WO2018003796A1 - Ophthalmic product and method for suppressing decrease in viscosity - Google Patents

Ophthalmic product and method for suppressing decrease in viscosity Download PDF

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Publication number
WO2018003796A1
WO2018003796A1 PCT/JP2017/023572 JP2017023572W WO2018003796A1 WO 2018003796 A1 WO2018003796 A1 WO 2018003796A1 JP 2017023572 W JP2017023572 W JP 2017023572W WO 2018003796 A1 WO2018003796 A1 WO 2018003796A1
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Prior art keywords
acid
salt
enclosure
ophthalmic
hydrochloride
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PCT/JP2017/023572
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French (fr)
Japanese (ja)
Inventor
奥村　隆
香菜 内藤
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ライオン株式会社
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Application filed by ライオン株式会社 filed Critical ライオン株式会社
Priority to KR1020187022405A priority Critical patent/KR102665052B1/en
Priority to JP2018525176A priority patent/JP7040440B2/en
Publication of WO2018003796A1 publication Critical patent/WO2018003796A1/en
Priority to JP2021210334A priority patent/JP7314986B2/en

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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A61K31/125—Camphor; Nuclear substituted derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to an ophthalmic product in which a decrease in viscosity of a water-soluble polymer compound is suppressed.
  • a method in which a thickening agent such as a polymer compound is blended in order to improve effectiveness and maintain a refreshing feeling, thereby increasing drug retention on the ocular surface.
  • the improvement in retention of the active ingredient on the ocular surface is considered to be particularly beneficial for active ingredients that act on corneal epithelial cells on the ocular surface such as vitamin A.
  • a refreshing agent such as menthol is used.
  • a refreshing component such as vitamin A and menthol is a fat-soluble component, a surfactant is often blended at the same time in order to blend these components into an aqueous eye drop.
  • a method of blending vegetable oil such as sesame oil (Patent Document 1: Japanese Patent Laid-Open No. 2005-206598) or a method of blending castor oil (Patent Document 2: Japanese Patent Laid-Open No. 2005) No. -206599) and a method of adding mannitol or glycerin (Patent Document 3: Japanese Patent Laid-Open No. 11-71478) is known.
  • the decrease in viscosity of the ophthalmic composition blended with the polymer compound is caused by the influence of various blending components, and a surfactant used when blending fat-soluble components such as vitamin A and menthol was added. At that time, a decrease in viscosity is particularly likely to occur, and the above-described method was not sufficient in suppressing the decrease in viscosity.
  • the viscosity of the ophthalmic composition greatly contributes to improving the effectiveness of the drug and the sustainability of the refreshing agent, and also greatly affects the feeling of use resulting from the viscosity. For example, a viscosity that is too high is sticky or sticky, after use. There is a possibility of causing blurring of the field of view. Maintaining the design viscosity of the formulation without changing it is very important in terms of effectiveness and usability in maintaining the quality of the ophthalmic composition. Such a high viscosity stabilization method. Was desired.
  • the present invention tends to cause a decrease in viscosity particularly when the polymer compound is added. It has been found that this is particularly remarkable when oxyethylene polyoxypropylene glycol is used. It aims at providing the technique which suppresses such a viscosity fall.
  • the present inventors have formulated specific components and used specific packaging means in an ophthalmic composition containing a polymer compound, a surfactant, and a fat-soluble component.
  • a high viscosity reduction suppressing effect is exhibited.
  • the ophthalmic composition provided by the present invention exhibits a high retention during instillation and is excellent in a moist feeling sustaining effect.
  • the present invention provides the following. [1].
  • A a water-soluble polymer compound,
  • B polyoxyethylene polyoxypropylene glycol,
  • C one or more components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, and
  • D one or more components selected from the group consisting of (D-1) and (D-2) below (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, An ophthalmic composition containing chondroitin sulfate, a salt thereof, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic
  • A a water-soluble polymer compound
  • B polyoxyethylene polyoxypropylene glycol
  • C an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container
  • an ophthalmic product having an enclosure for packaging, (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorber into the enclosure, (3) Either an oxygen-absorbing vessel or (4) an enclosure with oxygen-absorbing capability
  • D (D) (D-1) and (D-2) below (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, Chondroitin,
  • a high viscosity reduction inhibitory effect can be obtained in a composition containing a polymer compound, a surfactant and a fat-soluble component.
  • water-soluble polymer compounds include cellulose polymer compounds such as hydroxypropylmethylcellulose (hypromellose), methylcellulose, and hydroxyethylcellulose; polyvinyl polymer compounds such as polyvinylpyrrolidone (povidone) and polyvinyl alcohol; hyaluronic acid and salts thereof; carboxy A vinyl polymer etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. By blending such components, it is possible to impart viscosity to the composition, improve the retention of the blended active ingredients on the ocular surface, and prevent drying of the ocular surface by retaining on the ocular surface. it can.
  • cellulose polymer compounds such as hydroxypropylmethylcellulose (hypromellose), methylcellulose, and hydroxyethylcellulose
  • polyvinyl polymer compounds such as polyvinylpyrrolidone (povidone) and polyvinyl alcohol
  • hyaluronic acid and salts thereof carboxy A vinyl polymer etc.
  • hydroxypropylmethylcellulose methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, hyaluronic acid and salts thereof are preferable, and hydroxypropylmethylcellulose is preferable.
  • the water-soluble polymer compound is a polymer compound that can be dissolved in an aqueous solution, and its weight average molecular weight is preferably 5,000 to 5,000,000, more preferably 10,000 to 2,500,000. preferable.
  • the measurement of a weight average molecular weight can be calculated
  • the compounding amount of the component (A) is preferably 0.01 to 10% (W / V% (mass / volume%, g / 100 mL or less)) in the composition, and more preferably 0.05 to 3%.
  • the content is preferably 0.05 to 5%, more preferably 0.1 to 3%, still more preferably 0.1 to 0.5%.
  • methylcellulose is blended, it is preferably 0.05 to 5% in the composition, more preferably 0.1 to 3%, and still more preferably 0.1 to 1%.
  • the content is preferably 0.05 to 5%, more preferably 0.1 to 3%, and still more preferably 0.1 to 1%.
  • the content is preferably 0.01 to 10%, more preferably 0.05 to 5%, and still more preferably 0.05 to 3%.
  • the content is preferably 0.01 to 5%, more preferably 0.05 to 3%, still more preferably 0.1 to 1%.
  • the content is preferably 0.01 to 3%, more preferably 0.01 to 1%, still more preferably 0.02 to 1%.
  • polyoxyethylene polyoxypropylene glycol polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) Glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol and the like alone Or two or more can be used in appropriate combination.
  • polyoxyethylene (200) polyoxypropylene (70) glycol is preferable.
  • the blending amount of the component (B) is preferably 0.1 to 10%, more preferably 0.1 to 5%, further preferably 0.4 to 3% in the composition.
  • (C) component etc. can be mix
  • Component (C) It is 1 or more types of components chosen from vitamin A, vitamin E, dibutylhydroxytoluene, and a refreshing agent, This fat-soluble component can be used individually by 1 type or in combination of 2 or more types.
  • Vitamin A has a corneal wound healing effect and the like, and in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters and the like can be mentioned. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate is preferred.
  • the blending amount is preferably 5,000 to 500,000 international units (IU) in 100 mL of the ophthalmic composition, more preferably 10,000 to 100,000 international units (IU). More preferably, 5,000-75,000 international units (IU).
  • IU international units
  • a corneal wound healing effect due to vitamin A can be expected at a lower limit value or more, and vitamin A stability can be further obtained at an upper limit value or less.
  • vitamin E examples include tocopherol acetate (dl- ⁇ -tocopherol acetate, d- ⁇ -tocopherol acetate (vitamin E)), tocopherol succinate, and derivatives thereof. Of these, d- ⁇ -tocopherol acetate is preferred.
  • the blending amount is preferably 0.005 to 0.5%, more preferably 0.01 to 0.1% in the ophthalmic composition.
  • the effect and stability can be further improved within the above range.
  • the blending amount is preferably 0.001 to 0.05%, more preferably 0.003 to 0.01% in the ophthalmic composition.
  • the effect and stability can be further improved within the above range.
  • Refreshing agents include menthol, camphor, cool mint, geraniol, mint water, borneol, eucalyptus oil, fennel oil, rose oil, bergamot oil, peppermint oil, spearmint oil, linalool, anethole, eugenol, cineol, N-ethyl- and p-menthane-carboxamide.
  • menthol is preferable.
  • the blending amount is preferably 0.001 to 0.5%, more preferably 0.005 to 0.3% in the ophthalmic composition. Within the above range, an effect and a good refreshing feeling upon instillation can be obtained.
  • [(D) component] (D) One or more selected from the group consisting of (D-1) and (D-2) below. (D) By mix
  • ethylenediamineacetic acid derivatives or salts thereof examples include edetic acid (ethylenediaminetetraacetic acid), ethylenediaminediacetic acid, diethylenetriaminepentaacetic acid, N- (2-hydroxyethyl) ethylenediaminetriacetic acid, sodium edetate (ethylenediaminetetraacetic acid sodium), ethylenediamine Examples thereof include disodium tetraacetate and hydrates thereof.
  • Examples of glycyrrhizic acid or a salt thereof include glycyrrhizic acid, dipotassium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, and the like.
  • Examples of chondroitin sulfate or a salt thereof include chondroitin sulfate, chondroitin polysulfate, sodium chondroitin sulfate, and the like.
  • Aspartic acid or a salt thereof includes, for example, sodium L-aspartate, potassium L-aspartate, magnesium L-aspartate, calcium L-aspartate, magnesium L-aspartate and potassium (L-aspartate and L- And an equivalent mixture with potassium aspartate).
  • the above can be used singly or in appropriate combination of two or more, among which trometamol, propylene glycol, allantoin and panthenol are preferable. Further, when two or more types are combined, it is preferably one or more types from the (D-1) group and one or more types from the (D-2) group.
  • the blending amount of the component (D) is preferably 0.001 to 10%, more preferably 0.01 to 5%, and still more preferably 0.01 to 3% in the ophthalmic composition. By setting it as this range, the viscosity fall by using the said (A) and (B) component together can be suppressed more.
  • Trometamol is 0.01 to 10%, more preferably 0.1 to 5%.
  • Propylene glycol is 0.01 to 10%, more preferably 0.1 to 5%.
  • the ethylenediamineacetic acid derivative or a salt thereof is 0.001 to 2%, more preferably 0.01 to 1.5%.
  • Tetrahydrozoline hydrochloride is 0.001 to 2%, more preferably 0.01 to 1%.
  • Epsilon aminocaproic acid is 0.01 to 10%, more preferably 0.1 to 5%.
  • Allantoin is 0.001 to 5%, more preferably 0.01 to 1%.
  • Glycyrrhizic acid or a salt thereof is 0.001 to 5%, more preferably 0.01 to 1%.
  • Chlorpheniramine maleate is 0.001-1%, more preferably 0.003-0.1%.
  • Pyridoxine hydrochloride is 0.001 to 2%, more preferably 0.01 to 1%.
  • Panthenol is 0.001 to 2%, more preferably 0.01 to 1%.
  • Chondroitin sulfate or a salt thereof is 0.001 to 5%, more preferably 0.01 to 2%.
  • Neostigmine methyl sulfate is 0.0001 to 0.05%, more preferably 0.001 to 0.01%.
  • Diphenhydramine hydrochloride is 0.001 to 0.5%, more preferably 0.01 to 0.1%.
  • Cyanocobalamin is 0.001 to 0.5%, more preferably 0.005 to 0.05%.
  • Sodium chloride is 0.01 to 5%, more preferably 0.05 to 1%.
  • Aspartic acid or a salt thereof is 0.01 to 10%, more preferably 0.05 to 5%.
  • Aminoethylsulfonic acid is 0.01 to 5%, more preferably 0.05 to 3%.
  • ophthalmic composition of the present invention various components used in the ophthalmic composition can be blended as necessary within a range not impairing the effects of the present invention.
  • Preferred compounding ingredients include drugs, buffers, stabilizers, tonicity agents, antioxidants, preservatives and the like. These can be used individually by 1 type or in combination of 2 or more types, and can mix
  • Examples of the drug include a decongestant component other than the component (D), an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial component Or a bactericide component, saccharides, polysaccharides other than (A) component or derivatives thereof, polyhydric alcohol, local anesthetic components, steroid components, glaucoma treatment components, cataract treatment components, mydriasis components and the like. Specific examples are shown below.
  • Decongestant ⁇ -adrenergic agonist, for example, imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), ⁇ -phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and their pharmaceutically or physiologically acceptable Salts (for example, inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, and methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate) and the like.
  • imidazoline derivatives naphazoline, tetrahydrozoline, etc.
  • ⁇ -phenylethylamine derivatives phenyleph
  • O Eye muscle modulator component cholinesterase inhibitor having an active center similar to acetylcholine, tropicamide, atropine sulfate and the like.
