Silver salt-containing aqueous ophthalmic composition filled in resin container

Abstract

To provide preservatives / systems that can be widely used in aqueous ophthalmic compositions, regardless of the type of active ingredients or additives.SOLUTION: Provided is an aqueous ophthalmic composition containing silver salt, the aqueous ophthalmic composition being filled in a polyester resin container or a polypropylene-free polyolefin resin container. Provided is an ophthalmic preservative containing silver salt, the ophthalmic preservative being filled in a polyester resin container or a polypropylene-free polyolefin resin container. Provided is a method of imparting to an aqueous ophthalmic composition a preservative efficacy that meets the preservative efficacy test criteria of the Japanese Pharmacopoeia, the method comprising adding a silver salt to an aqueous ophthalmic composition, and filling the aqueous ophthalmic composition into a polyester resin container or a polypropylene-free polyolefin resin container.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an aqueous ophthalmic 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 technology]

[0002] Since aqueous ophthalmic compositions are mainly administered by instillation into the eyes, and are often instilled into the eyes several times a day, from the viewpoint of convenience, the compositions are preferably filled in a container that allows repeated instillation, i.e., a multi-dose eye drop container. When the compositions are filled 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 when used at high concentrations. It is also known that benzalkonium chloride adsorbs to soft contact lenses and deforms them. To avoid such disadvantages, aqueous ophthalmic compositions containing no preservatives are also used in the treatment of ophthalmic diseases. For example, "Mucosta (登録商標) As described in the package insert for "Mucosta UD 2% Eye Drops" (Non-Patent Document 1), (登録商標) No preservatives are added to "Mucosta UD 2% Eye Drops." (登録商標) Eye drops UD 2% are single-use disposables, so as mentioned above, there are still issues in terms of convenience.

[0004] On the other hand, there are also multi-dose aqueous ophthalmic compositions containing preservatives that are safer than benzalkonium chloride. (登録商標) As described in the package insert for "Diquas ophthalmic solution 3%" (Non-patent document 2), (登録商標)The 3% eye drops contain chlorhexidine gluconate as a preservative, rather than the commonly used benzalkonium chloride. Japanese Patent Application Laid-Open Publication No. 2017-2036 (Patent Document 1) describes that chlorhexidine gluconate does not deform soft contact lenses. However, it is unclear whether chlorhexidine gluconate can always be used in place of benzalkonium chloride, regardless of the types of active ingredients and additives contained in the aqueous ophthalmic composition.

[0005] Silver nitrate eye drops "Bon Happy" (登録商標) The package insert (Non-Patent Document 3) describes the use of silver nitrate eye drops for the treatment of neonatal pyorrhea. However, Non-Patent Document 3 does not describe the use of silver nitrate as a preservative for aqueous ophthalmic compositions. Furthermore, JP 2016-507469 A (Patent Document 2) discloses an emulsion composition containing difluprednate and an antibacterial metal, exemplifying silver salts as antibacterial metals, and also describes that the emulsion composition can be used as an ophthalmic composition. However, Patent Document 2 does not describe or suggest what material of container the composition should be filled into. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 2017-2036 [Patent Document 2] Special Publication No. 2016-507469 [Non-patent literature]

[0007] [Non-Patent Document 1] Mucosta (registered trademark) Ophthalmic Solution UD 2% package insert [Non-patent document 2] Diquas (registered trademark) ophthalmic solution 3% package insert [Non-patent document 3] Silver nitrate eye drops "Bonhappy (registered trademark)" package insert Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a preservative / system that can be widely used in aqueous ophthalmic compositions, regardless of the type of active ingredient or additive. [Means for solving the problem]

[0009] As a result of intensive research conducted by the present inventors to solve the above-mentioned problems, they found that an aqueous ophthalmic 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, has sufficient preservative effectiveness over a long period of time, and thus arrived at the present invention.

[0010] The present inventors have also found that the aqueous ophthalmic composition of the present invention can be administered by instillation to eyes wearing soft contact lenses (SCLs) because silver salts do not deform the SCLs.

[0011] That is, the present invention relates to the following: (1) An aqueous ophthalmic composition containing a silver salt, which is filled in a polyester resin container or a polyolefin resin container other than polypropylene (hereinafter also referred to as "the aqueous ophthalmic composition").

[0012] (2) The aqueous ophthalmic composition according to (1), wherein the polyester resin is polyethylene terephthalate.

[0013] (3) The aqueous ophthalmic composition according to (1), wherein the polyolefin resin is polyethylene.

[0014] (4) The aqueous ophthalmic composition according to any one of (1) to (3), wherein the concentration of the silver salt in the aqueous ophthalmic composition is 0.001% (w / v) or less.

[0015] (5) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of the silver salt in the aqueous ophthalmic composition is 0.000003 to 0.0003% (w / v).

[0016] (6) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of the silver salt in the aqueous ophthalmic composition is 0.00001 to 0.0001% (w / v).

[0017] (7) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of the silver salt in the aqueous ophthalmic composition is 0.00002 to 0.0001% (w / v).

[0018] (8) The aqueous ophthalmic composition according to any one of (1) to (7), further comprising an ionic tonicity agent.

[0019] (9) The aqueous ophthalmic 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.

[0020] (10) The aqueous ophthalmic composition according to any one of (1) to (9), which is administered by instillation into the eye.

[0021] (11) The aqueous ophthalmic composition according to any one of (1) to (10), which is administered by instillation to an eye wearing a soft contact lens.

[0022] (12) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the silver salt is silver nitrate.

[0023] (13) The aqueous ophthalmic composition according to any one of (1) to (12), which contains an active ingredient.

[0024] (14) The aqueous ophthalmic composition according to (13), wherein the active ingredient is rebamipide, diquafosol, or a salt thereof.

[0025] (15) The aqueous ophthalmic composition according to (13), wherein the active ingredient is sirolimus or a salt thereof.

[0026] (16) The aqueous ophthalmic composition according to (13), which contains an active ingredient other than sirolimus or a salt thereof.

