Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/14—Details; Accessories therefor
  • A61J1/1468—Containers characterised by specific material properties
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4704—2-Quinolinones, e.g. carbostyril
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions

Definitions

• the present invention relates to an aqueous ophthalmic composition containing a silver salt, which is filled in a polyester resin container or a polyolefin resin container excluding polypropylene.
• the aqueous ophthalmic composition is mainly administered by eye drops, the aqueous ophthalmic composition is often instilled several times a day, and from the viewpoint of convenience, a container that can be repeatedly instilled, a so-called multi-dose type. It is preferable to fill the eye drop container. When filled in a multi-dose type eye drop container, it is common to add benzalkonium chloride as a preservative in order to prevent contamination by bacteria.
• benzalkonium chloride can cause corneal damage when used at high concentrations. Further, it is known that benzalkonium chloride is adsorbed on soft contact lenses and deforms soft contact lenses.
• aqueous ophthalmic compositions containing no preservatives are also used in the treatment of ophthalmic diseases. For example, as described in "Mucosta ® ophthalmic solution UD2%" package insert (Non-Patent Document 1), the "Mucosta ® ophthalmic solution UD2%" has not been added preservative. However, since “Mucosta (registered trademark) ophthalmic solution UD2%" is used up once, there remains a problem from the viewpoint of convenience as described above.
• Non-Patent Document 2 Japanese Patent Application Laid-Open No. 2017-2036 (Patent Document 1) describes that chlorhexidine gluconic acid does not deform soft contact lenses. However, it is not clear whether chlorhexidine gluconic acid can always be used in place of benzalkonium chloride, regardless of the type of active ingredient or additive contained in the aqueous ophthalmic composition.
• Non-Patent Document 3 describes that silver nitrate ophthalmic solution is used for the treatment of neonatal pyorrhea.
• Non-Patent Document 3 does not describe that silver nitrate can be used as a preservative for aqueous ophthalmic compositions.
• Patent Document 2 discloses an emulsion composition containing difluprednate and an antibacterial metal, and silver salt is exemplified as the antibacterial metal. It is also described that the emulsion composition can be an ophthalmic composition.
• Patent Document 2 does not describe or suggest what kind of material the composition should be filled in a container.
• An object of the present invention is to provide a preservative / system that can be widely used in an aqueous ophthalmic composition regardless of the type of active ingredient or additive.
• the present inventors have made an aqueous composition for ophthalmology containing a silver salt and filled it in a polyester resin container or a polyolefin resin container excluding polypropylene.
• the aqueous composition for ophthalmic use has a sufficient preservative effect for a long period of time, and has reached the present invention.
• the present inventors have also found that the aqueous ophthalmic composition of the present invention can be instilled into an eye wearing SCL because the silver salt does not deform the soft contact lens (SCL).
• aqueous composition for ophthalmology containing a silver salt, which is filled in a container made of polyester resin or a container made of polyolefin resin excluding polypropylene (hereinafter, "aqueous composition for ophthalmology”). Also called “things”).
• the present invention also relates to the following.
• An ophthalmic preservative containing a silver salt which is filled in a polyester resin container or a polyolefin resin container excluding polypropylene (hereinafter, also referred to as “main ophthalmic preservative”). say).
• a method for imparting a preservative effect to an aqueous ophthalmic composition that meets the storage efficacy test standards of the Japanese Pharmacopoeia the step of adding a silver salt to the aqueous composition for ophthalmology, and the aqueous composition for ophthalmology.
• a method (hereinafter, also referred to as "the present method"), which comprises a step of filling a container made of a polyester resin or a container made of a polyolefin resin excluding polypropylene.
• this aqueous composition for ophthalmology has a sufficient storage effect for a long period of time, it can be used as a multi-dose type eye drop and can also be administered to SCL-wearing eyes.
• the silver salt is, 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. , Protein silver and the like, but preferably means silver nitrate.
• the concentration of the silver salt contained in the aqueous composition for ophthalmology is preferably 1% (w / v) or less, more preferably 0.1% (w / v) or less, and further preferably 0. It is 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 composition for ophthalmology is preferably 0.000000001% (w / v) or more, more preferably 0.000001% (w / v) or more, and further.
• the concentration of the silver salt contained in the aqueous composition for ophthalmology was set to 0. It is also preferable that it is 00002% (w / v) or more.
