JP2019034979A - Use of combination for reducing friction in eye part, and method for producing ophthalmic composition - Google Patents

Abstract

To provide an ophthalmic composition for reducing friction in an eye part.SOLUTION: An ophthalmic composition contains polyvinyl pyrrolidone (A) with a K value of 40 or more, at least one selected from the group consisting of biguanide bactericides and trometamol (B), and at least one selected from the group consisting of amino acids and thickeners (C).SELECTED DRAWING: None

Description

  The present invention relates to an ophthalmic composition and a method for imparting a friction reducing effect thereto.

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

In the eye, friction is generated when blinking or other movement is applied between the eyelid, cornea, or conjunctiva, which is said to be one of the causes of abnormalities in the cornea, tear film, or eyelid. Yes. Further, particularly when a contact lens is worn, it is considered that friction occurs between the contact lens and these tissues, and this friction leads to deterioration of the wearing feeling of the contact lens.
At present, the method for reducing the friction in the eye has 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 polyvinyl pyrrolidone (A) having a K value of 40 or more among the polyvinyl pyrrolidones as components of the 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 Surprisingly, it has been found that the composition can remarkably reduce the friction in the eye part, and the present invention has been completed.

That is, the present invention provides the following [1] to [7].
[1] Selected from the group consisting of 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 amino acids and thickeners An ophthalmic composition containing at least one (C).
[2] The ophthalmic composition according to [1], wherein the content of the 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 of [1] to [4], wherein the component (C) is at least one selected from the group consisting of aspartic acid, aminoethylsulfonic acid, mucopolysaccharide, cellulose derivatives, and salts thereof. An ophthalmic composition according to 1.
[6] Any one of [1] to [5], further comprising at least one (D) selected from the group consisting of a nonionic surfactant, edetic acid and salts thereof, inorganic salts, and terpenoids An ophthalmic composition as described.
[7] An ophthalmic composition comprising 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 A method for imparting an effect of reducing friction 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 selected from the group consisting of biguanide fungicides and trometamol (B), amino acids and thickeners. By containing at least one selected from the group consisting of (C), friction in the eye can be reduced.

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

In the present specification, “w / v%”, which is a unit of content, indicates the ratio of mass to volume, and is synonymous with “g / 100 mL”.
In this specification, unless otherwise specified, the abbreviation “POE” means polyoxyethylene.
In the present specification, unless otherwise specified, the abbreviation “POP” means polyoxypropylene.

  The ophthalmic composition according to this embodiment includes a polyvinyl pyrrolidone (A) having a K value of 40 or more, at least one (B) selected from the group consisting of a biguanide fungicide and trometamol, amino acids, and thickening. And at least one selected from the group consisting of agents (C). Hereinafter, it demonstrates in order.

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

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

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

  Among these, polyvinyl pyrrolidone having a K value of 50 or more is preferable, polyvinyl pyrrolidone having a K value of 70 or more is more preferable, and polyvinyl pyrrolidone having a K value of 90 or more is more preferable from the viewpoint of achieving the effects of the present invention more remarkably. Preferably, polyvinylpyrrolidone having a K value of 90 to 120 is even more preferable. Of these, 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 of the 16th revised Japanese pharmacopoeia "Povidone". For example, "K90" is the above formula The viscosity characteristic value (K value) calculated by applying to (1) is in the range of 81.0 to 97.2.

  The polyvinyl pyrrolidone K90 may be synthesized by a known method. However, Eifact K-90 (Daiichi Kogyo Seiyaku Co., Ltd.), Kollidon K90 (BASF Japan K.K.), and Plasdon K90 (YSP Japan Co., Ltd.) ), Commercially available products such as Povidone K90 (DSP Gokyo Food & Chemical Co., Ltd.) may be used. And these may be used individually by 1 type, or may be used in combination of 2 or more type.

  And although content of the said (A) component is not specifically limited, For example, the total content of (A) component is 0.001 on the basis of the total amount of the ophthalmic composition which concerns on this embodiment. It is preferably 10 to 10 w / v%, more preferably 0.005 to 5.0 w / v%, still more preferably 0.01 to 3.0 w / v%, and 0.03 to 1 Particularly preferred is 0.0 w / v%. The content of the component (A) is suitable from the viewpoint of more prominently achieving the effects of the present invention. Also, 0.001 to 0.5 w / v%, especially 0.002 to 0.4 w / v%, 0.003 to 0.3 w / v%, especially 0.005 to 0.1 w / v% Preferably used.

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

<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, It is a known disinfectant as a monomer having at least one group, a polymer composed of the monomer, and a compound in a salt form thereof, and may 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 (pharmaceutically) or physiologically acceptable. For example, the following general formula (2), ( The compounds represented by 3), (4) and (5) are exemplified. These compounds may be in the form of a salt.

  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, still more preferably an integer of 1 to 40, and particularly preferably 10. It is an integer of ~ 13.

  Specific examples of the biguanide fungicide used in the present embodiment include hexamethylene biguanide and its polymer (that is, polyhexamethylene biguanide (abbreviation: PHMB), polyhexanide), chlorhexidine, alexidine, hexidine and the like. From the viewpoint of exhibiting the effects of the invention more remarkably, preferably hexamethylene biguanide and its polymer, more preferably hexamethylene biguanide polymer are exemplified.

The salt of the biguanide fungicide used in the present embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of salts of biguanide fungicides used in this embodiment include 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 Organic acid salts such as acid, tartaric acid and citric acid; sulfonic acid salts such as methane sulfonate, isethionate, benzene sulfonate, and p-toluene sulfonate; Is more preferable.
Specific examples of the salt of the biguanide fungicide include polyhexanide hydrochloride (polyhexamethylene biguanide hydrochloride), alexidine hydrochloride and chlorhexidine gluconate, polyhexanide hydrochloride and chlorhexidine gluconate are preferred, and polyhexanide hydrochloride is more preferred.

