JP2021155414A - Ophthalmic composition for soft contact lens - Google Patents

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

The present invention relates to ophthalmic compositions for soft contact lenses. The present invention also relates to a method for suppressing the adsorption of zinc ions on soft contact lenses. The present invention also relates to a method for increasing the amount of mucin on the surface of the eye. The present invention also relates to a method for suppressing the precipitation of zinc compounds in ophthalmic compositions for soft contact lenses.

Zinc sulfate is blended as an anti-inflammatory agent in ophthalmic compositions such as eye drops and eyewashes. In addition, since zinc compounds such as zinc lactate have an anti-inflammatory effect, various proposals have been made to incorporate them into ophthalmic compositions.
In recent years, the use of digital devices has increased, and the number of complaints of subjective symptoms such as eye fatigue associated therewith has been increasing. The present inventors have found that blue light damages cells on the surface of the eye when using a digital device, and further confirmed by in vitro tests that zinc compounds have an effect of reducing damage to cells on the surface of the eye. doing. Therefore, in a situation where the use of digital devices is increasing, there is a strong demand for adding zinc compounds to ophthalmic compositions.

Here, if the components in the ophthalmic composition are adsorbed on the contact lens, there is a risk of giving a foreign substance feeling to the eye or deteriorating the contact lens. Therefore, the ophthalmic composition used in contact with the contact lens is a component of the contact lens. Is required not to be adsorbed. So far, eye drops containing a zinc compound such as zinc sulfate and which can be used when wearing hard contact lenses are 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 put on the market.

It has also been reported that wearing contact lenses reduces mucin on the surface of the eye, especially on the surface of the cornea (Non-Patent Document 1). From the inside, the surface of the eye is covered with three layers consisting of a membrane-bound mucin layer bound to the cell membrane, a liquid layer containing secretory mucin, and an oil layer. Since mucin has a function of stably retaining tear fluid, when mucin on the surface of the eye decreases, the tear fluid on the surface of the eye becomes partially thin and the three-layer structure is destroyed, causing dry eye. Damages the surface of the eye.
Therefore, there is a demand for an ophthalmic composition for contact lenses, which can suppress a decrease in the amount of mucin on the ocular surface due to wearing contact lenses.

In addition, Patent Document 1 proposes to add a zinc compound to an ophthalmic composition for soft contact lenses. According to Patent Document 1, at least one selected from the group consisting of ethylenediamineacetic acid, aminoacetic acid, hydroxyacetic acid, and salts thereof, and monoethanolamine, are contained in an ophthalmic composition for contact lenses containing a zinc compound. A lens produced when a zinc compound and a contact lens are brought into contact with each other by containing at least one selected from the group consisting of 2-amino-2-methyl-1,3-propanediol and salts thereof. It discloses that discoloration can be remarkably suppressed and the contact lens may be a soft contact lens.

Japanese Unexamined Patent Publication No. 2013-193984

Contact Lens and Anterior Eye, "The impact of contact lens wear on ocular surface mucins using a novel clinical fluorescence imaging system" Michael L. Reada, Maria Navascues-Cornagoa, Nancy Keirb, Carole Maldonado-Codinaa, Philip B. Morgana, https: // www. contact journal. com / article / S1376-0484 (19) 30224-3 / fullext

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

The present inventor has repeated research to solve the above problems and obtained the following findings.
(1) By blending citric acid, a salt thereof, and / or a hydrate thereof with an ophthalmic composition containing a zinc compound, the adsorption of zinc ions to soft contact lenses is suppressed.
(2) Adsorption of zinc ions to soft contact lenses is more effective by adding mucopolysaccharide and / or a salt thereof in addition to citric acid, a salt thereof, and / or a hydrate thereof. It is suppressed.
(3) The mucin expression level when the ophthalmic composition is brought into contact with human corneal epidermal cells is increased by adding a zinc compound to the ophthalmic composition, and citric acid, a salt thereof, and / or a zinc compound in addition to the zinc compound. It is further increased by blending those hydrates.

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 containing a zinc compound, citric acid, a salt thereof, and / or a hydrate thereof, and having 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 hydrates thereof.
[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 with respect to the total amount of the composition.
[4] Citric acid, a salt thereof, and / or a hydrate thereof is at least one selected from the group consisting of sodium citrate, sodium dihydrogen citrate, and disodium citrate, [1] to The ophthalmic composition for soft contact lenses according to any one of [3].
[5] Any of [1] to [4], wherein the concentration of citric acid, a salt thereof, and / or a hydrate thereof is 0.001 to 5% by mass with respect to the total amount of the composition. The ophthalmic composition for soft contact lenses described.
[6] The software according to any one of [1] to [5], which contains 0.001 to 800,000 parts by mass of citric acid, a salt thereof, and / or a hydrate thereof with respect to 1 part by mass of the zinc compound. Ophthalmic composition for contact lenses.
[7] The ophthalmic composition for soft contact lenses according to any one of [1] to [6], which further contains a mucopolysaccharide and / or a salt thereof.
[8] The ophthalmic composition for soft contact lenses according to [7], wherein the concentration of the mucopolysaccharide and / or a salt thereof is 0.00001 to 14% by mass with respect to the total amount of the composition.
[9] A method for suppressing the adsorption of zinc ions on soft contact lenses, in which citric acid, a salt thereof, and / or a hydrate thereof coexist in an ophthalmic composition for soft contact lenses containing a zinc compound and having a pH of 5 to 8. ..
[10] An ophthalmic composition for soft contact lenses in which a zinc compound and citric acid, a salt thereof, and / or a hydrate thereof are present in the ophthalmic composition for soft contact lenses having a pH of 5 to 8 of cells on the surface of the eye. A method of imparting the ability to increase mutin production.
[11] Precipitation of a zinc compound in an ophthalmic composition for soft contact lenses containing a zinc compound, citric acid, a salt thereof, and / or a hydrate thereof, which adjusts the pH to 5 to 8. Suppression method.