  • Anti-inflammatory or astringent components pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemetacin, ibuprofen, thiaprofenic acid, loxoprofen sodium, zinc thiaramide hydrochloride
  • salts for example, zinc sulfate, zinc chloride, zinc lactate, etc.
  • lysozyme lysozyme hydrochloride
  • methyl salicylate sodium azulene sulfonate
  • berberine chloride berberine sulfate and the like.
  • Antihistamine component or antiallergic component for example, ketotifen, acitazanolast, levocabastine, cromoglycic acid, tranilast, ibudilast, amlexanox, pemirolast and pharmaceutically or physiologically acceptable salts thereof (ketotifen fumarate, cromoglyc Acid sodium etc.).
  • Vitamins examples include flavin adenine dinucleotide sodium (active vitamin B 2 ), ascorbic acid and the like.
  • Amino acids for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, serine, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine, glycylglycine, ⁇ -amino
  • Examples include butyric acid, glutamic acid or a salt thereof (for example, cysteine hydrochloride and the like).
  • Antibacterial component or bactericidal component sulfonamides (for example, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.) ), Etc.), acrinol, alkylpolyaminoethylglycine, new quinolone (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), berberine or a salt thereof (eg, berberine chloride, berberine sulfate) ), ⁇ -lactam antibiotics (sulbenicillin, cefmenoxime, etc.), aminoglycoside antibiotics (kanamycin, gentamicin, tobramycin, sisomycin, dibekac
  • antiviral drugs doxuridine, acyclovir, adenine arabinoside, ganciclovir, foscarnet, valacyclovir, trifluorothymidine, cidophobia, carbocyclic oxetanocin G, etc.
  • antifungal drugs pimaricin, fluconazole, itraconazole, miconazole, Flucytosine, amphotericin B, etc.
  • saccharide examples include lactulose, raffinose, pullulan, glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, mannitol, sorbitol and the like.
  • Polysaccharides or derivatives thereof gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac gum, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, Examples include pectin, starch, polygalacturonic acid (alginic acid), chitin and derivatives thereof, chitosan and derivatives thereof, and elastin.
  • Polyhydric alcohol glycerin, butylene glycol, polyethylene glycol and the like.
  • Local anesthetic ingredients chlorobutanol, lidocaine, oxybuprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilucaine, mepivacaine, bupivacaine, cocaine and their salts (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) .
  • Steroid component Hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, parameterzone, betamethasone and their salts.
  • Glaucoma treatment ingredients distigmine bromide, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, isopropylunoprostone, dipivefrine hydrochloride, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide, metazolamide Etc.
  • pirenoxine pirenoxine
  • glutathione salivary gland hormone
  • thiopronin Dihydro azapdntacnd disulfonatd and salts thereof (for example, sodium 5,12-dihydrodacnddisdisfond etc.) and the like.
  • Mydriatic component cyclopentrate hydrochloride, tropicamide and the like.
  • an effective appropriate amount of each drug can be selected as the compounding amount.
  • 0.001 in the ophthalmic composition It is preferably in the range of ⁇ 5%.
  • the buffer for example, citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, and sodium hydrogen carbonate are preferably used.
  • the blending amount is preferably in the range of 0.003 to 4% in the composition.
  • the stabilizer examples include ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin and the like.
  • the blending amount is preferably in the range of 0.003 to 2% in the composition.
  • the isotonic agent examples include potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium carbonate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen sulfite and the like.
  • the blending amount is preferably in the range of 0.001 to 3% in the composition.
  • antioxidants examples include butylhydroxyanisole (BHA), hydroquinone, propyl gallate, sodium bisulfite and the like.
  • BHA butylhydroxyanisole
  • hydroquinone hydroquinone
  • propyl gallate sodium bisulfite
  • the blending amount is preferably in the range of 0.001 to 1% in the composition.
  • preservatives examples include parabens such as benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, chlorobutanol, and paraoxybenzoic acid ester, polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate And polyhexamethylene biguanide.
  • the blending amount thereof is preferably in the range of 0.0001 to 0.5% in the composition, and more preferably in the range of 0.001 to 0.5%.
  • the ophthalmic composition of the present invention can be produced by a known production method with the balance being water.
  • each of the above components can be obtained by dissolving in sterilized purified water, water such as ion exchange water, or a mixed solvent with water.
  • the fat-soluble component such as component (C) is dissolved in (B) polyoxyethylene polyoxypropylene glycol, and then charged into a high-temperature (70 to 95 ° C.) aqueous solution in which other aqueous components are dissolved, and then the pH is adjusted.
  • the osmotic pressure and the like can be appropriately adjusted with a pH adjusting agent or an isotonizing agent.
  • pH regulators include hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like.
  • the pH (20 ° C.) of the ophthalmic composition of the present invention is preferably 3.5 to 8.0, more preferably 4.5 to 7.7, and still more preferably 5.5 to 7.5. If the pH is too low or too high, the feeling of irritation can be strong.
  • the pH is measured at 20 ° C. using a pH osmometer (HSMO-1, Toa DKK Corporation).
  • As the pH adjuster sodium hydroxide, potassium hydroxide, hydrochloric acid and the like are preferable.
  • the ophthalmic composition of the present invention is preferably a liquid, and the viscosity at 20 ° C. is preferably 1 to 400 mPa ⁇ s, more preferably 1 to 100 mPa ⁇ s, still more preferably 1 to 60 mPa ⁇ s, and 1 to 50 mPa ⁇ s, 1 to 20 mPa ⁇ s is particularly preferable.
  • the viscosity is measured using a B-type viscometer.
  • the present invention is an ophthalmic product comprising an ophthalmic composition, a container filled with the ophthalmic composition, and an enclosure for packaging the container, wherein the oxygen concentration in the ophthalmic composition is reduced.
  • Means include (1) injecting inert gas into the enclosure, (2) bundling of oxygen absorbent into the enclosure, (3) container having oxygen absorption capacity, or (4) enclosure having oxygen absorption capacity. Etc. By such means, a decrease in viscosity due to the combined use of the above components (A) and (B) can be further suppressed.
  • the enclosure is preferably capable of sealing the container.
  • the container is preferably a plastic container, and materials such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, vinyl chloride, or a composite of these materials can be used. Polyethylene terephthalate is particularly preferable.
  • the oxygen permeability coefficient of the container is preferably 10 cc / m 2 ⁇ 24 hr ⁇ atm or more.
  • the envelope examples include polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil, polyvinyl alcohol / polyamide film deposited with aluminum, and polyvinylidene chloride. A composite or multilayer film of these, such as a film or a laminate film, may be mentioned.
  • the oxygen permeability coefficient of the envelope is preferably 10 cc / m 2 ⁇ 24 hr ⁇ atm or less (that is, 0 to 10 cc / m 2 ⁇ 24 hr ⁇ atm).
  • the inert gas includes nitrogen, helium, neon, argon, and the like. Of these, nitrogen gas is preferred.
  • the concentration of the inert gas is preferably 50% by volume or more, more preferably 80% by volume or more, and further preferably 90% by volume or more in the space volume formed between the enclosure and the plastic container.
  • An upper limit is not specifically limited, It is 100 volume% or less. In order to achieve such a concentration, the space formed between the enclosure and the plastic container may be replaced with an inert gas.
  • Container having oxygen absorbing ability An oxyblock manufactured by Toyo Seikan Co., Ltd., an oxyvanish manufactured by Mitsubishi Gas Chemical Co., Ltd., etc.
  • Oxycatch (registered trademark) ICA manufactured by Kyodo Printing Co., Ltd., Cryovac (registered trademark) OS film manufactured by Shield Air, Histar O2 manufactured by Star Plastic Industry Co., Ltd. Ageless Omak manufactured by Mitsubishi Gas Chemical Co., Ltd., Oxydec manufactured by Toyo Seikan Co., Ltd., etc. can be used.
  • the present invention (A) a water-soluble polymer compound, (B) polyoxyethylene polyoxypropylene glycol, (C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container
  • an ophthalmic product having an enclosure for packaging, (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorber into the enclosure, (3) Either an oxygen-absorbing vessel or (4) an enclosure with oxygen-absorbing capability Using means, (D) (D-1) and (D-2) below (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, pantheno
  • the present invention provides: (A) a water-soluble polymer compound, (B) polyoxyethylene polyoxypropylene glycol, (C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorbent in the enclosure, (3) Container having oxygen absorption capacity, or (4) Oxygen absorption In an ophthalmic product using any means of an enclosure having a function, in the ophthalmic composition, (D) (D-1) and (D-2) below (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative or salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid or salt thereof, chlorpheniramine maleate, pyridoxine
  • Examples and Comparative Examples The ophthalmic composition having the composition shown in the following table is dissolved in a polyoxyethylene polyoxypropylene glycol after dissolving a fat-soluble component and then poured into a high-temperature (70 to 95 ° C.) aqueous solution in which other aqueous components are dissolved. Ophthalmic compositions having the compositions shown in the table were produced. The obtained ophthalmic composition was filled in an eye drop container made of polyethylene terephthalate, and then a film package containing an oxygen absorbent (AGELESS: Z-20PK manufactured by Mitsubishi Gas Chemical Co., Ltd.) was applied.
  • AGELESS Z-20PK manufactured by Mitsubishi Gas Chemical Co., Ltd.
  • the viscosity before storage (20 ° C.) was measured with a B-type viscometer (digital viscometer DV2T, manufactured by Eihiro Seiki Co., Ltd.) and stored for 2 months in an environment of 50 ° C. and 75% RH. After storage, the eye drops were returned to room temperature (20 ° C.) and measured in the same manner as before storage. Based on the following formula, the viscosity retention rate (%) of each example was determined from the obtained viscosity, and the viscosity retention rate enhancement effect (%) with respect to Comparative Example 1 was calculated.
  • the “comparative examples described in each table” refers to a comparative example not including the component (D) corresponding to each example.
  • the film packaging is made by Ageless Omak manufactured by Mitsubishi Gas Chemical Co., Ltd.
  • the composition was excellent in viscosity stability. These ophthalmic products having such effects are excellent in the viscosity stability of the composition, and can maintain the retention effect on the ocular surface such as active ingredients and cooling agents.
  • the viscosity reduction of the ophthalmic composition due to the combination of the components (A) and (B) can be reduced by the addition of the above means and the component (D), or the component (D). It can suppress by addition and can maintain the retention effect in the ocular surface, such as an active ingredient of (C) component, a refreshing agent.
  • Hydroxypropyl methylcellulose Hypromellose (60SH-4000), Metrolose 60SH-4000, JP, Shin-Etsu Chemical Co., Ltd., weight average molecular weight 300,000 (g / mol)
  • Polyvinylpyrrolidone Kollidon 90F, JP, BASF Corp., weight average molecular weight 1 million (g / mol) Hydroxyethyl cellulose: HEC CF-V, supplementary regulations, Sumitomo Seika Co., Ltd., weight average molecular weight 900,000 (g / mol) Methylcellulose: Metrows SM-400, JP, Shin-Etsu Chemical Co., Ltd.
  • Sodium hyaluronate Sodium biohyaluronate, Shiseido carboxyvinyl polymer: Carbopol (registered trademark) 971PNF, Supplementary regulations, Lubrizol polyoxyethylene (200) Polyoxypropylene (70) glycol: Unilube 70DP-950B, Supplementary regulations, Japan Oil Co., Ltd. or Lutrol F127, Addendum, BASF Co., Ltd.
  • Retinol palmitic acid ester a Japanese pharmacy product (Retinol palmitic acid ester, DSM Nutrition Japan Co., Ltd.)
  • D- ⁇ -Tocopherol acetate an extra-regular product, (RIKEN E Acetate ⁇ , Riken Vitamin Co., Ltd.)
  • Dibutylhydroxytoluene Supplementary product, (Dibutylhydroxytoluene, Wako Pure Chemical Industries, Ltd.)
  • component (D) various raw materials conforming to official standards (Japanese Pharmacopoeia, Japanese Pharmacopoeia Pharmaceutical Standards, Pharmaceutical Additive Standards, etc.) standards were used.

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Abstract

An ophthalmic product including: an ophthalmic composition which comprises (A) a water-soluble polymeric compound, (B) polyoxyethylene polyoxypropylene glycol, (C) at least one component selected from vitamin A, vitamin E, dibutylhydroxytoluene and a cooling agent and (D) at least one component selected from the group consisting of (D-1) trometamol and propylene glycol and (D-2) an ethylenediamine acetic acid derivative or a salt thereof, tetrahydrozoline hydrochloride, epsilon-aminocaproic acid, allantoin, glycyrrhizic acid or a salt thereof, chlorphenyramine maleate, pyridoxine hydrochloride, panthenol, chondroitin sulfate or a salt thereof, neostigmine methylsulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid or a salt thereof and aminoethylsulfonic acid; a container which is filled with the ophthalmic composition; and a package body which packages the container.

Description

眼科用製品及び粘度低下抑制方法Ophthalmic product and method for suppressing viscosity reduction
　本発明は、水溶性高分子化合物の粘度低下が抑制された眼科用製品に関するものである。 The present invention relates to an ophthalmic product in which a decrease in viscosity of a water-soluble polymer compound is suppressed.