  And although content of the said biguanide type fungicide is not specifically limited, According to the kind, the component to be used together, content, etc., it sets suitably. The content of the biguanide fungicide is, for example, based on the total amount of the ophthalmic composition according to this embodiment, and the content of the biguanide fungicide is usually 0.0000001 to 0.1 w / v%, 0 0.00000 to 0.01 w / v% is preferred, 0.00001 to 0.001 w / v% is more preferred, 0.00001 to 0.00015 w / v% is even more preferred, Particularly preferred is 0.00002 to 0.0001 w / v%.

  In the ophthalmic composition according to the embodiment of the present invention, the content ratio of the biguanide fungicide with respect to the component (A) is not particularly limited, and the types of the component (A) and the biguanide antibacterial agent, the types and contents of other compounding components. It is appropriately set according to the amount, the use of the ophthalmic composition, the preparation form, and the like. The content ratio of the biguanide fungicide relative to the component (A) is, for example, from the viewpoint of more prominently achieving the effects of the present invention. 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. 1 part by mass is further preferable, and 0.00005 to 0.01 part by mass is even more preferable.

<Trometa Mall>
The trometamol is a known compound represented by the formula: C ₄ H ₁₁ NO ₃ , may be synthesized by a known method, or can be obtained as a commercial product.

  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, components used in combination, the content, and the like. As content of trometamol, it is preferable that content of trometamol is 0.001-20 w / v% on the basis of the total amount of the ophthalmic composition which concerns on this embodiment, for example, 0.005-10 w / v %, 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. Moreover, as content of trometamol, it is mention | raise | lifted as a preferable form that it is 0.2 w / v% or less.

  In the ophthalmic composition according to the embodiment of the present invention, the content ratio of trometamol with respect to the component (A) is not particularly limited, and the type of the component (A), the type and content of other compounding components, the use of the ophthalmic composition, and It is appropriately set according to the formulation form. As the content ratio of trometamol with respect to the component (A), from the viewpoint of more prominently achieving the effects of the present invention, for example, with respect to 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, and even more preferably 0.05 to 50 parts by mass, It is still more preferable that it is 0.1-20 mass parts.

  These (B) component biguanide fungicides and trometamol may be used alone or in any combination of two or more. Among the components (B), from the viewpoint of the friction reduction rate, it is preferably a biguanide fungicide, more preferably chlorhexidine gluconate or polyhexanide hydrochloride, and further preferably polyhexanide hydrochloride. From another point of view, polyhexanide hydrochloride, chlorhexidine gluconate, and trometamol may be preferable.

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

  In the ophthalmic composition according to the embodiment of the present invention, the content ratio of the component (B) to the component (A) is not particularly limited, and the types of the component (A) and the component (B), the types and contents of the other compounding components. It is appropriately set according to the amount, the use of the ophthalmic composition, the preparation form, and the like. The content ratio of the component (B) to the component (A) is, for example, from the viewpoint of more prominently achieving the effects of the present invention. 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 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 with respect to parts. More preferably, it is 0.00005 to 20 parts by mass.

<(C) component>
In the ophthalmic composition which concerns on this embodiment, at least 1 sort (C) selected from the group which consists of amino acids and a thickener is contained with the said (A) component and the said (B) component.

<Amino acids>
The amino acids mean a compound having an amino group and a carboxy group or a sulfo group in the molecule or a derivative thereof. Specific examples include amino acids, mucopolysaccharides and derivatives thereof, and salts thereof. 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, for example, salts with organic acids [eg, monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), Carboxylate (fumarate, maleate, etc.), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, Toluenesulfonate, etc.)], salts with inorganic acids (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, Salts with organic amines such as triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline), salts with inorganic bases [eg ammonium salts; alkali metals (sodium Potassium), alkaline earth metal (calcium, magnesium etc.), salts with metals such as aluminum, etc.] or the like can be exemplified, it is selected appropriately depending on the compound. Of these, salts with inorganic bases are preferred, and alkali metal salts and alkaline earth metal salts are more preferred. Among amino acids, examples of amino acids and salts thereof include monoamino monocarboxylic 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 acid and its salt may be any of L-form, D-form and DL-form, and examples thereof include potassium L-aspartate, magnesium L-aspartate, and a mixture of L-magnesium and potassium equivalents. . Among amino acids, examples of mucopolysaccharides and salts thereof include chondroitin sulfate, hyaluronic acid, alginic acid, and the like, and salts thereof.

  Among these amino acids, L-aspartic acid, aminoethylsulfonic acid, mucopolysaccharide and salts thereof are particularly preferable. L-aspartate potassium, L-aspartate magnesium, L-aspartate magnesium / potassium, etc. A quantity mixture, aminoethylsulfonic acid and mucopolysaccharide are more preferred, of which mucopolysaccharide is more preferred, sodium chondroitin sulfate and 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. L-aspartate potassium, L-aspartate magnesium, L-aspartate magnesium / potassium equivalent mixture 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.

  Content of the said amino acids is not specifically limited, It sets suitably according to the kind of amino acids, the (A) component used together, the kind and content of (B) component, etc. As the content of amino acids, for example, the total content of amino acids 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 5 w / v%, further preferably 0.001 to 4 w / v%, still more preferably 0.01 to 3 w / v%, and more preferably 0.1 to 2.5 w / v It is particularly preferable that it is v%. Moreover, as content of amino acids, 2 w / v% or less is also mentioned as a preferable form. The content of the amino acids is preferable from the viewpoint of more prominently achieving the effects of the present invention.

When the amino acids are chondroitin sulfate and its salt, for example, the total content of chondroitin sulfate and its salt is 0.01 to 5 w / v% based on the total amount of the ophthalmic composition according to this embodiment. Preferably, it is 0.05-3 w / v%, more preferably 0.1-1 w / v%.
When the amino acids are hyaluronic acid and its salt, for example, the total content of hyaluronic acid and its salt is 0.001 to 0.5 w / v based on the total amount of the ophthalmic composition according to this embodiment. %, More preferably 0.01 to 0.3 w / v%, still more preferably 0.05 to 0.1 w / v%.

