Water-based components for ophthalmology

Abstract

This invention provides an aqueous ophthalmic composition that suppresses weight changes in ophthalmic polybutylene terephthalate-containing resin containers. [Solution] (A) Polysaccharides; Monosaccharides; Vitamin B 12 Prepare an aqueous ophthalmic composition containing (B) a buffering agent, which includes: one or more vitamins selected from the group consisting of vitamin B2, vitamin A, and panthenol; one or more oils selected from the group consisting of vegetable oils, animal oils, and mineral oils; one or more surfactants selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate; one or more anti-allergic components; preservatives; thickening agents; polyhydric alcohols; anti-inflammatory components; antibacterial agents; and cooling agents. When this composition comes into contact with a polybutylene terephthalate-containing resin container, it is possible to suppress the weight change of the container.

Description

[Technical Field]

[0001] The present invention relates to an aqueous composition for ophthalmic use, a method for suppressing weight change of an ophthalmic polybutylene terephthalate-containing resin container, a method for suppressing deterioration of an ophthalmic polybutylene terephthalate-containing resin container, and a method for suppressing wetting of an ophthalmic polybutylene terephthalate-containing resin container. [Background technology]

[0002] Polybutylene terephthalate-containing resin (hereinafter also referred to as PBT-containing resin in this specification), a type of thermoplastic polyester resin that is widely used as a thermoplastic resin, has excellent moldability and a good balance of physical properties and price, and is therefore used as a container material for automobiles, electrical and electronic components, semiconductor substrate containers, and other applications.

[0003] Furthermore, it has been proposed to use a laminate made of PBT film and a heat-adhesive resin layer as a heat-resistant packaging bag that stores food products consisting of liquids and solids containing a lot of moisture, oil, and sugar, and is particularly resistant to punctures when heated in a microwave oven or other appliance (Patent Document 1). [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2006-143223 [Overview of the project] [Problems that the invention aims to solve]

[0005] Thus, while PBT-containing resins possess excellent properties, they also have the characteristic of absorbing moisture from the contents of the container when used as containers.

[0006] Furthermore, PBT-containing resins undergo hydrolysis when heated.

[0007] The present invention aims to provide an ophthalmic aqueous composition that can solve these problems. [Means for solving the problem]

[0008] The inventors of this invention conducted extensive research to solve the aforementioned problems and, as a result, discovered that by including a specific component in an ophthalmic aqueous composition, the PBT-containing resin container holding the composition can be stabilized and the deterioration of the container can be prevented, thus completing the present invention. Furthermore, they discovered that an ophthalmic aqueous composition containing the specific component can improve the wettability (i.e., suppress wetting) of the PBT-containing resin container, resulting in a new effect of improved liquid drainage.

[0009] In other words, the present invention is [1] (A) Polysaccharides; Monosaccharides; Vitamin B 12 One or more vitamins selected from the group consisting of vitamin B2, vitamin A, and panthenol; one or more oils selected from the group consisting of vegetable oils, animal oils, and mineral oils; one or more surfactants selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate; one or more anti-allergic ingredients selected from the group consisting of tranilast, ketotifen, diphenhydramine, and their salts; chlorhexidine, sorbic acid, and their salts An aqueous ophthalmic composition comprising: one or more selected preservatives; one or more thickening agents selected from the group consisting of carboxymethylcellulose, methylcellulose, vinyl polymer compounds, and salts thereof; a polyhydric alcohol; one or more anti-inflammatory agents selected from the group consisting of berberine, azulene sulfonic acid, allantoin, zinc sulfate, and salts thereof; one or more antibacterial agents selected from the group consisting of sulfamethoxazole and salts thereof; one or more cooling agents selected from the group consisting of eucalyptus oil and bergamot oil; and (B) a buffering agent, (C) An ophthalmic aqueous composition contained in a container in which part or all of the surface that comes into contact with the ophthalmic aqueous composition is molded from a resin containing polybutylene terephthalate; [2] Of the above components (A), one or more polysaccharides are selected from the group consisting of alginic acid, gellan gum, xanthan gum, hyaluronic acid, chondroitin sulfate, and their salts; one or more monosaccharides are glucose; one or more vitamins are selected from the group consisting of cyanocobalamin, retinol, panthenol, flavin adenine dinucleotide, and their salts; one or more oils are selected from the group consisting of sesame oil, castor oil, lanolin, petrolatum, and liquid paraffin; one or more surfactants are selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate; and the anti-allergic components are tranilast, ketotifen fumarate, and hydrochloric acid One or more selected from the group consisting of diphenhydramine; one or more selected from the group consisting of chlorhexidine gluconate and potassium sorbate as a preservative; one or more selected from the group consisting of carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, and salts thereof as a thickening agent; one or more selected from the group consisting of propylene glycol, glycerin, and mannitol as a polyhydric alcohol; one or more selected from the group consisting of berberine chloride, sodium azulene sulfonate, allantoin, and zinc sulfate as an anti-inflammatory agent; sodium sulfamethoxazole as an antibacterial agent; and a cooling agent selected from the group consisting of eucalyptus oil and bergamot oil, according to item [1]; [3] Furthermore, an aqueous ophthalmic composition according to item [1] or [2], containing sodium edetate; [4] The aqueous composition contains (A) polysaccharides; monosaccharides; vitamin B 12One or more vitamins selected from the group consisting of vitamin B2, vitamin A, and panthenol; one or more oils selected from the group consisting of vegetable oils, animal oils, and mineral oils; one or more surfactants selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate; one or more anti-allergic ingredients selected from the group consisting of tranilast, ketotifen, diphenhydramine, and salts thereof; one or more preservatives selected from the group consisting of chlorhexidine, sorbic acid, and salts thereof; A method for imparting a weight change suppression effect on a polybutylene terephthalate-containing resin container to an aqueous composition by coexisting with one or more of the following: (B) a buffering agent; one or more thickening agents selected from the group consisting of boxymethylcellulose, methylcellulose, vinyl polymer compounds, and salts thereof; polyhydric alcohol; one or more anti-inflammatory agents selected from the group consisting of berberine, azulene sulfonic acid, allantoin, zinc sulfate, and salts thereof; one or more antibacterial agents selected from the group consisting of sulfamethoxazole and salts thereof; one or more cooling agents selected from the group consisting of eucalyptus oil and bergamot oil; and (B) a buffering agent. [5] The aqueous composition contains (A) polysaccharides; monosaccharides; vitamin B 12One or more vitamins selected from the group consisting of vitamin B2, vitamin A, and panthenol; one or more oils selected from the group consisting of vegetable oils, animal oils, and mineral oils; one or more surfactants selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate; one or more anti-allergic ingredients selected from the group consisting of tranilast, ketotifen, diphenhydramine, and salts thereof; one or more preservatives selected from the group consisting of chlorhexidine, sorbic acid, and salts thereof; A method for imparting a wetting-suppressing effect on a polybutylene terephthalate-containing resin container to an aqueous composition by coexisting with (B) a buffering agent, comprising: one or more thickening agents selected from the group consisting of ruboxymethylcellulose, methylcellulose, vinyl polymer compounds, and salts thereof; polyhydric alcohol; one or more anti-inflammatory agents selected from the group consisting of berberine, azulene sulfonic acid, allantoin, zinc sulfate, and salts thereof; one or more antibacterial agents selected from the group consisting of sulfamethoxazole and salts thereof; one or more cooling agents selected from the group consisting of eucalyptus oil and bergamot oil; and (B) a buffering agent. [6] (A) Polysaccharides; Monosaccharides; Vitamin B 12One or more vitamins selected from the group consisting of vitamin B2, vitamin A, and panthenol; one or more oils selected from the group consisting of vegetable oils, animal oils, and mineral oils; one or more surfactants selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate; one or more anti-allergic ingredients selected from the group consisting of tranilast, ketotifen, diphenhydramine, and their salts; one or more preservatives selected from the group consisting of chlorhexidine, sorbic acid, and their salts; The present invention provides an agent for improving the liquid flow of ophthalmic polybutylene terephthalate-containing resin containers, comprising: one or more thickening agents selected from the group consisting of carboxymethylcellulose, methylcellulose, vinyl polymer compounds, and salts thereof; polyhydric alcohols; one or more anti-inflammatory agents selected from the group consisting of berberine, azulene sulfonic acid, allantoin, zinc sulfate, and salts thereof; one or more antibacterial agents selected from the group consisting of sulfamethoxazole and salts thereof; one or more cooling agents selected from the group consisting of eucalyptus oil and bergamot oil; and (B) a buffering agent.

