TW201722412A - Ophthalmic composition - Google Patents

Abstract

The present invention pertains to an ophthalmic composition containing (A) at least one compound selected from the group consisting of arginine, 2-amino-2-methyl-1, 3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and salts thereof, and (B) a polysaccharide.

Description

Ophthalmic composition

The present invention is directed to an ophthalmic composition.

The cornea is placed in a hypoxic state due to closed eyes during sleep, wearing of contact lenses, and the like. For corneas in such a hypoxic state, for example, it is known that when a contact lens is removed, radicals are generated by rapid changes in the oxygen partial pressure on the cornea, thereby causing corneal damage caused thereby (for example, refer to the patent document) 1).

Patent Document 1: Japanese Patent Laid-Open No. Hei 7-291870

However, for corneal damage as described above, there is currently no useful agent that is sufficiently satisfactory in terms of treatment or prevention.

It is an object of the present invention to provide an ophthalmic composition useful for the treatment or prevention of corneal damage caused by a hypoxic state.

The inventors of the present invention have repeatedly made efforts to solve the above problems, and as a result, Now: (A) is selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like. The ophthalmic composition in which one or more of the polysaccharides are combined with the (B) polysaccharide protects the corneal cells from the oxidative stress caused by the radical generated by the hypoxic state. The present invention is based on this finding and provides the following inventions.

[1] An ophthalmic composition containing (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol And one or more of the group consisting of these salts, and (B) a polysaccharide.

[2] The ophthalmic composition according to [1], wherein the component (A) is one or more selected from the group consisting of arginine and a salt thereof.

[3] The ophthalmic composition according to [1] or [2], wherein the component (B) is a mucopolysaccharide.

[4] The ophthalmic composition according to any one of [1] to [3] further comprising (C) a bactericide or a preservative.

[5] The ophthalmic composition according to any one of [1] to [4] which is used for a contact lens.

The ophthalmic composition of the present invention contains (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol and One or more of the group consisting of the salt and the (B) polysaccharide have an effect of protecting the corneal cells from the oxidative stress caused by the radical generated by the low oxygen state. Thereby, an ophthalmic composition useful for the treatment or prevention of corneal damage caused by a hypoxic state can be provided.

Hereinafter, the form for carrying out the invention will be described in detail. However, the present invention is not limited to the following embodiments.

In the present specification, the unit "%" of the content means "w/v%" unless otherwise specified, and has the same meaning as "g/100mL". In the present specification, the abbreviation "POE" means polyoxyethylene, and the abbreviation "POP" means polyoxypropylene unless otherwise specified.

[1. Ophthalmic composition]

The ophthalmic composition of the present embodiment contains (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, and tris(hydroxymethyl)aminomethane (also known as tromethamine). (trometamol)), 2-aminoethanol (also known as monoethanolamine) and one or more of the group consisting of such salts (also referred to as "(A) component"), and (B) polysaccharide ( It is also only expressed as "(B) component").

<(A) component>

The component (A) is selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like. One or more of the groups. The component (A) may be used singly or in combination of two or more.

Arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane and 2-aminoethanol may be in a free form, or may be pharmaceutically or pharmacologically ( Pharmaceutically or physiologically acceptable salts.

Specific examples of the salts of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane and 2-aminoethanol include hydrochlorides and the like. Inorganic acid salts, etc. Further, arginine and a salt thereof may be D, L or DL, and preferably L.

The salt of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane and 2-aminoethanol is preferably a mineral acid salt, more preferably a salt. Acid salt.

The component (A) is preferably a arginine acid or a salt thereof, more preferably a arginine acid or a mineral acid salt thereof, and further preferably a arginine acid, from the viewpoint of exhibiting the effect of the present invention more remarkably. Its hydrochloride is especially preferred for arginine.

The arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like can also be used commercially.

The content of the component (A) in the ophthalmic composition of the present embodiment is not particularly limited, and is appropriately set depending on the type of the component (A), the type and content of the other synthetic component, the use of the ophthalmic composition, and the form of the preparation. The content of the component (A) is more preferably 0.001 to 10 w/v%, based on the total amount of the ophthalmic composition, from the viewpoint of the effect of the component (A). More preferably, it is 0.01 to 10 w/v%, further preferably 0.1 to 3 w/v%, and still more preferably 0.1 to 2 w/v%.

<(B) component>

The component (B) is a polysaccharide. The component (B) may be used singly or in combination of two or more.

The polysaccharides include dextran, mucopolysaccharides, tri-sandwich, gellan gum, cellulose-based polymer compounds, and the like. The polysaccharide can be appropriately selected from known polysaccharides.

Specific examples of the dextran include dextran 40 and dextran 70.

Specific examples of the mucopolysaccharide include hyaluronic acid, chondroitin sulfate, polyglucosamine, heparin, heparan, alginic acid, and derivatives thereof (for example, B). Sputum) and such salts.

Among the mucopolysaccharides, hyaluronic acid, chondroitin sulfate, and the like are preferable from the viewpoint of exerting the effects of the present invention more significantly, and hyaluronic acid or a salt thereof is further preferable. The salt of hyaluronic acid or the salt of chondroitin sulfate is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The salt of hyaluronic acid or the salt of chondroitin sulfate is preferably an alkali metal salt, more preferably a sodium salt or a potassium salt, and still more preferably a sodium salt. Among the salts of the mucopolysaccharide, sodium hyaluronate, sodium chondroitin sulfate, and more preferably sodium hyaluronate are preferred.

The mucopolysaccharide may be used singly or in combination of two or more.

As the cellulose-based polymer compound, a cellulose-based polymer compound obtained by substituting a hydroxyl group of cellulose with another functional group can be used. Examples of the functional group of the hydroxyl group substituted for cellulose include a methoxy group, an ethoxy group, a hydroxymethoxy group, a hydroxyethoxy group, a hydroxypropoxy group, a carboxymethoxy group, and a carboxyethoxy group. A cellulose polymer compound can also be used by a commercial one.

Examples of the cellulose-based polymer compound include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose (hydroxypropyl). Hypromellose, carboxymethylcellulose, carboxyethylcellulose, and the like. Here, the salt may be pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and among them, an alkali metal salt is preferred, and a sodium salt or a potassium salt is more preferred.

Among the cellulose polymer compounds, methyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose (2208, 2906, 2910) are preferred from the viewpoint of exhibiting the effects of the present invention more significantly. Or hydroxypropylcellulose, carboxymethylcellulose or a salt thereof, more preferably hydroxypropylmethylcellulose, hydroxyethylcellulose, or sodium carboxymethylcellulose, and more preferably hydroxy Propylmethyl Cellulose, hydroxyethyl cellulose, and more preferably hydroxypropyl methylcellulose, especially hydroxypropyl methylcellulose 2208, hydroxypropyl methylcellulose 2906, hydroxypropyl methylcellulose 2910 Most preferred is hydroxypropyl methylcellulose 2906.

The cellulose-based polymer compound may be used singly or in combination of two or more.

The polysaccharide is preferably a mucopolysaccharide or a cellulose-based polymer compound, more preferably hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose, hydroxyethylcellulose, or the like, and further preferably Sodium hyaluronate, and sodium chondroitin, and more preferably sodium hyaluronate. Further, as another aspect, hyaluronic acid, hydroxypropylmethylcellulose, and the like are preferred, and sodium hyaluronate and hydroxypropylmethylcellulose are more preferred.

Polysaccharides can also be used commercially. The polysaccharides may be used alone or in combination of two or more.

The content of the component (B) in the ophthalmic composition of the present embodiment is not particularly limited, and is appropriately set depending on the type of the component (B), the type and content of the other synthetic component, the use of the ophthalmic composition, and the form of the preparation. The content of the component (B) is more preferably 0.0001 to 5 w/v%, based on the total amount of the ophthalmic composition, from the viewpoint of the effect of the present invention. More preferably, it is 0.0005 to 1 w/v%, further preferably 0.001 to 0.75 w/v%, further preferably 0.001 to 0.5 w/v%, and particularly preferably 0.001 to 0.1 w/v%.

