JP6452283B2 - Eye foreign substance feeling improving agent - Google Patents

Description

  The present invention relates to an ocular foreign body feeling improving agent.

  Most of sensory nerves distributed in the cornea are trigeminal nerves, and cornea perception is one of the most sensitive pains in the human body, and the degree of pain is extremely sharp. . Thus, because the cornea is very painful, even if foreign matter such as dust, pollen, or excessive amounts of protein adheres to the corneal epithelium, it immediately appears as a symptom of foreign body sensation or eye pain. In some cases, tearing may occur to discharge foreign matter. For this reason, it is important from the viewpoint of removing indefinite complaints and improving the quality of life to improve the adhesion of foreign matter to the eyeball surface such as protein stains and the resulting foreign matter sensation.

  In recent years, not only dust, pollen and protein stains, but also eyes caused by dirt such as cosmetics (mascara, eyeliner, eye shadow, lotion, milky lotion, eye cream, lame cosmetics, scrub eyewash, etc.) The feeling of foreign objects and eye damage are also serious problems. In order to wash and remove cosmetics or pollen adhering to the eyeball or eyelid, an eyewash having a monoterpene contained in a carboxyvinyl polymer and used in contact with a site to be cleaned at a time of 500 μL has been found (patent) Reference 1).

  In addition, since the pain of the cornea has developed, the eyes are irritated due to friction when rubbing the eyes due to inflammation due to allergies, drying with dry eyes, wearing contact lenses, ultraviolet rays, and stimulating drugs. Or a sense of incongruity that hits the eye when blinking may cause a sense of foreign matter in the eye.

As a pharmaceutical composition effective in treating dry eye disease the foreign body sensation in the eye with major symptoms, a pharmaceutical composition comprising an A ₃ adenosine receptor agonists have been reported (Patent Document 2).

JP 2011-93889 A Special table 2009-524647

  An object of the present invention is to provide an agent for improving ocular foreign body sensation.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that pyridoxine or a salt thereof has an effect of improving the foreign body sensation of the eye.

That is, the present invention provides the following [1] to [10].
[1] An ocular foreign body sensation improving agent containing at least one selected from the group consisting of pyridoxine and a salt thereof as an active ingredient.
[2] The foreign matter sensation improving agent according to [1], further comprising an amino acid as an active ingredient.
[3] The ocular foreign body sensation improving agent according to [2], wherein the amino acids are at least one selected from the group consisting of aminoethylsulfonic acid, chondroitin sulfate, and salts thereof.
[4] The foreign matter sensation-improving agent according to [1] to [3], wherein the total content of the component (A) is 0.0005 to 0.5 w / v%.
[5] The foreign substance sensation improving agent for eyes according to [2] to [4], wherein the total content of component (B) is 0.001 to 5 w / v%.
[6] The eye according to [2] to [5], wherein the total content of component (B) is 0.01 to 10000 parts by mass with respect to 1 part by mass of the total content of component (A). Foreign body feeling improving agent.
[7] The ocular foreign body sensation improving agent according to [1] to [6], which is an eye drop or an eye wash.
[8] A method of imparting an effect of improving ocular foreign body sensation to an ophthalmic composition, comprising at least one selected from the group consisting of pyridoxine and a salt thereof as an active ingredient in an ophthalmic composition how to.
[9] The method according to [8], further comprising blending amino acids into the ophthalmic composition as an active ingredient.
[10] The method according to [9], wherein the amino acids are at least one selected from the group consisting of aminoethylsulfonic acid, chondroitin sulfate, and salts thereof.

  The ocular foreign body sensation-improving agent and ophthalmic composition of the present invention are produced by friction caused when rubbing the eyes due to inflammation due to allergy, drying with dry eyes, wearing of contact lenses, stimulation of ultraviolet rays, drugs, etc. Can be used for the treatment and prevention of a foreign body sensation that causes a sense of incongruity, such as tingling or tingling or blinking. In addition, the foreign body sensation-improving agent and ophthalmic composition of the present invention are useful for the treatment and prevention of a foreign body sensation of the eye from the viewpoint of having an effect of suppressing the amount of foreign matter adsorbed to corneal epithelial cells.

  In the present specification, the unit of content “%” means “w / v%” and is synonymous with “g / 100 mL”.