[0010] The present invention allows the use of components and concentrations described later for the ophthalmic aqueous composition, the method for suppressing weight change, the method for suppressing deterioration, the method for suppressing wetting, the liquid drainage improving agent, and the method and manufacturing method for polybutylene terephthalate-containing resin containers. [Effects of the Invention]

[0011] When the ophthalmic aqueous composition of the present invention is contained in a PBT-containing resin container, the container is stabilized and its deterioration is suppressed. Furthermore, wetting suppression and improved liquid drainage can be expected, reducing the amount of liquid remaining in the container. [Brief explanation of the drawing]

[0012] [Figure 1]Figure 1 is a diagram showing the weight change of the PBT-containing resin piece before and after immersing the PBT-containing resin piece in the ophthalmic aqueous composition and performing heat treatment.

Mode for Carrying Out the Invention

[0013] In the present invention, the unit of content “w / v%” is synonymous with “g / 100 mL”. In the present invention, “formulation amount” is synonymous with “content”.

[0014] When the present inventors store an ophthalmic aqueous composition in a PBT-containing resin container, a weight change occurs in the PBT-containing resin, and problems such as a decrease in the strength of the container, cracking, deformation, and a decrease in airtightness occur. That is, when using a container formed of a PBT-containing resin in a mode where a drug such as an ophthalmic aqueous composition is used while being stored for a certain period, the problem of property change of the PBT-containing resin container becomes serious. The ophthalmic aqueous composition of the present invention can solve such problems.

[0015] The ophthalmic aqueous composition of the present invention comprises (A) polysaccharides; monosaccharides; vitamin B 12One or more vitamins selected from the group consisting of polysaccharides; monosaccharides; vitamin B2s, vitamin As, and panthenol; one or more oils selected from the group consisting of vegetable oils, animal oils, and mineral oils; one or more surfactants selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate; one or more anti-allergy components selected from the group consisting of tranilast, ketotifen, diphenhydramine, and their salts; one or more preservatives selected from the group consisting of chlorhexidine, sorbic acid, and their salts; one or more thickening components selected from the group consisting of carboxymethyl cellulose, methyl cellulose, vinyl-based polymer compounds, and their salts; polyhydric alcohols; one or more anti-inflammatory components selected from the group consisting of berberine, azulene sulfonic acid, allantoin, zinc sulfate, and their salts; one or more antibacterial agents selected from the group consisting of sulfamethoxazole and its salts; one or more cooling agents selected from the group consisting of eucalyptus oil and bergamot oil; one or more selected from the group consisting of, and (B) a buffer. The ophthalmic aqueous composition of the present invention is contained in a PBT-containing resin container.

[0016] In the present invention, the aqueous composition means a composition containing water. The aqueous composition preferably contains water at 50 w / v% or more, more preferably 70 w / v% or more, still more preferably 80 w / v% or more, still more preferably 85 w / v% or more, and particularly preferably 90 w / v% or more, based on the total amount of the aqueous composition. In the present invention, the ophthalmic aqueous composition is any ophthalmic-related aqueous composition such as eye drops (synonymous with eye drops or eye medicine), eye washes (synonymous with eye wash solutions or eye wash medicine), contact lens wearing solutions, contact lens cleaning solutions, contact lens storage solutions, or contact lens disinfectant solutions.

[0017] The ophthalmic aqueous composition of the present invention contains, as component (A), polysaccharides; monosaccharides; vitamin B 12One or more vitamins selected from the group consisting of vitamin B2, vitamin A, and panthenol; one or more oils selected from the group consisting of vegetable oils, animal oils, and mineral oils; one or more surfactants selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate; one or more anti-allergic ingredients selected from the group consisting of tranilast, ketotifen, diphenhydramine, and their salts; chlorhexidine, sorbic acid, and their One or more preservatives selected from the group consisting of salts of; one or more thickening agents selected from the group consisting of carboxymethylcellulose, methylcellulose, vinyl polymer compounds, and salts thereof; polyhydric alcohols; one or more anti-inflammatory agents selected from the group consisting of berberine, azulene sulfonic acid, allantoin, zinc sulfate, and salts thereof; one or more antibacterial agents selected from the group consisting of sulfamethoxazole and salts thereof; one or more cooling agents selected from the group consisting of eucalyptus oil and bergamot oil; one or more selected from the group consisting of

[0018] In the present invention, these components (A) can be used individually or in combination of two or more. Components (A) can be obtained from nature or chemically synthesized. All of the components (A) can also be commercially available.

[0019] In the present invention, the polysaccharide of component (A) is preferably an acidic polysaccharide. An acidic polysaccharide refers to one that contains a repeating structure of two or more monosaccharides and includes an acidic group. Here, the acidic group is not limited, but particularly refers to a carboxyl group or a sulfate group. The components of the repeating structure are not limited, but examples include uronic acids such as glucuronic acid, iduronic acid, mannuronic acid, and guluronic acid, amino sugars such as galactosamine and glucosamine, galactose, mannose, glucose, and rhamnose.

[0020] Examples of such acidic polysaccharides, though not limited to them, include hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, keratan sulfate, xanthan gum, gellan gum, alginic acid, and their salts.

[0021] The acidic polysaccharide of component (A) can be obtained from nature or chemically synthesized, and its origin is not particularly limited. Commercially available acidic polysaccharides can also be used. The acidic polysaccharide can also be used in the form of alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, metal salts such as iron and manganese, or other physiologically or pharmaceutically acceptable salts. Acetylated reaction products can also be used. These acidic polysaccharides can be used alone or in combination of two or more. Chondroitin sulfate, hyaluronic acid, xanthan gum, gellan gum, alginic acid, and their salts are preferred as the acidic polysaccharide of component (A), with sodium chondroitin sulfate, sodium hyaluronate, alginic acid, and gellan gum being particularly preferred.

[0022] The molecular weight of the acidic polysaccharide of component (A) varies depending on the number and type of repeating units and is not limited, but can range from several hundred to several million in weight-average molecular weight. From the viewpoint of more significantly demonstrating the effects of the present invention, such as suppressing the deterioration of PBT-containing resin containers, the molecular weight of the acidic polysaccharide of component (A) is preferably 0.01 to 5 million, and more preferably 0.05 to 3 million in weight-average molecular weight. More specifically, for example, the weight-average molecular weight of chondroitin sulfate or its salt is preferably 0.1 to 3 million, more preferably 0.5 to 1.5 million, and more preferably 10,000 to 500,000. More specifically, for example, the weight-average molecular weight of hyaluronic acid or its salt is preferably 100,000 to 5 million, more preferably 500,000 to 4 million, and more preferably 600,000 to 2.5 million.

[0023] In the present invention, the monosaccharides of component (A) include aldoses such as glucose, ribose, glyceraldehyde, erythrose, threose, lyxose, xylose, arabinose, allose, talose, growth, altrose, mannose, galactose, and idose, as well as ketoses such as dihydroxyacetone, erythrolose, xylulose, ribulose, psicose, fructose, sorbose, and tagatose. Of these, glucose, galactose, mannose, fructose, and sorbose are preferred, and glucose is particularly preferred. These can be used individually or in combination of two or more. Commercially available monosaccharides can also be used.

[0024] In the present invention, the vitamins of component (A) may be fat-soluble or water-soluble vitamins. Examples of fat-soluble vitamins include one or more selected from the group consisting of vitamin A compounds such as retinol, retinyl acetate, retinyl palmitate, retinal, retinoic acid, methyl retinoate, ethyl retinoate, retinyl retinoate, vitamin A fatty acid esters, d-δ-tocopheryl retinoate, α-tocopheryl retinoate, β-tocopheryl retinoate, carotene, dehydroretinal, lycopene, and salts thereof. Examples of water-soluble vitamins include vitamin B2 compounds such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, and their salts; and vitamin B compounds such as cyanocobalamin, hydroxocobalamin, methylcobalamin, deoxyadenosylcobalamin, and their salts. 12 It may be one or more selected from the group consisting of the following: and pantothenyl alcohol (panthenol).

[0025] The vitamins in component (A) are preferably one or more selected from the group consisting of cyanocobalamin, retinol, panthenol, flavin adenine dinucleotide, and salts thereof, and are particularly preferably one or more selected from the group consisting of cyanocobalamin, retinyl palmitate, retinyl acetate, panthenol, and flavin adenine dinucleotide sodium. Examples of vitamin A include retinol palmitate ester manufactured by DSM, where 0.550 μg is 1 IU of vitamin A. IU refers to the international unit determined by the method described in the 16th edition of the Japanese Pharmacopoeia, Vitamin A Quantitative Method, etc.

[0026] These vitamins can be used individually or in combination of two or more. Commercially available vitamins can also be used.

[0027] In the present invention, the oil component (A) may be one or more oils selected from the group consisting of vegetable oils, animal oils, and mineral oils. When using an oil component (A), vegetable oils and / or mineral oils are more preferred from the viewpoint of more significantly exhibiting the effects of the present invention.

