JP7195838B2 - Ophthalmic composition for contact lenses - Google Patents

Description

The present invention relates to an ophthalmic composition for contact lenses (CL).

With the aging of contact lens (hereinafter also referred to as CL) wearers, it is becoming increasingly important to keep the CL clean in order to prevent eye diseases.

Patent Document 1 discloses an ophthalmic silicone hydrogel contact lens containing at least one of neostigmine methyl sulfate and salts thereof, and at least one of glycyrrhizic acid, aminoethylsulfonic acid, aspartic acid, chondroitin sulfate, and salts thereof. It is disclosed that the adsorption of pollen proteins to silicone hydrogel soft contact lenses can be suppressed by using the composition.

JP 2011-136988 A

Further development of an ophthalmic composition capable of suppressing protein adsorption to CL is desired.

Accordingly, an object of the present invention is to provide an ophthalmic composition capable of suppressing protein adsorption to CL.

As a result of intensive studies by the present inventors to solve the above problems, it was found that the above problems could be solved by providing an ophthalmic composition for contact lenses containing a water-soluble antioxidant, and the present invention was completed. came to.

That is, the present invention provides contact lenses listed below.
[1] An ophthalmic composition for contact lenses containing a water-soluble antioxidant.
[2] The ophthalmic composition according to [1], wherein the water-soluble antioxidant is an inorganic compound.
[3] The water-soluble antioxidant is one or more selected from the group consisting of pyrosulfite, sulfite, hydrogen sulfite, thiosulfate, iodine, bromine and salts thereof, [1] or [ 2].
[4] The ophthalmic composition according to any one of [1] to [3], wherein the total content of the water-soluble antioxidant is 0.0001 to 1 w/v% relative to the total amount of the ophthalmic composition. thing.
[5] The ophthalmic composition according to any one of [1] to [4], further comprising a nonionic surfactant.
[6] Any one of [1] to [5], wherein the total content of dibutylhydroxytoluene, butylhydroxyanisole, or a mixture thereof is less than 0.025 w/v% relative to the total amount of the ophthalmic composition ophthalmic composition according to .
[7] The ophthalmic composition according to any one of [1] to [6], which is housed in a container whose part or all of the surface that comes into contact with the ophthalmic composition is made of plastic.

According to the present invention, protein adsorption to CL can be effectively suppressed by including a water-soluble antioxidant in the ophthalmic composition for CL.

FIG. 1 is a diagram showing the suppression rate of protein adsorption to CL in Examples according to the present invention and in Comparative Examples.

In this specification, the content unit "w/v%" is synonymous with "g/100 mL".

[Ophthalmic composition]
The ophthalmic composition of the present invention contains a water-soluble antioxidant.

As used herein, a water-soluble antioxidant refers to an antioxidant that can be dissolved in water. Here, the water-soluble antioxidants include antioxidants that are inherently insoluble in water but have been imparted with the property of being soluble in water by chemically changing the functional group. be

As the water-soluble antioxidant, known components are used as appropriate and are not limited, but from the viewpoint of exhibiting the effects of the present invention remarkably, it is preferably an inorganic compound such as pyrosulfurous acid, sulfurous acid, hydrogen sulfite, thiosulfuric acid, It is preferably one or more selected from the group consisting of iodine, bromine and salts thereof, and one or more selected from the group consisting of pyrosulfurous acid, sulfurous acid, hydrogen sulfite, thiosulfuric acid and salts thereof Two or more are more preferred, and one or two or more selected from the group consisting of pyrosulfite, sulfite, hydrogen sulfite and salts thereof is even more preferred.

Salts of these components are not particularly limited as long as they are pharmaceutically, pharmacologically or physiologically acceptable. Specific examples include inorganic acid salts, salts with inorganic bases, and organic acid salts. , or salts with organic bases. Examples of salts with inorganic bases include salts with alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, salts with metals such as aluminum, and various salts such as ammonium salts. Examples of organic acid salts include monocarboxylic acid salts such as acetate, trifluoroacetate, butyrate, palmitate, and stearate; Polyvalent carboxylates; oxycarboxylates such as lactate, tartrate and citrate; organic sulfonates such as methanesulfonate, toluenesulfonate and tosylate. Examples of inorganic acid salts include hydrochlorides, sulfates, nitrates, hydrobromides, and phosphates. Examples of salts with organic bases include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, and ethylenediamine. Pyrosulfite, sulfite, thiosulfate, iodine, bromine or salts thereof may be used singly or in any combination of two or more. "Pharmaceutically or physiologically acceptable salts" may include solvates or hydrates of salts.

Salts of pyrosulfite, sulfurous acid, hydrogen sulfite, thiosulfate, iodine, or bromine are not limited, but sodium salts or potassium salts are preferable from the viewpoint of exhibiting the effects of the present invention remarkably, and sodium pyrosulfite and pyrosulfite. One or more selected from the group consisting of potassium, sodium sulfite, potassium sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, sodium thiosulfate, potassium thiosulfate, sodium iodide, potassium iodide, and potassium bromide More preferably, one or more selected from the group consisting of sodium pyrosulfite, sodium sulfite, sodium hydrogensulfite, sodium thiosulfate, potassium iodide, and potassium bromide, sodium pyrosulfite, sodium sulfite, One or two or more selected from the group consisting of sodium bisulfite and sodium thiosulfite are more preferred, one or two or more selected from the group consisting of sodium pyrosulfite, sodium sulfite and sodium bisulfite is particularly preferred.