The present inventor has found that zinc ions are easily adsorbed on soft contact lenses. The ophthalmic composition for soft contact lenses of the present invention contains a zinc compound, but the adsorption of zinc ions to the soft contact lens is remarkably suppressed. Therefore, the feeling of foreign matter in the eye and the deterioration of the soft contact lens due to wearing the soft contact lens on which zinc ions are adsorbed are suppressed.

In addition, when the ophthalmic composition of the present invention is used, the expression level of mucin in cells on the surface of the eye is increased. As described above, since the amount of mutin on the surface of the eye decreases when contact lenses are worn, the ophthalmic composition of the present invention can be suitably used when wearing soft contact lenses, and damage to the eye surface due to wearing soft contact lenses and dry eye. Can be suppressed. Also, by using the soft contact lens while the person using the soft contact lens is removing the soft contact lens, the reduced amount of mucin on the eye surface can be recovered, and damage to the eye surface and dry eye can be suppressed.

Further, in general, a liquid pharmaceutical composition containing a metal salt may precipitate a metal during storage. Precipitation of metals in pharmaceutical compositions, especially in ophthalmic compositions used for the delicate tissue of the eye, not only gives the eye a sense of discomfort, but may also damage the eye, so avoid metal precipitation. There must be. In particular, when a contact lens is worn, the deposited metal is strongly rubbed against the eye, which increases the feeling of foreign matter and damage to the surface of the eye. Therefore, when a metal compound is blended in an ophthalmic composition for contact lenses, it is necessary to determine the composition so that the metal compound does not precipitate.
The present inventor has found that in an ophthalmic composition containing a zinc compound, citric acid, a salt thereof, and / or a hydrate thereof, the zinc compound is easily precipitated by storage. In this respect, the composition of the present invention has a pH of 8 or less, so that precipitation of the zinc compound due to storage is suppressed. Therefore, it is suppressed that the precipitation of the zinc compound gives the eye a feeling of foreign matter or damages the surface of the eye. When a contact lens is worn, the feeling of foreign matter and damage to the eyes due to metal precipitation become stronger due to friction with the contact lens. Therefore, the ophthalmic composition of the present invention can be suitably used as an ophthalmic composition for soft contact lenses.

In addition, the ophthalmic composition of the present invention does not cause unpleasant irritation to the eyes.

It is a figure which shows that zinc sulfate hydrate and sodium citrate hydrate increased the expression level of membrane-type mucin MUC16 in human corneal epithelial cells.

(1) Ophthalmic Composition for Soft Contact Lenses The ophthalmic composition for soft contact lenses of the present invention contains a zinc compound, citric acid, a salt thereof, and / or a hydrate thereof, and has a pH of 5 to 8. It is a composition.

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 zinc compounds include zinc; zinc sulfate, zinc halide (zinc chloride, zinc fluoride, zinc iodide, etc.), zinc nitrate, zinc oxide, zinc phosphate, zinc aluminate, zinc hydroxide, zinc carbonate. , Inorganic zinc salts such as zinc chromate, zinc picriate, sodium tripolyphosphate, zinc polyphosphonate; zinc lactate, zinc acetate, zinc gluconate, zinc citrate, zinc 2-oxoglutarate, zinc benzoate, paraaminobenzoate Zinc acid, zinc paradimethylaminobenzoate, zinc paraphenolsulfonate, 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 undecylate, Zinc ascorbate, Zincpyrthione, Hinokithiol zinc, Zinc dipicolinate, Zinc glycerolate complex, Zinc bizhistidin zinc complex , Zinc-3,4-dihydroxybenzoic acid complexes and other organic zinc salts; and hydrates thereof and the like.
As the zinc compound, one kind or two or more kinds can be used.

The concentration of the zinc compound in the composition of the present invention is 0.000005% by mass or more, particularly 0.00001% by mass or more, particularly 0.0001% by mass or more, particularly 0.00025% by mass, based on the total amount of the composition. The above is preferable. Further, 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 adhesion to soft contact lenses and a feeling of foreign matter due to precipitation are likely to occur. In addition, within this range, mucin production in cells on the surface of the eye can be enhanced.
The concentration of the zinc compound in the composition of the present invention is 1% by mass or less, particularly 0.5% by mass or less, particularly 0.25% by mass or less, particularly 0.2% by mass, based on the total amount of the composition. % Or less, more preferably 0.15% by mass or less. 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, citric acid, salts thereof, and / or hydrates thereof sufficiently suppress the adsorption and precipitation of zinc on soft contact lenses.
In the present invention, the content of the zinc compound is the total amount of the plurality of zinc compounds when they are blended.

Citric acid, its salt, and its hydrate The salt of citric acid may be any pharmacologically or physiologically acceptable salt, and in the case of salts with inorganic bases, alkali metals such as sodium salt and potassium salt. Examples include salts, calcium salts, alkaline earth metal salts such as magnesium salts, metal salts such as aluminum salts, ammonium salts and the like. Examples of the salt with the organic base include organic amine salts such as methylamine salt, triethylamine salt, triethanolamine salt, morpholin salt, piperazine salt, pyrrolidine salt, tripyridine salt and picolin salt.
Among them, inorganic bases are preferable, alkali metal salts are preferable, and sodium salts are particularly preferable, in that zinc adsorption to soft contact lenses can be effectively suppressed and mucin production can be effectively promoted. Examples of the sodium salt of citric acid include sodium citrate (trisodium citrate), disodium citrate, and sodium dihydrogen citrate, and sodium citrate is particularly preferable.
Citric acid and its salts may be either anhydrides or hydrates, but hydrates in that they can effectively suppress the adsorption of zinc on soft contact lenses and effectively enhance mutin production. Is preferable.
Citric acid, salts thereof, and / or hydrates thereof may be used alone or in combination of two or more.