[0028] Here, vegetable oil is not particularly limited as long as it is an oil derived from plants. Vegetable oil containing triglycerides is preferred. Specific examples of vegetable oils of component (A) are not limited to sesame oil, castor oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, olive oil, or derivatives thereof. As for the vegetable oil of component (A), sesame oil, castor oil, soybean oil, or derivatives thereof are preferred, with sesame oil and castor oil being particularly preferred. These vegetable oils can be used individually or in combination of two or more. Commercially available vegetable oils can also be used.

[0029] The animal oils in component (A) are not limited to but include squalane, lanolin, orange roughy oil, horse oil, whale oil, liver oil, mink oil, egg yolk oil, beef tallow, milk fat, and lard. Squalane, lanolin, egg yolk oil, or derivatives thereof are preferred for component (A), with squalane and refined lanolin being particularly preferred. Here, "animal oil" is not particularly limited as long as it is an oil derived from animals. These animal oils can be used individually or in combination of two or more. Commercially available animal oils can also be used.

[0030] (A) The mineral oil in component (A) is a natural petroleum-derived hydrocarbon oil, and refers to a liquid and grease-like chemical substance obtained by refining. Specifically, the mineral oil in component (A) is not limited to paraffin oil, liquid paraffin, petrolatum, etc., with liquid paraffin, light liquid paraffin, and white petrolatum being particularly preferred. These mineral oils can be used individually or in combination of two or more. Commercially available mineral oils can also be used. For example, as a liquid paraffin, Kaneda Corporation's Hycol M-202 can be cited.

[0031] In the present invention, the surfactant of component (A) may be one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate.

[0032] Examples of such surfactants include, specifically, poloxamer 407, polyoxyethylene (200) polyoxypropylene (70) glycol, poloxamer 188, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, tetronic, and other polyoxyethylene polyoxypropylene glycols; polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 6. Examples include polyoxyethylene hydrogenated castor oil such as 0, polyoxyethylene hydrogenated castor oil 100; polyoxyethylene castor oil 3, polyoxyethylene castor oil 4, polyoxyethylene castor oil 6, polyoxyethylene castor oil 7, polyoxyethylene castor oil 10, polyoxyethylene castor oil 13.5, polyoxyethylene castor oil 17, polyoxyethylene castor oil 20, polyoxyethylene castor oil 25, polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60; and polyoxyl stearate such as polyoxyl stearate 40, polyoxyl stearate 140.

[0033] Among the surfactants of component (A), poloxamer 407, polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 3, polyoxyethylene castor oil 10, polyoxyethylene castor oil 35, polyoxyl stearate 40, and polyoxyl stearate 140 are preferred, with poloxamer 407, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 10, polyoxyethylene castor oil 35, and polyoxyl stearate 40 being more preferred.

[0034] (A) The average number of moles of ethylene oxide added to polyoxyethylene castor oil used as component is not particularly limited, but can be, for example, 2 to 70 moles, preferably 2 to 60, more preferably 3 to 50, and most preferably 3 to 40. (A) The average number of moles of ethylene oxide added to polyoxyethylene polyoxypropylene glycol used as component is not particularly limited, but can be, for example, 10 to 350 moles, preferably 30 to 300, more preferably 50 to 300, and most preferably 100 to 250. (A) The average number of moles of ethylene oxide added to polyoxyethylene hydrogenated castor oil used as component is not particularly limited, but can be, preferably 3 to 120 moles, preferably 20 to 100, and more preferably 30 to 80. (A) The average number of moles of ethylene oxide added to polyoxyl stearate used as component is not particularly limited, but can be, preferably 3 to 200 moles, preferably 20 to 180, and more preferably 30 to 160.

[0035] In the present invention, component (A) may be one or more anti-allergic components selected from the group consisting of tranilast, ketotifen, diphenhydramine, and salts thereof. Among the anti-allergic components, tranilast, ketotifen fumarate, and diphenhydramine hydrochloride are preferred.

[0036] In the present invention, component (A) may be one or more preservatives selected from the group consisting of chlorhexidine, sorbic acid, and salts thereof. Among the preservatives, chlorhexidine gluconate, sorbic acid, and potassium sorbate are preferred.

[0037] In the present invention, the thickening component of component (A) may be a cellulosic polymer compound or a vinyl polymer compound. Cellulosic polymer compounds are not particularly limited, but may include, for example, carboxymethylcellulose, methylcellulose, and salts thereof. Vinyl polymer compounds are not particularly limited, but may include, for example, polyvinylpyrrolidone, polyvinyl alcohol (complete or partially saponified), carboxyvinyl polymer, and salts thereof. The thickening component of component (A) is preferably carboxymethylcellulose, methylcellulose, vinyl polymer compounds, and salts thereof, more preferably carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, and carboxyvinyl polymer, even more preferably carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, and carboxyvinyl polymer, and particularly preferably carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, and carboxyvinyl polymer.

[0038] In the present invention, component (A) may be a polyhydric alcohol. The polyhydric alcohol is not limited, but is preferably one or more polyhydric alcohols selected from the group consisting of propylene glycol, glycerin, and mannitol.

[0039] In the present invention, component (A) may be one or more anti-inflammatory components selected from the group consisting of berberine, azulene sulfonic acid, allantoin, zinc sulfate, or salts thereof. Among the anti-inflammatory components, berberine sulfate, berberine chloride, sodium azulene sulfonate, allantoin, and zinc sulfate are preferred.

[0040] In the present invention, component (A) may be one or more antimicrobial agents selected from the group consisting of sulfamethoxazole or a salt thereof. Here, the salt of sulfamethoxazole is preferably sulfamethoxazole sodium.

[0041] In the present invention, component (A) may be one or more cooling agents selected from the group consisting of eucalyptus oil and bergamot oil.

[0042] All of these (A) components may be used individually or in any combination of two or more. In particular, it is preferable to combine two or more. When there are two or more, for example, two or more different substances of the same classification may be used, or two or more different substances of different classifications may be used. For example, it is possible to include two or more types of polysaccharides, or to select and combine one or more polysaccharides and one or more vitamins. The same applies to (A) components such as monosaccharides, oils, surfactants, anti-allergic components, preservatives, thickeners, polyhydric alcohols, anti-inflammatory components, antibacterial agents, and cooling agents.

[0043] In the ophthalmic aqueous composition of the present invention, from the viewpoint of more significantly exhibiting the effects of the present invention, the total content of component (A) relative to the total amount of the ophthalmic aqueous composition is appropriately set according to the type of component (A), the types and content of other components. The total content of component (A) relative to the total amount of the ophthalmic aqueous composition is preferably 0.0001 w / v% or more, more preferably 0.001 w / v% or more, more preferably 0.005 w / v% or more, and even more preferably 0.01 w / v% or more. The total content of component (A) relative to the total amount of the ophthalmic aqueous composition is preferably 20 w / v% or less, more preferably 10 w / v% or less, even more preferably 5 w / v% or less, more preferably 3 w / v% or less, and most preferably 1 w / v% or less.

[0044] The total amount of polysaccharides relative to the total amount of the ophthalmic aqueous composition of the present invention is appropriately set according to the type of component (A), the types and amounts of other components. From the viewpoint of more significantly exhibiting the effects of the present invention, the total amount of polysaccharides relative to the total amount of the ophthalmic aqueous composition is preferably 0.0001 w / v% to 6 w / v%, more preferably 0.0005 w / v% to 4 w / v%, and particularly preferably 0.001 w / v% to 2 w / v%.

[0045] In a preferred embodiment, for example, when chondroitin sulfate or a salt thereof is included as component (A), it is preferable that the content of chondroitin sulfate or a salt thereof alone be 0.0001 w / v% to 5 w / v% of the total amount of the ophthalmic aqueous composition, and more preferably 0.005 w / v% to 3 w / v%. Similarly, in another preferred embodiment, for example, when hyaluronic acid or a salt thereof is included as component (A), it is preferable that the content of hyaluronic acid or a salt thereof alone be 0.0001 w / v% to 1 w / v% of the total amount of the ophthalmic aqueous composition, and more preferably 0.0005 w / v% to 0.5 w / v%.

[0046] The total amount of monosaccharides relative to the total amount of the ophthalmic aqueous composition of the present invention is appropriately set according to the type of component (A), the types and amounts of other components. From the viewpoint of more significantly exhibiting the effects of the present invention, the total amount of monosaccharides relative to the total amount of the ophthalmic aqueous composition is preferably 0.0001 w / v% to 3 w / v%, more preferably 0.005 w / v% to 1.5 w / v%, and particularly preferably 0.001 w / v% to 0.5 w / v%.

