Ophthalmic composition for soft contact lenses

Abstract

To provide ophthalmic compositions for soft contact lens that contain a zinc compound, the composition having the suppressed adsorption of zinc ions to a soft contact lens and being capable of increasing the mucin amount on the eye surface.SOLUTION: Provided is an ophthalmic composition for soft contact lens that contains a zinc compound, citric acid, a salt thereof, and / or a hydrate thereof, and has a pH of 5 to 8. Preferably, the zinc compound is zinc sulfate, zinc lactate, zinc chloride, and / or a hydrate thereof. Preferably, the concentration of the zinc compound is 0.00001 to 0.25 mass%, and preferably the concentration of citric acid, a salt thereof, and / or a hydrate thereof is 0.0025 to 5 mass%. The composition can also further contain mucopolysaccharides and / or a salt thereof.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to an ophthalmic composition for soft contact lenses. The present invention also relates to a method for suppressing the adsorption of zinc ions to soft contact lenses. The present invention also relates to a method for increasing the amount of mucin on the ocular surface. The present invention also relates to a method for suppressing the precipitation of zinc compounds in an ophthalmic composition for soft contact lenses.

Background Art

[0002] Zinc sulfate is formulated in ophthalmic compositions such as eye drops and eye washes as an anti-inflammatory agent. In addition, since zinc compounds such as zinc lactate have an anti-inflammatory effect, various proposals have been made to formulate them in ophthalmic compositions. In recent years, the use of digital devices has increased, and the complaints of subjective symptoms such as eye fatigue associated with it have been on the increase. The present inventors have found that cells on the ocular surface are damaged by blue light when using digital devices, and have confirmed in in vitro tests that zinc compounds have an effect of reducing the damage to cells on the ocular surface. Therefore, under the circumstances where the use of digital devices is increasing, there is a strong demand for formulating zinc compounds in ophthalmic compositions.

[0003] Here, when components in an ophthalmic composition are adsorbed to a contact lens, it may cause a foreign body sensation in the eye or the contact lens may deteriorate. Therefore, an ophthalmic composition used in contact with a contact lens is required not to adsorb components to the contact lens. So far, eye drops containing zinc compounds such as zinc sulfate and can be used when wearing hard contact lenses have been commercially available. However, soft contact lenses have a problem that components are easily adsorbed, and ophthalmic compositions used in contact with soft contact lenses have not yet been commercially available.

[0004] In addition, it has been reported that wearing contact lenses reduces mucin on the surface of the eye, particularly on the corneal surface (Non-Patent Document 1). The surface of the eye is covered by three layers from the inside: a membrane-bound mucin layer bound to the cell membrane, a liquid layer containing secreted mucin, and an oil layer. Since mucin has the function of stably retaining tears, when the mucin on the eye surface decreases, the tears on the eye surface become partially thinner or the three-layer structure is destroyed, causing dry eye and damaging the eye surface. Therefore, there is a need for an ophthalmic composition for contact lenses that can suppress a decrease in the amount of mucin on the eye surface caused by wearing contact lenses.

[0005] Patent Document 1 proposes blending a zinc compound into an ophthalmic composition for soft contact lenses. According to Patent Document 1, in an ophthalmic composition for contact lenses containing a zinc compound, at least one selected from the group consisting of ethylenediamine acetic acid, amino acetic acid, hydroxy acetic acid, and their salts, and at least one selected from the group consisting of monoethanolamine, 2-amino-2-methyl-1,3-propanediol, and their salts are contained, so that when the zinc compound comes into contact with the contact lens, the discoloration of the lens can be significantly suppressed, and it is disclosed that the contact lens may be a soft contact lens.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Non-Patent Documents

[0007]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] The inventor has found that zinc ions among the components of ophthalmic compositions are easily adsorbed onto soft contact lenses. Therefore, an object of the present invention is to provide an ophthalmic composition for soft contact lenses containing a zinc compound, in which the adsorption of zinc ions onto the soft contact lenses is suppressed and the amount of mucin on the ocular surface can be increased.

Means for Solving the Problems

[0009] The inventor has conducted extensive research to solve the above problems and obtained the following findings. (1) By blending citric acid, its salts, and / or their hydrates into an ophthalmic composition containing a zinc compound, the adsorption of zinc ions onto soft contact lenses is suppressed. (2) The adsorption of zinc ions onto soft contact lenses is more effectively suppressed by blending mucopolysaccharides and / or their salts in addition to citric acid, its salts, and / or their hydrates. (3) When the ophthalmic composition is brought into contact with human corneal epithelial cells, the amount of mucin expression increases by blending a zinc compound in the ophthalmic composition, and further increases by blending citric acid, its salts, and / or their hydrates in addition to the zinc compound.

[0010] The present invention has been completed based on the above findings, and provides the following [1] to

[11] . [1] An ophthalmic composition for soft contact lenses, which contains a zinc compound, citric acid, its salts, and / or their hydrates, and has a pH of 5 to 8. [2] The ophthalmic composition for soft contact lenses according to [1], wherein the zinc compound is at least one selected from the group consisting of zinc sulfate, zinc lactate, zinc chloride, and their hydrates. [3] The ophthalmic composition for soft contact lenses according to [1] or [2], wherein the concentration of the zinc compound is 0.000005 to 1% by mass based on the total amount of the composition. [4] The ophthalmic composition for soft contact lenses according to any one of [1] to [3], wherein citric acid, its salts, and / or their hydrates are at least one selected from the group consisting of sodium citrate, sodium dihydrogen citrate, and disodium citrate. [5] The ophthalmic composition for soft contact lenses according to any one of [1] to [4], wherein the concentration of citric acid, its salts, and / or their hydrates is 0.001 to 5% by mass based on the total amount of the composition. [6] The ophthalmic composition for soft contact lenses according to any one of [1] to [5], which contains 0.001 to 800,000 parts by mass of citric acid, its salts, and / or their hydrates per 1 part by mass of the zinc compound. [7] The ophthalmic composition for soft contact lenses according to any one of [1] to [6], which further contains mucopolysaccharides and / or their salts. [8] The ophthalmic composition for soft contact lenses according to [7], wherein the concentration of the mucopolysaccharides and / or their salts is 0.00001 to 14% by mass based on the total amount of the composition. 〔9〕A method for suppressing the adsorption of zinc ions onto a soft contact lens by coexisting citric acid, its salts, and / or their hydrates in an ophthalmic composition for soft contact lenses containing a zinc compound and having a pH of 5 to 8. 〔10〕A method for imparting the ability to increase the mucin production of cells on the ocular surface to an ophthalmic composition for soft contact lenses by presenting a zinc compound and citric acid, its salts, and / or their hydrates in the ophthalmic composition for soft contact lenses having a pH of 5 to 8. 〔11〕A method for suppressing the precipitation of a zinc compound in this ophthalmic composition by adjusting the pH of an ophthalmic composition for soft contact lenses containing a zinc compound and citric acid, its salts, and / or their hydrates to 5 to 8.

