WO2015029923A1 - Préparation ophtalmologique - Google Patents

Préparation ophtalmologique Download PDF

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WO2015029923A1
WO2015029923A1 PCT/JP2014/072100 JP2014072100W WO2015029923A1 WO 2015029923 A1 WO2015029923 A1 WO 2015029923A1 JP 2014072100 W JP2014072100 W JP 2014072100W WO 2015029923 A1 WO2015029923 A1 WO 2015029923A1
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weight
gga
retinal
geranylgeranylacetone
ophthalmic
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PCT/JP2014/072100
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English (en)
Japanese (ja)
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祐介 竹内
良宏 高井
孝弘 黒瀬
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ロート製薬株式会社
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    • 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
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an ophthalmic preparation.
  • retinal diseases such as glaucoma, prostaglandin drugs (prostaglandin F2 ⁇ derivatives), sympathetic nerve blockers, sympathomimetic stimulants, parasympathomimetic stimulants, carbonic anhydrase inhibitors, ROCK inhibitors, etc.
  • prostaglandin drugs prostaglandin F2 ⁇ derivatives
  • sympathetic nerve blockers a variety of drugs are known. These drugs improve retinal diseases by suppressing the progression of retinal nerve cell damage, mainly by reducing intraocular pressure.
  • Typical side effects of therapeutic agents for retinal diseases such as glaucoma include corneal inflammation and corneal disorders such as erosion, eye irritation, conjunctival hyperemia, etc. (Abstracts of Non-Patent Document 1 and Non-Patent Document 2, page 311 right) Column 1-5, page 312 left column 14-18). Since retinal diseases such as glaucoma are progressive chronic diseases, therapeutic agents are usually used for a long time. Therefore, it is desired to suppress the side effects of these retinal disease therapeutic agents as much as possible.
  • Patent Document 1 discloses that a specific derivative of prostaglandin A, B, D, E, or F suppresses local side effects of a conventional therapeutic agent for glaucoma and also has an effect of treating glaucoma due to a decrease in intraocular pressure.
  • Patent Document 2 further includes an anionic mucus-like polymer and a fine cation exchange resin in addition to a ⁇ -blocker that reduces the production of aqueous humor and a glaucoma treatment agent that contains carbachol that increases the outflow of aqueous humor. By doing so, it is disclosed that the side effects of ⁇ -blockers and carbachol can be reduced.
  • An object of the present invention is to provide an ophthalmic preparation containing a therapeutic agent for retinal diseases and having few side effects.
  • the present inventor has conducted research in order to solve the above problems, and is a side effect of a retinal disease therapeutic drug by using a retinal disease therapeutic drug in combination with geranylgeranylacetone (hereinafter sometimes referred to as “GGA”). It was found that conjunctival hyperemia and / or corneal injury is suppressed.
  • GGA geranylgeranylacetone
  • GGA for example, a mixture containing 5E, 9E, 13E geranylgeranylacetone and 5Z, 9E, 13E geranylgeranylacetone in a weight ratio of 3: 2 is commercially available under the trade name of Teprenone (Eisai Co., Ltd.).
  • Teprenone Esai Co., Ltd.
  • GGA in the ophthalmic preparation is a component that is significantly adsorbed in the ophthalmic container as compared with other drugs.
  • the amount of adsorbed containers is significantly higher than vitamin A and vitamin E, which are known to be easily adsorbed in containers among the components of ophthalmic preparations.
  • this inventor discovered that adsorption
  • the ophthalmic preparation is required to have as little turbidity as possible.
  • the present inventor improves the solubility of GGA by using GGA and a therapeutic agent for retinal diseases other than GGA, and the GGA-containing ophthalmology. It was found that the preparation for use became clearer.
  • the present inventor has found that the stability of GGA to heat and light is improved by using GGA together with a therapeutic agent for retinal diseases other than GGA.
  • Item 1 An ophthalmic preparation comprising (a) geranylgeranylacetone and (b) a retinal disease therapeutic agent (excluding geranylgeranylacetone).
  • Retinal diseases are prostaglandins, sympathetic blockers, sympathomimetics, parasympathomimetics, carbonic anhydrase inhibitors, ROCK inhibitors, calcium antagonists, EP2 Item 2.
  • the ophthalmic preparation according to Item 1 which is one or more selected from the group consisting of an agonist, an adenosine A2a receptor agonist, a VEGF aptamer, and a VEGF inhibitor.
  • Item 3. Item 3.
  • Retinal diseases are glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, retinal detachment, diabetic macular disease, hypertensive retinopathy, retinal vascular occlusion, retinal arteriosclerosis, retinal tear, retinal hole, macular Hole, fundus hemorrhage, posterior vitreous detachment, pigmented paravenous choroidal atrophy, gyrus reticulochoroidal atrophy, choroideremia, crystal retinopathy, white spot retinopathy, pyramidal dystrophy, central cricoid choroidal dystrophy, Doinbee's focal retinal dystrophy, yolk macular dystrophy, cystic macular edema, occult macular dystrophy, Stargardt's disease, retinoschisis, central serous chorioretinopathy, spinocerebellar degeneration type 7, familial exudative Vitreoretinopathy,
  • Item 5 Eye drops, intraocular injections, eye ointments, eye washes, contact lens mounting fluids, contact lens fluids, cornea-extracted eye tissue preservatives for transplantation, surgical perfusion fluids, sustained-release intraocular implants, Item 5.
  • Item 6. Item 6. The ophthalmic preparation according to any one of Items 1 to 5, which is an aqueous composition or an oily composition.
  • Item 7. Item 7. The ophthalmic preparation according to any one of Items 1 to 6, which is liquid, fluid, gel, or semi-solid.
  • Item 8. Item 8.
  • Item 9. Item 9. The ophthalmic preparation according to any one of Items 1 to 8, wherein adsorption of geranylgeranylacetone to the container is suppressed.
  • Item 12. The ophthalmic preparation according to any one of Items 1 to 11, containing 0.00001 to 90% by weight of geranylgeranylacetone relative to the total amount of the preparation.
  • Item 13. The ophthalmic preparation according to any one of Items 1 to 12, comprising 0.00001 to 90% by weight of a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) with respect to the total amount of the preparation.
  • Item 14. Item 14.
  • Item 16 By coexisting (a) geranylgeranylacetone and (b) retinal disease therapeutic agent (excluding geranylgeranylacetone) in the ophthalmic composition, (b) retinal disease therapeutic agent (excluding geranylgeranylacetone) ) To suppress the conjunctival hyperemia and / or corneal injury to the ophthalmic composition.
  • Item 17 A method for suppressing white turbidity of an ophthalmic composition by coexisting (a) geranylgeranylacetone and (b) a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) in the ophthalmic composition.
  • a method for suppressing adsorption of geranylgeranylacetone to a container by coexisting (a) geranylgeranylacetone and (b) a therapeutic agent for retinal diseases (excluding geranylgeranylacetone) in an ophthalmic composition.
  • Item 19 Improve heat and / or light stability of geranylgeranylacetone by coexisting (a) geranylgeranylacetone and (b) retinal disease therapeutic agent (excluding geranylgeranylacetone) in the ophthalmic composition.
  • GGA acts directly on retinal neurons to protect the cells from damage, suppress cell death, and improve survival. In addition, by inducing or promoting cell neurite outgrowth, cell function is improved and damaged retinal cells are regenerated. Therefore, GGA is a drug that enables fundamental treatment of retinal diseases.