The total content of water-soluble antioxidants is appropriately set according to the type and content of other compounding ingredients, the formulation form of the ophthalmic composition, etc., but is preferably 0.0001 w based on the total amount of the ophthalmic composition. /v% or more, more preferably 0.0005w/v% or more, still more preferably 0.001w/v% or more, and particularly preferably 0.002w/v% or more. The total content of water-soluble antioxidants is preferably 1 w/v% or less, more preferably 0.5 w/v% or less, still more preferably 0.2 w/v% or less, relative to the total amount of the ophthalmic composition. , particularly preferably 0.1 w/v% or less. The total content of water-soluble antioxidants is preferably 0.0001 to 1 w/v%, more preferably 0.0005 to 0.5 w/v%, still more preferably, relative to the total amount of the ophthalmic composition. is 0.001 to 0.2 w/v%, particularly preferably 0.002 to 0.1 w/v%.

Although not limited, in a preferred embodiment, for example, when pyrosulfurous acid or a salt thereof is contained as a water-soluble antioxidant, the content of pyrosulfuric acid or a salt thereof alone is 0.0001 relative to the total amount of the ophthalmic composition. The content is preferably ~0.5 w/v%, more preferably 0.0005 to 0.2 w/v%, even more preferably 0.001 to 0.1 w/v%, and 0.002 It is particularly preferable to contain up to 0.05 w/v%.

Although not limited, in a preferred embodiment, for example, when sulfurous acid or a salt thereof is contained as a water-soluble antioxidant, the content of sulfurous acid or a salt thereof alone is 0.0001 to 0 with respect to the total amount of the ophthalmic composition. .5 w/v%, more preferably 0.0005 to 0.2 w/v%, even more preferably 0.001 to 0.1 w/v%, 0.002 to 0 A content of 0.05 w/v % is particularly preferred.

Although not limited, in a preferred embodiment, for example, when hydrogen sulfite or a salt thereof is contained as a water-soluble antioxidant, the content of hydrogen sulfite or a salt thereof alone is 0.0001 relative to the total amount of the ophthalmic composition. The content is preferably ~0.5 w/v%, more preferably 0.0005 to 0.2 w/v%, even more preferably 0.001 to 0.1 w/v%, and 0.002 It is particularly preferable to contain up to 0.05 w/v%.

Although not limited, in a preferred embodiment, for example, when thiosulfuric acid or a salt thereof is contained as a water-soluble antioxidant, the content of thiosulfuric acid or a salt thereof alone is 0.0001 relative to the total amount of the ophthalmic composition. It is preferable to contain ~1 w/v%, more preferably 0.0005 to 0.5 w/v%, even more preferably 0.001 to 0.2 w/v%, and 0.002 to 0 .1 w/v % is particularly preferred.

Although not limited, in a preferred embodiment, for example, when iodine or a salt thereof is contained as a water-soluble antioxidant, the content of iodine or a salt thereof alone is 0.0001 to 1 w with respect to the total amount of the ophthalmic composition. /v%, more preferably 0.0005 to 0.5w/v%, even more preferably 0.001 to 0.2w/v%, 0.002 to 0.1w /v% is particularly preferred.

Although not limited, in a preferred embodiment, for example, when bromine or its salt is contained as a water-soluble antioxidant, the content of bromine or its salt alone is 0.0001 to 1 w with respect to the total amount of the ophthalmic composition. /v%, more preferably 0.0005 to 0.5w/v%, even more preferably 0.001 to 0.2w/v%, 0.002 to 0.1w /v% is particularly preferred.

The ophthalmic composition of the present invention preferably further contains a nonionic surfactant. As the nonionic surfactant, any nonionic surfactant can be used as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. ) POE sorbitan fatty acid esters such as sorbitan (polysorbate 20), monooleic acid POE (20) sorbitan (polysorbate 80), POE sorbitan monostearate (polysorbate 60), POE sorbitan tristearate (polysorbate 65); POE hardened castor POE hydrogenated castor oils such as 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 100; POE castor oil 3 , POE castor oil 10, POE castor oil 20, POE castor oil 40, POE castor oil 50, POE castor oil 60, POE castor oil 70; POE castor oils such as poloxamer 407, poloxamer 235, poloxamer 188 - Polyoxypropylene block copolymers (hereinafter also referred to as polyoxyethylene polyoxypropylene copolymers); POE-POP block copolymer adducts of ethylenediamines such as poloxamine; POE alkyl ethers such as POE (9) lauryl ether; POE (20) POE/POP alkyl ethers such as POP (4) cetyl ether; POE (10) POE alkylphenyl ethers such as nonylphenyl ether; polyethylene glycol monostearate such as polyoxyl 10 stearate and polyoxyl 40 stearate; is mentioned. POE indicates polyoxyethylene, POP indicates polyoxypropylene, and the numbers in parentheses indicate the number of added moles.

Among these nonionic surfactants, one selected from the group consisting of POE sorbitan fatty acid esters, POE hydrogenated castor oils, POE castor oils and polyoxyethylene-polyoxypropylene block copolymers is preferred. or two or more, particularly preferably one or more selected from the group consisting of polysorbate 80, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, POE castor oil 10, POE castor oil 35, and poloxamer 407 Two or more.

In the ophthalmic composition of the present invention, the above nonionic surfactants may be used singly or in combination of two or more.

The total content of the nonionic surfactant is appropriately set depending on the type and content of other compounding ingredients, the formulation form of the ophthalmic composition, etc., but it is preferably 0.00 to the total amount of the ophthalmic composition. 001 to 5 w/v%, more preferably 0.001 to 1.5 w/v%, more preferably 0.001 to 1 w/v%, still more preferably 0.005 to 0.5 w/v%, especially It is preferably 0.05 to 0.3 w/v%.

