JP7251923B2 - OPHTHALMIC COMPOSITION AND METHOD FOR IMPROVING FRICTION REDUCING EFFECT THEREOF - Google Patents

Description

The present invention relates to ophthalmic compositions and methods of imparting friction-reducing action thereto.

Polyvinylpyrrolidone is used in the field of ophthalmic compositions, for example, as a solubilizing agent (Patent Document 1).

In the eye, friction occurs between the eyelid, cornea, and conjunctiva when motion such as blinking is applied, and this is said to be one of the causes of abnormalities in the keratoconjunctiva, tear film, and eyelid. there is In addition, especially when a contact lens is worn, friction is also generated between the contact lens and these tissues, and this friction is thought to lead to deterioration of the feeling of wearing the contact lens.
At present, methods for reducing friction in the eye have not been sufficiently studied.

JP-A-1-294620

An object of the present invention is to provide an ophthalmic composition that reduces friction in the eye.

As a result of intensive studies to solve the above problems, the present inventors selected polyvinylpyrrolidone (A) having a K value of 40 or more among polyvinylpyrrolidones as a component of an ophthalmic composition. Ophthalmology obtained by combining at least one (B) selected from the group consisting of biguanide fungicides and trometamol and at least one (C) selected from the group consisting of amino acids and thickeners The inventors have unexpectedly found that the composition can remarkably reduce the friction in the eye area, leading to the completion of the present invention.

That is, the present invention provides the following [1] to [7].
[1] Polyvinylpyrrolidone (A) having a K value of 40 or more, at least one selected from the group consisting of biguanide fungicides and trometamol (B), and selected from the group consisting of amino acids and thickeners An ophthalmic composition comprising at least one (C) of
[2] The ophthalmic composition according to [1], wherein the content of component (A) is 0.001 to 10 w/v%.
[3] The ophthalmic composition according to [1] or [2], wherein the component (A) is polyvinylpyrrolidone K90.
[4] The ophthalmic composition according to any one of [1] to [3], wherein the component (B) is a biguanide fungicide.
[5] Any one of [1] to [4], wherein the component (C) is at least one selected from the group consisting of aspartic acid, aminoethylsulfonic acid, mucopolysaccharides, cellulose derivatives and salts thereof. ophthalmic composition according to .
[6] Any one of [1] to [5], further comprising at least one (D) selected from the group consisting of nonionic surfactants, edetic acid and its salts, inorganic salts, and terpenoids An ophthalmic composition as described.
[7] Polyvinylpyrrolidone (A) having a K value of 40 or more, at least one (B) selected from the group consisting of biguanide fungicides and trometamol, and amino acids and thickeners in the ophthalmic composition A method of imparting a friction-reducing effect to an ophthalmic composition, comprising containing at least one (C) selected from the group consisting of:

The ophthalmic composition of the present invention comprises polyvinylpyrrolidone (A) having a K value of 40 or more, at least one (B) selected from the group consisting of biguanide fungicides and trometamol, amino acids and a thickener. By containing at least one (C) selected from the group consisting of, friction in the eye can be reduced.

Next, an embodiment of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

As used herein, the content unit "w/v %" indicates the ratio of mass to volume, and is synonymous with "g/100 mL".
As used herein, unless otherwise specified, the abbreviation "POE" means polyoxyethylene.
As used herein, unless otherwise specified, the abbreviation "POP" means polyoxypropylene.

The ophthalmic composition according to the present embodiment comprises polyvinylpyrrolidone (A) having a K value of 40 or more, at least one (B) selected from the group consisting of biguanide fungicides and trometamol, amino acids and a thickener. and at least one selected from the group consisting of agents (C). They will be described in order below.

<(A) Component>
The polyvinylpyrrolidone (A) having a K value of 40 or more is a nonionic water-soluble polymer, and the relative viscosity value (25° C.) measured by a capillary viscometer is applied to the following formula (1). The viscosity characteristic value (K value) calculated as above is 40 or more.

〔formula〕
K=(1.5logη _rel −1)/(0.15+0.003c)+[300clogη _rel +(c+1.5clogη _rel ) ² ] ^1/2 /(0.15c+0.003c ² ) (1)
η _rel : Relative viscosity of polyvinylpyrrolidone aqueous solution to water c: Polyvinylpyrrolidone concentration (%) in polyvinylpyrrolidone aqueous solution

Examples of polyvinylpyrrolidone (A) having a K value of 40 or more include polyvinylpyrrolidone K40, polyvinylpyrrolidone K50, polyvinylpyrrolidone K60, polyvinylpyrrolidone K80, polyvinylpyrrolidone K85, polyvinylpyrrolidone K90, and polyvinylpyrrolidone K120.

Among these, polyvinylpyrrolidone with a K value of 50 or more is preferable, polyvinylpyrrolidone with a K value of 70 or more is more preferable, and polyvinylpyrrolidone with a K value of 90 or more is further preferable, from the viewpoint of exhibiting the effects of the present invention more remarkably. Even more preferred is polyvinylpyrrolidone with a K value of 90-120. Among them, polyvinylpyrrolidone K90 is particularly preferably used. Here, the K value is 90 to 108% of the displayed K value according to the description of the K value in the Japanese Pharmacopoeia 16th Edition "Povidone", so for example, "K90" is the above formula The viscosity characteristic value (K value) calculated by applying (1) is in the range of 81.0 to 97.2.

The above-mentioned polyvinylpyrrolidone K90 may be synthesized by a known method. ), Povidone K90 (manufactured by DSP Gokyo Food & Chemical Co., Ltd.) and other commercially available products may be used. And these may be used individually by 1 type, or may be used in combination of 2 or more type.

Although the content of the component (A) is not particularly limited, for example, the total content of the component (A) is 0.001 based on the total amount of the ophthalmic composition according to the present embodiment. ~10 w/v%, more preferably 0.005 to 5.0 w/v%, even more preferably 0.01 to 3.0 w/v%, and 0.03 to 1 0 w/v % is particularly preferred. The content of the above component (A) is suitable from the viewpoint of exhibiting the effects of the present invention more remarkably. Also, 0.001 to 0.5 w/v%, especially 0.002 to 0.4 w/v%, further 0.003 to 0.3 w/v%, especially 0.005 to 0.1 w/v% It is preferably used.

<(B) Component>
The ophthalmic composition according to the present embodiment contains at least one (B) selected from the group consisting of biguanide fungicides and trometamol together with the above component (A) and the component (C) described below.

<Biguanide fungicide>
The biguanide fungicide is a compound having at least one biguanide group represented by the formula: -NH-C (= NH) -NH-C (= NH) -NH- in the structural formula, and biguanide It is a known fungicide as a monomer having at least one group, a polymer composed of the monomer, and a salt form compound thereof, and can be produced by a known method or obtained as a commercial product.

The biguanide fungicide used in the present embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Compounds represented by 3), (4) and (5) are exemplified. These compounds may be in the form of salts.

In the general formulas (2) and (3), n is an integer of 1 or more, preferably an integer of 1 to 500, more preferably an integer of 1 to 100, more preferably an integer of 1 to 40, particularly preferably 10 ˜13 integers.