  • therapeutic agents for retinal diseases other than GGA suppress the progression of retinal nerve cell damage by reducing intraocular pressure. Therefore, the ophthalmic preparation of the present invention protects various retinal cells from degeneration, damage, or death by a multifaceted action, and exhibits remarkable effects in prevention, improvement, or treatment of various retinal diseases. That is, in the ophthalmic preparation of the present invention, the combined use of GGA and other therapeutic agents for retinal diseases significantly improves the prevention, improvement or therapeutic effect of retinal diseases.
  • conjunctival hyperemia and / or corneal injury which are side effects of retinal disease therapeutic agents other than GGA
  • conjunctival hyperemia and / or corneal injury which are side effects of retinal disease therapeutic agents other than GGA
  • GGA corneal epithelial damage
  • GGA is considered to suppress eye irritation at the time of instillation with a therapeutic agent for retinal diseases other than GGA.
  • GGA itself is a widely used drug with established safety
  • the ophthalmic preparation of the present invention is a drug with excellent safety. Since retinal diseases are progressive chronic diseases, therapeutic agents are generally used for a long time, but the present invention provides an ophthalmic preparation that can be used safely for a long time for the purpose of prevention, improvement or treatment of retinal diseases. It was.
  • the ophthalmic preparation of the present invention is remarkably suppressed in the adsorption of GGA to an ophthalmic container (hereinafter also referred to as “container”) and the stability of GGA to heat and light.
  • the amount of GGA inside is maintained.
  • the range of selection of container materials is widened because of excellent light stability, and management during distribution and storage is easy because of excellent thermal stability.
  • the ophthalmic preparation of the present invention contains GGA that is difficult to dissolve in water, but its turbidity is kept low.
  • the ophthalmic preparation of the present invention suppresses white turbidity over time due to storage, particularly storage at low temperatures, by using in combination with a therapeutic agent for retinal diseases other than GGA. Since the ophthalmic preparation is required to suppress turbidity as much as possible from the viewpoint of uniform dosing and patient preference, the ophthalmic preparation of the present invention with less turbidity is excellent.
  • the ophthalmic preparation of the present invention has a wide range of preparations for dissolving GGA, and it is easy to manage distribution and storage in winter and cold regions.
  • the ophthalmic preparation of the present invention contains (a) GGA and (b) a therapeutic agent for retinal diseases other than GGA as active ingredients.
  • 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. Among them, in order to exhibit the effect of the present application more remarkably, including all-trans isomers and GGA geometric isomer mixtures containing 80% by weight or more of all-trans isomers (especially all-trans isomers and monocis isomers (especially 5Z monocis isomers)) , A mixture in which the ratio of the all-trans isomer is 80% by weight or more), a monocis isomer, and a GGA geometric isomer mixture (in particular, a monocis isomer (especially a 5Z monocis isomer)) and an all-trans isomer And a mixture of all-trans isomers and 5Z monocis isomers in a weight ratio of 3: 2 is preferred.
  • all-trans isomers and GGA geometric isomer mixtures containing 80% by weight or more of all-trans isomers especially all-trans isomers and
  • 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 because it is easily available.
  • 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 80% by weight or more of the all-trans isomer can be obtained by adding the all-trans isomer to commercially available teprenone.
  • a mixture of a 5Z monocis isomer and an all-trans isomer containing 80% by weight or more of the 5Z monocis isomer can be obtained by adding the 5Z monocis isomer to commercially available teprenone.
  • Reagents for retinal diseases other than component (a) (component (b))
  • the therapeutic agent for retinal diseases other than GGA (hereinafter sometimes referred to as “retinal disease therapeutic agent”) is not particularly limited.
  • a therapeutic agent for retinal diseases having side effects such as conjunctival hyperemia and / or corneal disorder is preferable from the standpoint of remarkable effects of the present invention.
  • prostaglandin drugs prostaglandin F2 ⁇ derivatives
  • sympathetic blockers sympathetic ⁇ blockers, sympathetic ⁇ 1 selective blockers, sympathetic ⁇ 1 blockers
  • Sympathetic ⁇ 2 blockers Sympathetic ⁇ 2 blockers, sympathetic ⁇ blockers
  • sympathomimetics non-selective stimulators, ⁇ 2 stimulants
  • parasympathomimetics cholinergic agonists, cholinesterase inhibitors
  • carbonic anhydrase inhibitors ROCK inhibitors
  • calcium antagonists EP2 agonists, adenosine A2a receptor agonists
  • VEGF aptamers VEGF inhibitors and the like.
  • prostaglandin drugs particularly preferred are prostaglandin drugs, sympathetic ⁇ -blockers, ROCK inhibitors (Rho kinase inhibitors), and carbonic anhydrase inhibitors.
  • Prostaglandin-based retinal disease drugs include, but are not limited to, prost drugs such as latanoprost, travoprost, tafluprost, and bimatoprost (prostamides, prostanoids); such as isopropyl unoprostone Prostone drugs and the like. These are prostaglandin F2 ⁇ derivatives. Of these, prost drugs are preferable, and latanoprost is particularly preferable.
  • Sympathetic blockade include, but are not limited to, non-selective ⁇ -blockers such as timolol maleate, gelled timolol, carteolol hydrochloride, gelated carteolol; ⁇ 1-selective ⁇ -blockers such as betaxolol hydrochloride An ⁇ blocker such as levobunolol hydrochloride and nipradilol; an ⁇ 1 blocker such as bunazosin hydrochloride; Among them, a non-selective ⁇ blocker is preferable, and timolol maleate is particularly preferable.
  • ROCK inhibitor Rho kinase inhibitor
  • Rho kinase inhibitor There are two isoforms of Rho kinase, Rho kinase ⁇ / ROK ⁇ / ROCK2 and Rho kinase ⁇ / ROK ⁇ / ROCK1.
  • the ROCK inhibitor hereinafter sometimes referred to as “ROCK inhibitor” may be any of those that inhibit ROCK2, those that inhibit ROCK1, and those that inhibit both. Further, it may be an agent that inhibits other serine / threonine kinases that are activated by the activation of Rho.
  • ROCK inhibitors include, but are not limited to, Fasudil hydrochloride (Wako Pure Chemical), Y-27632 (Wako Pure Chemical), K-115 (Kowa), SNJ-1656 (Senju Pharmaceutical), AR-12286 (Aerie Pharmaceuticals) ), INS-117548 (Inspire Pharmaceuticals) and the like. Of these, fasudil hydrochloride is preferred.
  • Carbonic anhydrase inhibitors include, but are not limited to, acetazolamide, dorzolamide hydrochloride, brinzolamide and the like. Of these, Dorzolamide hydrochloride is preferred.
  • VEGF aptamers include pegaptanib sodium and the like. Examples of VEGF inhibitors include ranibizumab and bevacizumab.
  • a therapeutic agent for retinal diseases selected from the group consisting of prostaglandin drugs, sympathetic ⁇ -blockers, ROCK inhibitors, and carbonic anhydrase inhibitors can be used alone or in combination of two or more.
  • two or more kinds of drugs of the same strain for example, prostaglandin drugs may be combined, or different kinds of drugs, for example, prostaglandin drugs and sympathetic ⁇ -blockers may be combined. Good.
