds may be used, or extracts obtained from natural sources (e.g., vitamin A oil) may be used. Vitamin A oil refers to fatty oil obtained from animal tissues containing retinol, or its concentrate, or a mixture thereof to which vegetable oil is appropriately added. Commercially available vitamin A derivatives may also be used. Vitamin A derivatives may be used individually or in combination of two or more types.

[0313] (E) When vitamin A is used as component, the vitamin A content in the ophthalmic composition according to this embodiment may be 0.1 million to 100,000 IU / 100mL, 0.5 million to 75,000 IU / 100mL, or 10,000 to 50,000 IU / 100mL based on the total amount of the ophthalmic composition.

[0314] "IU" refers to the International Unit determined by the method described in the 17th Revised Japanese Pharmacopoeia, Vitamin A Quantitative Determination Method, etc. For example, in the individual articles of the 17th Revised Japanese Pharmacopoeia, it is stated that retinol acetate contains 2.5 million units or more of vitamin A per gram, and retinyl palmitate contains 1.5 million units or more of vitamin A per gram.

[0315] When vitamin A compounds are used as component (E), the ratio of vitamin A compounds to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the types of component (A) and vitamin A compounds, the types and amounts of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of further enhancing the third effect of the present invention, the ratio of vitamin A compounds to component (A) may be, for example, 0.01 to 1,000,000 IU / g, 0.05 to 750,000 IU / g, or 10,000 to 500,000 IU / g per 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment.

[0316] [Vitamin B group] Vitamin B compounds are not particularly restricted as long as they are medically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0317] Specific examples of B vitamins include flavin adenine dinucleotide and its salts (e.g., flavin adenine dinucleotide sodium), cobalamins (e.g., cyanocobalamin, methylcobalamin), pantothenic acid and its salts (e.g., sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), panthenol, pyridoxine or its salts (e.g., pyridoxine hydrochloride), and pyridoxal and its salts (e.g., pyridoxal phosphate). Panthenol, pyridoxine or its salts are more preferred among the B vitamins.

[0318] You can also use commercially available B vitamins. B vitamins may be used individually or in combination of two or more.

[0319] (E) When vitamin B compounds are used as an ingredient, the amount of vitamin B compounds in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of vitamin B compounds, the type and amount of other ingredients, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of more significantly exhibiting the third effect of the present invention, the amount of vitamin B compounds may be 0.0005 to 0.5 w / v%, 0.001 to 0.25 w / v%, or 0.01 to 0.1 w / v%, based on the total amount of the ophthalmic composition.

[0320] When vitamin B compounds are used as component (E), the ratio of water-soluble vitamins to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and vitamin B compounds, the type and content of other components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of further enhancing the third effect of the present invention, the ratio of vitamin B compounds to component (A) may be, for example, 0.0005 to 5 parts by mass, 0.001 to 2.5 parts by mass, or 0.01 to 1 part by mass of total vitamin B compounds per 1 part by mass of total component (A) contained in the ophthalmic composition according to this embodiment.

[0321] [Vitamin E derivatives] Vitamin E derivatives are not particularly limited as long as they are medically, pharmacologically (pharmaceutically), or physiologically acceptable. Specific examples of vitamin E derivatives include, for example, tocopherol, tocotrienol and their derivatives, and their salts. Tocopherol and tocotrienol may be α-, β-, γ-, or δ-, and may be either d-isomers or dl-isomers.

[0322] Examples of vitamin E derivatives include esters with organic acids such as tocopherol acetate, tocopherol succinate, tocopherol nicotinate, and tocopherol linolenic acid.

[0323] Examples of vitamin E salts include organic acid salts (lactate, acetate, butyrate, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate, malonate, methanesulfonate, toluenesulfonate, tosylate, palmitate, stearate, etc.), inorganic acid salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, amino acids, tripyridine, picoline, etc.), and salts with inorganic bases (e.g., salts with ammonium salts, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and metals such as aluminum, etc.).

[0324] Preferred vitamin E derivatives include d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E acetate (e.g., tocopherol acetate), vitamin E nicotinate, vitamin E succinate, and vitamin E linolenic acid, with tocopherol acetate (e.g., d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.) being more preferred.