Specific examples of the biguanide fungicide used in the present embodiment include hexamethylene biguanide and its polymers (that is, polyhexamethylene biguanide (abbreviation: PHMB), polyhexanide), chlorhexidine, alexidine, hexetidine, and the like. Hexamethylenebiguanide and its polymer are preferred, and hexamethylenebiguanide polymer is more preferred, from the viewpoint of exhibiting the effects of the invention more remarkably.

The biguanide fungicide salt used in this embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Salts of biguanide fungicides used in the present embodiment include, for example, inorganic acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid, phosphoric acid, nitric acid; acetic acid, gluconic acid, maleic acid, ascorbic acid, stearin acid, tartaric acid, organic acid salts such as citric acid; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, etc.; is more preferred.
Specific examples of the salts of biguanide fungicides include polyhexanide hydrochloride (polyhexamethylenebiguanide hydrochloride), alexidine hydrochloride, and chlorhexidine gluconate. Polyhexanide hydrochloride and chlorhexidine gluconate are preferred, and polyhexanide hydrochloride is more preferred.

The content of the biguanide-based fungicide is not particularly limited, but is appropriately set according to the type, the components used in combination, the content, and the like. As the content of the biguanide fungicide, for example, based on the total amount of the ophthalmic composition according to the present embodiment, the content of the biguanide fungicide is usually 0.0000001 to 0.1 w/v%, and 0 preferably 0.000001 to 0.01 w/v%, more preferably 0.00001 to 0.001 w/v%, even more preferably 0.00001 to 0.00015 w/v%, 0.00002 to 0.0001 w/v% is particularly preferred.

In the ophthalmic composition according to the embodiment of the present invention, the content ratio of the biguanide fungicide to the component (A) is not particularly limited, and the types of the component (A) and the biguanide antibacterial agent, and the types and contents of other ingredients It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The content ratio of the biguanide fungicide to the component (A) is, from the viewpoint of exhibiting the effect of the present invention more remarkably, for example, the total content of the component (A) contained in the ophthalmic composition according to the present embodiment is 1 mass. The total content of the biguanide fungicide is preferably 0.000001 to 1 part by mass, more preferably 0.000005 to 0.5 part by mass, and 0.00001 to 0.5 part by mass. It is more preferably 1 part by mass, and even more preferably 0.00005 to 0.01 part by mass.

<Trometamol>
Trometamol is a known compound represented by the formula: C ₄ H ₁₁ NO ₃ , and may be synthesized by a known method or commercially available.

The content of trometamol in the ophthalmic composition according to the present embodiment is not particularly limited, but is appropriately set according to the type, the components used in combination, the content, and the like. The content of trometamol is, for example, preferably 0.001 to 20 w/v%, preferably 0.005 to 10 w/v, based on the total amount of the ophthalmic composition according to the present embodiment. %, more preferably 0.01 to 5 w/v%, even more preferably 0.05 to 1 w/v%, and 0.05 to 0.5 w/v% It is particularly preferred to have Moreover, as a content of trometamol, 0.2 w/v% or less is mentioned as a preferable form.

The content ratio of trometamol to component (A) in the ophthalmic composition according to the embodiment of the present invention is not particularly limited, and the type of component (A), the type and content of other compounding components, the use of the ophthalmic composition and the It is appropriately set according to the formulation form and the like. The content ratio of trometamol to the component (A) is, from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to the present embodiment. the total content of trometamol is preferably 0.005 to 500 parts by mass, more preferably 0.01 to 100 parts by mass, even more preferably 0.05 to 50 parts by mass, Even more preferably, it is 0.1 to 20 parts by mass.

The biguanide fungicide and trometamol of component (B) may be used singly or in any combination of two or more. Among component (B), from the viewpoint of friction reduction rate, biguanide fungicides are preferred, chlorhexidine gluconate and polyhexanide hydrochloride are more preferred, and polyhexanide hydrochloride is even more preferred. From another point of view, polyhexanide hydrochloride, chlorhexidine gluconate, and trometamol are sometimes preferred.

As for the content of component (B), for example, the content of component (B) is usually 0.0000001 to 20 w/v% and 0.000001 based on the total amount of the ophthalmic composition according to the present embodiment. It is preferably 5 w/v %, more preferably 0.00001 to 1 w/v %, even more preferably 0.00002 to 0.5 w/v %.

In the ophthalmic composition according to the embodiment of the present invention, the content ratio of component (B) to component (A) is not particularly limited. It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. As for the content ratio of component (B) to component (A), from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, the total content of component (A) contained in the ophthalmic composition according to the present embodiment is 1 mass. parts, the total content of component (B) is preferably 0.000001 to 500 parts by mass, more preferably 0.000005 to 100 parts by mass, and 0.00001 to 50 parts by mass. more preferably 0.00005 to 20 parts by mass.

<(C) Component>
The ophthalmic composition according to the present embodiment contains at least one (C) selected from the group consisting of amino acids and thickeners, along with the components (A) and (B).

<Amino acids>
The above amino acids mean compounds or derivatives thereof having an amino group and a carboxy group or a sulfo group in the molecule. Specifically, amino acids, mucopolysaccharides and derivatives thereof, and salts thereof are exemplified. Salts of amino acids, mucopolysaccharides and their derivatives include pharmaceutically, pharmacologically or physiologically acceptable salts. Examples of salts of amino acids, mucopolysaccharides and derivatives thereof include salts with organic acids [e.g., monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.) carboxylic acid salt (fumarate, maleate, etc.), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, etc.)], salts with inorganic acids (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc.), salts with organic bases (e.g., methylamine, triethylamine, salts with organic amines such as triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, and picoline), salts with inorganic bases [e.g., ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc.], etc., and are appropriately selected depending on the compound. Among them, salts with inorganic bases are preferred, and alkali metal salts and alkaline earth metal salts are more preferred. Among amino acids, amino acids and salts thereof include, for example, monoaminomonocarboxylic acids such as glycine, alanine, γ-aminobutyric acid, and γ-aminovaleric acid; monoaminodicarboxylic acids such as aspartic acid and glutamic acid; and salts thereof. diaminomonocarboxylic acids such as arginine and lysine and salts thereof; derivatives such as aminoethylsulfonic acid (taurine) and salts thereof. The amino acids and salts thereof may be L-, D-, or DL-forms, and examples thereof include potassium L-aspartate, magnesium L-aspartate, and a mixture of equal amounts of magnesium and potassium L-aspartate. . Among amino acids, mucopolysaccharides and salts thereof include, for example, chondroitin sulfate, hyaluronic acid, alginic acid and salts thereof.

Among such amino acids, L-aspartic acid, aminoethylsulfonic acid, mucopolysaccharides and salts thereof are particularly preferred, such as potassium L-aspartate, magnesium L-aspartate, and magnesium/potassium L-aspartate. Aminoethylsulfonic acid, mucopolysaccharides are more preferred, mucopolysaccharides are more preferred, sodium chondroitin sulfate, sodium hyaluronate are even more preferred, and sodium chondroitin sulfate is particularly preferred. From another point of view, L-aspartic acid, aminoethylsulfonic acid, chondroitin sulfate, hyaluronic acid and salts thereof are preferable. , aminoethylsulfonic acid, sodium chondroitin sulfate and sodium hyaluronate are more preferable, and potassium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate and sodium hyaluronate are more preferable.