  • GGA and a prostaglandin drug As a combination of GGA and a prostaglandin drug, a sympathetic ⁇ -blocker, a ROCK inhibitor, and a retinal disease therapeutic agent selected from the group consisting of carbonic anhydrase inhibitors, Combinations of GGA and prostaglandins such as GGA and latanoprost, GGA and travoprost, GGA and tafluprost, GGA and bimatoprost A combination of GGA and a prostone drug such as a combination of GGA and isopropyl unoprostone), Combinations of GGA and sympatholytic agents (GGA such as combination of GGA and timolol maleate, combination of GGA and gelled timolol, combination of GGA and carteolol hydrochloride, combination of GGA and gelled carteolol A combination of GGA and ⁇ 1-selective ⁇ -blocker, such as a combination of GGA and betaxol
  • combinations of GGA, latanoprost and timolol maleate, combinations of GGA, latanoprost and gelled timolol, combinations of GGA, travoprost and timolol maleate, combinations of GGA, travoprost and gelled timolol A combination of GGA, a prostaglandin and a sympathetic beta-blocker, A combination of GGA, a sympathetic ⁇ -blocker, and a carbonic anhydrase inhibitor, such as a combination of GGA, timolol maleate, and dorzolamide hydrochloride, and a combination of GGA, gelled timolol, and dorzolamide hydrochloride are also included.
  • the properties of the pharmaceutical ophthalmic formulation are not particularly limited, and may be any property such as liquid, fluid, gel, semi-solid, or solid.
  • liquids, fluids, gels, semi-solids, or solids that have been prepared upon 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 type of ophthalmic preparation 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 ophthalmic agent may be an aqueous composition (mainly including an aqueous or hydrophilic base or carrier), and an oily composition (an oil or hydrophobic base or carrier is mainly used). 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, pharmaceutically acceptable additives for ophthalmic preparations, and other active ingredients (physiologically active ingredients 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 include surfactants, fragrances or refreshing agents, preservatives, bactericides or antibacterial agents, pH adjusting agents, isotonic agents, chelating agents, buffering agents, stabilizers, antioxidants, and Examples thereof include a thickening agent.
  • Intraocular injections may contain solubilizers, suspending agents, isotonic agents, buffers, soothing agents, stabilizers, preservatives, and the like.
  • An additive can be used individually by 1 type or in combination of 2 or more types.
  • Surfactant For example, polyoxyethylene (hereinafter also referred to as “POE”)-polyoxypropylene (hereinafter also referred to as “POP”) block copolymer (for example, Poloxamer 407, Poloxamer 235, Poloxamer 188), POE-POP block copolymer adduct of ethylenediamine (for example, poloxamine), POE sorbitan fatty acid ester (for example, polysorbate 20, polysorbate 60, polysorbate 80 (TO-10, etc.)), POE hydrogenated castor oil (for example, POE (60) cured) Castor oil (such as HCO-60)), POE castor oil, POE alkyl ethers (eg, polyoxyethylene (9) lauryl ether, polyoxyethylene (20) polyoxypropylene (4) cetyl ether), and stearin
  • Nonionic surfactants such as polyoxyl
  • Amphoteric surfactants such as g
  • 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.
  • Preservatives, bactericides or antibacterials for example, polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, dehydroacetic acid Sodium, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide or its hydrochloride) , And glow kill (made by Rhodia).
  • polydronium chloride alkyldiaminoethylglycine hydrochloride
  • sodium benzoate ethanol
  • benzalkonium chloride benzethonium chloride
  • 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 ophthalmic preparation is further suppressed. Further, white turbidity during storage at a low temperature is further suppressed, adsorption of GGA to the contact lens is suppressed, and an effect that stability against heat and light is further 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 further preferably 0.01% by weight or more, based on the total amount of the preparation, in terms of anhydride. More preferably, 0.05% 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 preparation is preferably 10% by weight or less, more preferably 7% by weight or less, and more preferably 5% by weight or less based on the total amount of the preparation in terms of anhydride. Even more preferred is 3% by weight or less. If it is the said range, there is little irritation
  • 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% by weight, based on the total amount of the preparation, in terms of anhydride.
  • 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 is preferably 5000 parts by weight or less, more preferably 1000 parts by weight or less, and even more preferably 500 parts by weight or less with respect to 1 part by weight of GGA in terms of anhydride. 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.
  • a phosphate buffer is contained in the composition containing GGA.
  • the content of the phosphate buffer is an amount in the composition containing GGA.
  • 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 preparation may contain a fat-soluble antioxidant, which further suppresses the adsorption of the ophthalmic agent to the container wall and consequently the decrease in the content of GGA in the composition. Further, the adsorption of GGA to the contact lens is suppressed, and the stability of GGA to heat and light is further 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 preparation is preferably 0.00001% by weight or more, more preferably 0.00005% by weight or more, and even more preferably 0.0001% by weight or more based on the total amount of the preparation. Preferably, 0.0005% 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 preparation 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 preparation. % 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, about 0.00001 to 2% by weight, based on the total amount of the preparation, About 0.00001 to 1% by weight, about 0.00005 to 10% by weight, about 0.00005 to 5% by weight, about 0.00005 to 2% by weight, about 0.00005 to 1% by weight, about 0.0001 to 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, and about 0.0005 to 1% by weight.
  • the content of the fat-soluble antioxidant in the ophthalmic preparation 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.
  • the above is even more preferable, and 0.01 parts 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 agent is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, 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 preparation of the present invention is a two-component or more concomitant agent
  • the composition containing GGA contains a fat-soluble antioxidant.
  • the content of the fat-soluble antioxidant is an amount in the composition containing GGA.
  • Thickening agent guar gum, hydroxypropyl guar gum, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, cellulose polymer such as sodium carboxymethylcellulose, gum arabic, karaya gum, xanthan gum, agar, alginic acid, ⁇ -cyclodextrin, Dextrin, dextran, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, hyaluronate (sodium salt, etc.), chondroitin sulfate sodium, starch, chitin and its derivatives, chitosan and its derivatives, carrageenan, sorbitol, polyvinylpyrrolidone, polyvinyl Alcohol, polyvinyl polymer compounds such as polyvinyl methacrylate, polyacrylate Carboxyvinyl polymers such as alkali metal
  • the ophthalmic preparation may contain a pharmacologically active ingredient or a physiologically active ingredient other than the preventive, ameliorative, or therapeutic ingredient for retinal diseases.
  • pharmacologically active ingredients or physiologically active ingredients can be used singly or in combination of two or more.
  • 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, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, 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.
  • Antibacterial component or bactericidal component for example, alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxa Zole monoethanolamine, sodium sulfisomezole, sodium sulfisomidine, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, and acyclovir.
  • alkylpolyaminoethylglycine for example, chloramphenicol, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxa Zole monoethanolamine, sodium sulfisomezole, sodium s
  • Sugars For example, monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like.
  • Macromolecular compounds for example, alginic acid, sodium alginate, dextrin, dextran, pectin, hyaluronic acid, chondroitin sulfate, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, carboxyvinyl polymer, macrogol and its pharmaceutically acceptable Such as salt.
  • Cellulose or derivatives thereof For example, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxyethyl cellulose, nitrocellulose and the like.
  • Local anesthetic ingredients for example, chlorobutanol, procaine hydrochloride, lidocaine hydrochloride, etc.
  • sustained release intraocular implants As examples of ophthalmic preparations, sustained release intraocular implants can also be mentioned.
  • Various methods for preparing sustained-release intraocular implants are known.
  • a matrix preparation obtained by mixing GGA and / or a therapeutic agent for retinal diseases other than GGA with a carrier containing a polymer substance, and a core containing a therapeutic agent for retinal diseases other than GGA and / or GGA are coated with a polymer film.
  • the preparation include capsule preparations in which GGA and / or a therapeutic agent for retinal diseases other than GGA are encapsulated in fine capsules made of a polymer substance.