The content ratio of the nonionic surfactant to the water-soluble antioxidant is not particularly limited, and is appropriately set according to the type of the water-soluble antioxidant, the type of the nonionic surfactant, and the like. As the content ratio of the nonionic surfactant to the water-soluble antioxidant, from the viewpoint of significantly exhibiting the effects of the present invention, the nonionic surfactant is added to the total content of 1 part by mass of the water-soluble antioxidant. The total content of the agent is preferably 0.0001 to 10000 parts by mass, more preferably 0.0005 to 1000 parts by mass, still more preferably 0.001 to 500 parts by mass, particularly preferably 0.005 to 100 parts by mass. Department.

The ophthalmic composition of the present invention may contain dibutylhydroxytoluene, butylhydroxyanisole, or a mixture thereof as long as the effects of the present invention are not hindered, but these components adsorb to CL (especially SCL). Therefore, from the viewpoint of eye safety, it is preferable to reduce these components, and more preferably not to contain these components.

When the ophthalmic composition of the present invention contains dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), or a mixture thereof, the total content of these is 0.025w based on the total weight of the ophthalmic composition. /v%, more preferably 0.01 w/v% or less, even more preferably 0.001 w/v% or less, particularly 0.0001 w/v% or less 0 w/v % (no content) is most preferred.

The ophthalmic composition of the present invention preferably further contains an antihistamine or anti-inflammatory ingredient. Any antihistamine or anti-inflammatory ingredient can be used as long as it is pharmaceutically, pharmacologically or physiologically acceptable.

Antihistamines include, but are not limited to, chlorpheniramine, diphenhydramine, iproheptine, ketotifen, clemastine, azelastine, oxatomide, mequitazine, terfenadine, emedastine, epinastine, evastine, cetirizine, clemastine, levocabastine, olopatadine, loratadine, fexofenadine, cetirizine. , and pharmacologically or physiologically acceptable salts thereof (chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptine hydrochloride, ketotifen fumarate, ketotifen fumarate, ketotifen fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, etc.) is mentioned. Among these antihistamines, chlorpheniramine or its salts and diphenhydramine or its salts are preferred, and chlorpheniramine maleate and diphenhydramine hydrochloride are particularly preferred, from the viewpoint of exhibiting the effects of the present invention remarkably.

Anti-inflammatory ingredients include, but are not limited to, epsilon aminocaproic acid, allantoin, tranexamic acid, berberine, azulenes (azulene, camaazulene, guaiazulene, etc.), glycyrrhizic acid, glycyrrhetinic acid, zincs, lysozyme, celecoxib, rofecoxib, indomethacin, diclofenac, pranoprofen, piroxicam, meloxicam, methyl salicylate, glycol salicylate, ibuprofen, ibuprofen piconol, bufexamac, butyl flufenamate, bendazac, piroxicam, ketoprofen, felbinac and pharmacologically or physiologically acceptable salts thereof (For example, berberine chloride, berberine sulfate, sodium azulene sulfonate, sodium guaiazulene sulfonate, diclofenac sodium, sodium glycyrrhizinate, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme chloride, etc.). Among these anti-inflammatory components, pranoprofen, glycyrrhizic acid or a salt thereof, allantoin, berberine, and azulenes are preferred from the viewpoint of exhibiting the effects of the present invention remarkably, and pranoprofen, dipotassium glycyrrhizinate, allantoin, and berberine chloride. , berberine sulfate and sodium azulene sulfonate are particularly preferred.

In the ophthalmic composition of the present invention, the above antihistamines or anti-inflammatory ingredients may be used singly or in combination of two or more.

The total content of the antihistamine or anti-inflammatory component is appropriately set according to the type and content of other compounding components, the formulation form of the ophthalmic composition, etc., but is preferably 0.0001 with respect to the total amount of the ophthalmic composition. ~10 w/v%, more preferably 0.001 to 8 w/v%, still more preferably 0.01 to 6 w/v%, particularly preferably 0.02 to 1 w/v%, most preferably 0.03 ~0.8 w/v%.

The content ratio of the antihistamine or anti-inflammatory component to the water-soluble antioxidant is not particularly limited, and is appropriately set according to the type of water-soluble antioxidant. As the content ratio of the antihistamine or anti-inflammatory component to the water-soluble antioxidant, from the viewpoint of significantly exhibiting the effects of the present invention, the content of the antihistamine or anti-inflammatory component is 1 part by mass of the total content of the water-soluble antioxidant. The total content is preferably 0.0005 to 100000 parts by mass, more preferably 0.001 to 50000 parts by mass, still more preferably 0.05 to 20000 parts by mass, particularly preferably 0.1 to 10000 parts by mass, Most preferably, it is 0.2 to 8000 parts by mass.

The ophthalmic composition of the present invention preferably further contains fat-soluble vitamins. Examples of fat-soluble vitamins include vitamin A, vitamin E, derivatives thereof, and salts thereof.

In the present invention, vitamin A is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable. Examples of vitamin A include vitamin A, mixtures containing vitamin A (eg, vitamin A oil), and derivatives having vitamin A activity. The vitamin A oil is a fatty oil obtained from a retinol-containing aquatic animal tissue or the like, or a concentrate thereof, or a mixture thereof to which a vegetable oil is appropriately added.

