Aqueous eye drops containing a polymer compound, silver salt, and ionic isotonic agent.

Abstract

A stable aqueous ophthalmic solution containing a silver salt and an ionic tonicity agent is provided. [Solution] An aqueous ophthalmic solution containing a cellulose-based polymer compound, at least one polymer compound selected from hyaluronic acid or its salt and polyvinylpyrrolidone, a silver salt, and an ionic tonicity agent. A method for stabilizing an aqueous ophthalmic solution, comprising adding polyvinylpyrrolidone, a cellulose-based polymer compound, or hyaluronic acid or its salt to an aqueous ophthalmic solution containing a silver salt and an ionic tonicity agent. A method for suppressing cloudiness of an aqueous ophthalmic solution, comprising adding polyvinylpyrrolidone, a cellulose-based polymer compound, or hyaluronic acid or its salt to an aqueous ophthalmic solution containing a silver salt and an ionic tonicity agent. A method for stabilizing a silver salt, comprising adding polyvinylpyrrolidone, a cellulose-based polymer compound, or hyaluronic acid or its salt to an aqueous ophthalmic solution containing a silver salt and an ionic tonicity agent.

Description

Technical Field

[0001] The present invention relates to an aqueous ophthalmic solution containing at least one polymer compound selected from the group consisting of a cellulose-based polymer compound, hyaluronic acid or its salt, and polyvinylpyrrolidone, a silver salt, and an ionic tonicity agent. The present invention also relates to an aqueous ophthalmic solution containing polyvinylpyrrolidone, a silver salt, and an ionic tonicity agent. Hereinafter, these aqueous ophthalmic solutions are also referred to as "the present ophthalmic solution". Further, the present invention also relates to a method for stabilizing an aqueous ophthalmic solution, a method for suppressing the turbidity of an aqueous ophthalmic solution, and a method for stabilizing a silver salt.

Background Art

[0002] Ophthalmic solutions include a type that is used multiple times over a certain period after opening (multi-dose ophthalmic solution) and a single-use type (unit-dose ophthalmic solution). In particular, multi-dose ophthalmic solutions generally contain a preservative in order to prevent product spoilage due to microbial contamination during use and ensure the storage stability of the ophthalmic solution. As preservatives for ophthalmic solutions, benzalkonium chloride, chlorhexidine gluconate, etc. are used. In addition to benzalkonium chloride and the like, there are also multiple preservatives for ophthalmic solutions. For example, Japanese Patent Application Laid-Open No. 2016-507469 (Patent Document 1) discloses an emulsion composition containing difluprednate and an antibacterial metal, and a silver salt is exemplified as the antibacterial metal. It is also described that the emulsion composition can be used as an ophthalmic composition.

[0003] In addition to the active ingredients and the preservatives mentioned above, eye drops contain various additives as needed. For example, isotonic agents are used to adjust the osmotic pressure to be close to that of the physiological state of tears. Known isotonic agents include ionic isotonic agents such as sodium chloride and potassium chloride, and nonionic isotonic agents such as mannitol and concentrated glycerin. Eye drops are prepared by combining these active ingredients and additives. Generally, if the active ingredient is easily soluble in water, it is prepared as an aqueous eye drop, and if the active ingredient is not easily soluble in water, it is prepared as a suspension eye drop. In particular, aqueous eye drops are required to be free of insoluble foreign matter, and even slight turbidity of the solution cannot be ignored. Therefore, when preparing aqueous eye drops, it is strongly desirable to avoid the formation of turbidity in the solution. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Special Publication No. 2016-507469 [Overview of the project] [Problems that the invention aims to solve]

[0005] The present invention aims to provide a stable aqueous eye drop solution containing a silver salt and an ionic isotonic agent. [Means for solving the problem]

[0006] The inventors of this invention discovered that when silver salts and ionic isotonic agents coexist, turbidity occurs during the preparation of aqueous eye drops. They also discovered that the solubility of silver ions in aqueous eye drops decreases. After diligently investigating methods to suppress turbidity in aqueous eye drops and stabilize the silver salts contained in them, they surprisingly found that at least one polymer compound selected from the group consisting of polymer compounds, particularly cellulosic polymer compounds, hyaluronic acid or its salts, and polyvinylpyrrolidone, suppresses turbidity in aqueous eye drops and also stabilizes the silver salts contained in them, thus completing the present invention.

[0007] In other words, the present invention provides the following:

[0008] (1)(A) At least one polymer compound selected from the group consisting of cellulose polymer compounds, hyaluronic acid or its salts, and polyvinylpyrrolidone, (B) Silver halide and (C) Aqueous eye drops containing an ionic isotonic agent.

