WO2015029924A1 - Composition ophtalmologique - Google Patents

Composition ophtalmologique Download PDF

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Publication number
WO2015029924A1
WO2015029924A1 PCT/JP2014/072101 JP2014072101W WO2015029924A1 WO 2015029924 A1 WO2015029924 A1 WO 2015029924A1 JP 2014072101 W JP2014072101 W JP 2014072101W WO 2015029924 A1 WO2015029924 A1 WO 2015029924A1
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Prior art keywords
weight
parts
gga
composition
geranylgeranylacetone
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PCT/JP2014/072101
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English (en)
Japanese (ja)
Inventor
祐介 竹内
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ロート製薬株式会社
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Priority to JP2015534188A priority Critical patent/JPWO2015029924A1/ja
Publication of WO2015029924A1 publication Critical patent/WO2015029924A1/fr

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    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide

Definitions

  • the present invention relates to an ophthalmic composition.
  • Teprenone (Eisai) is a mixture containing 5E, 9E, 13E geranylgeranylacetone and 5Z, 9E, 13E geranylgeranylacetone in a weight ratio of 3: 2. Teprenone is widely used as a therapeutic agent for peptic ulcer for oral administration. It has also been proposed to use teprenone in the ophthalmic field. For example, Patent Document 1 teaches the use of teprenone as an active ingredient in a preventive or therapeutic agent for dry eye, fatigued eye, or dry eye.
  • Non-Patent Document 1 teaches that when geranylgeranylacetone was intraperitoneally administered to an animal into which retinal detachment was introduced, expression of heat shock protein 70 was induced, and apoptosis of photoreceptor cells was significantly reduced.
  • Geranylgeranylacetone used in Non-Patent Document 1 is teprenone.
  • Patent Document 2 discloses that a clear eye drop can be obtained by adding a phospholipid in addition to a synthetic surfactant to an eye drop containing teprenone.
  • An object of the present invention is to provide an ophthalmic composition containing geranylgeranylacetone, which is practically satisfactory.
  • the present inventor has conducted research to solve the above-mentioned problems, and has found that geranylgeranylacetone is a component that is very easily adsorbed on a container and a contact lens.
  • the present inventors have found that the degree is orders of magnitude greater than vitamin A, vitamin E, and the like, which are ophthalmic components known to be easily adsorbed in containers.
  • the present inventors surprisingly blended (a) an ophthalmic composition containing geranylgeranylacetone with a component (b) selected from the group consisting of (b1) preservatives and (b2) thickeners.
  • An ophthalmic composition comprising (a) geranylgeranylacetone and at least one component selected from the group consisting of (b) (b1) preservatives and (b2) thickeners.
  • Preservatives are parabens, alcohols, organic acids, phenol derivatives, polydronium chloride, alkyldiaminoethylglycine hydrochloride, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, oxyquinoline sulfate, zinc chloride, thimerosal, biguanide compounds, glowul Item 2.
  • composition according to Item 1 wherein the composition is at least one selected from the group consisting of a bactericide and an antibacterial agent.
  • Thickener is cellulose polymer compound, mucopolysaccharide, polysaccharide, polyvinyl polymer compound, carboxyvinyl polymer, casein, gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, Item 3.
  • Any one of Items 1 to 3, which is an eye drop, an intraocular injection, an eye ointment, an eye wash, a contact lens mounting solution, a contact lens solution, a cornea excision preserving agent for transplantation, or a perfusion solution during surgery A composition according to 1.
  • Item 5. The composition according to any one of Items 1 to 4, which is an aqueous composition or an oily composition.
  • the composition according to any one of Items 1 to 5 which is liquid, fluid, gel, semi-solid, or solid.
  • composition according to any one of Items 1 to 7, comprising 0.000001 to 10% by weight of the preservative based on the total amount of the composition.
  • Item 9. Item 8. The composition according to any one of Items 1 to 7, wherein the thickener is contained in an amount of 0.00001 to 50% by weight based on the total amount of the composition.
  • Item 10. Item 10. The composition according to any one of Items 1 to 9, wherein adsorption of geranylgeranylacetone to the container and / or contact lens is suppressed.
  • Item 11 Item 11. The composition according to any one of Items 1 to 10, wherein the stability of geranylgeranylacetone to heat is improved.
  • Item 12 In the ophthalmic composition, by coexisting (a) geranylgeranylacetone and at least one component selected from the group consisting of (b) (b1) preservative and (b2) thickener, geranylgeranylacetone A method for suppressing adsorption to a container. Item 13. In the ophthalmic composition, by coexisting (a) geranylgeranylacetone and at least one component selected from the group consisting of (b) (b1) preservative and (b2) thickener, geranylgeranylacetone A method for suppressing adsorption to contact lenses. Item 14. A method of improving the heat stability of geranylgeranylacetone by coexisting (a) geranylgeranylacetone and (b1) at least one preservative in an ophthalmic composition.
  • the adsorption of geranylgeranylacetone (hereinafter sometimes referred to as “GGA”) to the container is reduced by the combination of the preservative and / or the thickener.
  • the thermal stability of GGA is improving by mix
  • the present inventors have also found the following effect. The present inventor found for the first time that GGA is easily adsorbed to contact lenses, and further found that the adsorption of GGA to contact lenses is reduced by further adding a preservative and / or thickener.
  • the ophthalmic composition of the present invention suppresses the adsorption of GGA to the contact lens, and suppresses the contamination of the contact lens by GGA and the deterioration of the visual field.
  • the ophthalmic composition according to the present invention has specific requirements for ophthalmic compositions such as component stability, comfort, compatibility with containers, in addition to efficacy and safety against diseases. Satisfies.
  • the ophthalmic composition of the present invention is a composition comprising at least one component selected from the group consisting of (a) GGA and (b) (b1) preservative and (b2) thickener.
  • Geranylgeranylacetone (component (a))
  • Types of geometric isomers GGA has eight types of geometric isomers. Specifically, (5E, 9E, 13E) -6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one (5E, 9E, 13EGGA) (all-trans body), (5Z, 9E, 13E) -6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one (5Z, 9E, 13EGGA) (5Z monocis form), (5Z, 9Z, 13E) -6,10,14,18-Tetramethyl-5,9,13,17-nonadecatetraen-2-one (5Z, 9Z, 13EGGA) (13E monotrans form) (5Z, 9Z, 13Z) -6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one (5Z, 9Z, 13
  • the type of GGA is not limited, and one type can be used alone, or two or more types can be used in any combination.
  • the ratio of all-trans isomer is 80% by weight or more, preferably 82% by weight or more, more preferably 84% by weight or more, and further 86% by weight or more. More preferably, 88 wt% or more is even more preferable, 90 wt% or more is even more preferable, 92 wt% or more is even more preferable, 94 wt% or more is even more preferable, 96 wt% or more is even more preferable, 98 wt% % Or more is even more preferable. If it is the said range, it will come to show a remarkable effect in prevention, improvement, or treatment of a retinal disease.
  • the ratio of the monocis body is 80% by weight or more, preferably 82% by weight or more, more preferably 84% by weight or more, and further 86% by weight or more. More preferably, 88 wt% or more is even more preferable, 90 wt% or more is even more preferable, 92 wt% or more is even more preferable, 94 wt% or more is even more preferable, 96 wt% or more is even more preferable, 98 wt% % Or more is even more preferable. If it is the said range, it will come to show a remarkable effect in prevention, improvement, or treatment of a retinal disease.
  • a general-purpose geometric isomer mixture containing an all-trans isomer and a 5Z monocis isomer at a weight ratio of 3: 2 is preferable from the viewpoint of easy availability.
  • the all-trans isomer can be synthesized by the method described in Bull. Korean Chem. Soc., 2009, Vol. 30, No. 9, 215-217, for example.