Examples of vitamin A include retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, derivatives thereof (eg, retinol acetate, retinol palmitate, etc.), and salts thereof. Among these, retinol acetate and retinol palmitate are preferable from the viewpoint of exhibiting the effects of the present invention more remarkably. Vitamin A may be either a natural product or a synthetic product. Also, the vitamin A may be one containing BHT or BHA as an antioxidant. However, since BHT and BHA are adsorbed to CL (particularly SCL), from the viewpoint of eye safety, those containing no BHT or BHA can be more preferably used.

As vitamin A, more specifically, for example, retinol palmitate (1,740,000 IU) manufactured by DSM Nutrition Japan, retinol palmitate (1,700,000 IU) manufactured by BASF Japan, etc. can be mentioned. In addition, IU means an international unit calculated|required by the method of description in the 17th revision Japanese Pharmacopoeia vitamin A determination method.

These vitamins A may be used singly or in any combination of two or more.

In the present invention, vitamin E is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable. Specific examples of vitamin E include tocopherol, tocotrienol, derivatives thereof, and salts thereof. Tocopherols and tocotrienols may be α-, β-, γ-, or δ-, and may be d- or dl-forms. Examples of these derivatives include esters such as acetates, nicotinates, succinates and linolenates. Vitamin E may be either a natural product or a synthetic product. These salts include, for example, organic acid salts (lactate, acetate, butyrate, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate, malonate, methane sulfonate, toluenesulfonate, tosylate, palmitate, stearate, etc.), inorganic salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), organic base (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, amino acids, tripyridine, picoline, etc.), salts with inorganic bases (e.g., ammonium salts, sodium, potassium alkali metals such as calcium, alkaline earth metals such as magnesium, salts with metals such as aluminum, etc.).

As vitamin E, more specifically, for example, d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E acetate (e.g., tocopherol acetate), vitamin E nicotinic acid ester, vitamin E succinic acid ester, vitamin E linolenic acid ester and the like. Among these, tocopherol acetate (eg, d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.) is preferable from the viewpoint of exhibiting the effects of the present invention more remarkably.

These vitamin E may be used singly or in any combination of two or more.

The content of fat-soluble vitamins is appropriately set according to the type and content of other compounding ingredients, the formulation form of the ophthalmic composition, etc., but is preferably 10 to 500,000 with respect to the total amount of the ophthalmic composition. Unit (IU)/100 mL, more preferably 100 to 300,000 units/100 mL, still more preferably 500 to 200,000 units/100 mL, still more preferably 1000 to 100,000 units/100 mL, particularly preferably 2 ,000-80,000 units/100 mL, most preferably 3,000-50,000 units/100 mL. The content of fat-soluble vitamins is preferably 0.0005 to 0.5 w/v%, more preferably 0.001 to 0.1 w/v%, although it depends on the unit of fat-soluble vitamins to be blended. 0.005 to 0.05 w/v% is more preferred.

The content ratio of the fat-soluble vitamins to the water-soluble antioxidant is not particularly limited, and is appropriately set according to the type of the water-soluble antioxidant. As the content ratio of fat-soluble vitamins to water-soluble antioxidants, the content of fat-soluble vitamins with respect to 1 part by mass of the total content of water-soluble antioxidants from the viewpoint of significantly exhibiting the effects of the present invention. Is preferably 0.0001 to 10000 parts by mass, more preferably 0.0005 to 1000 parts by mass, still more preferably 0.001 to 500 parts by mass, particularly preferably 0.005 to 100 parts by mass, most preferably It is 0.01 to 50 parts by mass.

The ophthalmic composition of the present invention may contain, in addition to the above components, a combination of various pharmacologically active ingredients and physiologically active ingredients in appropriate amounts as long as the effects of the present invention are not impaired. Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various pharmaceuticals described in the 2015 version of the Standards for Approval for Manufacturing and Marketing of OTC Drugs (supervised by the Japanese Society of Regulatory Science). Specifically, the following components are mentioned.

Decongestants: for example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine bitartrate, naphazoline nitrate, etc. . These may be d-, l- or dl-isomers.
Bactericides: For example, acrinol, cetylpyridinium, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylenebiguanide hydrochloride, and the like.
Vitamins other than fat-soluble vitamins: For example, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, ubiquinone derivatives and the like.
Amino acids: for example, L-aspartic acid or salts thereof (for example, potassium L-aspartate, sodium L-aspartate, magnesium L-aspartate, calcium L-aspartate, magnesium potassium L-aspartate (L-asparagine an equal mixture of magnesium acid and potassium L-aspartate)), aminoethylsulfonic acid (taurine), chondroitin sulfate or its salts (e.g. sodium chondroitin sulfate), glutamic acid or its salts (e.g. sodium glutamate, magnesium glutamate) , creatinine, glycine, alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, hyaluronic acid or salts thereof (eg, sodium hyaluronate), alginic acid or salts thereof (eg, sodium alginate), and the like.
Astringents: For example, zinc white, zinc lactate, zinc sulfate and the like.
Local anesthetic ingredients: e.g. chlorobutanol, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate hydrochloride, pipelocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, hydrochloric acid lidocaine and the like.
Others: For example, neostigmine methyl sulfate, sodium cromoglycate, sulfamethoxazole, sulfamethoxazole sodium, purple root, horse chestnut, and salts thereof.