  • polymers used for sustained-release intraocular implants can be used without limitation.
  • the sustained-release intraocular implant can contain pharmacologically active components or physiologically active components other than the retinal disease therapeutic agent. As this component, for example, those exemplified above can be used.
  • the sustained-release intraocular implant is not limited to a solid, and can take properties such as semi-solid, gel, fluid, and liquid.
  • Sustained-release contact lens preparations include sustained-release contact lens preparations in which the contact lens itself contains GGA and / or a therapeutic agent for retinal diseases other than GGA.
  • sustained-release preparations can be used in contact lens solutions containing, for example, GGA and / or retinal disease therapeutic agents other than GGA, such as cleaning solutions, storage solutions, disinfectants, multipurpose solutions, package solutions, etc. Can be prepared by soaking.
  • contact lens manufacturing raw materials for example, contact lens polymer constituent monomers (hydroxyethyl methacrylate, methyl methacrylate, vinyl pyrrolidone, divinylbenzene, methacrylic acid, ethylene glycol dimethacrylate, benzoin methyl ether, etc.), colorants, or ultraviolet absorbers
  • contact lens polymer constituent monomers hydroxyethyl methacrylate, methyl methacrylate, vinyl pyrrolidone, divinylbenzene, methacrylic acid, ethylene glycol dimethacrylate, benzoin methyl ether, etc.
  • colorants for example, contact lens polymer constituent monomers (hydroxyethyl methacrylate, methyl methacrylate, vinyl pyrrolidone, divinylbenzene, methacrylic acid, ethylene glycol dimethacrylate, benzoin methyl ether, etc.), colorants, or ultraviolet absorbers
  • the sustained-release contact lens preparation can contain a pharmacologically active ingredient or a physiologically active ingredient other than the retinal disease therapeutic agent.
  • a pharmacologically active ingredient or a physiologically active ingredient other than the retinal disease therapeutic agent for example, those exemplified above can be used.
  • the sustained-release intraocular implant and the sustained-release contact lens preparation may contain both GGA and a therapeutic agent for retinal diseases other than GGA, or may contain only one of them. When only one is contained, an ophthalmic preparation containing the other may be applied separately to the eye.
  • the content of GGA in the ophthalmic preparation is preferably 0.00001% by weight or more, more preferably 0.00003% by weight or more, more preferably 0.00005% by weight or more based on the total amount of the composition.
  • 0.0008 wt% or more is more preferable, 0.0001 wt% or more is more preferable, 0.0003 wt% or more is more preferable, 0.0005 wt% or more is more preferable, 0.0008 wt% or more is more preferable, 0 0.001% by weight or more is even more preferable.
  • it may be 0.003% by weight or more, 0.005% by weight or more, 0.008% by weight or more, 0.01% by weight or more, It may be 0.03% by weight or more, 0.05% by weight or more, 0.08% by weight or more, 0.1% by weight or more, It may be 3% by weight or more, 0.5% by weight or more, 0.8% by weight or more, or 1% by weight or more.
  • conjunctival hyperemia and corneal injury due to the component (b) are sufficiently suppressed, and the prevention, improvement, or treatment effect of retinal diseases is sufficiently obtained.
  • the content of GGA in the ophthalmic preparation is preferably 90% by weight or less, more preferably 50% by weight or less, and still more preferably 30% by weight or less with respect to the total amount of the preparation. Moreover, 10 weight% or less may be sufficient. If it is the said range, while being able to fully obtain the prevention, improvement, or treatment effect of a retinal disease, it will become a clearer formulation which is hard to produce fog vision.
  • the ophthalmic preparation is a preparation other than a solid preparation, for example, a liquid form, a fluid form, a gel form, or a semi-solid form
  • the content of GGA in the preparation is based on the total amount of the preparation. Is preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 3% by weight or less, and even more preferably 2% by weight or less.
  • the content of GGA in the ophthalmic preparation is about 0.00001 to 90% by weight, about 0.00001 to 50% by weight, about 0.00001 to 30% by weight, about 0.0. 00001-10%, about 0.00003-90%, about 0.00003-50%, about 0.00003-30%, about 0.00003-10%, about 0.00005-90% About 0.00005 to 50 wt%, about 0.00005 to 30 wt%, about 0.00005 to 10 wt%, about 0.00008 to 90 wt%, about 0.00008 to 50 wt%, about 0.00008 -30 wt%, about 0.00008-10 wt%, about 0.0001-90 wt%, about 0.0001-50 wt%, about 0.0001-30 wt%, about 0.0001-10 wt%, About 0.000 -90 wt%, about 0.0003-50 wt%, about 0.0003-30 wt%, about 0.0003-10 wt%, about 0.0005-90 wt%, about
  • the ophthalmic preparation is a preparation other than a solid preparation, for example, a liquid form, a fluid form, a gel form, or a semi-solid form
  • the content of GGA in the preparation is the total amount of the preparation.
  • the content of GGA in the preparation is preferably 0.001 mg or more, more preferably 0.01 mg or more, and still more preferably 0.1 mg or more in the whole preparation. If it is the said range, while the prevention, improvement, or therapeutic effect of a retinal disease will fully be acquired, the side effect by retinal disease therapeutic agents other than GGA will fully be suppressed. Further, the content of GGA is preferably 1000 mg or less, more preferably 100 mg or less, and even more preferably 10 mg or less in the whole preparation. If it is the said range, the prevention, improvement, or therapeutic effect of a retinal disease will fully be acquired.
  • the content of GGA in the solid preparation is about 0.001 to 1000 mg, about 0.001 to 100 mg, about 0.001 to 10 mg, about 0.01 to 1000 mg, about 0.01 to the total amount of the preparation. To about 100 mg, about 0.01 to 10 mg, about 0.1 to 1000 mg, about 0.1 to 100 mg, and about 0.1 to 10 mg.
  • the content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is preferably 0.00001% by weight or more, more preferably 0.00003% by weight or more, and 0.00005% by weight or more with respect to the total amount of the preparation. Is more preferably 0.00008% by weight or more, more preferably 0.0001% by weight or more, more preferably 0.0003% by weight or more, and even more preferably 0.0005% by weight or more.
  • fever and light stability improvement of GGA is fully acquired, and the prevention, improvement, or therapeutic effect of retinal disease is fully acquired. .
  • the content of the therapeutic agent for retinal diseases other than GGA is preferably 90% by weight or less, more preferably 50% by weight or less, and still more preferably 10% by weight or less based on the total amount of the preparation. It may be 5% by weight or less, or 1% by weight or less. If it is the said range, the side effect by retinal disease therapeutic agents other than GGA is fully suppressed.
  • the content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is about 0.00001 to 90% by weight, about 0.00001 to 50% by weight, about 0.00001 to 10% with respect to the total amount of the preparation. %, About 0.00001-5%, about 0.00001-1%, about 0.00003-90%, about 0.00003-50%, about 0.00003-10%, about 0% 0.00003-5 wt%, about 0.00003-1 wt%, about 0.00005-90 wt%, about 0.00005-50 wt%, about 0.00005-10 wt%, about 0.00005-5 wt% %, About 0.00005 to 1% by weight, about 0.00008 to 90% by weight, about 0.00008 to 50% by weight, about 0.00008 to 10% by weight, about 0.00008 to 5% by weight, about 0.0.