Advantages of the Invention

[0011] The inventor has found that zinc ions are likely to adsorb onto soft contact lenses. And the ophthalmic composition for soft contact lenses of the present invention contains a zinc compound, but the adsorption of zinc ions onto the soft contact lenses is significantly suppressed. Therefore, the foreign body sensation in the eye caused by wearing a soft contact lens adsorbed with zinc ions and the deterioration of the soft contact lens are suppressed.

[0012] In addition, when the ophthalmic composition of the present invention is used, the amount of mucin expression in cells on the ocular surface increases. As described above, when a contact lens is worn, the amount of mucin on the surface of the eye decreases. Therefore, the ophthalmic composition of the present invention can be suitably used when a soft contact lens is worn, and can suppress damage to the ocular surface and dry eye caused by wearing a soft contact lens. Also, by using it while a person wearing a soft contact lens has removed the soft contact lens, the reduced amount of mucin on the ocular surface can be restored, and damage to the ocular surface and dry eye can be suppressed.

[0013] In general, metal salts may precipitate during storage in liquid pharmaceutical compositions. When metal precipitates in pharmaceutical compositions, especially in ophthalmic compositions used in the eyes, which are delicate tissues, it not only causes a foreign body sensation in the eyes but may also damage the eyes. Therefore, metal precipitation must be avoided. In particular, when wearing contact lenses, the precipitated metal strongly rubs against the eyes, increasing the foreign body sensation and damage to the eye surface. Therefore, when formulating a metal compound in an ophthalmic composition for contact lenses, it is necessary to determine the composition so that no precipitation of the metal compound occurs. The inventor has found that in an ophthalmic composition containing a zinc compound, citric acid, its salts, and / or their hydrates, the zinc compound is likely to precipitate during storage. In this regard, the composition of the present invention suppresses the precipitation of the zinc compound during storage by having a pH of 8 or less. Therefore, the precipitation of the zinc compound is suppressed from causing a foreign body sensation in the eyes or damaging the eye surface. When wearing contact lenses, the friction with the contact lenses intensifies the foreign body sensation and eye damage caused by the precipitation of the metal. Therefore, the ophthalmic composition of the present invention can be suitably used as an ophthalmic composition for soft contact lenses.

[0014] In addition, the ophthalmic composition of the present invention does not give an unpleasant stimulus to the eyes.

Brief Description of the Drawings

[0015]

Figure 1

Modes for Carrying Out the Invention

[0016] (1) Ophthalmic composition for soft contact lenses The ophthalmic composition for soft contact lenses of the present invention is a composition containing a zinc compound, citric acid, its salts, and / or their hydrates, and having a pH of 5 to 8.

[0017] Zinc compound The zinc compound may be any pharmacologically or physiologically acceptable one, and examples thereof include zinc, inorganic zinc salts, organic zinc salts, and hydrates thereof. Examples of the zinc compound include, for example, zinc; inorganic zinc salts such as zinc sulfate, zinc halides (such as zinc chloride, zinc fluoride, zinc iodide, etc.), zinc nitrate, zinc oxide, zinc phosphate, zinc aluminate, zinc hydroxide, zinc carbonate, zinc chromate, zinc picrate, sodium tripolyphosphate zinc, zinc polyphosphonate; organic zinc salts such as zinc lactate, zinc acetate, zinc gluconate, zinc citrate, zinc 2-oxoglutarate, zinc benzoate, zinc para-aminobenzoate, zinc para-dimethylaminobenzoate, zinc para-phenolsulfonate, zinc paramethoxycinnamate, zinc 2-mercaptopyridine-N-oxide, zinc aspartate, zinc naphthenate, zinc salicylate, zinc phenolsulfonate, zinc sebacate, zinc stearate, zinc caprate, zinc laurate, zinc myristate, zinc palmitate, zinc oleate, zinc undecylenate, zinc ascorbate, zinc pyrithione, zinc hinokitiol, zinc dipicolinate, zinc glycerolate complex, bishistidine zinc complex, zinc-3,4-dihydroxybenzoic acid complex; and hydrates thereof. One or more zinc compounds can be used.

[0018] The concentration of the zinc compound in the composition of the present invention is preferably 0.000005% by mass or more, more preferably 0.00001% by mass or more, still more preferably 0.0001% by mass or more, and particularly preferably 0.00025% by mass or more, based on the total amount of the composition. Also, it may be 0.001% by mass or more, 0.01% by mass or more, or 0.05% by mass or more. Within this range, problems such as foreign body sensations due to adsorption and precipitation on the soft contact lens are likely to occur. Also, within this range, the production of mucin in the cells on the eye surface can be enhanced. In addition, the concentration of the zinc compound in the composition of the present invention is preferably 1% by mass or less, more preferably 0.5% by mass or less, still more preferably 0.25% by mass or less, yet more preferably 0.2% by mass or less, and most preferably 0.15% by mass or less, based on the total amount of the composition. Further, it may be 0.1% by mass or less, 0.01% by mass or less, 0.005% by mass or less, or 0.0025% by mass or less. Within this range, adsorption and precipitation of zinc onto the soft contact lens can be sufficiently suppressed by citric acid, its salts, and / or their hydrates. In the present invention, when a plurality of zinc compounds are blended, the content of the zinc compound is the total amount thereof.

[0019] Citric acid, its salts, and their hydrates The salt of citric acid may be any pharmacologically or physiologically acceptable one. Examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt, and ammonium salt. Examples of the salt with an organic base include organic amine salts such as methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, and picoline salt. Among them, inorganic bases are preferred, and among them, alkali metal salts are preferred, and among them, sodium salt is preferred, in terms of effectively suppressing the adsorption of zinc onto the soft contact lens and effectively promoting mucin production. The sodium salts of citric acid include trisodium citrate, disodium citrate, and sodium dihydrogen citrate, and sodium citrate is particularly preferred. Citric acid and its salts may be either anhydrous or hydrated, but hydrates are preferred in terms of effectively suppressing the adsorption of zinc onto the soft contact lens and effectively enhancing mucin production. One or more of citric acid, its salts, and / or their hydrates can be used.