　眼科用組成物において、有効性の向上や清涼感の持続のために高分子化合物等の粘稠剤を配合し、眼表面での薬物滞留性を高める方法が知られている。有効成分の眼表面での滞留性の向上は、ビタミンＡ等の眼表面の角膜上皮細胞に作用する有効成分において、特に有益であると考えられる。また、清涼感を持続させるためには、メントール等の清涼化剤が用いられる。さらに、ビタミンＡや、メントール等の清涼化成分は脂溶性成分であるため、これらの成分を水性点眼剤に配合するためには、界面活性剤も同時に配合されることが多い。 In an ophthalmic composition, a method is known in which a thickening agent such as a polymer compound is blended in order to improve effectiveness and maintain a refreshing feeling, thereby increasing drug retention on the ocular surface. The improvement in retention of the active ingredient on the ocular surface is considered to be particularly beneficial for active ingredients that act on corneal epithelial cells on the ocular surface such as vitamin A. In order to maintain a refreshing feeling, a refreshing agent such as menthol is used. Furthermore, since a refreshing component such as vitamin A and menthol is a fat-soluble component, a surfactant is often blended at the same time in order to blend these components into an aqueous eye drop.
　セルロース系高分子化合物の粘度低下抑制のために、ゴマ油等の植物油を配合する方法（特許文献１：特開２００５－２０６５９８号公報）や、ヒマシ油を配合する方法（特許文献２：特開２００５－２０６５９９号公報）、マンニトールや、グリセリンを添加する方法（特許文献３：特開平１１－７１４７８号公報）が知られている。しかしながら、高分子化合物配合の眼科用組成物の粘度低下は、様々な配合成分による影響を受けて生じるものであり、ビタミンＡやメントール等の脂溶性成分の配合時に用いられる界面活性剤を添加した際には、粘度低下が特に生じやすく、上記のような方法では粘度低下抑制効果が十分ではなかった。 A method of blending vegetable oil such as sesame oil (Patent Document 1: Japanese Patent Laid-Open No. 2005-206598) or a method of blending castor oil (Patent Document 2: Japanese Patent Laid-Open No. 2005) No. -206599) and a method of adding mannitol or glycerin (Patent Document 3: Japanese Patent Laid-Open No. 11-71478) is known. However, the decrease in viscosity of the ophthalmic composition blended with the polymer compound is caused by the influence of various blending components, and a surfactant used when blending fat-soluble components such as vitamin A and menthol was added. At that time, a decrease in viscosity is particularly likely to occur, and the above-described method was not sufficient in suppressing the decrease in viscosity.
　眼科用組成物の粘度は、薬剤の有効性や清涼化剤の持続性向上に大きく寄与すると共に、粘度から生じる使用感にも大きく影響し、例えば、高すぎる粘度は粘つきやべたつき、使用後の視界のぼやけ感等を招く可能性がある。製剤の設計粘度を極力変化させることなく維持することは、眼科用組成物の品質維持において、有効性の面からも使用感の面からも非常に重要であり、そのような高い粘度安定化方法が望まれていた。 The viscosity of the ophthalmic composition greatly contributes to improving the effectiveness of the drug and the sustainability of the refreshing agent, and also greatly affects the feeling of use resulting from the viscosity. For example, a viscosity that is too high is sticky or sticky, after use. There is a possibility of causing blurring of the field of view. Maintaining the design viscosity of the formulation without changing it is very important in terms of effectiveness and usability in maintaining the quality of the ophthalmic composition. Such a high viscosity stabilization method. Was desired.
特開２００５－２０６５９８号公報JP 2005-206598 A 特開２００５－２０６５９９号公報JP 2005-206599 A 特開平１１－７１４７８号公報Japanese Patent Laid-Open No. 11-71478
　本発明は、ビタミンＡのような脂溶性成分、及び界面活性剤を配合した高分子化合物配合の眼科用組成物において、高分子化合物を配合すると、特に粘度低下が生じやすく、界面活性剤としてポリオキシエチレンポリオキシプロピレングリコールを用いた場合に、特に顕著であることを知見した。このような粘度低下を抑制する技術を提供することを目的とする。 In the ophthalmic composition containing a polymer compound containing a fat-soluble component such as vitamin A and a surfactant, the present invention tends to cause a decrease in viscosity particularly when the polymer compound is added. It has been found that this is particularly remarkable when oxyethylene polyoxypropylene glycol is used. It aims at providing the technique which suppresses such a viscosity fall.
　本発明者らは、上記目的を達成するため鋭意検討した結果、高分子化合物、界面活性剤及び脂溶性成分を含有する眼科用組成物において、特定の成分を配合し、特定の包装手段を用いることで、高い粘度低下抑制効果を発揮することを見出した。また、本発明によって提供される眼科用組成物は、点眼時に高い滞留性を発揮し、うるおい感の持続効果に優れている。 As a result of intensive studies to achieve the above object, the present inventors have formulated specific components and used specific packaging means in an ophthalmic composition containing a polymer compound, a surfactant, and a fat-soluble component. Thus, it has been found that a high viscosity reduction suppressing effect is exhibited. In addition, the ophthalmic composition provided by the present invention exhibits a high retention during instillation and is excellent in a moist feeling sustaining effect.
　従って、本発明は下記を提供する。
[１]．（Ａ）水溶性高分子化合物、
（Ｂ）ポリオキシエチレンポリオキシプロピレングリコール、
（Ｃ）ビタミンＡ、ビタミンＥ、ジブチルヒドロキシトルエン及び清涼化剤から選ばれる１種以上の成分、及び
（Ｄ）下記（Ｄ－１）及び（Ｄ－２）からなる群から選ばれる１種以上
（Ｄ－１）トロメタモール、プロピレングリコール
（Ｄ－２）エチレンジアミン酢酸誘導体、その塩、塩酸テトラヒドロゾリン、イプシロンアミノカプロン酸、アラントイン、グリチルリチン酸、その塩、クロルフェニラミンマレイン酸塩、ピリドキシン塩酸塩、パンテノール、コンドロイチン硫酸、その塩、ネオスチグミンメチル硫酸塩、ジフェンヒドラミン塩酸塩、シアノコバラミン、塩化ナトリウム、アスパラギン酸、その塩、アミノエチルスルホン酸
を含有する眼科用組成物と、この眼科用組成物が充填された容器と、この容器を包装する包囲体とを有する眼科用製品であって、
　（１）包囲体内への不活性ガス注入、（２）包囲体内への酸素吸収剤の同梱、（３）酸素吸収能を有する容器又は（４）酸素吸収能を有する包囲体のいずれかの手段を用いた眼科用製品。
[２]．（Ｄ）成分が、（Ｄ－１）群から１種以上及び（Ｄ－２）群から１種以上である[１]記載の眼科用製品。
[３]．（Ａ）成分が、ヒドロキシプロピルメチルセルロース、メチルセルロース、ヒドロキシエチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ヒアルロン酸及びその塩から選ばれる１種以上である[１]又は[２]記載の眼科用製品。
[４]．（Ｃ）成分が、レチノールパルミチン酸エステル、酢酸ｄ－α－トコフェロール、ジブチルヒドロキシトルエン及びメントールから選ばれる１種以上である[１]～[３]のいずれかに記載の眼科用製品。
[５]．（Ａ）水溶性高分子化合物、
（Ｂ）ポリオキシエチレンポリオキシプロピレングリコール、
（Ｃ）ビタミンＡ、ビタミンＥ、ジブチルヒドロキシトルエン及び清涼化剤から選ばれる１種以上の脂溶性成分を含有する眼科用組成物と、この眼科用組成物が充填された容器と、この容器を包装する包囲体とを有する眼科用製品において、
　（１）包囲体内への不活性ガス注入、（２）包囲体内への酸素吸収剤の同梱、（３）酸素吸収能を有する容器又は（４）酸素吸収能を有する包囲体のいずれかの手段を用いると共に、
（Ｄ）下記（Ｄ－１）及び（Ｄ－２）
（Ｄ－１）トロメタモール、プロピレングリコール
（Ｄ－２）エチレンジアミン酢酸誘導体、その塩、塩酸テトラヒドロゾリン、イプシロンアミノカプロン酸、アラントイン、グリチルリチン酸、その塩、クロルフェニラミンマレイン酸塩、ピリドキシン塩酸塩、パンテノール、コンドロイチン硫酸、その塩、ネオスチグミンメチル硫酸塩、ジフェンヒドラミン塩酸塩、シアノコバラミン、塩化ナトリウム、アスパラギン酸又はその塩、アミノエチルスルホン酸からなる群から選ばれる１種以上を配合することを特徴とする、上記眼科用組成物の粘度低下抑制方法。
[６]．（Ａ）水溶性高分子化合物、
（Ｂ）ポリオキシエチレンポリオキシプロピレングリコール、
（Ｃ）ビタミンＡ、ビタミンＥ、ジブチルヒドロキシトルエン及び清涼化剤から選ばれる１種以上の脂溶性成分を含有する眼科用組成物と、この眼科用組成物が充填された容器と、この容器を包装する包囲体とを有し、（１）包囲体内への不活性ガス注入、（２）包囲体内への酸素吸収剤の同梱、（３）酸素吸収能を有する容器又は（４）酸素吸収能を有する包囲体のいずれかの手段を用いた眼科用製品において、上記眼科用組成物に、
（Ｄ）下記（Ｄ－１）及び（Ｄ－２）
（Ｄ－１）トロメタモール、プロピレングリコール
（Ｄ－２）エチレンジアミン酢酸誘導体、その塩、塩酸テトラヒドロゾリン、イプシロンアミノカプロン酸、アラントイン、グリチルリチン酸、その塩、クロルフェニラミンマレイン酸塩、ピリドキシン塩酸塩、パンテノール、コンドロイチン硫酸、その塩、ネオスチグミンメチル硫酸塩、ジフェンヒドラミン塩酸塩、シアノコバラミン、塩化ナトリウム、アスパラギン酸又はその塩、アミノエチルスルホン酸
からなる群から選ばれる１種以上を配合することを特徴とする、上記眼科用組成物の粘度低下抑制方法。 Accordingly, the present invention provides the following.
[1]. (A) a water-soluble polymer compound,
(B) polyoxyethylene polyoxypropylene glycol,
(C) one or more components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, and (D) one or more components selected from the group consisting of (D-1) and (D-2) below (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, An ophthalmic composition containing chondroitin sulfate, a salt thereof, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid, a salt thereof, aminoethylsulfonic acid, and a container filled with the ophthalmic composition; And the enclosure that wraps this container To a ophthalmic products,
(1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorber into the enclosure, (3) Either an oxygen-absorbing vessel or (4) an enclosure with oxygen-absorbing capability Ophthalmic product using means.
[2]. The ophthalmic product according to [1], wherein the component (D) is one or more from the group (D-1) and one or more from the group (D-2).
[3]. The ophthalmic product according to [1] or [2], wherein the component (A) is at least one selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, hyaluronic acid and salts thereof. .
[4]. The ophthalmic product according to any one of [1] to [3], wherein the component (C) is at least one selected from retinol palmitate, d-α-tocopherol acetate, dibutylhydroxytoluene, and menthol.
[5]. (A) a water-soluble polymer compound,
(B) polyoxyethylene polyoxypropylene glycol,
(C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container In an ophthalmic product having an enclosure for packaging,
(1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorber into the enclosure, (3) Either an oxygen-absorbing vessel or (4) an enclosure with oxygen-absorbing capability Using means,
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, Chondroitin sulfate, a salt thereof, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid or a salt thereof, and at least one selected from the group consisting of aminoethylsulfonic acid A method for suppressing a decrease in viscosity of a composition.
[6]. (A) a water-soluble polymer compound,
(B) polyoxyethylene polyoxypropylene glycol,
(C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorbent in the enclosure, (3) Container having oxygen absorption capacity, or (4) Oxygen absorption In an ophthalmic product using any means of an enclosure having a function, in the ophthalmic composition,
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, Chondroitin sulfate, a salt thereof, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid or a salt thereof, and at least one selected from the group consisting of aminoethylsulfonic acid A method for suppressing a decrease in viscosity of a composition.
　本発明によれば、高分子化合物、界面活性剤及び脂溶性成分を含有する組成物において、高い粘度低下抑制効果を得ることができる。 According to the present invention, a high viscosity reduction inhibitory effect can be obtained in a composition containing a polymer compound, a surfactant and a fat-soluble component.
　以下、本発明について詳細に説明する。
[（Ａ）成分]
　水溶性高分子化合物としては、ヒドロキシプロピルメチルセルロース（ヒプロメロース）、メチルセルロース、ヒドロキシエチルセルロース等のセルロース系高分子化合物、ポリビニルピロリドン（ポビドン）、ポリビニルアルコール等のポリビニル系高分子化合物、ヒアルロン酸及びその塩、カルボキシビニルポリマー等が挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。このような成分を配合することで、組成物に粘度を付与し、配合された有効成分の眼表面での滞留性を向上し、眼表面に滞留することにより眼表面の乾燥を防止することができる。中でも、ヒドロキシプロピルメチルセルロース、メチルセルロース、ヒドロキシエチルセルロース、ポリビニルピロリドン、カルボキシビニルポリマー、ヒアルロン酸及びその塩が好ましく、ヒドロキシプロピルメチルセルロースが好ましい。 Hereinafter, the present invention will be described in detail.