[0047] In another preferred embodiment, when glucose is included as component (A), it is preferable that the glucose content alone be 0.0001 w / v% to 3 w / v% of the total amount of the ophthalmic aqueous composition, more preferably 0.005 w / v% to 1.5 w / v%, and particularly preferably 0.001 w / v% to 0.5 w / v%.

[0048] The total amount of vitamins relative to the total amount of the ophthalmic aqueous composition of the present invention is appropriately set according to the type of component (A), the types and amounts of other components. From the viewpoint of more significantly exhibiting the effects of the present invention, the total amount of vitamins relative to the total amount of the ophthalmic aqueous composition is preferably 0.00001 w / v% to 1.6 w / v%, more preferably 0.0005 w / v% to 0.8 w / v%, and particularly preferably 0.0005 w / v% to 0.4 w / v%.

[0049] In a preferred embodiment, for example, when retinyl palmitate is included as component (A), the content of retinyl palmitate alone is preferably 10 to 500,000 units / 100mL of the total amount of the ophthalmic aqueous composition, more preferably 100 to 300,000 units / 100mL, and even more preferably 500 to 200,000 units / 100mL. Depending on the units of retinyl palmitate included, a content of 0.005 to 0.5 W / V% is preferred, a content of 0.001 to 0.4 W / V% is more preferred, and a content of 0.01 to 0.3 W / V% is even more preferred. Similarly, in another preferred embodiment, for example, cyanocobalamin is preferably included as a single component (A) in an amount of 0.00001 w / v% to 1 w / v%, more preferably 0.00005 w / v% to 0.5 w / v%, and particularly preferably 0.0001 w / v% to 0.02 w / v% of the total amount of the ophthalmic aqueous composition.

[0050] The total oil content relative to the total amount of the ophthalmic aqueous composition of the present invention is appropriately set according to the type of component (A), the types and amounts of other components. From the viewpoint of more significantly exhibiting the effects of the present invention, the total oil content relative to the total amount of the ophthalmic aqueous composition is preferably 0.00001 w / v% to 6 w / v%, more preferably 0.0005 w / v% to 3 w / v%, and particularly preferably 0.0001 w / v% to 1 w / v%.

[0051] In a preferred embodiment, for example, when sesame oil is included as component (A), it is preferable that the amount of sesame oil alone be 0.00001 w / v% to 5 w / v% of the total amount of the ophthalmic aqueous composition, and more preferably 0.0001 w / v% to 1 w / v%. Similarly, in another preferred embodiment, for example, when castor oil is included as component (A), it is preferable that the amount of castor oil alone be 0.00001 w / v% to 5 w / v% of the total amount of the ophthalmic aqueous composition, and more preferably 0.0001 w / v% to 1 w / v%. Similarly, in another preferred embodiment, for example, when liquid paraffin is included as component (A), it is preferable that the amount of liquid paraffin alone be 0.00001 w / v% to 2 w / v% of the total amount of the ophthalmic aqueous composition, and more preferably 0.0001 w / v% to 1 w / v%. Similarly, in another preferred embodiment, for example, when petrolatum is included as component (A), it is preferable that the petrolatum alone be present in an amount of 0.00001 w / v% to 5 w / v% of the total amount of the ophthalmic aqueous composition, and more preferably 0.00005 w / v% to 1 w / v%.

[0052] The total amount of surfactant relative to the total amount of the ophthalmic aqueous composition of the present invention is appropriately set according to the type of component (A), the type and amount of other components. From the viewpoint of more significantly exhibiting the effects of the present invention, the total amount of surfactant relative to the total amount of the ophthalmic aqueous composition is preferably 0.00001 w / v% to 10 w / v%, more preferably 0.0001 w / v% to 8 w / v%, and particularly preferably 0.001 w / v% to 5 w / v%.

[0053] In a preferred embodiment, for example, when polyoxyethylene polyoxypropylene glycol is included as component (A), it is preferable that the content of polyoxyethylene polyoxypropylene glycol alone be 0.00001 w / v% to 10 w / v%, more preferably 0.0001 w / v% to 8 w / v%, and particularly preferably 0.001 w / v% to 5 w / v% of the total amount of the ophthalmic aqueous composition. Similarly, in another preferred embodiment, for example, when polyoxyethylene castor oil is included as component (A), it is preferable that the content of polyoxyethylene castor oil alone be 0.00001 w / v% to 10 w / v%, more preferably 0.0001 w / v% to 5 w / v%, and particularly preferably 0.001 w / v% to 3 w / v% of the total amount of the ophthalmic aqueous composition.

[0054] From the viewpoint of more significantly exhibiting the effects of the present invention, the total content of the anti-allergic component relative to the total amount of the ophthalmic aqueous composition of the present invention is preferably 0.00001 w / v% to 5 w / v%, more preferably 0.0005 w / v% to 1 w / v%, and particularly preferably 0.0005 w / v% to 0.5 w / v% relative to the total amount of the ophthalmic aqueous composition.

[0055] From the viewpoint of more significantly exhibiting the effects of the present invention, the total amount of preservatives relative to the total amount of the ophthalmic aqueous composition of the present invention is preferably 0.00001 w / v% to 2 w / v%, more preferably 0.00005 w / v% to 1 w / v%, and particularly preferably 0.0001 w / v% to 0.5 w / v% relative to the total amount of the ophthalmic aqueous composition.

[0056] From the viewpoint of more significantly exhibiting the effects of the present invention, the total content of the thickening component relative to the total amount of the ophthalmic aqueous composition is preferably 0.0001 w / v% to 10 w / v%, more preferably 0.0005 w / v% to 8 w / v%, and particularly preferably 0.001 w / v% to 5 w / v% relative to the total amount of the ophthalmic aqueous composition.

[0057] From the viewpoint of more significantly exhibiting the effects of the present invention, the total content of polyhydric alcohols relative to the total amount of the ophthalmic aqueous composition of the present invention is preferably 0.00005 w / v% to 10 w / v%, more preferably 0.0001 w / v% to 8 w / v%, and particularly preferably 0.005 w / v% to 5 w / v% relative to the total amount of the ophthalmic aqueous composition.

[0058] From the viewpoint of more significantly exhibiting the effects of the present invention, the total content of the anti-inflammatory component relative to the total amount of the ophthalmic aqueous composition of the present invention is preferably 0.00001 w / v% to 3 w / v%, more preferably 0.00005 w / v% to 1.5 w / v%, and particularly preferably 0.0001 w / v% to 0.6 w / v% relative to the total amount of the ophthalmic aqueous composition.

[0059] From the viewpoint of achieving a more pronounced effect according to the present invention, the total content of the antibacterial component relative to the total amount of the ophthalmic aqueous composition of the present invention is preferably 0.01 w / v% to 6 w / v%, more preferably 0.05 w / v% to 5 w / v%, and particularly preferably 0.4 w / v% to 4 w / v% relative to the total amount of the ophthalmic aqueous composition.

[0060] From the viewpoint of more significantly exhibiting the effects of the present invention, the total content of the cooling agent relative to the total amount of the ophthalmic aqueous composition of the present invention is preferably 0.0001 w / v% to 1 w / v%, more preferably 0.0005 w / v% to 0.5 w / v%, and particularly preferably 0.001 w / v% to 0.1 w / v% relative to the total amount of the ophthalmic aqueous composition.

[0061] In the present invention, the buffering agent of component (B) may be an inorganic buffering agent or an organic buffering agent.

[0062] The inorganic buffering agent of component (B) of the present invention is preferably boric acid or a salt of boric acid. The salt of boric acid is not particularly limited as long as it is physiologically or pharmaceutically acceptable. Examples include salts of boric acid with alkali metal salts, alkaline earth metal salts, organic bases, etc. More specifically, salts of boric acid with sodium, potassium, calcium, magnesium, ammonium, or diethanolamine, ethylenediamine, etc. Preferred examples of borates are not limited to borax, but specifically include borax, sodium borate, ammonium borate, potassium tetraborate, etc. Of these, borax is particularly preferred.

[0063] The organic buffering agent of component (B) of the present invention is preferably epsilon-aminocaproic acid, phosphoric acid, citric acid, carbonic acid, or 2-amino-2-hydroxymethyl-1,3-propanediol (tris, trometamol, trishydroxymethylaminomethane), or a salt thereof. These salts are not particularly limited, as long as they are physiologically or pharmaceutically acceptable. Examples include salts of epsilon-aminocaproic acid, phosphoric acid, citric acid, carbonic acid, or 2-amino-2-hydroxymethyl-1,3-propanediol with alkali metal salts, alkaline earth metal salts, organic bases, etc. Preferably, salts with sodium, potassium, calcium, magnesium, ammonium, or diethanolamine, ethylenediamine, etc.

[0064] In the present invention, these (B) components can be used individually or in combination of two or more. Component (B) can be obtained from nature or chemically synthesized. All of the (B) components can also be commercially available.

