Silver salt-containing ophthalmic aqueous composition filled in a resin container

Abstract

The present invention relates to an ophthalmic aqueous composition containing a silver salt, which is filled in a polyester resin container or a polyolefin resin container other than polypropylene. The present invention also relates to an ophthalmic preservative containing a silver salt, and a method for imparting a preservative efficacy to an ophthalmic aqueous composition that meets the criteria of the Japanese Pharmacopoeia Preservative Efficacy Test. The ophthalmic preservative is filled in a polyester resin container or a polyolefin resin container other than polypropylene, and the method comprises the steps of adding a silver salt to the ophthalmic aqueous composition and filling the polyester resin container or the polyolefin resin container other than polypropylene with the ophthalmic aqueous composition. The present invention provides a preservative / system that can be widely used in ophthalmic aqueous compositions, regardless of the type of active ingredient or additive.

Description

Technical Field

[0001] The present invention relates to an ophthalmic aqueous composition containing a silver salt, which is filled in a container made of a polyester resin or a container made of a polyolefin resin other than polypropylene. Background Art

[0002] Since ophthalmic aqueous compositions are primarily administered as eye drops, they are often administered multiple times a day. For convenience, they are preferably filled in a container capable of repeated eye drops, so-called multi-dose eye drop containers. When filling in a multi-dose eye drop container, benzalkonium chloride is generally added as a preservative to prevent bacterial contamination.

[0003] However, it is known that benzalkonium chloride may cause corneal damage if used in high concentrations. In addition, it is known that benzalkonium chloride may cause deformation of soft contact lenses if adsorbed on them. In order to avoid such adverse effects, ophthalmic aqueous compositions that do not contain any preservatives are also used in the treatment of ophthalmic diseases. For example, "Mucosta (注册商标) The instructions for the eye drops UD 2%" (Non-Patent Document 1) state that "Mucosta (注册商标) No preservatives are added to the eye drops UD 2%". However, due to the (注册商标) "UD 2% eye drops" are single-use packaging, so as mentioned above, there are problems in terms of convenience.

[0004] On the other hand, there are also multi-dose ophthalmic aqueous compositions containing preservatives that are safer than benzalkonium chloride. For example, "Diquas (注册商标) The instructions for "Diquas Eye Drops 3%" (Non-Patent Document 2) state that (注册商标) "3% eye drops" contain chlorhexidine gluconate as a preservative instead of the commonly used benzalkonium chloride. It should be noted that Japanese Patent Application Laid-Open No. 2017-2036 (Patent Document 1) states that chlorhexidine gluconate does not deform soft contact lenses. However, it is unclear whether chlorhexidine gluconate can be used instead of the commonly used benzalkonium chloride regardless of the types of active ingredients and additives contained in the ophthalmic aqueous composition.

[0005] Silver nitrate eye drops "Born Happy (注册商标)"The drug insert (Non-Patent Document 3) describes the use of silver nitrate eye drops for the treatment of neonatal gonococcal conjunctivitis. However, Non-Patent Document 3 does not describe the use of silver nitrate as a preservative for aqueous ophthalmic compositions. In addition, Japanese Patent Publication No. 2016-507469 (Patent Document 2) discloses an emulsion composition containing difluprednate and an antibacterial metal, citing a silver salt as the antibacterial metal, and also describes that the emulsion composition can be used as an ophthalmic composition. However, Patent Document 2 does not describe or suggest what kind of container the composition should be filled with.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: Japanese Patent Application Laid-Open No. 2017-2036

[0009] Patent Document 2: Japanese Patent Application No. 2016-507469

[0010] Non-patent literature

[0011] Non-Patent Document 1: "Mucosta (registered trademark) eye drops UD 2%" package insert

[0012] Non-Patent Document 2: "Diquas (registered trademark) eye drops 3%" package insert

[0013] Non-Patent Document 3: Silver Nitrate Eye Drops "Born Happy (Registered Trademark)" Package Insert Summary of the Invention

[0014] Problems to be solved by the invention

[0015] An object of the present invention is to provide a preservative / system that can be widely used in ophthalmic aqueous compositions regardless of the types of active ingredients and additives.

[0016] Means for solving problems

[0017] The inventors of the present application have conducted intensive studies to solve the above-mentioned problems and, as a result, have discovered that an ophthalmic aqueous composition filled in a polyester resin container or a polyolefin resin container other than polypropylene has sufficient preservation efficacy for a long period of time, and that the ophthalmic aqueous composition contains a silver salt, thereby completing the present invention.

[0018] Furthermore, the inventors of the present application have found that, since silver salts do not deform soft contact lenses (SCLs), the ophthalmic aqueous composition of the present invention can also be administered as eye drops to eyes wearing SCLs.

[0019] That is, the present invention relates to the following contents.

[0020] (1) An ophthalmic aqueous composition (hereinafter also referred to as "the present ophthalmic aqueous composition") containing a silver salt, which is filled in a container made of a polyester resin or a container made of a polyolefin resin other than polypropylene.

[0021] (2) The ophthalmic aqueous composition according to (1), wherein the polyester resin is polyethylene terephthalate.

[0022] (3) The ophthalmic aqueous composition according to (1), wherein the polyolefin-based resin is polyethylene.

[0023] (4) The ophthalmic aqueous composition according to any one of (1) to (3), wherein the concentration of the silver salt in the ophthalmic aqueous composition is 0.001% (w / v) or less.

[0024] (5) The ophthalmic aqueous composition according to any one of (1) to (4), wherein the concentration of the silver salt in the ophthalmic aqueous composition is 0.000003 to 0.0003% (w / v).

[0025] (6) The ophthalmic aqueous composition according to any one of (1) to (4), wherein the concentration of the silver salt in the ophthalmic aqueous composition is 0.00001 to 0.0001% (w / v).

[0026] (7) The ophthalmic aqueous composition according to any one of (1) to (4), wherein the concentration of the silver salt in the ophthalmic aqueous composition is 0.00002 to 0.0001% (w / v).

[0027] (8) The ophthalmic aqueous composition according to any one of (1) to (7), further comprising an ionic isotonic agent.

[0028] (9) The ophthalmic aqueous composition according to any one of (1) to (8), wherein the polyester resin container or the polyolefin resin container is a multi-dose eye drop container.

[0029] (10) The ophthalmic aqueous composition according to any one of (1) to (9), which is administered as an eye drop.

[0030] (11) The ophthalmic aqueous composition according to any one of (1) to (10), which is administered as an eye drop to an eye wearing a soft contact lens.

[0031] (12) The ophthalmic aqueous composition according to any one of (1) to (11), wherein the silver salt is silver nitrate.

[0032] (13) The ophthalmic aqueous composition according to any one of (1) to (12), comprising an active ingredient.

[0033] (14) The ophthalmic aqueous composition according to (13), wherein the active ingredient is rebamipide, diquafosol, or a salt thereof.

[0034] (15) The ophthalmic aqueous composition according to (13), wherein the active ingredient is sirolimus or a salt thereof.