Furthermore, in the ophthalmic composition of the present invention, various additives other than those mentioned above may be selected, and at least one of them may be used in combination in an appropriate amount as long as the effects of the present invention are not hindered. Examples of such additives include various additives described in Pharmaceutical Excipients Encyclopedia 2013 (edited by Japan Pharmaceutical Excipients Association). Typical ingredients include the following additives.
Carrier: Aqueous carriers such as water and hydrous ethanol.
Perfume or cooling agent: for example, terpenes (specifically, anethole, eugenol, camphor, geraniol, cineole, borneol, menthol, limonene, ryuno, etc. These may be d-, l- or dl-isomers. ), essential oils (fennel oil, cool mint oil, cinnamon oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc.).
Sugars: For example, glucose, cyclodextrin, and the like.
Surfactants other than nonionic surfactants: glycine type such as alkyldiaminoethylglycine, betaine acetate type such as lauryldimethylaminoacetate betaine, amphoteric surfactant such as imidazoline type; alkyl ether carboxylate, tetradecene sulfone sulfonates such as sodium lauryl sulfate, alkyl sulfates such as sodium lauryl sulfate, N-acyl taurate salts such as sodium N-cocoyl methyl taurate, POE alkyl ether phosphates such as POE (10) sodium lauryl ether phosphate and salts thereof , N-acyl amino acid salts such as sodium lauroylmethylalanine, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, anionic surfactants such as α-olefin sulfonates, and the like.
Tonicity agent: sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, magnesium sulfate, sodium hydrogen phosphate and the like.
pH adjusters: hydrochloric acid, sulfuric acid, lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon aminocaproic acid, glutamic acid, aminoethylsulfonic acid , phosphoric acid, polyphosphoric acid, boric acid, gluconolactone, ammonium acetate, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, monoethanolamine, triethanolamine, diisopropanol amines, triisopropanolamine, lysine, borax, etc., and pharmacologically acceptable salts thereof;
Stabilizers: For example, sodium formaldehyde sulfoxylate (Rongalit), aluminum monostearate, glyceryl monostearate and the like.
Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA) and the like.
Buffers: citrate buffer, acetate buffer, carbonate buffer, borate buffer, phosphate buffer and the like. Specifically, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, boric acid, borax, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid potassium dihydrogen, etc.
Water-soluble polymeric substances: for example, gelatin, polyacrylic acid and its salts, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxyethylcellulose, methylcellulose, ethylcellulose, methyl Vinyl ether/maleic anhydride copolymer, alginic acids (alginic acid, sodium alginate, potassium alginate, etc.), polyethylene oxide, gum arabic, xanthan gum, tragacanth gum, and the like.
Polyhydric alcohols: eg glycerin, sorbitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol, ethylene glycol and the like.
Preservatives or antibacterial agents: for example, sodium benzoate, ethanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, Phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyquaternium, polyhexanide hydrochloride, etc.), Glokyl (trade name, manufactured by Rhodia), and the like.
Inorganic salts: for example, sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium acetate and the like.

[Physical properties of the ophthalmic composition]
The pH 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. .5, preferably 4.5 to 9.0, more preferably 5.0 to 8.5, still more preferably 5.5 to 8.0, particularly preferably 6.0 to 8.0. mentioned.

The ophthalmic composition of the present invention can be further adjusted to have an osmotic pressure ratio within a range acceptable to living organisms, if necessary. Appropriate osmotic pressure ratio varies depending on application site, dosage form, etc., but is usually in the range of 0.5 to 5.0, more preferably 0.6 to 3.0, and still more preferably 0.7 to 2.0. be done. Adjustment of the osmotic pressure can be performed by a method known in the art using inorganic salts, polyhydric alcohols and/or sugars. 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 revision of the Japanese Pharmacopoeia. Freezing point depression method). The standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) was obtained by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then placing it in a desiccator (silica gel). Allow to cool, accurately weigh 0.900 g, dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v % sodium chloride aqueous solution).

The viscosity of the ophthalmic composition of the present invention is appropriately set according to the type and content of ingredients, formulation form, method of use, etc., as long as it is within a pharmaceutically, pharmacologically, or physiologically acceptable range. be. The viscosity at 20 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34' × R24) is preferably 1 to 1000 mPa s, and 1 to 100 mPa s. more preferably 1 to 20 mPa·s.

[Method for producing ophthalmic composition]
The ophthalmic composition of the present invention can be prepared by conventional methods. For example, a water-soluble antioxidant and, if necessary, other ingredients may be dispersed in an aqueous carrier, homogenized, dissolved or emulsified using a homogenizer or the like, and the pH may be adjusted with a pH adjuster. .

[Dosage form of ophthalmic composition]
The dosage form of the ophthalmic composition of the present invention is not particularly limited as long as it can be used in the field of ophthalmology, and examples thereof include liquid and ointment. Among these, the liquid form is preferred. Among the liquids, an aqueous liquid is preferred. When the ophthalmic composition of the present invention is made into an aqueous liquid, pharmaceutically, pharmacologically or physiologically acceptable water may be used as an aqueous carrier. , ordinary water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like. These definitions are based on the 17th revision of the Japanese Pharmacopoeia. As used herein, the term "aqueous liquid" means a liquid form containing water, and usually the water content in the ophthalmic composition is 1% or more, preferably 5% or more, more preferably 20% or more, and still more preferably. means a content of 50% or more, more preferably 70% or more, and even more preferably 80% or more.