[0325] Vitamin E derivatives may be either natural or synthetic. Commercially available vitamin E derivatives can also be used. Vitamin E derivatives may be used individually or in combination of two or more types.

[0326] (E) When vitamin E derivatives are used as component, the amount of vitamin E derivatives in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of vitamin E derivatives, the type and amount of other components, the use of the ophthalmic composition and the form of formulation, etc. The amount of vitamin E derivatives may be 0.0001 to 0.5 w / v%, 0.0005 to 0.1 w / v%, or 0.005 to 0.05 w / v%, based on the total amount of the ophthalmic composition.

[0327] When vitamin E compounds are used as component (E), the ratio of vitamin E compounds to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the types of component (A) and vitamin E compounds, the types and amounts of other components, the use of the ophthalmic composition and the form of formulation, etc. From the viewpoint of further enhancing the third effect of the present invention, the ratio of vitamin E compounds to component (A) may be, for example, 0.0001 to 5 parts by mass, 0.0005 to 1 part by mass, or 0.005 to 0.5 parts by mass per 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment.

[0328] [Amino acids and their salts] Amino acids and their salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0329] Examples of amino acids and their salts include L-aspartic acid or its salts (e.g., potassium L-aspartate, sodium L-aspartate, magnesium L-aspartate, calcium L-aspartate, magnesium-potassium L-aspartate (an equimolar mixture of magnesium L-aspartate and potassium L-aspartate)), aminoethylsulfonic acid or its salts, L-arginine, glutamic acid, glycine, alanine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, trimethylglycine and their salts. Commercially available amino acids and their salts can also be used. The amino acids and their salts may be L-isomers, D-isomers, or DL-isomers, with examples including potassium L-aspartate, magnesium L-aspartate, and an equimolar mixture of magnesium-potassium L-aspartate. Among the amino acids and their salts, aspartic acid, aminoethylsulfonic acid and their salts are preferred from the viewpoint of further enhancing the third effect of the present invention, and aminoethylsulfonic acid is particularly preferred.

[0330] (E) When amino acids and their salts are used as components, the content of amino acids and their salts in the ophthalmic composition according to this embodiment may be, for example, 0.001 to 5 w / v%, 0.01 to 3 w / v%, or 0.1 to 2 w / v%, based on the total amount of the ophthalmic composition, from the viewpoint of more significantly exhibiting the third effect of the present invention.

[0331] When amino acids and their salts are used as component (E), the content ratio of amino acids and their salts to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and amino acids and their salts, the type and content of other components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of further enhancing the third effect of the present invention, the content ratio of amino acids and their salts to component (A) may be, for example, 0.001 to 50 parts by mass, 0.01 to 30 parts by mass, or 0.1 to 20 parts by mass per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0332] [Cellulose-based polymer compounds] Cellulosic polymer compounds are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0333] Examples of cellulosic polymer compounds include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), carboxymethylcellulose, carboxyethylcellulose, and their salts. Hydroxyethylcellulose, hydroxypropylmethylcellulose, and their salts are preferred as cellulosic polymer compounds, and hydroxypropylmethylcellulose and its salts are more preferred. Examples of such salts include salts with organic bases (amine salts, basic ammonium salts such as arginine, etc.) and salts with inorganic bases (ammonium salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, etc.), with sodium salts, potassium salts, and calcium salts being more preferred, and sodium salts being particularly preferred.

[0334] As the cellulose polymer compound, commercially available products can also be used. The cellulose polymer compound may be used alone or in combination of two or more types.

[0335] (E) When a cellulose polymer compound is used as component, the content of the cellulose polymer compound in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of cellulose polymer compound, the types and content of other components, the use of the ophthalmic composition and the formulation form. From the viewpoint of more significantly exhibiting the third effect of the present invention, the content of the cellulose polymer compound may be 0.001 to 3 w / v%, 0.005 to 1 w / v%, or 0.01 to 0.6 w / v%, based on the total amount of the ophthalmic composition.