  • 0.0001-90 wt% about 0.0001-50 wt%, about 0.0001-10 wt%, about 0.0001-5 wt%, about 0.0001-1 wt%, about 0.0003-90 %, About 0.0003 to 50%, about 0.0003 to 10%, about 0.0003 to 5%, about 0.0003 to 1%, about 0.0005 to 90%, about 0% .0005-50 wt%, about 0.0005-10 wt%, about 0.0005-5 wt%, about 0.0005-1 wt%, about 0.0008-90 wt%, about 0.0008-50 wt% %, About 0.0008 to 10%, about 0.0008 to 5%, about 0.0008 to 1%, about 0.001 to 90%, about 0.001 to 50%, about 0.005%.
  • the content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is preferably 0.0001 parts by weight or more, more preferably 0.0003 parts by weight or more, and 0.0005 parts by weight with respect to 1 part by weight of GGA. More preferably, 0.0008 parts by weight or more, more preferably 0.001 parts by weight or more, more preferably 0.003 parts by weight or more, more preferably 0.005 parts by weight or more, and 0.008 parts by weight. The above is more preferable, and 0.01 parts by weight or more is even more preferable. Moreover, 0.1 weight part or more may be sufficient.
  • the content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is preferably 100000 parts by weight or less, more preferably 8000 parts by weight or less, and more preferably 5000 parts by weight or less with respect to 1 part by weight of GGA.
  • 3000 parts by weight or less is more preferable, 1000 parts by weight or less is more preferable, 800 parts by weight or less is more preferable, 500 parts by weight or less is more preferable, 300 parts by weight or less is more preferable, and 100 parts by weight or less is even more preferable. Moreover, 10 weight part or less may be sufficient. If it is the said range, the side effect by retinal disease therapeutic agents other than GGA is fully suppressed.
  • the content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is about 0.0001 to 100,000 parts by weight, about 0.0001 to 8000 parts by weight, about 0.0001 to about 1 part by weight of GGA. 5000 parts by weight, about 0.0001 to 3000 parts by weight, about 0.0001 to 1000 parts by weight, about 0.0001 to 800 parts by weight, about 0.0001 to 500 parts by weight, about 0.0001 to 300 parts by weight, about 0.0001-100 parts by weight, about 0.0001-10 parts by weight, about 0.0003-100000 parts by weight, about 0.0003-8000 parts by weight, about 0.0003-5000 parts by weight, about 0.0003-3000 Parts by weight, about 0.0003 to 1000 parts by weight, about 0.0003 to 800 parts by weight, about 0.0003 to 500 parts by weight, about 0.0003 to 300 parts by weight, about 0.0003 100 parts by weight, about 0.0003 to 10 parts by weight, about 0.0005 to 100000 parts by weight, about 0.0005 to 8000 parts by weight,
  • the content of the therapeutic agent for retinal diseases other than GGA in the ophthalmic preparation is preferably 0.001 mg or more, more preferably 0.01 mg or more, and more preferably 0.1 mg or more. Is even more preferred. If it is the said range, while each effect of container adsorption
  • the content of the therapeutic agent for retinal diseases other than GGA is preferably 1000 mg or less, more preferably 100 mg or less, and even more preferably 10 mg or less in the whole preparation. If it is the said range, the side effect by retinal disease therapeutic agents other than GGA is fully suppressed.
  • the content of the therapeutic agent for retinal diseases other than GGA in the solid preparation is 0.001 to 1000 mg, 0.001 to 100 mg, 0.001 to 10 mg, 0.01 to 1000 mg, 0.01 to 100 mg in the whole preparation. 0.01 to 10 mg, 0.1 to 1000 mg, 0.1 to 100 mg, and 0.1 to 10 mg.
  • the pH is preferably 4 or more, more preferably 5.5 or more, still 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
  • Viscosity The viscosity of the ophthalmic preparation of the present invention is appropriately set according to the type and content of the ingredients, the form of preparation, the method of use, etc., as long as it is physiologically or pharmaceutically acceptable.
  • the viscosity at 20 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ ⁇ R24) 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.
  • the ophthalmic preparation of the present invention may be a one-part preparation (combination) containing GGA and a therapeutic agent for retinal diseases other than GGA in one composition, or two or more. Two or more types of preparations (combination agents) using the above composition may be used. Examples of the latter include GGA-containing ophthalmic compositions, and combined use (combination agents) of retinal disease therapeutic drug-containing ophthalmic compositions other than GGA, which have uses in combination therewith. Or the combined use (combination agent) of the retinal disease therapeutic agent containing ophthalmic composition other than GGA and the GGA containing ophthalmic composition is illustrated.
  • each composition may be filled in a separate container, or may be a ready-to-use preparation filled in a container that can be mixed at the time of use.
  • any type such as a two-drug type or a three-drug type can be adopted.
  • composition comprising GGA and a therapeutic agent for retinal diseases other than GGA from the standpoint of prominently exhibiting the effect of suppressing white turbidity, the effect of suppressing adsorption to containers, the effect of stabilizing heat, and / or the effect of stabilizing light of the present invention.
  • the formulation contained therein is preferred.
  • the agent of the present invention is a combined preparation of a composition containing GGA and a composition containing other components
  • the GGA content described above and the content of a therapeutic agent for retinal diseases other than GGA are as follows. Is a content ratio with respect to the total amount.
  • the ophthalmic preparation 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 preparation 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 parts only one or all of the parts may be composed of the above materials, and different types of materials may be used for each part of the above materials.
  • 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 preparation of the present invention has a retinal disease such as a disease in which degeneration, damage or cell death of cells constituting the retina occurs, or a disease caused by degeneration, damage or cell death of cells constituting the retina. Can be targeted.
  • diseases include 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 occlusion), retinal arteriosclerosis, retinal tear, retinal hole, macular hole, fundus hemorrhage, posterior vitreous detachment, pigmented paravenous choroidal atrophy, cerebral gyrus Reticulochoroidal atrophy, Colloideremia, Crystalline retinopathy, White spotted retinopathy, Cone dystrophy, Central crested choroidal dystrophy, Dinbee's nest retinal dystrophy, Yolk macular dystrophy, Cystic tissue macular edema, Occult macular dystrophy, Stargardt disease, retinal sequestration
  • the ophthalmic preparation of the present invention can be used for diseases in which any cell constituting the retina is damaged, or diseases caused by damage to any cell 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 preparation of the present invention comprises the layers constituting the retina, that is, the inner boundary membrane, nerve fiber layer, ganglion cell layer, inner reticular membrane, inner granule layer, outer reticular layer, outer granule layer, outer boundary membrane, visual
  • the layers constituting the retina that is, the inner boundary membrane, nerve fiber layer, ganglion cell layer, inner reticular membrane, inner granule layer, outer reticular layer, outer granule layer, outer boundary membrane, visual
  • any of the cell layer and the retinal pigment epithelium layer is damaged, or a disease caused by a failure in any of these layers can be targeted.
  • 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.
  • the ophthalmic preparation of the present invention can be used for the prevention, amelioration, or treatment of retinal diseases, the suppression of retinal cell degeneration, damage, or cell death, or the protection of retinal cells.
  • GGA has an action of inducing neurite outgrowth of cells such as the retina, (retinal) neurite outgrowth promotion or induction, (retinal) cell function improvement, or A preparation for improving or improving the survival state of retinal cells can also be used.
  • 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 eye drop containing GGA at the above-mentioned concentration is, for example, about 1 to 5 drops, preferably about 1 to 3 drops, more preferably about 1 to 2 per dose. Drops may be instilled about 1 to 7 times, preferably about 1 to 5 times, more preferably about 1 to 3 times a day.
  • the preparation 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 5 times a day. Wash your eyes once.