In the case where a mucopolysaccharide is used as the component (B), the content of the mucopolysaccharide is further increased in terms of the effect of the present invention, for example, based on the total amount of the ophthalmic composition, the total content of the mucopolysaccharide. It is preferably 0.0001 to 1 w/v%, more preferably 0.0005 to 0.7 w/v%, still more preferably 0.0005 to 0.6 w/v%.

In the case where sodium hyaluronate is used as the component (B), the total content of sodium hyaluronic acid is preferably as a reference, based on the total amount of the ophthalmic composition, as a result of further increasing the effect of the present invention. 0.0001~0.5w/v%, preferably 0.0005~0.3w/v%, more preferably 0.0005~0.1w/v%, further preferably 0.001~0.05w/v%, and even more preferably 0.001~0.02w /v%, especially preferably 0.001~0.01w/v%.

In the case of using the cellulose-based polymer compound as the component (B), the content of the cellulose-based polymer compound is based on the total amount of the ophthalmic composition, for example, from the viewpoint of further improving the effects of the present invention. The total content of the cellulose-based polymer compound is usually 0.0001 to 1 w/v%, preferably 0.0005 to 1 w/v%, more preferably 0.001 to 0.5 w/v%, still more preferably 0.005 to 0.1 w/v%. More preferably, it is 0.01 to 0.05 w/v%.

The content ratio of the component (B) to the component (A) in the ophthalmic composition of the present embodiment is not particularly limited, and depending on the type of the component (A) and the component (B), the type and content of other synthetic components, and ophthalmology The composition is appropriately set as the use of the composition, the form of the preparation, and the like. The content of the component (B) is more than the content of the component (A), and the total content of the component (A) contained in the ophthalmic composition of the present embodiment is, for example, the viewpoint of the effect of the present invention. The total content of the component (B) is preferably 0.0005 to 5 parts by mass, more preferably 0.001 to 1 part by mass, still more preferably 0.005 to 0.5 part by mass, still more preferably 0.01 to 0.1 part by mass, per part by mass.

In the case where the mucopolysaccharide is used as the component (B), the total content of the mucopolysaccharide is preferably 0.0001 to 50 with respect to 1 part by mass of the total content of the component (A) contained in the ophthalmic composition of the present embodiment. The mass part is preferably 0.0005 to 10 parts by mass, more preferably 0.001 to 1 part by mass.

In the case where sodium hyaluronate is used as the component (B), it is compared with the present embodiment. The total content of the component (A) contained in the ophthalmic composition is 1 part by mass, and the total content of sodium hyaluronate is preferably 0.00001 to 1 part by mass, preferably 0.0001 to 0.5 part by mass, more preferably 0.0001 to 0.1 part by mass. The portion is further preferably 0.0005 to 0.05 parts by mass, and more preferably 0.001 to 0.01 parts by mass.

When the cellulose-based polymer compound is used as the component (B), the total content of the cellulose-based polymer compound is 1 part by mass based on the total content of the component (A) contained in the ophthalmic composition of the present embodiment. It is preferably 0.0005 to 1 part by mass, preferably 0.001 to 0.5 part by mass, more preferably 0.005 to 0.1 part by mass, still more preferably 0.01 to 0.05 part by mass.

<(C) component>

The ophthalmic composition of the present embodiment preferably further contains (C) a bactericide or a preservative (also referred to as "(C) component"). The ophthalmic composition further contains the component (C), and the effects of the present invention are more prominently exhibited.

A bactericide or a preservative is a compound having a bactericidal or bacteriostatic action and a salt thereof. The preservative can be suitably selected from known preservatives or antibacterial agents.

Specific examples of the bactericide or the preservative include a cationic bactericide (preservative) (benzamide, benzothonium, lohexidine, alexidine, polyhexyl guanidine). Etc., alkyl polyaminoethylglycine, benzoic acid, chlorobutanol, sorbic acid, dehydroacetic acid, parabens (eg methylparaben, p-hydroxybenzoic acid) Ethyl ester, propyl paraben and butyl paraben, hydroxyquinoline, phenylethyl alcohol, benzyl alcohol, polytetraammonium salt (polidronium chloride) Etc.), Gurokiru (manufactured by Rhodia, trade name), zinc, sulfonamide Oxazole and sulfamethoxazole Azole, and the salts thereof.

Specific examples of the salt of the bactericide or the preservative include, for example, alkyldiamine ethylglycine hydrochloride, sodium benzoate, benzalkonium chloride, bensin chloride, lohcetin gluconate, Potassium sorbate, sodium dehydroacetate, hydroxyquinoline sulfate, polyhexamidine hydrochloride, zinc chloride, sodium sulfamethazine, and sulfamethoxazole Sodium azole.

As the bactericide or preservative, it is preferably a cationic bactericide (preservative), a polytetra-ammonium salt, more preferably benzalkonium chloride, lohcetin gluconate, alexidine, or hexahydrochloride. It is preferably bismuth, bromochloroammonium, and further preferably polyhexamidine hydrochloride, alexidine, and perichloroammonium chloride, and more preferably polyhexamidine hydrochloride.

In view of the effect of the present invention, the sterilizing agent or the preservative is more preferably used in combination of two or more. Among them, a combination of a cationic sterilizing agent (preservative) and a polytetra-ammonium salt is preferred, and a combination of a bolli ammonium chloride and a cationic bactericide (preservative) is preferred, and further preferably a borley ammonium chloride. In combination with polyheximidine hydrochloride or beryl ammonium chloride and alexidine.

A biocide or a preservative can also be used by a commercially available person. The bactericide or the preservative may be used singly or in combination of two or more.

The content of the component (C) in the ophthalmic composition of the present embodiment is not particularly limited, and is appropriately set depending on the type of the component (C), the type and content of other synthetic components, the use of the ophthalmic composition, and the form of the preparation. The content of the component (C) is more preferably 0.00001 to 2 w/v%, based on the total amount of the ophthalmic composition, for example, based on the total amount of the ophthalmic composition. More preferably, it is 0.00001 to 1 w/v%, further preferably 0.00005 to 0.5 w/v%, and still more preferably 0.00005 to 0.1 w/v%.

In the case where the bactericide or preservative is alexidine, polyhexamidine hydrochloride or polibium chloride, the total content of the preservative is preferably 0.000001 based on the total amount of the ophthalmic composition. ~0.01w/v%, preferably 0.000001~0.005w/v%, of which 0.000005~0.002w/v% is preferred, wherein 0.000005~0.001w/v% is preferred, and 0.00001~0.0005 is preferred. w/v%, preferably 0.00005 to 0.0004 w/v%, of which 0.00007 to 0.0002 w/v% is preferred.

The content ratio of the component (C) to the component (A) in the ophthalmic composition of the present embodiment is not particularly limited, and depending on the type of the component (A) and the component (C), the type and content of other synthetic components, and ophthalmology The composition is appropriately set as the use of the composition, the form of the preparation, and the like. The content of the component (C) is more than the content of the component (A), and the total content of the component (A) contained in the ophthalmic composition of the present embodiment is, for example, the viewpoint of the effect of the present invention. The total content of the component (C) is preferably 0.0000001 to 0.1 part by mass, more preferably 0.000001 to 0.01 part by mass, still more preferably 0.000005 to 0.001 part by mass, still more preferably 0.00001 to 0.0005 part by mass.

In view of further improving the effects of the present invention, the ophthalmic composition of the present embodiment preferably further contains a nonionic surfactant.