[0027] (17) An aqueous ophthalmic composition containing rebamipide, polyvinylpyrrolidone, and silver nitrate, the aqueous ophthalmic composition being filled in a multi-dose polyethylene eye dropper container.

[0028] (18) An aqueous ophthalmic composition containing diquafosol sodium, polyvinylpyrrolidone, and silver nitrate, the aqueous ophthalmic composition being filled in a multi-dose polyethylene eye dropper container.

[0029] (19) An aqueous ophthalmic composition containing sirolimus, a surfactant, and silver nitrate, the aqueous ophthalmic composition being filled in a multi-dose polyethylene eye dropper container.

[0030] (20) An aqueous ophthalmic composition containing 0.00001 to 0.0001% (w / v) of silver nitrate, the aqueous ophthalmic composition being filled in a multi-dose polyethylene terephthalate eye dropper container.

[0031] (21) An aqueous ophthalmic composition containing 0.00002 to 0.0001% (w / v) of silver nitrate, the aqueous ophthalmic composition being filled in a multi-dose polyethylene terephthalate eye dropper container.

[0032] Furthermore, the present invention also relates to the following: (22) An ophthalmic preservative containing a silver salt, which is filled in a polyester resin container or a polyolefin resin container other than polypropylene (hereinafter also referred to as "this ophthalmic preservative").

[0033] (23) A method for imparting preservative effectiveness to an aqueous ophthalmic composition that satisfies the preservative effectiveness test standards of the Japanese Pharmacopoeia, the method comprising the steps of adding a silver salt to the aqueous ophthalmic composition and filling the aqueous ophthalmic composition into a polyester-based resin container or a polyolefin-based resin container other than polypropylene (hereinafter also referred to as "the method"). [Effects of the Invention]

[0034] The present aqueous ophthalmic composition has sufficient preservative effectiveness for a long period of time, and therefore can be used as a multi-dose eye drop, and can also be administered by instillation to eyes wearing SCLs. DETAILED DESCRIPTION OF THE INVENTION

[0035] In the present invention, silver salts include, 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, but preferably silver nitrate.

[0036] The concentration of the silver salt contained in the aqueous ophthalmic 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. The concentration of the silver salt contained in the aqueous ophthalmic 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. From the viewpoint of ensuring sufficient preservative effectiveness without being affected by the active ingredients, additives, etc. contained in the aqueous ophthalmic composition, it is also preferable that the concentration of the silver salt contained in the aqueous ophthalmic composition be 0.00002% (w / v) or more. The concentration range of the silver salt contained in the present aqueous ophthalmic composition is preferably 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 viewpoint of obtaining sufficient preservative effectiveness without being affected by the active ingredients, additives, etc. contained in the present aqueous ophthalmic composition, the concentration range of the silver salt contained in the present aqueous ophthalmic composition is preferably 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).

[0037] In the present invention, the aqueous ophthalmic composition refers to an aqueous composition that is administered topically to the eyes of a subject, for example, by eye drops or local ocular injection. A preferred aqueous ophthalmic composition is an aqueous composition that is administered topically to the eyes of a subject, and is also called an eye drop.

[0038] In the present invention, the aqueous composition refers to a composition based on water, regardless of its form. The aqueous composition includes a solution (aqueous solution), a suspension (aqueous suspension), and an emulsion based on water.

[0039] In the present invention, a "polyester resin container" refers to a container in which at least the portion of the container that comes into contact with the aqueous composition is made of a polyester resin. Therefore, for example, a container having a polyester resin layer as the inner layer that comes into contact with the aqueous ophthalmic composition and a resin of another material laminated on the outer surface also falls under the category of a "polyester resin container." The dicarboxylic acids and diols that constitute the polyester resin are not particularly limited. Examples of dicarboxylic acids include phthalic acid, terephthalic acid, and 2,6-naphthalenedicarboxylic acid. Examples of diols include ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,4-cyclohexanedimethanol, and bisphenol. The polyester resin may be a polymer of a single type of polyester unit or a polymer of multiple types of polyester units. In the case of a polymer of multiple types of polyester units, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited.

[0040] Examples of polyester-based resins include homopolyesters such as polyalkylene terephthalates (e.g., polyethylene terephthalate, polybutylene terephthalate), polyalkylene naphthalates (e.g., polyethylene naphthalate, polybutylene naphthalate), polycycloalkylene terephthalates (e.g., poly(1,4-cyclohexylene dimethylene terephthalate)), and polyarylates (e.g., resins composed of bisphenol and phthalic acid), as well as copolyesters containing these homopolyester units as the main component, and copolymers of the above homopolyesters, and these can be used alone or in combination of two or more.

[0041] The most preferred polyester resin in the present invention is polyethylene terephthalate.

[0042] In the present invention, "made of polyester-based resin" means that at least a part of the material contains polyester-based resin, and for example, a mixture of two or more resins, such as polyester-based resin and other resins (polymer alloy), is also included in "made of polyester-based resin."

[0043] In the present invention, a "polyolefin resin container" refers to a container in which at least the portion of the container that comes into contact with the aqueous composition is made of a polyolefin resin. Therefore, for example, a container in which a polyolefin resin layer is provided as an inner layer that comes into contact with the aqueous ophthalmic composition and another resin material is laminated on the outer surface also falls under the category of a "polyolefin resin container." The polyolefin resin is not particularly limited, and may be a polymer (homopolymer) of a single type of monomer or a copolymer (copolymer) of multiple types of monomers. Furthermore, in the case of a copolymer, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited.

[0044] Examples of polyolefin resins include polyethylene, cyclic polyolefin, poly(4-methylpentene), polytetrafluoroethylene, ethylene-propylene copolymer, ethylene-α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, etc., and these can be used alone or in combination of two or more. Specific examples of the polyethylene include low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, and medium-density polyethylene.

