TWI746662B - Ophthalmic products and methods for suppressing viscosity reduction - Google Patents

Abstract

An ophthalmic product, comprising an ophthalmic composition, a container filled with the ophthalmic composition, and a package for packaging the container, the ophthalmic composition comprising: (A) a water-soluble polymer compound; ( B) One or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and polyethylene glycol monostearate; (C) ) One or more ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene and cooling agents; and (D) selected from the group consisting of the following (D-1) and (D-2) One or more (D-1) tromethamine, propylene glycol (D-2) ethylenediamine acetic acid derivatives, etc.; and the ophthalmic products are used in the package with deoxidizers and other means.

Description

Ophthalmic products and methods for suppressing viscosity reduction

The present invention relates to an ophthalmic product that suppresses the decrease in the viscosity of a water-soluble polymer compound.

In ophthalmic compositions, in order to improve the effectiveness or maintain the refreshing sensation, there is known a method of compounding a viscous agent such as a polymer compound to increase the retention of the drug on the surface of the eye. It is believed that the improvement of the retention of the active ingredient on the surface of the eye is particularly beneficial to the active ingredient that acts on the corneal epithelial cells on the surface of the eye, such as vitamin A. In addition, in order to maintain the cooling sensation, a cooling agent such as menthol is used. Furthermore, refreshing ingredients such as vitamin A and menthol are fat-soluble ingredients. Therefore, in order to prepare these ingredients in aqueous eye drops, in most cases, a surfactant is also prepared at the same time.

In order to suppress the decrease in the viscosity of cellulose-based polymer compounds, a method of blending vegetable oils 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 Japanese Patent Laid-Open No. 2005-206599), a method of adding mannitol or glycerin (Patent Document 3: Japanese Patent Laid-Open No. 11-71478). However, the decrease in viscosity of ophthalmic compositions formulated with polymer compounds is caused by the influence of various formulation ingredients. When surfactants used in the formulation of fat-soluble ingredients such as vitamin A or menthol are added, viscosity is particularly likely to occur. Reduction, the effect of suppressing the decrease in viscosity in the above-mentioned general method is insufficient.

The viscosity of the ophthalmic composition greatly contributes to the effectiveness of the medicament or the continuous improvement of the cooling agent, and also greatly affects the feeling of use caused by the viscosity. For example, the presence of excessive viscosity leads to stickiness or stickiness, and the visual field after use. Possibility of ambiguity etc. For the quality maintenance of ophthalmic compositions, it is very important to maintain the effectiveness and the feeling of use without changing the design viscosity of the pharmaceutical as much as possible. Such a high-viscosity stabilization method is expected.

[Prior Art Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2005-206598

[Patent Document 2] Japanese Patent Laid-Open No. 2005-206599

[Patent Document 3] Japanese Patent Laid-Open No. 11-71478

The inventors of the present invention found that an ophthalmic composition prepared with a high molecular compound such as vitamin A and a fat-soluble component and a surfactant is prone to decrease in viscosity caused by time. When polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, or monostearic acid polyethylene glycol is used as a surfactant, the viscosity reduction is particularly significant. Therefore, the object of the present invention is to provide a technique for suppressing such a decrease in viscosity.

The inventors of the present invention have made diligent studies to achieve the above-mentioned object. As a result, they have found that the Special ingredients are blended in the scientific composition, and a special packaging method is used to exert a high effect of suppressing the decrease in viscosity. In addition, the ophthalmic composition provided by the present invention exhibits retention properties when instilled into the eye, and is excellent in the sustained effect of the moisturizing feeling.

Therefore, the present invention provides the following.

[1]. An ophthalmic product comprising an ophthalmic composition, a container filled with the ophthalmic composition, and a package for packaging the container, the ophthalmic composition comprising: (A) high water solubility Molecular compound; (B) one or more of the interfacial activity selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and monostearic acid polyethylene glycol Agent; (C) one or more ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene and cooling agents; and (D) selected from the following (D-1) and (D-2) One or more (D-1) tromethamol (tromethamol), propylene glycol (D-2) ethylenediamineacetic acid derivatives, ethylenediamineacetic acid derivative salts, tetrahydroxazoline hydrochloride (Tetrahydroxazoline hydrochloride), ε-Aminocaproic acid (epsilon-Aminocaproic acid), allantoin (allantoin), glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate (chlorpheniramine maleate), pyridoxine hydrochloride (pyridoxine hydrochloride) , Panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine (neostigmine) methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium (flavin adenine dinucleotide sodium), cyanocobalamin, aspartic acid, aspartate, aminoethyl Sulfonic acid; used in the ophthalmic products (1) injecting inert gas into the package, (2) attaching a deoxidizer to the package, (3) a container with oxygen absorption capacity, or (4) having oxygen absorption Any one or more means of the package of capabilities.

[2]. The ophthalmic product according to [1], wherein the component (D) is one or more selected from the group (D-1) and one or more selected from the group (D-2).

[3]. The ophthalmic product as described in [1] or [2], wherein component (A) is selected from the group consisting of hydroxypropyl methyl cellulose, methyl cellulose, hydroxy ethyl cellulose, and polyvinylpyrrolidine One or more of ketone, polyvinyl alcohol, carboxyvinyl polymer, hyaluronic acid and its salt.

[4]. The ophthalmic product according to any one of [1] to [3], wherein component (C) is selected from retinol palmitate, d-α-tocopherol acetate (d- One or more of α-tocopherol acetate), dibutylhydroxytoluene, and menthol.