• the concentration range of the silver salt contained in the aqueous composition for ophthalmology is preferably 0.000000001 to 0.01% (w / v) and 0.000001 to 0.001% (w / v).
• the concentration range of the silver salt contained in the aqueous composition for ophthalmology is set.
• 0.00002 to 0.01% (w / v) is more preferable, and 0.00002 to 0.0001% (w / v) is most preferable.
• the aqueous composition for ophthalmology means that it is locally administered to the eyes of a subject, and means, for example, an aqueous composition administered by eye drops or local injection into the eye.
• a preferred aqueous composition for ophthalmology is an aqueous composition that is instilled into the eyes of a subject and is also referred to as an eye drop.
• the aqueous composition means a composition based on water, and its properties are not limited.
• Aqueous compositions include water-based solutions (aqueous solutions), suspensions (aqueous suspensions), and emulsions.
• the "polyester-based resin container” means a container in which at least the portion of the container in contact with the aqueous composition is made of polyester-based resin. Therefore, for example, a container in which a polyester-based resin layer is provided on the inner layer in contact with the aqueous composition for ophthalmology and a resin or the like of another material is laminated on the outer layer also falls under the category of "polyester-based resin container”.
• the dicarboxylic acid and diol constituting the polyester resin are not particularly limited, and examples of the dicarboxylic acid include phthalic acid, terephthalic acid, and 2,6-naphthalenedicarboxylic acid, and examples of the diol include ethylene glycol and 1 , 3-Propanediol, 1,4-butanediol, 1,4-cyclohexanedimethanol, bisphenol and the like. Further, it may be a polymer of a single type of polyester unit or a polymer of a plurality of types of polyester units.
• the polymerization mode is not particularly limited, and random polymerization or block polymerization may be used. Furthermore, its stereoregularity (tacticity) is not particularly limited.
• polyester-based resins include polyalkylene terephthalates (eg, polyethylene terephthalate, polybutylene terephthalate, etc.), polyalkylene naphthalates (eg, polyethylene naphthalate, polybutylene naphthalate, etc.), and polycycloalkylene terephthalates (eg, poly (eg, poly (eg, poly).
• Homopolyesters such as 1,4-cyclohexylene methylene terephthalate), polyarylates (for example, resins composed of bisphenol and phthalic acid), copolyesters containing these homopolyester units as main components, and further. Examples thereof include the homopolyester copolymer, and one or a combination of two or more of these can be used.
• the most preferable polyester resin in the present invention is polyethylene terephthalate.
• the term "made of polyester resin” means that at least a part of the material contains the polyester resin, and for example, a mixture of two or more kinds of resins of the polyester resin and another resin ( Polymer alloy) is also included in the polyester resin.
• the "polyolefin-based resin container” means a container in which at least a portion of the container in contact with the aqueous composition is made of a polyolefin-based resin. Therefore, for example, a container in which a layer of a polyolefin-based resin is provided on an inner layer in contact with an aqueous composition for ophthalmology and a resin or the like of another material is laminated on the outer side thereof also falls under the category of a “polyolefin-based resin container”.
• the polyolefin-based resin is not particularly limited, and may be a polymer of a single type of monomer (homopolymer) or a copolymer of a plurality of types of monomers (copolymer). Further, in the case of a copolymer, the polymerization mode is not particularly limited, and random polymerization or block polymerization may be used. Furthermore, its stereoregularity (tacticity) is not particularly limited.
• polyolefin resins examples include polyethylene, cyclic polyolefin, poly (4-methylpentene), polytetrafluoroethylene, ethylene / propylene copolymer, ethylene / ⁇ -olefin copolymer, ethylene / acrylic acid copolymer, and the like.
• examples thereof include ethylene / methacrylic acid copolymer, ethylene / vinyl acetate copolymer, ethylene / ethyl acrylate copolymer, and the like, and one or a combination of two or more of these can be used.
• specific examples of the polyethylene include low density polyethylene (including linear low density polyethylene), high density polyethylene, medium density polyethylene and the like.
• the most preferable polyolefin resin in the present invention is polyethylene, and low density polyethylene or high density polyethylene is preferable.
• polypropylene is a kind of polyolefin resin, but when the aqueous composition for this ophthalmology is filled in a polypropylene container, silver salt is adsorbed on the container and sufficient storage effect cannot be guaranteed. Therefore, for this ophthalmology.
• Polypropylene shall be excluded as the material of the resin container filled with the aqueous composition.