  • a method shown in the following synthesis scheme is described. Specifically, in the above reaction formula, geranyl linalool 1, compound 2 and aluminum isopropoxide are mixed, and this mixture is gradually heated to 130 ° C. and reacted. At the end of the reaction, the residual compound 2 is removed and the reaction mixture is diluted with 5% sodium carbonate to quench the residual aluminum propoxide. Thereby, an all-trans form is obtained. Further, the all-trans isomer may be purified by silica gel chromatography using dichloromethane as an eluent.
  • ⁇ Monocis> 5Z, 9E, 13EGGA 5Z monocis
  • 5Z monocis has the following structural formula It is a compound represented by these.
  • 5Z monocis can be obtained by separation of commercially available teprenone.
  • GGA geometric isomers can also be produced by those skilled in the art with reference to the above method.
  • a mixture of an all-trans isomer and a 5Z monocis isomer containing more than 60% by weight of the all-trans isomer can be obtained by adding the all-trans isomer to commercially available teprenone.
  • a mixture of 5Z monocis and all-trans isomers containing more than 40% by weight of 5Z monocis can be obtained by adding 5Z monocis to commercial teprenone.
  • the content of GGA in the ophthalmic composition is preferably 0.00001% by weight or more, more preferably 0.00005% by weight or more, and 0.0001% by weight or more based on the total amount of the composition. Is more preferable, 0.0005% by weight or more is more preferable, and 0.001% by weight or more is even more preferable. Further, it may be 0.005% by weight or more, 0.01% by weight or more, 0.05% by weight or more, 0.1% by weight or more, It may be 0.5% by weight or more, or 1% by weight or more. If it is the said range, the pharmacological activity of GGA will be fully acquired by application to eyes.
  • the content of GGA in the ophthalmic composition is preferably 10% by weight or less, more preferably 8% by weight or less, more preferably 5% by weight or less, and more preferably 4% by weight or less based on the total amount of the composition. Is more preferable, and 3% by weight or less is even more preferable. It may be 2% by weight or less. If it is the said range, while being able to fully obtain the pharmacological activity of GGA by application to eyes, it will become a clearer formulation which is hard to produce fog vision.
  • the content of GGA in the ophthalmic composition is about 0.00001 to 10% by weight, about 0.00001 to 8% by weight, about 0.00001 to 5% by weight, 0.00001-4 wt%, about 0.00001-3 wt%, about 0.00001-2 wt%, about 0.00005-10 wt%, about 0.00005-8 wt%, about 0.00005-5 %, About 0.00005-4%, about 0.00005-3%, about 0.00005-2%, about 0.0001-10%, about 0.0001-8%, about 0% .0001-5 wt%, about 0.0001-4 wt%, about 0.0001-3 wt%, about 0.0001-2 wt%, about 0.0005-10 wt%, about 0.0005-8 wt% %, About 0.0005 to 5% by weight, about 0.0005 to 4% by weight About 0.0005 to 3 wt%, about 0.0005 to 2 wt%, about 0.001 to 10 wt%, about 0.001 to 8 w
  • the preservative may be any preservative that can be used in the ophthalmic composition, and is not particularly limited.
  • parabens such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, benzyl paraoxybenzoate; alcohols such as phenethyl alcohol, benzyl alcohol, chlorobutanol, ethanol; benzoic acid Organic acids such as sodium, sorbic acid, potassium sorbate, dehydroacetic acid, sodium dehydroacetate; phenol derivatives such as parachlorometaxylenol, chlorcresol; polydronium chloride, alkyldiaminoethylglycine hydrochloride, benzalkonium chloride, benzethonium chloride Chlorhexidine gluconate, oxyquinoline sulfate, zinc chloride, thimerosal, biguanide compounds (
  • parabens, alcohols, organic acids, polydronium chloride, alkyldiaminoethylglycine hydrochloride, benzalkonium chloride, benzethonium chloride, polyhexanide hydrochloride, chlorhexidine gluconate, zinc chloride, and biguanide compounds are preferred, parabens, alcohols, Organic acids, benzalkonium chloride, and polyhexanide hydrochloride are more preferable, and benzalkonium chloride, polyhexanide hydrochloride, methyl paraben, chlorobutanol, and potassium sorbate are particularly preferable.
  • preservatives of the present invention those referred to as bactericides or antibacterial agents in ophthalmic preparations are also included.
  • antibacterial and antibacterial components include alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, Examples include sulfisoxazole monoethanolamine, sulfisomezole sodium, sulfisomidine sodium, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, and acyclovir.
  • a preservative can be used individually by 1 type or in combination of 2 or more types.
  • the content of the preservative in the ophthalmic composition is preferably 0.000001% by weight or more, more preferably 0.000003% by weight or more, and 0.000005% by weight based on the total amount of the composition. % Or more, more preferably 0.000008% by weight or more, more preferably 0.00001% by weight or more, more preferably 0.00003% by weight or more, and even more preferably 0.00005% by weight or more. If it is the said range, while preserving effect will fully be acquired, adsorption
  • the content of the preservative in the ophthalmic composition is preferably 10% by weight or less, more preferably 8% by weight or less, more preferably 5% by weight or less, and more preferably 3% by weight with respect to the total amount of the composition.
  • the following is more preferable, and 1% by weight or less is even more preferable. If it is the said range, eye irritation is suppressed.
  • the preservative content in the ophthalmic composition is about 0.000001 to 10% by weight, about 0.000003 to 10% by weight, about 0.000005 to 10% by weight, based on the total amount of the composition, About 0.000008 to 10 wt%, about 0.00001 to 10 wt%, about 0.00003 to 10 wt%, about 0.00005 to 10 wt%, about 0.000001 to 8 wt%, about 0.000003 to 8 wt%, about 0.000005-8 wt%, about 0.000008-8 wt%, about 0.00001-8 wt%, about 0.00003-8 wt%, about 0.00005-8 wt%, about 0.000001-5 wt%, about 0.000003-5 wt%, about 0.000005-5 wt%, about 0.000008-5 wt%, about 0.00001-5 wt%, about 0.00003-5 %
  • weight approx.
  • 0.0005-5 wt% about 0.000001-3 wt%, about 0.000003-3 wt%, about 0.000005-3 wt%, about 0.000008-3 wt%, about 0.00001-3 wt% %, About 0.00003 to 3% by weight, about 0.00005 to 3% by weight, about 0.000001 to 1% by weight, about 0.000003 to 1% by weight, about 0.000005 to 1% by weight, about 0.0. 000008 to 1% by weight, about 0.00001 to 1% by weight, about 0.00003 to 1% by weight, and about 0.00005 to 1% by weight.
  • the content of the preservative is preferably 0.0000001 parts by weight or more, more preferably 0.0000003 parts by weight or more, more preferably 0.0000005 parts by weight or more, with respect to 1 part by weight of GGA.
  • the content of the preservative in the ophthalmic composition is preferably 1000 parts by weight or less, more preferably 800 parts by weight or less, more preferably 500 parts by weight or less, and more preferably 300 parts by weight with respect to 1 part by weight of GGA.
  • the following is more preferable, 100 parts by weight or less is more preferable, 80 parts by weight or less is more preferable, 50 parts by weight or less is more preferable, 30 parts by weight or less is more preferable, and 10 parts by weight or less is even more preferable. If it is the said range, eye irritation is suppressed.
  • the content of the preservative with respect to 1 part by weight of GGA is about 0.0000001 to 1000 parts by weight, about 0.0000003 to 1000 parts by weight, about 0.0000005 to 1000 parts by weight, about 0.0000008 to 1000 parts by weight, About 0.000001 to 1000 parts by weight, about 0.000003 to 1000 parts by weight, about 0.000005 to 1000 parts by weight, about 0.000008 to 1000 parts by weight, about 0.00001 to 1000 parts by weight, about 0.0000001 to about 800 parts by weight, about 0.0000003 to 800 parts by weight, about 0.0000005 to 800 parts by weight, about 0.0000008 to 800 parts by weight, about 0.000001 to 800 parts by weight, about 0.000003 to 800 parts by weight, about 0.000005 to 800 parts by weight, about 0.000008 to 800 parts by weight, about 0.