[0035] (16) The ophthalmic aqueous composition according to (13), which contains an active ingredient other than sirolimus or a salt thereof.

[0036] (17) An ophthalmic aqueous composition comprising rebamipide, polyvinyl pyrrolidone, and silver nitrate, the composition being filled in a multi-dose polyethylene eye drop container.

[0037] (18) An ophthalmic aqueous composition comprising diquafosol sodium, polyvinyl pyrrolidone, and silver nitrate, the composition being filled in a multi-dose polyethylene eye drop container.

[0038] (19) An ophthalmic aqueous composition comprising sirolimus, a surfactant, and silver nitrate, the composition being filled in a multi-dose polyethylene eye drop container.

[0039] (20) An ophthalmic aqueous composition comprising 0.00001 to 0.0001% (w / v) of silver nitrate, the composition being filled in a multi-dose polyethylene terephthalate eye drop container.

[0040] (21) An ophthalmic aqueous composition comprising 0.00002 to 0.0001% (w / v) of silver nitrate, the composition being filled in a multi-dose polyethylene terephthalate eye drop container.

[0041] In addition, the present invention also relates to the following.

[0042] (22) An ophthalmic preservative (hereinafter also referred to as "the present ophthalmic preservative"), which is an ophthalmic preservative containing a silver salt and is filled in a container made of a polyester resin or a container made of a polyolefin resin other than polypropylene.

[0043] (23) A method (hereinafter also referred to as "the present method") for imparting a preservative efficacy to an ophthalmic aqueous composition that complies with the preservative efficacy test criteria of the Japanese Pharmacopoeia, the method comprising: adding a silver salt to the ophthalmic aqueous composition; and filling the ophthalmic aqueous composition into a container made of a polyester resin or a container made of a polyolefin resin other than polypropylene.

[0044] Effects of the Invention

[0045] The present ophthalmic aqueous composition has sufficient long-term preservation efficacy and can therefore be prepared as a multi-dose eye drop and can also be administered as an eye drop to an eye wearing an SCL. DETAILED DESCRIPTION

[0046] In the present invention, the silver salt includes, for example, 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, and preferably refers to silver nitrate.

[0047] The concentration of the silver salt contained in the present ophthalmic aqueous composition is preferably 1% (w / v) or less, more preferably 0.1% (w / v) or less, even more preferably 0.01% (w / v) or less, particularly preferably 0.001% (w / v) or less, and most preferably 0.0001% (w / v) or less. Furthermore, the concentration of the silver salt contained in the present ophthalmic aqueous composition is preferably 0.0000001% (w / v) or more, more preferably 0.000001% (w / v) or more, even more preferably 0.000003% (w / v) or more, and most preferably 0.00001% (w / v) or more. In order to achieve sufficient preservative efficacy without being affected by the active ingredients, additives, etc. contained in the present ophthalmic aqueous composition, the concentration of the silver salt contained in the present ophthalmic aqueous composition is preferably 0.00002% (w / v) or more. The concentration of the silver salt contained in the present ophthalmic aqueous composition is preferably in the range of 0.0000001 to 0.01% (w / v), more preferably 0.000001 to 0.001% (w / v), even more preferably 0.000003 to 0.0003% (w / v), and most preferably 0.00001 to 0.0001% (w / v). Furthermore, from the perspective of achieving sufficient preservative efficacy without being affected by the active ingredients, additives, etc. contained in the present ophthalmic aqueous composition, the concentration of the silver salt contained in the present ophthalmic aqueous composition is preferably in the range of 0.00002 to 0.01% (w / v), more preferably 0.00002 to 0.001% (w / v), even more preferably 0.00002 to 0.0003% (w / v), and most preferably 0.00002 to 0.0001% (w / v).

[0048] In the present invention, the ophthalmic aqueous composition refers to an aqueous composition that is topically administered to a subject's eyes, for example, by eye drops or local ocular injection. Preferably, the ophthalmic aqueous composition is an aqueous composition that is administered to a subject's eyes as eye drops, also known as eye drops.

[0049] In the present invention, an aqueous composition refers to a composition based on water, regardless of its properties. Aqueous compositions include solutions (aqueous solutions), suspensions (aqueous suspensions), and emulsions based on water.

[0050] In the present invention, a "polyester resin container" refers to a container in which at least the portion in contact with the aqueous composition is made of a polyester resin. Therefore, for example, a container in which a polyester resin layer is provided in the inner layer in contact with the ophthalmic aqueous composition and a resin of another material is stacked on the outside also belongs to a "polyester resin container". Here, the dicarboxylic acid and diol constituting the polyester resin are not particularly limited. Examples of dicarboxylic acids include phthalic acid, terephthalic acid, 2,6-naphthalene dicarboxylic acid, and the like. Examples of diols include ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, 1,4-cyclohexanedimethanol, bisphenol, and the like. In addition, it may be a polymer of a single type of polyester unit or a polymer of multiple polyester units. In the case of a polymer of multiple polyester units, the polymerization method is not particularly limited and may be random polymerization or block polymerization. In addition, its tacticity is not particularly limited.

[0051] Examples of polyester resins include homopolyesters such as polyalkylene terephthalates (e.g., polyethylene terephthalate, polybutylene terephthalate, etc.), polyalkylene naphthalates (e.g., polyethylene naphthalate, polybutylene naphthalate, etc.), polycycloalkylene terephthalates (e.g., poly(1,4-cyclohexylenedimethylene terephthalate, etc.), and polyarylates (e.g., resins composed of bisphenol and phthalic acid), copolyesters containing these homopolyester units as main components, and copolymers of the aforementioned homopolyesters. These can be used alone or in combination of two or more.

[0052] The most preferred polyester resin in the present invention is polyethylene terephthalate.

[0053] In the present invention, polyester resin means that at least a part of the material contains polyester resin. For example, a mixture (polymer blend) of a polyester resin and two or more other resins is also included in the polyester resin.

[0054] In the present invention, a "polyolefin resin container" refers to a container in which at least the portion in contact with the aqueous composition is made of a polyolefin resin. Therefore, for example, a container in which a layer of a polyolefin resin is provided in the inner layer in contact with the ophthalmic aqueous composition, and a resin of another material is stacked on the outer side also falls under the category of "polyolefin resin container". Here, the polyolefin resin is not particularly limited and may be a polymer of a single type of monomer (homopolymer) or a copolymer of multiple monomers (copolymer). In addition, in the case of a copolymer, the polymerization method is not particularly limited and may be random polymerization or block polymerization. In addition, its tacticity is not particularly limited.

[0055] Examples of polyolefin resins include polyethylene, cyclic polyolefins, poly(4-methylpentene), polytetrafluoroethylene, ethylene-propylene copolymers, ethylene-α-olefin copolymers, ethylene-acrylic acid copolymers, ethylene-methacrylic acid copolymers, ethylene-vinyl acetate copolymers, and ethylene-ethyl acrylate copolymers. One of these or a combination of two or more thereof may be used. Specific examples of the polyethylene include low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, and medium-density polyethylene.