• "made of a polyolefin-based resin” means that at least a part of the material contains a polyolefin-based resin, for example, a mixture of two or more kinds of resins of a polyolefin-based resin and another resin.
• the body (polymer alloy) is also included in "made of polyolefin resin”.
• the resin container is preferably an eye drop container, and in particular, a so-called multi-dose type eye drop container in which the filled aqueous composition can be repeatedly instilled by opening and closing the cap is most preferable.
• Soft contact lenses shall be in accordance with Pharmaceutical Trial No. 645, March 31, 1999, "Handling of materials to be attached when applying for manufacturing (import) approval of soft contact lenses and disinfectants for soft contact lenses.” It is classified into four. That is, Group I (water content less than 50% and non-ionic), Group II (water content 50% or more and non-ionic), Group III (water content less than 50% and ionic). It is classified into Group IV (water content of 50% or more and ionic), and among the constituent monomers of the raw material polymer, those having an anionic molar% of 1% or more are ionic. Those with less than 1% are considered nonionic.
• soft contact lenses examples include 2-hydroxyethyl methacrylate (HEMA), (polyethylene glycol) monomethacrylate (PEGMA), glycerol methacrylate (GMA), N, N-dimethylacrylamide (DMA), and vinyl alcohol (VA). , N-vinylpyrrolidone (NVP or VP), methacrylic acid (MAA), fluorine-based methacrylate-based compounds, silicon-containing methacrylate-based compounds, silicone hydrogels, soft contact lenses containing cycloalkyl methacrylate and the like as main components, and the like. ..
• HEMA 2-hydroxyethyl methacrylate
• PEGMA polyethylene glycol) monomethacrylate
• GMA glycerol methacrylate
• DMA N-dimethylacrylamide
• VA vinyl alcohol
• MAA methacrylic acid
• fluorine-based methacrylate-based compounds silicon-containing methacrylate-
• administered by eye drops to an eye wearing soft contact lenses means that the aqueous composition for ophthalmology can be administered by eye drops while wearing soft contact lenses.
• the aqueous composition for ophthalmology may also be adsorbed on the polyolefin-based resin resin, so that the aqueous composition is ionic isotonic for the purpose of suppressing this.
• the agent can be added.
• the amount of the ionic isotonic agent added to the aqueous composition for ophthalmology is not particularly limited as long as the amount of the aqueous composition for ophthalmology is isotonic, but is, for example, 0.1 to 0.9. % (W / v) of an ionic isotonic agent can be added to the aqueous composition for ophthalmology.
• examples of the "ionic isotonic agent” include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
• polyvinylpyrrolidone can be added to the aqueous composition for ophthalmology.
• polyvinylpyrrolidone means a polymer compound in which N-vinyl-2-pyrrolidone is polymerized, and is also called povidone.
• the K value of polyvinylpyrrolidone contained in the aqueous composition for ophthalmology is preferably 17 or more, more preferably 17 to 120, further preferably 25 to 120, and particularly preferably 30 to 120. preferable.
• examples of “polyvinylpyrrolidone” include polyvinylpyrrolidone K15 (PVP K15), polyvinylpyrrolidone K17 (PVP K17), polyvinylpyrrolidone K25 (PVP K25), polyvinylpyrrolidone K30 (PVP K30), and polyvinylpyrrolidone K40 (PVP).
• polyvinylpyrrolidone K50 polyvinylpyrrolidone K50
• polyvinylpyrrolidone K60 polyvinylpyrrolidone K60
• polyvinylpyrrolidone K70 polyvinylpyrrolidone K70
• polyvinylpyrrolidone K80 polyvinylpyrrolidone K85
• polyvinylpyrrolidone K90 polyvinylpyrrolidone K90
• Polyvinylpyrrolidone K120 Polyvinylpyrrolidone K120 and the like.
• the K value of polyvinylpyrrolidone is a viscosity characteristic value that correlates with the molecular weight, and is a numerical value calculated by applying the relative viscosity value (25 ° C.) measured by a capillary viscometer to the following Fikenscher equation (1). be.
• ⁇ rel is the relative viscosity of the polyvinylpyrrolidone aqueous solution with respect to water
• c is the polyvinylpyrrolidone concentration (%) in the polyvinylpyrrolidone aqueous solution.
• K30 is the above formula. It means that the viscosity characteristic value (K value) calculated by applying (1) is in the range of 27 to 32.4, and "K90” is calculated by applying the above formula (1). Viscosity characteristic value (K value) is in the range of 81 to 97.2.