  • 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 1 day a day. 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 per day, preferably 1 It is sufficient to inject it once.
  • the preparation of the present invention is a contact lens solution (cleaning solution, preservative solution, disinfectant solution, multipurpose solution, package solution), a preservative for isolated eye tissue such as a cornea for transplantation, or a perfusate during surgery
  • a contact lens solution cleaning solution, preservative solution, disinfectant solution, multipurpose solution, package solution
  • a preservative for isolated eye tissue such as a cornea for transplantation, or a perfusate during surgery
  • Compositions containing GGA at the above concentrations may be used at the usual dosage of these formulations.
  • the preparation of the present invention is a sustained-release contact lens preparation
  • the contact lens containing the above-mentioned amount of GGA is replaced with a new one, for example, about 1 to 3 times, preferably once every 1 to 14 days. That's fine.
  • the preparation of the present invention when the preparation of the present invention is a sustained-release intraocular implant, it may not be replaced with a new implant, but may be replaced with a new implant containing the above amount of GGA. In this case, for example, it may be replaced once every about 1 day to 10 years. For example, some implants have a relatively long period of time for replacement, such as implants for the posterior segment of the eye, but other implants are replaced once every about 1 to 14 days.
  • the daily dosage of GGA when the ophthalmic preparation of the present invention is used 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 daily dose of the component (b) when using the ophthalmic preparation of the present invention is preferably 50 ng or more, more preferably 500 ng or more. Preferably, 5 ⁇ g or more is even more preferable.
  • the daily dose of component (b) is preferably 50 mg or less, more preferably 20 mg or less, and even more preferably 10 mg or less.
  • the daily dose of component (b) includes 50 ng to 50 mg, 500 ng to 50 mg, 5 ⁇ g to 50 mg, 50 ng to 20 mg, 500 ng to 20 mg, 5 ⁇ g to 20 mg, 50 ng to 10 mg, 500 ng to 10 mg, 500 ⁇ g to 10 mg. .
  • the ophthalmic preparation of the present invention is administered to the eye, and the administration method varies depending on the kind of the preparation, and includes eye drop, eye wash, application to the eye, spray on the eye, implantation in the eye, wearing of a contact lens, glass Examples include injection into the eye such as the body.
  • the ophthalmic preparation of the present invention is a combination preparation separately comprising a composition containing GGA and a composition containing component (b)
  • the composition containing GGA and the composition containing component (b) are simultaneously used.
  • any one of the composition containing GGA and the composition containing component (b) may be administered later at intervals of 12 hours, 6 hours, or 2 hours. .
  • the interval is set, any of these may be administered first. However, it is more effective to administer the composition containing GGA and then administer the composition containing component (b). Hyperemia can be suppressed.
  • the present invention allows (a) GGA and (b) retinal disease therapeutic agent (excluding GGA) to coexist in an ophthalmic composition, thereby (b) retinal disease therapeutic agent (provided that GGA).
  • the method for imparting an action to suppress conjunctival hyperemia and / or corneal injury to the ophthalmic composition comprises (a) GGA and (b) a retinal disease therapeutic agent (excluding GGA) in the ophthalmic composition, thereby (b) a retinal disease therapeutic agent (
  • it is a method of reducing the side effects of conjunctival hyperemia and / or corneal injury that GGA) (excluding GGA) has.
  • the coexistence of (a) GGA and (b) retinal disease therapeutic agent (excluding GGA) From the coexistence of (a) GGA and (b) retinal disease therapeutic agent (excluding GGA), the above side effects of (b) retinal disease therapeutic agent (excluding GGA) are suppressed or reduced.
  • the coexistence may be performed at a temperature of about 1 to 80 ° C., particularly about 1 to 70 ° C., especially 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 a method for suppressing white turbidity of an ophthalmic composition by allowing (a) GGA and (b) a retinal disease therapeutic agent (excluding GGA) to coexist in the ophthalmic composition. Is included.
  • the cloudiness of the ophthalmic composition containing GGA is likely to occur particularly when the GGA concentration in the ophthalmic composition is high.
  • the method of the present invention even when the GGA concentration is 0.01% by weight or more, particularly 0.03% by weight or more, particularly 0.05% by weight or more, particularly 0.08% by weight or more, and particularly 0.1% by weight or more, white turbidity is caused. Can be suppressed.
  • white turbidity is suppressed at a GGA concentration of 10% by weight or less.
  • coexistence that is, (b) combination of a therapeutic agent for retinal diseases (excluding GGA) into an ophthalmic composition containing GGA, or ( b)
  • the composition of GGA into the ophthalmic composition containing a therapeutic agent for retinal diseases (excluding GGA) may be performed at a temperature of about 1 to 80 ° C., particularly about 1 to 70 ° C.
  • the cloudiness of the ophthalmic composition at a low temperature is also suppressed.
  • the “low temperature” can be, for example, 10 ° C. or less, particularly 6 ° C. or less, especially 4 ° C. or less.
  • the lower limit of “low temperature” may be a temperature at which the composition does not freeze, but may be, for example, ⁇ 10 ° C. or higher, particularly ⁇ 5 ° C. or higher, and in particular, 0 ° C. or higher.
  • the coexistence may be performed under light shielding or non-light shielding, but is preferably performed under light shielding.
  • the present invention relates to a container for GGA (particularly, an ophthalmic container) by coexisting (a) GGA and (b) a therapeutic agent for retinal diseases (excluding GGA) in an ophthalmic composition.
  • adsorption suppression methods In other words, this method adsorbs to an ophthalmic container of GGA by coexisting (a) GGA and (b) a therapeutic agent for retinal diseases (excluding GGA) in the ophthalmic composition. This is a method for suppressing the property.
  • the type of the container (in particular, the ophthalmic container) is as described for the ophthalmic preparation of the present invention.
  • GGA and (b) retinal disease therapeutic agent (excluding GGA) coexist
  • adsorption of GGA to the container is suppressed, but preferably 1 day or more, 3 days or more Or coexist for one week or longer.
  • 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 present invention improves the stability of GGA to heat and / or light by coexisting (a) GGA and (b) a therapeutic agent for retinal diseases (excluding GGA) in an ophthalmic composition.
  • the method of making it Although the stability of GGA to heat and / or light is improved from the coexistence of (a) GGA and (b) retinal disease therapeutic agent (excluding GGA), What is necessary is just to coexist for 3 days or more, or 1 week or more.
  • improvement in heat stability was confirmed by increasing the residual ratio of GGA when the ophthalmic composition was allowed to stand at 40 ° C. for 7 days.
  • 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 method of the present invention whether or not an ophthalmic composition containing (a) GGA and component (b) or an ophthalmic composition being prepared is contained in a container (particularly an ophthalmic container) is used. If (a) GGA and (b) component are contained in the ophthalmic composition or the ophthalmic composition being prepared, it falls under “coexistence of (a) GGA and (b) component”. .
  • 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.
  • ⁇ GC measurement conditions Column: DB-1 (J & W scientific, 0.53 mm ⁇ 30 m, film thickness 1.5 ⁇ m) Column temperature: 200 ° C. ⁇ 5 ° C./min ⁇ 300° C. (10 minutes) Vaporization chamber temperature: 280 ° C Detector temperature: 280 ° C Carrier gas: Helium Hydrogen pressure: 60 kPa Air pressure: 50kPa Makeup gas pressure: 75 kPa (nitrogen gas) Total flow rate: 41 mL / min Column flow rate: 6.52 mL / min Linear velocity: 58.3 cm / sec Split ratio: 5: 1 Injection volume: 0.1 ⁇ L of 0.1 g / 100 mL (ethanol solution) sample
  • test substance was prepared as follows. That is, the test substances were four types of GGA containing all-trans isomers and 5Z monocis isomers in weight ratios of 10: 0, 8: 2, 6: 4, and 0:10. 100 mg of each GGA, 0.25 mg of DL- ⁇ -tocopherol acetate (Wako Pure Chemical Industries) as an antioxidant was weighed, dissolved in 789 mg of 100% ethanol, and prepared in the same manner except that it did not contain GGA As a base.