[0020] The concentration of citric acid, its salts, and / or their hydrates in the composition of the present invention is preferably 0.001% by mass or more, more preferably 0.0025% by mass or more, still more preferably 0.0125% by mass or more, and particularly preferably 0.025% by mass or more, based on the total amount of the composition. Within this range, the adsorption of zinc onto the soft contact lens can be suppressed. Also, within this range, the production of mucin in the cells on the ocular surface can be enhanced. Further, the concentration of citric acid, its salts, and / or their hydrates in the composition of the present invention is preferably 5% by mass or less, more preferably 4% by mass or less, still more preferably 3.5% by mass or less, particularly preferably 2% by mass or less, and most preferably 1% by mass or less, based on the total amount of the composition. Within this range, no unpleasant stimulation is given to the eye. A preferable concentration is 0.05% by mass. In the present invention, the content of citric acid, its salts, and / or their hydrates is the total amount thereof when a plurality of citric acid, its salts, and / or their hydrates are blended.

[0021] The ratio of the content of citric acid, its salts, and / or their hydrates to the content of the zinc compound in the composition of the present invention is preferably 0.001 part by mass or more, more preferably 0.008 part by mass or more, still more preferably 0.01 part by mass or more, particularly preferably 0.04 part by mass or more, most preferably 0.1 part by mass or more, and even most preferably 0.3 part by mass or more, per 1 part by mass of the zinc compound. Within this range, the adsorption of zinc onto the soft contact lens can be suppressed. Also, within this range, the production of mucin in the cells on the ocular surface can be enhanced. Further, the ratio of the content of citric acid, its salts, and / or their hydrates to the content of the zinc compound in the composition of the present invention is preferably 800000 parts by mass or less, more preferably 500000 parts by mass or less, still more preferably 350000 parts by mass or less, particularly preferably 20000 parts by mass or less, most preferably 400 parts by mass or less, even most preferably 100 parts by mass or less, still even most preferably 10 parts by mass or less, and particularly most preferably 2 parts by mass or less, per 1 part by mass of the zinc compound. Within this range, no unpleasant stimulation is given to the eye.

[0022] Mucopolysaccharides and their salts The ophthalmic composition for soft contact lenses of the present invention may further contain mucopolysaccharides and / or salts thereof, whereby the adsorption of zinc ions onto the soft contact lenses is more effectively suppressed. The salt may be any pharmacologically or physiologically acceptable one. Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts, and ammonium salts. Examples of salts with organic bases include organic amine salts such as methylamine salts, triethylamine salts, triethanolamine salts, morpholine salts, piperazine salts, pyrrolidine salts, tripyridine salts, and picoline salts. Examples of mucopolysaccharides and salts thereof include chondroitin sulfate, sodium chondroitin sulfate (sodium chondroitin sulfate ester), hyaluronic acid, sodium hyaluronic acid, heparin, heparin sulfate, heparan sulfate, keratan sulfate, and heparinoid. Among them, sodium chondroitin sulfate (sodium chondroitin sulfate ester) and sodium hyaluronic acid are preferable in terms of high zinc ion adsorption suppression effect on soft contact lenses, and sodium chondroitin sulfate is particularly preferable. One or more kinds of mucopolysaccharides and / or salts thereof can be used.

[0023] The concentration of mucopolysaccharides and / or salts thereof in the composition of the present invention is preferably 0.00001% by mass or more, particularly preferably 0.0001% by mass or more, and particularly preferably 0.001% by mass or more, based on the total amount of the composition. It may also be 0.05% by mass or more, or 0.1% by mass or more. Within this range, the adsorption of zinc onto the soft contact lenses can be sufficiently suppressed. In addition, the concentration of the mucopolysaccharide and / or its salt in the composition of the present invention is preferably 14% by mass or less, more preferably 10% by mass or less, still more preferably 5% by mass or less, still more preferably 3% by mass or less, and particularly preferably 0.5% by mass or less, based on the total amount of the composition. Further, it may be 0.1% by mass or less, 0.01% by mass or less, 0.001% by mass or less, or 0.005% by mass or less. Within this range, the viscosity of the ophthalmic composition will not become too high and the usability will not deteriorate. In the present invention, the content of the mucopolysaccharide and / or its salt is the total amount thereof when a plurality of mucopolysaccharides and / or their salts are blended.

[0024] The ratio of the content of the mucopolysaccharide and / or its salt to the content of the zinc compound in the composition of the present invention is preferably 0.00004 part by mass or more, more preferably 0.0004 part by mass or more, and still more preferably 0.004 part by mass or more, per 1 part by mass of the zinc compound. Within this range, the adsorption of zinc onto the soft contact lens can be sufficiently suppressed. In addition, the ratio of the content of the mucopolysaccharide and / or its salt to the content of the zinc compound in the composition of the present invention is preferably 500,000 parts by mass or less, more preferably 20,000 parts by mass or less. Further, it may be 10,000 parts by mass or less, 1,000 parts by mass or less, or 100 parts by mass or less. Within this range, the viscosity of the ophthalmic composition will not become too high and the usability will not deteriorate.

[0025] Other pharmacologically or physiologically active ingredients In addition, the composition of the present invention can contain one or more pharmacological or physiological active ingredients, as long as the effects of the present invention are not impaired. For example, the composition of the present invention can contain a decongestant (vasoconstrictor). Examples of decongestants include epinephrine or its salts (e.g., epinephrine hydrochloride, epinephrine bitartrate), ephedrine or its salts (e.g., ephedrine hydrochloride), methyl ephedrine or its salts (e.g., methyl ephedrine hydrochloride, particularly dl-methyl ephedrine hydrochloride), tetrahydrozoline or its salts (e.g., tetrahydrozoline hydrochloride), naphazoline or its salts (e.g., naphazoline hydrochloride, naphazoline nitrate), phenylephrine or its salts (e.g., phenylephrine hydrochloride), oxymetazoline or its salts (e.g., oxymetazoline hydrochloride), and the like.

[0026] The composition of the present invention can contain an ocular muscle regulator. Examples of ocular muscle regulators include neostigmine or its salts (particularly neostigmine methylsulfate), physostigmine or its salts (e.g., physostigmine salicylate, physostigmine sulfate), distigmine or its salts (e.g., distigmine bromide), tropicamide, atropine or its salts (particularly atropine heliene sulfate), pilocarpine or its salts (e.g., pilocarpine hydrochloride), and the like.