The content of the above amino acids is not particularly limited, and is appropriately set according to the type of amino acid, the type and content of components (A) and (B) used in combination, and the like. As for the content of amino acids, for example, the total content of amino acids is preferably 0.0001 to 10 w/v%, preferably 0.0005 to 10 w/v%, based on the total amount of the ophthalmic composition according to the present embodiment. It is more preferably 5 w/v%, even more preferably 0.001 to 4 w/v%, even more preferably 0.01 to 3 w/v%, and 0.1 to 2.5 w/v%. v% is particularly preferred. In addition, as a content of amino acids, 2 w/v % or less is also mentioned as a preferable form. The content of the above amino acids is preferable from the viewpoint of exhibiting the effects of the present invention more remarkably.

When the amino acids are chondroitin sulfate and salts thereof, for example, the total content of chondroitin sulfate and salts thereof is 0.01 to 5 w/v% based on the total amount of the ophthalmic composition according to the present embodiment. It is preferably 0.05 to 3 w/v%, more preferably 0.1 to 1 w/v%.
When the amino acids are hyaluronic acid and its salts, for example, based on the total amount of the ophthalmic composition according to the present embodiment, the total content of hyaluronic acid and its salts is 0.001 to 0.5 w/v. %, more preferably 0.01 to 0.3 w/v %, even more preferably 0.05 to 0.1 w/v %.

In the ophthalmic composition according to the embodiment of the present invention, the content ratio of amino acids to component (A) is not particularly limited. It is appropriately set according to the use of the product, the formulation form, and the like. As the content ratio of the amino acids to the component (A), from the viewpoint of exhibiting the effect of the present invention more significantly, for example, the total content of the component (A) contained in the ophthalmic composition according to the present embodiment is 1 part by mass. On the other hand, the total content of amino acids is preferably 0.00005 to 500 parts by mass, more preferably 0.0001 to 100 parts by mass, and further preferably 0.0005 to 50 parts by mass. More preferably, it is 0.001 to 10 parts by mass.

When the amino acids are chondroitin sulfate and its salt, the content ratio of chondroitin sulfate and its salt to the component (A) is, for example, the ophthalmological The total content of chondroitin sulfate and its salts is preferably 0.01 to 500 parts by mass, preferably 0.05 to 100 parts by mass, per 1 part by mass of the total content of component (A) contained in the composition. parts is more preferable, and 0.1 to 50 parts by mass is even more preferable.
When the amino acids are hyaluronic acid and its salts, the content ratio of hyaluronic acid and its salts to the component (A) is, for example, the ophthalmology according to the present embodiment, from the viewpoint of exhibiting the effects of the present invention more remarkably. The total content of hyaluronic acid and its salts is preferably 0.001 to 500 parts by mass, preferably 0.01 to 100 parts by mass, per 1 part by mass of the total content of component (A) contained in the composition. parts is more preferable, and 0.1 to 50 parts by mass is even more preferable.

<Thickener>
Examples of the thickener include polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30), carboxyvinyl polymer, cellulose derivatives [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose ) (2208, 2906, 2910, etc.), carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose or salts thereof], gum arabic, tragacanth, dextran (40, 70, etc.), etc., preferably polyvinyl alcohol (whole or partial saponified products), polyvinylpyrrolidone (K25, K30), carboxyvinyl polymer, cellulose derivatives, dextran (70), more preferably cellulose derivatives, still more preferably hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and still more Hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906 and hydroxypropylmethylcellulose 2910 are preferred, and hydroxypropylmethylcellulose 2906 is particularly preferred. These thickeners may be used singly or in any combination of two or more.

When the above-mentioned thickening agent is contained, its content is appropriately set according to the type of thickening agent, the type and content of other ingredients, and the like. As for the content of the thickening agent, for example, the total content of the thickening agent is preferably 0.0001 to 5 w/v%, based on the total amount of the ophthalmic composition according to the present embodiment. 001 to 3 w/v%, more preferably 0.005 to 1.5 w/v%, and particularly preferably 0.01 to 1 w/v%.

In the ophthalmic composition according to the embodiment of the present invention, the content ratio of the thickener to the component (A) is not particularly limited, and the types of the component (A) and the thickener, the types and contents of other ingredients, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the thickening agent to the component (A) is, for example, 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to the present embodiment, from the viewpoint of exhibiting the effects of the present invention more remarkably. The total content of the thickener is preferably 0.001 to 500 parts by mass, more preferably 0.005 to 100 parts by mass, and 0.01 to 50 parts by mass is more preferable, and 0.05 to 10 parts by mass is even more preferable.

When the above-mentioned thickening agent is contained, its content is appropriately set according to the type of component (C), the type and content of other components, and the like. As for the content of component (C), for example, the total content of component (C) is preferably 0.0001 to 10 w/v% based on the total amount of the ophthalmic composition according to the present embodiment, It is more preferably 0.0005 to 5 w/v%, even more preferably 0.001 to 3 w/v%, even more preferably 0.01 to 2 w/v%, and 0.1 to 1 w/v % is particularly preferred.

In the ophthalmic composition according to the embodiment of the present invention, the content ratio of the thickener to the component (A) is not particularly limited, and the types of components (A) and (C), the types and contents of other ingredients , is appropriately set according to the use and formulation form of the ophthalmic composition. As for the content ratio of component (C) to component (A), from the viewpoint of exhibiting the effect of the present invention more remarkably, for example, the total content of component (A) contained in the ophthalmic composition according to the present embodiment is 1 mass. The total content of the thickening agent is preferably 0.00005 to 500 parts by mass, more preferably 0.0001 to 100 parts by mass, and 0.0005 to 50 parts by mass. is more preferable, and 0.001 to 10 parts by mass is even more preferable.

<(D) Component>
Further, from the viewpoint of exhibiting the effects of the present invention more remarkably, the ophthalmic composition according to the present embodiment further includes a nonionic surfactant, edetic acid and its salts, inorganic salts, and terpenoids. It is preferable to contain at least one (D).

<Nonionic surfactant>
The nonionic surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Specific examples of nonionic surfactants include, for example, POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 80), POE sorbitan monostearate (polysorbate 60), POE sorbitan fatty acid esters such as POE sorbitan tristearate (polysorbate 65), POE hydrogenated castor oil 5, POE hydrogenated castor oil 10, POE hydrogenated castor oil 20, POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil such as POE hydrogenated castor oil 100, POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17 , POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, POE castor oil 50, polyethylene glycol monostearate (2E.O.), polyethylene glycol monostearate (4E .O.), polyethylene glycol monostearate (9 E.O.), polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (23 E.O.), polyethylene glycol monostearate (25 E.O.) ), polyethylene glycol monostearate (32 E.O.), polyethylene glycol monostearate (40 E.O., polyoxyl 40 stearate), polyethylene glycol monostearate (45 E.O.), polyethylene glycol monostearate ( 55 E.O.), polyethylene glycol monostearate (75 E.O.), polyethylene glycol monostearate such as polyethylene glycol monostearate (140 E.O., polyoxyl 140 stearate), POE (196) POP (67) Glycol (Poloxamer 407, Pluronic F127), POE(54) POP(39) Glycol (Poloxamer 235), POE(160) POP(30) Glycol (Poloxamer 188), POE(42) POP(67) Glycol (Poloxamer 403) POE-POP block copolymers such as POE(120)POP(40) glycol (poloxamer 237), POE(200)POP(70) glycol, POE-POP block copolymer adducts of ethylenediamine such as poloxamine, POE(9) lauryl Examples include POE alkyl ethers such as ethers, POE/POP alkyl ethers such as POE(20)POP(4) cetyl ether, and POE alkylphenyl ethers such as POE(10) nonylphenyl ether. The numbers in parentheses indicate the number of added moles.