[(A) component]
Examples of water-soluble polymer compounds include cellulose polymer compounds such as hydroxypropylmethylcellulose (hypromellose), methylcellulose, and hydroxyethylcellulose; polyvinyl polymer compounds such as polyvinylpyrrolidone (povidone) and polyvinyl alcohol; hyaluronic acid and salts thereof; carboxy A vinyl polymer etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. By blending such components, it is possible to impart viscosity to the composition, improve the retention of the blended active ingredients on the ocular surface, and prevent drying of the ocular surface by retaining on the ocular surface. it can. Among these, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, hyaluronic acid and salts thereof are preferable, and hydroxypropylmethylcellulose is preferable.
　水溶性高分子化合物の水溶性とは、水溶液に溶解可能な高分子化合物であり、その重量平均分子量は５，０００～５，０００，０００が好ましく、１０，０００～２，５００，０００がより好ましい。なお、重量平均分子量の測定はＧＰＣカラムを用いた液体クロマトグラフィーによる測定で求めることができる。 The water-soluble polymer compound is a polymer compound that can be dissolved in an aqueous solution, and its weight average molecular weight is preferably 5,000 to 5,000,000, more preferably 10,000 to 2,500,000. preferable. In addition, the measurement of a weight average molecular weight can be calculated | required by the measurement by the liquid chromatography using a GPC column.
　（Ａ）成分の配合量は、組成物中０．０１～１０％（Ｗ／Ｖ％（質量／容積％，ｇ／１００ｍＬ以下同様））が好ましく、０．０５～３％がより好ましい。また、ヒドロキシプロピルメチルセルロースを配合する場合は、組成物中０．０５～５％が好ましく、０．１～３％がより好ましく、０．１～０．５％がさらに好ましい。メチルセルロースを配合する場合は、組成物中０．０５～５％が好ましく、０．１～３％がより好ましく、０．１～１％がさらに好ましい。ヒドロキシエチルセルロースを配合する場合は、組成物中０．０５～５％が好ましく、０．１～３％がより好ましく、０．１～１％がさらに好ましい。ポリビニルピロリドンを配合する場合は、組成物中０．０１～１０％が好ましく、０．０５～５％がより好ましく、０．０５～３％がさらに好ましい。カルボキシビニルポリマーを配合する場合は、組成物中０．０１～５％が好ましく、０．０５～３％がより好ましく、０．１～１％がさらに好ましい。ヒアルロン酸及びその塩を配合する場合は、組成物中０．０１～３％が好ましく、０．０１～１％がより好ましく、０．０２～１％がさらに好ましい。上記以上とすることで粘度の付与効果が得られる。また、多すぎると粘度が高くなりすぎ、眼表面での流動性が悪く、ぼやけ、べたつき等の不具合を生じるおそれがある。 The compounding amount of the component (A) is preferably 0.01 to 10% (W / V% (mass / volume%, g / 100 mL or less)) in the composition, and more preferably 0.05 to 3%. In addition, when hydroxypropylmethylcellulose is blended, the content is preferably 0.05 to 5%, more preferably 0.1 to 3%, still more preferably 0.1 to 0.5%. When methylcellulose is blended, it is preferably 0.05 to 5% in the composition, more preferably 0.1 to 3%, and still more preferably 0.1 to 1%. When hydroxyethyl cellulose is blended, the content is preferably 0.05 to 5%, more preferably 0.1 to 3%, and still more preferably 0.1 to 1%. When blending polyvinyl pyrrolidone, the content is preferably 0.01 to 10%, more preferably 0.05 to 5%, and still more preferably 0.05 to 3%. When the carboxyvinyl polymer is blended, the content is preferably 0.01 to 5%, more preferably 0.05 to 3%, still more preferably 0.1 to 1%. When hyaluronic acid and a salt thereof are blended, the content is preferably 0.01 to 3%, more preferably 0.01 to 1%, still more preferably 0.02 to 1%. The effect of providing a viscosity can be obtained by setting the above. On the other hand, if the amount is too large, the viscosity becomes too high, the fluidity on the surface of the eye is poor, and problems such as blurring and stickiness may occur.
[（Ｂ）成分]
　ポリオキシエチレンポリオキシプロピレングリコールとしては、ポリオキシエチレン（２００）ポリオキシプロピレン（７０）グリコール、ポリオキシエチレン（１２０）ポリオキシプロピレン（４０）グリコール、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリオキシエチレン（４２）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（５４）ポリオキシプロピレン（３９）グリコール、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコールが挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。中でも、ポリオキシエチレン（２００）ポリオキシプロピレン（７０）グリコールが好ましい。 [(B) component]
As polyoxyethylene polyoxypropylene glycol, polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) Glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol and the like alone Or two or more can be used in appropriate combination. Among these, polyoxyethylene (200) polyoxypropylene (70) glycol is preferable.
　（Ｂ）成分の配合量は、組成物中０．１～１０％が好ましく、０．１～５％がより好ましく、０．４～３％がさらに好ましい。上記以上とすることで（Ｃ）成分等を安定に配合することができる。上限以下とすることで、（Ｂ）成分による刺激感のおそれがない。 The blending amount of the component (B) is preferably 0.1 to 10%, more preferably 0.1 to 5%, further preferably 0.4 to 3% in the composition. By setting it as the above or more, (C) component etc. can be mix | blended stably. By setting it to the upper limit or less, there is no fear of irritation due to the component (B).
[（Ｃ）成分]
　ビタミンＡ、ビタミンＥ、ジブチルヒドロキシトルエン及び清涼化剤から選ばれる１種以上の成分であり、この脂溶性成分を１種単独で又は２種以上を適宜組み合わせて用いることができる。ビタミンＡには角膜創傷治癒効果等があり、ビタミンＡそれ自体の他に、ビタミンＡ油等のビタミンＡ含有混合物、ビタミンＡ脂肪酸エステル等のビタミンＡ誘導体等が挙げられる。具体的には、レチノールパルミチン酸エステル、レチノール酢酸エステル、レチノール、レチノイン酸、レチノイド等が挙げられる。中でも、レチノールパルミチン酸エステルが好ましい。 [Component (C)]
It is 1 or more types of components chosen from vitamin A, vitamin E, dibutylhydroxytoluene, and a refreshing agent, This fat-soluble component can be used individually by 1 type or in combination of 2 or more types. Vitamin A has a corneal wound healing effect and the like, and in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters and the like can be mentioned. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate is preferred.
　ビタミンＡを配合する場合、その配合量は、眼科用組成物１００ｍＬ中５，０００～５００，０００国際単位（ＩＵ）が好ましく、１０，０００～１００，０００国際単位（ＩＵ）がより好ましく、１０，０００～７５，０００国際単位（ＩＵ）がさらに好ましい。下限値以上でビタミンＡによる角膜創傷治癒効果が期待でき、上限値以下で、ビタミンＡの安定性をより得ることができる。 When blending vitamin A, the blending amount is preferably 5,000 to 500,000 international units (IU) in 100 mL of the ophthalmic composition, more preferably 10,000 to 100,000 international units (IU). More preferably, 5,000-75,000 international units (IU). A corneal wound healing effect due to vitamin A can be expected at a lower limit value or more, and vitamin A stability can be further obtained at an upper limit value or less.
　ビタミンＥとしては、酢酸トコフェロール（酢酸ｄｌ－α－トコフェロール、酢酸ｄ－α－トコフェロール（ビタミンＥ））、コハク酸トコフェロール及びこれらの誘導体等が挙げられる。中でも、酢酸ｄ－α－トコフェロールが好ましい。 Examples of vitamin E include tocopherol acetate (dl-α-tocopherol acetate, d-α-tocopherol acetate (vitamin E)), tocopherol succinate, and derivatives thereof. Of these, d-α-tocopherol acetate is preferred.
　ビタミンＥを配合する場合、その配合量は、眼科用組成物中０．００５～０．５％が好ましく、０．０１～０．１％がより好ましい。上記範囲で効果と安定性をより図ることができる。 When blending vitamin E, the blending amount is preferably 0.005 to 0.5%, more preferably 0.01 to 0.1% in the ophthalmic composition. The effect and stability can be further improved within the above range.
　ジブチルヒドロキシトルエンを配合する場合、その配合量は、眼科用組成物中０．００１～０．０５％が好ましく、０．００３～０．０１％がより好ましい。上記範囲で効果と安定性をより図ることができる。 When dibutylhydroxytoluene is blended, the blending amount is preferably 0.001 to 0.05%, more preferably 0.003 to 0.01% in the ophthalmic composition. The effect and stability can be further improved within the above range.
　清涼化剤としては、メントール、カンフル、クールミント、ゲラニオール、ハッカ水、ボルネオール、ユーカリ油、ウイキョウ油、ローズ油、ベルガモット油、ペパーミント油、スペアミント油、リナロール、アネトール、オイゲノール、シネオール、Ｎ－エチル－ｐ－メンタン－カルボキシアミド等が挙げられる。中でも、メントールが好ましい。 Refreshing agents include menthol, camphor, cool mint, geraniol, mint water, borneol, eucalyptus oil, fennel oil, rose oil, bergamot oil, peppermint oil, spearmint oil, linalool, anethole, eugenol, cineol, N-ethyl- and p-menthane-carboxamide. Of these, menthol is preferable.
　清涼化剤を配合する場合、その配合量は、眼科用組成物中０．００１～０．５％が好ましく、０．００５～０．３％がより好ましい。上記範囲で効果と点眼時の良好な清涼感を得ることができる。 When blending a refreshing agent, the blending amount is preferably 0.001 to 0.5%, more preferably 0.005 to 0.3% in the ophthalmic composition. Within the above range, an effect and a good refreshing feeling upon instillation can be obtained.
［（Ｄ）成分］
　（Ｄ）下記（Ｄ－１）及び（Ｄ－２）からなる群から選ばれる１種以上である。（Ｄ）成分の配合により、上記（Ａ），（Ｂ）成分を併用することによる粘度低下を抑制することができる。
（Ｄ－１）トロメタモール、プロピレングリコール
（Ｄ－２）エチレンジアミン酢酸誘導体又はその塩、塩酸テトラヒドロゾリン、イプシロンアミノカプロン酸、アラントイン、グリチルリチン酸又はその塩、クロルフェニラミンマレイン酸塩、ピリドキシン塩酸塩、パンテノール、コンドロイチン硫酸又はその塩、ネオスチグミンメチル硫酸塩、ジフェンヒドラミン塩酸塩、シアノコバラミン、塩化ナトリウム、アスパラギン酸又はその塩、アミノエチルスルホン酸 [(D) component]
(D) One or more selected from the group consisting of (D-1) and (D-2) below. (D) By mix | blending a component, the viscosity fall by using the said (A) and (B) component together can be suppressed.
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative or salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid or salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, Chondroitin sulfate or its salt, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid or its salt, aminoethylsulfonic acid
　エチレンジアミン酢酸誘導体又はその塩としては、例えば、エデト酸（エチレンジアミン四酢酸）、エチレンジアミン二酢酸、ジエチレントリアミン五酢酸、Ｎ－（２－ヒドロキシエチル）エチレンジアミン三酢酸、エデト酸ナトリウム（エチレンジアミン四酢酸ナトリウム）、エチレンジアミン四酢酸二ナトリウム、これらの水和物等が挙げられる。グリチルリチン酸又はその塩としては、例えば、グリチルリチン酸、グリチルリチン酸二カリウム、グリチルリチン酸二ナトリウム、グリチルリチン酸二アンモニウム等が挙げられる。コンドロイチン硫酸又はその塩としては、例えば、コンドロイチン硫酸、コンドロイチン多硫酸エステル、コンドロイチン硫酸エステルナトリウム等が挙げられる。アスパラギン酸又はその塩としては、例えば、Ｌ－アスパラギン酸ナトリウム、Ｌ－アスパラギン酸カリウム、Ｌ－アスパラギン酸マグネシウム、Ｌ－アスパラギン酸カルシウム、Ｌ－アスパラギン酸マグネシウム・カリウム（Ｌ－アスパラギン酸マグネシウムとＬ－アスパラギン酸カリウムとの等量混合物）等が挙げられる。 Examples of ethylenediamineacetic acid derivatives or salts thereof include edetic acid (ethylenediaminetetraacetic acid), ethylenediaminediacetic acid, diethylenetriaminepentaacetic acid, N- (2-hydroxyethyl) ethylenediaminetriacetic acid, sodium edetate (ethylenediaminetetraacetic acid sodium), ethylenediamine Examples thereof include disodium tetraacetate and hydrates thereof. Examples of glycyrrhizic acid or a salt thereof include glycyrrhizic acid, dipotassium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, and the like. Examples of chondroitin sulfate or a salt thereof include chondroitin sulfate, chondroitin polysulfate, sodium chondroitin sulfate, and the like. Aspartic acid or a salt thereof includes, for example, sodium L-aspartate, potassium L-aspartate, magnesium L-aspartate, calcium L-aspartate, magnesium L-aspartate and potassium (L-aspartate and L- And an equivalent mixture with potassium aspartate).