  • the 10: 0, 8: 2 and 6: 4 GGA dissolved in 789 mg of 100% ethanol are 10% (v / v) horse serum (DS Pharma Biomedical), 5% (v / v) fetal bovine serum ( Diluted at a concentration corrected to include substantially 30 ⁇ M of all-trans form in Dulbecco's modified Eagle basal medium (DMEM) with a high glucose concentration (4.5 g / L) supplemented with Daiichi Kagaku)
  • DMEM Dulbecco's modified Eagle basal medium
  • the 0:10 GGA containing only was diluted to 30 ⁇ M.
  • the base was diluted at the same dilution ratio as that for preparing GGA having a weight ratio of 6: 4 between the all-trans isomer and the 5Z monocis isomer.
  • PC12 obtained from DS Pharma Biomedical was seeded on a collagen IV-coated 96-well microplate (IWAKI) at 100 ⁇ L to 2.0 ⁇ 10 4 cells per well, and the above DMEM was used at 37 ° C. The cells were cultured for 48 hours under conditions of 5% CO 2 .
  • the cell culture supernatant was removed, replaced with the previously prepared DMEM containing GGA, and cultured for 2 hours at 37 ° C. and 5% CO 2 .
  • the medium was replaced with DMEM with a low glucose concentration (1.0 g / L) supplemented with 2% horse serum and 1% fetal bovine serum, and aneropack 5% (37 ° C., 5% CO 2 , hypoxia conditions) (Mitsubishi Gas Chemical) was used to change to 0% O 2 and cultured for 8 hours.
  • the results are shown in FIG.
  • the extracted retinal tissue was treated with 100 U / mL penicillin, 100 ⁇ g / mL streptomycin, an additive for neuronal cell culture (B27 TM -Supplement, manufactured by Invitrogen), 1 ⁇ M L-cysteine (Kyowa Hakko Bio) and 15 U / mL papain ( It was transferred to a centrifuge tube containing 5 mL of a basal medium (Neurobasal, manufactured by Invitrogen) containing neuronal cell culture containing Sigma Aldrich and incubated at 37 ° C. for 30 minutes.
  • a basal medium Nerobasal, manufactured by Invitrogen
  • the supernatant was removed and washed twice with Neurobasal containing 100 U / mL penicillin, 100 ⁇ g / mL streptomycin, B27 TM -Supplement. After washing, 2 mL of Neurobasal was added, and the tissue was made into a small cell mass by pipetting with a dry heat sterilized Pasteur pipette (Hirgenberg) and transferred to 50 mL of Neurobasal prepared in advance. After centrifuging at 900 ⁇ g for 5 minutes to remove the supernatant, the suspension was again suspended with 6 mL of Neurobasal to prepare a cell suspension.
  • Neurobasal containing 100 U / mL penicillin, 100 ⁇ g / mL streptomycin, B27 TM -Supplement. After washing, 2 mL of Neurobasal was added, and the tissue was made into a small cell mass by pipetting with a dry heat sterilized Pasteur pipette (Hirgenberg) and transferred to 50
  • the cell suspension was passed through a 40 ⁇ m nylon mesh cell strainer (Japan BD) to remove the aggregated cell mass, and then the cells were seeded on a poly-D-lysine / laminin-coated 6-well plate (Japan BD). ° C., and cultured in a 5% CO 2 condition.
  • the test substances were 5 G mono isomers, and two types of GGA of a mixture containing all-trans isomers and 5 Z mono cis isomers in a weight ratio of 2: 8. 100 mg of each GGA and 0.25 mg of DL- ⁇ -tocopherol acetate (Wako Pure Chemical Industries) as an antioxidant were weighed, dissolved in 789 mg of 100% ethanol, and prepared in the same manner except that it did not contain GGA. A base was used. GGA mixture of 5Z monocis: all-trans isomer weight ratio of 0:10 (5Z monocis) and 2: 8 GGA dissolved in 789 mg of 100% ethanol will contain substantially 3 ⁇ M of 5Z monocis. And the base was added to the cell culture supernatant 2 hours after cell seeding so that the dilution ratio was the same as when preparing 6: 4 GGA, and the conditions were 37 ° C. and 5% CO 2 . Cultured for 48 hours.
  • GGA-containing eye drops were applied to only one eye on 6 rabbits (Japanese white species) combined with fasudil hydrochloride and GGA .
  • As GGA one containing an all-trans isomer and a 5Z monocis isomer at a weight ratio of 10: 0 was used.
  • 0.02 w / v% solution of fasudil hydrochloride (Wako Pure Chemical Industries) dissolved in PBS was instilled into both eyes of rabbits by 30 ⁇ L.
  • the conjunctiva of the upper eyelid of the rabbit was inverted, and the degree of hyperemia observed within 30 seconds was scored according to the criteria in Table 1 above.
  • GGA GGA having a weight ratio of 10: 0 to the all-trans isomer and the 5Z monocis isomer was used.
  • DMEM / F-12 Dulbecco's modified Eagle basal medium / Ham F12 equimixed liquid medium
  • Human corneal epithelial cells are seeded in a 96-well microplate (CORNING) so as to be 3.0 ⁇ 10 4 cells per well, 0.5% DMSO (Wako Pure Chemical Industries), 10 ng / Dulbecco's Modified Eagle Basal Medium / Ham F12 equimixed liquid supplemented with mL epidermal growth nutrient factor (R & D), 5 ⁇ g / mL insulin (Invitrogen), and 5% (v / v) fetal calf serum (first chemical) Culturing was performed in a medium (DMEM / F-12, manufactured by Invitrogen) at 37 ° C. and 5% CO 2 .
  • DMEM Dulbecco's Modified Eagle Basal Medium / Ham F12 equimixed liquid supplemented with mL epidermal growth nutrient factor (R & D), 5 ⁇ g / mL insulin (Invitrogen), and 5% (v /
  • an eye drop containing 0.5 w / v% timolol maleate (product name: timoptol eye drop 0.5% (Santen Pharmaceutical)) or an eye drop containing 1 w / v% dorzolamide hydrochloride ( (Product name: Torsopt ophthalmic solution 1%, MSD Co., Ltd.) was diluted and added so that the final concentration in the culture supernatant was 1%.
  • the above GGA solution or base was added to a final concentration of 3 to 30 ⁇ M in the culture supernatant and further cultured. After 48 hours of culture, the cell culture supernatant was removed, 200 ⁇ L of PBS was added, and PBS was immediately removed.
  • the turbidity of the GGA-containing composition was reduced, and white turbidity was suppressed.
  • Each eye drop was dispensed into a 15 mL plastic container by 5 mL with a glass hole pipette and sealed.
  • the container material and capacity will be described in Table 6 below.
  • a stability test was carried out in 8 hours at 40 ° C. and 75% RH in a state where these were left standing upright in a test tube stand. Under the above-mentioned HPLC conditions, immediately after production and after standing for 8 hours, teprenone (g / 100 mL) in each eye drop was quantified to calculate a GGA residual ratio (%).