[0009] (2) The aqueous eye drop solution according to (1), wherein the component in (A) above is a cellulose polymer compound.

[0010] (3) The aqueous eye drop solution according to (1) or (2), wherein the cellulosic polymer compound is at least one selected from the group consisting of methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate.

[0011] (4) The aqueous eye drop solution according to any one of (1) to (3), wherein the cellulosic polymer compound is at least one selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, and hydroxypropylmethylcellulose.

[0012] (5) The aqueous eye drop solution according to (1), wherein the component in (A) above is hyaluronic acid or a salt thereof.

[0013] (6) The aqueous eye drop solution according to (1), wherein the component in (A) above is polyvinylpyrrolidone.

[0014] (7) Aqueous eye drops containing polyvinylpyrrolidone, silver salt, and an ionic isotonic agent.

[0015] (8) The aqueous eye drop solution according to (1) or (7), wherein the silver salt is at least one selected from the group consisting of silver nitrate, silver sulfate, silver chloride, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, and silver protein.

[0016] (9) The aqueous eye drops according to (1), (7), or (8), wherein the silver salt is silver nitrate.

[0017] (10) The aqueous eye drop solution according to (1) or (7), wherein the ionic isotonic agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, boric acid, and borax.

[0018] (11) The aqueous eye drop solution according to (1), (7), or (10), wherein the ionic isotonic agent is sodium chloride.

[0019] (12) An aqueous eye drop solution according to any one of (1) to (11), wherein the pH of the aqueous eye drop solution is in the range of 6 to 8.

[0020] (13) An aqueous eye drop solution according to any one of (1) to (12), further containing an active ingredient.

[0021] (14) An aqueous ophthalmic solution according to any one of (1) to (13), characterized in that the aqueous ophthalmic solution is stabilized.

[0022] (15) An aqueous ophthalmic solution according to any one of (1) to (14), characterized in that the clouding of the aqueous ophthalmic solution is suppressed.

[0023] (16) An aqueous ophthalmic solution according to any one of (1) to (15), characterized in that the silver salt is stabilized.

[0024] (17) A method for stabilizing an aqueous ophthalmic solution, characterized by adding polyvinylpyrrolidone to an aqueous ophthalmic solution containing a silver salt and an ionic isotonic agent.

[0025] (18) A method for suppressing clouding of an aqueous ophthalmic solution, characterized by adding polyvinylpyrrolidone to an aqueous ophthalmic solution containing a silver salt and an ionic isotonic agent.

[0026] (19) A method for stabilizing a silver salt, characterized by adding polyvinylpyrrolidone to an aqueous ophthalmic solution containing a silver salt and an ionic isotonic agent.

[0027] (20) An aqueous ophthalmic solution containing a polymer compound, a silver salt and an ionic isotonic agent.

[0028] (21) A method for stabilizing an aqueous ophthalmic solution, characterized by adding a cellulose-based polymer compound to an aqueous ophthalmic solution containing a silver salt and an ionic isotonic agent.

[0029] (22) A method for suppressing clouding of an aqueous ophthalmic solution, characterized by adding a cellulose-based polymer compound to an aqueous ophthalmic solution containing a silver salt and an ionic isotonic agent.

[0030] (23) A method for stabilizing a silver salt, characterized by adding a cellulose-based polymer compound to an aqueous ophthalmic solution containing a silver salt and an ionic isotonic agent.

[0031] (24) A method for stabilizing an aqueous eye drop solution, characterized by adding hyaluronic acid or a salt thereof to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent.

[0032] (25) A method for suppressing the clouding of an aqueous eye drop solution, characterized by adding hyaluronic acid or a salt thereof to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent.

[0033] (26) A method for stabilizing a silver salt, characterized by adding hyaluronic acid or a salt thereof to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent.

[0034] Furthermore, any two or more of the above configurations (1) to (26) can be selected and combined. [Effects of the Invention]

[0035] According to the present invention, even when an aqueous eye drop solution containing a silver salt and an ionic isotonic agent is used, it does not become cloudy, and a clear aqueous eye drop solution can be obtained. Furthermore, the silver salt contained in the aqueous eye drop solution can be stabilized. [Modes for carrying out the invention]

[0036] The present invention will be described in more detail below.

[0037] In this invention, "aqueous eye drops" means eye drops that use water as a solvent (base). The aqueous eye drops in this invention are not particularly limited as long as they use water as a solvent (base). Examples include dissolving type aqueous eye drops and suspension type aqueous eye drops. Dissolving type aqueous eye drops are clear in appearance, and preferably colorless and clear. One embodiment of the aqueous eye drops in this invention is a dissolving type aqueous eye drop, and does not include suspension type aqueous eye drops. Another embodiment of the aqueous eye drops in this invention is a suspension type aqueous eye drop, and does not include dissolving type aqueous eye drops. Here, "eye drops" is synonymous with "eye drops" or "eye medicine," and eye drops for contact lenses are also included in the definition of eye drops.