• the polyvinylpyrrolidone contained in the aqueous composition for ophthalmology may be used alone or in any combination of two or more kinds of polyvinylpyrrolidones having different K values.
• a surfactant can be added to the aqueous composition for ophthalmology. ..
• a surfactant that can be used as an additive for pharmaceuticals can be appropriately blended in the aqueous composition for ophthalmology, for example, a cationic surfactant, an anionic surfactant, and an amphoteric surfactant. , Nonionic surfactants and the like, and these hydrates or solvates may be used.
• the "cationic surfactant” includes an alkylamine salt, an alkylamine polyoxyethylene adduct, a fatty acid triethanolamine monoester salt, an acylaminoethyl diethylamine salt, a fatty acid polyamine condensate, an alkylimidazoline, 1 -Amine salts such as acylaminoethyl-2-alkylimidazolin and 1-hydroxylethyl-2-alkylimidazolin; ammonium salts such as benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate can be mentioned.
• the "anionic surfactant” includes sulfonates such as alkylbenzene sulfonates, ⁇ -olefin sulfonates and ⁇ -sulfo fatty acid ester salts; alkyl sulfate ester salts and polyoxyethylene alkyl sulfate esters.
• Sulfonate salts such as salts; phosphates such as polyoxyethylene cetyl ether sodium phosphate and the like can be mentioned.
• the "nonionic surfactant” includes polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan trio.
• Polyoxyethylene sorbitan fatty acid esters such as rate and polysolvate 65; polyoxyethylene hydrogenated such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60.
• Additives other than the ionic tonicity agent, polyvinylpyrrolidone, and surfactant can be added to the aqueous composition for ophthalmology.
• Nonionic isotonic agents such as glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sculose; sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, dihydrogen phosphate.
• Buffering agents such as sodium, sodium citrate hydrate, sodium acetate, epsilon-aminocaproic acid; stabilizers such as sodium edetate, sodium edetate hydrate; antioxidants such as ascorbic acid; carboxylvinyl polymers, Thickening agents (also called thickeners) such as hydroxyethyl cellulose and hydroxypropyl methyl cellulose (hypromerose); can be prepared by selecting from pH adjusting agents such as hydrochloric acid and sodium hydroxide as necessary. The pH may be in the range acceptable for ophthalmic preparations, but is usually preferably in the range of 4-8.
• the active ingredient can be contained in the aqueous composition for ophthalmology.
• the active ingredient contained in the aqueous composition for ophthalmology include a drug for treating dry eye / corneal disease, an antiallergic drug, a steroidal anti-inflammatory drug, and a non-steroidal drug.
• examples include anti-inflammatory drugs, intraocular pressure lowering drugs, antiviral drugs, antibacterial drugs and the like.
• therapeutic agents for dry eye and corneal diseases include diquafosol, rebamipide, and salts thereof.
• therapeutic agents for dry eye and corneal diseases include cyclosporine, lifeglast, and salts thereof.
• antiallergic agents include olopatadine, levocabastine, ketotifen or salts thereof.
• steroidal anti-inflammatory agents include fluorometholone, hydrocortisone, triamcinolone, fluosinolone, dexamethasone, betamethasone or salts thereof.
• non-steroidal anti-inflammatory drugs include indomethacin, bromfenac, diclofenac olopatadine, levocabastine, ketotifen or salts thereof.
• intraocular pressure-lowering drugs include brimonidine, dorzolamide, brinzolamide, timolol, carteolol, bimatoprost, latanoprost, travoprost, ripasudil or salts thereof.
• antiviral drugs include acyclovir or a salt thereof.
• antibacterial agents include gatifloxacin, moxifloxacin, tosufloxacin or salts thereof.
• this active ingredient other than those listed above include sirolimus or a salt thereof.
• Diquafosol, rebamipide, sirolimus or salts thereof are preferable as the present active ingredient, and diquafosol sodium, rebamipide (free form) and sirolimus (free form) are particularly preferable.
• Diquafosol used in the present invention is a compound represented by the following formula.
• Rebamipide used in the present invention is a compound represented by the following formula.
• Sirolimus used in the present invention is a compound represented by the following formula.
• the salt of this active ingredient is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitrate, sulfuric acid, or phosphoric acid, 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, horseuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobion Organic acids such as acids, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sul
• a solvate such as a hydrate of the active ingredient is contained in the salt of the active ingredient.