　上記は１種単独で又は２種以上を適宜組み合わせて用いることができ、中でも、トロメタモール、プロピレングリコール、アラントイン、パンテノールが好ましい。また、２種以上を組み合わせる場合は、（Ｄ－１）群から１種以上及び（Ｄ－２）群から１種以上であることが好ましい。 The above can be used singly or in appropriate combination of two or more, among which trometamol, propylene glycol, allantoin and panthenol are preferable. Further, when two or more types are combined, it is preferably one or more types from the (D-1) group and one or more types from the (D-2) group.
　（Ｄ）成分の配合量は、眼科用組成物中０．００１～１０％が好ましく、０．０１～５％がより好ましく、０．０１～３％がさらに好ましい。この範囲とすることで、上記（Ａ），（Ｂ）成分を併用することによる粘度低下をより抑制することができる。 The blending amount of the component (D) is preferably 0.001 to 10%, more preferably 0.01 to 5%, and still more preferably 0.01 to 3% in the ophthalmic composition. By setting it as this range, the viscosity fall by using the said (A) and (B) component together can be suppressed more.
　各成分の眼科用組成物中のより好ましい配合量を下記に示す。トロメタモールは、０．０１～１０％、さらに好ましくは０．１～５％である。プロピレングリコールは、０．０１～１０％、さらに好ましくは０．１～５％である。エチレンジアミン酢酸誘導体又はその塩は、０．００１～２％であり、さらに好ましくは０．０１～１．５％である。塩酸テトラヒドロゾリンは、０．００１～２％、さらに好ましくは０．０１～１％である。イプシロンアミノカプロン酸は、０．０１～１０％であり、さらに好ましくは０．１～５％である。アラントインは、０．００１～５％であり、さらに好ましくは０．０１～１％である。グリチルリチン酸又はその塩は、０．００１～５％であり、さらに好ましくは０．０１～１％である。クロルフェニラミンマレイン酸塩は、０．００１～１％であり、さらに好ましくは０．００３～０．１％である。ピリドキシン塩酸塩は、０．００１～２％であり、さらに好ましくは０．０１～１％である。パンテノールは、０．００１～２％であり、さらに好ましくは０．０１～１％である。コンドロイチン硫酸又はその塩は、０．００１～５％であり、さらに好ましくは０．０１～２％である。ネオスチグミンメチル硫酸塩は、０．０００１～０．０５％であり、さらに好ましくは０．００１～０．０１％である。ジフェンヒドラミン塩酸塩は、０．００１～０．５％であり、さらに好ましくは０．０１～０．１％である。シアノコバラミンは、０．００１～０．５％であり、さらに好ましくは０．００５～０．０５％である。塩化ナトリウムは、０．０１～５％であり、さらに好ましくは０．０５～１％である。アスパラギン酸又はその塩は、０．０１～１０％であり、さらに好ましくは０．０５～５％である。アミノエチルスルホン酸は、０．０１～５％であり、さらに好ましくは０．０５～３％である。 More preferable amounts of each component in the ophthalmic composition are shown below. Trometamol is 0.01 to 10%, more preferably 0.1 to 5%. Propylene glycol is 0.01 to 10%, more preferably 0.1 to 5%. The ethylenediamineacetic acid derivative or a salt thereof is 0.001 to 2%, more preferably 0.01 to 1.5%. Tetrahydrozoline hydrochloride is 0.001 to 2%, more preferably 0.01 to 1%. Epsilon aminocaproic acid is 0.01 to 10%, more preferably 0.1 to 5%. Allantoin is 0.001 to 5%, more preferably 0.01 to 1%. Glycyrrhizic acid or a salt thereof is 0.001 to 5%, more preferably 0.01 to 1%. Chlorpheniramine maleate is 0.001-1%, more preferably 0.003-0.1%. Pyridoxine hydrochloride is 0.001 to 2%, more preferably 0.01 to 1%. Panthenol is 0.001 to 2%, more preferably 0.01 to 1%. Chondroitin sulfate or a salt thereof is 0.001 to 5%, more preferably 0.01 to 2%. Neostigmine methyl sulfate is 0.0001 to 0.05%, more preferably 0.001 to 0.01%. Diphenhydramine hydrochloride is 0.001 to 0.5%, more preferably 0.01 to 0.1%. Cyanocobalamin is 0.001 to 0.5%, more preferably 0.005 to 0.05%. Sodium chloride is 0.01 to 5%, more preferably 0.05 to 1%. Aspartic acid or a salt thereof is 0.01 to 10%, more preferably 0.05 to 5%. Aminoethylsulfonic acid is 0.01 to 5%, more preferably 0.05 to 3%.
　本発明眼科用組成物には、眼科用組成物に用いられる各種成分を、必要に応じて、本発明の効果を損なわない範囲で配合することができる。好ましい配合成分としては、薬物、緩衝剤、安定化剤、等張化剤、抗酸化剤、防腐剤等が挙げられる。これらは１種単独で又は２種以上を適宜組み合わせて用いることができ、適量を配合することができる。 In the ophthalmic composition of the present invention, various components used in the ophthalmic composition can be blended as necessary within a range not impairing the effects of the present invention. Preferred compounding ingredients include drugs, buffers, stabilizers, tonicity agents, antioxidants, preservatives and the like. These can be used individually by 1 type or in combination of 2 or more types, and can mix | blend suitable amount.
　薬物としては、例えば、（Ｄ）成分以外の充血除去成分、眼筋調節薬成分、抗炎症薬成分又は収斂薬成分、抗ヒスタミン薬成分又は抗アレルギー薬成分、ビタミン類、アミノ酸類、抗菌薬成分又は殺菌薬成分、糖類、（Ａ）成分以外の多糖類又はその誘導体、多価アルコール、局所麻酔薬成分、ステロイド成分、緑内障治療成分、白内障治療成分、散瞳成分等が挙げられる。具体例を下記に示す。 Examples of the drug include a decongestant component other than the component (D), an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial component Or a bactericide component, saccharides, polysaccharides other than (A) component or derivatives thereof, polyhydric alcohol, local anesthetic components, steroid components, glaucoma treatment components, cataract treatment components, mydriasis components and the like. Specific examples are shown below.
　充血除去成分：α－アドレナリン作動薬、例えば、イミダゾリン誘導体（ナファゾリン、テトラヒドロゾリン等）、β－フェニルエチルアミン誘導体（フェニレフリン、エピネフリン、エフェドリン、メチルエフェドリン等）、及びそれらの薬学上又は生理的に許容される塩（例えば、ナファゾリン塩酸塩、ナファゾリン硝酸塩、硝酸テトラヒドロゾリン、フェニレフリン塩酸塩、塩酸エピネフリン、エフェドリン塩酸塩、メチルエフェドリン塩酸塩等の無機酸塩；酒石酸水素エピネフリン等の有機酸塩等）等が挙げられる。 Decongestant: α-adrenergic agonist, for example, imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and their pharmaceutically or physiologically acceptable Salts (for example, inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, and methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate) and the like.
　眼筋調節薬成分：アセチルコリンと類似した活性中心を有するコリンエステラーゼ阻害剤、トロピカミド、アトロピン硫酸塩等が挙げられる。 O Eye muscle modulator component: cholinesterase inhibitor having an active center similar to acetylcholine, tropicamide, atropine sulfate and the like.
　抗炎症薬成分又は収斂薬成分：プラノプロフェン、セレコキシブ、ロフェコキシブ、インドメタシン、ジクロフェナク、ジクロフェナクナトリウム、ピロキシカム、メロキシカム、アスピリン、メフェナム酸、インドメタシンファルネシル、アセメタシン、イブプロフェン、チアプロフェン酸、ロキソプロフェンナトリウム、塩酸チアラミド、亜鉛塩（例えば、硫酸亜鉛、塩化亜鉛、乳酸亜鉛、等）、リゾチーム、リゾチーム塩酸塩、サリチル酸メチル、アズレンスルホン酸ナトリウム、ベルベリン塩化物、ベルベリン硫酸塩等が挙げられる。 Anti-inflammatory or astringent components: pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemetacin, ibuprofen, thiaprofenic acid, loxoprofen sodium, zinc thiaramide hydrochloride Examples thereof include salts (for example, zinc sulfate, zinc chloride, zinc lactate, etc.), lysozyme, lysozyme hydrochloride, methyl salicylate, sodium azulene sulfonate, berberine chloride, berberine sulfate and the like.
　抗ヒスタミン薬成分又は抗アレルギー薬成分：例えば、ケトチフェン、アシタザノラスト、レボカバスチン、クロモグリク酸、トラニラスト、イブジラスト、アンレキサノクス、ペミロラスト及びそれらの薬学上又は生理的に許容される塩（ケトチフェンフマル酸塩、クロモグリク酸ナトリウム等）等が挙げられる。 Antihistamine component or antiallergic component: for example, ketotifen, acitazanolast, levocabastine, cromoglycic acid, tranilast, ibudilast, amlexanox, pemirolast and pharmaceutically or physiologically acceptable salts thereof (ketotifen fumarate, cromoglyc Acid sodium etc.).
　ビタミン類：例えば、フラビンアデニンジヌクレオチドナトリウム（活性型ビタミンＢ2）、アスコルビン酸等が挙げられる。 Vitamins: Examples include flavin adenine dinucleotide sodium (active vitamin B 2 ), ascorbic acid and the like.
　アミノ酸類：例えば、ロイシン、イソイロイシン、バリン、メチオニン、トレオニン、アラニン、フェニルアラニン、トリプトファン、リジン、グリシン、セリン、プロリン、チロシン、システイン、ヒスチジン、オルニチン、ヒドロキシプロリン、ヒドロキシリジン、グリシルグリシン、γ－アミノ酪酸、グルタミン酸又はその塩（例えば塩酸システイン等）等が挙げられる。 Amino acids: for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, serine, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine, glycylglycine, γ-amino Examples include butyric acid, glutamic acid or a salt thereof (for example, cysteine hydrochloride and the like).
　抗菌薬成分又は殺菌薬成分：スルホンアミド類（例えば、スルファメトキサゾール、スルフイソキサゾール、スルフイソミジン及び薬理学的に許容される塩（スルファメトキサゾールナトリウム、スルフイソミジンナトリウム等）等）、アクリノール、アルキルポリアミノエチルグリシン、ニューキノロン剤（ロメフロキサシン、レボフロキサシン、シプロフロキサシン、オフロキサシン、ノルフロキサシン、シプロフロキサシン塩酸塩等）、ベルベリン又はその塩（例えば、ベルベリン塩化物、ベルベリン硫酸塩等）、βラクタム系抗菌薬（スルベニシリン、セフメノキシム等）、アミノグリコシド系抗菌薬（カナマイシン、ゲンタマイシン、トブラマイシン、シソマイシン、ジベカシン、ベカナマイシン、ミクロノマイシン等）、テトラサイクリン系抗菌薬（オシテトラサイクリン等）、マクロライド系抗菌薬（エリスロマイシン等）、クロラムフェニコール系抗菌薬（クロラムフェニコール等）、ポリペプチド系抗菌薬（コリスチン等）等。また、抗ウイルス薬（ドクスウリジン、アシクロビル、アデニンアラビノシド、ガンシクロビル、ホスカルネット、バラシクロビル、トリフルオロチミジン、シドフォビア、カルボサイクリック・オキセタノシンＧ等）、抗真菌薬（ピマリシン、フルコナゾール、イトラコナゾール、ミコナゾール、フルシトシン、アムホテリシンＢ等）等が挙げられる。 Antibacterial component or bactericidal component: sulfonamides (for example, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.) ), Etc.), acrinol, alkylpolyaminoethylglycine, new quinolone (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), berberine or a salt thereof (eg, berberine chloride, berberine sulfate) ), Β-lactam antibiotics (sulbenicillin, cefmenoxime, etc.), aminoglycoside antibiotics (kanamycin, gentamicin, tobramycin, sisomycin, dibekacin, bekanamycin, micronomycin, etc.), Tet Cyclin antibacterials (oscillation tetracycline, etc.), macrolide antibiotics (erythromycin, etc.), chloramphenicol antibacterials (chloramphenicol), polypeptide antibacterials (colistin, etc.) and the like. In addition, antiviral drugs (doxuridine, acyclovir, adenine arabinoside, ganciclovir, foscarnet, valacyclovir, trifluorothymidine, cidophobia, carbocyclic oxetanocin G, etc.), antifungal drugs (pimaricin, fluconazole, itraconazole, miconazole, Flucytosine, amphotericin B, etc.).