  • the thickener or thickener may be any thickener or thickener that can be used in the ophthalmic composition, and is not particularly limited.
  • cellulosic polymer compounds such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, or pharmaceutically acceptable salts thereof; heparin, heparinoid, heparin Mucopolysaccharides such as sulfuric acid, heparan sulfate, hyaluronic acid, hyaluronic acid salt (sodium salt), chondroitin sodium sulfate; guar gum, hydroxypropyl guar gum, gum arabic, caraya gum, xanthan gum, carrageenan, agar, gellan gum, alginic acid, alginate ( Sodium salt), ⁇
  • cellulose polymer compounds mucopolysaccharides, polysaccharides, polyvinyl polymer compounds, glycerin, polyethylene glycol, and macrogol are preferable, cellulose polymer compounds and polysaccharides are more preferable, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and methylcellulose.
  • Gellan gum, alginic acid, alginates are even more preferred.
  • a thickener can be used individually by 1 type or in combination of 2 or more types.
  • the content of the thickener in the ophthalmic composition is preferably 0.00001% by weight or more, more preferably 0.00003% by weight or more, based on the total amount of the composition. 00005% by weight or more is more preferable, 0.00008% by weight or more is more preferable, 0.0001% by weight or more is more preferable, 0.0003% by weight or more is more preferable, 0.0005% by weight or more is more preferable. 0008% by weight or more is more preferable, and 0.001% by weight or more is even more preferable. Moreover, 0.01 weight% or more may be sufficient, 0.1 weight% or more may be sufficient, and 1 weight% or more may be sufficient.
  • the content of the thickener in the ophthalmic composition is preferably 50% by weight or less, more preferably 20% by weight or less, still more preferably 10% by weight or less, and more preferably 5% with respect to the total amount of the composition. The following are even more preferred: If it is the said range, a favorable usability
  • the content of the thickener in the ophthalmic composition is about 0.00001 to 50% by weight, about 0.00003 to 50% by weight, and about 0.00005 to 50% by weight based on the total amount of the composition. , About 0.00008 to 50% by weight, about 0.0001 to 50% by weight, about 0.0003 to 50% by weight, about 0.0005 to 50% by weight, about 0.0008 to 50% by weight, about 0.001 -50 wt%, about 0.00001-20 wt%, about 0.00003-20 wt%, about 0.00005-20 wt%, about 0.00008-20 wt%, about 0.0001-20 wt%, About 0.0003-20% by weight, about 0.0005-20% by weight, about 0.0008-20% by weight, about 0.001-20% by weight, about 0.00001-10% by weight, about 0.00003- 10% by weight, about 0.00005 to 10 layers %, About 0.00008 to 10% by weight, about 0.0001 to 10% by weight, about 0.0003 to 10% by weight, about 0.0005 to 10%
  • 001-10 wt% about 0.00001-5 wt%, about 0.00003-5 wt%, about 0.00005-5 wt%, about 0.00008-5 wt%, about 0.0001-5 wt% About 0.0003 to 5% by weight, about 0.0005 to 5% by weight, about 0.0008 to 5% by weight, and about 0.001 to 5% by weight.
  • the content of the thickener is preferably 0.00001 part by weight or more, more preferably 0.00003 part by weight or more, more preferably 0.00005 part by weight or more, based on 1 part by weight of GGA.
  • 00008 parts by weight or more is more preferred, 0.0001 parts by weight or more is more preferred, 0.0003 parts by weight or more is more preferred, 0.0005 parts by weight or more is more preferred, 0.0008 parts by weight or more is more preferred, 001 parts by weight or more is even more preferable. If it is the said range, while thickening effect
  • the content of the thickener in the ophthalmic composition is preferably 1000 parts by weight or less, more preferably 800 parts by weight or less, more preferably 500 parts by weight or less, with respect to 1 part by weight of GGA. Part or less is more preferable, and 100 parts by weight or less is even more preferable. If it is the said range, a favorable usability
  • the content of the thickener with respect to 1 part by weight of GGA is about 0.00001 to 1000 parts by weight, about 0.00003 to 1000 parts by weight, about 0.00005 to 1000 parts by weight, and about 0.00008 to 1000 parts by weight.
  • the content of component (b) in the ophthalmic composition is preferably 0.000001% by weight or more based on the total amount of the composition, 0.000003 wt% or more is more preferable, 0.000005 wt% or more is more preferable, 0.000008 wt% or more is more preferable, 0.00001 wt% or more is more preferable, 0.00003 wt% or more is more preferable, Even more preferably 0.00005% by weight or more. Moreover, 0.0001 weight% or more may be sufficient.
  • the content of the component (b) in the ophthalmic composition is preferably 50% by weight or less, more preferably 20% by weight or less, and still more preferably 10% by weight or less based on the total amount of the composition. Moreover, 1 weight% or less may be sufficient. If it is the said range, eye irritation will be suppressed and a favorable usability
  • the content of the component (b) in the ophthalmic composition is about 0.000001 to 50% by weight, about 0.000003 to 50% by weight, and about 0.000005 to 50% by weight with respect to the total amount of the composition. %, About 0.000008 to 50% by weight, about 0.00001 to 50% by weight, about 0.00003 to 50% by weight, about 0.00005 to 50% by weight, about 0.0001 to 50% by weight, about 0.0.
  • the content of component (b) is preferably 0.0000001 parts by weight or more, more preferably 0.0000003 parts by weight or more, more preferably 0.0000005 parts by weight or more, based on 1 part by weight of GGA.
  • 0.00000 parts by weight or more is more preferable, 0.000001 parts by weight or more is more preferable, 0.000003 parts by weight or more is more preferable, 0.000005 parts by weight or more is more preferable, 0.000008 parts by weight or more is more preferable, and 0 Even more preferably 0.0001 part by weight or more. If it is the said range, while original effect
  • the content of the component (b) in the ophthalmic composition is preferably 1000 parts by weight or less, more preferably 800 parts by weight or less, more preferably 500 parts by weight or less, with respect to 1 part by weight of GGA. More preferred is less than or equal to parts by weight and even more preferred is less than or equal to 100 parts by weight. If it is the said range, eye irritation will be suppressed and a favorable usability
  • the content of component (b) with respect to 1 part by weight of GGA is about 0.0000001 to 1000 parts by weight, about 0.0000003 to 1000 parts by weight, about 0.0000005 to 1000 parts by weight, and about 0.0000008 to 1000 parts by weight. Parts, about 0.000001-1000 parts by weight, about 0.000003-1000 parts by weight, about 0.000005-1000 parts by weight, about 0.000008-1000 parts by weight, about 0.00001-1000 parts by weight, about 0.0.
  • the ophthalmic composition of the present invention may contain (b1) preservative, or (b2) thickener, or (b1) and (b2) as component (b). Good.
  • the property of the pharmaceutical ophthalmic composition is not particularly limited, and may be any property such as liquid, fluid, gel, semi-solid, or solid.
  • liquids, fluids, gels, semi-solids, solids, and the like that have been prepared at the time of use are also included.
  • the semi-solid state refers to a property having plasticity that can be deformed by applying force, such as an ointment.
  • the kind of formulation of the ophthalmic composition is not particularly limited.
  • eye drops including eye drops when wearing contact lenses
  • eye wash contact lens mounting liquid
  • contact lens liquid cleaning liquid
  • preservative liquid disinfecting liquid
  • multipurpose solution multipurpose solution
  • package solution transplant cornea
  • Preservatives for isolated ocular tissues, perfusate during surgery ointment (water-soluble ointment, oil-soluble ointment), intraocular injection (eg, intravitreal injection), sustained-release intraocular implant, and Examples include sustained-release contact lens preparations.
  • eye drops, intraocular injections, eye ointments, and eye washes are preferable, and eye drops are more preferable in terms of good transferability to the affected area.