[0027] The composition of the present invention can contain an anti-inflammatory agent other than zinc compounds. Such anti-inflammatory agents include epsilon-aminocaproic acid, pranoprofen, allantoin, berberine or its salts (e.g., berberine chloride, berberine sulfate), azulene sulfonic acid or its salts (e.g., sodium azulene sulfonate, potassium azulene sulfonate, calcium azulene sulfonate, magnesium azulene sulfonate), glycyrrhizic acid or its salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate), lysozyme or its salts (e.g., lysozyme chloride), indomethacin, diclofenac acid or its salts (e.g., diclofenac sodium), bromfenac acid or its salts (e.g., bromfenac sodium), and the like.

[0028] The composition of the present invention can contain an antihistamine. Examples of the antihistamine include diphenhydramine or its salts (e.g., diphenhydramine hydrochloride), chlorpheniramine or its salts (e.g., chlorpheniramine maleate, chlorpheniramine fumarate), ketotifen or its salts (e.g., ketotifen fumarate), olopatadine or its salts (e.g., olopatadine hydrochloride), iproheptine or its salts (e.g., iproheptine hydrochloride), levocabastine or its salts (e.g., levocabastine hydrochloride), and the like.

[0029] The composition of the present invention can contain vitamins. Examples of the vitamins include flavin adenine dinucleotide or its salts (e.g., flavin adenine dinucleotide sodium), cobalamin or its salts (e.g., cyanocobalamin, methylcobalamin, hydroxocobalamin, adenosylcobalamin), retinol or its salts (e.g., retinol acetate, retinol palmitate), pyridoxine or its salts (e.g., pyridoxine hydrochloride), panthenol, pantothenic acid or its salts (e.g., sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol or its salts (e.g., tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or its salts (e.g., pyridoxal phosphate), ascorbic acid or its salts (e.g., sodium ascorbate, calcium ascorbate), and the like.

[0030] The composition of the present invention can contain amino acids other than chondroitin sulfate or its salts. Examples of such amino acids include L-aspartic acid or its salts (e.g., potassium L-aspartate, sodium L-aspartate, magnesium L-aspartate, calcium L-aspartate, magnesium potassium L-aspartate (an equimolar mixture of magnesium L-aspartate and potassium L-aspartate)), aminoethylsulfonic acid (taurine), glutamic acid or its salts (e.g., sodium glutamate, magnesium glutamate), creatinine, glycine, alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, and the like.

[0031] The composition of the present invention can contain antibacterial components. Examples of antibacterial components include sulfamethoxazole or its salts (e.g., sodium sulfamethoxazole, potassium sulfamethoxazole, calcium sulfamethoxazole, magnesium sulfamethoxazole), sulfisoxazole, sulfisomidine or its salts (e.g., sodium sulfisomidine, potassium sulfisomidine, calcium sulfisomidine, magnesium sulfisomidine), sulfonamide antibacterial agents such as these, alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, and acyclovir, and the like.

[0032] The composition of the present invention can contain anti-allergy drugs. Examples of anti-allergy drugs include cromoglycic acid or its salts (e.g., sodium cromoglycate, potassium cromoglycate, calcium cromoglycate, magnesium cromoglycate), acitazanolast, anlexanox, ibudilast, tranilast, pemirolast potassium, and the like.

[0033] The composition of the present invention can contain antioxidants. Examples of fat-soluble antioxidants include butyl group-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbic acid esters such as ascorbyl palmitate, ascorbyl stearate, aminopropyl ascorbate phosphate, tocopherol ascorbate phosphate, ascorbyl trilinoleate, and ascorbyl palmitate phosphate; tocopherols such as α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol; tocopherol derivatives such as tocopheryl acetate, tocopheryl nicotinate, and tocopheryl succinate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2-one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins, and curcumin; CoQ10; and the like. Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (such as disodium ascorbate-2-sulfate, sodium ascorbate, magnesium ascorbate-2-phosphate, and sodium ascorbate-2-phosphate), sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetic acid or its salts (such as sodium edetate, disodium edetate, and tetrasodium edetate), and the like.

[0034] The composition of the present invention can contain a local anesthetic or a pain reliever. Examples of the local anesthetic or the pain reliever include chlorobutanol, oxybuprocaine hydrochloride, cocaine hydrochloride, corneocaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl paratoluenesulfonate hydrochloride, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride, and the like.

[0035] In addition, the composition of the present invention can contain any pharmacologically active or physiologically active ingredient as long as the effects of the present invention are not impaired.

[0036] Properties of the composition The ophthalmic composition of the present invention can take various dosage forms according to the purpose. Such dosage forms include, for example, solutions, gels, semi-solid agents (such as ointments), and the like.

[0037] Further, the composition of the present invention may be an aqueous composition (a composition in which the ratio of an aqueous or hydrophilic base in the base is 50% by mass or more), or an oily composition (a composition in which the ratio of an oily or hydrophobic base in the base is 50% by mass or more). However, from the viewpoint of more significantly exhibiting the effects according to the present invention, it is preferably an aqueous composition.

[0038] Base Examples of the base include aqueous bases such as water and ethanol; oily bases such as vegetable oils such as sesame oil and castor oil, animal oils such as squalane, and mineral oils such as liquid paraffin and petrolatum. One or more bases can be used.

[0039] Additive In the composition of the present invention, those used as additives for ophthalmic compositions can be blended within a range that does not impair the effects of the present invention. Examples of such additives include various additives described in the Pharmaceutical Additives Dictionary 2016 (edited by the Japan Pharmaceutical Additives Association) or the General Pharmaceutical Manufacturing and Sales Approval Standards 2012 Edition (The Regulatory Science Society, Incorporated Association). Examples of the additives include cooling agents, inorganic salts, thickening agents, preservatives, surfactants, buffering agents, pH adjusters, isotonic agents, stabilizers, saccharides, polyhydric alcohols, and the like. One or more additives can be used.

[0040] Examples of the cooling agent include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineole, borneol, limonene, and borneol. These may be any of the d-form, l-form, or dl-form. Essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, perilla oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil are also included.