[0336] When a cellulose polymer compound is used as component (E), the content ratio of the cellulose polymer compound to component (A) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (A) and the cellulose polymer compound, the type and content of other components, the use of the ophthalmic composition and the formulation form, etc. From the viewpoint of further enhancing the third effect of the present invention, the content ratio of the cellulose polymer compound to component (A) may be, for example, 0.001 to 30 parts by mass, 0.005 to 10 parts by mass, or 0.01 to 6 parts by mass per 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment.

[0337] A third embodiment of the ophthalmic composition according to the present invention may further contain component (C) (at least one selected from the group consisting of boric acid and its salts) in addition to components (A), (B), and (E). The further inclusion of component (C) in the ophthalmic composition provides more pronounced effects in reducing liquid residue in the container after use, suppressing viscosity changes due to ultraviolet light, making blinking easier regardless of the viscosity when the formulation is placed in the eye (even in the case of a high-viscosity formulation), and / or suppressing discomfort during blinking. The type and content of component (C) in this embodiment are as described above.

[0338] The ophthalmic composition according to this embodiment may further contain a surfactant. The inclusion of a surfactant in the ophthalmic composition further enhances the third effect of the present invention. The surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and may be a nonionic surfactant, an amphoteric surfactant, anionic surfactant, or cationic surfactant.

[0339] Examples of nonionic surfactants include POE(20) 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); POE hydrogenated castor oils such as POE(40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40) and POE(60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE(3) hydrogenated castor oil (polyoxyethylene castor oil 3), and POE(10) castor oil. Examples include POE castor oil such as (polyoxyethylene castor oil 10); POE alkyl ethers such as POE(9) lauryl ether; POE-POP alkyl ethers such as POE(20)POP(4) cetyl ether; polyoxyethylene-polyoxypropylene block copolymers such as POE(196)POP(67) glycol (poloxamer 407, pluronic F127) and POE(200)POP(70) glycol; and polyethylene glycol fatty acid esters such as polyethylene glycol monostearate (e.g., polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (40 E.O.) (polyoxyl 40 stearate)). In the compounds exemplified above, POE represents polyoxyethylene, POP represents polyoxypropylene, and the numbers in parentheses indicate the number of moles added.

[0340] Examples of amphoteric surfactants include alkyldiaminoethylglycine or its salts (e.g., hydrochloride salts).

[0341] Examples of anionic surfactants include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, and α-olefin sulfonic acid.

[0342] Examples of cationic surfactants include cetylpyridinium chloride, benzalkonium chloride, and benzethonium chloride.

[0343] Among these surfactants, nonionic surfactants are preferred, POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE castor oil, POE-POP block copolymer, and polyethylene glycol fatty acid esters are more preferred, and POE sorbitan fatty acid esters, POE(40) hydrogenated castor oil, POE(60) hydrogenated castor oil, POE(3) castor oil, POE(10) castor oil, POE-POP block copolymer, and polyethylene glycol fatty acid esters are even more preferred. Commercially available surfactants can also be used. Surfactants may be used individually or in combination of two or more.

[0344] The surfactant content in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of surfactant, the use of the ophthalmic composition, and the formulation form. From the viewpoint of more significantly exhibiting the third effect of the present invention, the surfactant content may be, for example, 0.001 to 3 w / v%, 0.005 to 1 w / v%, or 0.01 to 0.5 w / v%, based on the total amount of the ophthalmic composition.

[0345] In the ophthalmic composition according to this embodiment, the content ratio of the surfactant to component (A) is not particularly limited and is set appropriately depending on the type of component (A) and the surfactant, the type and content of other components, the use of the ophthalmic composition and the formulation form. As for the content ratio of the surfactant to component (A), from the viewpoint of further enhancing the third effect of the present invention, for example, the total content of the surfactant may be 0.001 to 30 parts by mass, 0.005 to 10 parts by mass, or 0.01 to 5 parts by mass per 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment.

[0346] The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, even more preferably 4.5 to 8.5, even more preferably 5.0 to 8.5, particularly preferably 5.0 to 8.0, even more particularly preferably 5.3 to 7.5, and most preferably 5.5 to 7.0.