  • the sustained-release intraocular implant includes preparations such as solid, semi-solid, gel, fluid, and liquid
  • the sustained-release contact lens preparation includes solid, semi-solid, Gelled and other preparations are included.
  • the ophthalmic composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier), and an oily composition (an oil or hydrophobic base or carrier). Mainly included).
  • the content of water in the case of the aqueous composition is preferably 50% by weight or more, more preferably 75% by weight or more, and still more preferably 90% by weight or more based on the total amount of the preparation.
  • the base or carrier may be composed only of water.
  • the content of water in the case of an oily composition is preferably 50% by weight or less, more preferably 30% by weight or less, and still more preferably 20% by weight or less based on the total amount of the preparation.
  • GGA is a pharmaceutically acceptable base or carrier, if necessary, a pharmaceutically acceptable ophthalmic composition additive, and other active ingredients (physiologically active or pharmacologically active ingredients other than GGA). It can be prepared by mixing with.
  • Base or carrier examples include water; aqueous solvents such as polar solvents; polyhydric alcohols; vegetable oils; Examples of the base or carrier for intraocular injection include distilled water for injection and physiological saline.
  • carrier can be used individually by 1 type or in combination of 2 or more types.
  • additives in addition to the preservative and thickener as component (b), for example, surfactants, fragrances or refreshing agents, pH adjusting agents, tonicity agents, chelating agents, buffering agents, stabilizing agents, etc. Agents, antioxidants, and the like. Intraocular injections may contain solubilizers, suspending agents, isotonic agents, buffers, soothing agents, stabilizers, and the like.
  • An additive can be used individually by 1 type or in combination of 2 or more types.
  • the composition of this invention contains surfactant further from the point of exhibiting the effect of this application more notably.
  • the surfactant is not particularly limited.
  • polyoxyethylene (hereinafter also referred to as “POE”)-polyoxypropylene (hereinafter also referred to as “POP”) block copolymer for example, poloxamer 407, poloxamer 235.
  • Poloxamer 188 Poloxamer 188
  • POE-POP block copolymer adduct of ethylenediamine eg, poloxamine
  • POE sorbitan fatty acid ester eg, polysorbate 20, polysorbate 60, polysorbate 80 (TO-10, etc.)
  • POE hydrogenated castor oil eg, POE (60) hydrogenated castor oil (HCO-60, etc.)
  • POE castor oil POE alkyl ether (for example, polyoxyethylene (9) lauryl ether, polyoxyethylene (20) polyoxypropylene (4) cetyl ether ),
  • nonionic surfactants such as polyoxyl stearate; glycine-type amphoteric surfactants (eg, alkyldiaminoethylglycine, alkylpolyaminoethylglycine), and betaine-type amphoteric surfactants (eg, lauryldimethylaminoacetic acid) Am
  • nonionic surfactants are preferable.
  • POE sorbitan fatty acid ester POE hydrogenated castor oil, POE castor oil, polyoxyl stearate, and polyoxyethylene-polyoxypropylene block copolymer are preferable.
  • poloxamer 407, polysorbate 80, POE hydrogenated castor oil 60, POE hydrogenated castor oil 40, POE castor oil 35, and POE castor oil 10 are more preferable.
  • the numbers in parentheses indicate the number of added moles.
  • Perfume or refreshing agent for example, camphor, borneol, terpenes (which may be d-form, l-form or dl-form), mint water, eucalyptus oil, bergamot oil, anethole, eugenol, geraniol, menthol, limonene, Essential oils such as peppermint oil, peppermint oil, and rose oil.
  • PH adjuster For example, hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid and the like.
  • Isotonizing agents for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.
  • Chelating agent For example, ascorbic acid, tetrasodium edetate, sodium edetate, and citric acid.
  • Buffers For example, phosphate buffers; citrate buffers such as citric acid and sodium citrate; acetate buffers such as acetic acid, potassium acetate and sodium acetate; carbonate buffers such as sodium bicarbonate and sodium carbonate Boric acid buffers such as boric acid and borax; taurine, aspartic acid and salts thereof (such as potassium salt), amino acid buffers such as epsilon-aminocaproic acid, and the like.
  • citrate buffers such as citric acid and sodium citrate
  • acetate buffers such as acetic acid, potassium acetate and sodium acetate
  • carbonate buffers such as sodium bicarbonate and sodium carbonate
  • Boric acid buffers such as boric acid and borax
  • taurine aspartic acid and salts thereof (such as potassium salt), amino acid buffers such as epsilon-aminocaproic acid, and the like.
  • a phosphate buffer it is preferable to adjust the pH using a phosphate buffer, whereby the adsorption of GGA to the container wall and thus the decrease in the content of GGA in the composition is further suppressed. Further, white turbidity during storage at low temperature is suppressed, adsorption of GGA to the contact lens is further suppressed, and an effect that stability against heat and light is improved can be obtained.
  • a phosphate buffer can be used individually by 1 type or in combination of 2 or more types. The phosphate buffer is not particularly limited.
  • phosphoric acid disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and tripotassium phosphate
  • Alkali metal salts of phosphoric acid such as: calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, monomagnesium phosphate, dimagnesium phosphate (magnesium hydrogen phosphate), alkalis of phosphoric acid such as trimagnesium phosphate Earth metal salts; ammonium salts of phosphoric acid such as diammonium hydrogen phosphate and ammonium dihydrogen phosphate.
  • the phosphate buffer may be either an anhydride or a hydrate.
  • phosphoric acid and alkali metal salts of phosphoric acid it is preferable to use at least one selected from the group consisting of phosphoric acid and alkali metal salts of phosphoric acid, and more preferable to use at least one selected from the group consisting of phosphoric acid and sodium salt of phosphoric acid. preferable.
  • a combination of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate and trisodium phosphate a combination of phosphoric acid, disodium hydrogen phosphate and sodium dihydrogen phosphate, Combination of phosphoric acid, disodium hydrogen phosphate and trisodium phosphate, combination of phosphoric acid, sodium dihydrogen phosphate and trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate and trisodium phosphate
  • disodium hydrogen phosphate and sodium dihydrogen phosphate In combination with disodium hydrogen phosphate and trisodium phosphate
  • sodium dihydrogen phosphate and phosphoric acid trisodium phosphate a combination of phosphoric acid, disodium
  • a combination of phosphoric acid, disodium hydrogen phosphate and sodium dihydrogen phosphate, a combination of phosphoric acid and disodium hydrogen phosphate, a combination of phosphoric acid and sodium dihydrogen phosphate, disodium hydrogen phosphate and A combination with sodium dihydrogen phosphate is preferred, and a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate is more preferred.
  • the content of the phosphate buffer is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, and more preferably 0.01% by weight or more based on the total amount of the composition in terms of anhydride. Even more preferred is 0.05% by weight or more. If it is the said range, the stabilization effect of GGA, the low-temperature white turbidity suppression effect, and the adsorption
  • the content of the phosphate buffer is about 0.001 to 10% by weight, about 0.001 to 7% by weight, and about 0.001 to 5% based on the total amount of the ophthalmic agent in terms of anhydride. %, About 0.001 to 3%, about 0.005 to 10%, about 0.005 to 7%, about 0.005 to 5%, about 0.005 to 3%, about 0% 0.01 to 10% by weight, about 0.01 to 7% by weight, about 0.01 to 5% by weight, about 0.01 to 3% by weight, about 0.05 to 10% by weight, about 0.05 to 7% by weight %, About 0.05 to 5% by weight, and about 0.05 to 3% by weight.
  • the content of the phosphate buffer is preferably 0.0005 parts by weight or more, more preferably 0.001 parts by weight or more, and more preferably 0.005 parts by weight with respect to 1 part by weight of GGA in terms of anhydride. Part or more is even more preferable, and 0.01 part by weight or more is even more preferable. If it is the said range, the stabilization effect of GGA, the low-temperature white turbidity suppression effect, and the adsorption
  • the content of the phosphate buffer in the ophthalmic composition is preferably 5000 parts by weight or less, more preferably 1000 parts by weight or less, more preferably 500 parts by weight, in terms of anhydride, with respect to 1 part by weight of GGA. Part or less is even more preferable, and 200 parts by weight or less is even more preferable. If it is the said range, there is little irritation
  • the content of the phosphate buffer is about 0.0005 to 5000 parts by weight, about 0.0005 to 1000 parts by weight, and about 0.0005 to 500 parts per 1 part by weight of GGA in terms of anhydride.