Specific examples of the nonionic surfactant include POE (20) sorbitan monolaurate (polysorbate 20) and POE (20) sorbitan monopalmitate (polysorbate 40). ), POE (20) sorbitan monostearate (polysorbate 60), POE (20) sorbitan tristearate (polysorbate 65), POE (20) sorbitan POE sorbitan fatty acid esters such as oleate (polysorbate 80); POE (5) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 5), POE (10) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil) 10), POE (20) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 20), POE (30) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 30), POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated tantalum) Sesame oil 40), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), POE (80) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 80), POE (100) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 100) and other POE hydrogenated castor oil; POE (3) castor oil (polyoxyethylene castor oil 3), POE (10) castor oil (polyoxyethylene castor oil 10 POE (35) castor oil (polyoxyethylene castor oil 35), POE (70) castor oil (polyoxyethylene castor oil 70) and other POE castor oil; POE (9) lauryl ether and other POE alkyl ether; POE ( 20) POE-POP alkyl ether such as POP (4) cetyl ether; POE (20) POP (20) diol (Pluronic L44), POE (42) POP (67) diol (Poloxamer 403, Pluronic P123), POE (54) POP (39) diol (Poloxamer 235, Pluronic P85), POE (120) POP (40) diol (Pluronic F87), POE (160) POP (30) diol (Poloxamer 188, Pluronic F68), POE (196) POE-POP diol such as POP (67) diol (Poloxamer 407, Pluronic F127), POE (200) POP (70) diol, polyoxyl stearate 10, stearic acid Polyethylene glycol monoester such as polyoxyl 40 ester. Further, in the above-exemplified compounds, the numbers in parentheses indicate the addition of the molar number.

The nonionic surfactant is preferably POE sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyethylene glycol monostearate, POE-POP diol, more preferably POE sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, POE-POP diol, further preferably POE sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and more preferably polysorbate 80, Polyoxyethylene hydrogenated castor oil 60, more preferably polyoxyethylene hydrogenated castor oil 60.

When POE-POP diol is used as the nonionic surfactant, POE (42) POP (67) diol, POE (120) POP (40) diol, POE (160) POP (30) are preferred. Glycol, POE (196) POP (67) diol, POE (200) POP (70) diol, more preferably POE (42) POP (67) diol, POE (196) POP (67) diol, Further preferred is POE (196) POP (67) diol.

Nonionic surfactants can also be used commercially. Nonionic surfactant can be single One type may be used alone or two or more types may be used in combination.

The content of the nonionic surfactant in the ophthalmic composition of the present embodiment is not particularly limited, and is appropriately selected depending on the type of the nonionic surfactant, the type and content of other synthetic components, the use of the ophthalmic composition, and the form of the preparation. set up. As a content of the nonionic surfactant, the total content of the nonionic surfactant is preferably 0.0001 to 10 w/v from the viewpoint of exerting the effects of the present invention more significantly, for example, based on the total amount of the ophthalmic composition. % is more preferably 0.001 to 5 w/v%, further preferably 0.005 to 1 w/v%, further preferably 0.01 to 0.5 w/v%, particularly preferably 0.01 to 0.1 w/v%, and particularly preferably 0.01. ~0.05w/v%.

The content ratio of the nonionic surfactant in the ophthalmic composition of the present embodiment to the component (A) is not particularly limited, and depending on the type of the component (A) and the nonionic surfactant, and the type and content of other mixed components It is appropriately set for the use of the ophthalmic composition, the form of the preparation, and the like. The ratio of the content ratio of the non-ionic surfactant to the component (A) is more remarkable in terms of the effect of the present invention, for example, the total amount of the component (A) contained in the ophthalmic composition of the present embodiment. The content of the nonionic surfactant is preferably 0.0001 to 10 parts by mass, more preferably 0.0005 to 5 parts by mass, still more preferably 0.001 to 3 parts by mass, still more preferably 0.01 to 1 part by weight. It is preferably 0.01 to 0.5 parts by mass.

In view of further improving the effects of the present invention, the ophthalmic composition of the present embodiment preferably further contains a buffer. The buffering agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such a buffer include a boric acid buffer, a phosphate buffer, a carbonic acid buffer, a citrate buffer, an acetic acid buffer, and a trishydroxymethylaminomethane buffer.

Examples of the boric acid buffer include boric acid or a salt thereof (alkali metal borate, boric acid) Alkaline earth metal salts, etc.). Examples of the phosphate buffer include phosphoric acid or a salt thereof (alkali metal phosphate, alkaline earth metal phosphate, etc.). Examples of the carbonic acid buffering agent include carbonic acid or a salt thereof (alkali carbonate metal salt, alkali carbonate metal salt, etc.). Examples of the citric acid buffer include citric acid or a salt thereof (alkali metal citrate, alkaline earth metal citrate, etc.). Examples of the acetic acid buffer include acetic acid or a salt thereof (alkali metal acetate or alkaline earth metal acetate). Further, a borate, a phosphate, a carbonate, a citrate or an acetate hydrate can also be used as the boric acid buffer, the phosphate buffer, the carbonate buffer, the citric acid buffer or the acetic acid buffer. More specific examples thereof include boric acid as a boric acid buffer or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphoric acid as a phosphate buffer or a salt thereof (hydrogen phosphate II) Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, etc.; carbonic acid or a salt thereof (carbonic acid sodium carbonate, sodium carbonate, ammonium carbonate) , potassium carbonate, calcium carbonate, potassium hydrogencarbonate, magnesium carbonate, etc.; citric acid or its salt as a citrate buffer (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate Ethyl acetate or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) or the like as an acetic acid buffer. Among these buffers, a boric acid buffer (for example, a combination of boric acid and borax), a phosphate buffer (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), and the like, a boric acid buffer is preferred.

A buffer can also be used by a commercially available person. The buffer may be used singly or in combination of two or more.

In the case of containing a buffering agent, the content of the buffering agent in the ophthalmic composition of the present embodiment is more remarkable in terms of the effect of the present invention, for example, based on the total amount of the ophthalmic composition, the buffering agent. The total content is preferably 0.001 to 10 w/v%, more preferably 0.005 to 5 w/v%, still more preferably 0.01 to 3 w/v%, still more preferably 0.1 to 2 w/v%.

The content ratio of the buffering agent to the component (A) in the ophthalmic composition of the present embodiment is not particularly limited, and depending on the type of the component (A) and the buffering agent, the type and content of other blending components, and the use of the ophthalmic composition. It is set as appropriate in the form of preparation and the like. The ratio of the content of the buffer component to the component (A) is more than 1% of the total content of the component (A) contained in the ophthalmic composition of the present embodiment, from the viewpoint of the effect of the present invention. The total content of the buffering agent is preferably 0.001 to 10 parts by mass, more preferably 0.0005 to 5 parts by mass, still more preferably 0.01 to 3 parts by mass, still more preferably 0.05 to 2 parts by mass.

The ophthalmic composition of the present embodiment preferably further contains a chelating agent from the viewpoint of further improving the effects of the present invention.

Examples of the chelating agent include ethylenediamine diacetic acid (EDDA), ethylenediaminetriacetic acid, edetic acid (EDTA), and N-(2-hydroxyethyl)ethylenediaminetriacetic acid ( HEDTA), di-ethyltriamine pentaacetic acid (DTPA), and etidronic acid. As a chelating agent, ethylenediaminetetraacetic acid is preferable from the viewpoint of exhibiting the effect of the present invention more remarkably.

A chelating agent can also be used by a commercial one. The chelating agent may be used singly or in combination of two or more.

The content of the chelating agent in the ophthalmic composition of the present embodiment is not particularly limited, and is appropriately set depending on the type of the chelating agent, the type and content of other synthetic components, the use of the ophthalmic composition, and the form of the preparation. The content of the chelating agent is preferably from 0.001 to 1 w/v%, more preferably 0.005, based on the total amount of the ophthalmic composition, as the content of the chelating agent. ~0.5 w/v%, further preferably 0.01 to 0.2 w/v%.

The chelating agent in the ophthalmic composition of the present embodiment is contained in relation to the component (A) The ratio is not particularly limited, and is appropriately set depending on the type of the component (A) and the chelating agent, the type and content of other synthetic components, the use of the ophthalmic composition, and the form of the preparation. The ratio of the content of the chelating agent to the component (A) is more than the total content of the component (A) contained in the ophthalmic composition of the present embodiment, for example, from the viewpoint of the effect of the present invention. The total content of the chelating agent is preferably 0.001 to 10 parts by mass, more preferably 0.005 to 5 parts by mass, still more preferably 0.005 to 3 parts by mass, still more preferably 0.01 to 1 part by mass, still more preferably 0.01% by weight. 0.5 parts by mass.

In view of further improving the effects of the present invention, the ophthalmic composition of the present embodiment preferably further contains an amino acid other than the component (A).