[0056] The most preferred polyolefin resin in the present invention is polyethylene, preferably low-density polyethylene or high-density polyethylene. It should be noted that, generally speaking, polypropylene is one type of polyolefin resin. However, if the present ophthalmic aqueous composition is filled in a polypropylene container, the silver salt will be adsorbed into the container, and sufficient preservation efficiency cannot be ensured. Therefore, polypropylene is excluded as a material for the resin container filled with the present ophthalmic aqueous composition.

[0057] In the present invention, "made of polyolefin resin" means that at least a part of the material contains polyolefin resin. For example, a mixture (polymer blend) of a polyolefin resin and two or more other resins is also included in "made of polyolefin resin".

[0058] In the present invention, the resin container is preferably an eye drop container, and most preferably a so-called multi-dose eye drop container that allows repeated instillation of the aqueous composition filled into the eye by opening and closing the container.

[0059] Soft contact lenses (SCLs) are classified into four categories according to the "Guidelines for Supplementary Documents Required in Applications for Manufacturing (Import) Permits for Soft Contact Lenses and Disinfectants for Soft Contact Lenses," issued by the Pharmaceutical and Food Safety Agency on March 31, 2001. These categories are Group I (water content less than 50%, non-ionic), Group II (water content 50% or more, non-ionic), Group III (water content less than 50%, ionic), and Group IV (water content 50% or more, ionic). SCLs are considered ionic if the molar percentage of anionic monomers in the constituent monomers of the raw material polymer is 1% or more, and nonionic if the molar percentage is less than 1%. In addition, examples of soft contact lenses include soft contact lenses whose main components include 2-hydroxyethyl methacrylate (HEMA), (polyethylene glycol) methacrylate (PEGMA), glyceryl methacrylate (GMA), N,N-dimethylacrylamide (DMA), vinyl alcohol (VA), N-vinyl pyrrolidone (NVP or VP), methacrylic acid (MAA), fluorine-containing methacrylate compounds, silicon-containing methacrylate compounds, silicone hydrogels, cycloalkyl methacrylates, and the like.

[0060] In the present invention, “administered as eye drops to an eye wearing a soft contact lens” means that the present ophthalmic aqueous composition can be administered as eye drops while the soft contact lens is worn.

[0061] As described below, in the present ophthalmic aqueous composition, when the concentration of the added silver salt is reduced, the silver salt may be adsorbed to the polyolefin resin. Therefore, an ionic isotonic agent may be added to suppress the adsorption.

[0062] The amount of the ionic isotonic agent added to the present ophthalmic aqueous composition is not particularly limited as long as it makes the present ophthalmic aqueous composition isotonic. For example, the ionic isotonic agent can be added to the present ophthalmic aqueous composition in an amount of 0.1 to 0.9% (w / v).

[0063] In the present invention, examples of the "ionic isotonic agent" include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like.

[0064] Furthermore, polyvinyl pyrrolidone can be added to the present ophthalmic aqueous composition. Polyvinyl pyrrolidone is a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone and is also called povidone.

[0065] The K value of the polyvinyl pyrrolidone contained in the present ophthalmic aqueous composition is preferably 17 or higher, more preferably 17 to 120, further preferably 25 to 120, and particularly preferably 30 to 120.

[0066] In the present invention, examples of “polyvinyl pyrrolidone” include polyvinyl pyrrolidone K15 (PVP K15), polyvinyl pyrrolidone K17 (PVP K17), polyvinyl pyrrolidone K25 (PVP K25), polyvinyl pyrrolidone K30 (PVPK30), polyvinyl pyrrolidone K40 (PVP K40), polyvinyl pyrrolidone K50 (PVP K50), polyvinyl pyrrolidone K60 (PVP K60), polyvinyl pyrrolidone K70 (PVP K70), polyvinyl pyrrolidone K80 (PVP K80), polyvinyl pyrrolidone K85 (PVP K85), polyvinyl pyrrolidone K90 (PVP K90), and polyvinyl pyrrolidone K120 (PVP K120).

[0067] The K value of polyvinyl pyrrolidone is an intrinsic viscosity value related to the molecular weight, and is a value calculated by applying the relative viscosity value (25° C.) measured by a capillary viscometer to the following Fikentscher formula (1).

[0068] [Mathematical formula 1]

[0069]

[0070] In formula (1), ηrel is the relative viscosity of the polyvinyl pyrrolidone aqueous solution relative to water, and c is the polyvinyl pyrrolidone concentration (%) in the polyvinyl pyrrolidone aqueous solution.

[0071] Here, according to the description of K value in the 17th revised edition of the Japanese Pharmacopoeia "Polyvidone", the K value is 90 to 108% of the apparent K value. Therefore, for example, "K30" means that the viscosity characteristic value (K value) calculated by applying the above formula (1) is within the range of 27 to 32.4, and "K90" means that the viscosity characteristic value (K value) calculated by applying the above formula (1) is within the range of 81 to 97.2.

[0072] The polyvinyl pyrrolidone contained in the present ophthalmic aqueous composition may be used alone or in any combination of two or more polyvinyl pyrrolidones having different K values.

[0073] Furthermore, in order to maintain the dispersibility and redispersibility of the active ingredient contained in the present ophthalmic aqueous composition and to suppress aggregation, a surfactant may be blended into the present ophthalmic aqueous composition.

[0074] The present ophthalmic aqueous composition may be appropriately formulated with a surfactant usable as a pharmaceutical additive, examples of which include cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants. Hydrates or solvates thereof may also be used.

[0075] In the present invention, examples of the "cationic surfactant" include amine salts such as alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxyethyl-2-alkylimidazolines; and ammonium salts such as benzalkonium chloride, benzethonium chloride, and chlorhexidine gluconate.

[0076] In the present invention, examples of the "anionic surfactant" include sulfonates such as alkylbenzenesulfonates, α-olefinsulfonates, and α-sulfofatty acid ester salts; sulfate ester salts such as alkylsulfate ester salts and polyoxyethylene alkylsulfate ester salts; and phosphates such as sodium polyoxyethylene cetyl ether phosphate.

[0077] In the present invention, examples of the "nonionic surfactant" include polyoxyethylene fatty acid esters such as polyoxyl stearate 40; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65; polyoxyethylene hydrogenated castor oils such as polyoxyethylene 10 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 50 hydrogenated castor oil, and polyoxyethylene 60 hydrogenated castor oil; polyoxyethylene 5 castor oil, polyoxyethylene Polyoxyethylene castor oils such as polyoxyethylene 9 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, and polyoxyethylene 40 castor oil; polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid esters such as sucrose stearate; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), etc.

[0078] The present ophthalmic aqueous composition may also contain additives other than ionic isotonic agents, polyvinyl pyrrolidone, and surfactants. For example, the following additives may be selected and used as needed: nonionic isotonic agents such as glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, and sucrose; buffers such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium citrate hydrate, sodium acetate, and ε-aminocaproic acid; stabilizers such as sodium edetate and sodium edetate hydrate; antioxidants such as ascorbic acid; thickeners (also called thickeners) such as carboxyvinyl polymers, hydroxyethyl cellulose, and hydroxypropyl methylcellulose (hydroxypropyl methylcellulose); and pH adjusters such as hydrochloric acid and sodium hydroxide. The pH may be within the acceptable range for ophthalmic preparations, and is generally preferably within the range of 4 to 8.