  • Stabilizer trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate and the like.
  • Antioxidants Ascorbic acid, ascorbic acid derivatives (ascorbic acid-2-sodium sulfate, sodium ascorbate, ascorbic acid-2-magnesium phosphate, ascorbic acid-2-sodium phosphate, etc.), sodium bisulfite, sodium sulfite Water-soluble antioxidants such as sodium thiosulfate.
  • the ophthalmic composition may contain a fat-soluble antioxidant, which further suppresses the adsorption of the ophthalmic composition to the wall of the ophthalmic container and consequently the decrease in the content of GGA in the composition. Is done. Further, the adsorption of GGA to the contact lens is further suppressed, and the stability of GGA to heat and light is improved.
  • the fat-soluble antioxidant examples include butyl group-containing phenols such as butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbyl palmitate, ascorbate stearate, Ascorbic acid esters such as aminopropyl phosphate, ascorbyl phosphate tocopherol, ascorbyl triphosphate, ascorbyl phosphate palmitate; ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, tocopherols such as ⁇ -tocopherol; Tocopherol derivatives such as tocopherol acetate, tocopherol nicotinate, tocopherol succinate; ethyl gallate, propyl gallate, octyl gallate, dodecyl gallate Gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2one; vegetable oils such as soybean oil, rapeseed
  • butyl group-containing phenol NDGA, ascorbic acid ester, tocopherol, tocopherol derivative, gallic acid ester, propyl gallate, 3-butyl-4-hydroxyquinolin-2-one, vegetable oil, and vitamin A are preferable.
  • butyl group-containing phenols, tocopherols, tocopherol derivatives, vegetable oils and vitamin A are preferred, butyl group-containing phenols, vegetable oils, retinol or retinol esters are more preferred, and BHT, BHA, sesame oil, and retinol palmitate are even more preferred.
  • the fat-soluble antioxidant can be used alone or in combination of two or more.
  • the content of the fat-soluble antioxidant in the ophthalmic composition is preferably 0.00001% by weight or more, more preferably 0.00005% by weight or more, and 0.0001% by weight or more based on the total amount of the composition. Even more preferred is 0.0005% by weight or more. If it is the said range, the GGA adsorption
  • the content of the fat-soluble antioxidant in the ophthalmic composition is preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 2% by weight or less, based on the total amount of the composition. 1% by weight or less is even more preferable. Within the above range, there is little eye irritation.
  • the content of the fat-soluble antioxidant in the ophthalmic agent is about 0.00001 to 10% by weight, about 0.00001 to 5% by weight, and about 0.00001 to 2% by weight with respect to the total amount of the ophthalmic agent.
  • % About 0.00001-1 wt%, about 0.00005-10 wt%, about 0.00005-5 wt%, about 0.00005-2 wt%, about 0.00005-1 wt%, about 0.0. 0001-10 wt%, about 0.0001-5 wt%, about 0.0001-2 wt%, about 0.0001-1 wt%, about 0.0005-10 wt%, about 0.0005-5 wt% About 0.0005 to 2% by weight, about 0.0005 to 1% by weight.
  • the content of the fat-soluble antioxidant in the ophthalmic composition is preferably 0.0001 parts by weight or more, more preferably 0.001 parts by weight or more, and 0.005 parts by weight with respect to 1 part by weight of GGA. Part or more is even more preferable, and 0.01 part by weight or more is even more preferable. If it is the said range, the GGA adsorption
  • the content of the fat-soluble antioxidant in the ophthalmic composition is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, and still more preferably 10 parts by weight or less, relative to 1 part by weight of GGA. Even more preferably 5 parts by weight or less. If it is the said range, there is also little irritation
  • the content of the fat-soluble antioxidant in the ophthalmic preparation is about 0.0001 to 100 parts by weight, about 0.0001 to 50 parts by weight, and about 0.0001 to 10 parts by weight with respect to 1 part by weight of GGA. Parts, about 0.0001-5 parts by weight, about 0.001-100 parts by weight, about 0.001-50 parts by weight, about 0.001-10 parts by weight, about 0.001-5 parts by weight, about 0. 005-100 parts by weight, about 0.005-50 parts by weight, about 0.005-10 parts by weight, about 0.005-5 parts by weight, about 0.01-100 parts by weight, about 0.01-50 parts by weight About 0.01 to 10 parts by weight, and about 0.01 to 5 parts by weight.
  • the ophthalmic composition of the present invention may contain a component for preventing or treating retinal diseases by a mechanism of action different from that of GGA. That is, the ophthalmic composition of the present invention can contain a combination of GGA and other components as an active ingredient for preventing, improving, or treating retinal diseases. Components for preventing, improving, or treating retinal diseases other than GGA can be used singly or in combination of two or more.
  • Such combinations include, but are not limited to, for example, combinations of GGA and prost drugs (GGA and latanoprost, GGA and travoprost, GGA and tafluprost, GGA and bimatoprost, etc.), combinations of GGA and prostone drugs
  • a combination of GGA and a prostaglandin F2 ⁇ derivative such as (GGA and isopropyl unoprostone); a combination of GGA and a ⁇ -blocker (GGA and timolol maleate, GGA and gelled timolol, GGA and carteolol hydrochloride, GGA And gelled carteolol), combinations of GGA and ⁇ 1 blockers (such as GGA and betaxolol hydrochloride), combinations of GGA and ⁇ blockers (such as GGA and levobunolol hydrochloride, GGA and nipradilol), GGA and ⁇ 1 blockers Combinations of GGA and sympathetic blockers
  • the combination of GGA and a prostaglandin F2 ⁇ derivative, the combination of GGA and a sympathetic nerve blocker are preferred.
  • a combination of GGA and a ROCK inhibitor, and a combination of GGA and a carbonic anhydrase inhibitor are preferred.
  • the ophthalmic composition of the present invention may contain a pharmacologically active component or a physiologically active component other than a preventive, ameliorative, or therapeutic component for retinal diseases.
  • pharmacologically active ingredients or physiologically active ingredients can be used singly or in combination of two or more.
  • examples of such pharmacologically active components and physiologically active components include neurotrophic factor, decongestant component, eye muscle modulator component, anti-inflammatory component or astringent component, antihistamine component or antiallergic component, vitamins, Examples include amino acids, polymer compounds, cellulose or derivatives thereof, and local anesthetic components. Specific examples of these drugs are illustrated below.
  • Neurotrophic factor Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and the like.
  • NGF Nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • GDNF glial cell line-derived neurotrophic factor
  • serum contains nutrient factors including neurotrophic factor, it is possible to add a serum collected from a patient to prepare a preparation for use in the patient.
  • Decongestant for example, ⁇ -adrenergic agonist, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, and naphazoline nitrate .
  • ⁇ -adrenergic agonist specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, and naphazoline nitrate .
  • Eye muscle modulator component For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, and atropine sulfate.
  • Anti-inflammatory component or astringent component for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diammonium glycyrrhizinate, Diclofenac sodium, bromfenac sodium, berberine chloride, and berberine sulfate.
  • astringent component for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diammonium glycyrr
  • Antihistamine component or antiallergic agent component for example, salt such as acitazanolast, diphenhydramine or its hydrochloride, chlorpheniramine maleate, ketotifen fumarate, levocabastine or its hydrochloride, etc., anlexanox, ibudilast, tazanolast, tranilast, Salts such as oxatomide, suplatast or its tosylate, sodium cromoglycate, and pemirolast potassium.