  In the present specification, unless otherwise specified, the abbreviation “POE” means polyoxyethylene. In this specification, unless otherwise specified, the abbreviation “POP” means polyoxypropylene.

  The ocular foreign body sensation-improving agent and ophthalmic composition according to the present embodiment contain at least one selected from the group consisting of pyridoxine and a salt thereof (hereinafter sometimes simply referred to as component (A)). To do.

  Pyridoxine is a compound also called 5-hydroxy-6-methylpyridine-3,4-dimethanol. Pyridoxine and / or a salt thereof is a compound known as vitamin B6, which is a water-soluble vitamin, and may be synthesized by a known method or obtained as a commercial product.

  The salt of pyridoxine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, an organic acid salt [for example, a monocarboxylate ( Acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.), oxycarboxylate ( Lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salt (eg hydrochloride, sulfate, nitrate, odor) Hydride, phosphate, etc.).

  These pyridoxine and / or its salt may be used individually by 1 type, and may be used in combination of 2 or more types arbitrarily. From the viewpoint of improving the foreign body sensation of the eye, the component (A) is preferably an inorganic acid salt of pyridoxine, more preferably a hydrochloride or phosphate of pyridoxine, and still more preferably a hydrochloride of pyridoxine.

The content of the component (A) in the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type, formulation form, usage method, and the like of the component (A). The As the content of the component (A), for example, the total content of the component (A) is 0.0005 to 0.00 based on the total amount of the foreign body sensation improving agent and the ophthalmic composition according to this embodiment. It is preferably 5 w / v%, more preferably 0.001 to 0.2 w / v%, still more preferably 0.005 to 0.1 w / v%, and 0.01 to 0. 1 w / v% is particularly preferred.
The content of the component (A) is preferable from the viewpoint of improving the feeling of foreign matter in the eye.

  Furthermore, the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment are a combination of the component (A) and amino acids (hereinafter sometimes simply referred to as the component (B)). It is possible to further improve the foreign body feeling of the eye.

  In this embodiment, amino acids include amino acids and salts thereof, and amino acid analogs, and mean compounds having amino groups and carboxyl groups or sulfo groups in the molecule or derivatives thereof.

  Examples of amino acids used in the present embodiment include monoamino monocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid; monoaminodicarboxylic acids such as aspartic acid and glutamic acid; and salts thereof; arginine And diaminomonocarboxylic acids such as lysine or salts thereof; aminoethylsulfonic acid (taurine) or salts thereof; chondroitin sulfate or salts thereof; hyaluronic acid or salts thereof. Specific examples of amino acids used in the present embodiment include glycine, alanine, γ-aminobutyric acid, γ-aminovaleric acid, chondroitin sulfate, epsilon aminocaproic acid, aspartic acid, glutamic acid, arginine, aminoethylsulfonic acid, hyaluronic acid. And salts thereof.

  The amino acid salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable salts. Such salts include salts with organic acids [for example, monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate , Maleate, etc.), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate) Etc.], salts with inorganic acids (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, Salts with organic amines such as morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium) Etc.), alkaline earth metal (calcium, magnesium etc.), etc. and salts with metals such as aluminum] can be exemplified, it is appropriately selected depending on the amino acids used.

These amino acids and / or salts thereof may be used alone or in any combination of two or more. From the viewpoint of improving the feeling of foreign matter in the eye, the component (B) is preferably epsilon aminocaproic acid, aspartic acid, chondroitin sulfate, aminoethylsulfonic acid, hyaluronic acid or a salt thereof.
Especially, as a (B) component, an aminoethylsulfonic acid, a chondroitin sulfate, or those salts are preferable from a viewpoint of remarkably improving the foreign-body feeling of eyes.

  Aminoethylsulfonic acid is a known compound also called taurine.

  The salt of aminoethylsulfonic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As the salt of aminoethylsulfonic acid, specifically, a salt with an organic acid [for example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxyl Acid salts (fumarate, maleate, etc.), oxycarboxylates (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonates (methanesulfonate, toluenesulfone) Acid salts, tosylate salts, etc.], salts with inorganic acids (eg hydrochlorides, sulfates, nitrates, hydrobromides, phosphates etc.), salts with organic bases (eg methylamine, Salts with organic amines such as triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [eg ammonium salts; alkali metals ( Thorium, potassium, etc.), alkaline earth metal (calcium, magnesium etc.), salts with metals such as aluminum, etc.] and the like.