More preferably, one or more nonionic surfactants having an HLB value of less than 10 are combined with the ophthalmic composition according to the present embodiment.

Examples of nonionic surfactants having an HLB value of less than 10 include POE hydrogenated castor oil and POE castor oil 3 having an average added mole number of ethylene oxide of less than 20, such as POE hydrogenated castor oil 5 and POE hydrogenated castor oil 10. , POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, etc. with an average added mole number of ethylene oxide of less than 23 Some POE castor oil, polyethylene glycol monostearate (2E.O.), polyethylene glycol monostearate (4E.O.), and other polyethylene glycol monostearate in which the average number of added moles of ethylene oxide is less than 7. Among them, POE hydrogenated castor oil in which the average number of moles of ethylene oxide added is less than 20, and POE castor oil in which the average number of moles of ethylene oxide added is less than 23, from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferred, POE castor oil having an average added mole number of ethylene oxide of less than 23 is more preferred, and POE castor oil 3 and POE castor oil 10 are even more preferred.

When the above nonionic surfactant is contained, its content depends on the type of nonionic surfactant used, the type and content of other ingredients, the application of the ophthalmic composition, the formulation form, the method of use, etc. Although it is set appropriately, for example, the total content of the nonionic surfactant is preferably 0.001 to 3 w/v%, based on the total amount of the ophthalmic composition according to the present embodiment, and 0.005 It is more preferably ~2 w/v%, still more preferably 0.01 to 1 w/v%, and particularly preferably 0.05 to 1 w/v%.

<Edetic acid and its salts>
The edetic acid (ethylenediaminetetraacetic acid, EDTA) is a known compound represented by the formula: C ₁₀ H ₁₆ N ₂ O ₈ and can be synthesized by a known method or commercially available.
Examples of salts of edetic acid include alkali metals such as sodium edetate, disodium edetate, and tetrasodium edetate. Examples of hydrates include dihydrate of disodium edetate. edetate sodium hydrate.
Among these, disodium edetate dihydrate is preferably used.

When at least one of the edetic acid and its salt is contained, the content thereof is appropriately set according to the type of edetic acid and its salt, the type and content of other ingredients, and the like. The content of at least one kind of edetic acid and its salt is, for example, based on the total amount of the ophthalmic composition according to the present embodiment, the total content of at least one kind of edetic acid and its salt is from 0.001 to It is preferably 1 w/v %, more preferably 0.005 to 0.5 w/v %, even more preferably 0.01 to 0.1 w/v %.

<Inorganic salts>
Examples of the inorganic salts include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate and magnesium sulfate. Among them, potassium chloride, calcium chloride, sodium chloride, sodium hydrogen carbonate, sodium carbonate and magnesium sulfate are preferred, and potassium chloride and sodium chloride are more preferred.

When the above inorganic salts are contained, the content thereof is appropriately set according to the type of inorganic salts, the types and content of other ingredients, and the like. As for the content of inorganic salts, for example, the total content of inorganic salts is preferably 0.0001 to 5 w/v%, based on the total amount of the ophthalmic composition according to the present embodiment, and 0.001 to 3 w/v % is more preferable, and 0.005 to 1 w/v % is even more preferable.

<Terpenoid>
Terpenoids include, for example, menthol (l-menthol, dl-menthol, etc.), menthone, camphor (d-camphor, dl-camphor, etc.), borneol (d-borneol, dl-borneol, etc.), geraniol, cineol, citral, Examples include linalool, anethole, limonene, and eugenol. These may be d-, l-, or dl-forms, but from the viewpoint of exhibiting the effects of the present invention more remarkably, l-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, and geraniol are used. It is preferable to use Among them, l-menthol, d-camphor, dl-camphor and geraniol are preferred, and l-menthol is more preferred. The terpenoids can also be used in a state of being contained in essential oils, and preferred essential oils are peppermint oil, peppermint oil, eucalyptus oil, bergamot oil, fennel oil, cinnamon oil, rose oil, and the like. These terpenoids can be used singly or in combination of two or more.

The content of the terpenoid is not particularly limited, and is appropriately set according to the type of terpenoid, the type and content of other ingredients, and the like. As for the content of terpenoids, for example, based on the total amount of the ophthalmic composition according to the present embodiment, the total content of terpenoids is preferably 0.00001 to 0.3 w/v%, preferably 0.0001 to It is more preferably 0.1 w/v%, still more preferably 0.0005 to 0.05 w/v%, and particularly preferably 0.001 to 0.02 w/v%. The content of the terpenoid is preferable from the viewpoint of exhibiting the effects of the present invention more remarkably.

<Other optional ingredients>
The ophthalmic composition according to this embodiment preferably further contains a buffer in order to further enhance the effects of the present invention. Thereby, the effect of the present invention can be exhibited more remarkably. The buffering agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of such buffers include borate buffers, phosphate buffers, carbonate buffers, citrate buffers, acetate buffers, and the like. These buffering agents may be used singly or in combination of two or more. Examples of boric acid buffers include boric acid or salts thereof (alkali metal borates, alkaline earth metal borates, etc.). Phosphate buffers include phosphoric acid and salts thereof (alkali metal phosphate, alkaline earth metal phosphate, etc.). Carbonic acid buffering agents include carbonic acid and salts thereof (alkali metal carbonates, alkaline earth metal carbonates, etc.). Citric acid buffers include citric acid or salts thereof (alkali metal citrate, alkaline earth metal citrate, etc.). Acetate buffers include acetic acid and salts thereof (alkali metal acetate, alkaline earth metal acetate, etc.). In addition, borate, phosphate, carbonate, citrate or acetate hydrates are used as borate buffers, phosphate buffers, carbonate buffers, citrate buffers or acetate buffers. good too. More specific examples include boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a borate buffer; Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); or salts thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); calcium acetate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid or salts thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.), etc., can be exemplified as acetate buffers. Among these buffers, boric acid buffers (for example, a combination of boric acid and borax) and phosphate buffers (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) are preferred. Borate buffers are more preferred.

When the above buffer is contained, its content is appropriately set according to the type of buffer, the type and content of other components, and the like. As the content of the buffering agent, for example, the total content of the buffering agent is preferably 0.01 to 10 w/v%, based on the total amount of the ophthalmic composition according to the present embodiment, and 0.05 to It is more preferably 5 w/v %, still more preferably 0.1 to 3 w/v %, and particularly preferably 0.5 to 2 w/v %.