[0079] The present ophthalmic aqueous composition may contain an active ingredient. Examples of the active ingredient contained in the present ophthalmic aqueous composition (hereinafter also referred to as the "present active ingredient") include therapeutic agents for dry eye and corneal diseases, antiallergic drugs, steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, ocular hypotensive drugs, antiviral drugs, and antibacterial drugs.

[0080] Specific examples of the therapeutic drug for dry eye and corneal diseases include diquafosol, rebamipide, and salts thereof.

[0081] Other specific examples of the therapeutic drug for dry eye and corneal diseases include cyclosporine, rifalast, and salts thereof.

[0082] Specific examples of the antiallergic drug include olopatadine, levocabastine, ketotifen, and salts thereof.

[0083] Specific examples of steroidal anti-inflammatory drugs include fluorometholone, hydrocortisone, triamcinolone, fluorocinolone, dexamethasone, betamethasone, and salts thereof.

[0084] Specific examples of nonsteroidal anti-inflammatory drugs include indomethacin, bromfenac, diclofenac olopatadine, levocabastine, ketotifen, and salts thereof.

[0085] Specific examples of the ocular hypotensive drug include brimonidine, dorzolamide, brinzolamide, timolol, carteolol, bimatoprost, latanoprost, travoprost, rosudil, and salts thereof.

[0086] Specific examples of antiviral drugs include acyclovir or a salt thereof.

[0087] Specific examples of the antibacterial drug include gatifloxacin, moxifloxacin, tosufloxacin, and salts thereof.

[0088] Examples of the present active ingredient other than those listed above include sirolimus or a salt thereof.

[0089] As the active ingredient of the present invention, quafosol, rebamipide, sirolimus or salts thereof are preferred, and quafosol sodium, rebamipide (free form) and sirolimus (free form) are particularly preferred.

[0090] Diquafosol used in the present invention is a compound represented by the following formula.

[0091] [Chemical Formula 1]

[0092]

[0093] Rebamipide used in the present invention is a compound represented by the following formula.

[0094] [Chemical Formula 2]

[0095]

[0096] Sirolimus used in the present invention is a compound represented by the following formula.

[0097] [Chemical Formula 3]

[0098]

[0099] The salt of the present active ingredient is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts formed with acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic 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, dimethyl sulfate, naphthalenesulfonic acid, Salts formed with organic acids such as sulfosalicylic acid; quaternary ammonium salts formed with methyl bromide, methyl iodide, etc.; salts formed with halogen ions such as bromide ion, chloride ion, iodide ion; salts formed with alkali metals such as lithium, sodium, and potassium; salts formed with alkaline earth metals such as calcium and magnesium; metal salts formed with iron, zinc, etc.; salts formed with ammonia; salts formed 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-ethylenediamine, etc.

[0100] In the present invention, solvates such as hydrates of the present active ingredient are encompassed in the salts of the present active ingredient.

[0101] In the present invention, when geometric isomers or optical isomers exist in the present active ingredient or its salt, the isomers or their salts are also included in the scope of the present invention. In addition, when proton tautomers exist in the present active ingredient or its salt, the tautomers or their salts are also included in the scope of the present invention.

[0102] In the present invention, when the active ingredient or its salt exists in polymorphic forms or polymorphic groups (polymorphic systems), these polymorphic forms and polymorphic groups (polymorphic systems) are also included in the scope of the present invention. Here, the polymorphic group (polymorphic system) refers to each crystal form at each stage of crystal form change and the entire process thereof, depending on the conditions and conditions of production, crystallization, storage, etc. of these crystals (it should be noted that this state also includes the state of formulation).

[0103] In the present invention, as "diquafosol or a salt thereof", tetrasodium salt of diquafosol (hereinafter also referred to as "diquafosol sodium") represented by the following formula is preferred.

[0104] [Chemical Formula 4]

[0105]

[0106] In the present invention, as "rebamipide or a salt thereof", rebamipide (free form) is preferred.

[0107] In the present invention, "sirolimus or a salt thereof" is preferably sirolimus (free form).

[0108] When the active ingredient is diquafosol sodium, polyvinylpyrrolidone can be added to the present ophthalmic aqueous composition to reduce the frequency of eye drops. In this case, the K value of the polyvinylpyrrolidone is preferably 60 to 120, more preferably 60 to 90, and particularly preferably 90. Therefore, when the active ingredient is diquafosol sodium, polyvinylpyrrolidone K60, polyvinylpyrrolidone K70, polyvinylpyrrolidone K80, polyvinylpyrrolidone K85, polyvinylpyrrolidone K90, or polyvinylpyrrolidone K120 is preferably added to the present ophthalmic aqueous composition, with polyvinylpyrrolidone K90 being particularly preferred.

[0109] When the active ingredient is diquafosol sodium, the concentration of polyvinyl pyrrolidone added to the ophthalmic aqueous composition is preferably 0.1 to 10% (w / v), more preferably 0.1 to 5% (w / v), and even more preferably 1 to 5% (w / v).

[0110] That is, when the active ingredient is diquafosol sodium, the present ophthalmic aqueous composition contains diquafosol sodium, polyvinyl pyrrolidone, and silver nitrate, and can be filled in a multi-dose polyethylene eye drop container.

[0111] As described above, various additives can be added to the present ophthalmic aqueous composition. When the active ingredient is diquafosol sodium, in addition to polyvinylpyrrolidone, it is preferred to add an ionic isotonic agent such as sodium chloride, a buffer such as sodium hydrogen phosphate hydrate, a stabilizer such as sodium edetate hydrate, a pH adjuster, and the like to the present ophthalmic aqueous composition.

[0112] When the active ingredient is rebamipide, the addition of polyvinyl pyrrolidone to the ophthalmic aqueous composition can preferably adjust the average particle size (D50) of rebamipide contained in the ophthalmic aqueous composition to 0.01 to 10 μm, more preferably 0.05 to 5 μm, even more preferably 0.1 to 3 μm, and particularly preferably 0.5 to 1 μm. In this case, the K value of polyvinyl pyrrolidone is preferably 17 to 90, more preferably 17 to 60, and particularly preferably 30. Therefore, when the active ingredient is rebamipide, it is preferred to add polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K40, polyvinyl pyrrolidone K50, or polyvinyl pyrrolidone K60 to the ophthalmic aqueous composition, and polyvinyl pyrrolidone K30 is particularly preferred.

[0113] When the active ingredient is rebamipide, the concentration of polyvinyl pyrrolidone added to the present ophthalmic aqueous composition is preferably 0.1 to 2% (w / v), more preferably 0.5 to 2% (w / v), further preferably 1 to 2% (w / v), and most preferably 2% (w / v).