[0347] The ophthalmic composition according to this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the body, as needed. An appropriate osmotic pressure ratio can be set as appropriate depending on the use, formulation form, and method of use of the ophthalmic composition, but for example, it can be 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and even more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 17th edition of the Japanese Pharmacopoeia, and the osmotic pressure is measured by referring to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, then 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 by using a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

[0348] The viscosity of the ophthalmic composition according to this embodiment is not particularly limited, as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The viscosity of the ophthalmic composition according to this embodiment is preferably 1 to 10,000 mPa·s, more preferably 1 to 8,000 mPa·s, even more preferably 1 to 1,000 mPa·s, even more preferably 1 to 100 mPa·s, particularly preferably 1 to 20 mPa·s, and most preferably 1.5 to 10 mPa·s, as measured at 20°C with a rotational viscometer (TV-20 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' × R24).

[0349] The ophthalmic composition according to this embodiment may contain, in addition to the above components, an appropriate amount of components selected from various pharmacologically active components and physiologically active components, provided that the third effect of the present invention is not impaired. The components are not particularly limited, and examples include the active ingredients in ophthalmic drugs listed in the 2017 edition of the Standards for Approval of Manufacturing and Marketing of Prescription-Only and Over-the-Counter Drugs (supervised by the Regulatory Science Society of Japan). Specifically, examples of components used in ophthalmic drugs include the following components. Antiallergic agents: For example, sodium cromoglycate, tranilast, pemirolast potassium, acitazanol, anlexanox, ibudilast, etc. Steroids: For example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc. Vitamins: For example, ascorbic acid, sodium ascorbate, etc. Astringent agents: For example, zinc oxide. Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and their salts.

[0350] The ophthalmic composition according to this embodiment may contain, in accordance with conventional methods, various additives selected appropriately and used in combination in appropriate amounts, one or more types, depending on its use and formulation, as long as the third effect of the present invention is not impaired. Examples of such additives include the various additives listed in the 2016 Dictionary of Pharmaceutical Additives (edited by the Japan Pharmaceutical Additives Association). The following are examples of typical additives. Carrier: For example, an aqueous solvent such as water or aqueous ethanol. Chelating agents: For example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc. Base: For example, octyldodecanol, titanium dioxide, potassium bromide, Plastibase, etc. pH adjusters: For example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, etc. (B) Fragrances or cooling agents other than the main component: For example, menthone, camphor, borneol, geraniol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymene, terpineol, pinene, camphene, isoborneol, fenchen, nerol, myrcene, myrcenol, linalool acetate, lavandulol, eucalyptus oil, bergamot oil, fennel oil, cinnamon oil, rose oil, camphor oil, etc. These may be in d-form, l-form, or dl-form. Thickening agents other than cellulose-based polymer compounds: for example, guar gum; hydroxypropyl guar gum; gum arabic; karaya gum; xanthan gum; agar; alginic acid and its salts (sodium salt, etc.); mucopolysaccharides (other than component (A)) of heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and its salts (sodium salt, etc.); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan; monosaccharides such as glucose, etc. (C) Buffering agents other than component: for example, phosphate buffering agent, carbonate buffering agent, acetate buffering agent, lactic acid buffering agent, succinate buffering agent, citrate buffering agent, Tris buffering agent, AMPD buffering agent, etc. Stabilizers: For example, EDTA, EDTA salts (disodium EDTA, disodium calcium EDTA, trisodium EDTA, tetrasodium EDTA), sodium formaldehyde sulfoxylate (Longalit), aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, sodium bisulfite, sodium pyrosulfite, etc. Preservatives: For example, alkyl polyaminoethylglycine quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, polydronium chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), alexidine, etc.), Glokill (a trade name of Rhodia Corporation), etc. Isotonic agents: For example, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, sodium bisulfite, sodium sulfite, etc. Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin, etc. These may be in d-isomer, l-isomer, or dl-isomer. Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil, and olive oil; animal oils such as squalane; mineral oils such as liquid paraffin and petrolatum.

[0351] If the ophthalmic composition according to this embodiment contains water, from the viewpoint of more significantly exhibiting the third effect of the present invention, the water content is preferably 80 w / v% or more and less than 100 w / v%, more preferably 85 w / v% or more and 99.5 w / v%, and even more preferably 90 w / v% or more and 99.2 w / v%, based on the total amount of the ophthalmic composition.