The ophthalmic composition according to this embodiment may further contain a polyhydric alcohol from the viewpoint of further enhancing the effects of the present invention. Polyhydric alcohols include, for example, polyethylene glycol (400, 4000, 6000, etc.), propylene glycol, glycerin and the like. As the polyhydric alcohol, propylene glycol, glycerin, and polyethylene glycol are preferred, and polyethylene glycol is more preferred, from the viewpoint of exhibiting the effects of the present invention more remarkably. A commercially available polyhydric alcohol can also be used. A polyhydric alcohol may be used individually by 1 type, or may be used in combination of 2 or more type.

The content of the polyhydric alcohol that can be used in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the form and the like. As for the content of the polyhydric alcohol, from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, the total content of the polyhydric alcohol is 0.01 to 5 w/v% based on the total amount of the ophthalmic composition. preferably 0.05 to 2 w/v%, more preferably 0.1 to 1 w/v%, particularly 0.1 to 0.5 w/v% preferable.

The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. The pH of the ophthalmic composition is, for example, preferably 4.0 to 9.5, more preferably 5.0 to 9.0, even more preferably 5.5 to 8.5. .

Moreover, the osmotic pressure ratio of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a range acceptable to living organisms. The osmotic pressure ratio of the ophthalmic composition is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and further preferably 0.7 to 2.0. It is preferably 0.9 to 1.55, and particularly preferably 0.9 to 1.55. Adjustment of osmotic pressure can be performed by methods known in the art using inorganic salts, polyhydric alcohols, sugar alcohols or sugars. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w/v% sodium chloride aqueous solution) based on the 16th revision of the Japanese Pharmacopoeia, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia. (freezing point depression method). In addition, for the standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes, in a desiccator (silica gel) Allow to cool, accurately weigh 0.900 g, dissolve in purified water to prepare 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 according to this embodiment is not particularly limited as long as it is within a range acceptable to living organisms. The viscosity at 25 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34′ × R24) is, for example, preferably 1 to 1000 mPa s, 1 to 100 mPa s. s, more preferably 1 to 50 mPa·s.

In addition, the ophthalmic composition according to this embodiment may contain appropriate amounts of various pharmacologically active ingredients or physiologically active ingredients in addition to the above ingredients as long as the effects of the present invention are not impaired. Such ingredients are not particularly limited, and can be exemplified by, for example, active ingredients in various drugs described in the 2012 version of the Standards for Approval of Manufacturing and Marketing of OTC Drugs (supervised by the Japanese Society of Regulatory Science). Specifically, the components used in ophthalmic drugs include the following components.
Antihistamines: for example, iproheptine, diphenhydramine, chlorpheniramine maleate, ketotifen fumarate, olopatadine hydrochloride, levocabastine hydrochloride and the like.
Antiallergic agents: for example, sodium cromoglycate, tranilast, pemirolast potassium, acitazanolast and the like.
Steroid agents: for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide and the like.
Decongestants: for example, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride and the like.
Ocular muscle modulating agents: For example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methyl sulfate, tropicamide, helenien, atropine sulfate, and the like.
Anti-inflammatory agents: for example, glycyrrhetinic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, pranoprofen, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, ε-aminocaproic acid, berberine chloride, berberine sulfate, sodium azulene sulfonate, lysozyme, Licorice, etc.
Astringents: For example, zinc white, zinc lactate, zinc sulfate and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, retinol acetate, retinyl palmitate, tocopherol acetate and the like.
Local anesthetics: For example, lidocaine and the like.
Others: For example, sulfamethoxazole, sulfamethoxazole sodium and the like.

In addition, in the ophthalmic composition according to the present embodiment, various additives are appropriately selected according to a conventional method according to the application or formulation form, as long as the effects of the invention are not impaired. Two or more of them may be used in combination and contained in an appropriate amount. Examples of such additives include various additives described in Pharmaceutical Excipients Encyclopedia 2016 (edited by Japan Pharmaceutical Excipients Association). Typical ingredients include the following additives.
Carrier: For example, an aqueous carrier such as water or hydrous ethanol.
Sugars: For example, glucose, cyclodextrin, glucose and the like.
Sugar alcohols: for example xylitol, sorbitol, mannitol and the like. These may be d-, l- or dl-isomers.
Stabilizers: For example, sodium formaldehyde sulfoxylate (Rongalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, dibutylhydroxytoluene, sodium bisulfite, sodium sulfite and the like.
Anionic surfactants: for example, alkylbenzenesulfonates, alkylsulfates, polyoxyethylene alkylsulfates, α-sulfofatty acid ester salts, α-olefinsulfonic acids and the like.
Preservatives, bactericides or antibacterial agents other than component (B): for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorobutanol, sorbic acid, potassium sorbate, Sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol and the like.
pH adjusters: e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinate acid, gluconolactone, ammonium acetate and the like.
Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil and olive oil, animal oils such as squalane, mineral oils such as liquid paraffin and petrolatum.

The ophthalmic composition according to the present embodiment is prepared by adding the above components (A) to (C) and, if necessary, other optional components to a carrier so as to obtain the desired content. As the carrier, pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable water may be used, and examples of such water include distilled water, ordinary water, purified water, and sterilized water. Purified water, water for injection, distilled water for injection and the like are exemplified.

Then, for example, these components are dissolved or suspended in purified water, adjusted to a predetermined pH and osmotic pressure ratio, and sterilized by filtration sterilization or the like to prepare the ophthalmic composition according to the present embodiment. can be done.

The ophthalmic composition according to the present embodiment has a water content of 85 w/v% or more, preferably 90 w/v% or more, and 92 w/v% or more, relative to the total amount of the ophthalmic composition. is more preferably 94 w/v % or more, and particularly preferably 95 w/v % or more.

The ophthalmic composition according to this embodiment can take various formulation forms depending on the purpose. Formulations include, for example, liquids, gels, semi-solids (ointments, etc.) and the like. The ophthalmic composition according to this embodiment is preferably a liquid formulation.

The ophthalmic composition according to this embodiment is provided in an arbitrary container. The container for containing the ophthalmic composition according to this embodiment is not particularly limited, and may be made of glass or plastic, for example. It is preferably made of plastic. Examples of plastics include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, copolymers of these monomers, and mixtures of two or more of these. Preferred is polyethylene terephthalate. Further, the container containing the ophthalmic composition according to the present embodiment may be a transparent container in which the inside of the container is visible, or an opaque container in which the inside of the container is difficult to be seen. A transparent container is preferred. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container. The ophthalmic composition according to the present embodiment can be used, for example, by storing it in a colored and transparent plastic container or the like in the form of a multi-dose that can be used repeatedly. Moreover, as another aspect, it can be used by housing in the form of a unit dose.

The ophthalmic composition according to the present embodiment can be used as a pharmaceutical or quasi-drug formulation, in addition to so-called eye drops (where eye drops include eye drops that can be applied while wearing contact lenses). , eye wash (however, eye wash includes eye wash that can be washed while wearing contact lenses), contact lens composition [contact lens wetting solution, contact lens care composition (contact lens disinfectant, contact lens Preservatives, cleaning agents for contact lenses, cleaning and preserving agents for contact lenses, disinfecting, cleaning, and preserving solutions for contact lenses (multi-purpose solution), etc.], use as both contact lens wetting solutions and eye drops while wearing contact lenses eye drops for contact lenses, etc., used for Preferred examples of the present invention include eye drops, eye washes, contact lens-wearing solutions, and contact lens-wearing eye drops, and particularly preferred examples include eye drops, contact lens-wearing solutions, and contact lens-wearing eye drops. When used as a composition for contact lenses, hard contact lenses, soft contact lenses (including both ionic and non-ionic), silicone hydrogel contact lenses and non-silicone hydrogel contact lenses. It is applicable to any contact lens, including gel contact lenses.