[0065] In the ophthalmic aqueous composition of the present invention, from the viewpoint of more significantly exhibiting the effects of the present invention, the total content of component (B) relative to the total amount of the ophthalmic aqueous composition is preferably 0.001 w / v% or more, more preferably 0.01 w / v% or more, and even more preferably 0.1 w / v% or more. Furthermore, the total content of component (B) relative to the total amount of the ophthalmic aqueous composition is preferably 20 w / v% or less, more preferably 15 w / v% or less, even more preferably 10 w / v% or less, even more preferably 5 w / v% or less, and most preferably 3 w / v% or less.

[0066] In a preferred embodiment, for example, when epsilon-aminocaproic acid or 2-amino-2-hydroxymethyl-1,3-propanediol is included as component (B), it is preferable that the content of epsilon-aminocaproic acid or 2-amino-2-hydroxymethyl-1,3-propanediol alone be 0.001 w / v% to 6 w / v%, more preferably 0.01 w / v% to 8 w / v%, and particularly preferably 0.05 w / v% to 5 w / v% of the total amount of the ophthalmic aqueous composition. Similarly, in another preferred embodiment, for example, when boric acid, phosphoric acid, citric acid, carbonate, and salts thereof are included as component (B), it is preferable that the individual content of boric acid, phosphoric acid, citric acid, carbonate, and salts thereof be 0.001 w / v% to 5 w / v%, more preferably 0.005 w / v% to 4 w / v%, and particularly preferably 0.01 w / v% to 3 w / v% of the total amount of the ophthalmic aqueous composition.

[0067] In the ophthalmic aqueous composition of the present invention, from the viewpoint of more significantly exhibiting the effects of the present invention, the ratio of the content of component (B) to component (A) is preferably 0.00001 to 10000 parts by weight, more preferably 0.0001 to 5000 parts by weight, even more preferably 0.0005 to 3000 parts by weight, particularly preferably 0.001 to 2000 parts by weight, and most preferably 0.01 to 1000 parts by weight, per 1 part by weight of the total content of component (A).

[0068] In the ophthalmic aqueous composition of the present invention, the combination of component (A) and component (B) is not particularly limited and is appropriately set depending on the types of component (A) and component (B). Examples of combinations are shown in Table 1, which spans two pages below.

[0069] [Table 1] JPEG2026086873000003.jpg187170

[0070] In this invention, a PBT-containing resin container refers to an ophthalmic container in which part or all of the container is molded from a resin containing polybutylene terephthalate. Here, "part of the container" refers to at least a part of the portion that comes into contact with the ophthalmic aqueous composition contained inside. The portion that comes into contact with the ophthalmic aqueous composition may be a stopper, a perforated stopper, or the innermost layer of a structure consisting of multiple layers formed on the inner surface of the container. For example, in a container with a perforated stopper (nozzle), only the stopper portion may be made of PBT-containing resin. Alternatively, the container portion other than the stopper may be made of PBT-containing resin. Alternatively, the entire container may be molded from PBT-containing resin. It is sufficient that at least a portion of the surface that comes into contact with the ophthalmic aqueous composition is made of PBT-containing resin, but it is most preferable that the entire contact surface is made of PBT-containing resin. If a portion of the container is formed from a PBT-containing resin, there are no particular restrictions on the type of resin forming the other portions, but at least one polymer selected from the group consisting of polyethylene terephthalate (PET), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polycarbonate, polyethylene (PE), polypropylene (PP), polymethyl methacrylate, ethylene vinyl acetate copolymer, and ethylene vinyl alcohol copolymer may be included as a component.

[0071] In the present invention, the shape of the PBT-containing resin container and the capacity it can hold are not particularly limited. For example, if it is a container for ordinary eye drops or contact lens insertion solution, it may be a container that can hold a volume of 0.1 ml to 50 ml, preferably 2 ml to 40 ml, and more preferably 4 ml to 25 ml. If the PBT-containing resin container is a container for eye wash or contact lens care solution, the capacity it can hold may be 40 ml to 600 ml.

[0072] In addition, the PBT-containing resin container of the present invention may be a container capable of containing an ophthalmic aqueous composition for use with contact lenses.

[0073] The ophthalmic aqueous composition used in the present invention may be a multi-dose type containing amounts for multiple uses, or a unit-dose type containing amounts for a single use.

[0074] In the present invention, the PBT-containing resin container is preferably an eye drop container, an eye wash container, a contact lens insertion solution container, a contact lens care solution container (including a contact lens cleaning solution container, a contact lens storage solution container, a contact lens disinfectant solution container, a contact lens multi-purpose solution container, etc.), or a contact lens packaging solution container. Particularly preferred are eye drop containers, contact lens insertion solution containers, and contact lens care solution containers. The term "contact lens" as used herein refers to any type of contact lens, and may be either a soft contact lens or a hard contact lens.

[0075] The present invention also provides a product in which an ophthalmic aqueous composition is contained in a PBT-containing resin container. The present invention also provides eye drops, eye washes, and contact lens application products in containers containing an ophthalmic aqueous composition.

[0076] The PBT-containing resin in the PBT-containing resin container of the present invention includes polymers obtained by known polymerization methods, such as polycondensation of terephthalic acid or its ester-forming derivative with 1,4-butanediol. Additives such as stabilizers can also be added to such polymers to produce a PBT-containing resin. Commercially available PBT-containing resins can be used without particular limitation. Examples include "Novaduran® 5010R5," manufactured by Mitsubishi Engineering Plastics Corporation. The polymer synthesized by polycondensation of terephthalic acid or its ester-forming derivative with 1,4-butanediol may optionally contain other monomers as constituent components, and may also contain other polymers. Other polymers include, but are not limited to, polycarbonate, (meth)acrylic acid polymers, polystyrene (PS), polyethylene naphthalate (PEN), polyethylene terephthalate (PET), polyethylene (PE), polyarylate, and polypropylene (PP). While not limited, examples of ester-forming derivatives of terephthalic acid include dimethyl terephthalate. Preferably, the PBT-containing resin of the present invention contains a polymer synthesized by polycondensation of terephthalic acid or its ester-forming derivative with 1,4-butanediol, which accounts for 50% by weight or more, more preferably 60% by weight or more, and even more preferably 70% by weight or more of the polymer components constituting the resin. Commercially available polymers can also be used.

[0077] The PBT-containing resin of the present invention further includes resins reinforced with reinforcing agents such as glass fibers.

[0078] In the ophthalmic aqueous composition of the present invention, it is preferable to include other components that can be commonly used in ophthalmic aqueous compositions, in addition to components (A) and (B). Such components are not particularly limited, but from the viewpoint of more significantly exhibiting the effects of the present invention, sodium edetate is particularly preferred. In the present invention, commercially available sodium edetate can also be used.

[0079] In the ophthalmic aqueous composition of the present invention, from the viewpoint of more significantly exhibiting the effects of the present invention, the total content of sodium edetate relative to the total amount of the ophthalmic aqueous composition is preferably 0.0001 w / v% or more, more preferably 0.0005 w / v% or more, and even more preferably 0.001 w / v% or more. The total content of sodium edetate relative to the total amount of the ophthalmic aqueous composition is preferably 1 w / v% or less, more preferably 0.5 w / v% or less, and even more preferably 0.2 w / v% or less. The ratio of the content of sodium edetate to component (A) is preferably 0.0001 to 1000 parts by weight, more preferably 0.0005 to 500 parts by weight, and even more preferably 0.001 to 200 parts by weight, per 1 part by weight of the total content of component (A).

[0080] Other examples include the active ingredients in ophthalmic drugs listed in the 2012 edition of the General-Use Drug Manufacturing (Import) Approval Standards (supervised by the Japan Regulatory Science Society). Specifically, the following ingredients can be cited.

[0081] Antihistamine: Chlorpheniramine maleate Antiallergic agents: Acitazanol, Anlexanox, Ibudilast, Levocabastine hydrochloride, Sodium cromoglycate, Pemirolast potassium, Olopatadine hydrochloride, etc. Decongestants: Tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methyl ephedrine hydrochloride, etc. Amino acids: potassium aspartate, magnesium aspartate, aminoethylsulfonic acid, etc. Anti-inflammatory agents: Dipotassium glycyrrhizinate, lysozyme chloride, pranoprofen, bromfenac, ketrolactromethamine, nepafenac, etc. Astringent agents: Zinc oxide, zinc lactate, etc. Others: Sulfisoxazole, Sulfisomidine sodium, Neostigmine methylsulfate, Dibucaine, etc.

[0082] Furthermore, in the ophthalmic aqueous composition of the present invention, additives such as carriers, thickeners, pH adjusters, general sugars, general isotonic agents, fragrances, cooling agents, and chelating agents may be selected and at least one of them may be included in appropriate amounts. Examples of such additives include the various additives listed in the 2007 Dictionary of Pharmaceutical Additives (edited by the Japan Pharmaceutical Additives Association). The following are some typical additives.