[0041] Examples of inorganic salts other than zinc salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; carbonate salts such as sodium hydrogen carbonate, sodium carbonate (including anhydrous sodium carbonate), potassium hydrogen carbonate, potassium carbonate, ammonium carbonate, calcium carbonate, and magnesium carbonate; phosphate salts such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen diphosphate, and dipotassium hydrogen diphosphate; sulfate salts such as magnesium sulfate; sulfite salts such as sodium hydrogen sulfite and sodium sulfite; thiosulfate salts such as sodium thiosulfate; borate salts such as sodium tetraborate, sodium metaborate, potassium tetraborate, potassium metaborate, ammonium borate, and borax; acetate salts such as potassium acetate and sodium acetate.

[0042] Examples of thickening agents other than mucopolysaccharides and their salts include cellulose-based polymer compounds such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), carboxymethylcellulose and its salts, and carboxyethylcellulose and its salts; vinyl-based polymers such as polyvinyl alcohol (fully or partially saponified), polyvinylpyrrolidone (K17, K25, K30, K90, etc.), and carboxyvinyl polymer and its salts; dextran, macrogol 6000, macrogol 4000, macrogol 400, etc. (polyethylene glycol); gellan gum, alginic acid and its salts, α-cyclodextrin, dextrin, glucose, sorbitol, liquid paraffin, glycerin, and the like. Here, the salt is not particularly limited, but a sodium salt is preferred.

[0043] Examples of the preservative include alkylpolyaminoethylglycine, boric acid, alkyldiaminoethylglycine and / or its salt (for example, alkyldiaminoethylglycine hydrochloride), benzoic acid and / or its salt (for example, sodium benzoate, potassium benzoate), ethanol, quaternary ammonium salts (for example, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride), chlorhexidine and / or its salt (for example, chlorhexidine gluconate), chlorobutanol, sorbic acid and / or its salt (for example, potassium sorbate), sodium dehydroacetate, paraoxybenzoic acid esters (for example, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanides such as polyhexamethylene biguanide, glochil (trade name, Rhodia), polydronium chloride, and the like.

[0044] Among the surfactants, nonionic surfactants are preferred. Examples of nonionic surfactants include POE sorbitan fatty acid esters such as POE(20) sorbitan monolaurate (polysorbate 20), POE(20) sorbitan monopalmitate (polysorbate 40), POE(20) sorbitan monostearate (polysorbate 60), POE(20) sorbitan tristearate (polysorbate 65), and POE(20) sorbitan monooleate (polysorbate 80); POE·POP block copolymers such as poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 403, poloxamer 237, and poloxamer 124; POE hydrogenated castor oils such as POE hydrogenated castor oil 5, POE hydrogenated castor oil 10, POE hydrogenated castor oil 20, POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil 80, and POE hydrogenated castor oil 100; POE castor oils such as POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, and POE castor oil 50; polyethylene glycol monolaurates such as polyethylene glycol (2 E.O.) monolaurate, polyethylene glycol (4 E.O.) monolaurate, polyethylene glycol (9 E.O.) monolaurate, polyethylene glycol (10 E.O.) monolaurate, polyethylene glycol (23 E.O.) monolaurate, polyethylene glycol (25 E.O.) monolaurate, polyethylene glycol (32 E.O.) monolaurate, polyethylene glycol (40 E.O., polyoxyl 40 stearate), polyethylene glycol (45 E.O.) monolaurate, polyethylene glycol (55 E.O.) monolaurate, polyethylene glycol (75 E.O.) monolaurate, and polyethylene glycol (140 E.O.) monolaurate; POE alkyl ethers such as POE(9) lauryl ether; POE-POP alkyl ethers such as POE(20)POP(4) cetyl ether; and POE alkyl phenyl ethers such as POE(10) nonyl phenyl ether.In the above-exemplified compounds, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of added moles.

[0045] In addition, amphoteric surfactants such as glycine-type amphoteric surfactants (e.g., alkyldiaminoethyl glycine, alkylpolyaminoethyl glycine) and betaine-type amphoteric surfactants (e.g., lauryldimethylaminoacetic acid betaine, imidazolinium betaine); cationic surfactants such as alkyl quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride) can also be used.

[0046] Examples of buffers other than the citrate buffer include borate buffers, phosphate buffers, carbonate buffers, acetate buffers, epsilon-aminocaproic acid buffers, aspartic acid buffers, etc. Components of the borate buffer include boric acid, borates (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.). The borate may be a hydrate. Components of the phosphate buffer include phosphoric acid, phosphates (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, etc.). The phosphate may be a hydrate. Components of the carbonate buffer include carbonic acid, carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, magnesium carbonate, etc.). Components of the acetate buffer include acetic acid, acetates (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). Components of the aspartic acid buffer include aspartic acid, salts of aspartic acid (sodium aspartate, magnesium aspartate, potassium aspartate, etc.).

[0047] Examples of pH adjusters include hydrochloric acid, acetic acid, sulfuric acid, polyphosphoric acid, organic acids (such as propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, etc.

[0048] Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol, etc. Some of the isotonic agents are formulated as inorganic salts.

[0049] Examples of stabilizers include tromethamine, sodium formaldehyde sulfoxylate (rongalit), monoethanolamine, aluminum monostearate, and glycerin monostearate, sodium bisulfite, sodium pyrosulfite, etc.

[0050] Examples of saccharides include monosaccharides, disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol, etc. Some of the saccharides are formulated as thickening agents.

[0051] Examples of polyhydric alcohols include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, etc. Some of the polyhydric alcohols are formulated as thickening agents.

[0052] pH The pH of the composition of the present invention is 5 or more, and can also be 5.3 or more, 5.5 or more, 5.8 or more, or 6 or more. Within this range, irritation to the eyes is suppressed. Also, the pH of the composition of the present invention is 8 or less, preferably 7.8 or less, more preferably 7.5 or less, still more preferably 7.3 or less, still more preferably 7 or less, still more preferably 6.9 or less, still more preferably 6.8 or less, still more preferably 6.7 or less, still more preferably 6.6 or less, still more preferably 6.5 or less, and can also be 6.3 or less, or 6 or less. Within this range, the effect of suppressing the adsorption of zinc to the contact lens is remarkably exhibited, and the precipitation of the zinc compound is suppressed.