Examples of the amino acid other than the component (A) include aspartic acid, glutamic acid, aminoethylsulfonic acid (taurine), alanine, aspartame, glutamine, and guanamine. Acid, glycine, lysine, histidine, serine, methionine, threonine, cysteine, aminoacetic acid, valine, tryptophan, phenylalanine, leucine , isoleucine, and the like. From the viewpoint of exhibiting the effects of the present invention more significantly, the amino acid other than the component (A) is preferably aspartic acid, glutamic acid, aminoethylsulfonic acid, glycine, and The salt is preferably potassium aspartate or aminoethyl sulfonic acid.

The amino acid other than the component (A) may be a D form, an L form or a DL form, and is preferably a L form.

Amino acids other than the component (A) can also be used commercially. The amino acid other than the component (A) may be used alone or in combination of two or more.

The content of the amino acid other than the component (A) in the ophthalmic composition of the present embodiment is not particularly limited, and the type of the amino acid other than the component (A), the type and content of the other synthetic component, and the ophthalmic composition are not particularly limited. The application and the form of the preparation are appropriately set. As (A) into The content of the amino acid other than the component of the component (A) is preferably 0.001, based on the total amount of the ophthalmic composition, for example, based on the total amount of the ophthalmic composition. ~5w/v%, more preferably 0.01~2w/v%, further preferably 0.1~1w/v%.

In the ophthalmic composition of the present embodiment, the content ratio of the amino acid other than the component (A) to the component (A) is not particularly limited, and the type of the amino acid other than the component (A) and the component (A) is The type and content of other synthetic components, the use of the ophthalmic composition, and the form of the preparation are appropriately set. The content ratio of the amino acid other than the component (A) to the component (A) is more prominently exhibited in the ophthalmic composition of the present embodiment, for example, in view of the effect of the present invention. The total content of the components is 1 part by mass, and the total content of the amino acid other than the component (A) is preferably 0.001 to 5 parts by mass, more preferably 0.01 to 2 parts by mass, still more preferably 0.1 to 1 part by mass.

In view of further improving the effects of the present invention, the ophthalmic composition of the present embodiment preferably further contains a terpenoid. The class is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As such a kind, for example, menthol, menthone, camphor, borneol, geranyl alcohol, cineole, citronellol, fragrant celery, aniseed brain, eugenol, limonene, linalool, acetic acid Agarwood esters, such derivatives, and the like. These compounds may be D, L or DL. Further, in the present invention, an essential oil containing the above compound may also be used as the terpenoid. Examples of such an essential oil include eucalyptus oil, bergamot oil, peppermint oil, cooling peppermint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, and the like. These may be used singly or in combination of two or more.

Among these, menthol, camphor, borneol, etc. are preferred as such The preferred essential oils are, for example, cool mint oil, peppermint oil, peppermint oil, camphor oil, and the like. More preferably menthol.

Commercially available persons can also be used. One type may be used alone or two or more types may be used in combination.

When the content of the quinone in the ophthalmic composition of the present embodiment is more prominent, the effect of the present invention is more prominent, for example, based on the total amount of the ophthalmic composition, The total content is preferably 0.00005 to 1 w/v%, more preferably 0.0001 to 0.5 w/v%, still more preferably 0.001 to 0.1 w/v%.

The content ratio of the quinone in the ophthalmic composition of the present embodiment to the component (A) is not particularly limited, and the type and content of the component (A), the type and content of other mixed components, and the use of the ophthalmic composition are used. It is set as appropriate in the form of preparation and the like. In view of the effect of the present invention, the content of the component (A) is more than 1% by mass of the component (A) contained in the ophthalmic composition of the present embodiment. The total content of the terpenoids is preferably 0.00005 to 1 part by mass, more preferably 0.0001 to 0.5 part by mass, still more preferably 0.001 to 0.1 part by mass.

In view of further improving the effects of the present invention, the ophthalmic composition of the present embodiment preferably further contains a polyhydric alcohol.

Examples of the polyhydric alcohol include propylene glycol, glycerin, and polyethylene glycol (400, 4000, 6000, etc.). From the viewpoint of more effectively exhibiting the effects of the present invention, the propylene glycol is preferred.

Polyols can also be used by commercial consumers. The polyol may be used singly or in combination of two or more.

The content of the polyol in the ophthalmic composition of the present embodiment is not particularly limited, and is appropriately set depending on the type of the polyol, the type and content of the other blending component, the use of the ophthalmic composition, the form of the preparation, and the like. From the viewpoint of the effect of the present invention, the total content of the polyol is preferably 0.01 to 5 w/v%, more preferably 0.05, as the basis of the total amount of the ophthalmic composition. ~2w/v%, further preferably 0.1 to 1 w/v%.

The pH of the ophthalmic composition of the present embodiment is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The pH of the ophthalmic composition of the present embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, still more preferably 4.5 to 8.5, and still more preferably 5.0 to 8.5. It is 5.5~8.5.

The ophthalmic composition of the present embodiment can be adjusted to an osmotic pressure ratio within a range allowed by the living body as needed. The appropriate osmotic pressure ratio varies depending on the application site, the dosage form, and the like, and can be, for example, 0.4 to 5.0, preferably 0.6 to 3.0, and more preferably 0.7 to 2.0. The adjustment of the osmotic pressure can be carried out by using an inorganic salt, a polyhydric alcohol or the like and using a method known in the art. The osmotic pressure ratio is based on the 16th revised edition of the Japanese Pharmacopoeia and is set as the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of 0.9 w/v% aqueous sodium chloride solution). The osmotic pressure can be referred to the Japanese Pharmacopoeia. The osmotic pressure measurement method (the freezing point reduction method) was measured. Further, the osmotic pressure ratio measuring standard solution (0.9 w/v% sodium chloride aqueous solution) can be dried at 500 to 650 ° C for 40 to 50 minutes after the sodium chloride (Japanese Pharmacopoeia standard reagent) is dried in a desiccator (silicone). The mixture was cooled, accurately weighed 0.900 g, and dissolved in purified water to accurately prepare 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v% aqueous sodium chloride solution).

The viscosity of the ophthalmic composition of the present embodiment is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As this embodiment The viscosity of the ophthalmic composition is, for example, measured by a rotary viscometer (RE550 type viscometer, manufactured by Tosoh Corporation, rotor: 1°34'×R24). The viscosity at 20 ° C is preferably 0.01 to 10000 mPa. s, more preferably 0.05~8000mPa. s, further preferably 0.1 to 1000 mPa. s, and more preferably 1~100mPa. s, especially good for 1~10mPa. s, especially good for 1~5mPa. s.

The ophthalmic composition of the present embodiment may be combined with a component selected from various pharmacologically active components and physiologically active components in addition to the above components, as long as the effects of the present invention are not impaired. The ingredient is not particularly limited, and, for example, an active ingredient in an ophthalmic drug described in the 2012 edition of the general approval for the manufacture of pharmaceuticals and the approval of the general public. Specific examples of the components used in the ophthalmic administration include the following components.

Antihistamines: for example, iproheptine, diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, orolazine hydrochloride Olepatadine hydrochloride, levocabastine hydrochloride, and the like.

Antiallergic agents: for example, sodium cromoglycate, tranilast, potassium pemirolast, and the like.

Steroid agents: for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone dipropionate, flunisolide, and the like.

Anti-inflammatory agents: for example, glycyrrhetinic acid, dipotassium glycyrrhizinate, pranoprofen, methyl salicylate, ethylene glycol salicylate, allantoin, tranexamic acid, ε-aminohexanoic acid, Berberine, sodium azulene sulfonate, chlorinated lysozyme, zinc sulfate, zinc lactate, licorice, and the like.

Congestion remover: tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, adrenaline, adrenaline hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-hydrochloride Ephedrine and the like.

An ocular muscle regulating agent: for example, an anticholinesterase agent having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien , atropine sulfate and so on.

Vitamins: for example, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, retinyl palmitate, retinyl acetate , tocopheryl acetate and the like.