[0083] Carrier: Aqueous carriers such as water or aqueous ethanol. Thickening agents: Hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, etc. Sugar alcohols: xylitol, sorbitol, etc. These may be in d-isomer, l-isomer, or dl-isomer. Isotonic agents: aminoethylsulfonic acid, polyethylene glycol, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, etc. pH adjusters: hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, etc. Stabilizers: dibutylhydroxytoluene, sodium formaldehyde sulfoxylate (Longalit), sodium bisulfite, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, cyclodextrin, dextran, etc. Chelating agents: succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane 1-,1-diphosphonic acid, polyphosphate, metaphosphate, hexametaphosphate, etc. Fragrances or cooling agents: Menthol, camphor, borneol, geraniol, cineole, citronellol, carvone, anethole, eugenol, cineole, limonene, linalyl acetate, bonito flakes, menthone, etc. These may be in d-, l-, or dl-forms, and may also be incorporated as essential oils (peppermint oil, cool mint oil, spearmint oil, fennel oil, cinnamon oil, rose oil, etc.). Preservatives other than chlorhexidine, sorbic acid, and their salts: dibutylhydroxytoluene, butylhydroxyanisole, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, tyroxapol, benzalkonium chloride, benzethonium chloride, zinc chloride, chlorobutanol, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), etc.), polydronium chloride, chlorcresol, parachlormetaxylenol, Glokill (Rhodia brand name), etc.

[0084] The water used in the ophthalmic aqueous composition of the present invention may be any water that is physiologically or pharmaceutically acceptable. Examples of such water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection. These definitions are based on the 16th edition of the Japanese Pharmacopoeia.

[0085] In the present invention, "salt" refers to basic salts such as alkali metal salts, alkaline earth metal salts, and other inorganic bases, or salts with organic bases, and includes salts with sodium, potassium, calcium, magnesium, ammonium, or diethanolamine, ethylenediamine, etc. These salts can be obtained, for example, by converting sulfate groups or carboxyl groups present in liranaftate, etc., into salts by known methods. Furthermore, examples include salts of amines such as ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, and L-glucamine; or salts with basic amino acids such as lysine, δ-hydroxylysine, and arginine. Furthermore, in the present invention, "salt" refers to acidic salts, such as salts with inorganic acids like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid, gluconic acid, palmitic acid, etc.; or salts with acidic amino acids such as aspartic acid and glutamic acid.

[0086] In this invention, "physiologically or pharmaceutically acceptable salts" may include solvates or hydrates of salts.

[0087] The ophthalmic aqueous composition of the present invention may take any form that contains water, such as an aqueous solution, a gel, a suspension, or an emulsion, and is preferably an aqueous solution.

[0088] The ophthalmic aqueous compositions of the present invention may preferably have the following compositions, but are not limited to them: an ophthalmic aqueous composition comprising sodium hyaluronate, boric acid, and water; an ophthalmic aqueous composition comprising sodium hyaluronate, epsilon-aminocaproic acid, and water; an ophthalmic aqueous composition comprising sodium hyaluronate, sodium hydrogen phosphate, and water; an ophthalmic aqueous composition comprising sodium hyaluronate, sodium citrate, and water; an ophthalmic aqueous composition comprising sodium hyaluronate, sodium bicarbonate, and water; an ophthalmic aqueous composition comprising sodium hyaluronate, 2-amino-2-hydroxymethyl-1,3-propanediol, and water; an ophthalmic aqueous composition comprising sodium chondroitin sulfate, boric acid, and water; an ophthalmic aqueous composition comprising sodium chondroitin sulfate, epsilon-aminocaproic acid, and water; an ophthalmic aqueous composition comprising sodium chondroitin sulfate, sodium hydrogen phosphate, and water Ophthalmic aqueous compositions; ophthalmic aqueous compositions containing chondroitin sulfate sodium, sodium citrate, and water; ophthalmic aqueous compositions containing chondroitin sulfate sodium, sodium bicarbonate, and water; ophthalmic aqueous compositions containing chondroitin sulfate sodium, 2-amino-2-hydroxymethyl-1,3-propanediol, and water; ophthalmic aqueous compositions containing glucose, boric acid, and water; ophthalmic aqueous compositions containing glucose, epsilon-aminocaproic acid, and water; ophthalmic aqueous compositions containing glucose, sodium hydrogen phosphate, and water; ophthalmic aqueous compositions containing glucose, sodium citrate, and water; ophthalmic aqueous compositions containing glucose, sodium bicarbonate, and water; ophthalmic aqueous compositions containing glucose, 2-amino-2-hydroxymethyl-1,3-propanediol, and water.

[0089] The pH of the ophthalmic aqueous composition of the present invention is not limited as long as it is within a physiologically or pharmaceutically acceptable range, but for example, the pH is 3 or higher, preferably 4 or higher, more preferably 5 or higher, even more preferably 5.5 or higher, and even more preferably 6 or higher. The pH is 9 or lower, preferably 8.5 or lower, more preferably 8 or lower, even more preferably 7.5 or lower, and even more preferably 7 or lower.

[0090] The osmotic pressure ratio of the ophthalmic aqueous composition of the present invention is set appropriately according to the type and content of the constituent ingredients, the use of the ophthalmic aqueous composition, the formulation form, the method of use, etc., as long as it is within a physiologically or pharmaceutically acceptable range. For example, it can be 0.4 to 5, preferably 0.5 to 4, more preferably 0.6 to 3, and even more preferably 0.7 to 2. In the ophthalmic aqueous composition of the present invention, the osmotic pressure ratio is determined as the osmotic pressure ratio to physiological saline based on the osmotic pressure measurement method (osmolarity measurement method) of the 16th edition of the Japanese Pharmacopoeia.

[0091] The viscosity of the ophthalmic aqueous composition of the present invention is set appropriately according to the type and content of the constituent components, the use of the ophthalmic aqueous composition, the formulation form, the method of use, etc., as long as it is within a physiologically or pharmaceutically acceptable range. Preferably, the viscosity at 20°C measured with a rotational viscometer (RE550 type viscometer, manufactured by Higashi Sangyo Co., Ltd., rotor: 1°34' × R24) is 0.01 to 10000 mPa·s, and more preferably 0.05 to 8000 mPa·s.

[0092] The method of using the ophthalmic aqueous composition of the present invention is appropriately determined according to the type and content of the constituent components, the intended use of the ophthalmic aqueous composition, and the formulation form.

[0093] The ophthalmic aqueous composition of the present invention can also suppress the deterioration of PBT-containing resin containers, and therefore can be used as a deterioration inhibitor for PBT-containing resin containers.

[0094] Here, suppressing the deterioration of PBT-containing resin containers means, without limitation, that the container's properties change little even after a certain period of use or storage after containing an ophthalmic aqueous composition. For example, it means that the weight change is small. From the viewpoint of suppressing deterioration, the more the weight change is suppressed, the better. When ophthalmic aqueous compositions are contained in PBT-containing resin containers, weight changes occur in the PBT-containing resin, leading to problems such as a decrease in the strength of the container, cracking, deformation, and a decrease in airtightness. In other words, when using containers made of PBT-containing resin in a manner in which drugs such as ophthalmic aqueous compositions are stored and used for a certain period of time, the problem of changes in the properties of the PBT-containing resin container becomes serious.

[0095] The ophthalmic aqueous composition of the present invention can also be used as a liquid drainage enhancer for PBT-containing resin containers because it improves liquid drainage in PBT-containing resin containers and suppresses liquid residue in the containers.

[0096] Here, the term "liquid drainage enhancer for PBT-containing resin containers" is not limited to, but includes cases where the ophthalmic aqueous composition is difficult to wet with the container. An indicator of how difficult the ophthalmic aqueous composition is to wet with the container can be expressed, for example, by the magnitude of the dynamic contact angle, or advance contact angle. A larger advance contact angle indicates poor wetting and good liquid drainage, while a smaller advance contact angle, or a larger absolute value of a negative advance contact angle, indicates easier wetting and poor liquid drainage.

[0097] The ophthalmic aqueous composition of the present invention is provided in the form of a single unit or a kit, contained within a PBT-containing resin container. The PBT-containing resin container can effectively retain the ophthalmic aqueous composition of the present invention, and as a result, the properties of the ophthalmic aqueous composition are well maintained even after long-term storage.

[0098] The ophthalmic aqueous composition of the present invention is prepared by adding components (A) and (B) above, and optionally other components, to a carrier in desired amounts using known preparation methods. For example, it can be manufactured using the method described in the General Provisions of the Sixteenth Edition of the Japanese Pharmacopoeia. Specifically, for example, it can be prepared by dissolving or suspending the above components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by a known sterilization method. [Examples]

[0099] Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.