[0045] The most preferred polyolefin resin in the present invention is polyethylene, and low-density polyethylene or high-density polyethylene is preferred. Although polypropylene is generally a type of polyolefin resin, if the present aqueous ophthalmic composition is filled in a polypropylene container, the silver salt will be adsorbed to the container, making it impossible to ensure sufficient preservative effectiveness. Therefore, polypropylene is excluded from the materials for the resin container in which the present aqueous ophthalmic composition is filled.

[0046] In the present invention, "made of polyolefin-based resin" means that at least a portion of the material contains polyolefin-based resin, and for example, a mixture of two or more resins, i.e., a polyolefin-based resin and another resin (polymer alloy), is also included in "made of polyolefin-based resin."

[0047] In the present invention, the resin container is preferably an eye drop container, and in particular, a so-called multi-dose eye drop container, which can repeatedly instill the aqueous composition filled therein by opening and closing the stopper, is most preferred.

[0048] Soft contact lenses (SCLs) are classified into four groups in accordance with Notification No. 645 of the Pharmaceutical and Medical Affairs Agency, dated March 31, 1999, entitled "Handling of documents to be attached when applying for approval to manufacture (import) soft contact lenses and soft contact lens disinfectants." Namely, they are classified into Group I (non-ionic with a water content of less than 50%), Group II (non-ionic with a water content of 50% or more), Group III (ionic with a water content of less than 50%), and Group IV (ionic with a water content of 50% or more), with SCLs being classified as ionic if the molar percentage of monomers containing anions among the constituent monomers of the raw material polymer is 1% or more, and non-ionic if the molar percentage is less than 1%. Examples of soft contact lenses include soft contact lenses whose main component is 2-hydroxyethyl methacrylate (HEMA), (polyethylene glycol) monomethacrylate (PEGMA), glycerol methacrylate (GMA), N,N-dimethylacrylamide (DMA), vinyl alcohol (VA), N-vinylpyrrolidone (NVP or VP), methacrylic acid (MAA), fluorine-containing methacrylate compounds, silicon-containing methacrylate compounds, silicone hydrogel, cycloalkyl methacrylate, or the like.

[0049] In the present invention, "administered by instillation to an eye wearing a soft contact lens" means that the present aqueous ophthalmic composition can be administered by instillation to the eye while the soft contact lens is being worn.

[0050] As will be described later, when the concentration of the silver salt added to the present aqueous ophthalmic composition is reduced, the silver salt may also be adsorbed onto the polyolefin resin, and therefore, an ionic tonicity agent can be added to suppress this.

[0051] The amount of ionic tonicity agent added to the present aqueous ophthalmic composition is not particularly limited as long as it is an amount that makes the present aqueous ophthalmic composition isotonic. For example, 0.1 to 0.9% (w / v) of the ionic tonicity agent can be added to the present aqueous ophthalmic composition.

[0052] In the present invention, examples of the "ionic tonicity agent" include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc.

[0053] The aqueous ophthalmic composition may also contain polyvinylpyrrolidone, which is a polymer compound formed by polymerization of N-vinyl-2-pyrrolidone and is also known as povidone.

[0054] The K value of polyvinylpyrrolidone contained in the present aqueous ophthalmic composition is preferably 17 or more, more preferably 17-120, even more preferably 25-120, and particularly preferably 30-120.

[0055] 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).

[0056] The K value of polyvinylpyrrolidone is a viscosity characteristic value that correlates with molecular weight, and is calculated by applying the relative viscosity value (25°C) measured with a capillary viscometer to the following Fikentscher formula (1).

[0057]

number

[0058] In the formula (1), ηrel is the relative viscosity of the aqueous polyvinylpyrrolidone solution to water, and c is the concentration (%) of polyvinylpyrrolidone in the aqueous polyvinylpyrrolidone solution.

[0059] Here, the K value is 90 to 108% of the indicated K value in accordance with the description of the K value in the Seventeenth Edition of the Japanese Pharmacopoeia for "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 to 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 to 97.2.

[0060] The present aqueous ophthalmic composition may contain one type of polyvinylpyrrolidone alone, or two or more types of polyvinylpyrrolidone with different K values ​​may be used in any combination.

[0061] Furthermore, in order to maintain the dispersibility and redispersibility of the active ingredient contained in the present aqueous ophthalmic composition and to inhibit aggregation, a surfactant may be blended into the present aqueous ophthalmic composition.

[0062] The present aqueous ophthalmic composition can be appropriately blended with a surfactant that can be used as an additive for pharmaceuticals, such as a cationic surfactant, an anionic surfactant, an amphoteric surfactant, or a nonionic surfactant, and these may also be hydrates or solvates thereof.

[0063] In the present invention, examples of the "cationic surfactant" include amine salts such as alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxylethyl-2-alkylimidazolines; and ammonium salts such as benzalkonium chloride, benzethonium chloride, and chlorhexidine gluconate.

[0064] In the present invention, examples of the "anionic surfactant" include sulfonates such as alkylbenzenesulfonates, α-olefinsulfonates, and α-sulfofatty acid ester salts; sulfates such as alkyl sulfates and polyoxyethylene alkyl sulfates; and phosphates such as sodium polyoxyethylene cetyl ether phosphate.

[0065] In the present invention, examples of the "nonionic surfactant" include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; 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 hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, and polyoxyethylene hydrogenated castor oil. Polyoxyl castor oils such as Polyoxyl 35 castor oil and Polyoxyl 40 castor oil; polyoxyethylene polyoxypropylene glycols such as 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; and tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS).

[0066] The aqueous ophthalmic composition may contain additives other than ionic tonicity agents, polyvinylpyrrolidone, and surfactants. For example, the composition may be prepared by selecting from nonionic tonicity 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 epsilon-aminocaproic acid; stabilizers such as sodium edetate and sodium edetate hydrate; antioxidants such as ascorbic acid; thickeners (also known as thickeners) such as carboxyvinyl polymers, hydroxyethyl cellulose, and hydroxypropyl methylcellulose (hypromellose); and pH adjusters such as hydrochloric acid and sodium hydroxide. The pH may be within the range acceptable for ophthalmic formulations, preferably within the range of 4 to 8.