• the isomer or a salt thereof is also included in the scope of the present invention.
• the active ingredient or a salt thereof has proton tautomerism, the tautomer or a salt thereof is also included in the scope of the present invention.
• crystal polymorph system when the present active ingredient or a salt thereof has polymorphs and polymorphs (crystal polymorph system), those polymorphs and polymorphs (polymorph system) are also present. It is included in the scope of the present invention.
• the crystal polymorph group means that the crystal form changes depending on the conditions and conditions such as production, crystallization, and storage of the crystals (note that this state includes the formulated state). It means the individual crystal form at each stage and the whole process.
• diquafosol or salt thereof is a tetrasodium salt of diquafosol represented by the following formula (hereinafter, also simply referred to as "diquafosol sodium").
• rebamipide (free form) is preferable as "rebamipide or a salt thereof”.
• sirolimus (free form) is preferable as "sirolimus or a salt thereof".
• polyvinylpyrrolidone When the active ingredient is diquafosol sodium, polyvinylpyrrolidone can be added to the aqueous composition for ophthalmology for the purpose of reducing the number of eye drops.
• the preferable K value of polyvinylpyrrolidone in this case is 60 to 120, but 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 composition for ophthalmology. It is particularly preferable to add polyvinylpyrrolidone K90.
• the concentration of polyvinylpyrrolidone added to the aqueous composition for ophthalmology is preferably 0.1 to 10% (w / v), preferably 0.1 to 5%. It is more preferably (w / v), and even more preferably 1 to 5% (w / v).
• the ophthalmic aqueous composition is an ophthalmic aqueous composition containing diquafosol sodium, polyvinylpyrrolidone and silver nitrate, and is a multi-dose type polyethylene eye drop container.
• various additives can be added to the aqueous composition for ophthalmology, but when the active ingredient is diquafosol sodium, in addition to polyvinylpyrrolidone, ionic isotonic content such as sodium chloride is added. It is preferable to add an agent, a buffering agent such as sodium hydrogen phosphate hydrate, a stabilizer such as sodium edetate hydrate, a pH regulator, and the like to the aqueous composition for ophthalmology.
• a buffering agent such as sodium hydrogen phosphate hydrate, a stabilizer such as sodium edetate hydrate, a pH regulator, and the like
• the average particle size (D50) of rebamipide contained in the aqueous composition for ophthalmology is preferably 0.01 to 10 ⁇ m. , More preferably 0.05 to 5 ⁇ m, still more preferably 0.1 to 3 ⁇ m, and particularly preferably 0.5 to 1 ⁇ m.
• the preferable K value of polyvinylpyrrolidone in this case is 17 to 90, but it is more preferably 17 to 60, and particularly preferably 30.
• polyvinylpyrrolidone K30 polyvinylpyrrolidone K40, polyvinylpyrrolidone K50, and polyvinylpyrrolidone K60 to the aqueous composition for ophthalmology, and it is particularly preferable to add polyvinylpyrrolidone K30.
• the concentration of polyvinylpyrrolidone added to the aqueous composition for ophthalmology is preferably 0.1 to 2% (w / v), preferably 0.5 to 2% (w / v). ) Is more preferable, 1 to 2% (w / v) is more preferable, and 2% (w / v) is most preferable.
• the aqueous composition for ophthalmology is an aqueous composition for ophthalmology containing rebamipide, polyvinylpyrrolidone and silver nitrate, and is filled in a multi-dose polyethylene eye drop container for ophthalmology. It can be an aqueous composition for use.
• a carboxyl vinyl polymer can be added for the purpose of improving the viscosity of the aqueous composition for ophthalmology.
• the concentration of the carboxyl vinyl polymer is preferably 0.01 to 1% (w / v), more preferably 0.03 to 0.5% (w / v), and is 0.05. It is more preferably ⁇ 0.3% (w / v), and most preferably 0.05 to 0.2% (w / v).
• various additives can be added to the aqueous composition for ophthalmology, but when the active ingredient is levamipide, in addition to polyvinylpyrrolidone and carboxylvinyl polymer, sodium chloride, potassium chloride and the like can be added. It is preferable to add an ionic isotonic agent, a buffering agent such as sodium citrate hydrate, a pH adjuster, and the like to the aqueous composition for ophthalmology.
• a buffering agent such as sodium citrate hydrate, a pH adjuster, and the like
• the above-mentioned surfactant can be added to the aqueous composition for ophthalmology.