Examples of the ophthalmic composition of the present invention include eye drops, eye washes, contact lens wetting solutions, contact lens wetting solutions, contact lens care agents (contact lens disinfectants, contact lens disinfectants, contact lens preservatives). agent, contact lens cleaning agent, contact lens rinsing solution, contact lens cleaning and preserving agent, etc.), contact lens multi-purpose solution (multi-purpose solution), and the like. As used herein, a multi-purpose solution for contact lenses (multi-purpose solution) refers to a composition having at least two or more functions selected from the functions of cleaning, rinsing, preserving, and disinfecting contact lenses. Say.

Among these dosage forms, the ophthalmic composition of the present invention can suppress protein adsorption by using it for CL, and therefore, it can be used as eye drops, contact lens wetting solutions, contact lens care agents, and contact lenses. It is preferably used as a multi-purpose solution.

[Use]
The ophthalmic composition of the present invention is used for contact lenses (CL).

As used herein, CL means all types of contact lenses, including soft contact lenses (SCL) and hard contact lenses (HCL), oxygen permeable hard contact lenses.

As used herein, SCL includes both ionic and non-ionic, silicone hydrogel contact lenses and non-silicone hydrogel contact lenses, and color contact lenses of all materials. . In addition, all soft contact lenses that are currently on the market or will be on the market in the future are applicable.

Materials for SCL include, but are not limited to, hydroxyethyl methacrylate (HEMA), 2,3-dihydroxypropyl methacrylate (GMA), N-vinylpyrrolidone (NVP), methacrylic acid or its salt (MA), silicone elastomer poly Examples include dimethylsiloxane (PDMSi), n-butyl methacrylate (BMA), n-butyl acrylate (BA), copolymers thereof, and the like. Examples of material names based on USAN (United State Adopted Name) include Etafilcon A and the like. CL, which is a silicone hydrogel material, is obtained by copolymerizing a material containing silicone (such as TRIS or a TRIS derivative, which is a polymer of silicone and acrylate, etc.) with a hydrophilic monomer (such as hydroxyethyl methacrylate, dimethylacrylamide, etc.). It is a contact lens using materials.

Materials for hard contact lenses include methyl methacrylate (MMA), cellulose acetate butyrate (CAB), siloxanylstyrene, fluoromethacrylate, siloxanyl methacrylate, fluorine-containing methacrylate (FMA), silicone-containing methacrylate (SiMA), and methacrylic. acid, dimethacrylate, dextran ester, fluorosilicone, copolymers thereof, and the like.

Since the ophthalmic composition of the present invention suitably exerts the effect of suppressing protein adsorption, it is more preferably used as an ophthalmic composition for SCL, and is used as an ophthalmic composition for SCL of Group IV in the FDA contact lens classification. is more preferred.

In this specification, SCL refers to the Notification of the Director of the Examination and Management Division, Pharmaceutical Safety Bureau, Ministry of Health, Labor and Welfare (the Ministry of Health and Welfare at that time) dated March 31, 1999, Pharmaceutical Examination No. 645, "Manufacture (import) of soft contact lenses and disinfectants for soft contact lenses." It is classified based on the ``classification method of soft contact lenses'' stipulated in ``Handling of documents to be attached when applying for approval, etc.''. For example, SCLs belonging to Group IV in this classification have common properties that the moisture content is 50% or more and the mol % of monomers having anions among the constituent monomers of the raw material polymer is 1% or more. This classification follows the classification method of soft contact lenses conducted by the FDA (US Food and Drug Administration).

INDUSTRIAL APPLICABILITY The ophthalmic composition of the present invention is suitable for ameliorating eye disorders caused by proteins adsorbed on CL, since the effect of suppressing protein adsorption on contact lenses (CL) is suitably exhibited. The type of protein is not particularly limited as long as it is a substance that can be adsorbed by CL. Proteins denatured by the influence of body temperature etc. are also included. When the CL is not worn, the protein is removed from the ocular surface (tear exchange) through the lacrimal duct, but the protein remains adsorbed to the CL (particularly the CL surface) when the CL is worn. As a result, tear exchange does not remove the protein, resulting in constant exposure of the ocular surface to the protein. For example, when the ocular surface is constantly exposed to inflammatory mediators and pollen proteins during CL wearing, eye itching, inflammation, hyperemia, conjunctivitis (allergic, etc.) and the like may occur. For example, when the ocular surface is constantly exposed to proteins denatured by the effects of ultraviolet light, body temperature, etc., during CL wearing, the accumulation of such proteins causes the propagation of microorganisms (bacteria, fungi, amoebas, etc.), which can lead to eye damage. microbial infection (epidemic keratoconjunctivitis, giant papillary conjunctivitis, corneal ulcer, etc.), etc., and corneal damage due to denatured proteins.

Therefore, the ophthalmic composition of the present invention can be used for preventing, treating, and/or improving eye disorders caused by CL-adsorbed proteins and/or CL wearing. Such eye disorders are not particularly limited as long as they are caused by CL-adsorbed proteins and/or CL wearing. (epidemic keratoconjunctivitis, giant papillary conjunctivitis, corneal ulcer, etc.) and at least one selected from the group consisting of corneal injury.

As used herein, the prevention of eye disorders refers to preventing or delaying the occurrence of eye disorders, or reducing the risk of developing eye disorders.

As used herein, the treatment of eye disorders refers to alleviation or amelioration of eye diseases or symptoms, prevention or delay of worsening of diseases or symptoms, or prevention, delay, or reversal of progression of eye diseases or symptoms. Say.

As used herein, the improvement of eye disorders refers to alleviation or improvement of eye disorders, prevention or delay of deterioration of abnormal conditions, or prevention or delay of progression of eye disorders. , or reverse.