[0067] The present aqueous ophthalmic composition may contain an active ingredient, examples of which (hereinafter simply referred to as "the active ingredient") include drugs for treating dry eye and corneal diseases, antiallergic drugs, steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, intraocular pressure-reducing drugs, antiviral drugs, and antibacterial drugs.

[0068] Specific examples of the drug for treating dry eye and corneal diseases include diquafosol, rebamipide, or a salt thereof.

[0069] Other specific examples of the drug for treating dry eye and corneal diseases include cyclosporine, lifitegrast, or a salt thereof.

[0070] Specific examples of antiallergic drugs include olopatadine, levocabastine, ketotifen, or salts thereof.

[0071] Specific examples of the steroidal anti-inflammatory drug include fluorometholone, hydrocortisone, triamcinolone, fluocinolone, dexamethasone, betamethasone, or salts thereof.

[0072] Specific examples of non-steroidal anti-inflammatory drugs include indomethacin, bromfenac, diclofenac olopatadine, levocabastine, ketotifen, and salts thereof.

[0073] Specific examples of intraocular pressure-reducing drugs include brimonidine, dorzolamide, brinzolamide, timolol, carteolol, bimatoprost, latanoprost, travoprost, ripasudil, or salts thereof.

[0074] A specific example of the antiviral agent is acyclovir or a salt thereof. Specific examples of antibacterial agents include gatifloxacin, moxifloxacin, tosufloxacin, or salts thereof.

[0075] Examples of the active ingredient other than those listed above include sirolimus or a salt thereof.

[0076] The active ingredient is preferably diquafosol, rebamipide, sirolimus or a salt thereof, and diquafosol sodium, rebamipide (free form) or sirolimus (free form) is particularly preferred.

[0077] Diquafosol used in the present invention is a compound represented by the following formula:

[0078] [ka]

[0079] Rebamipide used in the present invention is a compound represented by the following formula:

[0080] [ka]

[0081] The sirolimus used in the present invention is a compound represented by the following formula:

[0082] [ka]

[0083] The salt of the active ingredient is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid, and salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic 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. salts with halogen ions such as bromide ion, chloride ion, and iodide ion; salts with alkali metals such as lithium, sodium, and potassium; salts with alkaline earth metals such as calcium and magnesium; metal salts with iron and zinc; 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.

[0084] In the present invention, solvates such as hydrates of the present active ingredient are included in the salts of the present active ingredient. In the present invention, when the active ingredient or a salt thereof has geometric or optical isomers, the isomers or salts thereof are also included in the scope of the present invention. In addition, when the active ingredient or a salt thereof has proton tautomerism, the tautomers or salts thereof are also included in the scope of the present invention.

[0085] In the present invention, when the active ingredient or its salt has a crystalline polymorphism or a crystalline polymorphism system, the crystalline polymorphism or the crystalline polymorphism system is also included in the scope of the present invention. Here, the crystalline polymorphism 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, storage, etc. of the crystals (including the state of formulation).

[0086] In the present invention, the "diquafosol or a salt thereof" is preferably the tetrasodium salt of diquafosol represented by the following formula (hereinafter also simply referred to as "diquafosol sodium").

[0087] [ka]

[0088] In the present invention, "rebamipide or a salt thereof" is preferably rebamipide (free form).

[0089] In the present invention, the "sirolimus or a salt thereof" is preferably sirolimus (free form).

[0090] When the active ingredient is diquafosol sodium, polyvinylpyrrolidone can be added to the aqueous ophthalmic composition to reduce the frequency of instillation. In this case, the K value of polyvinylpyrrolidone is preferably 60 to 120, more preferably 60 to 90, and particularly preferably 90. Therefore, when the active ingredient is diquafosol sodium, it is preferable to add polyvinylpyrrolidone K60, polyvinylpyrrolidone K70, polyvinylpyrrolidone K80, polyvinylpyrrolidone K85, polyvinylpyrrolidone K90, or polyvinylpyrrolidone K120 to the aqueous ophthalmic composition, and it is particularly preferable to add polyvinylpyrrolidone K90.

[0091] When the active ingredient is diquafosol sodium, the concentration of polyvinylpyrrolidone added to the aqueous ophthalmic 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).

[0092] That is, when the active ingredient is diquafosol sodium, the aqueous ophthalmic composition can be an aqueous ophthalmic composition containing diquafosol sodium, polyvinylpyrrolidone, and silver nitrate, and filled in a multi-dose polyethylene eye drop container.

[0093] As described above, various additives can be added to the aqueous ophthalmic composition. When the active ingredient is diquafosol sodium, it is preferable to add, in addition to polyvinylpyrrolidone, an ionic tonicity agent such as sodium chloride, a buffering agent such as sodium hydrogen phosphate hydrate, a stabilizer such as sodium edetate hydrate, a pH adjuster, or the like to the aqueous ophthalmic composition.

[0094] When the active ingredient is rebamipide, the average particle size (D50) of rebamipide contained in the aqueous ophthalmic composition can be adjusted to preferably 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 by adding polyvinylpyrrolidone to the aqueous ophthalmic composition. In this case, the K value of polyvinylpyrrolidone is preferably 17 to 90, more preferably 17 to 60, and particularly preferably 30. Therefore, when the active ingredient is rebamipide, the aqueous ophthalmic composition is preferably added with polyvinylpyrrolidone K30, polyvinylpyrrolidone K40, polyvinylpyrrolidone K50, or polyvinylpyrrolidone K60, and particularly preferably polyvinylpyrrolidone K30.

[0095] When the active ingredient is rebamipide, the concentration of polyvinylpyrrolidone added to the aqueous ophthalmic composition is preferably 0.1 to 2% (w / v), more preferably 0.5 to 2% (w / v), even more preferably 1 to 2% (w / v), and most preferably 2% (w / v).