[5]. A method for suppressing the decrease in viscosity, which suppresses the decrease in the viscosity of the following ophthalmic composition in an ophthalmic product, the ophthalmic product comprising the ophthalmic composition, a container filled with the ophthalmic composition, And a package for packaging the container, the ophthalmic composition comprising: (A) a water-soluble polymer compound; (B) selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, One or more surfactants in polyoxyethylene castor oil and polyethylene glycol monostearate; and (C) One or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene, and fresheners; and used in the ophthalmic products (1) injecting inert gas into the package, (2) A deoxidizer, (3) a container with oxygen absorption capability, or (4) a package with oxygen absorption capability is included in the package. The method for suppressing the decrease in viscosity is characterized by The composition (D) is selected from the following (D-1) and (D-2): (D-1) tromethamine, propylene glycol; (D-2) ethylene diamine acetic acid derivative, ethylene diamine Aminoacetic acid derivative salt, tetrahydrozoline hydrochloride, ε-aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, Chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartic acid One or more of the group consisting of salt and amino ethyl sulfonic acid.

[6] A method for suppressing a decrease in viscosity, which suppresses a decrease in the viscosity of the following ophthalmic composition, the method for suppressing a decrease in viscosity is characterized in that the ophthalmic composition includes a container filled with the ophthalmic composition , And a package for packaging the container, and use (1) inject inert gas into the package, (2) add a deoxidizer to the package, (3) a container with oxygen absorption capacity, or (4) have oxygen Any one or more of the means of a packaging body with absorptive capacity, the ophthalmic composition includes: (A) a water-soluble polymer compound; (B) One or two or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and polyethylene glycol monostearate; and (C) One or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene, and cooling agents; and the formulation (D) into the ophthalmic composition is selected from the following (D-1) And (D-2): (D-1) tromethamine, propylene glycol; (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, ε-aminohexyl Acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine One or more of the group consisting of methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, and amino ethyl sulfonic acid .

According to the present invention, a high viscosity reduction effect can be obtained in a composition containing a polymer compound, a surfactant, and a fat-soluble component.

Hereinafter, the present invention will be described in detail.

[(A) Ingredient]

Examples of water-soluble polymer compounds include: hydroxypropyl methyl cellulose (hypromellose), cellulose polymer compounds such as methyl cellulose and hydroxyethyl cellulose, polyvinylpyrrolidine Polyvinyl polymer compounds such as povidone and polyvinyl alcohol, hyaluronic acid and its salts, carboxyvinyl polymers, etc., can be used alone or in a suitable combination of two or more. By blending such ingredients, viscosity can be imparted to the composition, the retention of the formulated active ingredients on the eye surface can be improved, and the eye surface can be prevented from drying out by staying on the eye surface. Among them, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, hyaluronic acid and its salts are preferred, and hydroxypropylmethylcellulose is more preferred. .

The so-called water solubility of a water-soluble polymer compound is a polymer that can be dissolved in an aqueous solution, and its weight average molecular weight is preferably 5,000-5,000,000, more preferably 10,000-2,500,000. In addition, the measurement of the weight average molecular weight can be obtained by the measurement by liquid chromatography using a GPC column.

(A) The blending amount of the component in the composition is preferably 0.01%-10% (W/V% (mass/volume%, g/100mL, the same below)), more preferably 0.05%-3%. In addition, in the case of formulating hydroxypropyl methylcellulose, it is preferably 0.05% to 5% in the composition, more preferably 0.1% to 3%, and even more preferably 0.1% to 0.5%. In the case of formulating methyl cellulose, it is preferably 0.05% to 5% in the composition, more preferably 0.1% to 3%, and even more preferably 0.1% to 1%. In the case of blending hydroxyethyl cellulose, it is preferably 0.05% to 5% in the composition, more preferably 0.1% to 3%, and even more preferably 0.1% to 1%. In the case of compounding polyvinylpyrrolidone, in the composition Among them, it is preferably 0.01% to 10%, more preferably 0.05% to 5%, and still more preferably 0.05% to 3%. In the case of formulating a carboxyvinyl polymer, it is preferably 0.01% to 5% in the composition, more preferably 0.05% to 3%, and even more preferably 0.1% to 1%. In the case of blending hyaluronic acid and its salts, the composition is preferably 0.01% to 3%, more preferably 0.01% to 1%, and even more preferably 0.02% to 1%. By setting it as the above, the effect of imparting viscosity can be obtained. In addition, if it is too large, the viscosity will become too high, the fluidity on the surface will be poor, and problems such as blurring and stickiness may occur.

[(B) Ingredient]

(B) Component is one or two or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and polyethylene glycol monostearate .

As polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil), several types are known based on the average number of added moles of ethylene oxide by addition polymerization of hydrogenated castor oil. Specifically, examples include: polyoxyethylene hydrogenated castor oil 5 (the value is the average number of ethylene oxide added moles, the same below), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene Hydrogenated castor oil 30, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, polyoxyethylene hydrogenated castor oil 100, and the like. These polyoxyethylene hydrogenated castor oils can be used individually by 1 type or in combination of 2 or more types suitably. From the viewpoint of safety, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.

Examples of polyoxyethylene sorbitan fatty acid esters include: monolauric acid POE (20) sorbitan (POE is polyoxyethylene, the value is the average number of moles added to ethylene oxide, the same below), monopalmitate POE (20) sorbitan (polysorbate 40) , Monostearate POE (20) Sorbitan (Polysorbate 60), Tristearate POE (20) Sorbitan (Polysorbate 65), Monooleate POE (20) Sorbitol anhydride (polysorbate 80) etc. can be used individually by 1 type or in combination of 2 or more types suitably. Among them, monooleic acid POE (20) sorbitan (polysorbate 80) is preferred.

As polyoxyethylene castor oil (POE castor oil), a polyoxyethylene castor oil having an average added mole number of ethylene oxide in the range of 3 mol to 60 mol is preferred, for example: polyoxyethylene Ethylene castor oil 3 (the value is the average added mole of ethylene oxide, the same below), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil Oxyethylene castor oil 50, polyoxyethylene castor oil 60. The number of ethylene oxide addition moles is more preferably 10-50, and still more preferably 20-40. In addition, polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil are different components.