  These aminoethylsulfonic acids and / or salts thereof may be used alone or in any combination of two or more. Aminoethylsulfonic acid and / or a salt thereof is preferably aminoethylsulfonic acid from the viewpoint of improving the feeling of foreign matter in the eye.

Chondroitin sulfate is a kind of glycosaminoglycan having a structure in which sulfuric acid is bound to a sugar chain in which two sugars of D-glucuronic acid and N-acetyl-D-galactosamine are repeated.
The chondroitin sulfate used in this embodiment is not particularly limited in its origin as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. For example, cartilage of mammals or fish Those derived from (such as salmon cartilage) can be used.

  The salt of chondroitin sulfate is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As a salt of chondroitin sulfate, for example, one having the same form as the salt that can be taken by the aminoethylsulfonic acid can be exemplified.

  These chondroitin sulfates and / or their salts may be used alone or in any combination of two or more. From the viewpoint of improving the feeling of foreign matter in the eye, chondroitin sulfate and / or a salt thereof is preferably a salt of chondroitin sulfate with an inorganic base, more preferably an alkali metal salt of chondroitin sulfate, and even more preferably sodium chondroitin sulfate. Chondroitin sulfate is also called chondroitin sulfate, and sodium chondroitin sulfate is also called sodium chondroitin sulfate.

The content of the component (B) in the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment is not particularly limited, and the type, formulation form, usage method, and the like of the component (A) and the component (B) are not limited. It is set accordingly. As content of (B) component, for example, the total content of amino acids is 0.001 to 5 w / v% based on the total amount of the foreign body sensation improving agent and ophthalmic composition according to the present embodiment. Is preferably 0.005 to 3 w / v%, more preferably 0.01 to 2 w / v%, and particularly preferably 0.05 to 1 w / v%. .
From the viewpoint of use as an ophthalmic composition such as eye drops and eyewashes, the total content of amino acids is preferably 0.002 to 7.5 w / v%, and 0.01 to 4 w / v%. It is more preferable that it is 0.02-1.5 w / v%.

  When the component (B) is aminoethylsulfonic acid and / or a salt thereof, the content of aminoethylsulfonic acid and / or the salt thereof is, for example, an ocular foreign body sensation improving agent and an ophthalmic composition according to the present embodiment. Based on the total amount of the product, the total content of aminoethylsulfonic acid and / or salt thereof is preferably 0.01 to 3 w / v%, and preferably 0.05 to 1.5 w / v%. More preferably, it is 0.1-1 w / v%.

  When the component (B) is chondroitin sulfate and / or a salt thereof, the content of chondroitin sulfate and / or the salt thereof is, for example, the total amount of the ocular foreign body sensation improving agent and the ophthalmic composition according to the present embodiment. As a reference, the total content of chondroitin sulfate and / or a salt thereof is preferably 0.005 to 2 w / v%, more preferably 0.01 to 1 w / v%, and 0.05 to 0 More preferably, it is 5 w / v%.

  The content ratio of the component (B) to the component (A) in the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment is not particularly limited, and the types and formulation forms of the component (A) and the component (B) It is set as appropriate according to the method of use. As a content ratio of the component (B) to the component (A), for example, relative to 1 part by mass of the total content of the component (A) contained in the ocular foreign body feeling improving agent and the ophthalmic composition according to the present embodiment. The total content of component (B) is preferably 0.01 to 10000 parts by mass, more preferably 0.05 to 2000 parts by mass, and further preferably 0.1 to 500 parts by mass. The amount is particularly preferably 0.5 to 200 parts by mass, and more preferably 1 to 50 parts by mass.

  When the component (B) is aminoethylsulfonic acid and / or a salt thereof, the content ratio of the aminoethylsulfonic acid and / or salt thereof to the component (A) is, for example, a total content of component (A) of 1 mass. The total content of aminoethylsulfonic acid and / or salt thereof is preferably 0.02 to 5000 parts by mass, more preferably 0.1 to 2000 parts by mass, and 0.5 parts by mass. More preferably, it is -500 mass parts, It is especially preferable that it is 1-100 mass parts, It is still more preferable that it is 1-20 mass parts.