[0100] <Evaluation of weight change 1> (Example 1) (A) Sodium hyaluronate (weight-average molecular weight 850,000 to 1,600,000), and (B) boric acid and borax were dissolved in purified water at approximately 70°C to prepare ophthalmic aqueous compositions at the concentrations shown in Table 2. The pH was measured at room temperature using a HORIBA pH meter.

[0101] (Examples 2-3) The ophthalmic aqueous compositions of Examples 2 and 3 shown in Table 2 were prepared in the same manner as in Example 1.

[0102] (Comparative Examples 1-3) Aqueous ophthalmic compositions for Comparative Examples 1 to 3, shown in Table 2, were prepared in the same manner as in Example 1.

[0103] [Table 2]

[0104] (Test method) The test solutions for Examples 1-3 and Comparative Examples 1-3 were filled into 10 mL transparent glass vials (septum caps) at a capacity of 3 mL each. One piece of PBT-containing resin (product name: PBT Natural, manufactured by Aram Co., Ltd.), approximately 1.0 cm in diameter, weighing approximately 205 mg, and thick approximately 2.0 mm, was then immersed in each vial and promptly sealed. After heat treatment by standing in a constant temperature bath at 70°C for 2 weeks, the weight of each resin was measured, and the weight change per unit volume was calculated using Equation 1. This heat treatment is equivalent to storage at room temperature for approximately 3 years. The weight change relative to the initial weight can also be evaluated. The volume of the PBT-containing resin can also be calculated from the density and weight of the resin. (Equation 1) Weight change per unit volume (mg / cm³) 3 )= (Weight of resin piece after heat treatment - Weight of resin piece before heat treatment) / Resin volume

[0105] The results of the tests conducted in this manner are shown in the lower section of Table 2.

[0106] Furthermore, these results were represented in a graph as shown in Figure 1.

[0107] As shown in Table 2 and Figure 1, in Comparative Example 1, where PBT-containing resin pieces were immersed in purified water, an increase in the weight of the PBT-containing resin pieces was observed compared to before heat treatment. However, in Comparative Examples 2 and 3, which contained sodium hyaluronate (an acidic polysaccharide) and glucose (a monosaccharide), the weight increase of the PBT-containing resin pieces was confirmed to be greater than that of purified water. However, in Examples 1 to 3, where boric acid and borax were added, the weight change per unit volume of the PBT resin was suppressed more than when purified water alone was used (Comparative Example 1). From this, it was confirmed that boric acid and borax suppress the weight change of PBT-containing resin caused by ophthalmic aqueous compositions containing one or more selected from the group consisting of acidic polysaccharides and monosaccharides, and thereby suppress the deterioration of the PBT-containing resin. Although the mechanism of action is not clear, it was considered possible that the hydrogen ions in the ophthalmic aqueous composition due to the buffering capacity of component (B) had some effect on the chain-like molecular structure of the PBT-containing resin.

[0108] <Evaluation of weight change 2> (Examples 4 to 10) Ophthalmic aqueous compositions shown in Tables 3 to 6 were prepared. Their pH was measured at room temperature using a HORIBA pH meter.

[0109] (Comparative Examples 4 to 12) In the same manner as in Examples 4 to 10, ophthalmic aqueous compositions of Comparative Examples 4 to 12 shown in Tables 3 to 6 were prepared.

[0110] [Table 3]

[0111] [Table 4]

[0112] [Table 5]

[0113] [Table 6]

[0114] (Test method) The test solutions of Examples 4 to 10 and Comparative Examples 4 to 12 were each filled with 3 mL into a 10 mL transparent glass vial (septum cap), and further, one piece of PBT-containing resin (product name: PBT Natural, manufactured by Aram Co., Ltd.) with a diameter of about 1.0 cm, a weight of about 205 mg, and a thickness of about 2.0 mm was immersed, and immediately sealed. After heat treatment of standing at 75 °C for 2 weeks in a thermostatic bath, the weight of each resin was measured, and the weight change per unit volume was calculated by Equation 1. It can also be evaluated by the weight change with respect to the initial weight. The volume of the PBT-containing resin can also be calculated from the density and weight of the resin. (Equation 1) Weight change per unit volume (mg / cm 3 ) = (Weight of resin piece after heat treatment - Weight of resin piece before heat treatment) / Resin volume

[0115] The results of the tests conducted in this manner are shown in the lower section of Tables 3-6.

[0116] As shown in the table, an increase in the weight of the PBT-containing resin pieces was observed in each comparative example compared to before heat treatment. However, in the examples in which boric acid and borax were added, the weight change per unit volume of the PBT-containing resin was suppressed more than in the comparative examples. From this, it was confirmed that boric acid and borax suppress the weight change of the PBT-containing resin caused by the ophthalmic aqueous composition containing component (A), and thereby suppress the degradation of the PBT-containing resin. Although the mechanism of action is not clear, it was considered possible that the hydrogen ions in the ophthalmic aqueous composition due to the buffering capacity of component (B) may have some effect on the chain molecular structure of the PBT-containing resin.

[0117] <Evaluation of weight change 3> (Examples 11-18) Ophthalmic aqueous compositions were prepared to the concentrations shown in Tables 7 to 13. Their pH was measured at room temperature using a HORIBA pH meter.

[0118] (Comparative Examples 13-22) Aqueous ophthalmic compositions for Comparative Examples 13 to 22, shown in Tables 7 to 13, were prepared in the same manner as in Examples 11 to 18.

[0119] [Table 7]

[0120] [Table 8]

[0121] [Table 9]

[0122] [Table 10]

[0123] [Table 11]

[0124] [Table 12]

[0125] [Table 13]

[0126] (Test method) The test solutions for the examples and comparative examples were filled into 10 mL transparent glass vials (septum caps) with 2 mL of each solution. A piece of PBT-containing resin (product name: PBT Natural, manufactured by Aram Co., Ltd.), approximately 1.0 cm in diameter, weighing approximately 205 mg, and 2.0 mm thick, was then immersed in each vial and promptly sealed. After heat treatment at 75°C for one week in a constant temperature bath, the weight of each resin was measured, and the weight change per unit volume was calculated using Equation 1. Evaluation can also be performed based on the weight change relative to the initial weight. The volume of the PBT-containing resin can also be calculated from the density and weight of the resin. (Equation 1) Weight change per unit volume (mg / cm³) 3 )= (Weight of resin piece after heat treatment - Weight of resin piece before heat treatment) / Resin volume

[0127] The results of the tests conducted in this manner are shown in the lower section of Tables 7-13.

[0128] As shown in the table, an increase in the weight of the PBT-containing resin pieces was observed in each comparative example compared to before heat treatment. However, in the example where the buffering agent was added, the weight change per unit volume of the PBT-containing resin was suppressed more than in the comparative examples. From this, it was confirmed that the buffering agent suppressed the weight change of the PBT-containing resin caused by the ophthalmic aqueous composition containing component (A), and thereby suppressed the degradation of the PBT-containing resin. Although the mechanism of action is not clear, it was considered possible that the hydrogen ions in the ophthalmic aqueous composition due to the buffering capacity of component (B) had some effect on the chain molecular structure of the PBT-containing resin.