In addition, in the present embodiment, it is possible to reduce the friction that occurs at the time of blinking or the like in the eye regardless of whether the contact lens is worn with the naked eye or when the contact lens is worn. Since friction is generated between the contact lens and the cornea, etc., the effect of reducing friction is more pronounced. Therefore, the ophthalmic composition is preferably for contact lenses, particularly preferably for soft contact lenses. Among soft contact lenses, colored contact lenses with colors or patterns printed on the surface by a method such as printing have greater friction on the contact lens surface than non-colored contact lenses. Ophthalmic compositions are particularly preferred. In addition, silicone hydrogel contact lenses, which generally tend to have higher hardness than other soft contact lenses, have a large impact on the surface of the eyeball due to friction. is particularly preferred.

(I) Friction-Reducing Effect By using the ophthalmic composition according to the present embodiment, an effect of reducing friction in the eye can be expected.

(II) Cell activating effect In general, wear of contact lenses reduces the fluidity of tears and deterioration of tear quality due to aging, etc., which exposes the eye to malnutrition. Although the survival rate of corneal cells may decrease, the use of the ophthalmic composition according to the present embodiment significantly increases the survival rate of corneal cells (activation of corneal cells).

(III) Oxidative stress resistance after exposure to hypoxia In general, when the contact lens is worn and the eye becomes hypoxic, and then the contact lens is removed, or when waking up from sleep, an excessive amount of oxygen is released. As a result, oxidative stress occurs on the keratoconjunctiva, and inflammation, corneal damage, etc. tend to occur. can be reduced.
Since IL-6 is released when inflammation occurs, the degree of inflammation due to oxidative stress after exposure to hypoxia can be measured by measuring the expression level of the IL-6 gene.
In addition, mucins are important for the homeostasis of tears and the ocular surface, and it has been reported that oxidative stress reduces the expression of mucins on the corneal surface. Corneal damage caused by oxidative stress after exposure to hypoxia can be evaluated using the expression level of MUC1, a gene involved in mucin expression, as an index.
On the other hand, with the occurrence of damage to the cornea due to oxidative stress after exposure to hypoxia, various antioxidant factors are secreted to reduce oxidative stress. By measuring genes caused by antioxidant factors such as GSTp-1 (one of the genes related to the expression of antioxidant factors) and HMOX-1 (one of the genes related to the expression of antioxidant factors), the can measure resistance to oxidative stress in

(IV) The ophthalmic composition according to the present embodiment is selected from the group consisting of pranoprofen or a salt thereof, an anti-allergic agent, an anti-inflammatory agent, and a water-soluble vitamin, from the viewpoint of more preferably expressing the above effects. It is preferable to exclude from the ophthalmic composition according to the present embodiment a combination of formulations containing at least one compound of the present embodiment, and it is preferable that the ophthalmic composition does not contain pranoprofen or a salt thereof, particularly It is preferably free of pranoprofen.

Further, from the viewpoint of more preferably exhibiting the above action, when the ophthalmic composition according to the present embodiment is used as an eye drop, an amphoteric surfactant, particularly an amphoteric surfactant represented by the following general formula (6) is preferably excluded from the ophthalmic composition according to the present embodiment.

In general formula (6) above, R ¹ is R or (CH ₂ ) _n —NHC(O)R, where R is C ₈ -C ₁₆ alkyl optionally substituted with hydroxyl; n is 2, 3 or 4, R ² and R ³ are each independently selected from methyl, ethyl, propyl or isopropyl, and R ⁴ is C ₂ -C ₈ alkylene optionally substituted by hydroxyl is.

The ophthalmic composition according to the present embodiment includes a target portion (conjunctiva [conjunctiva of the eyelid margin: lid wiper]), cornea, contact lens (surface Frictional resistance on the [surface that contacts the outside world when worn], the back [surface that contacts the eyeball when worn], and edges), etc., are reduced and smoothed, resulting in discomfort in the eye and rubbing of the eye when blinking. It reduces eye sensation, difficulty in blinking, foreign body sensation in the eyes (rubbery feeling, etc.), and contact lens sticking sensation, and provides a good feeling of use for a long time even when wearing contact lenses. play. Furthermore, since friction generated between the contact lens and the conjunctiva and between the contact lens and the cornea is reduced when the contact lens is worn, damage to the conjunctiva and the cornea due to the contact lens can be reduced.
Therefore, as one embodiment of the present invention, polyvinylpyrrolidone (A) having a K value of 40 or more, at least one selected from the group consisting of biguanide fungicides and trometamol (B), amino acids and thickeners There is provided a friction reducing agent (preferably a friction reducing agent during contact lens wear) comprising an ophthalmic composition containing at least one selected from the group consisting of agents (C).

Furthermore, as one embodiment of the present invention, the ophthalmic composition contains polyvinylpyrrolidone (A) having a K value of 40 or more, and at least one selected from the group consisting of biguanide fungicides and trometamol (B), A method of adding at least one (C) selected from the group consisting of amino acids and thickeners to give an ophthalmic composition a friction-reducing effect (preferably a friction-reducing effect during wearing of contact lenses). is provided.

Furthermore, as one embodiment of the present invention, there is provided a method for reducing friction during contact lens wear, wherein the method is selected from the group consisting of polyvinylpyrrolidone (A) having a K value of 40 or more, a biguanide fungicide and trometamol. and at least one (C) selected from the group consisting of amino acids and thickeners to a contact lens. In the method, the ophthalmic composition may be applied to the contact lens while wearing the contact lens or at the time of wearing the contact lens.

At least one of the components (A) to (C) of the present invention may be contained as an active ingredient.

EXAMPLES The present invention will be described in detail below with reference to examples and test examples, but the present invention is not limited to these examples.
The unit of each component amount in Tables 1 to 19 below is all "w/v %". In addition, "appropriate amount" in Tables 1 to 7 and 15 to 19 indicates an amount to obtain a predetermined pH.

[Test Example 1: Friction Evaluation (1)]
One piece of soft contact lens (product name: Proclear One Day (omafilcon A), soft contact lens classification according to U.S. Food and Drug Administration (FDA) standards: Group II, manufactured by Coopervision), phosphate-buffered saline Rinse with water (sodium chloride: 0.83 w/v%, sodium hydrogen phosphate dodecahydrate: 0.5993 w/v%, sodium dihydrogen phosphate dihydrate: 0.0528 w/v%), After wiping off the excess liquid adhering, it was immersed for 10 seconds in each formulation having the formulation shown in Table 1 below. After that, the soft contact lens was adhered to the contactor of a friction tester (Tribomaster TL201Ts, manufactured by Trinity Lab). On the other hand, an artificial leather immersed in physiological saline for 1 hour was attached to a moving table of a friction tester, and 4 mL of physiological saline was spread over the artificial leather so as to sufficiently cover the entire surface on which the contactor could move. Next, a weight of 20 g was attached to the measuring unit. The contact to which the soft contact lens was adhered was attached to the measurement unit, and measurement was performed 100 times per second for 20 seconds. The average value of the friction coefficients obtained from the measurement results for 5 to 20 seconds after the start of measurement was calculated and used as the friction coefficient (μk) of the formulation.
According to the following formula (7), when the friction coefficient of the corresponding comparative example (Comparative Example 1-1 (reference)) is set to 1, other prescription examples, that is, Comparative Examples 1-2 to 1-7 and the implementation The friction coefficient ratios of Examples 1-1 and 1-2 were calculated. The results are shown together in Tables 1 and 2 below.