  The content ratio of the amino acids to the component (A) in the ophthalmic composition according to the embodiment of the present invention is not particularly limited, and the types of the component (A) and amino acids, the types and contents of other compounding components, the ophthalmic composition It is appropriately set according to the use of the product and the form of preparation. The content ratio of amino acids to component (A) is, for example, from the viewpoint of more prominently achieving the effects of the present invention, for example, to 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment. 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. Preferably, it is 0.001 to 10 parts by mass.

In the case where the amino acids are chondroitin sulfate and a salt thereof, the content ratio of chondroitin sulfate and the salt thereof relative to the component (A) is, for example, from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, the ophthalmology according to the present embodiment The total content of chondroitin sulfate and its salt is preferably 0.01 to 500 parts by mass, and 0.05 to 100 parts by mass with respect to 1 part by mass of the total content of component (A) contained in the composition. More preferably, it is 0.1 to 50 parts by mass.
When the amino acids are hyaluronic acid and a salt thereof, the content ratio of the hyaluronic acid and the salt to the component (A) is, for example, from the viewpoint of more prominently achieving the effects of the present invention, It is preferable that the total content of hyaluronic acid and a salt thereof is 0.001 to 500 parts by mass with respect to 1 part by mass of the total content of component (A) contained in the composition, and 0.01 to 100 parts by mass. More preferably, it is 0.1 to 50 parts by mass.

<Thickener>
Examples of the thickener include polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K25, K30), carboxyvinyl polymer, cellulose derivative [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose). ) (2208, 2906, 2910, etc.), carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose or their salts], gum arabic, tragacanth, dextran (40, 70, etc.), etc., preferably polyvinyl alcohol (completely or partially Saponified product), polyvinylpyrrolidone (K25, K30), carboxyvinyl polymer, cellulose derivative, dextran (70) More preferably a cellulose derivative, still more preferably hydroxyethyl cellulose or hydroxypropylmethylcellulose, still more preferably hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, or hydroxypropylmethylcellulose 2910, particularly preferably hydroxy. Propylmethylcellulose 2906. These thickeners may be used alone or in any combination of two or more.

  When the thickener is contained, the content is appropriately set according to the type of the thickener, the type and content of other components. As content of a thickener, it is preferable that the total content of a thickener is 0.0001-5 w / v% on the basis of the total amount of the ophthalmic composition which concerns on this embodiment, for example. It is more preferably 001 to 3 w / v%, further 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 with respect to the component (A) is not particularly limited, the type of the component (A) and the thickener, the type and content of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the thickener to the component (A) is, for example, from the viewpoint of more prominently achieving the effects of the present invention, for example, 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to this embodiment. 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 it is still more preferable that it is 0.05-10 mass parts.

  When it contains the said thickener, the content is suitably set according to the kind of (C) component, the kind of other containing component, content, etc. As the content of the component (C), for example, based on the total amount of the ophthalmic composition according to the present embodiment, the total content of the component (C) is preferably 0.0001 to 10 w / v%, It is more preferably 0.0005 to 5 w / v%, further preferably 0.001 to 3 w / v%, still more preferably 0.01 to 2 w / v%, 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 the components (A) and (C), the types and contents of the other compounding components. It is set as appropriate according to the use of the ophthalmic composition and the formulation form. The content ratio of the component (C) to the component (A) is, for example, 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 thickener 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 with respect to parts. Is more preferable, and it is still more preferable that it is 0.001-10 mass parts.

<(D) component>
Further, the ophthalmic composition according to the present embodiment is further selected from the group consisting of nonionic surfactants, edetic acid and salts thereof, inorganic salts, and terpenoids from the viewpoint of more prominently achieving the effects of the present invention. 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 (pharmaceutically) or physiologically acceptable. Specific examples of the nonionic surfactant include, for example, monolauric acid POE (20) sorbitan (polysorbate 20), monooleic acid POE (20) sorbitan (polysorbate 80), POE sorbitan monostearate (polysorbate 60), POE sorbitan fatty acid ester 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, PO Castor oil 25, POE castor oil 30, POE castor oil 35, POE castor oil such as POE castor oil 50, polyethylene glycol monostearate (2E.O.), polyethylene glycol monostearate (4E.O.), monostearate Polyethylene glycol (9E.O.), polyethylene glycol monostearate (10E.O.), polyethylene glycol monostearate (23E.O.), polyethylene glycol monostearate (25E.O.), polyethylene monostearate Glycol (32 EO), polyethylene glycol monostearate (40 EO, polyoxyl 40 stearate), polyethylene glycol monostearate (45 EO), polyethylene glycol monostearate (55 O.), polyethylene glycol monostearate (75 EO), polyethylene glycol monostearate (140 EO, 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, and POE-POP bromine of ethylenediamine such as poloxamine POE alkyl ethers such as POE (9) lauryl ether, POE / POP alkyl ethers such as POE (20) POP (4) cetyl ether, POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether, etc. It is done. The numbers in parentheses indicate the number of added moles.

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

  Examples of the nonionic surfactant 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. Examples include POE castor oil, polyethylene glycol monostearate (2E.O.), polyethylene glycol monostearate (4E.O.), etc. In particular, from the viewpoint of achieving the effects of the present invention more remarkably, the average of ethylene oxide can be obtained. POE hydrogenated castor oil having an addition mole number of less than 20, POE castor oil having an average addition mole number of ethylene oxide of less than 23 is preferable, and POE castor oil having an average addition mole number of ethylene oxide of less than 23 is more preferable, POE castor oil 3 and POE castor oil 10 are more preferable.

  When the nonionic surfactant is contained, the content depends on the type of nonionic surfactant to be used, the type and content of other compounding ingredients, the use of the ophthalmic composition, the formulation form, the method of use, etc. 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 is 0.005, for example. It is more preferably ˜2 w / v%, further preferably 0.01 to 1 w / v%, and particularly preferably 0.05 to 1 w / v%.