[0096] That is, when the active ingredient is rebamipide, the aqueous ophthalmic composition can be an aqueous ophthalmic composition containing rebamipide, polyvinylpyrrolidone, and silver nitrate, and filled in a multi-dose polyethylene eye drop container.

[0097] When the active ingredient is rebamipide, a carboxyl vinyl polymer can be added to the aqueous ophthalmic composition to increase its viscosity. In this case, the concentration of the carboxyl vinyl polymer is preferably 0.01 to 1% (w / v), more preferably 0.03 to 0.5% (w / v), even more preferably 0.05 to 0.3% (w / v), and most preferably 0.05 to 0.2% (w / v).

[0098] As described above, various additives can be added to the aqueous ophthalmic composition. When the active ingredient is rebamipide, it is preferable to add, in addition to polyvinylpyrrolidone and a carboxyvinyl polymer, an ionic tonicity agent such as sodium chloride or potassium chloride, a buffering agent such as sodium citrate hydrate, a pH adjuster, or the like to the aqueous ophthalmic composition.

[0099] When the active ingredient is sirolimus, the above-mentioned surfactants can be added to the aqueous ophthalmic composition.Preferred surfactants to be added to the aqueous ophthalmic composition are one or more surfactants selected from the group consisting of polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyl castor oil, polyoxyethylene alkyl ether phosphate, polyoxyl 40 stearate, polysorbate 80, polyoxyl 35 castor oil, and polyoxyethylene cetyl ether sodium phosphate, with polysorbate 80 being particularly preferred.

[0100] When the active ingredient is sirolimus, the concentration of the surfactant added to the aqueous ophthalmic 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), even more preferably 0.01 to 0.5% (w / v), and particularly preferably 0.01 to 0.1% (w / v).

[0101] Furthermore, when the active ingredient is sirolimus, the pH of the aqueous ophthalmic composition may be within a pharmaceutically acceptable range, but from the viewpoint of the stability of the aqueous ophthalmic composition, it is preferably around 5. Specifically, when the active ingredient is sirolimus, the pH of the aqueous ophthalmic composition is preferably 4 to 6, more preferably 4.0 to 6.0, more preferably 4.1 to 5.9, still more preferably 4.5 to 5.5, still more preferably 4.7 to 5.3, and particularly preferably 5.0.

[0102] That is, when the active ingredient is sirolimus, the aqueous ophthalmic composition can be an aqueous ophthalmic composition containing sirolimus, a surfactant, and silver nitrate, filled in a multi-dose polyethylene eye dropper container, and having a pH of 4 to 6.

[0103] Furthermore, the average particle size (D50) of sirolimus contained in the present aqueous ophthalmic 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.

[0104] When the active ingredient is sirolimus, the aqueous ophthalmic composition can further contain a dispersant.Examples of dispersants include cellulose polymers such as methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, etc.; polyvinylpyrrolidone; polyvinyl alcohol, polyethylene glycol, etc. polyhydric alcohol; carboxyvinyl polymer; mucopolysaccharides such as sodium hyaluronate, chondroitin sulfate, etc., and may be their hydrates or solvates.

[0105] As mentioned above, various additives can be added to the present aqueous ophthalmic composition. When the active ingredient is sirolimus, it is preferable to add to the present aqueous ophthalmic composition, in addition to a surfactant and a dispersant, an ionic tonicity agent such as sodium chloride or potassium chloride, a stabilizer such as sodium edetate hydrate, a buffering agent such as sodium citrate hydrate, a pH adjuster, etc.

[0106] The present aqueous ophthalmic composition is an aqueous ophthalmic composition containing an active ingredient (excluding sirolimus or a salt thereof) and a silver salt, and can also be an aqueous ophthalmic composition filled in a polyester-based resin container or a polyolefin-based resin container other than polypropylene.

[0107] The definitions of terms, preferred examples, preferred numerical ranges, etc. described above in relation to the present aqueous ophthalmic composition also apply to the present ophthalmic preservative and the present method.

[0108] In addition, in this method, "conferring preservative effectiveness that complies with the preservative effectiveness testing standards of the Japanese Pharmacopoeia" means that when the target composition is tested in accordance with the preservative effectiveness testing method of the 17th edition of the Japanese Pharmacopoeia, the composition has preservative effectiveness that complies with the preservative effectiveness testing standards of the Japanese Pharmacopoeia.

[0109] The results of tests performed using the present aqueous ophthalmic composition and formulation examples are shown below, but these examples are intended to provide a better understanding of the present invention and are not intended to limit the scope of the present invention. [Example]

[0110] [Test 1] The preservative effectiveness of diquafosol sodium-containing aqueous solutions was investigated when silver nitrate was added at various concentrations to the aqueous solutions.

[0111] (Sample preparation method) 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 edetate 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 make 100 mL, and a pH adjuster was added to adjust the pH to 7.5.

[0112] Formulations 1-2 to 1-5: Formulations 1-2 to 1-5 were prepared according to the formulations shown in Table 1 in the same manner as formulation 1-1.

[0113] [Table 1]

[0114] (Test Method) The preservative effectiveness test was conducted in accordance with the preservative effectiveness test method of the 17th edition of the Japanese Pharmacopoeia. The test bacteria used in this test were Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis).

[0115] (result) The test results are shown in Table 2. Formulations 1-1 to 1-5 were shown to comply with the preservative effectiveness test standards of the Japanese Pharmacopoeia. The test results in Table 8 show the log reduction of the viable bacterial count at the time of testing compared to the inoculated bacterial count. For example, a value of "1" indicates that the viable bacterial count at the time of testing was reduced to 10% of the inoculated bacterial count.

[0116] [Table 2]

[0117] (Consideration) It has become clear that silver salts such as silver nitrate can be used as a new preservative to replace existing preservatives such as benzalkonium chloride and chlorhexidine gluconate in preparing aqueous eye drops.