• Preferred surfactants to be added to the aqueous composition for ophthalmology are polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl castor oil, and polyoxyethylene alkyl ether phosphorus.
• the concentration of the surfactant added to the aqueous composition for ophthalmology is preferably 0.0001 to 5% (w / v), preferably 0.001 to 2% (w / v). More preferably, 0.001 to 1% (w / v) is more preferable, 0.002 to 1% (w / v) is more preferable, 0.005 to 1% (w / v) is more preferable, and 0. 005 to 0.5% (w / v) is more preferable, 0.01 to 1% (w / v) is more preferable, 0.01 to 0.5% (w / v) is further preferable, and 0.01. ⁇ 0.1% (w / v) is particularly preferable.
• the pH of the aqueous composition for ophthalmology may be within the range acceptable for pharmaceutical products, but it is preferably around 5 from the viewpoint of stability of the aqueous composition for ophthalmology. ..
• the pH of the aqueous composition for ophthalmology is preferably 4 to 6, more preferably 4.0 to 6.0, and 4.1 to 5. It is more preferably 9, more preferably 4.5 to 5.5, still more preferably 4.7 to 5.3, and particularly preferably 5.0.
• the aqueous composition for ophthalmology is an aqueous composition for ophthalmology containing silolims, a surfactant and silver nitrate, and is filled in a multi-dose polyethylene eye drop container. It can be an aqueous composition for ophthalmology having a pH of 4 to 6.
• the average particle size (D50) of silolimus contained in the aqueous composition for ophthalmology is 0.001 to 45 ⁇ m, preferably 0.001 to 15 ⁇ m, and more preferably 0.001 to 10 ⁇ m. It is more preferably 0.001 to 8 ⁇ m, more preferably 0.001 to 5 ⁇ m, more preferably 0.001 to 2.5 ⁇ m, more preferably 0.001 to 1 ⁇ m, and even more preferably 0. It is 0.01 to 0.5 ⁇ m, more preferably 0.1 to 1 ⁇ m.
• the average particle size is particularly preferably 0.01 to 0.3 ⁇ m.
• a dispersant can be further added to the aqueous composition for ophthalmology.
• dispersants include 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.
• Cellulose-based polymers such as ethyl cellulose and cellulose acetate phthalate; polyvinylpyrrolidone; polyhydric alcohols such as polyvinyl alcohol and polyethylene glycol; carboxyvinyl polymers; mucopolysaccharides such as sodium hyaluronate and chondroitin sulfate, and the like, and these waters It may be a Japanese product or a solvent-containing product.
• various additives can be added to the aqueous composition for ophthalmology, but when the active ingredient is silolimus, in addition to the surfactant and dispersant, sodium chloride, potassium chloride and the like can be added. It is preferable to add an ionic isotonic agent, a stabilizer such as sodium edetate hydrate, a buffering agent such as sodium citrate hydrate, a pH adjuster, and the like to the aqueous composition for ophthalmology.
• the present aqueous composition for ophthalmology is an aqueous composition for ophthalmology containing an active ingredient (excluding silolims or a salt thereof) and a silver salt, and is filled in a polyester resin container or a polyolefin resin container excluding polypropylene. It can also be an aqueous composition for ophthalmology.
• "giving a preservative efficacy conforming to the Japanese Pharmacopoeia's preservative efficacy test standard” means that the target composition is used in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law. When performed, it means that the composition has a preservative efficacy that meets the preservative efficacy test standards of the Japanese Pharmacopoeia.
• Formulation 1-1 was prepared according to the formulations shown in Table 1. Specifically, sodium diquafosol (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 make pH 7.5.
• Formulations 1-2 to 1-5 were prepared in the same manner as Formulation 1-1 according to the formulation shown in Table 1.
• the storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law.
• Escherichia coli E. coli
• Pseudomonas aeruginosa P. aeruginosa
• Staphylococcus aureus S. aureus
• Candida albicans Candida albicans
• Candida albicans Candida albicans
• test results are shown in Table 2.
• Formulations 1-1 to 1-5 have been shown to meet the Japanese Pharmacopoeia's storage efficacy test criteria.
• the test results in Table 8 show how much the viable cell count at the time of the test decreased compared to the number of inoculated bacteria by log reduction. For example, in the case of "1", the viable cell count at the time of the test is shown. Shows that the number of inoculated bacteria has decreased to 10%.