[0352] The water used in the ophthalmic composition according to this embodiment may be any water that is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable. Examples of such water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection. Their definitions are based on the 17th edition of the Japanese Pharmacopoeia.

[0353] The ophthalmic composition according to this embodiment can be prepared by adding and mixing desired amounts of component (A), component (B), and other components as needed, to the desired concentration. For example, it can be prepared by dissolving or dispersing these components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like.

[0354] The ophthalmic composition according to this embodiment can take various formulation forms depending on the purpose. Examples of formulation forms include liquids, gels, and semi-solid preparations (such as ointments), and a liquid is preferred from the viewpoint of more significantly exhibiting the third effect of the present invention.

[0355] The ophthalmic compositions according to this embodiment can be used, for example, as eye drops (also called eye solutions or eye medicines; eye drops include eye drops that can be used while wearing contact lenses), artificial tears, eye washes (also called eye wash solutions or eye medicines; eye washes include eye washes that can be used while wearing contact lenses), and contact lens compositions [contact lens insertion solutions, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaning agents, contact lens cleaning and preservation agents), contact lens packaging solutions, etc.]. Note that "contact lenses" include hard contact lenses and soft contact lenses (including both ionic and nonionic types, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0356] The ophthalmic composition according to this embodiment is preferably an eye drop (including eye drops that can be instilled while wearing contact lenses) because it can more clearly exhibit the third effect of the present invention. When the ophthalmic composition according to this embodiment is an eye drop, the method of use and dosage are not particularly limited as long as they are effective and have few side effects, but for example, for adults (15 years of age or older) and children 7 years of age or older, examples include instilling 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops at a time, 2 to 4 times or 5 to 6 times a day.

[0357] The ophthalmic composition according to this embodiment is provided in any container. The container for containing the ophthalmic composition according to this embodiment is not particularly limited and may be made of glass or plastic, for example. Plastic is preferred. Examples of plastics include polyethylene terephthalate (PET), polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide and copolymers of monomers constituting these, and mixtures of two or more of these. Polyethylene terephthalate is preferred. The container for containing the ophthalmic composition according to this embodiment may be a transparent container that allows visibility of the inside of the container, or an opaque container that makes it difficult to see inside the container. A transparent container is preferred. Here, "transparent container" includes both colorless transparent containers and colored transparent containers.

[0358] A nozzle may be attached to the container for containing the ophthalmic composition according to this embodiment. The material of the nozzle is not particularly limited and may be made of glass or plastic, for example. Plastic is preferred. Examples of plastics include polybutylene terephthalate, polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate and copolymers of monomers constituting these, and mixtures of two or more of these. As for the material of the nozzle, from the viewpoint of further enhancing the third effect of the present invention, polypropylene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate are preferred, and polyethylene is more preferred.

[0359] The container for containing the ophthalmic composition according to this embodiment may be a multi-dose type that contains multiple doses, or a unit-dose type that contains a single dose.

[0360] The ophthalmic composition according to this embodiment is preferably filled in a container with an internal volume of 4 to 30 mL, more preferably in a container with an internal volume of 5 to 20 mL, even more preferably in a container with an internal volume of 6 to 16 mL, and even more preferably in a container with an internal volume of 10 to 15 mL. It may also be filled in a container with an internal volume of 0.1 to 3 mL, or in a container with an internal volume of 0.2 to 1 mL.