[0118] [Test 2] The preservative effect of aqueous suspensions containing rebamipide was investigated by adding various concentrations of silver nitrate to the suspension. We also investigated whether the silver nitrate concentration in the suspensions changed during storage.

[0119] (Sample preparation method) Formulation 2-1: Formulation 2-1 was prepared according to the formulation 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 polyvinylpyrrolidone K30, carboxyvinyl polymer (CARBOPOL(登録商標) 0.11 g of 971PNF and 0.00004 g of silver nitrate were dissolved in water, 2.0 g of rebamipide was added, and the mixture was stirred and suspended. The pH was adjusted to 5.9, and water was added to make 100 mL.

[0120] Formulations 2-2 to 2-3: Prepared in the same manner as formulation 2-1 according to the formulations shown in Table 3.

[0121] [Table 3]

[0122] (Test Method) <Preservative effectiveness test> The preservative effectiveness test was conducted in accordance with the preservative effectiveness test method of the 17th edition of the Japanese Pharmacopoeia. The test bacteria used in this test were Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus braziliensis (A. braziliensis).

[0123] <Stability test> Five mL of each of Formulations 2-1 and 2-3 was placed in a low-density polyethylene (LDPE) eye dropper container and stored at 40°C for three months or under light exposure of 1.2 million lx·hr. The silver nitrate content in the solution before and after storage was measured using the Japanese Pharmacopoeia inductively coupled plasma mass spectrometry method.

[0124] (Test results) The test results are shown in Tables 4 and 5. Formulations 2-1 to 2-3 were shown to comply with the preservative effectiveness test standards of the Japanese Pharmacopoeia. Furthermore, no change in the silver nitrate concentration in the rebamipide-containing aqueous suspension was observed during the storage period.

[0125] [Table 4]

[0126] [Table 5]

[0127] (Consideration) It has been revealed that silver salts such as silver nitrate can also be used as new preservatives in aqueous ophthalmic suspensions, replacing existing preservatives such as benzalkonium chloride and chlorhexidine gluconate. In other words, it has been shown that silver salts such as silver nitrate can be used as preservatives in both aqueous ophthalmic suspensions and aqueous ophthalmic suspensions.

[0128] It was also revealed that silver salts such as silver nitrate are stable in aqueous suspensions containing rebamipide.

[0129] [Test 3] The stability of silver nitrate and chlorhexidine gluconate in aqueous ophthalmic solutions containing diquafosol sodium was compared.

[0130] (Sample preparation method) 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 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.

[0131] Comparative Formulations 3-1 to 3-4: According to the formulations shown in Table 6, comparative formulations 3-1 to 3-4 were prepared in the same manner as formulation 3-1.

[0132] [Table 6]

[0133] (Test Method) The silver ion content of Formulation 3-1 was quantified using inductively coupled plasma atomic emission spectroscopy (ICP-AES) after storage at 60°C for 4 weeks, and the residual rate (%) was calculated. Furthermore, the chlorhexidine gluconate content of Comparative Formulations 3-1 and 3-2 was quantified using high-performance liquid chromatography (HPLC) after storage at 60°C for 4 weeks, and the residual rate (%) was calculated. Furthermore, the chlorhexidine gluconate content of Comparative Formulations 3-3 and 3-4 was quantified using high-performance liquid chromatography (HPLC) after storage at 60°C for 2 weeks, and the residual rate (%) was calculated.

[0134] (Test results) The test results are shown in Table 7. No change in the silver ion content was observed in Formulation 3-1, which contained diquafosol sodium as the active ingredient and PVP K30 or the like as an additive. On the other hand, a decrease in the chlorhexidine gluconate content was observed in Comparative Formulations 3-2 to 3-4, which contained diquafosol sodium as the active ingredient and PVP K30 or PVP K90 or the like as an additive.

[0135] [Table 7]

[0136] (Consideration) As explained in the Background Art section, chlorhexidine gluconate is used in aqueous ophthalmic compositions as a preservative that is safer than benzalkonium chloride, but it has been shown that it is destabilized in the composition depending on the types of active ingredient and additives used. On the other hand, silver salts such as silver nitrate have shown high stability in aqueous ophthalmic solutions containing diquafosol sodium, demonstrating that they are widely usable and stable preservatives regardless of the active ingredient, additives, properties of the ophthalmic solution, etc. used.

[0137] [Test 4] The stability of chlorhexidine gluconate in aqueous ophthalmic solutions containing rebamipide was investigated.

[0138] (Sample preparation method) Comparative prescription 4-1: Commercially available "Mucosta (登録商標) Eye drops UD 2% were used.

[0139] 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. The pH was adjusted to 6.0, and water was added to make 100 mL.

[0140] Comparative Formulation 4-3: Prepared in the same manner as Comparative Formulation 4-2 according to the formulation shown in Table 8. (Test Method) The preservative effectiveness test was conducted in accordance with the preservative effectiveness test method of the 17th edition of the Japanese Pharmacopoeia. In this test, all or part of Esherichia 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 content of chlorhexidine gluconate was measured by the "Japanese Pharmacopoeia High Performance Liquid Chromatography Method."

[0141] (result) The measurement results are shown in Table 8. Comparative formulations 4-1 to 4-3 did not pass the preservative effectiveness test.

[0142] [Table 8]

[0143] (Consideration) As explained in the Background Art section, chlorhexidine gluconate is used in aqueous ophthalmic compositions as a preservative safer than benzalkonium chloride, but it was suggested that it may undergo compatibility changes depending on the types of active ingredients and additives used, and may not be able to exert sufficient preservative effectiveness. On the other hand, as explained in Test 2, no compatibility changes were observed with silver salts such as silver nitrate in aqueous ophthalmic solutions containing rebamipide, demonstrating that they are widely usable and stable preservatives, regardless of the active ingredients, additives, or properties of the ophthalmic solutions used.

[0144] [Test 5] The effects of silver nitrate on soft contact lenses (SCLs) were investigated.

[0145] (Sample preparation method) 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.