  When the component (B) is chondroitin sulfate and / or a salt thereof, the content ratio of the chondroitin sulfate and / or salt thereof to the component (A) is, for example, relative to 1 part by mass of the total content of the component (A) The total content of chondroitin sulfate and / or a salt thereof is preferably 0.01 to 5000 parts by mass, more preferably 0.05 to 1000 parts by mass, and 0.1 to 200 parts by mass. More preferably, it is 0.5-50 mass parts, It is especially preferable that it is 0.5-20 mass parts.

  The content of the component (B) and the content ratio of the component (B) with respect to the component (A) are suitable in this embodiment from the viewpoint of the use of improving the feeling of foreign objects in the eye.

  The ocular foreign body sensation improving agent and the ophthalmic composition according to the present embodiment may further contain a surfactant. The surfactant is a solution that improves the solubility of various pharmacologically active ingredients, physiologically active ingredients, additives, and the like described later depending on the purpose of use of the ophthalmic composition according to the present embodiment. Effective as an adjuvant.

  The surfactant that can be contained in the ocular foreign body sensation-improving agent and ophthalmic composition according to the present embodiment is particularly pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. It is not limited, and any of nonionic surfactants and ionic (amphoteric, negative, positive) surfactants may be used.

  Specific examples of the nonionic surfactant that can be contained in the ocular foreign body sensation-improving agent and the ophthalmic composition according to this embodiment include monouraric acid POE (20) sorbitan (polysorbate 20) and monopalmitic acid. POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80), etc. POE sorbitan fatty acid ester; POE cured castor oil such as POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE (10) castor Oil (Polyoxyethylene castor oil 1 POE castor oil such as POE (35) castor oil (polyoxyethylene castor oil 35); POE alkyl ether such as POE (9) lauryl ether; POE-POP alkyl such as POE (20) POP (4) cetyl ether Ethers; polyoxyethylene / polyoxypropylene block copolymers such as POE (196) POP (67) glycol (poloxamer 407, Pluronic F127), POE (200) POP (70) glycol; polyethylene monostearate such as polyoxyl 40 stearate Glycol and the like. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.

Specific examples of the amphoteric surfactant that can be contained in the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment include alkyldiaminoethylglycine and a salt thereof (for example, hydrochloride). it can.
Further, as an anionic surfactant that can be contained in the ocular foreign body sensation improving agent and the ophthalmic composition according to the present embodiment, specifically, alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl Examples thereof include sulfates, α-sulfo fatty acid ester salts, α-olefin sulfonic acids and the like.
Specific examples of the cationic surfactant that can be contained in the ocular foreign body sensation improving agent and the ophthalmic composition according to this embodiment include benzalkonium chloride and benzethonium chloride.

  In the ocular foreign body sensation-improving agent and the ophthalmic composition according to this embodiment, the surfactant may be used alone or in combination of two or more. Among the surfactants that can be contained in the ocular foreign body sensation improving agent and the ophthalmic composition according to the present embodiment, a nonionic surfactant is preferable from the viewpoint of improving the ocular foreign body sensation. . As the nonionic surfactant, POE sorbitan fatty acid ester, POE hydrogenated castor oil, POE castor oil, or POE / POP block copolymer is preferable, and polysorbate 80, POE hydrogenated castor oil 60, or poloxamer 407 is more preferable.

  When the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment contain a surfactant, the content thereof includes the type of the surfactant, the type and content of other compounding components, and the ophthalmic use. It is appropriately set according to the use of the composition, the form of preparation, the method of use and the like. As the content of the surfactant, for example, the total content of the surfactant is preferably 0.001 to 3 w / v% based on the total amount of the ophthalmic composition according to the present embodiment. It is more preferably 005 to 2 w / v%, further preferably 0.01 to 1 w / v%, and particularly preferably 0.05 to 1 w / v%.

  The ocular foreign body sensation improving agent and the ophthalmic composition according to the present embodiment may further contain a buffer. Thereby, pH of the ocular foreign material feeling improving agent and ophthalmic composition which concern on this embodiment can be adjusted.