[0038] In this specification, "%(w / v)" means the mass (g) of the target component contained in 100 mL of the aqueous eye drop solution of the present invention.

[0039] This eye drop solution contains a polymer compound. Examples of polymer compounds are not limited to methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate; polyvinylpyrrolidone, polyvinyl alcohol, and carboxyvinyl polymers; natural polymer compounds such as xanthan gum, sodium chondroitin sulfate, hyalein or its salts (specifically, sodium hyaluronate); and synthetic polymer compounds such as polyethylene glycol. Polyvinyl polymer compounds are preferred, and polyvinylpyrrolidone is particularly preferred. Polyvinylpyrrolidone refers to a polymer compound formed by the polymerization of N-vinyl-2-pyrrolidone and is also called povidone.

[0040] The high-molecular-weight compounds contained in this eye drop solution may be used individually, or two or more high-molecular-weight compounds may be used in any combination.

[0041] The concentration of the high molecular weight compound contained in this ophthalmic solution is not particularly limited, but for example, 0.001 to 10% (w / v) is preferred, 0.01 to 10% (w / v) is more preferred, 0.05 to 10% (w / v) is even more preferred, 0.1 to 10% (w / v) is even more preferred, 0.1 to 5% (w / v) is particularly preferred, 0.1 to 1% (w / v) is especially preferred, and 0.1 to 0.5% (w / v) is even more particularly preferred.

[0042] The concentration of the cellulose-based polymer compound contained in this ophthalmic solution is not particularly limited, but for example, 0.001 to 10% (w / v) is preferred, 0.01 to 10% (w / v) is more preferred, 0.05 to 10% (w / v) is even more preferred, 0.1 to 10% (w / v) is even more preferred, 0.1 to 5% (w / v) is particularly preferred, 0.1 to 1% (w / v) is especially preferred, and 0.1 to 0.5% (w / v) is even more particularly preferred.

[0043] The concentration of hydroxypropylcellulose contained in this ophthalmic solution is not particularly limited, but for example, 0.001 to 10% (w / v) is preferred, 0.01 to 10% (w / v) is more preferred, 0.05 to 10% (w / v) is even more preferred, 0.1 to 10% (w / v) is even more preferred, 0.1 to 5% (w / v) is particularly preferred, 0.1 to 1% (w / v) is especially preferred, and 0.1 to 0.5% (w / v) is even more particularly preferred.

[0044] The potassium (K) value of polyvinylpyrrolidone contained in this ophthalmic solution is preferably 17 or higher, more preferably 17 to 120, even more preferably 25 to 120, and particularly preferably 30 to 120.

[0045] In the present invention, examples of "polyvinylpyrrolidone" include polyvinylpyrrolidone K15 (PVP K15), polyvinylpyrrolidone K17 (PVP K17), polyvinylpyrrolidone K25 (PVP K25), polyvinylpyrrolidone K30 (PVP K30), polyvinylpyrrolidone K40 (PVP K40), polyvinylpyrrolidone K50 (PVP K50), polyvinylpyrrolidone K60 (PVP K60), polyvinylpyrrolidone K70 (PVP K70), polyvinylpyrrolidone K80 (PVP K80), polyvinylpyrrolidone K85 (PVP K85), polyvinylpyrrolidone K90 (PVP K90), and polyvinylpyrrolidone K120 (PVP K120).

[0046] The K value of polyvinylpyrrolidone is a viscous characteristic value that correlates with molecular weight. It is calculated by applying the relative viscosity value (at 25°C) measured by a capillary viscometer to Fikentscher's formula (1) below.

[0047]

number

[0048] In formula (1), η rel is the relative viscosity of the polyvinylpyrrolidone aqueous solution with respect to water, and c is the concentration (%) of polyvinylpyrrolidone in the polyvinylpyrrolidone aqueous solution.

[0049] Here, the K value is 90-108% of the indicated K value, in accordance with the description of the K value in the 17th edition of the Japanese Pharmacopoeia "Povidone". For example, "K30" means that the viscosity characteristic value (K value) calculated by applying the above formula (1) is in the range of 27-32.4, and "K90" means that the viscosity characteristic value (K value) calculated by applying the above formula (1) is in the range of 81-97.2.