As polyethylene glycol monostearate (polyethylene glycol monostearate), polyoxyethylene stearate 10 (polyethylene glycol monostearate (10), the value is ethylene glycol The average number of moles added, the same below), polyoxyethylene stearate 40, polyoxyethylene stearate 45, polyoxyethylene stearate 55, etc., of which polyoxyethylene stearate is preferred酸酸40。 Ester 40.

These surfactants may be used singly, or two or more of them may be appropriately combined for use. For example, polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester can be suitably used in combination. In this case, it is particularly preferable to hydrogenate polyoxyethylene Sesame oil 60 is used in combination with monooleic acid POE (20) sorbitan (polysorbate 80).

The blending amount of the (B) component is preferably 0.01% to 7% in the composition in the form of the total amount of the (B) component, more preferably 0.05% to 5%, and still more preferably 0.1% to 3%. By setting it as the said lower limit or more, (C)component etc. can be mix|blended more stably. By setting it as the upper limit or less, there is no concern about the irritation caused by the component (B).

[(C) Ingredient]

(C) A component is one or more components selected from vitamin A, vitamin E, dibutylhydroxytoluene, and a cooling agent, and this fat-soluble component can be used individually by 1 type or in combination of 2 or more types suitably. Vitamin A has a corneal wound healing effect. In addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil and vitamin A derivatives such as vitamin A fatty acid esters can also be cited. Specifically, retinol palmitate, retinol acetate, retinol, retinoic acid, retinoids, etc. can be mentioned. Among them, retinol palmitate is preferred.

In the case of compounding vitamin A, the compounding amount is preferably 5,000 international units (IU) to 500,000 international units (IU) in 100 mL of the ophthalmic composition, and more preferably 10,000 international units (IU) to 100,000 international units (IU) ), and more preferably 30,000 International Units (IU) ~ 75,000 International Units (IU). If it is more than the lower limit, the corneal wound healing effect of vitamin A can be expected, and if it is less than the upper limit, the stability of vitamin A can be further obtained.

Examples of vitamin E include tocopherol acetate (d1-α-tocopherol acetate, d-α-tocopherol acetate (vitamin E)), tocopherol succinate and these Derivatives and so on. Among them, d-α-tocopherol acetate is preferred.

In the case of formulating vitamin E, the formulating amount in the ophthalmic composition is preferably 0.005% to 0.5%, more preferably 0.01% to 0.1%. Within the range, the effect and stability can be further achieved.

In the case of compounding dibutylhydroxytoluene, the compounding amount in the ophthalmic composition is preferably 0.001% to 0.05%, more preferably 0.003% to 0.01%. Within the range, the effect and stability can be further achieved.

Examples of cooling agents include menthol, camphor, ice mint, geraniol, peppermint water, borneol, eucalyptus oil, fennel oil, rose oil, bergamot oil, peppermint oil, spearmint oil, linalool, and anethole , Eugenol, eucalyptol, N-ethyl-p-methane-carboxyamide, etc. These refreshing agents can be used alone or in a suitable combination of two or more. Among them, menthol is preferred, and when two or more of them are combined, it is preferred to combine menthol with other cooling agents.

In the case of blending the cooling agent, the blending amount in the ophthalmic composition is preferably 0.001% to 0.5%, more preferably 0.005% to 0.3%. Within the above-mentioned range, an effect and a good cooling sensation during eye drops can be obtained.

[(D) Ingredient]

(D) One or more selected from the group consisting of the following (D-1) and (D-2). By blending the component (D), the decrease in viscosity caused by the combined use of the component (A) and the component (B) can be suppressed.

(D-1) Tromethamine, propylene glycol

(D-2) Ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrochloride Oxazoline, ε-aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, chondroitin sulfate, chondroitin sulfate, Sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, amino ethyl sulfonic acid

Examples of ethylenediamineacetic acid derivatives or salts thereof include edetic acid (ethylenediaminetetraacetic acid), ethylenediaminediacetic acid, diethylenetriaminepentaacetic acid, N-(2-hydroxyethyl (Base) ethylenediaminetriacetic acid, sodium acetate (sodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate), hydrates of these, etc. As glycyrrhizic acid or its salt, glycyrrhizic acid, dipotassium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, etc. are mentioned, for example. Examples of chondroitin sulfate or its salt include chondroitin sulfate, chondroitin polysulfate, and chondroitin sulfate sodium salt. Examples of aspartic acid or its salt include: L-aspartic acid sodium, L-aspartic acid potassium, L-aspartic acid magnesium, L-aspartic acid calcium, Magnesium potassium L-aspartate (equivalent mixture of magnesium L-aspartate and potassium L-aspartate) and the like.

The above can be used alone or in a suitable combination of two or more. Among them, the component (D-1): tromethamine, propylene glycol, and the component (D-2) are preferably allantoin, Panthenol, chlorpheniramine maleate, pyridoxine hydrochloride. In addition, in the case of combining two or more types, it is preferable to use one or more selected from the group (D-1) and one or more selected from the group (D-2).

(D) The compounding amount of the component in the ophthalmic composition is preferably 0.001% to 10%, more preferably 0.005% to 5%, and still more preferably 0.01% to 3%. By setting it in this range, the stickiness caused by the combined use of the (A) component and (B) component can be further suppressed. The degree is reduced.