[0114] That is, when the active ingredient is rebamipide, the ophthalmic aqueous composition contains rebamipide, polyvinyl pyrrolidone, and silver nitrate, and can be filled in a multi-dose polyethylene eye drop container.

[0115] When the active ingredient is rebamipide, a carboxyvinyl polymer may be added to increase the viscosity of the ophthalmic aqueous composition. In this case, the concentration of the carboxyvinyl polymer is preferably 0.01 to 1% (w / v), more preferably 0.03 to 0.5% (w / v), further preferably 0.05 to 0.3% (w / v), and most preferably 0.05 to 0.2% (w / v).

[0116] As described above, various additives can be added to the present ophthalmic aqueous composition. However, when the active ingredient is rebamipide, it is preferred to add, in addition to polyvinyl pyrrolidone and carboxyvinyl polymer, ionic isotonic agents such as sodium chloride and potassium chloride, buffers such as sodium citrate hydrate, and pH adjusters to the present ophthalmic aqueous composition.

[0117] When the active ingredient is sirolimus, the aforementioned surfactant can be added to the present ophthalmic aqueous composition. The surfactant added to the present ophthalmic aqueous composition is preferably one or more surfactants selected from the group consisting of polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene alkyl ether phosphate, polyoxyl stearate 40, polysorbate 80, polyoxyethylene 35 castor oil, and polyoxyethylene cetyl ether sodium phosphate, with polysorbate 80 being particularly preferred.

[0118] When the active ingredient is sirolimus, the concentration of the surfactant added to the present ophthalmic aqueous composition is preferably 0.0001 to 5% (w / v), more preferably 0.001 to 2% (w / v), more preferably 0.001 to 1% (w / v), more preferably 0.002 to 1% (w / v), more preferably 0.005 to 1% (w / v), more preferably 0.005 to 0.5% (w / v), more preferably 0.01 to 1% (w / v), further preferably 0.01 to 0.5% (w / v), and particularly preferably 0.01 to 0.1% (w / v).

[0119] When the active ingredient is sirolimus, the pH of the ophthalmic aqueous composition may be within the range permitted for pharmaceuticals, but is preferably approximately 5 from the viewpoint of the stability of the ophthalmic aqueous composition. Specifically, when the active ingredient is sirolimus, the pH of the ophthalmic aqueous composition is preferably 4 to 6, more preferably 4.0 to 6.0, more preferably 4.1 to 5.9, more preferably 4.5 to 5.5, further preferably 4.7 to 5.3, and particularly preferably 5.0.

[0120] That is, when the active ingredient is sirolimus, the present ophthalmic aqueous composition is an ophthalmic aqueous composition containing sirolimus, a surfactant, and silver nitrate, and can be prepared as an ophthalmic aqueous composition having a pH of 4 to 6 that can be filled in a multi-dose polyethylene eye drop container.

[0121] The average particle size (D50) of sirolimus contained in the present ophthalmic aqueous composition is 0.001 to 45 μm, preferably 0.001 to 15 μm, more preferably 0.001 to 10 μm, more preferably 0.001 to 8 μm, more preferably 0.001 to 5 μm, more preferably 0.001 to 2.5 μm, more preferably 0.001 to 1 μm, more preferably 0.01 to 0.5 μm, and even more preferably 0.1 to 1 μm. The average particle size is particularly preferably 0.01 to 0.3 μm.

[0122] When the active ingredient is sirolimus, a dispersant may be added to the ophthalmic aqueous composition. Examples of dispersants include cellulose-based polymers such as methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate; polyvinyl pyrrolidone; polyols such as polyvinyl alcohol and polyethylene glycol; carboxyvinyl polymers; and mucopolysaccharides such as sodium hyaluronate and chondroitin sulfate. Hydrates or solvates thereof may also be mentioned.

[0123] As described above, various additives can be added to the present ophthalmic aqueous composition. When the active ingredient is sirolimus, in addition to the surfactant and dispersant, it is preferred to add an ionic isotonic agent such as sodium chloride or potassium chloride, a stabilizer such as sodium edetate hydrate, a buffer such as sodium citrate hydrate, a pH adjuster, and the like to the present ophthalmic aqueous composition.

[0124] The present ophthalmic aqueous composition contains an active ingredient (except sirolimus or its salt) and a silver salt, and can be filled in a polyester resin container or a polyolefin resin container other than polypropylene.

[0125] The definitions, preferred examples, preferred numerical ranges, and the like of the above terms described in connection with the present ophthalmic aqueous composition also apply to the present ophthalmic preservative and the present method.

[0126] In the present method, "imparting a preservative efficacy that complies with the preservative efficacy test criteria of the Japanese Pharmacopoeia" means that when the subject composition is tested according to the preservative efficacy test method of the 17th revised edition of the Japanese Pharmacopoeia, the composition has a preservative efficacy that complies with the preservative efficacy test criteria of the Japanese Pharmacopoeia.

[0127] The following shows the results of tests using the present ophthalmic aqueous composition and formulation examples. However, these examples are provided for better understanding of the present invention and do not limit the scope of the present invention.

[0128] Example

[0129] [Test 1]

[0130] The preservation efficacy of aqueous solutions containing diquafosol sodium was investigated when various concentrations of silver nitrate were added to the aqueous solutions.

[0131] (Sample Preparation Method)

[0132] Formulation 1-1: Formulation 1-1 was prepared according to the formulation shown in Table 1. Specifically, diquafosol sodium (3 g), silver nitrate (0.00008 g), sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediaminetetraacetic acid hydrate (0.01 g), polyvinylpyrrolidone K30 (PVP K30) (2 g), concentrated glycerin (1.2 g), and hydroxyethyl cellulose (0.25 g) were dissolved in sterile purified water to 100 mL, and a pH adjuster was added to adjust the pH to 7.5.

[0133] Formulations 1-2 to 1-5: According to the formulations shown in Table 1, formulations 1-2 to 1-5 were prepared in the same manner as formulation 1-1.

[0134] [Table 1]

[0135] (In Table 1, the unit is g / 100mL)

[0136]

[0137] (Test method)

[0138] The preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 17th revised edition of the Japanese Pharmacopoeia. Test bacteria used in this test included Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis).

[0139] (result)

[0140] The test results are shown in Table 2. Formulations 1-1 to 1-5 meet the Japanese Pharmacopoeia's preservative efficacy test criteria. It should be noted that the test results in Table 8 use log reduction to indicate the extent to which the viable bacterial count during testing has decreased compared to the inoculated bacterial count. For example, a log reduction of "1" indicates that the viable bacterial count during testing has decreased to 10% of the inoculated bacterial count.

[0141] [Table 2]

[0142] (Number: logarithmic reduction)

[0143]

[0144] (discuss)

[0145] It is clarified that when preparing aqueous eye drops, silver salts such as silver nitrate can be used as new preservatives to replace existing preservatives such as benzalkonium chloride and chlorhexidine gluconate.

[0146] [Test 2]

[0147] The preservation efficacy of aqueous suspensions containing rebamipide was investigated by adding various concentrations of silver nitrate to the suspensions. Furthermore, whether the concentration of silver nitrate in the suspensions changed during storage was also investigated.