Inorganic salts: for example, chlorides of metals such as calcium chloride, magnesium chloride, sodium chloride, potassium chloride, ammonium chloride, sulfates of metals such as calcium sulfate, magnesium sulfate, sodium sulfate, potassium sulfate, ammonium sulfate, and the like.

Astringents: for example, zinc white, zinc lactate, zinc sulfate, and the like.

Local anesthetics: such as lidocaine, procaine, etc.

Other: rebamipide and so on.

In the ophthalmic composition of the present embodiment, as long as the effects of the present invention are not impaired, various additives may be appropriately selected according to the use and the form of the preparation according to the usual method, and one or more kinds may be used in an appropriate amount. . As such an additive, various additives described in the Pharmaceutical Additives Code 2007 (edited by the Japan Pharmaceutical Additives Association) can be exemplified. As a representative component, the following additives are mentioned.

Carrier: an aqueous solvent such as water, aqueous ethanol or the like.

Base: for example, octyldodecanol, titanium oxide, potassium bromide, Plastibase, liquid paraffin, light liquid paraffin, refined lanolin, white petrolatum, and the like.

pH adjusting agent: hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine, and the like.

Sugars: for example, monosaccharides and disaccharides, specifically, glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol, and the like.

Stabilizer: dibutylhydroxytoluene, butylhydroxyanisole, sodium sulfoxylate (rongalite), sodium hydrogen sulfite, sodium metabisulfite, aluminum monostearate, glycerol monostearate, ring Dextrin and the like.

Anionic surfactants: polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, alkyl sulfates, N-mercapto taurates, and the like.

Amphoteric surfactant: lauryl dimethylamino acetic acid betaine and the like.

Vinyl polymer: polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, and the like.

Further, the ophthalmic composition of the present embodiment preferably does not substantially contain pyrrolidinone carboxylic acid, and more preferably does not contain pyrrolidone carboxylic acid.

The ophthalmic composition of the present embodiment can be prepared, for example, by adding and mixing the component (A), the component (B), and optionally other components in a desired amount. Specifically, for example, the above components can be dissolved or suspended by using purified water, adjusted to a specific pH and osmotic pressure, and sterilized by filtration sterilization or the like.

The ophthalmic composition of the present embodiment can be used in various dosage forms depending on the purpose, and examples thereof include a liquid preparation, a gel, a semi-solid agent (an ointment, etc.). Among these, a liquid agent is preferred. Further, in the liquid preparation, an aqueous liquid preparation is preferred. When the ophthalmic composition of the present embodiment is used as an aqueous liquid preparation, the content of the ophthalmic composition is, for example, 50 w/v% or more, preferably 70 w/v% or more, more preferably 80w/v% or more, and more preferably 90w/v% or more. More preferably, it is 95w/v% or more. As the water to be used in the ophthalmological composition of the present embodiment, water, which is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, may be used. Examples of such water include distilled water and ordinary water. , purified water, sterilized purified water, water for injection, distilled water for injection.

The ophthalmic composition of the present embodiment is not limited as long as it is a user in the field of ophthalmology. For example, eye drops (including eye drops for contact lenses (eye drops which can be used in the state of wearing contact lenses)), eye washes (including eye wash for contact lenses) (which can be used for wearing contact lenses) Eyewash used in the state)), contact lens wearing solution, contact lens maintenance liquid (contact lens disinfectant, contact lens preservation solution, contact lens cleaning solution, contact lens cleaning/preservation solution, and contact lens disinfection/cleaning / preservation solution (multipurpose solution), etc.).

In addition, Acanthamoeba corneal infection is the most common in contact lens wearers, and contact lens wearers strongly demand the bactericidal effect of Acanthamoeba. Therefore, as a preferred form of the ophthalmic composition of the present embodiment, an eye drop for contact lenses (an eye drop which can be used in the state in which a contact lens is worn) or an eye wash for a contact lens can be used. An ophthalmic composition for contact lenses such as an eye-washing agent used in the state of wearing a contact lens, a contact lens wearing solution, and a contact lens maintenance liquid, and particularly preferably a liquid for contact lens maintenance.

When the ophthalmic composition of the present embodiment is used as an ophthalmic composition for contact lenses, the type of the contact lens to be applied is not particularly limited, and all contact lenses currently available or commercially available (including soft invisibility) may be used. Any of glasses, hard contact lenses, and oxygen-permeable rigid contact lenses. Also, soft contact lenses, which contain both ionic and nonionic, and contain polyoxyl hydrogel contact lenses and non-polythene Oxygen hydrogel contact lens Both of them are applicable.

Acanthamoeba corneal infection is mostly caused by soft contact lens wearers in contact lens wearers, while soft contact lens wearers strongly demand the bactericidal effect of Acanthamoeba. Therefore, the preparation form of the ophthalmic composition of the present embodiment is preferably an ophthalmic composition for soft contact lenses (that is, an ophthalmic composition for contact lenses in which the application lens is a soft contact lens).

Further, when the ophthalmic composition of the present embodiment is used as the ophthalmic composition for soft contact lenses, the moisture content of the soft contact lens to be applied is not particularly limited, and may be, for example, 90% or less, preferably 60%. Hereinafter, it is more preferably 50% or less. Furthermore, soft contact lenses contain at least more than 0% moisture.

The ophthalmic composition of the present embodiment is used in accordance with the method of use corresponding to the form of the preparation. For example, when the ophthalmic composition is an eye drop (including an eye drop for a contact lens), an appropriate amount of the eye drop may be added to the naked eye or the eye wearing the contact lens. Further, in the case where the ophthalmic composition is an eye-washing agent (including an eye-washing agent for contact lenses), an appropriate amount of the eye-washing agent may be used for eye wash for the naked eye or the eye wearing the contact lens. Moreover, when the ophthalmic composition is a contact lens wearing solution, the contact lens is used by contacting the appropriate amount of the wearing solution when the contact lens is worn. Further, when the ophthalmic composition is a contact lens maintenance liquid preparation, the contact lens is immersed in an appropriate amount of the maintenance liquid preparation, or the contact lens is brought into contact with the maintenance liquid agent, and scrubbed or the like. use. In the case of immersing the contact lens, the immersion time is usually 1 minute or longer, preferably 10 minutes or longer, more preferably 1 hour or longer, and still more preferably 4 hours or longer.

As a container for accommodating the ophthalmic composition of the present embodiment, it can be used as a container. The container normally used for the container of the ophthalmic composition may be made of glass or plastic. In the case of using a plastic container to accommodate the container of the ophthalmic composition of the present embodiment, the material of the plastic container is not particularly limited, and examples thereof include polyethylene naphthalate, polyarylate, and polyphenylene terephthalate. Any one of ethylene formate, polypropylene, polyethylene, polyimine, and polycarbonate, a copolymer of the above, or a mixture of two or more thereof. Further, examples of the copolymer include any one of ethylenediamine 2,6-naphthalenedicarboxylate unit, aryl ester unit, ethylene terephthalate unit, propylene unit, ethylene unit, and quinone unit. The main body and a copolymer of other polyester units and quinone units. Further, in the present invention, for example, when it is described as a container made of polyethylene terephthalate, it is usually required to contain polyethylene terephthalate with respect to the entire weight of the constituent material of the container. It is contained in an amount of 10 w/w% or more, preferably 50 w/w% or more.

In addition, the structure, the constituent material, and the like of the container injection port peripheral portion such as the nozzle provided in the container for accommodating the ophthalmic composition of the present embodiment are not particularly limited. The structure of the peripheral portion of the container injection port such as a nozzle may be a structure generally used as a drip outlet (for example, a nozzle) of a container for an ophthalmic composition (for example, an eye drop container), and may be integrally formed with the container body. It can be formed separately from the container body. The constituent material of the peripheral portion of the injection port or the drip outlet (for example, the nozzle) may be, for example, the same as the constituent material of the plastic container.

In particular, from the viewpoint of further improving the unevenness of the flexibility, the cost, and/or the amount of dripping, it is preferred to include polyethylene or polypropylene as a drip outlet for the constituent material.

Examples of the type of the polyethylene include high-density polyethylene and low-density polyethylene. Among them, a low-density polyethylene is preferably used as a drip outlet for the constituent material. Further, as the drip outlet, a nozzle used for the eye drop container is preferable.