The more preferable compounding amount of each component in the ophthalmic composition is shown below. The tromethamine is 0.01% to 10%, and more preferably 0.1% to 5%. Propylene glycol is 0.01% to 10%, and more preferably 0.1% to 5%. The ethylenediamine acetic acid derivative or its salt is 0.001% to 2%, and more preferably 0.01% to 1.5%. Tetrahydrozoline hydrochloride is 0.001% to 2%, and more preferably 0.01% to 1%. ε-aminocaproic acid is 0.01% to 10%, and more preferably 0.1% to 5%. Allantoin is 0.001% to 5%, and more preferably 0.01% to 1%. Glycyrrhizic acid or its salt is 0.001% to 5%, and more preferably 0.01% to 1%. Chlorpheniramine maleate is 0.001% to 1%, and more preferably 0.003% to 0.1%. Pyridoxine hydrochloride is 0.001% to 2%, and more preferably 0.01% to 1%. Panthenol is 0.001% to 2%, and more preferably 0.01% to 1%. Chondroitin sulfate or its salt is 0.001% to 5%, and more preferably 0.01% to 2%. Sodium chloride is 0.01%~2%, and more preferably 0.05%~1%. Neostigmine methyl sulfate is 0.0001% to 1%, and more preferably 0.0005% to 0.1%. Zinc sulfate is 0.001% to 2%, and more preferably 0.025% to 1%. Sodium flavin adenine dinucleotide is 0.0001% to 1%, and more preferably 0.005% to 0.1%. Cyanocobalamin is 0.001% to 1%, and more preferably 0.002% to 0.1%. Aspartic acid or its salt is 0.01% to 5%, more preferably 0.05% to 2%. The amino ethyl sulfonic acid is 0.01% to 5%, and more preferably 0.05% to 2%.

In the ophthalmic composition of the present invention, if necessary, various components used in the ophthalmic composition can be blended within a range that does not impair the effects of the present invention. Examples of preferred formulation ingredients include drugs, buffers, stabilizers, tonicity agents, antioxidants, preservatives, and the like. These can be used alone or in a suitable combination of two or more, And can adjust the right amount.

Examples of drugs include: decongestion components other than component (D), ocular muscle regulator components, anti-inflammatory drugs or astringent components, antihistamine or antiallergic components, vitamins, amino acids, antibacterial Medicinal ingredients or antibacterial ingredients, sugars, polysaccharides or their derivatives other than ingredient (A), polyols, local anesthetics ingredients, steroid ingredients, glaucoma treatment ingredients, cataract treatment ingredients, mydriatic ingredients, etc. Specific examples are shown below.

Examples of decongestant components include: α-adrenergic agonists such as imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine) , Epinephrine (epinephrine), ephedrine (ephedrine), methylephedrine, etc.), and the pharmaceutically or physiologically acceptable salts (for example, naphazoline hydrochloride, naphazoline Nitrate, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride and other inorganic acid salts; epinephrine bitartrate and other organic Acid salt, etc.) and so on.

Examples of the ocular muscle modulator components include cholinesterase inhibitors (cholinesterase inhibitors), tropicamides, and atropine sulfates having an activation center similar to acetylcholine.

Anti-inflammatory or astringent ingredients include: pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium ( diclofenac sodium), piroxicam (piroxicam), meloxicam (meloxicam), aspirin, mefenamic acid, indometacin farnesil, acemetacin, ibuprofen, thiaprofen acid (tiaprofenic acid), loxoprofen sodium, tiaramide hydrochloride, zinc salt (for example, zinc chloride, zinc lactate, etc.), lysozyme, lysozyme hydrochloride , Methyl salicylate, sodium azulene sulfonate, berberine chloride, berberine sulfate, etc.

Examples of antihistamine ingredients or antiallergic ingredients include: ketotifen, acitazanolast, diphenhydramine, levocabastine, cromoglycic acid ), tranilast (tranilast), ibudilast (ibudilast), amlexanox (amlexanox), pemirolast (pemirolast) and the pharmacologically or physiologically acceptable salts (phenhydral Ming hydrochloride, ketotifen fumarate, cromolyn sodium, etc.).

Examples of vitamins include ascorbic acid, thiamine, nicotinic acid, vitamin D, vitamin K, and the like.

Examples of amino acids include leucine, isoleucine, valine, methionine, hydroxybutine, alanine, phenylalanine, tryptophan, lysine, glycine, and seramine Acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine, glycine glycine, γ-aminobutyric acid, glutamine Wait.

Examples of antibacterial or bactericidal ingredients include: sulfonamides (e.g., sulfamethoxazole, sulfisoxazole, sulfisomidine) and pharmacologically acceptable salts (sulfamethoxazole sodium , Sulfaxocil sodium, etc.) etc.), Rivanol (acrinol), alkyl polyaminoethylglycine, quinolone agents (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfoxacin) Norfloxacin (norfloxacin), ciprofloxacin hydrochloride, etc.), β-lactam series antibacterial drugs (sulbenicillin, cefmenoxime, etc.), aminoglycoside antibacterial drugs (Kana Kanamycin, gentamycin, tobramycin, sisomicin, dibekacin, bekanamycin, micronosium (Micronomicin, etc.), tetracycline-based antibiotics (oxytetracycline, etc.), macrolide-based antibiotics (erythromycin, etc.), chloramphenicol-based antibiotics (chloramphenicol) Etc.), peptide antibacterial drugs (colistin, etc.), etc. In addition, examples include antiviral drugs (idoxuridine, acyclovir, adenine arabinoside, ganciclovir, foscarnet, and valacyclovir). (valaciclovir), trifluorothymidine, cidofovir, carbocyclic oxetanocin-G, etc.), antifungal drugs (pimaricin), fluconazole ), itraconazole, miconazole, flucytosine, amphotericin B, etc.).

Examples of sugars include lactulose, raffinose, triglucose, glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, mannitol, sorbitol, and the like.

Polysaccharides or their derivatives can include: gum arabic, karaya gum, sanxian Gum, carob gum, guar gum, guaiac, quince seed, daruman gum, tragacanth, benzoin gum, locust bean gum (locust bean gum), casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid (alginic acid), chitin and its derivatives Substances, chitosan and its derivatives, elastin, etc.