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

  In the case of containing at least one of the edetic acid and its salt, the content is appropriately set according to the kind of edetic acid and its salt, the kind and content of other components, and the like. As the content of at least one of edetic acid and its salt, for example, the total content of at least one of edetic acid and its salt is 0.001 to 0.001 based on the total amount of the ophthalmic composition according to this embodiment. It is preferably 1 w / v%, more preferably 0.005 to 0.5 w / v%, and still 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, magnesium sulfate and the like. Of these, potassium chloride, calcium chloride, sodium chloride, sodium bicarbonate, sodium carbonate, and magnesium sulfate are preferable, and potassium chloride and sodium chloride are more preferable.

  When the inorganic salt is contained, the content is appropriately set according to the type of inorganic salt, the type and content of other components, and the like. As 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, for example, 0.001 to It is more preferably 3 w / v%, and further preferably 0.005 to 1 w / v%.

<Terpenoid>
Examples of terpenoids include 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, eugenol and the like. These may be any of d-form, l-form, or dl-form, but from the viewpoint of more prominently achieving the effects of the present invention, l-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, geraniol It is preferable to use it. Of these, l-menthol, d-camphor, dl-camphor and geraniol are preferable, and l-menthol is more preferable. The terpenoid can also be used in the state of being contained in essential oil, and preferred essential oils are mint oil, peppermint oil, eucalyptus oil, bergamot oil, fennel oil, cinnamon oil, rose oil and the like. These terpenoids can be used alone or in combination of two or more.

  Content of the said terpenoid is not specifically limited, It sets suitably according to the kind of terpenoid, the kind of other compounding ingredients, content, etc. As the content of terpenoid, for example, the total content of terpenoid is preferably 0.00001 to 0.3 w / v%, based on the total amount of the ophthalmic composition according to the present embodiment. It is more preferably 0.1 w / v%, further preferably 0.0005 to 0.05 w / v%, and particularly preferably 0.001 to 0.02 w / v%. The content of the terpenoid is suitable from the viewpoint of more prominently achieving the effects of the present invention.

<Other optional components>
The ophthalmic composition according to this embodiment preferably further contains a buffering agent in order to further enhance the effects of the present invention. Thereby, the effect of this invention can be exhibited more notably. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such a buffer include a borate buffer, a phosphate buffer, a carbonate buffer, a citrate buffer, and an acetate buffer. These buffering agents may be used alone or in combination of two or more. Examples of the boric acid buffer include boric acid or a salt thereof (alkali metal borate, alkaline earth metal borate, etc.). Examples of the phosphate buffer include phosphoric acid or a salt thereof (such as an alkali metal phosphate or an alkaline earth metal phosphate). Examples of the carbonate buffer include carbonic acid or a salt thereof (an alkali metal carbonate, an alkaline earth metal carbonate, etc.). Examples of the citrate buffer include citric acid or salts thereof (alkali metal citrate, alkaline earth metal citrate, etc.). Examples of the acetate buffer include acetic acid or a salt thereof (alkali metal acetate, alkaline earth metal acetate, etc.). Also, using borate, phosphate, carbonate, citrate or acetate hydrate as borate buffer, phosphate buffer, carbonate buffer, citrate buffer or acetate buffer Also good. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, Acid calcium, sodium dihydrogen citrate, disodium citrate, etc.) As the acetic acid buffer, acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) and the like. Among these buffering agents, boric acid buffering agents (for example, combinations of boric acid and borax, etc.) and phosphate buffering agents (for example, combinations of disodium hydrogen phosphate and sodium dihydrogen phosphate, etc.) are preferable, A borate buffer is more preferred.

  When it contains the said buffering agent, the content is suitably set according to the kind of buffering agent, the kind of other containing component, content, etc. As the content of the buffering agent, for example, based on the total amount of the ophthalmic composition according to this embodiment, the total content of the buffering agent is preferably 0.01 to 10 w / v%, It is more preferably 5 w / v%, further 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. Examples of the polyhydric alcohol include polyethylene glycol (400, 4000, 6000, etc.), propylene glycol, glycerin and the like. As the polyhydric alcohol, propylene glycol, glycerin, and polyethylene glycol are preferable, and polyethylene glycol is more preferable from the viewpoint of more prominently achieving the effects of the present invention. And as a polyhydric alcohol, a commercially available thing 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, and the type of polyhydric alcohol, the type and content of other compounding components, the use and formulation of the ophthalmic composition It is set appropriately according to the form and the like. As the content of the polyhydric alcohol, from the viewpoint of more prominently achieving the effects of the present invention, for example, the total content of the polyhydric alcohol is 0.01 to 5 w / v% on the basis of the total amount of the ophthalmic composition. Preferably, it is 0.05 to 2 w / v%, more preferably 0.1 to 1 w / v%, particularly preferably 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 range that is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable. The pH of the ophthalmic composition is, for example, preferably 4.0 to 9.5, more preferably 5.0 to 9.0, and still more preferably 5.5 to 8.5. .

  In addition, 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 for a living body. 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. Preferably, it is 0.9-1.55. The adjustment of the osmotic pressure can be performed by a method known in the art using inorganic salt, polyhydric alcohol, sugar alcohol, sugar or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measure with reference to (freezing point depression method). In addition, about 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 500-650 degreeC for 40-50 minutes, it is in a desiccator (silica gel). It is allowed to cool, and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be used. .

  The viscosity of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a range acceptable for a living body. The viscosity at 25 ° C. measured with a rotational viscometer (RE550 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × R24) is preferably, for example, 1 to 1000 mPa · s, and 1 to 100 mPa · s. It is more preferable that it is s, and it is further more preferable that it is 1-50 mPa * s.