  • salt such as acitazanolast, diphenhydramine or its hydrochloride, chlorpheniramine maleate, ketotifen fumarate, levocabastine or its hydrochloride, etc.
  • anlexanox ibudilast
  • tazanolast tranilast
  • Salts such as oxatomide, suplatast or its tosylate, sodium cromoglycate, and pemirolast potassium.
  • Vitamins for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate, tocopherol nicotinate, succinic acid Tocopherol, calcium tocopherol succinate, and ubiquinone derivatives.
  • Amino acids for example, aminoethyl sulfonic acid (taurine), glutamic acid, creatinine, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate mixture, glutamic acid, sodium glutamate, magnesium glutamate, epsilon-aminocaproic acid, glycine , Alanine, arginine, lysine, ⁇ -aminobutyric acid, ⁇ -aminovaleric acid, sodium chondroitin sulfate and the like. These may be d-form, l-form or dl-form.
  • Sugars For example, monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like.
  • Local anesthetic ingredients for example, chlorobutanol, procaine hydrochloride, lidocaine hydrochloride, etc.
  • the pH of the composition is preferably 4 or more, more preferably 5.5 or more, even more preferably 6 or more, and even more preferably 6.5 or more. . If it is the said range, it will become a formulation with favorable stability with respect to the heat
  • the viscosity of the ophthalmic composition of the present invention is within a physiologically or pharmaceutically acceptable range, it depends on the type and content of the compounding ingredients, the use of the ophthalmic composition, the formulation form, the method of use, etc. Set as appropriate.
  • the viscosity at 20 ° C. measured with a rotational viscometer is preferably 0.01 to 10000 mPa ⁇ s, and 0.05 to 8000 mPas. More preferred is s, and more preferred is 0.5 to 1000 mPa ⁇ s.
  • Kits The composition of the present invention may be a one-drug composition containing all components, or may be any type of kit such as a two-drug type or a three-drug type.
  • a kit a kit comprising a composition containing GGA and component (b), and a composition comprising a pharmacologically active component or a physiologically active component other than GGA and component (b), and a composition containing specific additives
  • each composition may be filled in a separate container, or may be a ready-to-use composition filled in a container that can be mixed at the time of use.
  • composition of the present invention is a kit of a composition containing GGA and the component (b) and a composition containing other components, it is also prepared in use even in the case of a kit in which each composition is filled in a separate container. Also in the case of the type kit, the GGA content and the (b) component content of each preparation described above are ratios relative to the total amount after mixing each composition.
  • the ophthalmic composition of the present invention is usually contained or filled in a container (particularly an ophthalmic container).
  • a container particularly an ophthalmic container.
  • the kind of container is not specifically limited, For example, a plastic container, a metal container, a glass container, etc. are mentioned.
  • at least a part or all of the contact surface with the preparation is made of plastic (for example, polyolefin, acrylic resin, terephthalic acid ester, 2,6-naphthalenedicarboxylic acid ester, polycarbonate, polymethylterpene, fluororesin, polyvinyl chloride , Polyamide, ABS resin, AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, hydrocarbons optionally substituted with halogen atoms), metals (such as aluminum), and glass
  • plastic for example, polyolefin, acrylic resin, terephthalic acid ester, 2,6-naphthalenedicar
  • the container comprised with said material is 50 weight% or more per weight of container (main body), Preferably it is 60 weight% or more, More preferably, it is a ratio of 70 weight% or more.
  • Container containing Further, a mixture of the above materials or a copolymer may be used.
  • polyolefins examples include polyethylene (including high density polyethylene, low density polyethylene, ultra low density polyethylene, linear low density polyethylene, ultra high molecular weight polyethylene, etc.), polypropylene (isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene). And ethylene-propylene copolymer.
  • acrylic resin examples include acrylic esters such as methyl acrylate, methacrylic esters such as methyl methacrylate, cyclohexyl methacrylate, and t-butyl cyclohexyl methacrylate.
  • terephthalic acid ester examples include polyethylene terephthalate, polytrimethylene terephthalate, and polybutylene terephthalate.
  • 2,6-naphthalenedicarboxylic acid esters examples include polyethylene naphthalate and polybutylene naphthalate.
  • Fluorine resins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene / hexafluoropropylene copolymer, ethylene / tetra Examples thereof include a fluorinated ethylene copolymer and an ethylene / chlorotrifluoroethylene copolymer.
  • polyamide examples include nylon.
  • polyacetals include those containing only oxymethylene units and those containing some oxyethylene units.
  • modified polyphenylene ether examples include polystyrene-modified polyphenylene ether.
  • polyarylate examples include amorphous polyarylate.
  • polyimide examples include aromatic polyimides such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.
  • cellulose acetate examples include cellulose diacetate and cellulose triacetate.
  • hydrocarbons such as methane, ethane, propane, butane, ethylene, propylene, 1-butene, 2-butene, 1,3-butadiene; fluoromethane, difluoromethane, fluoro Form, tetrafluoromethane, 1,1-difluoroethane, 1,2-difluoroethane, 1-fluoropropane, 2-fluoropropane, 1,2-fluoropropane, 1,3-fluoropropane, 1-fluorobutane, 2- Fluorobutane, vinyl fluoride, 1,1-difluoroethylene, 1,2-difluoroethylene, trifluoroethylene, tetrafluoroethylene, 3-fluoropropene, 1,3-fluoropropene, 1,1,4,4-tetra Hydrocarbons substituted with fluorine atoms such as fluorobutadiene and perflu
  • Container materials are terephthalic acid ester (especially polyethylene terephthalate), polycarbonate, polymethylterpene, fluorine-substituted polyethylene (especially polytetrafluoroethylene), 2,6-naphthalenedicarboxylic acid ester (especially polyethylene naphthalate, polybutylene naphthalate). It is preferably at least one selected from the group consisting of phthalates), polyolefins (particularly polyethylene, polypropylene), and methacrylic acid esters (particularly methyl methacrylate).
  • the container may be formed with a layer or film composed of the above material on the inner surface of the container, or the container itself may be molded with the above material. Moreover, it is sufficient that at least a part of the surface in contact with the ophthalmic composition is composed of the above material, but it is preferable that the entire contact surface is composed of the above material.
  • the container may be integrally molded, or may be a container composed of two or more types of parts.
  • a container composed of two or more types of components only one type or two or more types of components may be composed of the above materials, and different types of materials are used for each component among the above materials. May be.
  • the entire part including the spout or nozzle may be formed of the above-mentioned material, and other than the spout or nozzle. Only the main body portion may be molded from the above material.
  • the layer or film comprised with the said material may be formed in the inner surface of all the parts, and the layer or film comprised with the said material may be formed only in the inner surface of the main-body part.
  • the shape of the container, the capacity, the thickness of the container wall, etc. are not particularly limited. Depending on the type of container, commonly used shapes, capacities, and container wall thicknesses can be employed.
  • the volume of the container may be about 0.01 to 1000 mL, preferably about 0.1 to 500 mL, more preferably about 1 to 100 mL, and more preferably about 1 to 20 mL.
  • the thickness of the container wall is about 0.01 to 10 mm, preferably about 0.05 to 5 mm, more preferably about 0.1 to 3 mm.
  • the layer or film which consists of said material when the layer or film which consists of said material is formed in the container inner wall, what was laminated
  • molded layer or film may be a layer or by vapor deposition, plasma CVD, plasma polymerization, sputtering etc. A film may be formed.
  • the thickness of the layer or film made of the above material is not particularly limited, and can be, for example, about 10 nm to 5 mm.
  • the ophthalmic composition of the present invention can target retinal diseases, and the retinal diseases include diseases in which degeneration, damage, or cell death of cells constituting the retina occurs, or cells that constitute the retina. Any disease caused by degeneration, disorder, or cell death may be used, such as glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, retinal detachment, diabetic macular disease, hypertensive retinopathy, retinal vascular occlusion ( Retinal artery occlusion; central retinal vein occlusion, retinal vein occlusion such as central retinal vein branch occlusion), retinal arteriosclerosis, retinal tear, retinal hole, macular hole, fundus hemorrhage, posterior vitreous detachment, pigmented Paravenous choroidal atrophy, cerebral reticular choroidal atrophy, choroideremia, crystal retinopathy, punctate retinopathy, pyramidal dystrophy, central crested
  • the ophthalmic composition of the present invention can be used for diseases in which any cell constituting the retina is damaged or diseases caused by any cell damage constituting the retina.