[0146] Comparative Formulations 5-1 to 5-4: According to the formulations shown in Table 9, comparative formulations 5-1 to 5-4 were prepared in the same manner as formulation 5-1.

[0147] [Table 9]

[0148] (Test Method) Soft contact lenses were immersed in each test formulation at room temperature for 30 minutes and then removed. The diameter and base curve of the soft contact lenses were measured. The soft contact lenses used were 2-week Acuvue lenses classified as Group IV. (登録商標) (Johnson & Johnson Co., Ltd.).

[0149] The diameter deformation amount and base curve deformation amount were calculated using the following formulas. Diameter deformation (mm) = (diameter after immersion) - (diameter before immersion) Base curve deformation (mm) = (base curve after immersion) - (base curve before immersion) (Test results) The test results are shown in Table 10.

[0150] [Table 10]

[0151] (Consideration) Benzalkonium chloride, which is known to deform SCLs, was also confirmed in this test to have a tendency to deform SCLs compared to other preservatives. On the other hand, the silver nitrate-containing formulation showed almost no SCL deformation, and this tendency was even more pronounced compared to the chlorhexidine gluconate-containing formulation, which is said not to deform SCLs. Therefore, it was revealed that aqueous ophthalmic compositions containing silver salts such as silver nitrate as a preservative do not deform SCLs and can be instilled into eyes wearing SCLs.

[0152] [Test 6] The adsorption of silver ions onto various resins was investigated.

[0153] (Sample preparation method) Formulation 6-1: A sample was prepared by diluting an aqueous solution containing 10 ppm of silver ions manufactured and sold by AEON Japan Co., Ltd. with pure water to a concentration of 3 ppm (0.0003% (w / v)).

[0154] (Test Method) Five mL of formulation 6-1 was filled into eye dropper containers made of low-density polyethylene (LDPE), polypropylene (PP), and polyethylene terephthalate (PET). The silver ion content immediately after filling and after storage at 60°C for 4 weeks was quantified using inductively coupled plasma atomic emission spectroscopy (ICP-AES), and the residual rate (%) after storage relative to immediately after filling was calculated.

[0155] (Test results) The test results are shown in Table 11. It was revealed that silver ions are strongly adsorbed to polypropylene.

[0156] [Table 11]

[0157] (Consideration) Generally, aqueous ophthalmic compositions are filled in resin containers. However, it has been shown that it is desirable to fill ophthalmic compositions containing silver salts such as silver nitrate in resin containers other than polypropylene containers in order to avoid a decrease in preservative effectiveness due to adsorption of silver ions.

[0158] [Test 7] The adsorption of silver ions onto a resin in aqueous ophthalmic solution containing diquafosol sodium was investigated.

[0159] (Sample preparation method) 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.

[0160] Formulation 7-2: Formulation 7-2 was prepared in the same manner as formulation 7-1 according to the formulation shown in Table 12.

[0161] [Table 12]

[0162] (Test Method) Formulations 7-1 and 7-2 were filled into low-density polyethylene (LDPE) eye dropper containers and stored at 60°C for 4 weeks. The silver ion content was quantified using inductively coupled plasma atomic emission spectroscopy (ICP-AES), and the residual rate (%) relative to that immediately after filling was calculated.

[0163] (Test results) The test results are shown in Table 13. In Formulation 7-2, it was confirmed that silver ions were adsorbed to the eye dropper container made of low-density polyethylene (LDPE), but this adsorption was completely suppressed by adding sodium chloride.

[0164] [Table 13]

[0165] (Consideration) In this test, the silver nitrate concentration added to the aqueous composition was 0.00004% (w / v), which is significantly lower than the concentration (0.003% (w / v)) used in Test 6. Therefore, it is believed that significant adsorption of silver ions to the low-density polyethylene (LDPE) eye dropper container was observed. However, it was suggested that such adsorption of silver ions to the resin container could be significantly suppressed by adding an ionic tonicity agent such as sodium chloride.

[0166] [Test 8] The preservative effect of sirolimus-containing aqueous suspensions containing various concentrations of silver nitrate was investigated. We also investigated whether the silver nitrate concentration in the suspensions changed during storage.

[0167] (Sample preparation method) 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 then wet-pulverized in a bead mill. Then, the additive solution shown in Table 14 was added and mixed, and a pH adjuster was added to adjust the pH to 5.

[0168] Formulations 8-1 and 8-2: Prepared in the same manner as formulation 8-1 according to the formulations shown in Table 14.

[0169] [Table 14]

[0170] (Test Method) <Preservative effectiveness test> The preservative effectiveness test was conducted in accordance with the preservative effectiveness test method of the 17th edition of the Japanese Pharmacopoeia. The test bacteria used in this test were Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus braziliensis (A. braziliensis).

[0171] <Stability test> 5 mL of Comparative Formulation 8-1 and Formulations 8-1 to 8-2 were placed in low-density polyethylene (LDPE) eye dropper containers and stored at 60° C. for 4 weeks. The silver nitrate content in the solutions before and after storage was measured using the Japanese Pharmacopoeia inductively coupled plasma mass spectrometry method.

[0172] (Test results) The test results are shown in Tables 15 and 16. Formulations 8-1 and 8-2 were shown to comply with the preservative effectiveness test standards of the Japanese Pharmacopoeia. In addition, no change in the silver nitrate concentration in the sirolimus-containing aqueous suspension was observed during the storage period.

[0173] [Table 15]

[0174] [Table 16]

[0175] (Consideration) It has been shown that silver salts such as silver nitrate can also be used as new preservatives to replace existing preservatives such as benzalkonium chloride and chlorhexidine gluconate in sirolimus-containing aqueous suspension ophthalmic solutions. Although sirolimus-containing aqueous suspension ophthalmic solutions contain a surfactant, unlike the diquafosol sodium-containing and rebamipide-containing aqueous suspension ophthalmic solutions mentioned above, sufficient preservative effectiveness can be achieved by including silver nitrate at a concentration of 0.00002% (w / v) or higher. This indicates that silver salts such as silver nitrate can be used as preservatives in both aqueous and aqueous suspension ophthalmic solutions, regardless of the type of active ingredient and additives.