[0361] [Third embodiment of the present invention] The third aspect of the present invention will be specifically described below based on test examples, but the third aspect of the present invention is not limited to these. Furthermore, the chondroitin sulfate sodium used in the following test examples is as follows, and the chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 is derived from sharks. Chondroitin Sodium Sulfate Weight-average molecular weight approximately 56,000: Seikagaku Corporation; Grade NK Weight-average molecular weight approximately 28,000: Seikagaku Corporation; Grade ND-K Weight-average molecular weight approximately 25,000: Maruha Nichiro Corporation; Non-pharmaceutical standard chondroitin sulfate sodium

[0362] [Test Example 1: User Experience Test (1)] Ophthalmic compositions for Comparative Examples 1-1, 1-2, and Examples 1-1, 1-2 were prepared according to conventional methods using the compositions shown in Table 30. The units for each component in Table 30 are w / v%. Each prepared ophthalmic composition was filtered through a 0.2 μm membrane filter and filled into sterile PET eye drop containers (15 mL capacity) to obtain sterile eye drops. These eye drops were evaluated for "unpleasant irritation" and "burning sensation" using the Visual Analog Scale (VAS) method. Specifically, six uncorrected subjects were given one drop of the above eye drop solution in each eye. A self-reported symptom questionnaire sheet with 10cm lines was used to assess the "unpleasant irritation" and "burning sensation" felt upon instillation. 0cm represented no discomfort or burning sensation, while 10cm represented a very strong sensation. Subjects checked the corresponding line, and the length (mm) of this check was measured to represent the severity of their symptoms. This length was used as the score for each item. The average score of the six subjects was calculated to evaluate each item. Based on the obtained values, the improvement rate of the VAS score was calculated using the following formula (I). Comparative Example 1-1 corresponds to Comparative Example 1-1, and Comparative Example 1-2 corresponds to Comparative Example 1-2. Formula (I): VAS improvement rate (%) = {(VAS value of the corresponding comparative example - VAS value of the example) / VAS value of the corresponding comparative example} × 100 The results are shown in Table 30.

[0363] [Table 30]

[0364] Compared to eye drops containing menthol and chondroitin sulfate sodium with a weight-average molecular weight of approximately 28,000 (Comparative Examples 1-1 and 1-2), eye drops containing chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 instead of chondroitin sulfate sodium with a weight-average molecular weight of approximately 28,000 (Examples 1-1 and 1-2) showed a significant improvement in "unpleasant irritation" and "burning sensation." Furthermore, when soft contact lens wearers were asked to evaluate "unpleasant irritation" and "burning sensation" using the same method as described above, the same trend was observed as in the case of uncorrected vision.

[0365] [Test Example 2: Measurement Test of Residual Liquid Volume in Eye Drop Bottle] Each ophthalmic composition was prepared according to conventional methods using the compositions shown in Tables 31 and 32, and used as test solutions. Unless otherwise specified in the tables, the units for each component in Tables 31 and 32 are w / v%. The tare weight of 10 mL PET eye drop bottles was measured, and 5 mL of each test solution was filled into each bottle. Next, the weight of each eye drop bottle after emptying the filled test solution was measured, and the residual volume (g) was calculated according to formula (II) below. For each formulation, the improvement rate of the residual volume relative to the residual volume of test solution 2-1 was calculated using formula (III) below. Formula (II): Residual volume (g) = Weight of the eye drop bottle after all test solution has been dispensed (g) - Weight of the eye drop bottle (g) Formula (III) Percentage improvement in residual volume for test solution 2-1 (%) = (1 - residual volume of each test solution (g) / residual volume of test solution 2-1 (g)) × 100 The results are shown in Tables 31 and 32.

[0366] [Table 31]

[0367] [Table 32]

[0368] When chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000 was also present in test solution 2-1, which contains menthol, the amount of residual solution decreased, making it easier to use up the ophthalmic composition in the eye drop bottle (test solution 2-2). Furthermore, when methyl neostigmine sulfate, allantoin, dipotassium glycyrrhizinate, tocopherol acetate, retinyl palmitate, aminoethylsulfonic acid, or hydroxyethylcellulose was also present in test solution 2-2, which contains menthol and chondroitin sulfate sodium with a weight-average molecular weight of approximately 56,000, the amount of residual solution decreased even further, making it easier to use up the ophthalmic composition in the eye drop bottle (test solutions 2-3 to 2-9).