[0053] Osmotic pressure The osmotic pressure ratio of the composition of the present invention is preferably 0.4 or more, more preferably 0.6 or more, and even more preferably 0.8 or more. Also, it is preferably 5 or less, more preferably 3 or less, and even more preferably 2 or less. Within this range, irritation to the eyes can be suppressed, and the above effects of the present invention can be obtained. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% aqueous sodium chloride solution) based on the 17th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 17th revised Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% aqueous sodium chloride solution) is prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 °C for 40 to 50 minutes, then cooling it in a desiccator (silica gel), accurately weighing 0.900 g of it, dissolving it in purified water, and making it exactly 100 mL, or using a commercially available standard solution for measuring the osmotic pressure ratio (0.9 w / v% aqueous sodium chloride solution).

[0054] Viscosity The viscosity of the ophthalmic composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically, or physiologically acceptable range. For example, the viscosity at 20°C measured with a rotational viscometer (TV-20 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1°34’×R24) is preferably 0.1 mPa·s or more, more preferably 1 mPa·s or more. Also, it is preferably 8000 mPa·s or less, more preferably 1000 mPa·s or less, even more preferably 100 mPa·s or less, and even more preferably 20 mPa·s or less. Within this range, the contact time with the eyeball and soft contact lens becomes sufficiently long, the efficacy of the ophthalmic composition can be exerted, and the above effects of the present invention can be obtained.

[0055] Dosage form Examples of the dosage form of the ophthalmic composition for soft contact lenses of the present invention include eye drops that can be instilled during soft contact lens wear, eye washes that can be used during soft contact lens wear, soft contact lens soaking solutions, and the like. Also, since it increases the production of mucin on the ocular surface, it can also be suitably used as an eye drop or eye wash while the soft contact lens is removed. That is, the ophthalmic composition of the present invention can be an ophthalmic composition for soft contact lens users. The eye drops contain artificial tears. In addition, the ophthalmic composition of the present invention can also be used as a solution for soft contact lens care, such as a soft contact lens storage solution, a soft contact lens cleaning solution, a soft contact lens cleaning and storage solution, a soft contact lens disinfectant solution, and a contact lens disinfection, cleaning, and storage solution (multi-purpose solution). The ophthalmic composition of the present invention is suitable for these dosage forms, but it may also be used for other purposes.

[0056] The ophthalmic composition for soft contact lenses of the present invention can be applied to all soft contact lenses currently on the market or those that will be marketed in the future. The soft contact lenses may be either silicone hydrogel contact lenses or non-silicone hydrogel contact lenses. Also, they may be either ionic or non-ionic, but since zinc ions are likely to adsorb to ionic soft contact lenses, ionic soft contact lenses are a preferred target of the present invention. Further, they may have either a high water content (water content of 50% or more) or a low water content (water content of less than 50%). The distinction between ionic or non-ionic and high water content or low water content is defined in the "Classification Method of Soft Contact Lenses" in the Notice of the Director of the Review and Management Division, Pharmaceutical Safety Bureau, Ministry of Health, Labour and Welfare, Pharmaceutical Review No. 645 dated March 31, 1999, "Handling of Documents to be Attached in the Application for Approval of the Manufacture (Import) of Soft Contact Lenses and Disinfectants for Soft Contact Lenses". The water content of the contact lenses is measured by a weight measurement method in accordance with ISO18369-4:2006.

[0057] Container The composition of the present invention is usually contained or filled in an ophthalmic container. The material of the container is not particularly limited, and examples include plastic containers, metal containers, glass containers, etc. Specifically, for example, plastics such as polyolefin, acrylic resin, terephthalic acid ester, 2,6-naphthalenedicarboxylic acid ester, polycarbonate, polymethylpentene, fluororesin, polyvinyl chloride, polyamide, ABS resin, AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, metals such as aluminum, and glass can be mentioned. The container may be composed of one kind of material or two or more kinds of materials. In the case of plastics, they may be mixtures or copolymers. Among them, plastic containers are preferred, and polyolefin containers and terephthalic acid ester containers are more preferred. The container here refers to the container body.

[0058] Examples of polyolefins include polyethylene (including high-density polyethylene, low-density polyethylene, ultra-low density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene, etc.), polypropylene (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), and ethylene-propylene copolymers. Examples of acrylic resins include acrylic esters such as methyl acrylate, and methacrylic esters such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate. Examples of terephthalic acid esters include polyethylene terephthalate, polytrimethylene terephthalate, and polybutylene terephthalate. Examples of 2,6-naphthalenedicarboxylic acid esters include polyethylene naphthalate and polybutylene naphthalate. Examples of fluororesins include fluorine-substituted polyethylene (such as polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, ethylene tetrafluoride - hexafluoropropylene copolymer, ethylene - perfluoroalkoxyethylene copolymer (PFA), ethylene - tetrafluoroethylene copolymer, and ethylene - chlorotrifluoroethylene copolymer. Examples of polyamides include nylon. Examples of polyacetals include those composed only of oxymethylene units and those containing some oxyethylene units. Examples of modified polyphenylene ethers include polystyrene-modified polyphenylene ether. Examples of polyarylates include amorphous polyarylate. Examples of polyimides include aromatic polyimides, such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether. Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

[0059] A nozzle may be attached to the container that houses the ophthalmic composition of the present invention. The material of the nozzle is not particularly limited, and for example, it may be made of glass or plastic. Preferably, it is made of plastic. Examples of plastics include polybutylene terephthalate, polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, copolymers of the monomers that constitute these, and mixtures of two or more of these.

[0060] Also, the container of the ophthalmic composition may be a multi-unit type container or a single-use unit dose type container.

[0061] (2) Method for suppressing adsorption of zinc ions The present invention provides a method for suppressing the adsorption of zinc ions to soft contact lenses by coexisting citric acid, its salts, and / or their hydrates in an ophthalmic composition for soft contact lenses containing a zinc compound and having a pH of 5 to 8. The types, contents, and other components that can be formulated, the properties, physical properties, and dosage forms of the ophthalmic composition are as described for the ophthalmic composition for soft contact lenses of the present invention. However, the content of each component is the content when the total amount of the composition after coexisting citric acid, its salts, and / or their hydrates is taken as the total amount.

[0062] (3) Method for imparting ability to promote mucin production on the ocular surface The present invention provides a method for imparting the ability to increase the production (expression) of mucin in cells on the ocular surface to an ophthalmic composition for soft contact lenses by causing a zinc compound and citric acid, its salts, and / or their hydrates to be present in the ophthalmic composition for soft contact lenses having a pH of 5 to 8. The types of each component, the content, other components that can be formulated, the properties, physical properties, and dosage form of the ophthalmic composition are as described for the ophthalmic composition for soft contact lenses of the present invention. However, the content of each component is the content when the total amount of the composition after the presence of the zinc compound and citric acid, its salts, and / or their hydrates is taken as the total amount.