〔formula〕
Friction coefficient ratio = friction coefficient in each prescription example/friction coefficient in corresponding comparative example (7)

As can be seen from the results in Tables 1 and 2 above, comparison with Comparative Examples 1-1, 1-2, 1-3, and 1-5 containing polyvinylpyrrolidone K90, polyhexanide hydrochloride, sodium chondroitin sulfate, or sodium hyaluronate alone Then, Examples 1-1 and 1-2 containing polyvinylpyrrolidone K90, polyhexanide hydrochloride, and sodium chondroitin sulfate or sodium hyaluronate unexpectedly had a greatly reduced friction coefficient ratio, and the friction reduction It was confirmed that the action was significantly improved. On the other hand, Comparative Examples 1-4 and 1-7, in which polyvinylpyrrolidone K25 was used instead of polyvinylpyrrolidone K90, did not exhibit a remarkable friction-reducing effect.

[Test Example 2: Friction Evaluation (2)]
The corresponding comparative example (Comparative Example 2- 1 (standard)), the ratio of the friction coefficients of the other prescription examples was determined. The results are also shown in Tables 3 to 5 below.

As can be seen from the results in Tables 3 to 5 above, when polyvinylpyrrolidone K90, polyhexanide hydrochloride, and hydroxypropylmethylcellulose 2906 are contained (Example 2-1), instead of hydroxypropylmethylcellulose 2906, sodium chondroitin sulfate or hyaluronic acid When containing sodium acid and varying the concentration of polyvinylpyrrolidone K90 (Examples 2-2 to 2-5), when containing polyvinylpyrrolidone K90, polyhexanide hydrochloride, aminoethylsulfonic acid (Example 2-6 ), and when chlorhexidine gluconate or trometamol is contained instead of polyhexanide hydrochloride (Examples 2-7 to 2-10), the friction coefficient ratio is larger than that in Comparative Example 2-1. It was confirmed that the friction reduction effect was significantly improved.

[Test Example 3: Friction Evaluation (3)]
As a prescription example, the corresponding comparative example (Comparative Example 3-1 When the friction coefficient of (reference)) is set to 1, the ratio of the friction coefficient of other prescription examples was obtained. The results are also shown in Table 6 below.

As can be seen from the results in Table 6 above, in addition to polyvinylpyrrolidone K90, polyhexanide hydrochloride, and sodium chondroitin sulfate, when polyoxyethylene castor oil 10, polyoxyl stearate 40, l-menthol, poloxamer 407, etc. are contained ( Also in Examples 3-1 to 3-3), the friction coefficient ratio was greatly reduced compared to Comparative Example 3-1, and it was confirmed that the friction reducing action was significantly improved.

[Test Example 4: Friction Evaluation (4)]
The corresponding comparative example (Comparative Example 4-1 ( Assuming that the friction coefficient of the standard)) is 1, the ratio of the friction coefficients of the other prescription examples was determined. The results are also shown in Table 7 below.

As can be seen from the results in Table 7 above, when polyvinylpyrrolidone K90, polyhexanide hydrochloride, and 0.1 w/v% sodium hyaluronate are contained (Example 4-1), chlorhexidine gluconate is contained instead of polyhexanide hydrochloride. In either case (Example 4-2), the friction coefficient ratio is greatly reduced compared to Comparative Example 4-1, and it is confirmed that the friction reduction effect is remarkably exhibited. was done.

[Test Example 5: Evaluation of cell activation effect (1)]
Each test solution (ophthalmic composition) was prepared according to the formulations shown in Tables 8 and 9 below.
Immortalized human corneal epithelial cells (HCE-T) were seeded in a 96-well plate at 2×10 ⁴ cells/well and cultured until confluent. After removing the medium, 100 μL of each test solution was added and incubated at 37° C. for 24 hours. At the same time, instead of each test solution, a buffer only was prepared as a control. Then, using Cell-counting kit-8, the cell viability (%) of each test solution relative to the control was determined. Then, using the following formula (8), other formulation examples when the cell viability of the corresponding comparative example (Comparative Example 5-1 (reference)) is 1, that is, Comparative Examples 5-2 and 5 -3, the cell survival rate of each test solution of Examples 5-1 and 5-2 was calculated. The results are also shown in Tables 8 and 9 below.

〔formula〕
Cell viability = cell viability of each test solution/cell viability of corresponding comparative example (8)

As can be seen from the results in Tables 8 and 9 above, the test solutions of Comparative Examples 5-2 and 5-3, in which polyhexanide hydrochloride and sodium hyaluronate were blended alone, compared with the test solution of Comparative Example 5-1, Almost no increase in cell viability was observed. On the other hand, in the test solutions of Examples 5-1 and 5-2, in which polyhexanide hydrochloride, sodium hyaluronate, or aminoethylsulfonic acid was added to polyvinylpyrrolidone K90, it was confirmed that the cell viability increased significantly. rice field.
From the above results, by using the ophthalmic composition of the present invention, the cell survival rate is significantly increased, so even when exposed to oligotrophic conditions, the decrease in the cell survival rate is reduced. That is, it was confirmed that the corneal cells were activated.

[Test Example 6: Evaluation of cell activation effect (2)]
In the same manner as in Test Example 5, except that the test solution was changed to those listed in Tables 10 and 11 below, and Comparative Example 6-1 (reference) was used as a corresponding comparative example, each formulation The cell survival rate in was calculated.

As can be seen from the results in Tables 10 and 11 above, in the test solution of Comparative Example 6-2 containing sodium hyaluronate alone, compared with the test solution of Comparative Example 6-1, almost no increase in the cell survival rate was observed. was not seen. On the other hand, it was confirmed that the test solution of Example 6-1, in which polyhexanide hydrochloride and sodium hyaluronate were added to polyvinylpyrrolidone K90, markedly increased the cell survival rate. In addition, it was confirmed that the test solution of Example 6-2, in which polyhexanide hydrochloride and aminoethylsulfonic acid were added to polyvinylpyrrolidone K90, markedly increased the cell survival rate.