  • retinal constituent cells include retinal ganglion cells, amacrine cells, horizontal cells, Müller glial cells, bipolar cells, retinal photoreceptor cells (cones and rods), and retinal pigment epithelial cells.
  • a disorder in which retinal ganglion cells or retinal pigment epithelial cells are damaged or caused by the damage of these cells is preferred.
  • the ophthalmic composition of the present invention comprises a layer constituting the retina, that is, an inner boundary membrane, a nerve fiber layer, a ganglion cell layer, an inner reticular membrane, an inner granular layer, an outer reticular layer, an outer granular layer, an outer boundary.
  • a disease in which any of the membrane, the photoreceptor layer, and the retinal pigment epithelium layer is damaged, or a disease caused by a failure in any of these layers is also a target.
  • disorder of the ganglion cell layer, inner granule layer, or outer granule layer is a suitable subject.
  • the target disease may be one type or two or more types.
  • prevention includes avoidance, delay, or reduction in the incidence of onset
  • improvement includes amelioration of symptoms, suppression of progression of symptoms, and cure or completeness.
  • the ophthalmic composition of the present invention is administered, for example, to patients with retinal diseases.
  • an eye drop containing GGA at the above concentration is, for example, about 1 to 5 drops, preferably about 1 to 3 drops, more preferably about 1 to 2 drops per dose. It may be instilled about 1 to 7 times, preferably about 1 to 5 times, more preferably about 1 to 3 times a day.
  • the composition of the present invention is an eye wash
  • the eye wash containing GGA at the above concentration is used, for example, about 1 to 20 mL per time, about 1 to 10 times a day, preferably about 1 to Wash 5 times.
  • an eye ointment containing GGA at the above concentration is, for example, about 0.001 to 5 g per time, about 1 to 7 times a day, preferably 1 to It may be applied to the eye 5 times, more preferably about 1 to 3 times.
  • the injection containing GGA at the above concentration is about 0.005 to 1 mL per time, about 1 to 3 times on 1 to 14 days, preferably One injection is sufficient.
  • composition of the present invention is a contact lens solution (cleaning solution, preservative solution, disinfectant solution, multipurpose solution, package solution), a preservative for an isolated ocular tissue such as a cornea for transplantation, or a perfusion solution during surgery.
  • compositions containing GGA at the above concentrations may be used at the usual dosage of these formulations.
  • the daily dose of GGA is preferably 50 ng or more, more preferably 500 ng or more, and even more preferably 5 ⁇ g or more.
  • the daily dose of GGA is preferably 50 mg or less, more preferably 20 mg or less, and even more preferably 10 mg or less.
  • the daily dosage of GGA is about 50 ng to 50 mg, about 50 ng to 20 mg, about 50 ng to 10 mg, about 500 ng to 50 mg, about 500 ng to 20 mg, about 500 ng to 10 mg, about 5 ⁇ g to 50 mg, about 5 ⁇ g to 20 mg, about Examples include 5 ⁇ g to 10 mg.
  • the administration period varies depending on the type of disease, stage, age, weight, sex, route of administration, etc., but can be appropriately selected within a range of about 1 day to 30 years, for example.
  • retinal diseases such as glaucoma, retinitis pigmentosa, age-related macular degeneration, and diabetic retinopathy
  • retinal diseases can be prevented and improved in a short administration period of about 1 to 20 years, particularly about 1 to 10 years. Or may be treatable.
  • the ophthalmic composition of the present invention suppresses the progression of retinal disease due to the retinal protective action, it may continue to be administered.
  • the present invention provides an ophthalmic composition comprising at least one selected from the group consisting of (a) GGA, (b) (b1) preservative, and (b2) thickener (component (b)).
  • a method for suppressing adsorption of GGA to contact lenses includes, in the ophthalmic composition, at least one selected from the group consisting of (a) GGA, (b) (b1) preservative, and (b2) thickener ((b)
  • This is a method for suppressing the property of being adsorbed to the contact lens of GGA by coexisting with the component).
  • the contact lens may be a soft contact lens or a hard contact lens.
  • Soft contact lens materials include hydroxyethyl methacrylate (HEMA), 2,3-dihydroxypropyl methacrylate (GMA), N-vinylpyrrolidone (NVP), methacrylic acid or its salt (MA), silicone elastomer polydimethylsiloxane (PDMSi), n-butyl methacrylate (BMA), n-butyl acrylate (BA), and copolymers thereof.
  • HEMA hydroxyethyl methacrylate
  • GMA 2,3-dihydroxypropyl methacrylate
  • NDP N-vinylpyrrolidone
  • MA methacrylic acid or its salt
  • PDMSi silicone elastomer polydimethylsiloxane
  • BMA n-butyl methacrylate
  • BA n-butyl acrylate
  • Hard contact lens materials include methyl methacrylate (MMA), cellulose acetate butyrate (CAB), siloxanyl styrene, fluoro methacrylate, siloxanyl methacrylate, fluorine-containing methacrylate (FMA), silicone-containing methacrylate (SiMA), methacryl Examples thereof include acids, dimethacrylic acid esters, dextran esters, fluorosilicones, and co-polymers thereof.
  • GGA and component (b) coexist with each other, but the adsorption of GGA to the contact lens is suppressed.
  • the coexistence is 1 day or more, 3 days or more, or 1 week or more. Good.
  • the coexistence may be performed at a temperature of about 1 to 80 ° C., particularly about 1 to 70 ° C., and more preferably about 1 to 30 ° C.
  • the coexistence may be performed under light shielding or non-light shielding, but is preferably performed under light shielding.
  • the present invention comprises (a) GGA and at least one selected from the group consisting of (b) (b1) preservative and (b2) thickener (component (b)).
  • a method for suppressing the adsorption of GGA onto a container (particularly an ophthalmic container) is included.
  • this method includes, in the ophthalmic composition, at least one selected from the group consisting of (a) GGA, (b) (b1) preservative, and (b2) thickener ((b) This is a method for suppressing the property of adsorbing to an ophthalmic container of GGA by coexisting with a component).
  • the types of containers are as described for the ophthalmic composition of the present invention.
  • (a) GGA and (b) component coexist adsorption of GGA to the container is suppressed, but it is preferable to coexist for 1 day or more, 3 days or more, or 1 week or more.
  • the coexistence may be performed at a temperature of about 1 to 80 ° C., particularly about 1 to 70 ° C., and more preferably about 1 to 30 ° C.
  • the coexistence may be performed under light shielding or non-light shielding, but is preferably performed under light shielding.
  • the present invention also provides an ophthalmic composition comprising at least one selected from the group consisting of (a) GGA, (b) (b1) preservative, and (b2) thickener (component (b)). And a method for improving the stability of GGA to heat.
  • a method for improving the stability of GGA to heat is improved after coexisting (a) GGA and component (b), it is preferable to coexist for 1 day or more, 3 days or more, or 1 week or more.
  • the stability to heat is improved by increasing the residual ratio of GGA when the ophthalmic composition is allowed to stand at 40 ° C. for 7 days, specifically, the method described in the examples. Confirm by.
  • the coexistence may be performed at a temperature of about 1 to 80 ° C., particularly about 1 to 70 ° C., and particularly about 1 to 30 ° C.
  • the coexistence may be performed under light shielding or non-light shielding, but is preferably performed under light shielding.
  • the prepared ophthalmic composition is usually stored at a temperature of about 1 to 30 ° C., but during the preparation of the ophthalmic composition, a temperature of about 1 ° C. or more and about 70 ° C. or less or about 80 ° C. or less. May be placed underneath.