[0050] The polyvinylpyrrolidone contained in this eye drop solution may be used alone, or two or more types of polyvinylpyrrolidone with different potassium values ​​may be used in any combination.

[0051] The concentration of polyvinylpyrrolidone contained in this ophthalmic solution is not particularly limited, but for example, 0.001 to 10% (w / v) is preferred, 0.01 to 10% (w / v) is more preferred, 0.05 to 10% (w / v) is even more preferred, 0.1 to 10% (w / v) is even more preferred, 0.1 to 5% (w / v) is particularly preferred, and 1 to 5% (w / v) is especially preferred.

[0052] The concentration of hyaleic acid or its salt contained in this eye drop solution is not particularly limited, but for example, 0.001 to 1% (w / v) is preferred, 0.01 to 1% (w / v) is more preferred, 0.05 to 0.5% (w / v) is even more preferred, and 0.1 to 0.5% (w / v) is particularly preferred.

[0053] In the present invention, examples of silver salts include silver nitrate, silver sulfate, silver chloride, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, and silver protein, but silver nitrate is preferred.

[0054] The concentration of silver salt contained in this eye drop solution is not particularly limited, but the lower limit is, for example, 0.00000001% (w / v) or higher, 0.0000001% (w / v) or higher, 0.000001% (w / v) or higher, 0.0000025% (w / v) or higher, 0.000004% (w / v) or higher, 0.000005% ( Preferably, the w / v is 0.000008%(w / v) or more, 0.00001%(w / v) or more, 0.000016%(w / v) or more, 0.000025%(w / v) or more, 0.00004%(w / v) or more, 0.00005%(w / v) or more, 0.00008%(w / v) or more, or 0.0001%(w / v) or more. Furthermore, the upper limit is preferably, for example, 1%(w / v) or less, 0.5%(w / v) or less, 0.1%(w / v) or less, 0.05%(w / v) or less, 0.005%(w / v) or less, or 0.001%(w / v) or less.

[0055] The concentration range of the silver salt contained in this ophthalmic solution is not particularly limited, but for example, it is preferably 0.00000001 to 1% (w / v), more preferably 0.0000001 to 0.01% (w / v), even more preferably 0.000001 to 0.001% (w / v), even more preferably 0.000003 to 0.0003% (w / v), especially preferably 0.00001 to 0.0001% (w / v), and particularly preferably 0.0001 to 0.001% (w / v).

[0056] In the present invention, examples of ionic isotonic agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, boric acid, and borax, but sodium chloride and potassium chloride are preferred, and sodium chloride is more preferred.

[0057] The concentration of the ionic isotonic agent contained in this ophthalmic solution is not particularly limited as long as it is an amount that makes the ophthalmic solution isotonic; however, for example, a 0.1-0.9% (w / v) ionic isotonic agent can be added to this ophthalmic solution.

[0058] In addition to the ingredients listed above, this eye drop solution may contain pharmaceutically acceptable additives as needed, using commonly available techniques. For example, buffering agents such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid; nonionic isotonic agents such as concentrated glycerin and mannitol; surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, and polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate, sodium citrate hydrate, sodium edetate, and sodium edetate hydrate; and preservatives such as benzalkonium chloride and chlorhexidine gluconate may be selected and added as needed.

[0059] The pH of this ophthalmic solution should be within the range acceptable for ophthalmic preparations, but is generally preferred to be in the range of pH 4 to 8, more preferably in the range of pH 6 to 8, and particularly preferred to be around pH 7. More specifically, for example, pH 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0 are preferred. pH adjusting agents such as hydrochloric acid and sodium hydroxide may be added to this ophthalmic solution as appropriate.

[0060] This ophthalmic solution can be stored in an airtight container, specifically an eye drop container. An example of an eye drop container in which this composition is filled is a "multi-dose eye drop container."

[0061] In the present invention, "multi-dose eye drop container" refers to an eye drop container comprising a container body and a cap that can be attached to the container body, wherein the cap can be freely opened and resealed. The multi-dose eye drop container usually contains multiple doses of eye drop solution for use over a certain period of time. The amount of eye drop solution to be filled into the multi-dose eye drop container is preferably, for example, 1 to 20 mL, more preferably 1 to 15 mL, even more preferably 1 to 10 mL, even more preferably 2.5 to 10 mL, and particularly preferably 5 mL.

[0062] In this invention, "ophthalmic medicated product" refers to an ophthalmic medicated product in which the eye drop solution is filled into an eye drop container. Here, "ophthalmic medicated product" can refer to, for example, an eye drop product. The definitions of each term in "ophthalmic medicated product" in this invention are the same as the definitions of each term in the eye drop solution.