Examples of polyhydric alcohols include glycerin, butylene glycol, polyethylene glycol, and the like.

The ingredients of local anesthetics include: chlorobutanol, lidocain, oxybuprocaine, dibucaine, procaine, ethyl aminobenzoate, and US Meprylcaine, mepivacaine, bupivacaine, cocaine and their salts (lidocaine hydrochloride, obucaine hydrochloride, etc.), etc. .

Steroid components include: hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, paramethasone, Betamethasone (betamethasone) and these salts, etc.

The ingredients for glaucoma treatment include: distigmine bromide, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, Latanoprost, isopropyl unoprostone, dipivefrin hydrochloride, araclonidine hydrochloride, pilocarpine hydrochloride Salt, carbachol, dorzolamide hydrochloride, acetazole Amine (acetazolamide), methazolamide (methazolamide) and so on.

Cataract treatment ingredients include: pirenoxine, glutathione, salivary gland hormone, tiopronin, Dihydro azapentacene disulfonate and these (For example, sodium 5,12-dihydro azapentacene disulfonate (Sodium5,12-dihydro azapentacene disulfonate) etc.).

Examples of mydriatic components include cyclopentolate hydrochloride, tropicamide, and the like.

In the case of compounding drugs, the compounding amount can be selected from the effective appropriate amount of each drug. In terms of irritation to the eyes, stability of the composition, etc., it is preferably 0.0001% to 5 in ophthalmic compositions. The range of% is more preferably the range of 0.001% to 5%.

As a buffer, for example, citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, acetic acid, sodium acetate, glacial acetic acid, sodium carbonate, sodium bicarbonate are preferably used. ,Sulfite. In the case of blending a buffer, the blending amount is preferably in the range of 0.003% to 4% in the composition.

Examples of stabilizers include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. In the case of blending the stabilizer, the blending amount is preferably in the range of 0.003% to 2% in the composition.

Examples of tonicity agents 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. In the case of formulating the tonicity agent, the formulating amount in the composition is preferably 0.001%~3% range.

Examples of antioxidants include butylhydroxyanisole (BHA), hydroquinone, propyl gallate, sodium bisulfite, and the like. In the case of blending antioxidants, the blending amount is preferably in the range of 0.001% to 1% in the composition.

Examples of preservatives include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, chlorobutanol, and p-hydroxybenzyl. Acid esters and other parabens, polidronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, polyhexamethylene biguanide, etc. In the case of compounding the preservative, the compounding amount in the composition is preferably in the range of 0.0001% to 0.5%, more preferably in the range of 0.001% to 0.5%. Furthermore, in the case where vitamin A, which has a corneal wound healing effect, etc., is formulated as the component (C), etc., in order to further reduce the irritation to the cornea, it is a safer composition, and it is best not to mix these antiseptics Agent.

The ophthalmic composition of the present invention can be manufactured by a known manufacturing method using water as the remaining part. For example, it can be obtained by dissolving the above-mentioned components in water such as sterilized purified water, ion-exchanged water, or a mixed solvent with water. It is preferable to dissolve fat-soluble components such as component (C) in the surfactant of component (B) and put it in a high-temperature (70°C to 95°C) aqueous solution that dissolves other aqueous components, and adjust the pH to adjust the pH. It is necessary to appropriately adjust the osmotic pressure with a pH adjuster and a tonicity agent, thereby obtaining an ophthalmic composition.

Examples of pH adjusters include: hydrochloric acid, sulfuric acid, phosphoric acid, and hydroxide Sodium, potassium hydroxide, magnesium hydroxide, calcium hydroxide, etc. 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 even more preferably 5.5 to 7.5. If the pH is too high or too low, there is a possibility that the irritation will become stronger. In addition, the pH measurement was performed at 20°C using a pH osmometer (HSMO-1, Toa DKK Co., Ltd.). As a pH adjuster, sodium hydroxide, potassium hydroxide, hydrochloric acid, etc. are preferable.

[Composition for Ophthalmology]

The ophthalmic composition of the present invention is preferably a liquid, and the viscosity at 20°C is preferably 1 mPa. s~400mPa. s, more preferably 1mPa. s~100mPa. s, more preferably 1mPa. s~60mPa. s, particularly preferably 1mPa. s~30mPa. s. Furthermore, the method of measuring viscosity is to use a B-type viscometer.

The ophthalmic composition of the present invention can be used as a preparation for contact lens care in addition to medicines and quasi-drugs suitable for eyes. For example, it can be used as eye drops (including ordinary eye drops, artificial tears, eye drops that can be used when wearing contact lenses, etc.), eye washes (including eye washes for the naked eye, and can be used when wearing contact lenses. An eye wash that is used to wash the eyes, an eye wash that is used after the contact lens is removed, etc.), contact lens installation solution, contact lens extraction solution, contact lens care agent (including contact lens disinfectant, contact lens preservative, and contact lens use Cleansers, cleaning and preservatives for contact lenses, etc.), preservatives for cornea removal for transplantation, ophthalmic ointments, etc. Among these, eye drops, eye washes, and contact lens installation liquids are preferred formulation forms of the ophthalmic composition of the present invention, and eye drops are particularly preferred. In addition, in this specification, when it simply describes as a contact lens, all contact lenses including hard contact lenses and soft contact lenses are included.

[Ophthalmic products]

The present invention is an ophthalmic product comprising an ophthalmic composition, a container filled with the ophthalmic composition, and a package for packaging the container, and uses an ophthalmic product stored in a state where the oxygen concentration in the ophthalmic composition is reduced Means, and it is possible to further suppress the decrease in viscosity due to the combined use of the (A) component and (B) component. Examples of the means include (1) injecting an inert gas into the package, (2) attaching a deoxidizer to the package, (3) a container with oxygen absorption capability, or (4) a package with oxygen absorption capability. By this means, it is possible to further suppress the decrease in viscosity due to the combined use of the (A) component and (B) component. Furthermore, the packaging body is preferably one that can be a sealable container.