Further, the ophthalmic composition according to the present embodiment may contain appropriate amounts of various pharmacologically active components or physiologically active components in addition to the above components, as long as the effects of the present invention are not hindered. Such components are not particularly limited, and examples thereof include active ingredients in various drugs described in the OTC Drug Manufacturing and Sales Approval Standards 2012 edition (supervised by the Japanese Society for Regulatory Science). Specific examples of components used in ophthalmic drugs include the following components.
Antihistamines: for example, iproheptin, diphenhydramine, chlorpheniramine maleate, ketotifen fumarate, olopatadine hydrochloride, levocabastine hydrochloride, etc.
Antiallergic agents: for example, sodium cromoglycate, tranilast, pemirolast potassium, acitazanolast and the like.
Steroid agents: For example, fluticasone propionate, fluticasone furancarboxylate, mometasone furancarboxylate, beclomethasone propionate, flunisolide and the like.
Decongestant: For example, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride.
Eye muscle modulating agent: for example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, atropine sulfate, etc.
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.
Astringent: 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, retinol palmitate, tocopherol acetate, etc.
Local anesthetic: For example, lidocaine.
Other: 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 use or the form of the preparation, as long as the effects of the invention are not impaired. Two or more types may be used in combination to contain an appropriate amount. Examples of these additives include various additives described in Pharmaceutical Additives Dictionary 2016 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Carrier: An aqueous carrier such as water or hydrous ethanol.
Sugars: For example, glucose, cyclodextrin, glucose and the like.
Sugar alcohol: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Stabilizers: For example, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, dibutylhydroxytoluene, sodium hydrogensulfite, sodium sulfite and the like.
Anionic surfactant: For example, alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, α-sulfo fatty acid ester salt, α-olefin sulfonic acid and the like.
(B) Preservatives, bactericides or antibacterial agents other than components: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorobutanol, sorbic acid, potassium sorbate, Sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol and the like.
pH regulators: for example, 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, succinic acid Acids, 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 other optional components as necessary to a carrier so as to have a desired content. As the carrier, water that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable may be used, and as such water, specifically, distilled water, normal water, purified water, sterilization, and the like. Examples include purified water, water for injection, and distilled water for injection.

  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 this embodiment. Can do.

  In the ophthalmic composition according to the present embodiment, the water content is 85 w / v% or more, preferably 90 w / v% or more, and preferably 92 w / v% or more with respect to the total amount of the ophthalmic composition. More preferably, it is more preferably 94 w / v% or more, and particularly preferably 95 w / v% or more.

  The ophthalmic composition according to the present embodiment can take various preparation forms depending on the purpose. Examples of the dosage form include liquids, gels, semi-solids (such as ointments) and the like. The ophthalmic composition according to this embodiment is preferably a liquid agent.

  The ophthalmic composition according to the present embodiment is provided by being accommodated in an arbitrary container. The container for storing the ophthalmic composition according to the present embodiment is not particularly limited, and may be made of glass or plastic, for example. Preferably it is made of plastic. Examples of the plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, a copolymer of monomers constituting these, and a mixture of these two or more. Polyethylene terephthalate is preferable. Moreover, the container which accommodates the ophthalmic composition which concerns on this embodiment may be a transparent container which can visually recognize the inside of a container, and may be an opaque container where it is difficult to visually recognize the inside of a container. A transparent container is preferable. 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, in a multi-dose form that can be used repeatedly in a colored transparent plastic container or the like. Moreover, as another aspect, it can also be accommodated and used in the form of a unit dose.

  The ophthalmic composition according to this embodiment can be used as a pharmaceutical preparation or a quasi-drug preparation, in addition to so-called eye drops (however, eye drops include eye drops that can be applied while wearing contact lenses). , Eyewash (however, eyewash contains eyewash that can be washed while wearing contact lens), contact lens composition [contact lens mounting fluid, contact lens care composition (contact lens disinfectant, contact lens use) Preservatives, contact lens cleaning agents, contact lens cleaning preservatives, contact lens disinfecting / cleaning / preserving solutions <multipurpose solutions>), etc.], contact lens mounting solutions and eye drops while wearing contact lenses And ophthalmic solutions with contact lenses used in the above. Preferable examples of the present invention include eye drops, eye wash, contact lens mounting liquid, and contact lens mounting eye drops, and particularly preferable examples include eye drops, contact lens mounting liquid, and contact lens mounting eye drops. When used as a contact lens composition, hard contact lenses and soft contact lenses (including both ionic and non-ionic types, both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses) It is applicable to any contact lens including a gel contact lens.

  In addition, in this embodiment, it is possible to reduce the friction generated at the time of blinking or the like in the eye part regardless of whether it is naked or wearing a contact lens, but during contact lens wearing, between the contact lens and the conjunctiva Since friction occurs between the contact lens and the cornea, the effect of reducing friction is more remarkably exhibited. Therefore, the ophthalmic composition is preferably for contact lenses, and particularly preferably for soft contact lenses. Among the soft contact lenses, color contact lenses with colors and patterns printed on the surface by printing or other methods have higher friction on the contact lens surface than contact lenses other than color contact lenses. An ophthalmic composition is particularly preferred. In addition, silicone hydrogel contact lenses, which generally tend to have higher hardness than other soft contact lenses, have a great influence on the surface of the eyeball due to friction, so they are ophthalmic compositions for silicone hydrogel contact lenses. Is particularly preferred.

(I) Friction reduction action And, by using the ophthalmic composition according to the present embodiment, the effect of reducing friction in the eye can be expected.

(II) Cell activating action Generally, due to a decrease in tear fluidity due to wearing a contact, a decrease in tear quality due to aging, etc., the eye is exposed to an oligotrophic state, There is a possibility that the cell viability of the cornea may be reduced, but when the ophthalmic composition according to the present embodiment is used, the viability of the cornea cells is significantly increased (the corneal cells are activated).

(III) Oxidative stress tolerance after exposure to hypoxia In general, when an eye is hypoxic after wearing a contact, and then the contact lens is removed, or when waking up from sleep, excess oxygen Oxidative stress occurs on the keratoconjunctiva due to the effect, and inflammation and corneal damage tend to occur. However, when the ophthalmic composition according to this embodiment is used, inflammation and corneal damage caused by oxidative stress after hypoxic exposure Can be reduced.
Since IL-6 is released when inflammation occurs, the degree of inflammation due to oxidative stress after hypoxic exposure can be measured by measuring the expression level of the IL-6 gene.
In addition, mucin is important for maintaining homeostasis of tears and ocular surfaces, but it has been reported that mucin expression on the corneal surface is reduced by oxidative stress. Corneal damage caused by oxidative stress after hypoxic exposure can be evaluated using the expression level of MUC1, which is 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 low oxygen, various antioxidant factors are secreted to reduce oxidative stress. After exposure to hypoxia by measuring genes caused by antioxidant factors such as GSTp-1 (one of the genes related to the expression of antioxidant factors), HMOX-1 (one of the genes related to the expression of antioxidant factors) Resistance to oxidative stress in can be measured.