The concentration of citric acid, salts thereof, and / or hydrates thereof in the composition of the present invention is 0.001% by mass or more, particularly 0.0025% by mass or more, and particularly 0, based on the total amount of the composition. .0125% by mass or more, particularly 0.025% by mass or more is preferable. Within this range, the adsorption of zinc on soft contact lenses can be suppressed. In addition, within this range, mucin production in cells on the surface of the eye can be enhanced.
Further, the concentration of citric acid, a salt thereof, and / or a hydrate thereof in the composition of the present invention is 5% by mass or less, particularly 4% by mass or less, particularly 3.5, based on the total amount of the composition. It is preferably mass% or less, particularly 2 mass% or less, and particularly preferably 1 mass% or less. Within this range, no unpleasant irritation to the eyes is given. A preferable concentration is 0.05% by mass.
In the present invention, the content of citric acid, salts thereof, and / or hydrates thereof is the total amount of a plurality of citric acids, salts thereof, and / or hydrates thereof when blended. ..

The ratio of the content of citric acid, a salt thereof, and / or their hydrate to the content of the zinc compound in the composition of the present invention is 0.001 part by mass or more with respect to 1 part by mass of the zinc compound. Among them, 0.008 parts by mass or more, particularly 0.01 parts by mass or more, particularly 0.04 parts by mass or more, particularly 0.1 parts by mass or more, and particularly preferably 0.3 parts by mass or more. Within this range, the adsorption of zinc on soft contact lenses can be suppressed. In addition, within this range, mucin production in cells on the surface of the eye can be enhanced.
The ratio of the content of citric acid, its salt, and / or its hydrate to the content of the zinc compound in the composition of the present invention is 800,000 parts by mass or less with respect to 1 part by mass of the zinc compound. Among them, 500,000 parts by mass or less, particularly 350,000 parts by mass or less, particularly 20,000 parts by mass or less, particularly 400 parts by mass or less, particularly 100 parts by mass or less, particularly 10 parts by mass or less, particularly 2 parts by mass or less is preferable. Within this range, no unpleasant irritation to the eyes is given.

Mucopolysaccharides and salts thereof The ophthalmic composition for soft contact lenses of the present invention can further contain mucopolysaccharides and / or salts thereof, whereby adsorption of zinc ions to soft contact lenses is more effective. Is suppressed.
The salt may be any pharmacologically or physiologically acceptable salt, and in the case of salts with inorganic bases, alkali metal salts such as sodium salt and potassium salt, and alkaline earth metals such as calcium salt and magnesium salt. Examples thereof include salts, metal salts such as aluminum salts, and ammonium salts. Examples of the salt with the organic base include organic amine salts such as methylamine salt, triethylamine salt, triethanolamine salt, morpholin salt, piperazine salt, pyrrolidine salt, tripyridine salt and picolin salt.
Examples of mucopolysaccharides and salts thereof include chondroitin sulfate, sodium chondroitin sulfate (sodium chondroitin sulfate), hyaluronic acid, sodium hyaluronate, heparin, heparin sulfate, heparan sulfate, keratosulfate, and heparinoid.
Of these, sodium chondroitin sulfate (sodium chondroitin sulfate) and sodium hyaluronate are preferable, and sodium chondroitin sulfate is particularly preferable, because the effect of suppressing the adsorption of zinc ions on soft contact lenses is high.
As the mucopolysaccharide and / or a salt thereof, one kind or two or more kinds can be used.

The concentration of the mucopolysaccharide and / or its salt in the composition of the present invention is 0.00001% by mass or more, particularly 0.0001% by mass or more, particularly 0.001% by mass or more, based on the total amount of the composition. preferable. Further, it may be 0.05% by mass or more, or 0.1% by mass or more. Within this range, the adsorption of zinc on soft contact lenses can be sufficiently suppressed.
The concentration of the mucopolysaccharide and / or a salt thereof in the composition of the present invention is preferably 14% by mass or less, particularly preferably 10% by mass or less, and particularly 5% by mass or less, based on the total amount of the composition. Of these, 3% by mass or less is preferable, and 0.5% by mass or less is particularly preferable. 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 does not become too high and the usability does not deteriorate.
In the present invention, the content of the mucopolysaccharide and / or the salt thereof is the total amount of the plurality of mucopolysaccharides and / or the salt thereof when they are blended.

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 0.00004 parts by mass or more, particularly 0.0004 mass, with respect to 1 part by mass of the zinc compound. More than parts, especially 0.004 parts by mass or more. Within this range, the adsorption of zinc on soft contact lenses can be sufficiently suppressed.
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, and more preferably 20,000 parts by mass or less. Further, it may be 10000 parts by mass or less, 1000 parts by mass or less, or 100 parts by mass or less. Within this range, the viscosity of the ophthalmic composition does not become too high and the usability does not deteriorate.

Other Pharmacologically Active or Physiologically Active Ingredients The composition of the present invention may also contain one or more kinds of pharmacologically active or physiologically 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 the decongestant include phenylephrine or a salt thereof (eg, phenylephrine hydrochloride, epinephrine hydrogen tartrate), ephedrine or a salt thereof (eg, ephedrine hydrochloride), methylephedrine or a salt thereof (eg, methylephrine hydrochloride, in particular, dl-methylmethyl hydrochloride). Ephedrine), tetrahydrozoline or a salt thereof (eg, tetrahydrozoline hydrochloride), naphazoline or a salt thereof (eg, naphazoline hydrochloride, nafazoline nitrate), phenylephrine or a salt thereof (eg, phenylephrine hydrochloride), oxymetazoline or a salt thereof (eg, oxymetazoline). Metazoline) and the like.

The composition of the present invention can include an eye muscle regulator. Examples of the eye muscle regulator include neostigmine or a salt thereof (particularly neostigmine methylsulfate), physostigmine or a salt thereof (eg, physostigmine salicylate, physostigmine sulfate), dystigmine or a salt thereof (eg, dystigmine bromide), tropicamide, atropine or a salt thereof. (In particular, atropine helenien sulfate), pilocarpine or a salt thereof (for example, pilocarpine hydrochloride) and the like can be mentioned.