As the container, a plastic container is preferred, and materials such as polyethylene, polyethylene terephthalate, polypropylene, polybutene, polycarbonate, polyarylate, vinyl chloride, etc., or those containing these materials can be used. Complex people and so on. Especially preferred is polyethylene terephthalate. The oxygen permeability coefficient of the container is preferably 10cc/m ² . 24hr. Above atm. The amount of the ophthalmic composition in the product can be appropriately selected according to the product and its method of use. For example, in the case of eye drops, it is preferably 2mL-20mL, more preferably 5mL-20mL. In addition, the capacity of the container is preferably selected appropriately according to the amount of the ophthalmic composition to be filled, and is preferably 100% to 150% with respect to the amount of the ophthalmic composition to be filled. For example, in the case of eye drops, it is preferably 2 mL to 30 mL. The eye drops are not particularly limited, and may be multi-dose eye drops or disposable eye drops.

Examples of packages include polyethylene, polyethylene terephthalate, polypropylene, polybutene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil, Polyvinyl alcohol series made by vapor deposition of aluminum. Polyamide-based films, polyvinylidene chloride-coated films, laminated films, etc., composites of these, multilayer films, and the like. And it is preferable that the oxygen permeability coefficient of the package is 10cc/m ² . 24hr. atm or less ^{(i.e., 0cc / m 2 .24hr.atm ~ /} m 2 .24hr.atm 10cc) an oxygen-impermeable package.

(1) Inject inert gas into the package

Examples of the inert gas include nitrogen, helium, neon, and argon. Among them, nitrogen is preferred. Regarding the concentration of the inert gas, in the volume of the space formed between the packaging body and the plastic container, it is preferably 50% by volume or more, more preferably 80% by volume or more, and even more preferably 90% by volume or more. The upper limit is not particularly limited, but is 100% by volume or less. In order to set this concentration, it is only necessary to replace the space formed between the package and the plastic container with an inert gas.

(2) Deoxidizer is included in the package

)、發瑪克普(pharmakeep)，常盤產業(股)製造的巴特隆(vitalon)，博洋(股)製造的桑少萊斯(sansoresu)，粉體技術(powdertech)(股)製造的萬達克普(wonderkeep)，阿里斯精細產品(irisfine products)(股)製造的桑索卡特(sansocut)等。 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

), Pharmakeep, Vitalon manufactured by Tokiwa Industry Co., Ltd., Sansoresu manufactured by Boyang Co., Ltd., and Wanda manufactured by Powdertech Co., Ltd. Wonderkeep, sansocut manufactured by irisfine products (stock), etc.

(3) Containers with oxygen absorption capacity

Specifically, oxyblock manufactured by Toyo Tank Co., Ltd., oxyvanish manufactured by Mitsubishi Gas Chemical Co., Ltd., and the like can be used.

(4) Package with oxygen absorption capacity

Specifically, oxycatch manufactured by Joint Printing (stock) can be used (Registered trademark) ICA, Cryovac manufactured by Sealed Air (Registered trademark) OS film, Hyster O2 manufactured by Starplastic Industries Co., Ltd., Ageless-OMAC manufactured by Mitsubishi Gas Chemical Co., Ltd., Toyo Can ( Stocks) manufactured by Oxidco (oxydec) and so on.

The means can be combined appropriately, preferably (2), (4), more preferably (1)+(2), (1)+(4).

The present invention provides a method for suppressing the decrease in viscosity, which suppresses the decrease in the viscosity of the following ophthalmic composition in an ophthalmic product, the ophthalmic product comprising the ophthalmic composition, a container filled with the ophthalmic composition, and The package for packaging the container, the ophthalmic composition comprising: (A) a water-soluble polymer compound; (B) selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester One or two or more surfactants among oxyethylene castor oil and polyethylene glycol monostearate; and (C) one or more surfactants selected from vitamin A, vitamin E, dibutylhydroxytoluene and cooling agents Fat-soluble ingredients; and used in the ophthalmic products (1) inert gas is injected into the package, (2) a deoxidizer is added to the package, (3) a container with oxygen absorption capacity, or (4) with oxygen Any one or more of the means of the packaging body with absorptive capacity, the method for suppressing the decrease in viscosity is characterized in that (D) is blended into the ophthalmic composition selected from the following (D-1) and (D-2): (D-1) Tromethamine, propylene glycol; (D-2) Ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, ε-aminocaproic acid, allantoin, licorice Acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate , Sodium flavin adenine dinucleotide, cyanocobalamin, aspartic acid, aspartate, and amino ethyl sulfonic acid. Preferably, the amount, etc. are the same as described above.

The present invention provides a method for suppressing the decrease in viscosity, which suppresses the decrease in the viscosity of the following ophthalmic composition. The method for suppressing the decrease in viscosity is characterized in that the ophthalmic composition includes a container filled with the ophthalmic composition, And a package for packaging the container, and use (1) inject inert gas into the package, (2) add a deoxidizer to the package, (3) a container with oxygen absorption capacity, or (4) have oxygen absorption Any one or more means of a packaging body of the ability, the ophthalmic composition comprising: (A) a water-soluble polymer compound; (B) selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester , Polyoxyethylene castor oil and one or more than two kinds of surfactants in polyethylene glycol monostearate; and (C) one selected from vitamin A, vitamin E, dibutyl hydroxytoluene and cooling agent The above fat-soluble components; and the formulation (D) into the ophthalmic composition is selected from the following (D-1) and (D-2): (D-1) Tromethamine, propylene glycol; (D-2) Ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, ε-aminocaproic acid, allantoin, licorice Acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate , Sodium flavin adenine dinucleotide, cyanocobalamin, aspartic acid, aspartate, and amino ethyl sulfonic acid. Preferably, the amount, etc. are the same as described above.