  The buffer that can be contained in the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Not limited. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Tris buffer, and the like.

  Examples of the boric acid buffer include boric acid, or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphates and phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonic acid, or carbonates such as alkali metal carbonate and alkaline earth metal carbonate. Examples of the citrate buffer include citric acid, alkali metal citrate, and alkaline earth metal citrate. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium 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, citric acid, etc.) Acid calcium, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid As an agent, acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); As a Tris buffer, tris (hydroxymethyl) aminomethane or a salt thereof (hydrochloride, acetate, sulfonate, etc.), etc. Can be illustrated.

  The buffering agent contained in the ocular foreign body sensation-improving agent and the ophthalmic composition according to this embodiment may be used alone or in any combination of two or more. Among these buffers, a borate buffer or a phosphate buffer can be preferably used, and a borate buffer can be more preferably used. As the boric acid buffer, a combination of boric acid and borax is preferable. Further, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate is preferable as the phosphate buffer.

  When the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment contain a buffering agent, the content thereof includes the type of the buffering agent, the type and content of other compounding components, and the ophthalmic composition. Is appropriately set according to the use, formulation form, method of use and the like. As the content of the buffer, for example, based on the total amount of the ophthalmic composition according to the present embodiment, the total content of the buffer is preferably 0.01 to 15 w / v%, 0.05 It is more preferably 10 to 10 w / v%, further preferably 0.1 to 7.5 w / v%, and particularly preferably 0.5 to 5 w / v%.

  The pH of the ocular foreign body sensation-improving agent and ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. . As an example of the pH of the ophthalmic composition according to this embodiment, it is preferably 4.0 to 9.5, more preferably 5.0 to 9.0, and 5.5 to 8.5. More preferably it is.

The ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment may further contain an isotonic agent. Thereby, the osmotic pressure of the foreign body sensation improving agent and the ophthalmic composition according to the present embodiment can be adjusted.
The isotonic agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of isotonic agents include disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, acetic acid. Sodium, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol and the like can be mentioned. Among these isotonic agents, glycerin, propylene glycol, polyethylene glycol, glucose, sodium chloride, potassium chloride, calcium chloride or magnesium chloride are preferable, sodium chloride, potassium chloride or propylene glycol is more preferable, and sodium chloride is particularly preferable. . These isotonic agents may be used alone or in any combination of two or more.

  When the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment contain an isotonic agent, the content depends on the type of tonicity agent, the type and content of other components, and the like. Is set as appropriate. The content of the tonicity agent is, for example, 0.01 to 10 w / v% of the total content of the tonicity agent based on the total amount of the ocular foreign body feeling improving agent and the ophthalmic composition. Is preferable, it is more preferable that it is 0.05-5 w / v%, and it is still more preferable that it is 0.1-3 w / v%.

  The ocular foreign body sensation improving agent and the ophthalmic composition according to the present embodiment may further contain a thickening agent. Thereby, the viscosity of the ocular foreign material feeling improving agent and ophthalmic composition according to the present embodiment can be adjusted.

As the thickener, for example, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, polyoxyethylene-polyoxypropylene block copolymer (BASF Wyandotte Corporation, Pluronic, TE) Tronic, etc.), cellulose derivatives [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910, etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or their salts], polyethylene glycol (macrogol) 300, Macrogol 400, Macrogol 1500, Macrogo 4000, Macrogol 6000, etc.), chondroitin sodium sulfate, gum arabic, tragacanth, dextran (40, 70, etc.), glucose, sorbitol, etc., preferably polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K25) , K30, K90), carboxyvinyl polymer, cellulose derivatives (methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910), carboxymethylcellulose or a salt thereof), polyethylene glycol (Macrogol 300, Macrogol) 400, macrogol 4000, macrogol 6000), dextran (70), more preferably polyvinyl alcohol. Lucol (completely or partially saponified), polyvinylpyrrolidone (K25, Kollidon (R) K30, Kollidon (R) K90), carboxyvinyl polymer, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910), carboxymethylcellulose or These salts are polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, Macrogol 6000) and Dextran (70).
These thickening agents may be used alone or in any combination of two or more.