  • 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
  • GGA-containing ophthalmic composition contains prostaglandin latanoprost, sympathetic ⁇ -blocker timolol maleate, or ROCK inhibitor fasudil hydrochloride, revealing the residual rate of GGA Improved. Since there is a difference in the content of GGA between polystyrene containers containing eye drops and polypropylene containers, the mixing of latanoprost, timolol maleate, or fasudil hydrochloride suppressed the adsorption of GGA to the container wall. I understand.
  • each buffer solution was mixed and stirred to obtain a uniform solution, and the pH and osmotic pressure were adjusted with hydrochloric acid or sodium hydroxide.
  • This solution was 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. It should be noted that in each operation, teprenone is adsorbed to a device or the like, and the content does not decrease.
  • aseptic eye drops An agent was prepared.
  • a 10 mL capacity transparent glass container (manufactured by Nippon Denka Glass) was aseptically filled. These eye drops were subjected to a stability test at 40 ° C. and 75% RH for 7 days with the container upright. Under the above HPLC conditions, the teprenone content (g / 100 mL) in the eye drop was quantified immediately after production and after standing for 7 days, and the residual rate (%) was calculated.
  • GGA-containing ophthalmic composition contains prostaglandin latanoprost, sympathetic ⁇ -blocker timolol maleate, or ROCK inhibitor fasudil hydrochloride, revealing the residual rate of GGA Improved. It turns out that the stability with respect to the heat
  • 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.
  • This solution was 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.
  • a sterile eye drop was prepared after confirming in advance by HPLC described later that the content of GGA was not reduced by adsorbing to an instrument or the like.
  • the prepared eye drop was aseptically filled into a polyethylene terephthalate container (Rohto Pharmaceutical, ROH Dry Aid EX container; capacity of about 8 mL). Each eye drop was irradiated with light under the following conditions, the teprenone content in the sample immediately after production and after irradiation was quantified, and the residual rate (%) was calculated.
  • Irradiation device LTL-200A-15WCD (manufactured by Nagano Science)
  • Light source D-65 lamp
  • Total irradiation amount 1.3 million lx ⁇ h (4000 lx ⁇ 325 hours)
  • Temperature and humidity 25 ° C 60%
  • Light irradiation direction Irradiation from above with the container upright on the internal rotating disk
  • GGA-containing ophthalmic composition contains prostaglandin latanoprost, sympathetic ⁇ -blocker timolol maleate, or ROCK inhibitor fasudil hydrochloride, revealing the residual rate of GGA Improved. It can be seen that the light stability of GGA was improved by blending latanoprost, timolol maleate, and fasudil hydrochloride.
  • the ophthalmic preparation of the present invention is excellent in the effect of preventing, improving, or treating retinal diseases, and is safe for a long time because conjunctival hyperemia and / or corneal disorders, which are side effects of retinal disease therapeutic agents other than GGA, are suppressed. It is a useful preparation that can be used in Further, the ophthalmic preparation of the present invention has advantageous properties as an ophthalmic preparation, such as excellent clarity, suppression of GGA adsorption to a container, and excellent GGA light stability. It is useful for.

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Abstract

La présente invention concerne une composition ophtalmologique dans laquelle coexistent (a) de la géranylgéranylacétone (GGA) et (b) un médicament thérapeutique contre la maladie rétinienne (autre que la GGA). Grâce à ladite composition, les effets secondaires tels que l'hyperémie conjonctivale et/ou les troubles de la cornée, provoqués par ledit médicament thérapeutique contre la maladie rétinienne (autre que la GGA) (b) sont supprimés. En outre, on empêche la composition ophtalmologique de se troubler et l'adsorption de la GGA dans les récipients. La stabilité de la GGA à la chaleur et/ou la lumière est également améliorée.
PCT/JP2014/072100 2013-08-26 2014-08-25 Préparation ophtalmologique WO2015029923A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2017064119A1 (fr) * 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la non-perfusion des capillaires de la rétine
EP4088719A1 (fr) * 2015-10-13 2022-11-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Procédés et compositions pharmaceutiques pour le traitement de non-perfusion capillaire rétinienne

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6532959B2 (ja) * 2015-11-30 2019-06-19 ロート製薬株式会社 眼科組成物
JP7343964B2 (ja) * 2018-09-21 2023-09-13 小林製薬株式会社 医薬組成物

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08133967A (ja) * 1994-11-02 1996-05-28 Eisai Co Ltd ドライアイ治療剤
WO2002083175A1 (fr) * 2001-04-11 2002-10-24 Senju Pharmaceutical Co., Ltd. Agents ameliorant la fonction visuelle
JP2006503913A (ja) * 2002-10-24 2006-02-02 スキャンポ・アーゲー・（ユーエスエイ）・インク 高眼圧症および緑内障の処置のための方法およびラタノプロスト含有組成物
JP2009242368A (ja) * 2008-03-31 2009-10-22 Nidek Co Ltd ドルゾラミド塩酸塩点眼液
WO2012026609A1 (fr) * 2010-08-27 2012-03-01 わかもと製薬株式会社 Composition aqueuse pour administration ophtalmique
JP2013511494A (ja) * 2009-11-19 2013-04-04 ノバガリ ファーマ エスエー 角膜および結膜病変を治癒させるためのプロスタグランジンＦ２αおよび類似体の使用
WO2013129322A1 (fr) * 2012-02-27 2013-09-06 ロート製薬株式会社 Composition ophtalmique
WO2013129319A1 (fr) * 2012-02-27 2013-09-06 ロート製薬株式会社 Composition ophtalmique

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08133967A (ja) * 1994-11-02 1996-05-28 Eisai Co Ltd ドライアイ治療剤
WO2002083175A1 (fr) * 2001-04-11 2002-10-24 Senju Pharmaceutical Co., Ltd. Agents ameliorant la fonction visuelle
JP2006503913A (ja) * 2002-10-24 2006-02-02 スキャンポ・アーゲー・（ユーエスエイ）・インク 高眼圧症および緑内障の処置のための方法およびラタノプロスト含有組成物
JP2009242368A (ja) * 2008-03-31 2009-10-22 Nidek Co Ltd ドルゾラミド塩酸塩点眼液
JP2013511494A (ja) * 2009-11-19 2013-04-04 ノバガリ ファーマ エスエー 角膜および結膜病変を治癒させるためのプロスタグランジンＦ２αおよび類似体の使用
WO2012026609A1 (fr) * 2010-08-27 2012-03-01 わかもと製薬株式会社 Composition aqueuse pour administration ophtalmique
WO2013129322A1 (fr) * 2012-02-27 2013-09-06 ロート製薬株式会社 Composition ophtalmique
WO2013129319A1 (fr) * 2012-02-27 2013-09-06 ロート製薬株式会社 Composition ophtalmique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CAPRIOLI, J. ET AL.: "Retinal ganglion cell protection with geranylgeranylacetone, a heat shock protein inducer, in a rat glaucoma model, Trans.", AM. OPHTHALMOL. SOC., vol. 101, 2003, pages 39 - 51 *
GUO, X. ET AL.: "Effect of geranylgeranylacetone on optic neuritis in experimental autoimmune encephalomyelitis", NEUROSCI. LETT., vol. 462, no. 3, 2009, pages 281 - 285 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017064119A1 (fr) * 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la non-perfusion des capillaires de la rétine
EP4088719A1 (fr) * 2015-10-13 2022-11-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Procédés et compositions pharmaceutiques pour le traitement de non-perfusion capillaire rétinienne

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