[0176] [Formulation example] The pharmaceutical agent of the present invention will be explained in more detail with reference to formulation examples, but the present invention is not limited to these formulation examples.

[0177] (Formulation Example 1) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01~0.9g Disodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.0000001~0.01g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 7.0-8.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0178] (Formulation Example 2) in 100mL Rebamipide 3g Sodium citrate hydrate 0.01-0.5g Sodium chloride 0.01~0.9g Potassium chloride 0.01-0.9g Polyvinylpyrrolidone K30 0.1~2g Silver nitrate 0.0000001~0.01g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 5.5–6.5 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0179] (Formulation Example 3) in 100mL Sodium chloride 0.01~0.9g Potassium chloride 0.01-0.9g Silver nitrate 0.0000001~0.01g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 7.8~8.0 The above preparation is filled into a multi-dose eye dropper container made of polyethylene terephthalate.

[0180] (Formulation Example 4) in 100mL Sirolimus 0.01-0.1g Polysorbate 80 0.005-0.1g Hydroxypropyl methylcellulose 0.0001~0.01g Sodium citrate hydrate 0.05-0.1g Disodium edetate hydrate 0.01-0.075g Concentrated glycerin 1.2-2.0g Silver nitrate 0.00002~0.01g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 5.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0181] (Formulation Example 5) in 100mL Sirolimus 0.01-0.1g Polysorbate 80 0.005-0.1g Hydroxypropyl methylcellulose 0.0001~0.01g Sodium citrate hydrate 0.05-0.1g Disodium edetate hydrate 0.01-0.075g Sodium chloride 0.7-1.2g Silver nitrate 0.00002~0.01g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 5.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0182] (Formulation Example 6) in 100mL Sirolimus 0.01-0.1g Polysorbate 80 0.005-0.1g Sodium carboxymethylcellulose 0.001~0.01g Sodium citrate hydrate 0.05-0.1g Disodium edetate hydrate 0.01-0.075g Concentrated glycerin 1.2-2.0g Silver nitrate 0.00002~0.01g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 5.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0183] (Formulation Example 7) in 100mL Sirolimus 0.01-0.1g Polysorbate 80 0.005-0.1g Sodium carboxymethylcellulose 0.001~0.01g Sodium citrate hydrate 0.05-0.1g Disodium edetate hydrate 0.01-0.075g Sodium chloride 0.7-1.2g Silver nitrate 0.00002~0.01g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 5.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0184] (Formulation Example 8) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01~0.9g Disodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K60 0.0001~10g Silver nitrate 0.0000001~0.01g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 7.0-8.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0185] (Formulation Example 9) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01~0.9g Disodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K30 0.0001~10g Silver nitrate 0.0000001~0.01g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 7.0-8.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0186] (Formulation Example 10) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01~0.9g Disodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.0000001~0.01g Hydroxyethyl cellulose 0.0001~5g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 7.0-8.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0187] (Formulation Example 11) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01~0.9g Disodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K60 0.0001~10g Silver nitrate 0.0000001~0.01g Hydroxyethyl cellulose 0.0001~5g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 7.0-8.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE).

[0188] (Formulation Example 12) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01~0.9g Disodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K30 0.0001~10g Silver nitrate 0.0000001~0.01g Hydroxyethyl cellulose 0.0001~5g pH adjuster (appropriate amount) Purified water (appropriate amount) pH 7.0-8.0 The above preparation is filled into a multi-dose eye dropper container made of low-density polyethylene (LDPE). [Industrial Applicability]

[0189] The present invention relates to an aqueous ophthalmic composition containing a silver salt, which is filled in a container made of a polyester resin or a polyolefin resin other than polypropylene. The aqueous ophthalmic composition has sufficient preservative effect over a long period of time, and therefore can be used as a multi-dose eye drop and can also be administered by instillation to eyes wearing SCLs.

Claims

1. An ophthalmic preservative 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.

2. 2. The ophthalmic preservative according to claim 1, wherein the polyester resin is polyethylene terephthalate.

3. 2. The ophthalmic preservative according to claim 1, wherein the polyolefin resin is polyethylene.

4. 4. The ophthalmic preservative according to claim 1, wherein the concentration of the silver salt in the ophthalmic preservative is 0.001% (w / v) or less.

5. 5. The ophthalmic preservative according to claim 1, wherein the concentration of the silver salt in the ophthalmic preservative is 0.000003 to 0.0003% (w / v).

6. 5. The ophthalmic preservative according to claim 1, wherein the concentration of the silver salt in the ophthalmic preservative is 0.00001 to 0.0001% (w / v).

7. 5. The ophthalmic preservative according to claim 1, wherein the concentration of the silver salt in the ophthalmic preservative is 0.00002 to 0.0001% (w / v).

8. The ophthalmic preservative according to any one of claims 1 to 7, further comprising an ionic tonicity agent.

9. The ophthalmic preservative according to any one of claims 1 to 8, wherein the polyester-based resin container or the polyolefin-based resin container is a multi-dose eye drop container.

10. The ophthalmic preservative according to any one of claims 1 to 9, which is administered by instillation into the eye.

11. The ophthalmic preservative according to any one of claims 1 to 10, which is administered by instillation to an eye wearing a soft contact lens.

12. 12. The ophthalmic preservative according to claim 1, wherein the silver salt is silver nitrate.

13. An ophthalmic preservative containing 0.00001 to 0.0001% (w / v) silver nitrate, the ophthalmic preservative being filled in a multi-dose polyethylene terephthalate eye dropper container.

14. An ophthalmic preservative containing 0.00002 to 0.0001% (w / v) silver nitrate, the ophthalmic preservative being filled in a multi-dose polyethylene terephthalate eye dropper container.

Images