[0148] (Sample Preparation Method)

[0149] Formula 2-1: Formula 2-1 was prepared according to the formula shown in Table 3. Specifically, 0.146 g of sodium citrate hydrate, 0.65 g of sodium chloride, 0.18 g of potassium chloride, 2 g of polyvinyl pyrrolidone K30, and 1 g of carboxyvinyl polymer (CARBOPOL (注册商标) 971PNF) 0.11 g and silver nitrate 0.00004 g were dissolved in water, and 2.0 g of rebamipide was added and suspended with stirring to adjust the pH to 5.9. Water was then added to make the volume 100 mL.

[0150] Formulation 2-2~2~3: Prepared in the same manner as Formulation 2-1 according to the formulation shown in Table 3.

[0151] [Table 3]

[0152] (In Table 3, the unit is g / 100mL)

[0153] Element Recipe 2-1 Recipe 2-2 Recipe 2-3 Ribapat 2 2 2 Partially saponified polyvinyl alcohol - - - Polyvinylpyrrolidone K30 2 2 2 Carboxyvinyl polymer 0.11 0.11 0.11 Silver nitrate 0.00004 0.00003 0.00002 Sodium citrate hydrate 0.146 0.146 0.146 Sodium chloride 0.65 0.65 0.65 potassium chloride 0.18 0.18 0.18 pH 5.9 5.9 5.9

[0154] (Test method)

[0155] <Preservation Effectiveness Test>

[0156] The preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 17th revised edition of the Japanese Pharmacopoeia. Test bacteria used in this test included Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus braziliensis (A. braziliensis).

[0157] <Stability test>

[0158] 5 mL of Formulation 2-1 and Formulation 2-3 were placed in low-density polyethylene (LDPE) eye drop containers and stored at 40°C for 3 months or under a light intensity of 1.2 million 1x / hr. The silver nitrate content in the solution before and after storage was measured using the Japanese Pharmacopoeia Inductively Coupled Plasma Mass Spectrometry method.

[0159] (Test Results)

[0160] The test results are shown in Tables 4 and 5. It was shown that Formulations 2-1 to 2-3 met the Japanese Pharmacopoeia's preservative efficacy test criteria. Furthermore, no change in the silver nitrate concentration in the rebamipide-containing aqueous suspension was observed during the storage period.

[0161] [Table 4]

[0162] (Number: logarithmic reduction)

[0163]

[0164] [Table 5]

[0165] Sample name Ag concentration (μg / L) Recipe 2-1_Initial 220 Recipe 2-1_Light 1.2 million lux 210 Formula 2-1_40℃3M 220 Recipe 2-3_Initial 120 Recipe 2-3_Light 1.2 million lux 100 Formula 2-3_40℃3M 110

[0166] (discuss)

[0167] The study clarified that silver salts such as silver nitrate can be used as new preservatives in aqueous suspension eye drops, replacing existing preservatives such as benzalkonium chloride and chlorhexidine gluconate. This indicates that silver salts such as silver nitrate can be used as preservatives in both aqueous eye drops and aqueous suspension eye drops.

[0168] In addition, it was also clarified that silver salts such as silver nitrate are stable in aqueous suspensions containing rebamipide.

[0169] [Test 3]

[0170] Comparison of the stability of silver nitrate and chlorhexidine gluconate in aqueous eye drops containing diquafosol sodium.

[0171] (Sample Preparation Method)

[0172] Formulation 3-1: Formulation 3-1 was prepared according to the formulation shown in Table 3. Specifically, diquafosol sodium (3 g), silver nitrate (0.00008 g), PVP K30 (2 g), hydroxyethyl cellulose (0.25 g), sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediaminetetraacetic acid hydrate (0.01 g), and sodium chloride (0.45 g) were dissolved in water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0173] Comparative formulations 3-1 to 3-4: Comparative formulations 3-1 to 3-4 were prepared according to the formulations shown in Table 6 in the same manner as formulation 3-1.

[0174] [Table 6]

[0175] (In Table 6, the unit is g / 100mL)

[0176]

[0177] (Test method)

[0178] High-frequency inductively coupled plasma atomic emission spectrometry (ICP-AES) was used to quantify the silver ion content of formula 3-1 when stored at 60°C for 4 weeks, and its residual rate (%) was calculated. In addition, high-performance liquid chromatography (HPLC) was used to quantify the chlorhexidine gluconate content of comparative formulas 3-1 and 3-2 when stored at 60°C for 4 weeks, and its residual rate (%) was calculated. In addition, high-performance liquid chromatography (HPLC) was used to quantify the chlorhexidine gluconate content of comparative formulas 3-3 and 3-4 when stored at 60°C for 2 weeks, and its residual rate (%) was calculated.

[0179] (Test Results)

[0180] The test results are shown in Table 7. In formulation 3-1, which contained diquafosol sodium as an active ingredient and PVP K30 as an additive, no change in the silver ion content was observed. On the other hand, in comparative formulations 3-2 to 3-4, which contained diquafosol sodium as an active ingredient and PVP K30 or PVP K90 as additives, a decrease in the chlorhexidine gluconate content was observed.

[0181] [Table 7]

[0182]

[0183] (discuss)

[0184] As described in the "Background Art" section, chlorhexidine gluconate, a preservative safer than benzalkonium chloride, is used in aqueous ophthalmic compositions. However, it has been shown to be unstable in the compositions depending on the active ingredient and additives used. On the other hand, silver salts such as silver nitrate exhibit high stability in aqueous eye drops containing diquafosol sodium, demonstrating that they are widely applicable and stable preservatives, independent of the active ingredient, additives, or properties of the eye drops used.

[0185] [Test 4]

[0186] To investigate the stability of chlorhexidine gluconate in aqueous eye drops containing rebamipide.

[0187] (Sample Preparation Method)

[0188] Comparative Formulation 4-1: Using commercially available “Mucosta(注册商标) Eye drops UD2%".

[0189] Comparative Formulation 4-2: Comparative Formulation 4-2 was prepared according to the formulation shown in Table 8. Specifically, 0.15 g of sodium citrate hydrate, 0.72 g of sodium chloride, 0.18 g of potassium chloride, 1 g of partially saponified polyvinyl alcohol, and 0.01 g of chlorhexidine gluconate were dissolved in water, 2 g of rebamipide was added and the mixture was stirred and suspended to adjust the pH to 6.0, and water was added to make the volume 100 mL.

[0190] Comparative Formulation 4-3: According to the formulation shown in Table 8, it was prepared in the same manner as Comparative Formulation 4-2.

[0191] (Test method)

[0192] The preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 17th revised edition of the Japanese Pharmacopoeia. In this test, all or part of Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus braziliensis (A. braziliensis) were used as test bacteria. The chlorhexidine gluconate content was measured using the "Japanese Pharmacopoeia High Performance Liquid Chromatography Method."

[0193] (result)

[0194] The measurement results are shown in Table 8. Comparative formulations 4-1 to 4-3 did not meet the preservation efficacy test.