[container]
The ophthalmic composition of the present invention is preferably housed in a container in which part or all of the surface that comes into contact with the ophthalmic composition is molded from plastic. At least 20% or more of the surface that comes into contact with the ophthalmic composition is preferably a container molded of plastic, more preferably 50% or more, even more preferably 70% or more, and 90% or more. is particularly preferred, and 95% or more is most preferred.

The constituent material of the plastic is not particularly limited. Polymers, or mixtures of two or more of these may be mentioned. From the viewpoint of moldability and resistance, polyethylene terephthalate, polypropylene, polyethylene, copolymers thereof, or mixtures of two or more of these are preferred, and in the case of multi-dose containers, containers containing polyethylene terephthalate are more preferred. In the case of unit dose containers, containers containing polyethylene are more preferred.

The container in which the ophthalmic composition of the present invention is stored may be a transparent container (container with sufficient transparency to observe foreign matter) or a light-shielded container. . Light shielding may be achieved, for example, by adding a coloring agent or an ultraviolet absorber to the constituent material of the container, or by covering the outer surface of the container with a shrink film, an outer box, a sachet-like exterior, or the like.

A dropping nozzle (perforated inner plug) can also be installed in the container in which the ophthalmic composition of the present invention is stored. As for the constituent material of the dropping nozzle, for example, plastic is preferable. Although not particularly limited, for example, a dropping nozzle containing polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, or elastomer as a constituent material is preferable. Types of polyethylene include high-density polyethylene, low-density polyethylene, and the like. The dripping nozzle installed in the container containing the ophthalmic composition of the present invention should be installed so as not to come into contact with the contained ophthalmic composition when the container is erected with the dripping opening facing upward. is preferred.

[Dosage and usage when used as an eye drop and/or dressing solution]
When the ophthalmic composition of the present invention is used as an eye drop, it can be designed so that the amount per drop is 5 to 100 μL. From the viewpoint of exhibiting the effects of the present invention remarkably, the drop amount per drop of the eye drop is preferably 10 to 80 μl, more preferably 20 to 60 μl, and even more preferably 30 to 50 μl.

When the ophthalmic composition of the present invention is used as an eye drop, the form of use includes a form of direct instillation into the eye when the CL is worn, and a form of instillation into the eye before wearing the CL. Such an eye drop can also be used in a form that also serves as a dressing solution for CL. An eye drop used in a form that also serves as a dressing solution is sometimes referred to as a CL dressing eye drop.

When the ophthalmic composition of the present invention is used as an eye drop and/or a dressing solution, the number of instillations per day is not limited, but the number is usually in the range of 1 to 10 times, preferably 1 to 6 times, particularly preferably 1 to 6 times. 5-6 times.

[Container capacity, etc. when used as an eye drop and/or a dressing solution]
When the ophthalmic composition of the present invention is used as a multi-dose eye drop and/or dressing solution, it is preferably packed in a container with an internal volume of 4 to 30 mL, more preferably in a container with an internal volume of 5 to 25 mL. More preferably, it is filled in a container of 6 to 18 mL.

When the ophthalmic composition of the present invention is used as a unit dose type eye drop and/or eye dressing solution, it is preferably packed in a container having an internal volume of 0.3 to 10 mL, preferably 0.3 to 5 mL. More preferably, it is filled in a container of 0.3 to 2 mL.

When the ophthalmic composition of the present invention is used as an eye drop and/or a dressing solution, the inner diameter of the drip port of the drip nozzle of the container is not limited, but can be, for example, less than 5 mm, and is 0.01 to 5 mm. 0.05 to 4 mm, more preferably 0.1 to 3 mm, and most preferably 0.5 to 2 mm. As used herein, the dripping port refers to an outlet where droplets are formed when the ophthalmic composition is filled in the container, the dripping nozzle is attached, and then the container is opened and turned upside down.

When the ophthalmic composition of the present invention is filled in an eye drop container provided with a dropping nozzle, the maximum outer width of the container in the direction orthogonal to the extending direction of the dropping nozzle is not limited, but from the viewpoint of ease of eye drop. Therefore, for example, it can be 55 mm or less, preferably 50 mm or less, more preferably 45 mm or less, still more preferably 40 mm or less, particularly preferably 38 mm or less, and 36 mm or less. is most preferred. In addition, the maximum outer width of the container in the direction perpendicular to the extending direction of the dropping nozzle is not limited, but from the viewpoint of ease of instillation, it can be, for example, 10 mm or more, preferably 11 mm or more. , 12 mm or more, more preferably 13 mm or more, particularly preferably 14 mm or more, and most preferably 15 mm or more. In addition, the maximum outer width of the container in the direction orthogonal to the extending direction of the dropping nozzle is not limited, but from the viewpoint of ease of instillation, it can be, for example, 10 mm to 55 mm, preferably 11 mm to 50 mm. is preferred, 12 mm to 45 mm is more preferred, 13 mm to 40 mm is even more preferred, 14 mm to 38 mm is particularly preferred, and 15 mm to 36 mm is most preferred.

[Method for Suppressing Protein Adsorption to CL]
In another embodiment, the present invention can also provide a method for inhibiting protein adsorption to CL, comprising applying an ophthalmic composition containing a water-soluble antioxidant to CL.

[Method for producing an ophthalmic composition imparted with an inhibitory effect on protein adsorption to CL]
In another embodiment, the present invention can also provide a method for producing an ophthalmic composition imparted with an inhibitory effect on protein adsorption to CL, comprising blending a water-soluble antioxidant into the ophthalmic composition. is.