The composition of the present invention can contain an anti-inflammatory agent other than the zinc compound. Such anti-inflammatory agents include epsilon-aminocaproic acid, planoprofen, allantin, berberine or salts thereof (eg, berberine chloride, berberine sulfate), azulene sulfonic acid or salts thereof (eg, azulene sulfonic acid). Sodium, potassium azulene sulfonate, calcium azulene sulfonate, magnesium azulene sulfonate), glycyrrhizinic acid or a salt thereof (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), lysoteam or a salt thereof (eg, lysoteam chloride), indomethacin, Examples thereof include diclofenacic acid or a salt thereof (for example, diclofenac sodium), bromfenacic acid or a salt thereof (for example, bromfenac sodium) and the like.

The compositions of the present invention can include antihistamines. Examples of the antihistamine include diphenhydramine or a salt thereof (for example, diphenhydramine hydrochloride), chlorpheniramine or a salt thereof (for example, chlorpheniramine maleate, chlorpheniramine fumarate), ketotiphen or a salt thereof (for example, ketotiphen fumarate), oropatadin. Or a salt thereof (for example, olopatazine hydrochloride), iproheptin or a salt thereof (for example, iproheptin hydrochloride), levocabastine or a salt thereof (for example, levocabastine hydrochloride) and the like.

The compositions of the present invention can include vitamins. Vitamins include flavin adenin dinucleotide or a salt thereof (eg, flavin adenin dinucleotide sodium), cobalamine or a salt thereof (eg cyanocobalamin, methylcobalamin, hydroxocobalamine, adenosyl cobalamine), retinol or a salt thereof (eg acetic acid). Retinol, retinol palmitate), pyridoxine or a salt thereof (eg, pyridoxine hydrochloride), pantenol, pantothenic acid or a salt thereof (eg, sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol or a salt thereof (For example, tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or a salt thereof (for example, pyridoxal phosphate), ascorbic acid or a salt thereof (for example, sodium ascorbate, calcium ascorbate) and the like.

The composition of the present invention can contain amino acids other than chondroitin sulfate or a salt thereof. Examples of such amino acids include L-aspartic acid or a salt thereof (for example, potassium L-aspartate, sodium L-aspartate, magnesium L-aspartate, calcium L-aspartate, magnesium-potassium L-aspartate (for example). Equal mixture of magnesium L-aspartate and potassium L-aspartate)), aminoethylsulfonic acid (taurine), glutamic acid or salts thereof (eg, sodium glutamate, magnesium glutamate), creatinine, glycine, alanine, arginine, lysine , Γ-Aminobutyric acid, γ-aminovaleric acid and the like.

The composition of the present invention can contain an antibacterial component. Examples of the antibacterial component include sulfamethoxazole or a salt thereof (for example, sodium sulfamethoxazole, potassium sulfamethoxazole, calcium sulfamethoxazole, magnesium sulfamethoxazole), and sulfisomidine. , Sulfa-based antibacterial agents such as sulfisomidine or salts thereof (eg, sodium sulfisomidine, potassium sulfisomidine, calcium sulfisomidine, magnesium sulfisomidine), alkylpolyaminoethylglycine, chloramphenicol, Ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, acyclovir and the like can be mentioned.

The compositions of the present invention can include antiallergic agents. Examples of the antiallergic agent include cromoglycic acid or a salt thereof (for example, sodium cromoglycate, potassium cromoglycate, calcium cromoglycate, magnesium cromoglycate), amlexanox, amlexanox, ibudilast, tranilast, pemirolast potassium and the like.

The compositions of the present invention can contain antioxidants.
Fat-soluble antioxidants include butyl group-containing phenols such as dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA); nordihydroguayaletic acid (NDGA); ascorbic acid palmitate, ascorbic acid esterate, ascorbin. Ascorbic acid esters such as aminopropyl acid phosphate, tocopherol ascorbate, triphosphate ascorbate, palmitate ascorbate; tocopherols such as α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol; acetic acid Tocopherol derivatives such as tocopherol, tocopherol nicotinate, tocopherol succinate; propyl acid ester such as ethyl gallate, propyl asbestos, octyl asbestos, dodecyl as cholate; propyl gallate; 3-butyl-4-hydroxyquinoline- 2 on; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins and curcumin; CoQ10 and the like.
As water-soluble antioxidants, ascorbic acid and ascorbic acid derivatives (sodium ascorbic acid-2-sulfate, sodium ascorbate, magnesium ascorbate-2-phosphate, sodium ascorbate-2-phosphate, etc.) , Sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetonic acid or salts thereof (sodium edetate, disodium edetate, tetrasodium edetate) and the like.

The composition of the present invention can contain a local anesthetic or a soothing agent. Examples of local anesthetics or soothing agents include chlorobutanol, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, parabutylaminobenzoate diethylaminoethyl hydrochloride, piperokine hydrochloride, procaine hydrochloride, proparakine hydrochloride, and hydrochloric acid. Examples include hexotiocaine and lidocaine hydrochloride.

In addition to this, the composition of the present invention may contain any pharmacologically active or physiologically active ingredient as long as the effects of the present invention are not impaired.

Properties of Composition The ophthalmic composition of the present invention can take various pharmaceutical forms depending on the purpose. Examples of such a pharmaceutical form include a liquid agent, a gel agent, a semi-solid agent (ointment, etc.) and the like.

Further, the composition of the present invention may be an aqueous composition (composition in which the ratio of the aqueous or hydrophilic base in the base is 50% by mass or more), or an oil-based composition (oil-based in the base). Alternatively, the composition may have a hydrophobic base ratio of 50% by mass or more), but an aqueous composition is preferable from the viewpoint of exerting the effect according to the present invention more remarkably.

As a base substrate, for example, water, an aqueous base such as ethanol; include sesame, vegetable oils such as castor oil, animal oils such as squalane, liquid paraffin, etc. oleaginous base such as a mineral oil such as petrolatum ..
As the base, one kind or two or more kinds can be used.