[0195] [Table 8]

[0196] (In Table 8, the unit is g / 100mL)

[0197]

[0198] *NI: No increase

[0199] (discuss)

[0200] As described in the "Background Art" section, chlorhexidine gluconate is used in aqueous ophthalmic compositions as a preservative safer than benzalkonium chloride. However, this has been shown to cause variations in the formulation depending on the active ingredient and additives used, preventing adequate preservative efficacy. On the other hand, as described in Experiment 2, silver salts such as silver nitrate have not been observed to exhibit variations in the formulation of aqueous eye drops containing rebamipide, demonstrating that silver salts are widely applicable and stable preservatives, independent of the active ingredient, additives, or properties of the eye drops used.

[0201] [Test 5]

[0202] To study the effect of silver nitrate on soft contact lenses (SCL).

[0203] (Sample Preparation Method)

[0204] Formulation 5-1: Formulation 5-1 was prepared according to the formulation shown in Table 9. Specifically, silver nitrate (0.0004 g), sodium hydrogen phosphate hydrate (0.2 g), and sodium chloride (0.9 g) were dissolved in water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.0.

[0205] Comparative formulations 5-1 to 5-4: Comparative formulations 5-1 to 5-4 were prepared according to the formulations shown in Table 9 in the same manner as formulation 5-1.

[0206] [Table 9]

[0207]

[0208] (Test method)

[0209] The soft contact lenses were immersed in each test preparation at room temperature for 30 minutes and then removed. The diameter and base curve of the soft contact lenses were measured. It should be noted that the soft contact lenses used were Two-week Acuvue (注册商标) (Johnson & Johnson Co., Ltd.).

[0210] It should be noted that the diameter deformation amount and the base arc deformation amount are calculated using the following calculation formulas.

[0211] Diameter deformation (mm) = (diameter after immersion) - (diameter before immersion)

[0212] Base arc deformation (mm) = (base arc after dipping) - (base arc before dipping)

[0213] (Test Results)

[0214] The test results are shown in Table 10.

[0215] [Table 10]

[0216]

[0217] (discuss)

[0218] Benzalkonium chloride, known to cause SCL deformation, was also confirmed to have a tendency to cause SCL deformation in this test compared to other preservatives. On the other hand, little SCL deformation was observed with the formulation containing silver nitrate, and this tendency was significant even when compared to the formulation containing chlorhexidine gluconate, which is said not to cause SCL deformation. Therefore, it was clarified that aqueous ophthalmic compositions containing silver salts such as silver nitrate as preservatives do not cause SCL deformation and can be applied to eyes wearing SCLs.

[0219] [Test 6]

[0220] The adsorption of silver ions on various resins was studied.

[0221] (Sample Preparation Method)

[0222] Formulation 6-1: A sample was prepared by diluting an aqueous solution containing 10 ppm of silver ions, manufactured and sold by Japan Ion Co., Ltd., to 3 ppm (0.0003% (w / v)) with pure water.

[0223] (Test method)

[0224] 5 mL of formula 6-1 was filled into low-density polyethylene (LDPE) eye drop containers, polypropylene (PP) eye drop containers, and polyethylene terephthalate (PET) eye drop containers. The silver ion content immediately after filling and after storage at 60°C for 4 weeks was quantified using high-frequency inductively coupled plasma atomic emission spectrometry (ICP-AES), and the residual rate (%) after storage relative to that immediately after filling was calculated.

[0225] (Test Results)

[0226] The test results are shown in Table 11. It was found that a large amount of silver ions were adsorbed on polypropylene.

[0227] [Table 11]

[0228] LDPE container PP container PET container Residual rate 89％ 0% (ND) 110％

[0229] (discuss)

[0230] It has been shown that ophthalmic aqueous compositions are generally filled in resin containers, but ophthalmic compositions containing silver salts such as silver nitrate are preferably filled in resin containers other than polypropylene containers in order to avoid a decrease in preservation efficacy due to adsorption of silver ions.

[0231] [Test 7]

[0232] To study the adsorption of silver ions on resin in aqueous eye drops containing diquafosol sodium.

[0233] (Sample Preparation Method)

[0234] Formulation 7-1: Formulation 7-1 was prepared according to the formulation shown in Table 12. Specifically, diquafosol sodium (3 g), silver nitrate (0.00004 g), PVP K30 (2 g), hydroxyethyl cellulose (0.25 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), and sodium chloride (0.45 g) were dissolved in water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0235] Formulation 7-2: According to the formulation shown in Table 12, Formulation 7-2 was prepared in the same manner as Formulation 7-1.

[0236] [Table 12]

[0237] (In Table 12, the unit is g / 100 mL)

[0238] Element Recipe 7-1 Recipe 7-2 Diquafosol sodium 3 3 Silver nitrate (preservative) 0.00004 0.00004 PVP K30 2 2 Hydroxyethyl cellulose 0.25 0.25 Sodium hydrogen phosphate hydrate 0.2 0.2 Sodium EDTA hydrate 0.01 0.01 Sodium chloride 0.45 - D-Mannitol - 2.2 pH adjusters qs qs pH 7.5 7.5

[0239] (Test method)

[0240] Formula 7-1 and Formula 7-2 were filled into low-density polyethylene (LDPE) eye drop containers, and the silver ion content was quantified when stored at 60°C for 4 weeks using high-frequency inductively coupled plasma atomic emission spectrometry (ICP-AES), and the residual rate (%) relative to that immediately after filling was calculated.

[0241] (Test Results)

[0242] The test results are shown in Table 13. In Formulation 7-2, adsorption of silver ions was also confirmed on the low-density polyethylene (LDPE) eye drop container, but the adsorption was completely suppressed by adding sodium chloride.

[0243] [Table 13]

[0244] Recipe 7-1 Recipe 7-2 Residual rate 102％ 9％

[0245] (discuss)

[0246] In this experiment, the concentration of silver nitrate added to the aqueous composition was 0.00004% (w / v), significantly lower than the concentration used in Experiment 6 (0.003% (w / v)). Therefore, it is believed that non-negligible adsorption of silver ions was also observed in low-density polyethylene (LDPE) eye drop containers. On the other hand, this suggests that the adsorption of silver ions into resin containers can be significantly suppressed by adding an ionic isotonic agent such as sodium chloride.

[0247] [Test 8]

[0248] The preservation efficacy of sirolimus-containing aqueous suspensions was investigated when various concentrations of silver nitrate were added to the suspensions. Furthermore, whether the silver nitrate concentration in the suspensions changed during storage was also investigated.

[0249] (Sample Preparation Method)

[0250] Comparative Formulation 8-1: Comparative Formulation 8-1 was prepared according to the formulation shown in Table 14. Specifically, sirolimus, polysorbate 80, and purified water were mixed and wet-pulverized using a bead mill. The additive solution listed in Table 14 was then added and mixed, and a pH adjuster was added to adjust the pH to 5.

[0251] Formulation 8-1 to 8-2: Prepared in the same manner as Formulation 8-1 according to the formulation shown in Table 14.