[0063] (4) Method for suppressing precipitation of zinc compounds The present invention provides a method for suppressing the precipitation of a zinc compound in an ophthalmic composition for soft contact lenses containing a zinc compound and citric acid, its salts, and / or their hydrates by adjusting the pH of the ophthalmic composition to 5 to 8. The types of each component, the content, other components that can be formulated, the properties, physical properties, and dosage form of the ophthalmic composition are as described for the ophthalmic composition for soft contact lenses of the present invention.

Examples

[0064] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Test Example 1 (Evaluation of suppression of zinc adsorption onto soft contact lenses (SCL)) Ophthalmic compositions of Examples 1 to 4, 9 to 12, Reference Example 1, and Comparative Examples 1 to 4 having the compositions shown in Tables 1 and 2 were prepared according to a conventional method. Also, SCL (Johnson & Johnson VISION CARE, INC., 2-week Acuvue) was equilibrated by immersing it in Otsuka physiological saline for 24 hours. Each ophthalmic composition was filled into a tetrafluoroethylene-perfluoroalkoxyethylene copolymer (PFA) (Sanplatec Corporation, product number: 25430) container in an amount of 4 mL each, and two equilibrated SCLs were immersed, and immersed for 48 hours while shaking at 34°C and 120 rpm to obtain test samples. Also, each ophthalmic composition was filled into a PFA container in an amount of 4 mL each, and those without SCL were also immersed for 48 hours while shaking at 34°C and 120 rpm to obtain control samples.

[0065] Next, zinc ions in the test sample and the control sample were quantified by ion chromatography under the following conditions. Measurement conditions for ion chromatography (a) Zinc sulfate-containing compositions (Examples 1 to 4, Reference Example 1, Comparative Examples 1 to 3) Detector: Conductivity detector (polarity: -) Column: Shodex IC YS-50 (inner diameter 4.6 mm, length 12.5 mm) Column temperature: Constant temperature around 40 °C Mobile phase: 3 mM methanesulfonic acid aqueous solution Flow rate: 0.95 mL / min (b) Zinc chloride-containing compositions (Examples 9 to 12, Comparative Example 4) Detector: Conductivity detector (polarity: -) Column: Shodex IC YS-50 (inner diameter 4.6 mm, length 12.5 mm) Column temperature: Constant temperature around 40 °C Mobile phase: 2 mM methanesulfonic acid / 3 mM 18-crown-6 aqueous solution Flow rate: 0.93 mL / min

[0066] Since a zinc compound was used as the standard for ion chromatography, the adsorption amount of the zinc compound onto the soft contact lens was calculated according to the following formula. Adsorption amount of zinc compound onto soft contact lens (μg / piece) = (Zinc compound content (μg) in control sample - Zinc compound content (μg) in test sample) / 2 For each ophthalmic composition, three samples were prepared and quantified, and the average value of the zinc compound adsorption amount was determined. The results are shown in Table 1 and Table 2.

[0067]

Table 1

[0068]

Table 2

[0069] When sodium citrate hydrate was added to the ophthalmic composition containing zinc sulfate hydrate, the amount of zinc sulfate adsorbed onto the SCL decreased significantly in a dose-dependent manner. Furthermore, when sodium chondroitin sulfate was added, the amount of zinc sulfate adsorbed onto the SCL decreased further. Also, the lower the pH, the greater the effect of reducing the amount of zinc sulfate adsorbed due to the addition of sodium citrate hydrate. Moreover, when the ophthalmic compositions of Examples 1 to 4 were instilled into the eyes, no unpleasant irritation was felt.

[0070] When sodium citrate hydrate was added to the ophthalmic composition containing zinc chloride hydrate, the amount of zinc chloride adsorbed onto the SCL decreased significantly. Since the zinc chloride concentration was very low, no clear difference in the zinc ion adsorption inhibitory effect was observed among Examples 9 to 12, and the adsorption of zinc ions was suppressed to the same extent. Moreover, when the ophthalmic compositions of Examples 9 to 12 were instilled into the eyes, no unpleasant irritation was felt.

[0071] Test Example 2 (Evaluation of suppression of precipitation of zinc compounds The ophthalmic compositions of Examples 1, 2, 5, 6, and Reference Example 1 having the compositions shown in Table 3 were prepared according to a conventional method. Each composition was filled into a glass ampoule in an amount of 10 mL each, allowed to stand at 60°C for 1 week, and precipitation was visually observed and evaluated according to the following criteria. - : No precipitation + : The precipitate thinly covers a part of the bottom of the ampoule and floats up when stirred. ++: The precipitate thickly covers the entire bottom of the ampoule. The results are shown in Table 3.

[0072]

Table 3

[0073] Test Example 3 (Evaluation of promotion of mucin expression) Ophthalmic compositions of Example 7, Reference Example 2, and Comparative Example 4 having the compositions shown in Table 4 were prepared according to a conventional method. In addition, immortalized human corneal epithelial cells (HCE-T) were seeded on a culture plate (one having conditions usually used for culturing immortalized human corneal epithelial cells. The culture plate has an area such that the cells at confluence are completely covered with 150 μl of the composition.) at 1.2×10 5 / cm 2 and cultured for 2 days under conditions of 37°C, 5% CO 2 , and 90% humidity, and the medium was changed. After further culturing for 1 day, it was confirmed that the cells had become confluent. The ophthalmic composition having the composition shown in Table 4 below was diluted 50-fold with the culture medium, and 150 μl was added to the cells. In addition, the one obtained by diluting Reference Example 2 50-fold with the culture medium and adding 150 μl to the cells was used as a control. Further, the one obtained by adding only 150 μl of the culture medium to the cells was used as Reference Example 3. Total RNA was extracted from the cells after 24 hours. The extraction of total RNA was performed using the RNeasy Mini Kit (manufactured by QIAGEN). Reverse transcription PCR was carried out using ReverTra Ace qPCR RT Master Mix with dDNA Remover (manufactured by TOYOBO) to prepare cDNA. The mRNA expression level of MUC16 was evaluated by quantitative real-time PCR method using Taq man probe (manufactured by Applied Biosystems) with Applied Biosystems QuantStudio 3 (manufactured by Thermo Fisher Scientific). After quantitative real-time PCR, the CT value of each sample was calculated by the automatic analysis of QuantStudio TM Design &Analysis Software. The ΔCt value of the target factor in each sample was calculated from Equation (1), and the ΔΔCt value was calculated from Equation (2). Equation (1): ΔCt value = (Ct value of the target factor) - (T value of GAPDH) Equation (2): ΔΔCt value = (ΔCt value of the target factor) - (average value of the ΔCt values of the target factor in Reference Example 2) Furthermore, the relative mRNA expression level of each sample with respect to Reference Example 2 was calculated from Equation (3). Equation (3): Relative mRNA expression level of each sample = 2 -ΔΔCt値 The average value and SD value of the relative mRNA expression levels of each group were calculated. For culturing, DMEM / F-12 (Dulbecco’s Modified Eagle Medium / Nutrient Mixture F-12, manufactured by Gibco) medium supplemented with insulin (5 μg / mL), hEGF (10 μg / mL), sterile DMSO (0.5%), and FBS (5%) was used.