  When the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment contain a thickening agent, the content thereof includes the type of the thickening agent, the type and content of other compounding components, and the ophthalmic use. It is appropriately set according to the use of the composition, the form of preparation, the method of use and the like. As the content of the thickener, for example, the total content of the thickener is 0.01 to 10 w / v% on the basis of the total amount of the ocular foreign body sensation improving agent and the ophthalmic composition according to the present embodiment. It is preferable that it is 0.01-5 w / v%, and it is further more preferable that it is 0.05-3 w / v%.

  In addition, the osmotic pressure of the ocular foreign body sensation improving agent and 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. As an example of the osmotic pressure ratio of the ocular foreign body sensation improving agent and the ophthalmic composition according to the present embodiment, it is preferably 0.5 to 5.0, more preferably 0.6 to 3.0, It is more preferable that it is 0.7-2.0, and it is especially preferable that it is 0.8-1.55. The adjustment of the osmotic pressure can be performed by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a 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 ocular foreign body sensation-improving agent and 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. For example, the viscosity at 25 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × R24) is preferably 0.1 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 1-10 mPa * s.

In addition, the ocular foreign body sensation-improving agent and ophthalmic composition according to the present embodiment contain appropriate amounts of various pharmacologically active ingredients and physiologically active ingredients in addition to the above ingredients, as long as the effects of the present invention are not hindered. It may be. Ingredients are not particularly limited, and examples include active ingredients in various pharmaceuticals described in the OTC Drug Manufacturing and Sales Approval Standards 2012 edition (supervised by the Japanese Society for Regulatory Science). For example, specific examples of components used in ophthalmic drugs include the following components.
Antihistamine or antiallergic agent: for example, ketotifen fumarate, diphenhydramine hydrochloride, chlorpheniramine maleate, cromoglycate sodium, tranilast, pemirolast potassium, olopatadine hydrochloride and the like.
Decongestant: Tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.
Eye muscle modulating agent: for example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide and the like.
Bactericides: for example, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biguanide hydrochloride, etc.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, panthenol, calcium pantothenate, tocopherol acetate and the like.
Anti-inflammatory agent: for example, glycyrrhizic acid, azulene sulfonic acid, allantoin, berberine, lysozyme and the like.
Astringent: for example, zinc lactate, zinc sulfate and the like.
Other: For example, sulfamethoxazole and salts thereof.

In addition, in the ocular foreign body sensation-improving agent and ophthalmic composition according to the present embodiment, various additives may be added according to conventional methods according to the use and formulation form, as long as the effects of the invention are not impaired. An appropriate amount may be selected and one or more may be used in combination. Examples of these additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (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, alginic acid and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be any of D-form, L-form and DL-form.
Antiseptics, bactericides or antibacterials: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, dehydroacetic acid Sodium, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide), glowul (rhodia) Company name).
Refreshing agents: menthol, menthone, camphor, borneol, geraniol, nerol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, acetic acid, eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, cinnamon oil, Spearmint oil, camphor oil, cool mint, peppermint oil, etc.
Stabilizers: sodium edetate, dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.

  The ocular foreign body sensation improving agent and ophthalmic composition according to the present embodiment are preferably aqueous compositions. In this embodiment, the aqueous composition means a composition having a water content of 85 w / v% or more based on the total amount of the aqueous composition. The water content in the ocular foreign body sensation-improving agent and ophthalmic composition according to this embodiment is preferably 90 w / v% or more, more preferably 92 w / v% or more, and 94 w / v%. More preferably, it is more preferably 96 w / v% or more. As water used in the ocular foreign body sensation-improving agent and ophthalmic composition according to the present embodiment, water that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable may be used. Specific examples of such water include distilled water, normal water, purified water, sterilized purified water, water for injection, and distilled water for injection. In addition, the dosage form of the ocular foreign body sensation improving agent and the ophthalmic composition according to the present embodiment is not particularly limited, and examples thereof include liquids and semisolids (such as ointments), and are preferably liquids. These definitions are based on the 16th revised Japanese Pharmacopoeia.

  The ocular foreign body sensation-improving agent and ophthalmic composition according to the present embodiment are used in a carrier so that a desired amount of the above-mentioned component (A), component (B), and other compounding components as required may be a desired concentration. It can be prepared by adding. For example, in the case of an aqueous composition, it can be prepared by dissolving or suspending the above components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like. Regarding the dissolution of the above component (A), component (B), and other highly hydrophobic components, after stirring together with a component having a solubilizing action such as a surfactant, purified water is further added. It may be dissolved or suspended.