• Formulation 2-1 was prepared according to the formulations shown in Table 3. Specifically, sodium citrate hydrate 0.146 g, sodium chloride 0.65 g, potassium chloride 0.18 g, polyvinyl pyrrolidone K30 2 g, carboxyvinyl polymers (CARBOPOL (TM) 971PNF) 0.11g, nitrate 0. 00004 g was dissolved in water, 2.0 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.
• Table 3 Table 3. Specifically, sodium citrate hydrate 0.146 g, sodium chloride 0.65 g, potassium chloride 0.18 g, polyvinyl pyrrolidone K30 2 g, carboxyvinyl polymers (CARBOPOL (TM) 971PNF) 0.11g, nitrate 0. 00004 g was dissolved in water, 2.0 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.
• Formulations 2-2 to 2-3 Prepared in the same manner as Formulation 2-1 according to the formulas shown in Table 3.
• the storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law. In this test, Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans) were used as test bacteria. ..
• Formulations 2-1 and 2-3 were placed in 5 mL of a low density polyethylene (LDPE) eye drop container and stored at 40 ° C. for 3 months or at 1.2 million lux ⁇ hr of light.
• the content of silver nitrate in the chemical solution before and after storage was measured by "Japanese inductively coupled plasma mass spectrometry".
• Test results The test results are shown in Tables 4 and 5. Prescriptions 2-1 to 2-3 were shown to meet the Japanese Pharmacopoeia's storage efficacy test criteria. In addition, no change in the silver nitrate concentration in the rebamipide-containing aqueous suspension was observed during the storage period.
• silver salts such as silver nitrate can replace existing preservatives such as benzalkonium chloride and chlorhexidine gluconate in the aqueous suspension ophthalmic solution. That is, it was shown that a silver salt such as silver nitrate can be used as a preservative in both an aqueous ophthalmic solution and an aqueous suspended ophthalmic solution.
• silver salts such as silver nitrate are stable in a rebamipide-containing aqueous suspension.
• Formulation 3-1 was prepared according to the formulation shown in Table 3. Specifically, sodium diquafosol (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 make pH 7.5.
• Comparative formulations 3-1 to 3-4 Comparative formulations 3-1 to 3-4 were prepared in the same manner as formulation 3-1 according to the formulations shown in Table 6.
• Test results The test results are shown in Table 7. No change was observed in the silver ion content in Formulation 3-1 containing diquafosol sodium as an active ingredient and PVP K30 as an additive. On the other hand, in the comparative formulations 3-2 to 3-4 containing diquafosol sodium as an active ingredient and PVP K30 or PVP K90 as an additive, a decrease in the content of chlorhexidine gluconate was observed.
• chlorhexidine gluconate is used in aqueous ophthalmic compositions as a safer preservative than benzalkonium chloride, but the active ingredients and additives used. It has been shown that some types are destabilized in the composition. On the other hand, silver salts such as silver nitrate showed high stability in diquafosol sodium-containing aqueous eye drops, so they can be widely used regardless of the active ingredients, additives, and properties of the eye drops used. It has been shown to be a possible and stable preservative.
• Comparative prescription 4-1 Commercially available "Mucosta (registered trademark) ophthalmic solution UD 2%" was used.
• Comparative prescription 4-2 was prepared according to the prescription 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 polyvinyl alcohol partial saponified product, and 0.01 g of chlorhexizing luconate are dissolved in water, and 2 g of levamipide is added. The mixture was stirred and suspended to adjust the pH to 6.0, and water was added to make 100 mL.
• 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 storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law. In this test, as test bacteria, Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans). Some were used. The content of chlorhexidine gluconate was measured by "Japan High Performance Liquid Chromatography".
• chlorhexidine gluconate is used in aqueous ophthalmic compositions as a safer preservative than benzalkonium chloride, but the active ingredients and additives used. It was suggested that some types had different formulations and could not exert sufficient preservative effect.
• silver salts such as silver nitrate did not show any change in the composition of the rebamipide-containing aqueous ophthalmic solution, and did not depend on the active ingredients, additives, properties of the ophthalmic solution, etc. used. , Has been shown to be a widely usable and stable preservative.
• 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 (q.s.) was used. Was added to adjust the pH to 7.0.
• Comparative formulations 5-1 to 5-4 Comparative formulations 5-1 to 5-4 were prepared in the same manner as formulation 5-1 according to the formulations shown in Table 9.