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

  In addition, from the viewpoint of more preferably expressing the above action, when the ophthalmic composition according to the present embodiment is used as an eye drop, an amphoteric surfactant, in particular, an amphoteric surfactant represented by the following general formula (6) is used. Is preferably removed from the ophthalmic composition according to this embodiment.

In the general formula (6), R ¹ is R or (CH ₂ ) _n —NHC (O) R, wherein R is C ₈ -C ₁₆ alkyl optionally substituted by 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 a C ₂ -C ₈ alkylene optionally substituted by hydroxyl It is.

The ophthalmic composition according to the present embodiment includes a target part (including a conjunctiva [conjunctiva of lid lid]), a cornea, and a contact lens (surface) at the time of blinking or wearing a contact lens. Frictional resistance is reduced and smooth on the back surface [including the surface that contacts the outside during wearing], the back surface (including the surface that contacts the eyeball when wearing), and the edge portion, and the eyes are uncomfortable and the eyes rub during blinking. Feeling, feeling that blinks are difficult, feeling of foreign body of eyes (feeling groggy), contact lens sticking feeling, etc. are reduced, and even when using contact lenses, a good feeling can be obtained over a long period of time Play. Further, when the contact lens is worn, friction generated between the contact lens and the conjunctiva and between the contact lens and the cornea is reduced, so that damage to the conjunctiva and cornea by the contact lens can be reduced.
Therefore, as one embodiment of the present invention, polyvinyl pyrrolidone (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 thickening There is provided a friction reducing agent (preferably a friction reducing agent during wearing of a contact lens) comprising an ophthalmic composition containing at least one (C) selected from the group consisting of agents.

  Furthermore, as one embodiment of the present invention, the ophthalmic composition includes a polyvinyl pyrrolidone (A) having a K value of 40 or more, at least one selected from the group consisting of a biguanide fungicide and trometamol (B), A method of containing at least one selected from the group consisting of amino acids and thickeners (C) and imparting a friction reducing action to the ophthalmic composition (preferably a friction reducing action during contact lens wearing) Is provided.

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

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

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like.
The units of each component amount in Tables 1 to 19 below are all “w / v%”. Further, “appropriate amount” in Tables 1 to 7 and 15 to 19 indicates an amount for obtaining a predetermined pH.

[Test Example 1: Friction evaluation (1)]
One soft contact lens (product name: Pro Clear One Day (omafilcon A), soft contact lens classification according to the US Food and Drug Administration (FDA) standard: Group II, manufactured by Cooper Vision), phosphate buffered saline Rinse with water (sodium chloride: 0.83 w / v%, sodium hydrogenphosphate dodecahydrate: 0.5993 w / v%, sodium dihydrogenphosphate dihydrate: 0.0528 w / v%) After wiping off the excess liquid adhering, it was immersed for 10 seconds in each preparation of the formulation shown in Table 1 below. Thereafter, a soft contact lens was bonded to a contact of a friction tester (Tribomaster TL201Ts, manufactured by Trinity Lab). On the other hand, artificial leather soaked in physiological saline for 1 hour was attached to the moving table of the friction tester, and 4 mL of physiological saline was spread on the artificial leather so that it could spread over the entire surface where the contacts could move. Next, a 20 g weight was attached to the measurement unit. A contact having a soft contact lens adhered thereto 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 5 to 20 seconds after the start of the measurement was calculated and used as the friction coefficient (μk) of the preparation.
According to the following formula (7), when the friction coefficient of the corresponding comparative example (Comparative Example 1-1 (reference)) is 1, other prescription examples, that is, Comparative Examples 1-2 to 1-7 and the implementation The ratio of the friction coefficient of Examples 1-1 and 1-2 was calculated. The results are shown in Tables 1 and 2 below.

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

  As can be seen from the results in Tables 1 and 2, compared with Comparative Examples 1-1, 1-2, 1-3 and 1-5 containing polyvinylpyrrolidone K90, polyhexanide hydrochloride, sodium chondroitin sulfate or sodium hyaluronate alone. In Examples 1-1 and 1-2 containing polyvinyl pyrrolidone K90, polyhexanide hydrochloride, and sodium chondroitin sulfate or sodium hyaluronate, the ratio of the coefficient of friction was unexpectedly greatly reduced. It was confirmed that the effect was remarkably improved. On the other hand, Comparative Examples 1-4 and 1-7 using polyvinylpyrrolidone K25 instead of polyvinylpyrrolidone K90 did not show a significant friction reducing action.

[Test Example 2: Friction evaluation (2)]
As a formulation example, except that the formulations shown in Tables 3 to 5 below were used and the corresponding comparative example was set to Comparative Example 2-1, the same comparative example (Comparative Example 2- The ratio of the coefficient of friction of the other prescription examples when the coefficient of friction of 1 (reference) is 1 was determined. The result is combined with following Tables 3-5, and is shown.

  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), sodium chondroitin sulfate or hyaluron instead of hydroxypropylmethylcellulose 2906 When sodium acid is contained and the concentration of polyvinylpyrrolidone K90 is changed (Examples 2-2 to 2-5), when polyvinylpyrrolidone K90, polyhexanide hydrochloride and aminoethylsulfonic acid are contained (Example 2-6) ) In any case of containing chlorhexidine gluconate or trometamol (Examples 2-7 to 2-10) instead of polyhexanide hydrochloride, the friction coefficient ratio is larger than that of Comparative Example 2-1. Reduced and reduced friction Use it was confirmed to be significantly improved.