Additives The compositions of the present invention can be blended with those used as additives for ophthalmic compositions as long as the effects of the present invention are not impaired. As such additives, for example, the active ingredient (pharmacological activity) described in the Encyclopedia of Pharmaceutical Additives 2016 (edited by the Japan Pharmaceutical Additives Association) or the 2012 edition of the OTC Drug Manufacturing and Marketing Approval Standards (General Incorporated Association Regulatory Science Society). Examples thereof include various additives described in (Ingredients, Physiologically Active Ingredients, etc.) and the like. Examples of the additive include a cooling agent, an inorganic salt, a thickening agent, a preservative, a surfactant, a buffer, a pH adjuster, an isotonic agent, a stabilizer, a saccharide, and a polyhydric alcohol.
As the additive, one kind or two or more kinds can be used.

Examples of the refreshing agent include menthol, anethole, eugenol, camphor, geraniol, cineole, borneol, limonene, terpenoids such as Ryunou and the like. These may be d-form, l-form, or dl-form. Also included are essential oils such as peppermint oil, cool mint oil, sparemint oil, peppermint oil, uikyo oil, kehi oil, bergamot oil, eucalyptus oil and rose oil.

Inorganic salts other than zinc salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride; sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), potassium hydrogen carbonate, potassium carbonate, ammonium carbonate. , Calcium carbonate, carbonates such as magnesium carbonate; phosphates such as sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate Salts; sulfates such as magnesium sulfate; sulfites such as sodium hydrogen sulfite, sodium sulfite; thiosulfates such as sodium thiosulfate; sodium tetraborate, sodium borate, potassium tetraborate, potassium metaborate, boro Borates such as ammonium acid, borosand, etc .; acetates such as potassium acetate, sodium acetate, etc. may be mentioned.

Examples of the thickening agent other than mucopolysaccharide and its salt include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromerose), carboxymethyl cellulose and its salt, carboxyethyl cellulose and its salt and the like. Vinyl polymers such as polymer compounds, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K17, K25, K30, K90, etc.), carboxyvinyl polymers and salts thereof, dextran, macrogol 6000, macrogol 4000 , Macrogol (polyethylene glycol) such as Macrogol 400, gellan gum, alginic acid and salts thereof, α-cyclodextrin, dextrin, glucose, sorbitol, liquid paraffin, glycerin and the like.
Here, the salt is not particularly limited, but a sodium salt is preferable.

Preservatives include alkylpolyaminoethylglycine, boric acid, alkyldiaminoethylglycine and / or salts thereof (eg, alkyldiaminoethylglycine hydrochloride), benzoic acid and / or salts thereof (eg, sodium benzoate, potassium benzoate). , Ethanol, quaternary ammonium salts (eg, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride), chlorhexidine and / or salts thereof (eg, chlorhexidine gluconate), chlorobutanol, sorbic acid and / or salts thereof (eg , Potassium sorbate), sodium dehydroacetate, paraoxybenzoic acid ester (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, polyhexa Examples thereof include bigamides such as methylenebiguanide, glokill (trade name, Rhodia), and polydronium chloride.

Of the surfactants, nonionic surfactants are preferred.
Non-ionic surfactants include POE monolaurate (20) sorbitan (polysorbate 20), POE monopalmitate (20) sorbitan (polysorbate 40), POE monostearate (20) sorbitan (polysorbate 60), and POE tristearate. (20) POE sorbitan fatty acid esters such as sorbitan (polysolvate 65) and monooleic acid POE (20) sorbitan (polysolvate 80); POP block copolymers; POE cured castor oil 5, POE cured castor oil 10, POE cured castor oil 20, POE cured castor oil 40, POE cured castor oil 50, POE cured castor oil 60, POE cured castor oil 80, POE cured castor oil 80, POE cured castor oil 80 POE hardened castor oil such as oil 100; 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, POE castor oil 50 and the like; polyethylene glycol monostearate (2EO), polyethylene glycol monostearate (4EO), Polyethylene glycol monostearate (9EO), polyethylene glycol monostearate (10EO), polyethylene glycol monostearate (23EO), polyethylene glycol monostearate (25EO), monostearate. Polyethylene Glycolate (32EO), Polyethylene Monostearate (40EO, Polyoxyl 40 Stearate), Polyethylene Monostearate (45EO), Polyethylene Monostearate (55EO) , Polyethylene glycol monostearate (75EO), Polyethylene glycol monostearate (140EO); POE alkyl ethers such as POE (9) lauryl ether; POE (20) POP (4) POE-POP alkyl ethers such as cetyl ether; POE alkylphenyl ethers such as POE (10) nonylphenyl ether and the like can be mentioned. In the above-exemplified compounds, POE indicates polyoxyethylene, POP indicates polyoxypropylene, and the numbers in parentheses indicate the number of added moles.

Other amphoteric interfaces such as glycine-type amphoteric surfactants (eg, alkyldiaminoethylglycine, alkylpolyaminoethylglycine) and betaine-type amphoteric surfactants (eg, lauryldimethylaminoacetate betaine, imidazolinium betaine). Activator; Cationic surfactants such as alkyl quaternary ammonium salts (eg, benzalkonium chloride, benzethonium chloride) can also be used.

Examples of the buffer other than the citrate buffer include borate buffer, phosphate buffer, carbon dioxide buffer, acetate buffer, epsilon-aminocaproic acid buffer, aspartic acid buffer and the like. Examples of the components of the boric acid buffer include boric acid and borate (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.). The borate may be a hydrate. The components of the phosphate buffer include phosphoric acid, phosphate (monosodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, (Calcium dihydrogen phosphate, etc.) and the like. The phosphate may be a hydrate. Examples of the components of the carbonic acid buffer include carbonic acid and carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, magnesium carbonate, etc.). Examples of the components of the acetate buffer include acetic acid and acetates (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). Examples of the components of the aspartic acid buffer include aspartic acid and salts of aspartic acid (sodium aspartate, magnesium aspartate, potassium aspartate, etc.).