[0369] [Test Example 3: Viscosity Stability Test by Light Irradiation] Each ophthalmic composition was prepared according to conventional methods using the compositions shown in Tables 33 and 34, and used as test solutions. Unless otherwise specified in the tables, the units for each component in Tables 33 and 34 are w / v%. Each test solution was filled into a 10 mL glass bottle and tested at 35°C using a SUNTESTER XLS+ (manufactured by Toyo Seiki Co., Ltd., 1700 W xenon air-cooled lamp light source) with an ultraviolet light irradiance of 765 (W / m²). 2 The solutions were irradiated for 96 hours. For each test solution (600 μL) before and after irradiation, the viscosity was measured at 34°C for different shear rates (1 to 1000 (1 / s)) using a rheometer (MCR302 (Anton Paar)) and a cone-plate measuring jig (CP50-1, d: 0.102 mm). The viscosity reduction rate before and after the test was calculated using the viscosity (mPa·s) at a shear rate of 100 (1 / s) according to the following formula (IV). For test solution 3-2, the percentage of viscosity reduction was calculated relative to the viscosity reduction rate of test solution 3-1, which was set to 1. For test solutions 3-3 to 3-8, the improvement rate of viscosity reduction rate relative to test solution 3-2 was calculated for each formulation using the following formula (V). Formula (IV): Viscosity reduction rate (%) = {(Viscosity of each test solution before light irradiation (mPa·s) - Viscosity of each test solution after light irradiation (mPa·s)) / Viscosity of each test solution before light irradiation (mPa·s)} × 100 Formula (V): Viscosity reduction improvement rate (%) = {(Viscosity reduction rate of test solution 3-2 - Viscosity reduction rate of each formulation example) / Viscosity reduction rate of test solution 3-2} × 100 The results are shown in Tables 33 and 34. A smaller viscosity reduction rate indicates less viscosity change due to light, and that the ophthalmic composition maintains equivalent physical properties.

[0370] [Table 33]

[0371] [Table 34]

[0372] In test solution 3-1, which contains menthol, a significant decrease in viscosity was observed when sodium chondroitin sulfate, which has a weight-average molecular weight of approximately 56,000, was also present (test solution 3-2). On the other hand, in test solutions 3-3 to 3-8, which contained menthol and sodium chondroitin sulfate (weight-average molecular weight of approximately 56,000), and were further compounded with neostigmine methyl sulfate, allantoin, zinc sulfate, panthenol, potassium aspartate, or aminoethylsulfonic acid, respectively, the viscosity reduction was significantly improved, and it was confirmed that the stability of the ophthalmic composition under ultraviolet irradiation was enhanced.

[0373] [Test Example 4: Measurement of Viscosity] Each ophthalmic composition was prepared according to conventional methods using the compositions shown in Tables 35 and 36, and used as test solutions. Unless otherwise specified in the tables, the units for each component in Tables 35 and 36 are w / v%. The viscosity of each prepared test solution (600 μL) was measured using a rheometer (MCR302 (Anton Paar)) with a cone-plate measuring jig (CP50-1, d: 0.102 mm) to determine the viscosity against shear rate at 34°C. For the viscosity (mPa·s) at a shear rate of 10000 (1 / s), the viscosity ratio of test solution 4-2 was calculated, with the viscosity of test solution 4-1 set to 1. For test solutions 4-3 to 4-11, the viscosity reduction rate (%) relative to test solution 4-2 was calculated using the following formula (VI). Note that the shear rate of 10000 (1 / s) is assumed to be the blink speed. The viscosity at a shear rate of 10,000 (1 / s) represents the viscosity during blinking. A decrease in this value indicates that blinking is less likely to cause discomfort and is easier. Formula (VI): Viscosity reduction rate (%) = (1 - Viscosity of each test solution (mPa·s) / Viscosity of test solution 4-2 (mPa·s)) × 100 The results are shown in Tables 35 and 36.

[0374] [Table 35]

[0375] [Table 36]

[0376] In test solution 4-1, which contains only sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000, the viscosity at a shear rate of 10,000 (1 / s) improved when menthol was present (test solution 4-2). On the other hand, in test solution 4-2, which contains sodium chondroitin sulfate with a weight-average molecular weight of approximately 56,000 and menthol, the viscosity at a shear rate of 10,000 (1 / s) decreased significantly when tetrahydrozoline hydrochloride, neostigmine methyl sulfate, allantoin, dipotassium glycyrrhizinate, zinc sulfate, chlorpheniramine maleate, panthenol, potassium aspartate, or aminoethylsulfonic acid was also present.