  The ocular foreign body sensation improving agent according to this embodiment can be suitably used as an ophthalmic composition. Moreover, the eye foreign substance improving agent according to the present embodiment can alleviate the feeling of foreign substances in the eye by suppressing the foreign substance adsorption of corneal epithelial cells. For this reason, the foreign body sensation improving agent for eyes according to this embodiment can also be used as a foreign matter adsorption inhibitor for corneal epithelial cells.

  This embodiment is a method for imparting an effect of improving ocular foreign body sensation to an ophthalmic composition from another viewpoint, characterized in that the component (A) is blended into the ophthalmic composition as an active ingredient. A method is provided. In addition to the component (A), there is also provided a method for imparting an effect of improving ocular foreign body feel to the ophthalmic composition by blending the component (B) as an active ingredient into the ophthalmic composition. As the component (B), at least one selected from the group consisting of aminoethylsulfonic acid, chondroitin sulfate, and salts thereof can be suitably used.

  Here, the ocular foreign body sensation improving agent and the ophthalmic composition include, for example, eye drops (also referred to as eye drops or eye drops. The eye drops include eye drops that can be instilled while wearing contact lenses). Ophthalmic compositions such as artificial tears, eyewashes (also called eyewashes or eyewashes. Eyewashes include eyewashes that can be washed while wearing contact lenses), eye ointments, etc .; Compositions [contact lens mounting liquid, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative), etc.] and the like. In addition, the said composition for contact lenses is applicable to all contact lenses including a hard contact lens and a soft contact lens. In view of the pharmacological action of the component (A) and the component (B), the eye foreign substance feeling improving agent and the ophthalmic composition according to the present embodiment are preferably eye drops and eye drops, and are eye drops. Is more preferable.

  In addition, since the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment can improve the ocular foreign body sensation caused by dry eye, allergy, inflammation, etc., the anti-allergy, anti-inflammatory, etc. It is effective as an ophthalmic composition to be used, and can be suitably used as an antiallergic eye drop.

  The ocular foreign body sensation-improving agent and ophthalmic composition according to the present embodiment can not only improve subjective symptoms but also suppress the adhesion of foreign substances. A foreign body sensation means a subjective symptom such as tingling or tingling caused by dry eyes, inappropriate use of contact lenses, allergic conjunctivitis due to adhesion of foreign substances such as pollen and house dust. The foreign body sensation is further enhanced by accompanying inflammation. The ophthalmic solution according to the present embodiment can be applied for the purpose of prevention or treatment for various symptoms accompanied by a foreign body sensation, and from the viewpoint of suppressing the adhesion of foreign materials, allergic conjunctivitis due to the adhesion of foreign materials, etc. It is suitable for a foreign body sensation caused, and particularly suitable for a foreign body sensation associated with allergies caused by hay fever or house dust.

  On the other hand, the ocular foreign body sensation-improving agent and the ophthalmic composition according to the present embodiment can be applied to any contact lens including a hard contact lens and a soft contact lens, but the foreign body sensation is applied. From the viewpoint of the improvement effect, it is preferable to apply the contact lens without wearing a contact lens, in particular, a soft contact lens, especially a silicone hydrogel contact lens, because it has a strong influence on the feeling of foreign matter. Silicone hydrogel contact lenses are included in soft contact lenses and are both ionic and nonionic, but ionic silicone contact lenses are known to have the property of adsorbing proteins that are allergens. Silicone hydrogel contact lenses are harder than other soft contact lenses, making it easier to feel a foreign body, and more easily causing physical damage to the corneal epithelium. Therefore, the influence on the effect of improving the foreign body feeling is immeasurable. However, it is not recommended that the eye drop according to the present embodiment be instilled while wearing the silicone hydrogel contact lens.

  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.