[0063] This eye drop solution may contain active ingredients. Examples of active ingredients contained in this eye drop solution (hereinafter also simply referred to as "the active ingredients") include dry eye and corneal disease treatments, anti-allergic drugs, steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, intraocular pressure lowering drugs, antiviral drugs, and antibacterial drugs.

[0064] As for the salt of this active ingredient, there are no particular restrictions as long as it is a salt that is permitted as a medicine, and it can be salted with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid, or with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid. Examples include salts of ammonium compounds; quaternary ammonium salts with methyl bromide, methyl iodide, etc.; salts with halogen ions such as bromide, chloride, and iodide; salts with alkali metals such as lithium, sodium, and potassium; salts with alkaline earth metals such as calcium and magnesium; metal salts with iron, zinc, etc.; salts with ammonia; and salts with organic amines such as triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethanediamine.

[0065] In the present invention, solvates such as the hydrate of the active ingredient are contained in the salt of the active ingredient.

[0066] In the present invention, if geometric isomers or optical isomers exist for the active ingredient or its salts, those isomers or their salts are also included within the scope of the present invention. Furthermore, if proton tautomerism exists for the active ingredient or its salts, those tautomers or their salts are also included within the scope of the present invention.

[0067] In the present invention, if the active ingredients or their salts contain crystalline polymorphs and groups of crystalline polymorphs (crystalline polymorph systems), these crystalline polymorphs and groups of crystalline polymorphs (crystalline polymorph systems) are also included within the scope of the present invention. Here, a group of crystalline polymorphs (crystalline polymorph systems) refers to the individual crystalline forms at each stage and the entire process when the crystalline form changes depending on the conditions and states of the crystals, such as their production, crystallization, and storage (this state includes the formulated state).

[0068] Specific examples of this active ingredient used in the treatment of dry eye and corneal diseases include diquafosol, rebamipide, or salts thereof.

[0069] Examples of active ingredients other than those listed above include sirolimus or its salts.

[0070] Diquafosol is a compound represented by the following chemical structure.

[0071] [ka]

[0072] As for "diquafosol salts," there are no particular restrictions as long as they are salts that are permitted as medicines, including metal salts with lithium, sodium, potassium, calcium, magnesium, zinc, etc.; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples include salts with organic acids such as p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; quaternary ammonium salts with methyl bromide and methyl iodide; salts with halogen ions such as bromide, chloride, and iodide; salts with ammonia; and salts with organic amines such as triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethanediamine.

[0073] In the present invention, "diquafosol or its salt" also includes diquafosol (free form) or hydrates and organic solvent hydrates of its salt.

[0074] If diquafosol or its salts have crystalline polymorphs and groups of crystalline polymorphs (polymorphic systems), then these crystalline polymorphs and groups of crystalline polymorphs (polymorphic systems) are also included within the scope of the present invention. Here, a group of crystalline polymorphs (polymorphic system) refers to the individual crystalline forms at each stage and the entire process when the crystalline form changes depending on the conditions and states of the production, crystallization, and storage of those crystals.

[0075] The preferred "diquafosol or its salt" in the present invention is the sodium salt of diquafosol, and the tetrasodium diquafosol salt (hereinafter also simply referred to as "diquafosol sodium") shown in the following chemical structural formula is particularly preferred.

[0076] [ka]

[0077] Diquafosol or its salts can be produced by methods such as those disclosed in Japanese Patent Publication No. 2001-510484.

[0078] This ophthalmic solution may contain active ingredients other than diquafosol or its salts, but preferably it may contain diquafosol or its salts as the sole active ingredient. In other embodiments of this ophthalmic solution, it may not contain diquafosol or its salts as an active ingredient.

[0079] The concentration of diquafosol or its salt in this ophthalmic solution is, for example, 0.1 to 10% (w / v), preferably 1 to 10% (w / v), more preferably 1 to 5% (w / v), and particularly preferably 3% (w / v).

[0080] Rebamipide is a compound represented by the following chemical structure.

[0081] [ka]

[0082] In the present invention, the preferred "rebamipide or its salt" is rebamipide (free form).

[0083] One embodiment of this ophthalmic solution may contain rebamipide or a salt thereof as an active ingredient, but another embodiment of this ophthalmic solution may not contain rebamipide or a salt thereof as an active ingredient.

[0084] Sirolimus is a compound represented by the following chemical structure.

[0085] [ka]

[0086] In the present invention, the preferred "sirolimus or its salt" is sirolimus (free form).

[0087] One embodiment of this ophthalmic solution may contain sirolimus or a salt thereof as an active ingredient, but another embodiment of this ophthalmic solution may not contain sirolimus or a salt thereof as an active ingredient.