As a container and container injection port for accommodating the ophthalmic composition of the present embodiment A preferred combination of the side portions is a combination of a polyethylene terephthalate container and a peripheral portion of a polyethylene container injection port, and more preferably a polyethylene terephthalate eye drop container and a polyethylene nozzle. A combination of a polyethylene terephthalate eye drop container and a low density polyethylene nozzle is particularly preferred. Further, as a combination of the container for accommodating the ophthalmic composition of the present embodiment and the peripheral portion of the container injection port, a combination of a polyethylene terephthalate container and a polypropylene nozzle, and a polypropylene container and a polymer are preferable. A combination of propylene nozzles. Further, the combination of the container for accommodating the ophthalmic composition of the present embodiment and the peripheral portion of the container injection port is preferably a combination of a polyethylene container and a polyethylene nozzle, or a container integrally formed thereof, and particularly preferably low. A combination of a density polyethylene container and a low density polyethylene nozzle, or a container integrally formed therewith.

[2. Treatment or prevention of corneal damage caused by hypoxic state]

The ophthalmic composition of the present embodiment is useful for the treatment or prevention of corneal damage caused by a hypoxic state. Therefore, as an embodiment of the present invention, there is provided a method for imparting a therapeutic or preventive effect on corneal damage caused by a hypoxic state to an ophthalmic composition, comprising the feature that the ophthalmic composition contains (A) selected from the group consisting of One or more of a group consisting of aminic acid, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like; B) Polysaccharides.

Further, an embodiment of the present invention provides a therapeutic or prophylactic agent for corneal damage caused by a hypoxic state, which comprises an ophthalmic composition containing (A) selected from arginine, 2 -Amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and one or more of the group consisting of these salts, and (B) polysaccharides .

Further, as an embodiment of the present invention, there is provided an (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, and 2-amine. Ethanol and the The use of one or more of the group consisting of the salt and the use of the polysaccharide (B) for the manufacture of an ophthalmic composition for the treatment or prevention of corneal damage caused by a hypoxic state.

Furthermore, as an embodiment of the present invention, there is provided a method for treating or preventing corneal damage caused by a hypoxic state, wherein (A) is selected from the group consisting of arginine, 2-amino-2-methyl-1 Further, one or more of the group consisting of 3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like may be used in combination with the (B) polysaccharide.

In addition, the type and content of the component (A) in the above-described respective embodiments, the type and content of other components, and the preparation form and use of the ophthalmic composition are as described in [1. Ophthalmic composition].

[3. Activation of corneal cells]

The ophthalmic composition of the present embodiment exerts an effect of activating corneal cells. Therefore, as an embodiment of the present invention, there is provided a method for imparting an activation effect to a corneal cell to an ophthalmic composition, comprising the feature that the ophthalmic composition contains (A) selected from the group consisting of arginine and 2-amino-2. One or more selected from the group consisting of methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and (B) a polysaccharide.

Further, an embodiment of the present invention provides an activator for corneal cells, which comprises an ophthalmic composition containing (A) selected from the group consisting of arginine, 2-amino-2-methyl- One or more of the group consisting of 1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and (B) a polysaccharide.

Further, as an embodiment of the present invention, there is provided an (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, and 2-amine. Use of one or more of the group consisting of basal ethanol and such salts, and (B) polysaccharides for the manufacture of corneal fines An ophthalmic composition for cell activation.

Further, as an embodiment of the present invention, there is provided a method for activating corneal cells, which comprises (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, and tris(hydroxyl) One or more of the group consisting of methyl)aminomethane, 2-aminoethanol, and the like, is used in combination with the (B) polysaccharide.

In addition, the type and content of the component (A) in the above-described respective embodiments, the type and content of other components, and the preparation form and use of the ophthalmic composition are as described in [1. Ophthalmic composition].

[4. Sterilization of Acanthamoeba]

The ophthalmic composition of the present embodiment exerts an effect of effectively sterilizing Acanthamoeba which is a cause of Acanthamoeba corneal infection.

Therefore, as an embodiment of the present invention, there is provided a method of imparting an action of sterilizing Acanthamoeba to an ophthalmic composition, comprising the feature that the ophthalmic composition contains (A) selected from the group consisting of arginine and 2-amine One or more of the group consisting of benzyl-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and (B) a polysaccharide.

Further, an embodiment of the present invention provides a fungicide of Acanthamoeba which is composed of an ophthalmic composition containing (A) selected from the group consisting of arginine and 2-amino-2-methyl One or more of the group consisting of 1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and (B) a polysaccharide.

Further, as an embodiment of the present invention, there is provided an (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, and 2-amine. Use of one or more of the group consisting of basal ethanol and such salts, and (B) a polysaccharide for use in the manufacture of arachidol Ophthalmic composition for the sterilization of Ba.

Furthermore, as an embodiment of the present invention, there is provided a method for sterilizing Acanthamoeba which is selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, and three One or more of the group consisting of (hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and the (B) polysaccharide are used in combination.

In addition, the type and content of the component (A) in the above-described respective embodiments, the type and content of other components, and the preparation form and use of the ophthalmic composition are as described in [1. Ophthalmic composition].

[5. Prevention of Acanthamoeba Corneal Infection]

The ophthalmic composition of the present embodiment exerts an effect of preventing acanthamoeba corneal infection.

Therefore, as an embodiment of the present invention, there is provided a method for imparting an action for preventing an acanthamoeba corneal infection to an ophthalmic composition, comprising the feature that the ophthalmic composition contains (A) selected from arginine, 2 -Amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and one or more of the group consisting of these salts, and (B) polysaccharides .

Further, an embodiment of the present invention provides a preventive agent for Acanthamoeba corneal infection, which comprises an ophthalmic composition containing (A) selected from the group consisting of arginine and 2-amino group- One or more selected from the group consisting of 2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and (B) a polysaccharide.

Further, as an embodiment of the present invention, there is provided an (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, and 2-amine. The use of one or more of the group consisting of basal ethanol and the salt thereof, and (B) a polysaccharide for use in the manufacture of an ophthalmic composition for the prevention of Acanthamoeba corneal infection.

Furthermore, as an embodiment of the present invention, there is provided a method for preventing acanthamoeba corneal infection, which comprises (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol And one or more of the group consisting of tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and the (B) polysaccharide are used in combination.

In addition, the type and content of the component (A) in the above-described respective embodiments, the type and content of other components, and the preparation form and use of the ophthalmic composition are as described in [1. Ophthalmic composition].

[7. Prevention of corneal epithelial damage]

The ophthalmic composition of the present embodiment exerts an effect of preventing corneal epithelial damage such as corneal staining.

Therefore, as an embodiment of the present invention, there is provided a method for imparting an effect of preventing corneal epithelial damage to an ophthalmic composition, comprising the feature that the ophthalmic composition contains (A) selected from the group consisting of arginine and 2-amino group- One or more selected from the group consisting of 2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and (B) a polysaccharide.

Further, an embodiment of the present invention provides a prophylactic agent for corneal epithelial damage, which comprises an ophthalmic composition containing (A) selected from the group consisting of arginine and 2-amino-2-methyl -1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and one or more of the group consisting of these salts, and (B) polysaccharide.

Further, as an embodiment of the present invention, there is provided an (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, and 2-amine. The use of one or more of the group consisting of basal ethanol and such a salt, and (B) a polysaccharide, for use in the manufacture of an ophthalmic composition for the prevention of corneal epithelial damage.

Furthermore, as an embodiment of the present invention, there is provided a method for preventing corneal epithelial damage A method of injury comprising the steps of: contacting an ophthalmic composition with a contact lens, the ophthalmic composition comprising (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, and tri ( A step of hydroxymethyl)aminomethane, 2-aminoethanol, and one or more of the group consisting of the salts thereof, and (B) a polysaccharide. This contacting step can be carried out in contact lens wear or in the case where the contact lens is not worn.

In addition, the type and content of the component (A) in the above-described respective embodiments, the type and content of other components, and the preparation form and use of the ophthalmic composition are as described in [1. Ophthalmic composition].