　糖類としては、ラクツロース、ラフィノース、プルラン、グルコース、マルトース、トレハロース、スクロース、シクロデキストリン、キシリトール、マンニトール、ソルビトール等が挙げられる。 Examples of the saccharide include lactulose, raffinose, pullulan, glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, mannitol, sorbitol and the like.
　多糖類又はその誘導体：アラビアゴム、カラヤガム、キサンタンガム、キャロブガム、グアーガム、グアヤク脂、クインスシード、ダルマンガム、トラガント、ベンゾインゴム、ローカストビーンガム、カゼイン、寒天、アルギン酸、デキストリン、デキストラン、カラギーナン、ゼラチン、コラーゲン、ペクチン、デンプン、ポリガラクツロン酸（アルギン酸）、キチン及びその誘導体、キトサン及びその誘導体、エラスチン等が挙げられる。 Polysaccharides or derivatives thereof: gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac gum, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, Examples include pectin, starch, polygalacturonic acid (alginic acid), chitin and derivatives thereof, chitosan and derivatives thereof, and elastin.
　多価アルコール：グリセリン、ブチレングリコール、ポリエチレングリコール等が挙げられる。 Polyhydric alcohol: glycerin, butylene glycol, polyethylene glycol and the like.
　局所麻酔薬成分：クロロブタノール、リドカイン、オキシブプロカイン、ジプカイン、プロカイン、アミノ安息香酸エチル、メプリルカイン、メピバカイン、ブピバカイン、コカイン及びそれらの塩（リドカイン塩酸塩、オキシブプロカイン塩酸塩等）等が挙げられる。 Local anesthetic ingredients: chlorobutanol, lidocaine, oxybuprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilucaine, mepivacaine, bupivacaine, cocaine and their salts (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) .
　ステロイド成分：ヒドロコルチゾン、プレドニゾロン、コルチゾール、メチルプレドニゾロン、トリアムシノロン、パラメタゾン、ベタメタゾン及びそれらの塩等が挙げられる。 Steroid component: Hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, parameterzone, betamethasone and their salts.
　緑内障治療成分：ジスチグミン臭化物、チモロールマレイン酸塩、カルテオロール塩酸塩、ベタキソロール塩酸塩、ラタノプロスト、イソプロピルウノプロストン、ジピベフリン塩酸塩、アプラクロニジン塩酸塩、ピロカルピン塩酸塩、カルバコール、ドルゾラミド塩酸塩、アセタゾラミド、メタゾラミド等が挙げられる。 Glaucoma treatment ingredients: distigmine bromide, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, isopropylunoprostone, dipivefrine hydrochloride, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide, metazolamide Etc.
　白内障治療成分：ピレノキシン、グルタチオン、唾液腺ホルモン、チオプロニン、Ｄｉｈｙｄｒｏ　ａｚａｐｄｎｔａｃｄｎｄ　ｄｉｓｕｌｆｏｎａｔｄ及びそれらの塩（例えばＳｏｄｉｕｍ５，１２－ｄｉｈｙｄｒｏ　ａｚａｐｄｎｔａｃｄｎｄ　ｄｉｓｕｌｆｏｎａｔｄ等）等が挙げられる。 Ingredients for treating cataract: pirenoxine, glutathione, salivary gland hormone, thiopronin, Dihydro azapdntacnd disulfonatd and salts thereof (for example, sodium 5,12-dihydrodacnddisdisfond etc.) and the like.
　散瞳成分：シクロペントラート塩酸塩、トロピカミド等が挙げられる。 Mydriatic component: cyclopentrate hydrochloride, tropicamide and the like.
　薬物を配合する場合、その配合量は、各薬物の有効な適性量を選択することができるが、眼への刺激性、組成物の安定性等の点から、眼科用組成物中０．００１～５％の範囲であることが好ましい。 When a drug is compounded, an effective appropriate amount of each drug can be selected as the compounding amount. From the viewpoint of irritation to the eye, stability of the composition, etc., 0.001 in the ophthalmic composition. It is preferably in the range of ˜5%.
　緩衝剤としては、例えば、クエン酸、クエン酸ナトリウム、ホウ酸、ホウ砂、リン酸、リン酸水素ナトリウム、リン酸二水素ナトリウム、氷酢酸、炭酸水素ナトリウムを使用することが好ましい。緩衝剤を配合する場合、その配合量は組成物中０．００３～４％の範囲であることが好ましい。 As the buffer, for example, citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, and sodium hydrogen carbonate are preferably used. When a buffering agent is blended, the blending amount is preferably in the range of 0.003 to 4% in the composition.
　安定化剤としては、例えば、α－シクロデキストリン、β－シクロデキストリン、γ－シクロデキストリン等が挙げられる。安定化剤を配合する場合、その配合量は組成物中０．００３～２％の範囲であることが好ましい。 Examples of the stabilizer include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and the like. When a stabilizer is blended, the blending amount is preferably in the range of 0.003 to 2% in the composition.
　等張化剤としては、例えば塩化カリウム、塩化カルシウム、塩化マグネシウム、酢酸カリウム、酢酸ナトリウム、炭酸ナトリウム、硫酸マグネシウム、リン酸水素二ナトリウム、リン酸二水素ナトリウム、亜硫酸水素ナトリウム等が挙げられる。等張化剤を配合する場合、その配合量は組成物中０．００１～３％の範囲であることが好ましい。 Examples of the isotonic agent include potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium carbonate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen sulfite and the like. When an isotonizing agent is blended, the blending amount is preferably in the range of 0.001 to 3% in the composition.
　抗酸化剤としては、ブチルヒドロキシアニソール（ＢＨＡ）、ヒドロキノン、没食子酸プロピル、亜硫酸水素ナトリウム等が挙げられる。抗酸化剤を配合する場合、その配合量は組成物中０．００１～１％の範囲であることが好ましい。 Examples of the antioxidant include butylhydroxyanisole (BHA), hydroquinone, propyl gallate, sodium bisulfite and the like. When an antioxidant is blended, the blending amount is preferably in the range of 0.001 to 1% in the composition.
　防腐剤としては、例えば塩化ベンザルコニウム、塩化ベンゼトニウム、グルコン酸クロルヘキシジン、ソルビン酸、ソルビン酸カリウム、クロロブタノール、パラオキシ安香酸エステル等のパラベン類、塩化ポリドロニウム、塩酸アルキルジアミノエチルグリシン、安息香酸ナトリウム、ポリヘキサメチレンビグアニド等が挙げられる。防腐剤を配合する場合、その配合量は組成物中０．０００１～０．５％の範囲であることが好ましく、０．００１～０．５％の範囲がより好ましい。 Examples of preservatives include parabens such as benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, chlorobutanol, and paraoxybenzoic acid ester, polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate And polyhexamethylene biguanide. When the preservative is blended, the blending amount thereof is preferably in the range of 0.0001 to 0.5% in the composition, and more preferably in the range of 0.001 to 0.5%.
　本発明の眼科用組成物は、残部を水とし、公知の製造方法で製造することができる。例えば上記各成分を滅菌精製水、イオン交換水等の水、又は水との混合溶媒等に溶解させて得ることができる。好ましくは、（Ｃ）成分等の脂溶性成分を（Ｂ）ポリオキシエチレンポリオキシプロピレングリコールに溶解した後、他の水溶液成分を溶解した高温（７０～９５℃）の水溶液に投入した後、ｐＨを調整し、さらに必要に応じて浸透圧等をｐＨ調整剤、等張化剤により適宜調整することによって得ることができる。 The ophthalmic composition of the present invention can be produced by a known production method with the balance being water. For example, each of the above components can be obtained by dissolving in sterilized purified water, water such as ion exchange water, or a mixed solvent with water. Preferably, the fat-soluble component such as component (C) is dissolved in (B) polyoxyethylene polyoxypropylene glycol, and then charged into a high-temperature (70 to 95 ° C.) aqueous solution in which other aqueous components are dissolved, and then the pH is adjusted. And, if necessary, the osmotic pressure and the like can be appropriately adjusted with a pH adjusting agent or an isotonizing agent.
　ｐＨ調節剤としては、塩酸、硫酸、リン酸、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、水酸化カルシウム等が挙げられる。本発明の眼科用組成物のｐＨ（２０℃）は、３．５～８．０が好ましく、より好ましくは４．５～７．７、さらに好ましくは５．５～７．５である。ｐＨが低すぎても、高すぎても、刺激感が強くなる可能性がある。なお、ｐＨの測定は、２０℃でｐＨ浸透圧計（ＨＳＭＯ－１、東亜ディーケーケー（株））を用いて行う。ｐＨ調整剤としては、水酸化ナトリウム、水酸化カリウム、塩酸等が好ましい。 Examples of pH regulators include hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like. The pH (20 ° C.) of the ophthalmic composition of the present invention is preferably 3.5 to 8.0, more preferably 4.5 to 7.7, and still more preferably 5.5 to 7.5. If the pH is too low or too high, the feeling of irritation can be strong. The pH is measured at 20 ° C. using a pH osmometer (HSMO-1, Toa DKK Corporation). As the pH adjuster, sodium hydroxide, potassium hydroxide, hydrochloric acid and the like are preferable.
　本発明の眼科用組成物は液体が好ましく、２０℃における粘度は、１～４００ｍＰａ・ｓが好ましく、１～１００ｍＰａ・ｓがより好ましく、１～６０ｍＰａ・ｓがさらに好ましく、１～５０ｍＰａ・ｓ、１～２０ｍＰａ・ｓが特に好ましい。なお、粘度の測定方法はＢ型粘度計を用いて測定する。 The ophthalmic composition of the present invention is preferably a liquid, and the viscosity at 20 ° C. is preferably 1 to 400 mPa · s, more preferably 1 to 100 mPa · s, still more preferably 1 to 60 mPa · s, and 1 to 50 mPa · s, 1 to 20 mPa · s is particularly preferable. The viscosity is measured using a B-type viscometer.
[眼科用製品]
　本発明は、眼科用組成物と、この眼科用組成物が充填された容器と、この容器を包装する包囲体とを有する眼科用製品であって、眼科用組成物中の酸素濃度が低減された状態で保存される手段を用いて、上記（Ａ），（Ｂ）成分を併用することによる粘度低下をより抑制することができる。手段としては、（１）包囲体内への不活性ガス注入、（２）包囲体内への酸素吸収剤の同梱、（３）酸素吸収能を有する容器又は（４）酸素吸収能を有する包囲体等が挙げられる。このような手段により、上記（Ａ），（Ｂ）成分を併用することによる粘度低下をより抑制することができる。なお、包囲体は容器を密封できるものが好ましい。 [Ophthalmic products]
The present invention is an ophthalmic product comprising an ophthalmic composition, a container filled with the ophthalmic composition, and an enclosure for packaging the container, wherein the oxygen concentration in the ophthalmic composition is reduced. Using the means stored in a wet state, it is possible to further suppress the decrease in viscosity due to the combined use of the above components (A) and (B). Means include (1) injecting inert gas into the enclosure, (2) bundling of oxygen absorbent into the enclosure, (3) container having oxygen absorption capacity, or (4) enclosure having oxygen absorption capacity. Etc. By such means, a decrease in viscosity due to the combined use of the above components (A) and (B) can be further suppressed. The enclosure is preferably capable of sealing the container.
　容器としては、プラスチック製容器が好ましく、ポリエチレン、ポリエチレンテレフタレート、ポリプロピレン、ポリブチレン、ポリカーボネート、ポリアリレート、塩化ビニル等の材質またはこれら材質の複合体からなるもの等を用いることができる。特にポリエチレンテレフタレートが好ましい。容器の酸素透過係数は、１０ｃｃ／ｍ2・２４ｈｒ・ａｔｍ以上が好ましい。 The container is preferably a plastic container, and materials such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, vinyl chloride, or a composite of these materials can be used. Polyethylene terephthalate is particularly preferable. The oxygen permeability coefficient of the container is preferably 10 cc / m 2 · 24 hr · atm or more.
　包囲体としては、例えば、ポリエチレン、ポリエチレンテレフタレート、ポリプロピレン、ポリブチレン、ポリカーボネート、ポリエステル、ナイロン、セロファン、ポリ塩化ビニルフィルム、アルミ箔、アルミニウムを蒸着したポリビニルアルコール系・ポリアミド系フィルム、ポリ塩化ビニリデンをコートしたフィルムまたはラミネートフィルム等、これらの複合、多層フィルム等が挙げられる。包囲体の酸素透過係数は、１０ｃｃ／ｍ2・２４ｈｒ・ａｔｍ以下（即ち、０～１０ｃｃ／ｍ2・２４ｈｒ・ａｔｍ）の酸素非透過性包囲体が好ましい。 Examples of the envelope include polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil, polyvinyl alcohol / polyamide film deposited with aluminum, and polyvinylidene chloride. A composite or multilayer film of these, such as a film or a laminate film, may be mentioned. The oxygen permeability coefficient of the envelope is preferably 10 cc / m 2 · 24 hr · atm or less (that is, 0 to 10 cc / m 2 · 24 hr · atm).