Acidity regulators include hydrochloric acid, acetic acid, sulfuric acid, polyphosphate, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, potassium hydroxide, etc. Examples thereof include calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine and diisopropanolamine.

Examples of the tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, propylene glycol and the like. Some tonicity agents are compounded as inorganic salts.

Stabilizers include tromethamole, sodium formaldehyde sulfoxylate (longalit), monoethanolamine, aluminum monostearate, and glycerin monostearate, sodium bisulfite, sodium pyrosulfite and the like.

Examples of saccharides include monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like. Some sugars are compounded as a thickening agent.

Examples of the polyhydric alcohol include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol and the like. Some polyhydric alcohols are formulated as thickeners.

pH
The pH of the composition of the present invention is 5 or more, and may 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. The pH of the composition of the present invention is 8 or less, especially 7.8 or less, especially 7.5 or less, especially 7.3 or less, especially 7 or less, especially 6.9 or less, especially 6.8 or less. Among them, it is preferably 6.7 or less, particularly 6.6 or less, particularly 6.5 or less, and may be 6.3 or less, or 6 or less. Within this range, the effect of suppressing the adsorption of zinc on the contact lens is remarkably exhibited, and the precipitation of the zinc compound is suppressed.

Osmotic pressure ratio of the composition of the osmotic pressure present invention is preferably 0.4 or more, more preferably 0.6 or more, even more preferably 0.8 or more. Further, 5 or less is preferable, 3 or less is more preferable, and 2 or less is even more preferable. Within this range, irritation to the eyes can be suppressed and the above-mentioned 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% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point drop method) described in the 17th revised Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then in a desiccator (silica). Allow to cool, weigh accurately 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution).

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 rotary viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34'x R24) is preferably 0.1 mPa · s or more, and 1 mPa · s or more. Is more preferable. Further, 8000 mPa · s or less is preferable, 1000 mPa · s or less is more preferable, 100 mPa · s or less is further preferable, and 20 mPa · s or less is even more preferable. Within this range, the contact time with the eyeball or the soft contact lens becomes sufficiently long, the effect of the ophthalmic composition can be exhibited, and the above-mentioned effect of the present invention can be obtained.

The dosage form of the dosage forms soft contact lenses for ophthalmic compositions of the present invention, include eye drops can be instilled into the soft contact lens wear, collyrium available during soft contact lens wear, and soft contact lens wetting solution Be done. In addition, since it increases mucin production on the surface of the eye, it can be suitably used as an eye drop or an 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. Eye drops include artificial tears.
Further, the ophthalmic composition of the present invention is such as a soft contact lens preservative solution, a soft contact lens cleaning solution, a soft contact lens cleaning preservative solution, a soft contact lens disinfectant solution, a contact lens disinfection / cleaning / preservation solution (multipurpose solution). It can also be used as a soft contact lens care solution.
The ophthalmic compositions of the present invention are suitable for these dosage forms, but may also be used for other uses.

The ophthalmic composition for soft contact lenses of the present invention can be applied to all soft contact lenses currently on the market or in the future. The soft contact lens may be either a silicone hydrogel contact lens or a non-silicone hydrogel contact lens. Further, it may be either ionic or non-ionic, but since zinc ions are easily adsorbed on the ionic soft contact lens, the ionic soft contact lens is a suitable object of the present invention. Further, it 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 and non-ionic, high water content and low water content is the notification of the Director of Examination and Management Division, Pharmaceutical Safety Bureau, Ministry of Health, Labor and Welfare No. 645, March 31, 1999, "For soft contact lenses and soft contact lenses. It is stipulated in "Classification method of soft contact lenses" of "Handling of materials to be attached when applying for approval of manufacturing (import) of disinfectant". The water content of contact lenses is measured by a weight measuring method according to ISO18369-4: 2006.

Containers The compositions of the present invention are usually contained or filled in ophthalmic containers. The material of the container is not particularly limited, and examples thereof include a plastic container, a metal container, and a glass container. Specifically, for example, polyolefin, acrylic acid resin, terephthalic acid ester, 2,6-naphthalenedicarboxylic acid ester, polycarbonate, polymethylpentene, fluororesin, polyvinyl chloride, polyamide, ABS resin, AS resin, polyacetal, modification. Examples thereof include polyphenylene ether, polyarylate, polysulfone, polyimide, plastics such as cellulose acetate, metals such as aluminum, and glass. The container may be made of one kind of material or may be made of two or more kinds of materials. In the case of plastic, it may be a mixture or a copolymer.
Of these, plastic containers are preferable, and polyolefin containers and terephthalic acid ester containers are more preferable.
The container here refers to the container body.

Polyethylene includes polyethylene (including high-density polyethylene, low-density polyethylene, ultra-low-density polyethylene, linear low-density polyethylene, ultra-high-molecular-weight polyethylene, etc.), polypropylene (isotactic polypropylene, syndiotactic polypropylene, tactic polypropylene). Etc.), and polyethylene / propylene copolymers and the like.
Examples of the acrylate resin include acrylate esters such as methyl acrylate, methacrylic acid esters such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate.
Examples of the terephthalic acid ester include polyethylene terephthalate, polytrimethylene terephthalate, and polybutylene terephthalate.
Examples of the 2,6-naphthalenedicarboxylic acid ester include polyethylene naphthalate and polybutylene naphthalate.
Fluororesin includes fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, vinyl fluoride, perfluoroalkoxyfluororesin, ethylene tetrafluoride / propylene hexafluoride copolymer, tetrafluoride. Examples thereof include ethylene-perfluoroalkoxyethylene copolymer (PFA), ethylene / tetrafluoroethylene copolymer, and ethylene / chlorotrifluoroethylene copolymer.
Examples of the polyamide include nylon and the like.
Examples of polyacetals include those consisting of only oxymethylene units and those containing some oxyethylene units.
Examples of the modified polyphenylene ether include polystyrene-modified polyphenylene ether.
Examples of polyarylate include amorphous polyarylate.
Examples of the polyimide include an aromatic polyimide obtained by polymerizing pyromellitic acid dianhydride and 4,4'-diaminodiphenyl ether.
Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

A nozzle may be attached to the container containing the ophthalmic composition of the present invention. The material of the nozzle is not particularly limited, and may be made of glass or plastic, for example. It is preferably made of plastic. Examples of the plastic include polybutylene terephthalate, polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, a copolymer of monomers constituting these, and a mixture of two or more of these.