• Test method Soft contact lenses were immersed in each test product at room temperature for 30 minutes and removed. The diameter and base curve of soft contact lenses were measured. The soft contact lenses used are 2 Week AccuView (registered trademark) (Johnson & Johnson Co., Ltd.), which is classified into Group IV.
• Diameter deformation amount (mm) (diameter after immersion)-(diameter before immersion)
• Base curve deformation amount (mm) (base curve after immersion)-(base curve before immersion) (Test results) The test results are shown in Table 10.
• Silver ions of Formulation 6-1 were filled in 5 mL of a low density polyethylene (LDPE) eye dropper, a polypropylene (PP) eye drop container, and a polyethylene terephthalate (PET) eye drop container, and immediately after filling and stored at 60 ° C. for 4 weeks.
• the content was quantified using high frequency inductively coupled plasma emission spectrometry (ICP-AES), and the residual rate (%) after storage immediately after filling was calculated.
• ICP-AES inductively coupled plasma emission spectrometry
• Test results The test results are shown in Table 11. It was revealed that silver ions are strongly adsorbed on polypropylene.
• an aqueous ophthalmic composition is filled in a resin container, but for an ophthalmic composition containing a silver salt such as silver nitrate, in order to avoid a decrease in storage efficacy due to adsorption of silver ions, a container other than a polypropylene container is used. It has been shown that it is desirable to fill in resin containers.
• Formulation 7-1 was prepared according to the formulations shown in Table 12. Specifically, sodium diquafosol (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 make pH 7.5.
• Formulation 7-2 was prepared in the same manner as Formulation 7-1 according to the formulation shown in Table 12.
• High frequency inductively coupled plasma emission spectroscopy shows the silver ion content when Formulation 7-1 and Formulation 7-2 are filled in a low density polyethylene (LDPE) eye drop container and stored at 60 ° C. for 4 weeks. ) was used to quantify, and the residual rate (%) immediately after filling was calculated.
• LDPE low density polyethylene
• Test results The test results are shown in Table 13.
• Formulation 7-2 it was confirmed that silver ions were also adsorbed on the low-density polyethylene (LDPE) eye drop container, but the adsorption was completely suppressed by adding sodium chloride.
• LDPE low-density polyethylene
• Test 8 The storage efficacy of the suspension when various concentrations of silver nitrate were added to the sirolimus-containing aqueous suspension was investigated. We also examined whether the silver nitrate concentration in the suspension would fluctuate during the storage period.
• Comparative Formulation 8-1 was prepared according to the formulation shown in Table 14. Specifically, after mixing sirolimus, polysorbate 80 and purified water, wet pulverization is performed with a bead mill, and then the additive solutions shown in Table 14 are added and mixed, a pH adjuster is added, and pH 5 And said.
• Formulations 8-1 to 8-2 Prepared in the same manner as Formulation 8-1 according to the formulas shown in Table 14.
• the storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law. In this test, Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans) were used as test bacteria. ..
• Test results The test results are shown in Tables 15 and 16. Formulations 8-1 and 8-2 were shown to meet the Japanese Pharmacopoeia's storage efficacy test criteria. In addition, no change in the silver nitrate concentration in the sirolimus-containing aqueous suspension was observed during the storage period.
• sirolimus-containing aqueous suspension ophthalmic solution Even in sirolimus-containing aqueous suspension ophthalmic solution, it was revealed that silver salts such as silver nitrate are new preservatives that replace existing preservatives such as benzalkonium chloride and chlorhexidine gluconate. Unlike the above-mentioned diquafosol sodium-containing aqueous ophthalmic solution and rebamipide-containing aqueous suspended ophthalmic solution, the silolims-containing aqueous suspension ophthalmic solution contains a surfactant, but is 0.00002% (w / v). ) It was shown that a sufficient preservation effect can be obtained by containing silver nitrate at a concentration higher than that. That is, it was shown that a silver salt such as silver nitrate can be used as a preservative in both an aqueous ophthalmic solution and an aqueous suspended ophthalmic solution regardless of the type of active ingredient and
• the present invention relates to an aqueous ophthalmic composition containing a silver salt, which is filled in a polyester resin container or a polyolefin resin container excluding polypropylene. Since this aqueous composition for ophthalmology has a sufficient storage effect for a long period of time, it can be used as a multi-dose type eye drop and can also be administered to SCL-wearing eyes.

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