（１）包囲体内への不活性ガス注入
　不活性ガスとしては、窒素、ヘリウム、ネオン、アルゴン等が挙げられる。中でも窒素ガスが好ましい。不活性ガスの濃度は、包囲体とプラスチック製容器との間に形成された空間容積中、好ましくは５０容積％以上、より好ましくは８０容積％以上、さらに好ましくは９０容積％以上である。上限は特に限定されず、１００容積％以下である。このような濃度にするためには、包囲体とプラスチック製容器との間に形成された空間を、不活性ガスで置換すればよい。 (1) Inert gas injection into enclosure The inert gas includes nitrogen, helium, neon, argon, and the like. Of these, nitrogen gas is preferred. The concentration of the inert gas is preferably 50% by volume or more, more preferably 80% by volume or more, and further preferably 90% by volume or more in the space volume formed between the enclosure and the plastic container. An upper limit is not specifically limited, It is 100 volume% or less. In order to achieve such a concentration, the space formed between the enclosure and the plastic container may be replaced with an inert gas.
（２）包囲体内への酸素吸収剤の同梱、
　具体的には三菱ガス化学（株）製のエージレス（登録商標）（ＦＸ、ＳＰ、ＳＳ、ＳＰＥ、ＺＰ、Ｚ－ＰＴ、Ｚ－ＰＫＣ、ＧＬＳ、ＧＬ－Ｍ、Ｚ－２０ＰＫヤ）、ファーマキープ、（株）常盤産業製のバイタロン、（株）博洋製のサンソレス、パウダーテック（株）製のワンダーキープ、アイリス・ファインプロダクツ（株）製のサンソカット等を用いることができる。 (2) Enclosure of oxygen absorbent in the enclosure
Specifically, AGELESS (registered trademark) manufactured by Mitsubishi Gas Chemical Co., Ltd. (FX, SP, SS, SPE, ZP, Z-PT, Z-PKC, GLS, GL-M, Z-20PK), Pharma Keep Vitalon manufactured by Tokiwa Sangyo Co., Ltd., Sansoles manufactured by Hiroyo Co., Ltd., Wonder Keep manufactured by Powdertech Co., Ltd., Sanso Cut manufactured by Iris Fine Products Co., Ltd., and the like can be used.
（３）酸素吸収能を有する容器
　東洋製罐（株）製のオキシブロック、三菱ガス化学（株）製のオキシヴァニッシュ等を用いることができる。 (3) Container having oxygen absorbing ability An oxyblock manufactured by Toyo Seikan Co., Ltd., an oxyvanish manufactured by Mitsubishi Gas Chemical Co., Ltd., etc.
（４）酸素吸収能を有する包囲体
　共同印刷（株）製のオキシキャッチ（登録商標）ＩＣＡ、シールドエアー社製のＣｒｙｏｖａｃ（登録商標）ＯＳフィルム、スタープラスチック工業（株）製のハイスターＯ２、三菱ガス化学（株）製のエージレスオーマック、東洋製罐（株）製のオキシデック等を用いることができる。 (4) Enclosed body having oxygen absorbing ability Oxycatch (registered trademark) ICA manufactured by Kyodo Printing Co., Ltd., Cryovac (registered trademark) OS film manufactured by Shield Air, Histar O2 manufactured by Star Plastic Industry Co., Ltd. Ageless Omak manufactured by Mitsubishi Gas Chemical Co., Ltd., Oxydec manufactured by Toyo Seikan Co., Ltd., etc. can be used.
　上記手段は適宜組み合わせることができ、（２）が好ましく、（１）＋（２）、（１）＋（４）がより好ましい。 The above means can be combined as appropriate, and (2) is preferable, and (1) + (2) and (1) + (4) are more preferable.
　本発明は、
（Ａ）水溶性高分子化合物、
（Ｂ）ポリオキシエチレンポリオキシプロピレングリコール、
（Ｃ）ビタミンＡ、ビタミンＥ、ジブチルヒドロキシトルエン及び清涼化剤から選ばれる１種以上の脂溶性成分を含有する眼科用組成物と、この眼科用組成物が充填された容器と、この容器を包装する包囲体とを有する眼科用製品において、
　（１）包囲体内への不活性ガス注入、（２）包囲体内への酸素吸収剤の同梱、（３）酸素吸収能を有する容器又は（４）酸素吸収能を有する包囲体のいずれかの手段を用いると共に、
（Ｄ）下記（Ｄ－１）及び（Ｄ－２）
（Ｄ－１）トロメタモール、プロピレングリコール
（Ｄ－２）エチレンジアミン酢酸誘導体、その塩、塩酸テトラヒドロゾリン、イプシロンアミノカプロン酸、アラントイン、グリチルリチン酸、その塩、クロルフェニラミンマレイン酸塩、ピリドキシン塩酸塩、パンテノール、コンドロイチン硫酸、その塩、ネオスチグミンメチル硫酸塩、ジフェンヒドラミン塩酸塩、シアノコバラミン、塩化ナトリウム、アスパラギン酸又はその塩、アミノエチルスルホン酸からなる群から選ばれる１種以上を配合することを特徴とする、上記眼科用組成物の粘度低下抑制方法を提供する。好適なもの、量等は上記と同様である。 The present invention
(A) a water-soluble polymer compound,
(B) polyoxyethylene polyoxypropylene glycol,
(C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container In an ophthalmic product having an enclosure for packaging,
(1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorber into the enclosure, (3) Either an oxygen-absorbing vessel or (4) an enclosure with oxygen-absorbing capability Using means,
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, Chondroitin sulfate, a salt thereof, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid or a salt thereof, and at least one selected from the group consisting of aminoethylsulfonic acid Provided is a method for suppressing a decrease in viscosity of a composition for use. Suitable ones, amounts, etc. are the same as above.
　さらに、本発明は、
（Ａ）水溶性高分子化合物、
（Ｂ）ポリオキシエチレンポリオキシプロピレングリコール、
（Ｃ）ビタミンＡ、ビタミンＥ、ジブチルヒドロキシトルエン及び清涼化剤から選ばれる１種以上の脂溶性成分を含有する眼科用組成物と、この眼科用組成物が充填された容器と、この容器を包装する包囲体とを有し、（１）包囲体内への不活性ガス注入、（２）包囲体内への酸素吸収剤の同梱、（３）酸素吸収能を有する容器又は（４）酸素吸収能を有する包囲体のいずれかの手段を用いた眼科用製品において、上記眼科用組成物に、
（Ｄ）下記（Ｄ－１）及び（Ｄ－２）
（Ｄ－１）トロメタモール、プロピレングリコール
（Ｄ－２）エチレンジアミン酢酸誘導体又はその塩、塩酸テトラヒドロゾリン、イプシロンアミノカプロン酸、アラントイン、グリチルリチン酸又はその塩、クロルフェニラミンマレイン酸塩、ピリドキシン塩酸塩、パンテノール、コンドロイチン硫酸又はその塩、ネオスチグミンメチル硫酸塩、ジフェンヒドラミン塩酸塩、シアノコバラミン、塩化ナトリウム、アスパラギン酸又はその塩、アミノエチルスルホン酸からなる群から選ばれる１種以上を配合することを特徴とする、眼科用組成物の粘度低下抑制方法を提供する。好適なもの、量等は上記と同様である。 Furthermore, the present invention provides:
(A) a water-soluble polymer compound,
(B) polyoxyethylene polyoxypropylene glycol,
(C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorbent in the enclosure, (3) Container having oxygen absorption capacity, or (4) Oxygen absorption In an ophthalmic product using any means of an enclosure having a function, in the ophthalmic composition,
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative or salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid or salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, Chondroitin sulfate or a salt thereof, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid or a salt thereof, and at least one selected from the group consisting of aminoethylsulfonic acid, ophthalmic Provided is a method for suppressing a decrease in viscosity of a composition. Suitable ones, amounts, etc. are the same as above.
　以下、実施例及び比較例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。 Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.
　　［実施例、比較例］
　下記表に示す組成の眼科用組成物を、脂溶性成分をポリオキシエチレンポリオキシプロピレングリコールに溶解した後、他の水溶液成分を溶解した高温（７０～９５℃）の水溶液に投入することによって下記表に示す組成の眼科用組成物を製造した。得られた眼科用組成物をポリエチレンテレフタレート製の点眼剤容器に充填した後、酸素吸収剤（エージレス：Ｚ－２０ＰＫヤ　三菱ガス化学株式会社製）を同梱したフィルム包装を施した。保存前の粘度（２０℃）をＢ型粘度計（デジタル粘度計ＤＶ２Ｔ、英弘精機株式会社製）にて粘度を測定し、５０℃・７５％ＲＨ環境下で２ヶ月保存した。保存後、点眼剤を常温（２０℃）に戻し、保存前と同様に測定した。得られた粘度から下記式に基づき、各実施例の粘度維持率（％）を求め、比較例１に対する粘度維持率増強効果（％）を算出した。
　粘度維持率（％）＝保存後の粘度／保存前の粘度×１００
　粘度維持率増強効果（％）＝[各実施例の粘度維持率（％）／各表に記載された比較例の粘度維持率（％）－１]×１００
　なお、「各表に記載された比較例」とは、各実施例に対応する（Ｄ）成分を含まない比較例をいう。 [Examples and Comparative Examples]
The ophthalmic composition having the composition shown in the following table is dissolved in a polyoxyethylene polyoxypropylene glycol after dissolving a fat-soluble component and then poured into a high-temperature (70 to 95 ° C.) aqueous solution in which other aqueous components are dissolved. Ophthalmic compositions having the compositions shown in the table were produced. The obtained ophthalmic composition was filled in an eye drop container made of polyethylene terephthalate, and then a film package containing an oxygen absorbent (AGELESS: Z-20PK manufactured by Mitsubishi Gas Chemical Co., Ltd.) was applied. The viscosity before storage (20 ° C.) was measured with a B-type viscometer (digital viscometer DV2T, manufactured by Eihiro Seiki Co., Ltd.) and stored for 2 months in an environment of 50 ° C. and 75% RH. After storage, the eye drops were returned to room temperature (20 ° C.) and measured in the same manner as before storage. Based on the following formula, the viscosity retention rate (%) of each example was determined from the obtained viscosity, and the viscosity retention rate enhancement effect (%) with respect to Comparative Example 1 was calculated.
Viscosity maintenance ratio (%) = viscosity after storage / viscosity before storage × 100
Viscosity retention rate enhancement effect (%) = [viscosity retention rate of each example (%) / viscosity retention rate of comparative example described in each table (%) − 1] × 100
The “comparative examples described in each table” refers to a comparative example not including the component (D) corresponding to each example.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
　表１４，１５に記載の眼科用製品を、上記実施例と同様の方法で製造、充填、保存した結果、いずれも粘度低下が抑制されていた。 As a result of manufacturing, filling, and storing the ophthalmic products described in Tables 14 and 15 in the same manner as in the above Examples, viscosity reduction was suppressed in all cases.
　上記実施例を、フィルム包装と容器との間に形成された空間容積中、６０容積％を窒素ガスで置換したもの、フィルム包装を、三菱ガス化学（株）製のエージレスオーマックにしたものも、組成物の粘度安定性に優れていた。このような効果を有するこれらの眼科用製品は、組成物の粘度安定性に優れ、有効成分や清涼化剤等の眼表面での滞留効果を維持することができる。 In the above example, 60% by volume of the space volume formed between the film packaging and the container is replaced with nitrogen gas, and the film packaging is made by Ageless Omak manufactured by Mitsubishi Gas Chemical Co., Ltd. The composition was excellent in viscosity stability. These ophthalmic products having such effects are excellent in the viscosity stability of the composition, and can maintain the retention effect on the ocular surface such as active ingredients and cooling agents.
　上記結果から明らかであるように、上記眼科用製品において、（Ａ），（Ｂ）成分配合による眼科用組成物の粘度低下を、上記手段及び（Ｄ）成分の添加、又は（Ｄ）成分の添加により抑制し、（Ｃ）成分の有効成分や清涼化剤等の眼表面での滞留効果を維持することができる。 As is apparent from the above results, in the above ophthalmic product, the viscosity reduction of the ophthalmic composition due to the combination of the components (A) and (B) can be reduced by the addition of the above means and the component (D), or the component (D). It can suppress by addition and can maintain the retention effect in the ocular surface, such as an active ingredient of (C) component, a refreshing agent.