Further, the container of the ophthalmic composition may be a multi-unit type container or a single-use unit dose type container.

(2) Method for Inhibiting Zinc Ion Adsorption In the present invention, citric acid, a salt thereof, and / or a hydrate thereof coexist in an ophthalmic composition for soft contact lenses containing a zinc compound and having a pH of 5 to 8. Provided is a method for suppressing the adsorption of zinc ions on contact lenses.
The type and content of each component, other components that can be blended, the properties, physical properties, dosage form, etc. 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 coexistence of citric acid, a salt thereof, and / or a hydrate thereof is taken as the total amount.

(3) Method for imparting mutin production promoting ability on the ocular surface In the present invention, a zinc compound, citric acid, a salt thereof, and / or a hydrate thereof are present in an ophthalmic composition for soft contact lenses having a pH of 5 to 8. Provided is a method of imparting an ophthalmic composition for soft contact lenses to the ability to increase mutin production (expression) of cells on the surface of the eye.
The type and content of each component, other components that can be blended, the properties, physical properties, dosage form, etc. 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, citric acid, a salt thereof, and / or a hydrate thereof is taken as the total amount.

(4) Method for Inhibiting Precipitation of Zinc Compound The present invention sets the pH of an ophthalmic composition for soft contact lenses containing a zinc compound, citric acid, a salt thereof, and / or a hydrate thereof to 5 to 8. Provided is a method for suppressing the precipitation of zinc compounds in an ophthalmic composition.
The type and content of each component, other components that can be blended, the properties, physical properties, dosage form, etc. of the ophthalmic composition are as described for the ophthalmic composition for soft contact lenses of the present invention.

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 on soft contact lenses (SCL))
The 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.
In addition, SCL (Johnson & Johnson VISION CARE, INC., 2week Accuview) was equilibrated by immersing it in Otsuka saline for 24 hours.
Ethylene tetrafluoride-perfluoroalkoxyethylene copolymer (PFA) (Samplertec Co., Ltd., product number: 25430) was filled with 4 mL of each ophthalmic composition, and two equilibrated SCLs were immersed in the container at 34 ° C. and 120 rpm. The sample was soaked for 48 hours while being shaken with. Further, the PFA container was filled with 4 mL of each ophthalmic composition, and the one without SCL was also immersed for 48 hours while shaking at 34 ° C. and 120 rpm to prepare a control sample.

Then, zinc ions in the test sample and the control sample were quantified by ion chromatography under the following conditions.

Ion chromatography measurement conditions
(A) Zinc sulfate-containing composition (Examples 1 to 4, Reference Example 1, Comparative Examples 1 to 3)
Detector: Electrical 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 composition (Examples 9 to 12, Comparative Example 4)
Detector: Electrical 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

Since a zinc compound was used as a standard product for ion chromatography, the amount of zinc compound adsorbed on soft contact lenses was calculated according to the following formula.

Amount of zinc compound adsorbed on soft contact lenses (μg / sheet) = (Zinc compound content in control sample (μg) -Zinc compound content in test sample (μg)) / 2

Three samples were prepared and quantified for each ophthalmic composition, and the average value of the zinc compound adsorption amount was calculated. The results are shown in Tables 1 and 2.

When sodium citrate hydrate was added to the ophthalmic composition containing zinc sulfate hydrate, the amount of zinc sulfate adsorbed on SCL was significantly reduced in a dose-dependent manner. Further, when sodium chondroitin sulfate was added, the amount of zinc sulfate adsorbed on SCL was further reduced. In addition, the lower the pH, the greater the effect of reducing the amount of zinc sulfate adsorbed by blending sodium citrate hydrate.
Moreover, when the ophthalmic compositions of Examples 1 to 4 were instilled, no unpleasant irritation was felt.

In addition, when sodium citrate hydrate was added to the ophthalmic composition containing zinc chloride hydrate, the amount of zinc chloride adsorbed on SCL was significantly reduced. Since the zinc chloride concentration was very low, no difference in the zinc ion adsorption suppressing effect was clearly observed between Examples 9 to 12, and the zinc ion adsorption was suppressed to the same extent.
Moreover, when the ophthalmic compositions of Examples 9 to 12 were instilled, no unpleasant irritation was felt.

Test Example 2 (Evaluation of Inhibition of Precipitation of Zinc Compound)
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 in a glass ampoule in an amount of 10 mL each, allowed to stand at 60 ° C. for 1 week, and the precipitation was visually observed and evaluated according to the following criteria.
-: No precipitation +: Precipitate thinly covers a part of the bottom of the ampoule and soars when mixed.
++: Precipitates thickly cover the entire bottom of the ampoule.
The results are shown in Table 3.

ｐＨ７の眼科組成物は、静置１日後には、アンプルの底全体に亜鉛化合物が厚く析出した。ｐＨ６．５の眼科組成物は、静置７日後に、アンプルの底の一部に少量の亜鉛化合物が沈殿しており、アンプルを振って混ぜると、沈殿が煙のように立ち上った。ｐＨ６以下の眼科組成物は、７日間静置しても析出は全く認められなかった。
なお、上記処方及び上記保存条件では、ｐＨ６．５以下で亜鉛化合物の析出が抑制されたが、処方や保存条件によってはｐＨ８以下で亜鉛化合物の析出が抑制される。

In the ophthalmic composition having a pH of 7, a thick zinc compound was precipitated on the entire bottom of the ampoule after 1 day of standing. In the ophthalmic composition having a pH of 6.5, a small amount of zinc compound was precipitated on a part of the bottom of the ampoule after 7 days of standing, and when the ampoule was shaken and mixed, the precipitate rose like smoke. No precipitation was observed in the ophthalmic composition having a pH of 6 or less even after standing for 7 days.
In the above formulation and the above storage conditions, the precipitation of the zinc compound was suppressed at pH 6.5 or less, but the precipitation of the zinc compound was suppressed at the pH 8 or less depending on the formulation and the storage conditions.