[8. Improvement of the wearing feeling of contact lenses]

The ophthalmic composition of the present embodiment exerts an effect of improving the wearing feeling of the contact lens.

Therefore, as an embodiment of the present invention, there is provided a method for imparting an effect of improving the wearing feeling of a contact lens to an ophthalmic composition, comprising the feature that the ophthalmic composition contains (A) selected from the group consisting of arginine, 2- One or more of the group consisting of amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and (B) a polysaccharide.

Moreover, an embodiment of the present invention provides an improvement agent for a wearing feeling of a contact lens, which comprises an ophthalmic composition containing (A) selected from the group consisting of arginine and 2-amino-2. One or more selected from the group consisting of methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like, and (B) a polysaccharide.

Further, as an embodiment of the present invention, there is provided an (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, and 2-amine. The use of one or more of the group consisting of basal ethanol and the salt thereof, and (B) a polysaccharide, which is used for producing an ophthalmic composition for improving the wearing feeling of a contact lens.

Furthermore, as an embodiment of the present invention, there is provided a method for improving the wearing feeling of a contact lens, comprising the steps of: contacting an ophthalmic composition with a contact lens, the ophthalmic composition comprising (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and one or more of the group consisting of these salts, and (B) carbohydrate. This contacting step can be carried out in contact lens wear or in the case where the contact lens is not worn.

In addition, the type and content of the component (A) in the above-described respective embodiments, the type and content of other components, and the preparation form and use of the ophthalmic composition are as described in [1. Ophthalmic composition].

[Examples]

Hereinafter, the present invention will be specifically described based on test examples, but the present invention is not limited thereto.

[Test Example 1: Evaluation of tolerance to oxidative stress after hypoxia]

Each test liquid (ophthalmic composition) was prepared according to the formulation described in Table 1. The unit of each component amount in Table 1 is w/v%.

Immortalized human corneal epithelial cells (HCE-T) were seeded into 6-well plates in DMEM/F12 medium (Anti-anti 5 mL, DMSO 2.5 mL, EGF 0.5 mL, insulin 0.6 mL, and FBS were added to 470 mL of DMEM/F12 medium). The culture was carried out in 25 mL of the mixture until the fusion. After each test solution was diluted 10 times with the culture medium, 2 mL of each was added to each well, and the cells were cultured at 37 ° C for 18 hours under hypoxic conditions using AnaeroPack-Kenki (manufactured by Mitsubishi Gas Chemical Co., Ltd.). Thereafter, RNA was extracted from the cells using a QIAshredder & RNase Mini Kit (manufactured by QIAGEN), and reverse-transcribed into cRNA using SuperScript II (manufactured by Life Technologies), and then subjected to ABI QuantStudio Real Time PCR (manufactured by Thermo Fisher Co., Ltd.) for q- PCR (Quantitative Polymerase Chain Reaction, quantitative polymerase chain reaction), measuring the number of rising cycles (Ct) in the real-time PCR method. The relative expression ratio of the HMOX1, GPX1, and GSTp1 genes of Comparative Example 1-1 was determined by the following formula. The 18S gene (House Keeping gene) was used as an internal standard.

Performance ratio = 2 ^{- {(Ct value of the gene obtained by the test solution treatment) - (Ct value of 18S rRNA obtained by the test solution)}} /2 ^{- {(treated by Comparative Example 1-1) Ct value of the gene) - (Ct value of 18S rRNA obtained by the treatment of Comparative Example 1-1)}}

Further, HMOX1 is known to protect cells from oxidative stress, GPX1 is a gene that inhibits oxidative stress, and GSTp1 is a gene that acts on the repair of damaged cells.

The results are shown in Table 1.

Regarding the test liquid of Comparative Example 1-2 in which sodium hyaluronate was separately blended, the expression amount of these genes was hardly changed as compared with the test liquid of Comparative Example 1-1. On the other hand, with respect to the test liquids of Examples 1-1 and 1-2 in which arginine and sodium hyaluronate were blended, it was unexpectedly confirmed that the expression of these genes was remarkably increased.

According to the above results, it has been confirmed that the use of the ophthalmic composition of the present invention promotes "a gene that effectively acts on the oxidative stress generated by the hypoxic state" even when placed under a hypoxic condition. produce. Therefore, it was confirmed that the ophthalmic composition of the present invention is useful for the treatment or prevention of corneal damage caused by a hypoxic state.

[Test Example 2: Evaluation of cell activation]

Each test liquid (ophthalmic composition) was prepared according to the formulation described in Table 2. The unit of each component amount in Table 2 is w/v%.

Immortalized human corneal epithelial cells (HCE-T) were seeded to a 96-well plate in a manner of forming 1 × 10 ⁴ cells/well, and cultured until confluence. 100 μL of each test solution was added and incubated at 37 ° C for 20 minutes. At the same time, the following test preparations were prepared instead of the respective test solutions, that is, those obtained by performing the same treatment except for adding 100 μL of DMEM/F12 medium. Thereafter, the cell survival rate (%) of each test solution with respect to the control was determined using a Cell-counting kit-8. Then, the rate of increase (%) of the cell survival rate of each test liquid of Comparative Example 2-1 was calculated using the following formula.

The rate of increase in cell survival rate (%) with respect to Comparative Example 2-1 = {(cell survival rate of each test solution - cell survival rate of Comparative Example 2-1) / cell survival rate of Comparative Example 2-1} × 100

The results are shown in Table 2.

Regarding the test liquid of Comparative Example 2-2 in which sodium hyaluronate was separately blended, almost no increase in cell survival rate was observed as compared with the test liquid of Comparative Example 2-1. On the other hand, in the test liquids of Examples 2-1 to 2-3 in which arginine and sodium hyaluronate were blended, it was confirmed that the cell survival rate was remarkably increased.

From the above results, it was confirmed that the cell survival rate was remarkably increased by using the ophthalmic composition of the present invention, and therefore, even when placed in a state of lack of nutrition, the decrease in cell survival rate was reduced, that is, the corneal cells were activated.

[Test Example 3: Evaluation of the bactericidal power of Acanthamoeba]

Each test solution (contact lens disinfection/cleaning/preservation solution) was prepared according to the formulation described in Table 3. The unit of each component amount in Table 3 is w/v%. The sterilizing power against the nourishing type and the cyst type of Acanthamoeba was evaluated for each test liquid immediately after preparation and each test liquid stored at 60 ° C for 3 weeks.

Acanthamoeba castellanii was cultured in PYG liquid medium at 32.5 ° C for 3 days, and 1/4 RS (sodium chloride 0.215 g/100 mL, potassium chloride 0.0075 g/100 mL, CaCl ₂ .2H ₂ O) was used. After cleaning three times at 0.0083 g/100 mL, the mixture was adjusted so as to be about 2 × 10 ⁶ to 5 × 10 ⁶ cells/mL to obtain a microbial liquid. The test solution (10 mL) was taken out aseptically and placed in each of the three sterilized test containers, and inoculated with a microbial solution (0.1 mL), and finally set to about 2.0×10 ⁴ to 5.0×10 ⁴ cells/mL. .

After the obtained test liquid containing the microbial liquid was allowed to stand at 25 ° C for 4 hours, 0.5 mL of the test liquid containing the microbial liquid was taken out and added to the neutralizing solution (PYG liquid medium and DNB (Dey-Engley Neutralizing) A 10-fold diluted solution was prepared by neutralizing the test substance with Broth, Dey Engli and the culture solution) in a mixture of 8:1 (4.5 mL). This was added to each of 200 μL in a 96-well multiwell plate. Thereafter, 20 μL of each of the above 10-fold diluted solutions was added to each well of 180 μL of the PYG liquid medium, and the mixture was thoroughly mixed, and the above operation was repeated 4 times (until dilution 10 ⁴ times) to obtain a culture solution.