[Test Example 3: Friction evaluation (3)]
As a formulation example, the corresponding comparative example (Comparative Example 3-1) was used in the same manner as in Test Example 1 except that the formulation shown in Table 6 below was used and the corresponding comparative example was Comparative Example 3-1. The ratio of the friction coefficient of the other prescription examples when the friction coefficient of (reference) was 1 was determined. The results are also shown in Table 6 below.

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

[Test Example 4: Friction evaluation (4)]
As a prescription example, except that the prescription shown in the following Table 7 was used and the corresponding comparative example was set to Comparative Example 4-1, the corresponding comparative example (Comparative Example 4-1 ( The ratio of the friction coefficient of the other prescription examples when the friction coefficient of the standard)) was set to 1 was obtained. 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 sodium hyaluronate 0.1 w / v% were contained (Example 4-1), chlorhexidine gluconate was contained instead of polyhexanide hydrochloride. In any case (Example 4-2), the friction coefficient ratio is greatly reduced as compared with Comparative Example 4-1, and it is confirmed that the friction reducing effect is remarkably exhibited. It 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, only Buffer was prepared and used as a control. Thereafter, the cell viability (%) of each test solution relative to the control was determined using Cell-counting kit-8. Then, using the following formula (8), another formulation example when the cell survival rate 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 survival rate = cell survival rate of each test solution / cell survival rate of corresponding comparative example (8)

As can be seen from the results of Tables 8 and 9 above, in the test solutions of Comparative Examples 5-2 and 5-2, in which polyhexanide hydrochloride and sodium hyaluronate were blended alone, compared to the test solution of Comparative Example 5-1, Little increase in cell viability was observed. On the other hand, in the test solutions of Examples 5-1 and 5-2 in which polypyrrolidone hydrochloride, sodium hyaluronate or aminoethylsulfonic acid was further blended with polyvinylpyrrolidone K90, it was confirmed that the cell survival rate was significantly increased. It was.
From the above results, by using the ophthalmic composition of the present invention, since the cell survival rate is significantly increased, the decrease in the cell survival rate is reduced even when exposed to an oligotrophic state, That is, it was confirmed that the corneal cells were activated.

[Test Example 6: Evaluation for cell activation effect (2)]
Each formulation was changed in the same manner as in Test Example 5 except that the test solution was changed to the one shown in Tables 10 and 11 below and Comparative Example 6-1 (standard) was used as a corresponding Comparative Example. The cell survival rate in was calculated.

  As can be seen from the results in Tables 10 and 11 above, the test solution of Comparative Example 6-2 containing sodium hyaluronate alone had almost no increase in cell survival rate compared to the test solution of Comparative Example 6-1. I couldn't see it. On the other hand, in the test solution of Example 6-1 in which polyvinyl pyrrolidone K90 was further blended with polyhexanide hydrochloride and sodium hyaluronate, it was confirmed that the cell survival rate significantly increased. Further, it was confirmed that the cell survival rate significantly increased in the test solution of Example 6-2 in which polyvinyl pyrrolidone K90 was further blended with polyhexanide hydrochloride and aminoethylsulfonic acid.

[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 described in Tables 12 and 13 below.
Immortalized human corneal epithelial cells (HCE-T) were seeded in a 6-well plate and DMEM / F12 medium (DMEM / F12 medium 470 mL, Antibiotic-anticolytic 100 × 5 mL, DMSO 2.5 mL, EGF 0.5 mL, Insulin 0.6 mL and FBS 25 mL) 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 (Mitsubishi Gas Chemical Co., Ltd.). Subsequently, RNA was extracted from the cells using QIAshredder & RNase Mini Kit (manufactured by QIAGEN), reversely transcribed into cRNA using SuperScript II (manufactured by Life technologies), and then ABI QuantStudio RealTime PCR 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 relative to the corresponding comparative example was determined using the following formula (9). As an internal standard, 18S gene (House Keeping gene) was used. The expression ratio of the IL-6 gene of the other prescription examples was calculated with the IL-6 gene expression level of the subject example (blank) not containing the components (A) to (C) shown below as 1. The results are shown in Tables 12 and 13 below.
Corresponding comparative examples in Comparative Example 7-1 and Example 7-1 are target examples.

As can be seen from the results in Tables 12 and 13 above, in the test solution of Comparative Example 7-1 containing polyvinylpyrrolidone K90 alone, the expression ratio of IL-6 gene increases and the inflammatory reaction may be increased. It was confirmed that there was. Furthermore, in Example 7-1 containing polyhexanide hydrochloride and sodium chondroitin sulfate and Example 7-2 containing polyhexanide hydrochloride and sodium hyaluronate, the IL-6 gene was compared with the test solution of Comparative Example 7-1. It was confirmed that the expression ratio decreased and the inflammatory response tended to be suppressed.
Moreover, in the test liquid of Example 7-2, the tendency which raises notably was confirmed about the MUC1 conversion value and the GSTp-1 conversion value further (the conversion value when the target example is set to 1 is MUC1: 1. 23, GSTp-1: 1.13). MUC1 is one of the genes involved in mucin expression, and GSTp-1 is one of the genes involved in the expression of antioxidant factors. An increase in these conversion values reduces damage to the cornea during hypoxia and causes oxidative stress. It is sometimes thought to lead to the production of genes that work to protect the cornea.

  From the above results, even when exposed to hypoxic conditions, the ophthalmic composition according to the present embodiment can be used to reduce inflammation caused by oxidative stress caused by low oxygen exposure and to protect the cornea. It was confirmed that it has an action of promoting the production of working genes. Therefore, it was confirmed that the ophthalmic composition according to the present embodiment is useful for treating or preventing a corneal disorder caused by hypoxic exposure.

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

  As can be seen from the results of Table 14 above, Example 8-1 containing polyvinylpyrrolidone K90, polyhexanide hydrochloride and potassium aspartate has an expression ratio of IL-6 gene as compared with the test solution of Comparative Example 8-1. It was confirmed that there was a tendency to decrease and suppress the inflammatory response. Further, in the test solution of Example 8-1, it was confirmed that the MUC1 converted value and the HMOX-1 converted value were remarkably improved (the converted value when Comparative Example 8-1 was 1 was MUC1). : 3.22, HMOX-1: 2.74).