As used herein, suppression of protein adsorption to CL refers to reducing the amount of protein adsorbed to CL (especially to the CL surface). The type of protein is not particularly limited as long as it is a substance that can be adsorbed to CL. Types of proteins include, for example, proteins contained in tears such as albumin, globulin, lysozyme, mucin, and inflammatory mediators, pollen proteins, and proteins denatured by the effects of ultraviolet light, body temperature, and the like. Preferably, the amount of protein adsorption to CL is reduced by at least 10%, more preferably by 20%, even more preferably by 40%, compared to a control containing no water-soluble antioxidant. % reduction is even more preferred. The amount of protein adsorbed on CL can be determined by the method described in Examples below.

In the above method, the type and content (or blending amount) of the water-soluble antioxidant used, the type and content (or blending amount) of other ingredients, their ratio, the formulation form of the ophthalmic composition, The types of containers, their combinations, etc. are the same as those described in the above items such as [Ophthalmic composition].

EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.

An ophthalmic composition for CL having the composition shown in Table 1 was prepared according to a conventional method and used as a test solution.

[Test Example 1: Protein adsorption inhibition test]
A protein adsorption suppression test was performed according to the following procedure.
1. Soft contact lenses (Group IV; trade name “2Week Acuvue (registered trademark)” manufactured by Johnson & Johnson) were immersed one by one in 4 mL of physiological saline and stored at room temperature for 4 hours.

2. The lens was removed from the saline solution, quickly dipped (about 1 second) into 100 mL of saline solution to rinse excess liquid, and then lightly drained using the rim of a beaker. After that, the lenses were immersed in 4 mL of each test solution placed in a 12-well plate (Falcon 12 Well Clear Multiwell Plate #353043) and allowed to stand for 16 hours.

3. After removing the lens from the test solution and wiping off the liquid adhering to the surface of the lens, the lens is immersed in 2.0 mL of the protein solution having the composition shown in Table 2 in a glass screw-capped bottle, at 34° C. and 120 rpm for 4 hours. shaken. The protein solution in Table 2 has a composition similar to that of human tears (Reference: Bohnert et.al (1988). Adsorption of Proteins From Artificial Tear Solutions to Contact Lens Materials. Investigative Ophthalmology & Visual Science, Vol. 29, 362-373).

4. The lenses were removed from the protein solution, dipped quickly (approximately 1 second) into 100 mL of saline to rinse excess liquid, and then lightly drained using the rim of a beaker. After that, it was immersed in 2.0 mL of a protein separation solution (aqueous solution containing 1% sodium carbonate and 1% sodium dodecylsulfate) in a glass screw-capped bottle.

5. The lens was shaken at 34° C. and 120 rpm for 3 hours or more to separate the protein adsorbed to the lens into the protein separation liquid.

6. Using a micro BCA assay kit (Thermo Scientific, Pierce #23235), the amount of protein present in the protein separation solution was quantified in terms of albumin, and the amount of protein remaining in the lens (remaining protein amount). was calculated. In addition, when calculating the residual amount of protein, the absorbance of the background (the test solution and the extract from the lens not immersed in the protein solution) is subtracted from the absorbance of each sample, and the albumin conversion value is calculated. The amount of protein adsorbed on was determined.

7. The adsorption inhibition rate relative to the control was calculated by the following formula 1.
[Formula 1]
Adsorption inhibition rate to control (%) = {1-(protein adsorption amount of each test solution/protein adsorption amount of control)} x 100
In addition, when the adsorption inhibition rate with respect to the control was less than 0, it was set to 0.
The results are shown in Table 1 and FIG.

As shown in Table 1 and FIG. 1, when treated with the ophthalmic compositions for CL of Comparative Examples 1 and 2, the adsorption inhibition rate against the control was 0%, and no effect was observed. On the other hand, when treated with the ophthalmic compositions for CL of Examples 1 to 4, the rate of suppression of adsorption to the control was as high as 20% or more, and when treated with the ophthalmic compositions for CL of Examples 5 to 7, , the adsorption inhibition rate was 80% or more compared to the control.

These results indicate that the inclusion of a water-soluble antioxidant in the ophthalmic composition for CL exerts an inhibitory effect on protein adsorption, and the effect is further enhanced by the addition of a nonionic surfactant. .

[Manufacturing example]
According to the formulations shown in Tables 3 to 5 below, eye drops of Formulation Examples 1 to 29 were prepared by a conventional method.

Claims (6)

An ophthalmic composition for contact lenses containing a water-soluble antioxidant ,
the water-soluble antioxidant is pyrosulfite or a salt thereof;
The ophthalmic composition is at least one selected from the group consisting of eye drops, eye washes, contact lens wetting solutions, and contact lens wetting solutions.
An ophthalmic composition for contact lenses . The ophthalmic composition according to claim 1 , wherein the total content of said water-soluble antioxidants is 0.0001-1 w/v% relative to the total weight of the ophthalmic composition. 3. The ophthalmic composition according to claim 1 or 2 , further comprising a nonionic surfactant. The ophthalmic composition according to any one of claims 1 to 3, further comprising an antihistamine and/or vitamins A. 5. The composition according to any one of claims 1 to 4 , wherein the total content of dibutylhydroxytoluene, butylhydroxyanisole, or mixtures thereof is less than 0.025 w/v% relative to the total weight of the ophthalmic composition. Ophthalmic composition. 6. The ophthalmic composition according to any one of claims 1 to 5 , which is housed in a container partly or wholly of the surface that comes into contact with the ophthalmic composition is made of plastic.

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