[0377] [Test Example 5: User Experience Test (2)] Ophthalmic compositions for Comparative Example 5-1 and Example 5-1 were prepared according to conventional methods using the compositions shown in Table 37. The units for each component in Table 37 are w / v%. Each prepared ophthalmic composition was filtered through a 0.2 μm membrane filter and filled into sterile PET eye drop containers (15 mL capacity) to obtain sterile eye drops. These eye drops were evaluated for "unpleasant irritation" and "burning sensation" using the Visual Analog Scale (VAS) method. Specifically, three uncorrected subjects were given one drop of the above eye drop solution in each eye. A self-reported symptom questionnaire sheet with 10cm lines was used to assess the "unpleasant irritation" and "burning sensation" felt upon instillation. 0cm represented no discomfort or burning sensation, while 10cm represented a very strong sensation. Subjects checked the corresponding line, and the length (mm) of this check was measured to represent the severity of their subjective symptoms, which was used as the score for each item. The average score of the three subjects was calculated to evaluate each item. Based on the obtained values, the improvement rate of the VAS score was calculated using formula (I) from Test Example 1. Comparative Example 5-1 corresponds to Comparative Example 5-1. The results are also shown in Table 37.

[0378] [Table 37]

[0379] The same trend as in Test Example 1 was observed for the ophthalmic compositions shown in Table 37.

[0380] [Examples of formulations] Eye drops and artificial tears are prepared by conventional methods using the formulations listed in Tables 38-41 below. Note that the units for the amounts of each component in Tables 38-41 are w / v%, unless otherwise specified in the table. Formulation examples 1-10, 21-27, and 29-32 are eye drops, while formulation examples 11-16 and 28 are artificial tears. Furthermore, formulation examples 1-32 were filled into polyethylene terephthalate containers (15 mL capacity) and fitted with polyethylene nozzles, designated as formulation examples 1''-32'', those with a polybutylene terephthalate inner layer nozzle, and those with a polyethylene naphthalate inner layer nozzle.

[0381] [Table 38]

[0382] [Table 39]

[0383] [Table 40]

[0384] [Table 41]

Claims

1. An ophthalmic composition comprising at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000, and at least one selected from the group consisting of retinyl palmitate, allantoin and its salts, glycyrrhizic acid and its salts, pyridoxine and its salts, panthenol, tocopherol acetate, aminoethylsulfonic acid and its salts, aspartic acid and its salts, and neostigmine and its salts.

2. An ophthalmic composition for suppressing dry eyes, comprising at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000, and at least one selected from the group consisting of retinyl palmitate, glycyrrhizic acid and its salts, tocopherol acetate, aminoethylsulfonic acid and its salts, and aspartic acid and its salts.

3. An ophthalmic composition for inhibiting dryness of contact lenses, comprising at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000, and at least one selected from the group consisting of retinyl palmitate, allantoin and its salts, glycyrrhizic acid and its salts, pyridoxine and its salts, panthenol, tocopherol acetate, aminoethylsulfonic acid and its salts, aspartic acid and its salts, and neostigmine and its salts.

4. An ophthalmic composition comprising at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000, and at least one selected from the group consisting of chlorpheniramine and its salts, zinc sulfate, and tetrahydrozoline and its salts.

5. An ophthalmic composition comprising: at least one selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 40,000 to 70,000; menthol; and at least one selected from the group consisting of tetrahydrozoline and its salts, neostigmine and its salts, allantoin and its salts, glycyrrhizic acid and its salts, zinc sulfate, chlorpheniramine and its salts, retinyl palmitate, panthenol, tocopherol acetate, aminoethylsulfonic acid and its salts, and aspartic acid and its salts.

6. The ophthalmic composition according to claim 5, further comprising at least one selected from the group consisting of boric acid and salts thereof.

7. The ophthalmic composition according to claim 5 or 6, further comprising chlorobutanol.

8. The ophthalmic composition according to claim 5 or 6, further comprising a cellulose-based polymer compound.

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