[0088] The dosage of this ophthalmic solution can be appropriately changed depending on the dosage form, the severity of the patient's symptoms, age, weight, and the doctor's judgment. For example, if eye drops are selected as the dosage form, it can be administered locally to the eye in divided doses of 1 to 10 times a day, preferably 2 to 8 times a day, and more preferably 3 to 6 times a day.

[0089] This eye drop solution can be used with soft contact lenses, even while wearing them. Examples of soft contact lenses include contact lenses with hydroxyethyl methacrylate as the main component or silicone hydrogel contact lenses.

[0090] There are no particular restrictions on the type of soft contact lens to which this eye drop solution can be applied, and it does not matter whether the lens is ionic or nonionic, or whether it is hydrophilic or non-hydrophilic. For example, it can be applied to all soft contact lenses currently on the market or to be marketed in the future, including reusable lenses, as well as daily disposable lenses, weekly disposable lenses, and bi-weekly disposable lenses.

[0091] One aspect of the present invention is a method for stabilizing an aqueous eye drop solution, characterized by adding polyvinylpyrrolidone to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent. The detailed description of the aqueous eye drop solution of the present invention also applies to the method for stabilizing the aqueous eye drop solution of the present invention.

[0092] One aspect of the present invention is a method for suppressing the clouding of an aqueous eye drop solution, characterized by adding polyvinylpyrrolidone to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent. The detailed description of the aqueous eye drop solution of the present invention above also applies to the method for suppressing the clouding of the aqueous eye drop solution of the present invention.

[0093] One aspect of the present invention is a method for stabilizing a silver salt, characterized by adding polyvinylpyrrolidone to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent. The detailed description of the aqueous eye drop solution of the present invention also applies to the method for stabilizing the silver salt of the present invention.

[0094] One aspect of the present invention is a method for stabilizing an aqueous eye drop solution, characterized by adding a cellulosic polymer compound to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent. The detailed description of the aqueous eye drop solution of the present invention also applies to the method for stabilizing the aqueous eye drop solution of the present invention.

[0095] One aspect of the present invention is a method for suppressing the clouding of an aqueous eye drop solution, characterized by adding a cellulose polymer compound to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent. The detailed description of the aqueous eye drop solution of the present invention also applies to the method for suppressing the clouding of the aqueous eye drop solution of the present invention.

[0096] One aspect of the present invention is a method for stabilizing a silver salt, characterized by adding a cellulosic polymer compound to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent. The detailed description of the aqueous eye drop solution of the present invention also applies to the method for stabilizing the silver salt of the present invention.

[0097] One aspect of the present invention is a method for stabilizing an aqueous eye drop solution, characterized by adding hyaluronic acid or a salt thereof to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent. The detailed description of the aqueous eye drop solution of the present invention also applies to the method for stabilizing the aqueous eye drop solution of the present invention.

[0098] One aspect of the present invention is a method for suppressing the clouding of an aqueous eye drop solution, characterized by adding hyaluronic acid or a salt thereof to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent. The detailed description of the aqueous eye drop solution of the present invention above also applies to the method for suppressing the clouding of the aqueous eye drop solution of the present invention.

[0099] One aspect of the present invention is a method for stabilizing a silver salt, characterized by adding hyaluronic acid or a salt thereof to an aqueous eye drop solution containing a silver salt and an ionic isotonic agent. The detailed description of the aqueous eye drop solution of the present invention also applies to the method for stabilizing the silver salt of the present invention.

[0100] In the present invention, stabilization of aqueous eye drops means that the aqueous eye drops are stabilized. Specifically, as shown in the examples described later, this means that (1) the clouding of the aqueous eye drops is suppressed, and / or (2) the silver salt contained in the aqueous eye drops is stabilized. Preferably, this means that (1) the clouding of the aqueous eye drops is suppressed, and (2) the silver salt contained in the aqueous eye drops is stabilized. In the case of suspension-type aqueous eye drops, stabilization of the aqueous eye drops refers to the state in which (2) the silver salt contained in the aqueous eye drops is stabilized. [Examples]

[0101] The present invention will be described in detail below with reference to test examples and formulation examples, but these examples are for the purpose of better understanding the present invention and do not limit the scope of the present invention in any way.

[0102] [Test Example 1] (Sample preparation) Sample 1: Sample 1 was prepared according to the formulation shown in Table 1. Specifically, 3.2 mg of silver nitrate and 4.5 g of sodium chloride were dissolved in water to make 1000 mL of solution, and Sample 1 was prepared.

[0103] Samples 2-4: Samples 2-4 were prepared in the same manner as Sample 1, according to the formulation shown in Table 1.