[Example]

Hereinafter, examples and comparative examples are shown and the present invention will be specifically described, but the present invention is not limited to the following examples. Furthermore, the composition W/V% is g/100mL.

[Examples, Comparative Examples]

，三菱氣體化學股份有限公司製造)的膜包裝(包裝體)。另外，針對比較例4及實施例4-1~實施例4-4、以及比較例6及實施例6-1~實施例6-3，使用具有氧吸收能的膜(艾己萊斯歐馬克(ageless-OMAC)：三菱氣體化學股份有限公司製造)實施包裝(包裝體)。再者，包裝體的氧透過係數為10cc/m²．24hr．atm以下。利用B型黏度計(數位黏度計DV2T，英弘精機股份有限公司 製造)對保存前的黏度測定黏度，在50℃．75%RH環境下保存2個月。於保存後，恢復至常溫(20℃)，並與保存前同樣地對滴眼劑進行測定。根據所獲得的黏度並基於下述式來求出各實施例的黏度維持率(%)，如以下般算出黏度維持率增強效果(%)。 After dissolving the fat-soluble component in the component (B), the ophthalmic composition with the composition shown in the following table is poured into a high-temperature (70°C to 95°C) aqueous solution that dissolves other aqueous solution components to produce the following table An ophthalmic composition of the composition shown in. After filling the obtained ophthalmic composition (15 mL) into an eye drop container (16 mL) made of polyethylene terephthalate, it was carried out together with a deoxidizer (ageless: Z- 20PK

, A film packaging (package body) manufactured by Mitsubishi Gas Chemical Co., Ltd.). In addition, for Comparative Example 4 and Example 4-1 to Example 4-4, and Comparative Example 6 and Example 6-1 to Example 6-3, a film with oxygen absorption energy (Agilis Omac (ageless-OMAC): manufactured by Mitsubishi Gas Chemical Co., Ltd.) Implement packaging (package body). Furthermore, the oxygen permeability coefficient of the package is 10cc/m ² . 24hr. Below atm. Use a B-type viscometer (digital viscometer DV2T, manufactured by Yinghong Precision Machinery Co., Ltd.) to measure the viscosity before storage at 50°C. Store at 75%RH for 2 months. After storage, return to normal temperature (20°C), and measure the eye drops in the same way as before storage. Based on the obtained viscosity, the viscosity retention rate (%) of each example was calculated based on the following formula, and the viscosity retention rate enhancement effect (%) was calculated as follows.

Viscosity maintenance rate (%) = viscosity after storage/viscosity before storage×100

Viscosity maintenance rate enhancement effect (%)=[Viscosity maintenance rate of each example (%)/Viscosity maintenance rate of the comparative example corresponding to each example (%)-1]×100

In addition, the comparative example corresponding to each Example means the comparative example which does not contain (D) component.

[Table 7]

[Table 20]

[Table 22]

The addition of the (D) component can suppress the decrease in the viscosity of the ophthalmic composition caused by the blending of the (A) component and the (B) component, and can maintain the retention effect of the active ingredient or the cooling agent on the surface of the eye.

[Formulation example]

The ophthalmic composition of the composition shown in the following table is filled into the container of the present invention, and the ophthalmic product packaged in the packaging form of the present invention can be used to suppress the decrease in viscosity caused by time and is effective Or an eye drop with excellent durability of refreshing feeling and excellent durability of moisturizing feeling. In particular, formulation example 3, formulation example 5, formulation example 10 to formulation example 12 are suitable as contact eye drops that can be instilled when wearing soft contact lenses.

The raw materials used in the examples are shown below. In addition, as long as there is no special indication, the amount of each component in the table is the amount converted into purity.

. Hydroxypropyl methylcellulose: Metolose 60SH-4000, Japanese Pharmacopoeia, Shin-Etsu Chemical Co., Ltd., weight average molecular weight approximately 300,000 (g/mol)

. Methyl cellulose: Metolose SM-4000, Japanese Pharmacopoeia, Shin-Etsu Chemical Co., Ltd., weight average molecular weight approximately 360,000 (g/mol)

. Hydroxyethyl cellulose: HEC-CF-V, specifications for pharmaceutical additives, Sumitomo Seiki Co., Ltd., weight average molecular weight approximately 1 million (g/mol)

. Polyvinylpyrrolidone: Kollidon 90F, Japanese Pharmacopoeia, BASF (share), weight average molecular weight 1 million (g/mol)

. Carboxy ethylene polymer: Carbopol (registered trademark) 971PNF, pharmaceutical additives specifications, Lubrizol (Lubrizol)

. Sodium Hyaluronate: Biological Sodium Hyaluronate, Shiseido (shares)

. Polyoxyethylene hydrogenated castor oil 60: HCO60, pharmaceutical additives specifications, Japan Surfactant Industry Co., Ltd.

. Monooleic acid POE (20) sorbitan (polysorbate 80): Rheodol TW-0120V, Kao (stock)

. Polyoxyethylene castor oil 35: Nikko (NIKKOL) CO-35, Nikko Chemical Co., Ltd.

. Polyoxyethylene stearate 40: Nikko (NIKKOL) MYS-40MV, Nikko Chemical Co., Ltd.

. Retinol Palmitate: Retinol Palmitate, Japanese Pharmacopoeia, DSM Nutrition Japan (Stock)

. d-α-Tocopherol Acetate: Riken E Acetate Alpha, Japanese Pharmacopoeia external standard, Riken Vitamin (stock)

. Dibutyl hydroxytoluene: Dibutyl hydroxytoluene, pharmaceutical additives specifications, Wako Pure Chemical Industries, Ltd.

(D) Ingredients and other optional ingredients use various raw materials that meet the specifications of the official regulations (Japanese Pharmacopoeia, Japanese Pharmacopoeia specifications for drugs outside the Japanese Pharmacopoeia, specifications for pharmaceutical additives, etc.).