[Test Example 7: Evaluation of resistance to oxidative stress after exposure to hypoxia (1)]
Each test solution (ophthalmic composition) was prepared according to the formulations shown in Tables 12 and 13 below.
In a 6-well plate, immortalized human corneal epithelial cells (HCE-T) were seeded, DMEM/F12 medium (DMEM/F12 medium 470 mL, Antibiotic-antimycotic 100 × 5 mL, DMSO 2.5 mL, EGF 0.5 mL, 0.6 mL of Insulin and 25 mL of FBS) were cultured until confluent. 2 mL of each test solution was added to each well and incubated at 37° C. for 6 hours under hypoxic conditions using Aneropack Kenki (manufactured by Mitsubishi Gas Chemical Company). After that, RNA was extracted from the cells using QIAshredder & RNase Mini Kit (manufactured by QIAGEN), reverse transcribed into cRNA using SuperScript II (manufactured by Life technologies), and then subjected to ABI QuantStudio RealTime PCR (Thermo Fisher). (manufactured), q-PCR was performed, and the number of rising cycles (Ct) in the real-time PCR method was measured. The relative expression ratio of the IL-6 gene with respect to the corresponding comparative example was determined using the following formula (9). The 18S gene (House Keeping gene) was used as an internal standard. Assuming that the IL-6 gene expression level of a control example (blank) that does not contain components (A) to (C) shown below is 1, the expression ratio of the IL-6 gene in other formulation examples was calculated. The results are also shown in Tables 12 and 13 below.
The corresponding comparative examples in Comparative Example 7-1 and Example 7-1 are control examples.

As can be seen from the results in Tables 12 and 13 above, in the test solution of Comparative Example 7-1, which contained polyvinylpyrrolidone K90 alone, the IL-6 gene expression ratio was increased, and there was a possibility that the inflammatory reaction was high. One thing has been confirmed. Furthermore, in Example 7-1 containing polyhexanide hydrochloride and sodium chondroitin sulfate, and in Example 7-2 containing polyhexanide hydrochloride and sodium hyaluronate, compared with the test solution of Comparative Example 7-1, IL-6 gene It was confirmed that there was a tendency for the inflammatory reaction to be suppressed due to a decrease in the expression ratio of
In addition, in the test solution of Example 7-2, it was confirmed that the MUC1 conversion value and the GSTp-1 conversion value tended to increase significantly (the conversion value when the target example was set to 1 was MUC1:1. 23, GSTp-1:1.13). MUC1 is one of the genes involved in the expression of mucin, and GSTp-1 is one of the genes involved in the expression of antioxidant factors. It is thought that it sometimes leads to promotion of the production of genes that act to protect the cornea.

From the above results, even when exposed to hypoxic conditions, the use of the ophthalmic composition according to the present embodiment has the effect of reducing inflammation caused by oxidative stress caused by hypoxic exposure and protecting the cornea. It was confirmed that it has a production-promoting effect of working genes. Therefore, it was confirmed that the ophthalmic composition according to this embodiment is useful for treating or preventing corneal damage caused by exposure to hypoxia.

[Test Example 8: Evaluation of resistance to oxidative stress after hypoxia (2)]
The procedure was the same as in Test Example 7, except that a 12-well plate was used instead of the 6-well plate, and the formulation examples shown in Table 14 below were used. The corresponding comparative example is Comparative Example 8-1 (reference). The results are also shown in Table 14 below.

As can be seen from the results in Table 14 above, Example 8-1 containing polyvinylpyrrolidone K90, polyhexanide hydrochloride, and potassium aspartate showed an IL-6 gene expression ratio compared to the test solution of Comparative Example 8-1. It was confirmed that there was a tendency to decrease and suppress the inflammatory reaction. In addition, in the test solution of Example 8-1, it was confirmed that the MUC1 conversion value and the HMOX-1 conversion value tended to be significantly improved (the conversion value when Comparative Example 8-1 was set to 1 was MUC1 : 3.22, HMOX-1: 2.74).

From the above results, even when the prescription example is changed, the use of the ophthalmic composition according to the present embodiment reduces inflammation and corneal damage caused by oxidative stress caused by hypoxic exposure, and protects the cornea. It was confirmed that it has a production-promoting effect of working genes. Therefore, it was confirmed that the ophthalmic composition according to this embodiment is useful for treating or preventing corneal damage caused by exposure to hypoxia.

[Test Example 9: Usability test]
Each aqueous composition (contact lens-wearing ophthalmic solution) was prepared according to the formulation shown in Table 15 below and used as a test solution. 13 mL of each test solution was filled in a polyethylene terephthalate eye drop container having a capacity of 13 mL. After filling, the container was fitted with a polyethylene nozzle.
Four healthy subjects who usually wear soft contact lenses were used as subjects, and Example 9-1 was applied to the right eye, Comparative Example 9-1 was applied to the left eye, and the concave surface of the contact lens (inner side, the surface in contact with the cornea). ), and then put on the contact lens.
Eight hours after wearing the contact lens, various eye symptoms (feeling of rubbing when blinking, blinking The effect of improving the difficulty of application, the feeling of a foreign body in the eyes, the feeling that contact lenses stick to the eyes, the dryness of the eyes, the tiredness of the eyes, and the blurred vision was evaluated. The lower the score, the less these symptoms are felt and the more favorable the eye condition.
On another day, the same subject was evaluated in the same manner as described above, except that Comparative Example 9-1 and Example 9-1 were applied dropwise to the right eye and the left eye, respectively.
All the scores obtained when using each test liquid were averaged to obtain the average VAS score value of each test liquid.
Using the score of each test solution, the score reduction rate (%) in each item of Example 9-1 relative to Comparative Example 9-1 is calculated as the symptom improvement rate (%) using the following formula (10). bottom. The results are also shown in Table 15 below.

〔formula〕
Symptom improvement rate (score reduction rate) (%) = {(average VAS score value of test solution of Comparative Example 9-1 - average VAS score value of test solution of Example 9-1) / of test solution of Comparative Example 1 Average VAS score value}×100 (10)

As can be seen from the results in Table 15 above, by blending polyvinylpyrrolidone K90, polyhexanide hydrochloride, and hydroxypropylmethylcellulose, the friction in the eyes is reduced, the feeling of rubbing when blinking, the difficulty of blinking, and the eyes It was confirmed that the feeling of a foreign body and the sticking feeling of the contact lens were improved.
In addition, it was confirmed that the addition of polyvinylpyrrolidone K90, polyhexanide hydrochloride, and hydroxypropylmethylcellulose improved dry eyes, tired eyes, and blurred vision.

<Formulation example>
According to the formulations shown in Tables 16 to 19 below, eye drops (formulation examples 1 to 9), contact lens (CL) eye drops (formulation examples 10 to 23), contact lens attachment eye drops (formulation examples 24 to 26) is prepared.
The unit of each component amount in Tables 16 to 19 is all "w/v %".

In addition, the above Formulation Examples 1 to 26 were placed in a container made of polyethylene terephthalate (PET), and a nozzle made of polyethylene (PE) was attached (Formulation Examples 1' to 26').
In addition, in the same manner, formulations having exactly the same composition as those of Formulation Examples 1 to 26 were placed in a container made of polyethylene terephthalate (PET), and a nozzle made of polybutylene terephthalate (PBT) was attached (Formulation Example 1 ″). ~26").

INDUSTRIAL APPLICABILITY The present invention can be widely used as an ophthalmic composition for reducing friction in the eye when blinking or when wearing contact lenses.

Claims (2)

A polyvinylpyrrolidone having a K value of 40 or more (A), at least one selected from the group consisting of biguanide fungicides and trometamol (B), and at least one selected from the group consisting of amino acids (C). and wherein the component (C) is chondroitin sulfate or a salt thereof. excluding contact lens cleaning compositions containing a compound selected from 2. The friction reducer of claim 1 , wherein the friction is friction during contact lens wear.