The obtained culture solution was cultured at 25 ° C for 7 days, and the presence or absence of proliferation of the test microorganism was confirmed under an inverted microscope. The number of proliferating pores was counted, and the number of nourishing bacteria of Acanthamoeba was calculated by the Spearman-Karber method. Then, the number of bacteria before the culture was compared with the number of bacteria after 7 days of culture, and the amount of decrease in the number of bacteria was calculated as a log reduction value. In addition, the method was carried out by the same method as the nourishing type, except that the PYG liquid medium was cultured in the PYG liquid medium, and the PYG liquid medium was changed to the EM liquid medium and further cultured at 25 ° C for 14 days. The number of cystic bacteria and logarithmic reduction of Acanthamoeba.

For each of the nourishing type and the cystic type of Acanthamoeba, the amoebicidal improvement rate (%) with respect to Comparative Example 3-1 was calculated using the following formula.

Amoebic bactericidal improvement rate (%) = {(log reduction value of each test example - logarithmic reduction value of "Comparative Example 3-1") / Logarithmic reduction value of "Comparative Example 3-1"} × 100

The calculated amoebic bactericidal improvement rate is shown in Table 3.

With respect to the test solutions of Examples 3-1 and 3-2, it was confirmed that the sterilizing power and the cyst form of Acanthamoeba showed excellent bactericidal power.

[Test Example 4: Evaluation of corneal staining]

Each test solution (contact lens disinfection/cleaning/preservation solution) was prepared according to the formulation described in Table 4. The unit of each component amount in Table 4 is w/v%. A contact lens (Acuvue Advance (registered trademark), manufactured by Johnson & Johnson Co., Ltd.) was immersed in each test solution (3 mL) overnight, and then allowed to be worn by four healthy persons.

Two hours after wearing the contact lenses, the surface of the eye was stained with luciferin and observed with a slit lamp.

According to the method described in the reference (Cornea, Vol. 30, No. 10, October 2011, p. 1098-1104), the surface of the eyeball is divided into five regions, and the evaluation is performed according to the following evaluation criteria. The average of the scores obtained by summing the scores of the five regions was calculated as the dye score.

<Evaluation criteria>

0: completely without dyeing

1: there is a slight stain

2: Moderate staining

3: There is serious staining

For the average of the dyeing scores, the case where 0 points or more and less than 2.5 points is evaluated as "◎", and the case where 2.5 points or more and less than 5 points is evaluated as "○", and 5 points or more and less than 10 points are evaluated. The case was evaluated as "△", and the case of 10 points or more and 15 minutes or less was evaluated as "X", and is shown in Table 4.

With respect to the test solutions of Examples 4-1 to 4-3, it was confirmed that the dyeing score was low. That is, it was revealed that the contact lenses immersed in the test liquids of Examples 4-1 to 4-3 were less likely to cause corneal staining.

[Test Example 5: Evaluation of contact lens wear feeling]

Each test solution (contact lens disinfection/cleaning/preservation solution) was prepared according to the formulation described in Table 5. The unit of each component amount in Table 5 is w/v%. A contact lens (Acuvue Advance (registered trademark), manufactured by Johnson & Johnson Co., Ltd.) was immersed in each test solution (3 mL) overnight, and then allowed to be worn by four healthy persons.

After wearing the contact lens, after wearing for 2 hours, and after wearing for 8 hours, the feelings of the symptoms described in Table 5 were evaluated by VAS (Visual analog scale).

The evaluation by VAS was carried out in the following manner. On the subjective symptom questionnaire with a line of 100 mm, the situation of each symptom described in Table 5 is not felt to be 0 mm, and the symptom is strongly felt to be 100 mm. Tick the extent of the symptoms you feel. This length (mm) is set to the VAS value. That is, the higher the VAS value, the higher the symptom score of each symptom.

Further, the rate of change (%) of the score with respect to Comparative Example 5-1 was calculated using the following formula.

Rate of change of score (%) = {(VAS value of each test example - VAS value of "Comparative Example 5-1") / VAS value of "Comparative Example 5-1"} × 100

The calculated rate of change in scores is shown in Table 5.

When the test liquid of Example 5-1 was used, the contact lens wearing feeling improved, the foreign body sensation and the tingling sensation were improved as compared with the test liquid of Comparative Example 5-1 at each time point of the evaluation. Since the sense of dryness and the feeling of dryness are reduced, it is confirmed that after 8 hours from the wearing, it is difficult to feel unpleasant feeling and the wearing feeling is improved.

[Test Example 6: Evaluation of tolerance to oxidative stress after hypoxia (2)]

Each test liquid (ophthalmic composition) was prepared according to the formulation described in Table 6. Table 6 The unit of the component is (w/v%) except those recorded in the table.

The relative expression ratio of the HMOX1 gene to the control was calculated by the same method as in Test Example 1, except that the gene to be measured was HMOX1 only, and the control was used instead of Comparative Example 1-1. The control system was the same as Comparative Example 6-1 except that it did not contain sodium hyaluronate.

After calculating the performance ratio of each formulation, the rate of increase with respect to the performance ratio of the corresponding formulation was calculated using the following formula.

Performance ratio of the comparative example corresponding to the rate of increase (%) = {(performance ratio of each test example - comparison ratio of the corresponding comparative examples)} × 100

Here, the comparative examples corresponding to Examples 6-1 to 6-3 are Comparative Example 6-1, and the comparative examples corresponding to Examples 6-4 and 6-5 are Comparative Example 6-2.

The calculated performance ratio is shown in Table 6.

It was confirmed that when the 2-amino-2-methyl-1,3-propanediol or tris(hydroxymethyl)aminomethane and the polysaccharide were blended, the performance of the HMOX1 gene was also remarkably increased.

[Test Example 7: Evaluation of tolerance to oxidative stress after hypoxia (3)]

Each test liquid (ophthalmic composition) was prepared in accordance with the formulation described in Table 7. The unit of each component amount in Table 7 is w/v%.

Immortalized human corneal epithelial cells (HCE-T) were seeded into 6-well plates in DMEM/F12 medium (Anti-anti 5 mL, DMSO 2.5 mL, EGF 0.5 mL, insulin 0.6 mL, and FBS were added to 470 mL of DMEM/F12 medium). The culture was carried out in 25 mL of the mixture until the fusion. 2 mL of each test solution was added to each well, and the mixture was cultured at 37 ° C for 18 hours under hypoxic conditions using AnaeroPack-Kenki (manufactured by Mitsubishi Gas Chemical Co., Ltd.). Thereafter, RNA was extracted from the cells using a QIAshredder & RNase Mini Kit (manufactured by QIAGEN), and reverse-transcribed into cRNA using SuperScript II (manufactured by Life Technologies), and then subjected to ABI QuantStudio Real Time PCR (manufactured by Thermo Fisher Co., Ltd.) for q- PCR, measuring the number of rising cycles (Ct) in the real-time PCR method. The relative expression ratio of the HMOX1, GPX1, and GSTp1 genes of Comparative Example 7-1 was determined using the following formula. The 18S gene (House Keeping) was used as an internal standard.

Performance ratio = 2 ^{- {(Ct value of the gene obtained by the test solution) - (Ct value of 18S rRNA obtained by the test solution)}} /2 ^{- {(treated by Comparative Example 7-1) Ct value of the gene) - (Ct value of 18S rRNA obtained by the treatment of Comparative Example 7-1)}}

The results are shown in Table 7.

It was confirmed that when the 2-amino-2-methyl-1,3-propanediol, 2-aminoethanol or tris(hydroxymethyl)aminomethane and polysaccharide were blended, the performance of the above genes was also significantly increased. .

[Formulation Example]

Ophthalmic compositions were prepared according to the formulations described in Tables 8 and 9, and Formulations 1 to 18 were prepared. The units in the table are (w/v%) except those recorded in the table.

Claims (5)

An ophthalmic composition comprising (A) selected from the group consisting of arginine, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, 2-aminoethanol, and the like One or more of the group consisting of the salt and (B) the polysaccharide. The ophthalmic composition according to the first aspect of the invention, wherein the component (A) is one or more selected from the group consisting of arginine and a salt thereof. An ophthalmic composition according to claim 1 or 2, wherein the component (B) is a mucopolysaccharide. The ophthalmic composition according to any one of claims 1 to 3, which further comprises (C) a bactericide or a preservative. An ophthalmic composition according to any one of claims 1 to 4, which is for use in a contact lens.