　上記例で使用した原料を下記に示す。なお、特に明記がない限り、表中の各成分の量は純分換算量である。
ヒドロキシプロピルメチルセルロース：ヒプロメロース（６０ＳＨ－４０００）、メトローズ６０ＳＨ－４０００、日局、信越化学工業（株）、重量平均分子量３０万（ｇ／ｍｏｌ）
ポリビニルピロリドン：コリドン９０Ｆ、日局、ＢＡＳＦ（株）、重量平均分子量１００万（ｇ／ｍｏｌ）
ヒドロキシエチルセルロース：ＨＥＣ　ＣＦ－Ｖ、薬添規、住友精化（株）、重量平均分子量９０万（ｇ／ｍｏｌ）
メチルセルロース：メトローズＳＭ－４００、日局、信越化学工業（株）
ヒアルロン酸ナトリウム：バイオヒアルロン酸ナトリウム、資生堂
カルボキシビニルポリマー：Ｃａｒｂｏｐｏｌ（登録商標）９７１ＰＮＦ、薬添規、ルーブリゾール社
ポリオキシエチレン（２００）ポリオキシプロピレン（７０）グリコール：ユニルーブ７０ＤＰ－９５０Ｂ、薬添規、日油（株）又はＬｕｔｒｏｌ Ｆ１２７，薬添規、ＢＡＳＦ（株）
レチノールパルミチン酸エステル：日局品、（レチノールパルミチン酸エステル，ＤＳＭニュートリション ジャパン（株））
酢酸ｄ－α－トコフェロール：局外規品、（理研Ｅアセテートα，理研ビタミン（株））
ジブチルヒドロキシトルエン：薬添規品、（ジブチルヒドロキシトルエン，和光純薬工業（株））
（Ｄ）成分は、公定書（日本薬局方、日本薬局方外医薬品規格、医薬品添加物規格等）規格に適合した各種原料を使用した。 The raw materials used in the above examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.
Hydroxypropyl methylcellulose: Hypromellose (60SH-4000), Metrolose 60SH-4000, JP, Shin-Etsu Chemical Co., Ltd., weight average molecular weight 300,000 (g / mol)
Polyvinylpyrrolidone: Kollidon 90F, JP, BASF Corp., weight average molecular weight 1 million (g / mol)
Hydroxyethyl cellulose: HEC CF-V, supplementary regulations, Sumitomo Seika Co., Ltd., weight average molecular weight 900,000 (g / mol)
Methylcellulose: Metrows SM-400, JP, Shin-Etsu Chemical Co., Ltd.
Sodium hyaluronate: Sodium biohyaluronate, Shiseido carboxyvinyl polymer: Carbopol (registered trademark) 971PNF, Supplementary regulations, Lubrizol polyoxyethylene (200) Polyoxypropylene (70) glycol: Unilube 70DP-950B, Supplementary regulations, Japan Oil Co., Ltd. or Lutrol F127, Addendum, BASF Co., Ltd.
Retinol palmitic acid ester: a Japanese pharmacy product (Retinol palmitic acid ester, DSM Nutrition Japan Co., Ltd.)
D-α-Tocopherol acetate: an extra-regular product, (RIKEN E Acetate α, Riken Vitamin Co., Ltd.)
Dibutylhydroxytoluene: Supplementary product, (Dibutylhydroxytoluene, Wako Pure Chemical Industries, Ltd.)
As the component (D), various raw materials conforming to official standards (Japanese Pharmacopoeia, Japanese Pharmacopoeia Pharmaceutical Standards, Pharmaceutical Additive Standards, etc.) standards were used.

Claims (6)

  1. 　（Ａ）水溶性高分子化合物、
    （Ｂ）ポリオキシエチレンポリオキシプロピレングリコール、
    （Ｃ）ビタミンＡ、ビタミンＥ、ジブチルヒドロキシトルエン及び清涼化剤から選ばれる１種以上の成分、及び
    （Ｄ）下記（Ｄ－１）及び（Ｄ－２）からなる群から選ばれる１種以上
    （Ｄ－１）トロメタモール、プロピレングリコール
    （Ｄ－２）エチレンジアミン酢酸誘導体、その塩、塩酸テトラヒドロゾリン、イプシロンアミノカプロン酸、アラントイン、グリチルリチン酸、その塩、クロルフェニラミンマレイン酸塩、ピリドキシン塩酸塩、パンテノール、コンドロイチン硫酸、その塩、ネオスチグミンメチル硫酸塩、ジフェンヒドラミン塩酸塩、シアノコバラミン、塩化ナトリウム、アスパラギン酸、その塩、アミノエチルスルホン酸
    を含有する眼科用組成物と、この眼科用組成物が充填された容器と、この容器を包装する包囲体とを有する眼科用製品であって、
    　（１）包囲体内への不活性ガス注入、（２）包囲体内への酸素吸収剤の同梱、（３）酸素吸収能を有する容器又は（４）酸素吸収能を有する包囲体のいずれかの手段を用いた眼科用製品。     (A) a water-soluble polymer compound,
    (B) polyoxyethylene polyoxypropylene glycol,
    (C) one or more components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, and (D) one or more components selected from the group consisting of (D-1) and (D-2) below (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, An ophthalmic composition containing chondroitin sulfate, a salt thereof, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid, a salt thereof, aminoethylsulfonic acid, and a container filled with the ophthalmic composition; And the enclosure that wraps this container To a ophthalmic products,
    (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorber into the enclosure, (3) Either an oxygen-absorbing vessel or (4) an enclosure with oxygen-absorbing capability Ophthalmic product using means.
  2. 　（Ｄ）成分が、（Ｄ－１）群から１種以上及び（Ｄ－２）群から１種以上である請求項１記載の眼科用製品。 The ophthalmic product according to claim 1, wherein the component (D) is one or more from the (D-1) group and one or more from the (D-2) group.
  3. 　（Ａ）成分が、ヒドロキシプロピルメチルセルロース、メチルセルロース、ヒドロキシエチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ヒアルロン酸及びその塩から選ばれる１種以上である請求項１又は２記載の眼科用製品。 The ophthalmic product according to claim 1 or 2, wherein the component (A) is at least one selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, hyaluronic acid and salts thereof.
  4. 　（Ｃ）成分が、レチノールパルミチン酸エステル、酢酸ｄ－α－トコフェロール、ジブチルヒドロキシトルエン及びメントールから選ばれる１種以上である請求項１～３のいずれか１項記載の眼科用製品。 The ophthalmic product according to any one of claims 1 to 3, wherein the component (C) is one or more selected from retinol palmitate, d-α-tocopherol acetate, dibutylhydroxytoluene and menthol.
  5. 　（Ａ）水溶性高分子化合物、
    （Ｂ）ポリオキシエチレンポリオキシプロピレングリコール、
    （Ｃ）ビタミンＡ、ビタミンＥ、ジブチルヒドロキシトルエン及び清涼化剤から選ばれる１種以上の脂溶性成分を含有する眼科用組成物と、この眼科用組成物が充填された容器と、この容器を包装する包囲体とを有する眼科用製品において、
    　（１）包囲体内への不活性ガス注入、（２）包囲体内への酸素吸収剤の同梱、（３）酸素吸収能を有する容器又は（４）酸素吸収能を有する包囲体のいずれかの手段を用いると共に、
    （Ｄ）下記（Ｄ－１）及び（Ｄ－２）
    （Ｄ－１）トロメタモール、プロピレングリコール
    （Ｄ－２）エチレンジアミン酢酸誘導体、その塩、塩酸テトラヒドロゾリン、イプシロンアミノカプロン酸、アラントイン、グリチルリチン酸、その塩、クロルフェニラミンマレイン酸塩、ピリドキシン塩酸塩、パンテノール、コンドロイチン硫酸、その塩、ネオスチグミンメチル硫酸塩、ジフェンヒドラミン塩酸塩、シアノコバラミン、塩化ナトリウム、アスパラギン酸又はその塩、アミノエチルスルホン酸からなる群から選ばれる１種以上を配合することを特徴とする、上記眼科用組成物の粘度低下抑制方法。     (A) a water-soluble polymer compound,
    (B) polyoxyethylene polyoxypropylene glycol,
    (C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container In an ophthalmic product having an enclosure for packaging,
    (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorber into the enclosure, (3) Either an oxygen-absorbing vessel or (4) an enclosure with oxygen-absorbing capability Using means,
    (D) (D-1) and (D-2) below
    (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, Chondroitin sulfate, a salt thereof, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid or a salt thereof, and at least one selected from the group consisting of aminoethylsulfonic acid A method for suppressing a decrease in viscosity of a composition.
  6. 　（Ａ）水溶性高分子化合物、
    （Ｂ）ポリオキシエチレンポリオキシプロピレングリコール、
    （Ｃ）ビタミンＡ、ビタミンＥ、ジブチルヒドロキシトルエン及び清涼化剤から選ばれる１種以上の脂溶性成分を含有する眼科用組成物と、この眼科用組成物が充填された容器と、この容器を包装する包囲体とを有し、（１）包囲体内への不活性ガス注入、（２）包囲体内への酸素吸収剤の同梱、（３）酸素吸収能を有する容器又は（４）酸素吸収能を有する包囲体のいずれかの手段を用いた眼科用製品において、上記眼科用組成物に、
    （Ｄ）下記（Ｄ－１）及び（Ｄ－２）
    （Ｄ－１）トロメタモール、プロピレングリコール
    （Ｄ－２）エチレンジアミン酢酸誘導体、その塩、塩酸テトラヒドロゾリン、イプシロンアミノカプロン酸、アラントイン、グリチルリチン酸、その塩、クロルフェニラミンマレイン酸塩、ピリドキシン塩酸塩、パンテノール、コンドロイチン硫酸、その塩、ネオスチグミンメチル硫酸塩、ジフェンヒドラミン塩酸塩、シアノコバラミン、塩化ナトリウム、アスパラギン酸又はその塩、アミノエチルスルホン酸からなる群から選ばれる１種以上を配合することを特徴とする、上記眼科用組成物の粘度低下抑制方法。     (A) a water-soluble polymer compound,
    (B) polyoxyethylene polyoxypropylene glycol,
    (C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorbent in the enclosure, (3) Container having oxygen absorption capacity, or (4) Oxygen absorption In an ophthalmic product using any means of an enclosure having a function, in the ophthalmic composition,
    (D) (D-1) and (D-2) below
    (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, salt thereof, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, Chondroitin sulfate, a salt thereof, neostigmine methyl sulfate, diphenhydramine hydrochloride, cyanocobalamin, sodium chloride, aspartic acid or a salt thereof, and at least one selected from the group consisting of aminoethylsulfonic acid A method for suppressing a decrease in viscosity of a composition.
PCT/JP2017/023572 2016-06-30 2017-06-27 Ophthalmic product and method for suppressing decrease in viscosity WO2018003796A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019218270A (en) * 2018-06-15 2019-12-26 ライオン株式会社 Ophthalmic composition and defoaming promotion method
JP2021024829A (en) * 2019-08-07 2021-02-22 ライオン株式会社 Ophthalmic composition and ophthalmic product for soft contact lenses

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004123634A (en) * 2002-10-03 2004-04-22 Lion Corp Ophthalmic composition
WO2010150812A1 (en) * 2009-06-25 2010-12-29 ライオン株式会社 Ophthalmic composition and method for prevention of cloudiness/precipitation
WO2011001951A1 (en) * 2009-06-30 2011-01-06 ライオン株式会社 Ophthalmic composition
JP2011021002A (en) * 2009-06-16 2011-02-03 Lion Corp Ophthalmic composition
JP2013237638A (en) * 2012-05-15 2013-11-28 Lion Corp Ophthalmic composition
JP2015101582A (en) * 2013-11-28 2015-06-04 ライオン株式会社 Ophthalmic composition

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1171478A (en) 1997-08-29 1999-03-16 Santen Pharmaceut Co Ltd Process for preventing viscosity decrease
JP5382972B2 (en) 2003-12-26 2014-01-08 ロート製薬株式会社 Composition with reduced viscosity prevention
JP5382973B2 (en) 2003-12-26 2014-01-08 ロート製薬株式会社 Composition with reduced viscosity prevention
JP5649261B2 (en) 2004-05-07 2015-01-07 ロート製薬株式会社 High viscosity eye drops
CN102137454B (en) 2010-09-26 2013-09-25 华为技术有限公司 Content storage method and device in service overlay network

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004123634A (en) * 2002-10-03 2004-04-22 Lion Corp Ophthalmic composition
JP2011021002A (en) * 2009-06-16 2011-02-03 Lion Corp Ophthalmic composition
WO2010150812A1 (en) * 2009-06-25 2010-12-29 ライオン株式会社 Ophthalmic composition and method for prevention of cloudiness/precipitation
WO2011001951A1 (en) * 2009-06-30 2011-01-06 ライオン株式会社 Ophthalmic composition
JP2013237638A (en) * 2012-05-15 2013-11-28 Lion Corp Ophthalmic composition
JP2015101582A (en) * 2013-11-28 2015-06-04 ライオン株式会社 Ophthalmic composition

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019218270A (en) * 2018-06-15 2019-12-26 ライオン株式会社 Ophthalmic composition and defoaming promotion method
JP7102964B2 (en) 2018-06-15 2022-07-20 ライオン株式会社 Ophthalmic composition and defoaming promotion method
JP2021024829A (en) * 2019-08-07 2021-02-22 ライオン株式会社 Ophthalmic composition and ophthalmic product for soft contact lenses
JP7379913B2 (en) 2019-08-07 2023-11-15 ライオン株式会社 Ophthalmic compositions and products for soft contact lenses

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