  • the ophthalmic composition being prepared also corresponds to the ophthalmic composition. That is, each method of the present invention corresponds to “coexistence” from the time when (a) GGA and (b) component are both present in the composition to be an ophthalmic composition.
  • each component of the ophthalmic composition is as described for the ophthalmic composition of the present invention.
  • the content of the component may be expressed in w / v%. However, if the composition of each of these samples is taken into consideration, the component content expressed in w / v% is weight%. It becomes substantially the same value as the component content indicated by.
  • the container used in the following tests has a thickness of about 0.5 to 1.5 mm.
  • the concentration of GGA was measured by the following method.
  • Teprenone Waako Pure Chemical Industries
  • the area value (Ac) of the 5Z monocis isomer and the all-trans isomer under the following HPLC measurement conditions From the area value (At), the concentration of GGA contained in each eye drop was measured.
  • Detector UV absorption photometer (measurement wavelength: 210 nm)
  • Column YMC-Pack ODS-A (inner diameter 4.6 mm, length 15 cm, particle size 3 ⁇ m)
  • Column temperature 30 ° C
  • Mobile phase 90% acetonitrile solution
  • Flow rate 1.2 to 1.3 mL / min (eluted in the order of 5Z monocis and all-trans)
  • Injection amount 5 ⁇ L injection of 0.05 g / 100 mL sample
  • Each buffer solution was mixed and stirred to obtain a homogeneous solution, and the pH and osmotic pressure were adjusted with hydrochloric acid or sodium hydroxide.
  • the comparative preparation was prepared in the same manner as the preparation of the example except that no preservative was added. These solutions were filtered through a membrane filter having a pore size of 0.2 ⁇ m (a bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.) to obtain a clear sterile eye drop. In each operation, sterile eye drops were prepared after confirming in advance by HPLC that the content of GGA did not decrease due to adsorption to an instrument or the like.
  • the amount of GGA adsorbed to the contact lens was clearly reduced by adding a preservative to the GGA-containing eye drop.
  • each buffer solution is mixed and stirred to make a uniform solution, and hydrochloric acid or water
  • the pH and osmotic pressure were adjusted with sodium oxide.
  • the comparative preparation was prepared in the same manner as the preparation of the example except that no preservative was added. These solutions were filtered through a membrane filter having a pore size of 0.2 ⁇ m (a bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.) to obtain a clear sterile eye drop. In each operation, a sterile eye drop was prepared after confirming beforehand by HPLC that the content was not reduced by adsorption to teprenone.
  • the residual rate of GGA was clearly improved. It is considered that GGA was prevented from adsorbing to the container by blending the preservative, and the residual rate was improved.
  • the comparative preparation was prepared in the same manner as the preparation of the example except that no preservative was added. These solutions were filtered through a membrane filter having a pore size of 0.2 ⁇ m (a bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.) to obtain a clear sterile eye drop. In each operation, sterile eye drops were prepared after confirming beforehand by HPLC that will be described later that teprenone is adsorbed on an instrument or the like and the content does not decrease.
  • a 10 mL capacity transparent glass container (manufactured by Nidec Rika Glass) was dispensed 10 mL at a time with a glass hole pipette and sealed. These eye drops were allowed to stand at 40 ° C. and 75% RH for 7 days with the container upright. Immediately after production and after standing for 7 days, the GGA content (g / 100 mL) in the eye drop was quantified by HPLC, and the residual rate (%) of GGA in each preparation was calculated. The results are shown in Table 3.
  • the comparative preparation was prepared in the same manner as the preparation of the example except that no thickener was added. These solutions were filtered through a membrane filter having a pore size of 0.2 ⁇ m (a bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.) to obtain a clear sterile eye drop. In each operation, sterile eye drops were prepared after confirming beforehand by HPLC that will be described later that teprenone is adsorbed on an instrument or the like and the content does not decrease.
  • Each eye drop was dispensed into each container in a volume of 5 mL with a glass hole pipette and sealed.
  • the container material and capacity are described in Table 9.
  • the eye drops in Table 4 were allowed to stand at 40 ° C. and 75% RH for 24 hours, and the eye drops in Tables 5 and 6 were at 40 ° C. and 75% RH. It was allowed to stand for 16 hours.
  • GGA g / 100 mL
  • the residual ratio (%) of GGA in each preparation was calculated.
  • the residual ratio of GGA was clearly improved by adding a thickener to the GGA-containing eye drop. Since the GGA residual rate in the preparation varies depending on the container material, it is considered that the adsorption of GGA to the container was suppressed by the addition of the thickener, and the residual rate was improved.
  • the containers used in this example are described in Table 9. (The LDPE eye drop container was made for this test, and the container shape is the same as that of Rohto Pharmaceutical Co., Ltd., Namida Rohto Dry Eye (trade name) (currently sold in Japan as of April 2012) Is)
  • the ophthalmic composition of the present invention is excellent as a preparation, such as being excellent in the prevention, improvement or treatment effect of retinal diseases, and being suppressed from adsorbing to GGA containers and / or contact lenses.

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Abstract

En laissant au moins un type de composant sélectionné dans un groupe constitué par des antiseptiques et des épaississants coexister dans une composition ophtalmologique qui comprend de la géranylgéranylacétone, l'adsorption de GGA sur des contenants et/ou des lentilles de contact est supprimée, et la stabilité de la GGA à la chaleur est améliorée. Ainsi, la composition ophtalmologique est satisfaisante pour une utilisation pratique.
PCT/JP2014/072101 2013-08-26 2014-08-25 Composition ophtalmologique WO2015029924A1 (fr)

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JP2017197527A (ja) * 2016-04-22 2017-11-02 ロート製薬株式会社 眼科組成物
JP2017197524A (ja) * 2016-04-22 2017-11-02 ロート製薬株式会社 眼科組成物
JP2017197526A (ja) * 2016-04-22 2017-11-02 ロート製薬株式会社 眼科組成物
US11331390B2 (en) 2016-04-22 2022-05-17 Rohto Pharmaceutical Co., Ltd. Ophthalmic composition
JP2022160514A (ja) * 2016-04-22 2022-10-19 ロート製薬株式会社 眼科組成物
JP2022176963A (ja) * 2016-04-22 2022-11-30 ロート製薬株式会社 眼科組成物

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JPH08133967A (ja) * 1994-11-02 1996-05-28 Eisai Co Ltd ドライアイ治療剤
JP2000319170A (ja) * 1999-03-05 2000-11-21 Eisai Co Ltd テプレノン含有点眼剤
JP2006241085A (ja) * 2005-03-03 2006-09-14 Rohto Pharmaceut Co Ltd 粘膜適用組成物
WO2007007894A1 (fr) * 2005-07-11 2007-01-18 Senju Pharmaceutical Co., Ltd. Préparation de gouttes ophtalmiques comprenant de la gomme xanthique et un terpénoïde
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JP2017197527A (ja) * 2016-04-22 2017-11-02 ロート製薬株式会社 眼科組成物
JP2017197524A (ja) * 2016-04-22 2017-11-02 ロート製薬株式会社 眼科組成物
JP2017197526A (ja) * 2016-04-22 2017-11-02 ロート製薬株式会社 眼科組成物
US11331390B2 (en) 2016-04-22 2022-05-17 Rohto Pharmaceutical Co., Ltd. Ophthalmic composition
JP7125250B2 (ja) 2016-04-22 2022-08-24 ロート製薬株式会社 眼科組成物
JP2022160514A (ja) * 2016-04-22 2022-10-19 ロート製薬株式会社 眼科組成物
JP7159501B1 (ja) 2016-04-22 2022-10-24 ロート製薬株式会社 眼科組成物
JP2022176963A (ja) * 2016-04-22 2022-11-30 ロート製薬株式会社 眼科組成物
JP7387835B2 (ja) 2016-04-22 2023-11-28 ロート製薬株式会社 眼科組成物

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