  From the above results, even when the prescription example is changed, by using the ophthalmic composition according to the present embodiment, inflammation caused by oxidative stress caused by exposure to hypoxia, corneal damage reduction action, corneal protection It was confirmed that it has an action of promoting the production of working genes. Therefore, it was confirmed that the ophthalmic composition according to the present embodiment is useful for treating or preventing a corneal disorder caused by hypoxic exposure.

[Test Example 9: Usability test]
Each aqueous composition (contact lens ophthalmic solution) was prepared according to the formulation described in Table 15 below, and this was used as a test solution. Each test solution was filled in a 13 mL capacity polyethylene terephthalate eye drop container. After filling, a polyethylene nozzle was attached to the container.
Four healthy subjects who normally wear soft contact lenses are subjects, and Example 9-1 is applied to the right eye, Comparative Example 9-1 is applied to the left eye, and the concave surface of the contact lens (the inner surface that contacts the cornea). After dropping one drop for each lens, a contact lens was attached.
Eight hours after wearing the contact lens, various symptoms of the eyes (feeling of rubbing, blinking) with the “VAS method (Visual Analog Scale)” using a 10 cm straight line with a memory of 0 to 100 It was evaluated for the improvement effect on the difficulty of touching, feeling of foreign objects in the eyes, feeling of sticking of contact lenses, dry eyes, tired eyes, blurred eyes). The lower the score, the less the symptoms are felt and the better the eye state.
On the other day, evaluation was performed in the same manner as above except that the same subject dropped Comparative Example 9-1 on the right eye and Example 9-1 on the left eye.
All the scores when each test solution was used were averaged to obtain the average VAS score value of each test solution.
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). did. The results are also shown in Table 15 below.

〔formula〕
Symptom improvement rate (score reduction rate) (%) = {(average VAS score value of test liquid of Comparative Example 9-1−average VAS score value of test liquid of Example 9-1) / of test liquid 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, friction in the eye part is reduced, and the feeling of rubbing during blinking, difficulty in blinking, It was confirmed that the foreign object feeling and the feeling of sticking the contact lens were improved.
In addition, it was confirmed that by blending polyvinyl pyrrolidone K90, polyhexanide hydrochloride, and hydroxypropylmethylcellulose, eye irritation, eye fatigue, and blurred vision were improved.

<Formulation example>
In the formulations described in Tables 16 to 19 below, eye drops (Formulation Examples 1 to 9), eye drops for contact lenses (CL) (Formulation Examples 10 to 23), and contact lens wearing eye drops (Formulation Examples 24 to 24) 26) is prepared.
The units of each component amount in Tables 16 to 19 are all “w / v%”.

Moreover, the said formulation examples 1-26 were accommodated in the container made from a polyethylene terephthalate (PET), and the nozzle made from polyethylene (PE) was mounted | worn (formulation examples 1'-26 ').
Similarly, the preparations having the same composition in each of Preparation Examples 1 to 26 were accommodated in a polyethylene terephthalate (PET) container, and a nozzle made of polybutylene terephthalate (PBT) was attached (Formulation Example 1 ” ~ 26 ").

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

Claims (12)

Use of a combination to reduce friction in the eye,
The combination is selected from the group consisting of polyvinylpyrrolidone (A) having a K value of 40 or more, at least one selected from the group consisting of biguanide fungicides and trometamol (B), mucopolysaccharides and salts thereof A combination with at least one (C),
Use, wherein the combination is used as a component of an ophthalmic composition.   The use according to claim 1, wherein the component (A) is polyvinylpyrrolidone K90.   The use according to claim 1 or 2, wherein the component (B) is a biguanide fungicide.   The use according to any one of claims 1 to 3, wherein the component (C) is at least one selected from the group consisting of chondroitin sulfate, hyaluronic acid, and salts thereof.   The ophthalmic composition further comprises at least one selected from the group consisting of a nonionic surfactant, edetic acid and salts thereof, inorganic salts, terpenoids, and buffers. Or use as described in paragraph 1.   The use according to any one of claims 1 to 5, wherein the ophthalmic composition is an eye drop, an eye wash, a contact lens mounting solution, or a contact lens mounting eye drop. 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 at least one selected from the group consisting of mucopolysaccharides and salts thereof An ophthalmic composition comprising a seed (C) and menthol, wherein the content of the component (A) is 0.01 to 0.4 w / v% based on the total amount of the ophthalmic composition ( However, except for those containing pranoprofen or a salt thereof, except for those containing an amphoteric surfactant represented by the following general formula (6), further, chlorobutanol, polyethylene glycol monostearate and polyoxy Except for the composition applied to mucosa containing ethylene sorbitan fatty acid ester, an antihistamine, glycyrrhizic acid and / or a salt thereof And an ophthalmic composition for soft contact lenses containing sodium chondroitin sulfate and / or its salt and 0.5 w / v% or more polyvinylpyrrolidone and having a pH of 5.5 to 6.8. .

[In general formula (6), R ¹ is R or (CH ₂ ) _n —NHC (O) R, wherein R is C ₈ -C ₁₆ alkyl optionally substituted by 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 a C ₂ -C ₈ alkylene optionally substituted by hydroxyl It is. ]   The manufacturing method of Claim 7 whose said (A) component is polyvinylpyrrolidone K90.   The manufacturing method according to claim 7 or 8, wherein the component (B) is a biguanide fungicide.   The production method according to any one of claims 7 to 9, wherein the component (C) is at least one selected from the group consisting of chondroitin sulfate, hyaluronic acid and salts thereof.   The method further comprises containing at least one selected from the group consisting of a nonionic surfactant, edetic acid and salts thereof, inorganic salts, terpenoids (excluding menthol) and buffering agents. The manufacturing method as described in any one of 10-10.   The manufacturing method according to any one of claims 7 to 11, wherein the ophthalmic composition is an eye drop, an eye wash, a contact lens mounting solution, or a contact lens mounting eye drop.