[0252] [Table 14]

[0253] (In Table 14, the unit is g / 100 mL)

[0254]

[0255] (Test method)

[0256] <Preservation Effectiveness Test>

[0257] The preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 17th revised edition of the Japanese Pharmacopoeia. Test bacteria used in this test included Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus braziliensis (A. braziliensis).

[0258] <Stability test>

[0259] 5 mL of Comparative Formulation 8-1 and Formulations 8-1 to 8-2 were placed in low-density polyethylene (LDPE) eye drop containers and stored at 60° C. for 4 weeks. The silver nitrate content in the solution before and after storage was measured using the Japanese Pharmacopoeia Inductively Coupled Plasma Mass Spectrometry method.

[0260] (Test Results)

[0261] The test results are shown in Tables 15 and 16. It was demonstrated that Formulations 8-1 and 8-2 met the Japanese Pharmacopoeia's preservation efficacy test criteria. Furthermore, no change in the silver nitrate concentration in the sirolimus-containing aqueous suspension was observed during the storage period.

[0262] [Table 15]

[0263]

[0264] *NI: No increase

[0265] [Table 16]

[0266] Sample name Ag concentration (μg / L) Formula 8-1 Initial 142 Formula 8-1 After 4 weeks storage at 60℃ 128 Formula 8-2 Initial 264 Formula 8-2 After 4 weeks of storage at 60℃ 255

[0267] (discuss)

[0268] This study clarified that silver salts such as silver nitrate can also serve as a novel preservative in aqueous suspension eye drops containing sirolimus, replacing existing preservatives such as benzalkonium chloride and chlorhexidine gluconate. This study demonstrates that, unlike the aforementioned aqueous eye drops containing diquafosol sodium and rebamipide, aqueous suspension eye drops containing sirolimus, despite containing a surfactant, can achieve sufficient preservative efficacy by including silver nitrate at a concentration of 0.00002% (w / v) or higher. This demonstrates that silver salts such as silver nitrate can be used as preservatives in aqueous eye drops and aqueous suspension eye drops, regardless of the type of active ingredient or additive.

[0269] [Preparation Example]

[0270] The pharmaceutical agent of the present invention will be described in more detail with reference to formulation examples, but the present invention is not limited to these formulation examples.

[0271] (Preparation Example 1)

[0272] 100mL

[0273]

[0274] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0275] (Preparation Example 2)

[0276] 100mL

[0277]

[0278] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0279] (Preparation Example 3)

[0280] 100mL

[0281]

[0282]

[0283] The above preparation was filled into a polyethylene terephthalate multi-dose eye drop container.

[0284] (Preparation Example 4)

[0285] 100mL

[0286]

[0287] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0288] (Preparation Example 5)

[0289] 100mL

[0290]

[0291]

[0292] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0293] (Preparation Example 6)

[0294] 100mL

[0295]

[0296] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0297] (Preparation Example 7)

[0298] 100mL

[0299]

[0300]

[0301] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0302] (Preparation Example 8)

[0303] 100mL

[0304]

[0305] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0306] (Preparation Example 9)

[0307] 100mL

[0308]

[0309]

[0310] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0311] (Preparation Example 10)

[0312] 100mL

[0313]

[0314] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0315] (Preparation Example 11)

[0316] 100mL

[0317]

[0318] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0319] (Preparation Example 12)

[0320] 100mL

[0321]

[0322] The above preparation was filled into a multi-dose eye drop container made of low-density polyethylene (LDPE).

[0323] Industrial applicability

[0324] The present invention relates to an ophthalmic aqueous composition containing a silver salt, which is filled in a container made of a polyester resin or a container made of a polyolefin resin other than polypropylene. This ophthalmic aqueous composition has sufficient long-term shelf life and can be prepared as a multi-dose eye drop. It can also be administered to eyes wearing a surgical lens (SCL).

Claims

1. An ophthalmic aqueous composition comprising any one of rebamipide, diquafosol, sirolimus, and their respective salts as an active ingredient and a silver salt, wherein the concentration of the silver salt in the ophthalmic aqueous composition is 0.00004 to 0.001 w / v%, and the ophthalmic aqueous composition further comprises an ionic isotonic agent, wherein the ophthalmic aqueous composition is filled in a container made of a polyester resin or a polyolefin resin, wherein the polyester resin is polyethylene terephthalate, and the polyolefin resin is polyethylene.

2. The ophthalmic aqueous composition according to claim 1, wherein The concentration of the silver salt in the ophthalmic aqueous composition is 0.00004 to 0.0003 w / v%.

3. The ophthalmic aqueous composition according to claim 1, wherein The concentration of the silver salt in the ophthalmic aqueous composition is 0.00004 to 0.0001 w / v%.

4. The ophthalmic aqueous composition according to claim 1, wherein The polyester resin container or the polyolefin resin container is a multi-dose eye drop container.

5. The ophthalmic aqueous composition according to claim 1, wherein Eye drops are administered.

6. The ophthalmic aqueous composition according to claim 1, wherein Eye drops are applied to eyes wearing soft contact lenses.

7. The ophthalmic aqueous composition according to claim 1, wherein The silver salt is silver nitrate.

8. An ophthalmic aqueous composition comprising rebamipide, polyvinylpyrrolidone, and silver nitrate, wherein the concentration of the silver nitrate in the ophthalmic aqueous composition is 0.00004 to 0.001 w / v%, and further comprising an ionic isotonic agent, the composition being filled in a multi-dose polyethylene eye drop container.

9. An ophthalmic aqueous composition comprising diquafosol sodium, polyvinylpyrrolidone, and silver nitrate, wherein the concentration of the silver nitrate in the ophthalmic aqueous composition is 0.00004 to 0.001 w / v%. The ophthalmic aqueous composition further comprises an ionic isotonic agent, and the composition is filled in a multi-dose polyethylene eye drop container.

10. An ophthalmic aqueous composition comprising sirolimus, a surfactant, and silver nitrate, wherein the concentration of the silver nitrate in the ophthalmic aqueous composition is 0.00004 to 0.001 w / v%, and the ophthalmic aqueous composition further comprises an ionic isotonic agent, the composition being filled in a multi-dose polyethylene eye drop container.

11. An ophthalmic aqueous composition comprising any one of rebamipide, diquafosol, sirolimus, and their respective salts as an active ingredient and silver nitrate at a concentration of 0.00004 to 0.0001 w / v%, the ophthalmic aqueous composition further comprising an ionic isotonic agent, the composition being filled in a multi-dose polyethylene terephthalate eye drop container.

12. An eye drop filled with an ophthalmic aqueous composition comprising any one of rebamipide, diquafosol, sirolimus, and their respective salts as an active ingredient, a silver salt at a concentration of 0.00004-0.001 w / v%, and an ionic isotonic agent, wherein the ophthalmic aqueous composition is filled in a container made of a polyester resin or a container made of a polyolefin resin, wherein the polyester resin is polyethylene terephthalate and the polyolefin resin is polyethylene.

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