Claims (8)

An ophthalmic product, comprising an ophthalmic composition, a container filled with the ophthalmic composition, and a package for packaging the container, the ophthalmic composition comprising: (A) selected from hydroxypropyl One or more of methyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, hyaluronic acid and its salts; (B) selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene One or two or more surfactants among sorbitan fatty acid esters, polyoxyethylene castor oil, and polyethylene glycol monostearate; (C) selected from vitamin A, vitamin E, dibutyl hydroxytoluene And one or more components in the cooling agent; and (D) one or more selected from the group consisting of ε-aminocaproic acid, allantoin, pyridoxine hydrochloride, panthenol, and sodium flavin adenine dinucleotide And used in the ophthalmic products (1) injecting inert gas into the package, (2) attaching a deoxidizer to the package, (3) a container with oxygen absorption capacity, or (4) having Any one or more means of the packaged body of oxygen absorption capacity. The ophthalmic product according to the first item of the patent application, wherein the component (D) is one or more selected from panthenol and sodium flavin adenine dinucleotide. An ophthalmic product, comprising an ophthalmic composition, a container filled with the ophthalmic composition, and a package for packaging the container, the ophthalmic composition comprising: (A) selected from hydroxypropyl Methyl cellulose, methyl cellulose, hydroxyethyl fiber (B) selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol, carboxyvinyl polymer, hyaluronic acid and its salts; One or two or more surfactants in oxyethylene castor oil and monostearate polyethylene glycol; (C) one or more components selected from vitamin A, vitamin E, dibutylhydroxytoluene and cooling agents And (D) one or more selected from panthenol and sodium flavin adenine dinucleotide; and used in the ophthalmic products (1) injecting inert gas into the package, (2) in the The package body is accompanied by any one or more means of a deoxidizer, (3) a container with oxygen absorption capacity, or (4) a package body with oxygen absorption capacity. The ophthalmic product according to item 1 or item 2 of the scope of patent application, wherein the component (C) is selected from retinol palmitate, d-α-tocopherol acetate, dibutylhydroxytoluene And one or more of menthol. A method for suppressing the decrease in viscosity, which suppresses the decrease in the viscosity of the following ophthalmic composition in an ophthalmic product, the ophthalmic product comprising the ophthalmic composition, a container filled with the ophthalmic composition, and A package packaged in the container, the ophthalmic composition comprising: (A) selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and carboxyvinyl polymer , Hyaluronic acid and one or more of its salts; (B) one selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and monostearic acid polyethylene glycol Or two or more Surfactant; and (C) one or more fat-soluble ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene, and cooling agents; and used in the ophthalmic product (1) in the package Injecting an inert gas, (2) adding a deoxidizer to the package, (3) a container with oxygen absorption capacity, or (4) a package with oxygen absorption capacity, to the ophthalmology department The composition (D) is formulated with one or more selected from ε-aminocaproic acid, allantoin, pyridoxine hydrochloride, panthenol, and sodium flavin adenine dinucleotide. A method for suppressing the decrease in viscosity, which suppresses the decrease in the viscosity of the following ophthalmic composition in an ophthalmic product, the ophthalmic product comprising the ophthalmic composition, a container filled with the ophthalmic composition, and The packaging body packed in the container, the ophthalmic composition comprising: (A) selected from the group consisting of hydroxypropyl methyl cellulose, methyl cellulose, hydroxy ethyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol , Carboxyethylene polymer, hyaluronic acid and one or more of its salts; (B) selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene monostearate One or two or more surfactants in glycol; (C) one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and cooling agents; and in the ophthalmic product Use any of (1) injecting an inert gas into the package, (2) attaching a deoxidizer to the package, (3) a container with oxygen absorption capacity, or (4) a package with oxygen absorption capacity One or more means to blend (D) one or more selected from panthenol and sodium flavin adenine dinucleotide into the ophthalmic composition. A method for suppressing the decrease in viscosity, which suppresses the decrease in the viscosity of the following ophthalmic composition, the method for suppressing the decrease in viscosity is characterized in that the ophthalmic composition includes a container filled with the ophthalmic composition, And a package that packs the container, and uses (1) inert gas is injected into the package, (2) a deoxidizer is added to the package, (3) a container with oxygen absorption capacity, or ( 4) Any one or more means of a package with oxygen absorption capacity, the ophthalmic composition comprising: (A) selected from hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, poly One or more of vinyl alcohol, carboxyvinyl polymer, hyaluronic acid and its salts; (B) selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and monostearic acid One or two or more surfactants in polyethylene glycol; and (C) one or more fat-soluble ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene and cooling agents; and to the ophthalmology department One or more selected from the group consisting of ε-aminocaproic acid, allantoin, pyridoxine hydrochloride, panthenol, and sodium flavin adenine dinucleotide are blended with the composition (D). A method for suppressing the decrease in viscosity, which suppresses the decrease in the viscosity of the following ophthalmic composition, the method for suppressing the decrease in viscosity is characterized in that the ophthalmic composition includes a container filled with the ophthalmic composition, And a package that packs the container, and uses (1) inert gas is injected into the package, (2) a deoxidizer is added to the package, (3) a container with oxygen absorption capacity, or ( 4) Any one or more means of a package with oxygen absorption capacity, the ophthalmic composition comprising: (A) selected from hydroxypropyl methyl cellulose, methyl cellulose, hydroxy ethyl cellulose, polyethylene One or more of pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, hyaluronic acid and its salts; (B) selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil And one or two or more surfactants in monostearic acid polyethylene glycol; and (C) one or more fat-soluble ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene and cooling agents; In addition, one or more selected from panthenol and sodium flavin adenine dinucleotide (D) is blended into the ophthalmic composition.