[0074]

Table 4

[0075] The results are shown in Fig. 1. The vertical axis in Fig. 1 is the relative value of the MUC16 expression level in each example when the MUC16 expression level of the control is set to 1. By incorporating zinc sulfate hydrate, the mucin expression level increased, and by incorporating sodium citrate hydrate in addition to zinc sulfate hydrate, the mucin expression level increased further.

[0076] Formulation examples of the ophthalmic composition of the present invention are shown in Table 5 and Table 6. The unit of each component amount in Table 5 and Table 6 is "mass%".

Table 5

Table 6

Industrial Applicability

[0077] Although the ophthalmic composition of the present invention contains a zinc compound, adsorption of zinc ions and precipitation of the zinc compound onto the soft contact lens are suppressed, and a decrease in the amount of mucin produced by wearing the soft contact lens is also suppressed. The present invention has opened up a way to use an ophthalmic composition containing a zinc compound for soft contact lenses.

Claims

1. An ophthalmic composition for soft contact lenses containing at least one zinc compound selected from the group consisting of zinc sulfate, zinc lactate, zinc chloride, and hydrates thereof in an amount of 0.00025 to 0.25% by mass based on the total amount of the composition, and at least one selected from the group consisting of citric acid, sodium citrate, and hydrates thereof in an amount of 0.001 to 1% by mass based on the total amount of the composition, with a pH of 5 to 6.3 (provided that an aqueous composition containing sorbic acid or a salt thereof in an amount of 0.0001 to 10 w / v%, an aqueous ophthalmic composition containing at least one selected from the group consisting of chondroitin sulfate and a salt thereof in an amount of 0.8 w / v% or more based on the total amount of the composition, an eye drop containing at least one selected from the group consisting of alexidine and a salt thereof, and an aqueous composition containing pranoprofen or a salt thereof are excluded).

2. The ophthalmic composition for soft contact lenses according to Claim 1, containing at least one selected from the group consisting of citric acid, sodium citrate, and hydrates thereof in an amount of 0.01 to 10 parts by mass per 1 part by mass of the zinc compound.

3. The ophthalmic composition for soft contact lenses according to Claim 1 or 2, further containing a mucopolysaccharide and / or a salt thereof.

4. The ophthalmic composition for soft contact lenses according to Claim 3, wherein the concentration of the mucopolysaccharide and / or a salt thereof is 0.00001 to 14% by mass based on the total amount of the composition.

5. A method of co-existing at least one selected from the group consisting of zinc sulfate, zinc lactate, zinc chloride, and hydrates thereof in an ophthalmic composition for soft contact lenses having a pH of 5 to 8, wherein the concentration of the zinc compound after co-existence is 0.00025 to 0.25% by mass based on the total amount of the composition, and the concentration of at least one selected from the group consisting of citric acid, sodium citrate, and hydrates thereof after co-existence is 0.001 to 1% by mass based on the total amount of the composition. A method for suppressing the adsorption of zinc ions to soft contact lenses (provided that when the composition after co-existence is an aqueous composition containing 0.0001 to 10 w / v% of sorbic acid or a salt thereof, when it is an aqueous ophthalmic composition containing at least one selected from the group consisting of chondroitin sulfate and salts thereof at 0.8 w / v% or more based on the total amount of the composition, when it is an eye drop containing at least one selected from the group consisting of alexidine and salts thereof, and when it is an aqueous composition containing pranoprofen or a salt thereof are excluded).

6. A method of causing at least one zinc compound selected from the group consisting of zinc sulfate, zinc lactate, zinc chloride, and hydrates thereof and at least one selected from the group consisting of citric acid, sodium citrate, and hydrates thereof to be present in an ophthalmic composition for soft contact lenses having a pH of 5 to 8, wherein the concentration of the zinc compound after co-existence is 0.00025 to 0.25% by mass based on the total amount of the composition, and the concentration of at least one selected from the group consisting of citric acid, sodium citrate, and hydrates thereof after co-existence is 0.001 to 1% by mass based on the total amount of the composition. A method for imparting the ability to increase the mucin production of cells on the ocular surface to an ophthalmic composition for soft contact lenses (provided that when the composition after co-existence is an aqueous composition containing 0.0001 to 10 w / v% of sorbic acid or a salt thereof, when it is an aqueous ophthalmic composition containing at least one selected from the group consisting of chondroitin sulfate and salts thereof at 0.8 w / v% or more based on the total amount of the composition, when it is an eye drop containing at least one selected from the group consisting of alexidine and salts thereof, and when it is an aqueous composition containing pranoprofen or a salt thereof are excluded).

7. An ophthalmic composition for soft contact lenses containing at least one zinc compound selected from the group consisting of zinc lactate, zinc chloride, and hydrates thereof in an amount of 0.00025 to 0.25% by mass based on the total amount of the composition and at least one selected from the group consisting of citric acid, sodium citrate, and hydrates thereof in an amount of 0.001 to 1% by mass based on the total amount of the composition (however, an aqueous composition containing sorbic acid or a salt thereof in an amount of 0.0001 to 10 w / v%, an aqueous ophthalmic composition containing at least one selected from the group consisting of chondroitin sulfate and salts thereof in an amount of 0.8 w / v% or more based on the total amount of the composition, an eye drop containing at least one selected from the group consisting of alexidine and salts thereof, and an aqueous composition containing pranoprofen or a salt thereof are excluded). A method for suppressing precipitation of a zinc compound in this ophthalmic composition, which adjusts the pH of (the composition) to 5 to 6.3.

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