[0129] <Evaluation of advance contact angle 1> (Examples 19-87) The ophthalmic aqueous compositions shown in Tables 14-32 were prepared by conventional methods and used as test solutions. Using a DM-501 contact angle meter manufactured by Kyowa Interface Science Co., Ltd., the advancing contact angle, which is the contact angle when the solid-liquid interface moves, was measured according to the expansion / contraction method of the measuring device. Specifically, a plate-shaped PBT-containing resin (product name: PBT Natural, manufactured by Aram Co., Ltd.) with sides of 50 mm and a thickness of approximately 2 mm was placed on the stage of the contact angle meter, and the test solution was set in the dispenser. A 1 μL droplet of the test solution was dropped onto the PBT-containing resin plate to form a hemispherical droplet. Next, the tip of the liquid dispensing part of the dispenser was quickly placed on the top of the hemisphere. In this state, the test solution was continuously dispensed at a dispensing rate of 6 μL / second, and the shape of the droplet was photographed from the side 15 times at 0.1-second intervals. In order to match the measurement conditions of the corresponding comparative example and the example, measurements were taken consecutively at the same room temperature, and the same plate-shaped PBT-containing resin was used. Next, the left-right contact angles were determined for each image using the FAMAS analysis software of the measurement device. Here, the contact angle refers to the angle on the side containing the test liquid, of the angle formed by the tangent line drawn from the contact point P between the surface of the PBT-containing resin plate, the test liquid, and the air to the test liquid, and the tangent line drawn to the surface of the PBT-containing resin plate. As the droplet expanded by dispensing the test liquid, the contact angle changed and then showed behavior of becoming almost constant. Therefore, the average value of the left-right contact angles was calculated for each image, and when the average values ​​of the left-right contact angles were arranged in the order in which the images were taken and five consecutive values ​​were selected, the first contact angle at which the standard deviation of the average value of the five consecutive left-right contact angles first fell below 2.5° was defined as the advancing contact angle of the present invention. This was done three times for each test liquid to determine the advancing contact angle, and the average of the three values ​​was defined as the advancing contact angle of that test liquid. Similarly, even if the advancing contact angle did not change during the process of droplet expansion, the first contact angle at which the standard deviation of the average value of the five consecutive contact angles first fell below 2.5° was defined as the advancing contact angle of the present invention. The percentage increase in the advance contact angle of the embodiment relative to the advance contact angle of the corresponding comparative example was calculated using the following formula (2). <Formula (2)> Rate of increase (%) = {(Advancing contact angle of each test solution / Advancing contact angle of the comparative example) - 1} × 100 The comparative example refers to an ophthalmic aqueous composition that excludes component (B) included in the example. For example, the comparative example corresponding to Example 19 in Table 14 is an ophthalmic aqueous composition containing 0.5 w / v% chondroitin sulfate sodium, adjusted to pH 5.1, the same pH as Example 19, using hydrochloric acid and sodium hydroxide. Furthermore, unless otherwise noted in the table, the tests were conducted immediately after the test solutions were prepared.

[0130] [Table 14]

[0131] [Table 15]

[0132] [Table 16]

[0133] [Table 17]

[0134] [Table 18] Examples 41-45 and the corresponding comparative examples used solutions that had been heat-treated at 80°C for 1 day.

[0135] [Table 19]

[0136] [Table 20]

[0137] [Table 21]

[0138] [Table 22]

[0139] [Table 23]

[0140] [Table 24]

[0141] [Table 25]

[0142] [Table 26] In Example 68 and the corresponding comparative example, the solution used in the test was heat-treated at 75°C for 3 days.

[0143] [Table 27]

[0144] [Table 28]

[0145] [Table 29]

[0146] [Table 30]

[0147] [Table 31]

[0148] [Table 32] In Example 87 and the corresponding comparative example, the solution used in the test was heat-treated at 75°C for 3 days.

[0149] As shown in each table, the improvement rate in the examples was higher compared to the comparative example that did not contain component (B). From this, it was confirmed that the ophthalmic aqueous composition containing component (B) in addition to the ophthalmic aqueous composition containing component (A) was less likely to wet the PBT-containing resin during exercise. It was found that advantageous effects such as improved liquid drainage from the PBT-containing resin can be obtained.

[0150] <Evaluation of weight change 4> (Examples 88-122) Ophthalmic aqueous compositions were prepared containing components (A), (B), and other components shown in Tables 33-53 at the concentrations indicated in the tables. The pH was measured at room temperature using a HORIBA pH meter.

[0151] (Comparative Examples 23-63) Comparative aqueous ophthalmic compositions shown in Tables 33 to 53 were prepared in the same manner as in the examples.

[0152] (Test method) The test solutions for the examples and comparative examples were filled into 10 mL transparent glass vials (septum caps) with 3 mL of each solution. A piece of PBT-containing resin (product name: PBT Natural, manufactured by Aram Co., Ltd.), approximately 1.0 cm in diameter, weighing approximately 205 mg, and 2.0 mm thick, was then immersed in each vial and promptly sealed. After heat treatment in a constant temperature bath at the temperatures and for the number of days shown in the respective tables, the weight of each resin was measured, and the weight change per unit volume was calculated using Equation 1. Evaluation can also be performed by comparing the weight change to the initial weight. The volume of the PBT-containing resin can also be calculated from the density and weight of the resin. (Equation 1) Weight change per unit volume (mg / cm³) 3 )= (Weight of resin piece after heat treatment - Weight of resin piece before heat treatment) / Resin volume

[0153] The results of the tests conducted in this manner are shown in the lower column of each table.

[0154] [Table 33] The heat treatment for Comparative Examples 23 and 24 and Examples 88 and 89 involved standing at 50°C for 7 days.

[0155] [Table 34] The heat treatment for Comparative Examples 25-27 and Examples 90 and 91 involved standing at 75°C for 3 days.

[0156] [Table 35] The heat treatment for Comparative Examples 28 and 29 and Example 92 involved standing at 50°C for 12 days.

[0157] [Table 36] The heat treatment for Comparative Examples 30 and 31 and Example 93 involved standing at 50°C for 17 days.

[0158] [Table 37] The heat treatment for Comparative Examples 23, 32, and Example 94 involved standing at 50°C for 7 days.

[0159] [Table 38] The heat treatment for Comparative Examples 33 and 34 and Example 95 involved standing at 50°C for 12 days.

[0160] [Table 39] The heat treatment for Comparative Examples 23, 35-37, and Examples 96-100 involved standing at 50°C for 7 days.

[0161] [Table 40] The heat treatment for Comparative Examples 23, 38, and Example 101 involved standing at 50°C for 7 days.

[0162] [Table 41] The heat treatment for Comparative Examples 39 and 40 and Example 102 involved standing at 50°C for 7 days.

[0163] [Table 42] The heat treatment for Comparative Examples 41-43 and Examples 103 and 104 involved standing at 50°C for 12 days.

[0164] [Table 43] The heat treatment for Comparative Examples 44 and 45 and Example 105 involved standing at 75°C for 3 days.

[0165] [Table 44] The heat treatment for Comparative Examples 33, 46, and 47 and Examples 106 and 107 involved standing at 50°C for 12 days.

[0166] [Table 45] The heat treatment for Comparative Examples 23, 48-50, and Examples 108-110 involved standing at 50°C for 7 days.

[0167] [Table 46] The heat treatment for Comparative Examples 33, 51, and 52, and Examples 111 and 112, involved standing at 50°C for 12 days.

[0168] [Table 47] The heat treatment for Comparative Examples 23, 53, and 54 and Examples 113 and 114 involved standing at 50°C for 7 days.

[0169] [Table 48] The heat treatment for Comparative Examples 33, 55, and Example 115 involved standing at 50°C for 12 days.

[0170] [Table 49] The heat treatment for Comparative Examples 56, 57 and Example 116 involved standing at 50°C for 7 days.

[0171] [Table 50] The heat treatment for Comparative Examples 39, 58, and Example 117 involved standing at 50°C for 7 days.

[0172] [Table 51] The heat treatment for Comparative Examples 30, 59, and 60 and Examples 118 and 119 involved standing at 50°C for 17 days.

[0173] [Table 52] The heat treatment for Comparative Examples 39 and 61 and Example 120 involved standing at 50°C for 7 days.

[0174] [Table 53] The heat treatment for Comparative Examples 23, 62, and 63, and Examples 121 and 122, involved standing at 50°C for 7 days.

[0175] <Preparation of ophthalmic aqueous composition and example of container packaging> Prepare the ophthalmic aqueous compositions shown in Tables 54-57 below (Tables 56 and 57 each span two pages). Formulation Examples 2, 3, 6, 9, 10, 15, and 18-21 were filled into a container body made of PET-containing resin, a perforated inner stopper made of PBT-containing resin was attached to the opening of the body, and a lid made of PP-containing resin was placed over it. Formulation Examples 7-8 were filled into a container body made of PP-containing resin, a perforated inner stopper made of PBT-containing resin was attached to the opening of the body, and a lid made of ABS-containing resin was placed over it. Formulation Examples 4 and 14 were filled into a container body made of ethylene vinyl acetate copolymer-containing resin, a perforated inner stopper made of PBT-containing resin was attached to the opening of the body, and a lid made of PE-containing resin was placed over it. Formulation Examples 1, 5, and 17 were filled into a container body made of PBT-containing resin, a perforated inner stopper made of PE-containing resin was attached to the opening of the body, and a lid made of PS-containing resin was placed over it. Formulation Examples 11, 13, and 16 were filled into a container body made of PE-containing resin, a perforated inner stopper made of PBT-containing resin was attached to the opening of the body, and a lid made of PP-containing resin was placed over it. Formulation Example 12 was filled into a container in which the body and opening for containing the ophthalmic aqueous composition were made of the same PBT-containing resin, and a lid made of PP-containing resin was placed over it. The unit of the numerical values ​​in the formulation examples is "w / v%".

[0176] [Table 54]

[0177] [Table 55]

[0178] [Table 56] JPEG2026086873000059.jpg217164 [Table 57] JPEG2026086873000061.jpg209170POE(200)POP(70) represents polyoxyethylene(200)polyoxypropylene(70) glycol.

Claims

[Claim 1] The invention described in the specification.

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