[0104] For samples containing pH adjusters, the pH was adjusted to 7.5, while for formulations without pH adjusters, the pH was left as is.

[0105] [Table 1]

[0106] (Test method) For samples 1-4, the presence or absence of precipitates in the solution immediately after preparation was visually confirmed.

[0107] Furthermore, 5 mL of each sample (1-4) was filled into a low-density polyethylene (LDPE) eye drop container and stored in a cool, light-shielded place for one month. After storage, the entire contents of the samples were collected in a polypropylene centrifuge tube and centrifuged at 15,000 rpm for 30 minutes. Subsequently, the silver ion content of the sample supernatant was quantified using inductively coupled plasma atomic emission spectroscopy (ICP-AES), and the dissolved silver ion concentration in each sample was measured.

[0108] (Test results) Table 2 shows the results of visually inspecting the solution immediately after preparation for the presence or absence of precipitates.

[0109] [Table 2]

[0110] Table 3 shows the silver ion dissolution concentration (ppb) in the sample.

[0111] [Table 3]

[0112] As is clear from Table 2, turbidity was observed in samples containing silver nitrate and sodium chloride. Furthermore, turbidity was also observed in samples containing EDTA or sodium hydrogen phosphate. On the other hand, when polyvinylpyrrolidone was added to samples containing silver nitrate and sodium chloride, no turbidity was observed. In other words, surprisingly, it was found that polyvinylpyrrolidone suppresses the turbidity caused by silver nitrate and sodium chloride.

[0113] Furthermore, as is clear from Table 3, differences were observed in the solubility of silver ions. Specifically, when polyvinylpyrrolidone was added to a sample containing silver nitrate and sodium chloride (Sample 4), a higher amount of silver ions were found to dissolve compared to Samples 1-3.

[0114] The above results demonstrate that polyvinylpyrrolidone suppresses the turbidity caused by silver nitrate and sodium chloride, and also stabilizes the added silver salts.

[0115] [Test Example 2] (Sample preparation) Sample 5: Sample 5 was prepared according to the formulation shown in Table 4. Specifically, 3.2 mg of silver nitrate, 4.5 g of sodium chloride, and 5 g of hydroxypropyl cellulose were dissolved in water to make 1000 mL of solution, and Sample 5 was prepared.

[0116] Samples 6-8: Samples 6-8 were prepared in the same manner as Sample 5, according to the formulation shown in Table 4.

[0117] For samples containing pH adjusters, the pH was adjusted to 7.5, while for formulations without pH adjusters, the pH was left as is.

[0118] [Table 4]

[0119] (Test method) For samples 5-8, 5 mL was filled into low-density polyethylene (LDPE) eyedropper containers and stored in a cool, light-shielded place for one month. After storage, the entire volume of the samples was collected in a polypropylene centrifuge tube and centrifuged at 15,000 rpm for 30 minutes. Subsequently, the silver ion content of the sample supernatant was quantified using inductively coupled plasma atomic emission spectroscopy (ICP-AES), and the dissolved silver ion concentration in each sample was measured.

[0120] (Test results) Table 5 shows the silver ion dissolution concentration (ppb) in the sample.

[0121] [Table 5]

[0122] As is clear from Table 5, differences in the solubility of silver ions were observed. Specifically, when hydroxypropyl cellulose or sodium hyaluronate was added to samples containing silver nitrate and sodium chloride (samples 5-7), a higher amount of silver ions were found to dissolve compared to sample 8.

[0123] The above results demonstrate that hydroxypropyl cellulose and sodium hyaluronate stabilize the added silver salt.

[0124] [Examples of formulations] The present invention will be described in more detail below with reference to formulation examples, but the present invention is not limited to these formulation examples. In the formulation examples below, the amount of each component is the content in 100 mL of the formulation.

[0125] (Example of formulation 1: eye drops) in 100mL Polyvinylpyrrolidone K90 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0126] (Example of formulation 2: eye drops) in 100mL Polyvinylpyrrolidone K90 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0127] (Example of formulation 3: eye drops) in 100mL Polyvinylpyrrolidone K90 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0128] (Example of formulation 4: eye drops) in 100mL Polyvinylpyrrolidone K90 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0129] (Example of formulation 5: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly.

[0130] (Example of formulation 6: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K60 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly.

[0131] (Example of formulation 7: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K30 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly.

[0132] (Example of formulation 8: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly.

[0133] (Example of formulation 9: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Polyvinylpyrrolidone K60 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly.

[0134] (Example of formulation 10: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Polyvinylpyrrolidone K30 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly.

[0135] (Example of formulation 11: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Citric acid hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly.