Test Example 3 (Evaluation of Mucin Expression Promotion)
The 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) are used in a culture plate (under conditions normally used for culturing immortalized human corneal epithelial cells. The culture plate is completely composed of 150 μl of confluent cells. The cells were seeded at 1.2 × 10 ⁵ / cm ² and cultured at 37 ° C., 5% CO ₂ and 90% humidity for 2 days, and the medium was exchanged. After culturing for another day, it was confirmed that the cells were confluent. The ophthalmic composition having the composition shown in Table 4 below was diluted 50-fold with a culture medium, and 150 μl was added to the cells. In addition, Reference Example 2 was diluted 50-fold with a culture medium, and 150 μl was added to the cells as a control. In addition, reference example 3 was obtained by adding only 150 μl of the culture medium to the cells.
Total RNA was extracted from the cells after 24 hours. Total RNA was extracted using RNeasy Mini Kit (manufactured by QIAGEN). Reverse transcription PCR was performed using RiverTra Ace qPCR RT Master Mix with dDNA Remover (manufactured by TOYOBO) to prepare cDNA. Using a Taqman probe (manufactured by Applied Biosystems), the mRNA expression level of MUC16 was evaluated by a quantitative real-time PCR method using Applied Biosystems Quant Studio 3 (manufactured by Thermo Fisher Scientific). After quantitative real-time PCR, the CT values of each sample were calculated by automatic analysis of ^{QuantStudio TM Design & Analysis Software.}

The ΔCt value of the target factor in each sample was calculated from the equation (1), and the ΔΔCt value was calculated from the equation (2).

Equation (1): ΔCt value = (Ct value of target factor)-(T value of GAPDH)

Equation (2): ΔΔCt value = (ΔCt value of target factor)-(Average value of ΔCt value of target factor in Reference Example 2)

Furthermore, the relative mRNA expression level of each sample with respect to Reference Example 2 was calculated from the formula (3).

Equation (3): Relative mRNA expression level of each sample = 2- ^{ΔΔCt value}

The average value and SD value of the relative mRNA expression level of each group were calculated.

For culture, DMEM / F-12 (Dulvecco's Modified Eagle Medium /) supplemented with insulin (5 μg / mL), hEGF (10 μg / mL), sterile DMSO (0.5%), and FBS (5%). Nutrient Mixture F-12, manufactured by Gibco) medium was used.

The results are shown in FIG. The vertical axis of FIG. 1 is a relative value of the MUC16 expression level of each example when the MUC16 expression level of the control is 1.
The expression level of mutin was increased by adding zinc sulfate hydrate, and the expression level of mutin was further increased by adding sodium citrate hydrate in addition to zinc sulfate hydrate.

Examples of formulations of the ophthalmic composition of the present invention are shown in Tables 5 and 6. The unit of each component amount in Tables 5 and 6 is "mass%".

Although the ophthalmic composition of the present invention contains a zinc compound, adsorption of zinc ions to soft contact lenses and precipitation of zinc compounds are suppressed, and the amount of mutin produced by wearing soft contact lenses is also reduced. It is suppressed. The present invention paved the way for the use of ophthalmic compositions containing zinc compounds for soft contact lenses.

Claims (11)

An ophthalmic composition for soft contact lenses containing a zinc compound, citric acid, a salt thereof, and / or a hydrate thereof, and having a pH of 5 to 8. The ophthalmic composition for soft contact lenses according to claim 1, wherein the zinc compound is at least one selected from the group consisting of zinc sulfate, zinc lactate, zinc chloride, and hydrates thereof. The ophthalmic composition for soft contact lenses according to claim 1 or 2, wherein the concentration of the zinc compound is 0.000005 to 1% by mass with respect to the total amount of the composition. Any of claims 1 to 3, wherein the citric acid, a salt thereof, and / or a hydrate thereof is at least one selected from the group consisting of sodium citrate, sodium dihydrogen citrate, and disodium citrate. The ophthalmic composition for soft contact lenses described in Citrate. The soft contact lens according to any one of claims 1 to 4, wherein the concentration of citric acid, a salt thereof, and / or a hydrate thereof is 0.001 to 5% by mass based on the total amount of the composition. Ophthalmic composition for use. The ophthalmic composition for soft contact lenses according to any one of claims 1 to 5, which contains 0.001 to 800,000 parts by mass of citric acid, a salt thereof, and / or a hydrate thereof with respect to 1 part by mass of the zinc compound. thing. The ophthalmic composition for soft contact lenses according to any one of claims 1 to 6, further comprising a mucopolysaccharide and / or a salt thereof. The ophthalmic composition for soft contact lenses according to claim 7, 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. A method for suppressing the adsorption of zinc ions on soft contact lenses, in which citric acid, a salt thereof, and / or a hydrate thereof coexist in an ophthalmic composition for soft contact lenses containing a zinc compound and having a pH of 5 to 8. An ophthalmic composition for soft contact lenses in which a zinc compound and citric acid, a salt thereof, and / or a hydrate thereof are present in an ophthalmic composition for soft contact lenses having a pH of 5 to 8 is used to produce mutin in cells on the surface of the eye. A method of imparting the ability to increase. A method for suppressing precipitation of a zinc compound in an ophthalmic composition for soft contact lenses, which comprises a zinc compound, citric acid, a salt thereof, and / or a hydrate thereof, at a pH of 5 to 8.

Images