[0136] (Formulation example 12: Eye drops) in 100mL Polyvinylpyrrolidone K60 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0137] (Formulation example 13: Eye drops) in 100mL Polyvinylpyrrolidone K60 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0138] (Formulation example 14: Eye drops) in 100mL Polyvinylpyrrolidone K60 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0139] (Formulation example 15: Eye drops) in 100mL Polyvinylpyrrolidone K60 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0140] (Formulation example 16: Eye drops) in 100mL Polyvinylpyrrolidone K30 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0141] (Example of formulation 17: eye drops) in 100mL Polyvinylpyrrolidone K30 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0142] (Formulation example 18: Eye drops) in 100mL Polyvinylpyrrolidone K30 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0143] (Example of formulation 19: eye drops) in 100mL Polyvinylpyrrolidone K30 0.0001~10g Sodium hydrogen phosphate hydrate 0.1-0.5g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0144] (Example of formulation 20: eye drops) in 100mL Sodium hyaluronate 0.0001-1g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0145] (Example of formulation 21: eye drops) in 100mL Sodium hyaluronate 0.0001-1g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0146] (Formulation example 22: Eye drops) in 100mL Sodium hyaluronate 0.0001-1g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0147] (Example of formulation 23: eye drops) in 100mL Sodium hyaluronate 0.0001-1g Sodium hydrogen phosphate hydrate 0.1-0.5g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0148] (Formulation example 24: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Sodium hyaluronate 0.0001-1g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly.

[0149] (Formulation example 25: Eye drops) in 100mL Hydroxypropylcellulose 0.0001~1g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0150] (Formulation example 26: Eye drops) in 100mL Hydroxypropylcellulose 0.0001~1g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0151] (Formulation example 27: Eye drops) in 100mL Hydroxypropylcellulose 0.0001~1g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0152] (Formulation example 28: Eye drops) in 100mL Hydroxypropylcellulose 0.0001~1g Sodium hydrogen phosphate hydrate 0.1-0.5g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0153] (Example of formulation 29: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Hydroxypropylcellulose 0.0001~1g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly.

[0154] (Example of formulation 30: eye drops) in 100mL Hydroxyethylcellulose 0.0001~1g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0155] (Formulation example 31: Eye drops) in 100mL Hydroxyethylcellulose 0.0001~1g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0156] (Formulation example 32: Eye drops) in 100mL Hydroxyethylcellulose 0.0001~1g Sodium hydrogen phosphate hydrate 0.1-0.5g Sodium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0157] (Formulation example 33: Eye drops) in 100mL Hydroxyethylcellulose 0.0001~1g Sodium hydrogen phosphate hydrate 0.1-0.5g Potassium chloride 0.01-1g Silver nitrate 0.00001~0.01g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding the above components to sterile purified water, thoroughly stirring them, and adjusting the pH.

[0158] (Example of formulation 34: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Hydroxyethylcellulose 0.0001~1g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) Appropriate amount of sterile purified water The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly. [Industrial applicability]

[0159] The present invention provides a stable aqueous eye drop solution containing a silver salt and an ionic isotonic agent, which suppresses the occurrence of turbidity and stabilizes the silver salt contained in the aqueous eye drop solution.

Claims

1. (A) Hyaluronic acid or a salt thereof, (B) Silver halide and (C) An aqueous eye drop containing an ionic isotonic agent, Furthermore, it is an aqueous eye drop solution containing medications for treating dry eye and corneal diseases.

2. The aqueous eye drop solution according to claim 1, wherein the drug for treating dry eye and corneal disease is diquafosol or a salt thereof.

3. The aqueous eye drop solution according to claim 1, wherein the drug for treating dry eye and corneal disease is rebamipide or a salt thereof.

4. The aqueous eye drop solution according to claim 1, wherein the silver salt is at least one selected from the group consisting of silver nitrate, silver sulfate, silver chloride, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, and silver protein.

5. The aqueous eye drop solution according to claim 1 or 4, wherein the silver salt is silver nitrate.

6. The aqueous eye drop solution according to claim 1, wherein the ionic isotonic agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, boric acid, and borax.

7. The aqueous eye drop solution according to claim 1 or 6, wherein the ionic isotonic agent is sodium chloride.

8. The aqueous eye drop solution according to any one of claims 1 to 7, wherein the pH of the aqueous eye drop solution is in the range of 6 to 8.

9. The aqueous eye drop solution according to any one of claims 1 to 8, characterized in that the aqueous eye drop solution is stabilized.

10. The aqueous eye drop solution according to any one of claims 1 to 9, characterized in that the silver salt is stabilized.

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