Test Example 1 Test Regarding Ocular Foreign Body Sense Eye drops were prepared according to Table 1 below. Using these eye drops, the foreign body sensation was evaluated by the VAS (Visual Analogue Scale) method. Specifically, each eye drop was instilled on four persons complaining of a foreign body sensation in the eye, the left end of the scale with a total length of 114 mm was 0 points for “not feeling foreign body”, and the right end was 100 points for “feeling foreign body sensation”. Then, it was checked to what extent the degree of foreign body sensation perceived corresponds. The ophthalmic solution was instilled in a state where no contact lens was worn. The length from the 0 point (left end) to the checked point was measured, and the ratio when the total length was 100 was calculated as the foreign object feeling score. The lower the score, the better the foreign body feeling. The results are shown in Table 1 together with the average value of 4 persons.

  As shown in Table 1, the ophthalmic solution containing pyridoxine hydrochloride (Example 1) reduces the foreign body sensation score and improves the ocular sensation of the eye compared to the eye drop containing no active ingredient (Comparative Example 1). Was confirmed. In addition, eye drops containing aminoethylsulfonic acid (Example 2) or sodium chondroitin sulfate (Example 3) together with pyridoxine hydrochloride can significantly reduce the foreign body sensation score and further improve the foreign body sensation of the eye. Was confirmed.

Test Example 2 Measurement of the amount of foreign matter adsorbed on corneal epithelial cells (1)
According to Table 2 below, each ophthalmic composition was prepared and evaluated for impact on the foreign matter capture of corneal epithelial cells.
Culture medium for each well so that human corneal epithelial cell line HCE-T (RIKEN BioResource Center, No. RCB2280) is placed in a 96-well microplate (Corning) at a rate of 1.0 × 10 ⁵ cells / well. 200 μL each was seeded and cultured at 37 ° C. under 5% CO ₂ for 24 hours. After culturing, the culture medium was aspirated, fluorescently labeled 0.05% albumin respectively put the ophthalmic composition 100μL containing at FITC, was allowed to stand at room temperature for 30 minutes. After the treatment, the solution in the well is removed by suction, 200 μL of phosphate buffer solution is added, the solution in the well is removed by suction and washed, then 100 μL of phosphate buffer solution is added, and a fluorescent plate reader (Fluoroskan Ascent CF (Manufactured by Labsystems), the fluorescence value at an excitation wavelength of 485 nm / an emission wavelength of 527 nm was measured. The obtained fluorescence value was converted into the amount of foreign matter (albumin) based on a calibration curve of the amount of foreign matter and the fluorescence value. From the amount of foreign matter obtained, the foreign matter adsorption suppression rate (%) was calculated based on the formula (I). In Examples 4 and 5 and Comparative Example 2, the term “control” refers to an ophthalmic composition (control 1) containing neither component (A) nor component (B). The results are summarized in Table 2.
(Formula I)
Foreign matter adsorption suppression rate (%) = (1− (foreign matter amount of each comparative example or example) / (control foreign matter amount)) × 100

  As shown in Table 2, in corneal epithelial cells, when pyridoxine hydrochloride was added (Example 4), compared to the case where no active ingredient was added (Control 1), foreign substances (FITC-labeled albumin) to the corneal epithelial cells were reduced. An increase in the adsorption inhibition rate was observed. On the other hand, when aminoethylsulfonic acid was added, the adsorption inhibition rate rather decreased (Comparative Example 2). Nevertheless, surprisingly, when aminoethylsulfonic acid was added together with pyridoxine hydrochloride, an increase in the foreign matter adsorption rate was remarkably observed (Example 5).

Test Example 3 Measurement of the amount of foreign matter adsorbed on corneal epithelial cells (2)
According to the following Table 3, each drug was prepared in the culture medium, and the influence on the foreign substance adsorption to the corneal epithelial cells was evaluated.
Culture medium for each well so that human corneal epithelial cell line HCE-T (RIKEN BioResource Center, No. RCB2280) is placed in a 96-well microplate (Corning) at a rate of 1.0 × 10 ⁵ cells / well. 200 μL each was seeded and cultured at 37 ° C. under 5% CO ₂ for 24 hours. After culturing, the culture medium was removed by suction, 100 μL of each drug containing 0.1% of albumin fluorescently labeled with FITC was added, and allowed to stand at room temperature for 60 minutes. After the treatment, the solution in the well is removed by suction, 200 μL of phosphate buffer solution is added, the solution in the well is removed by suction and washed, then 100 μL of phosphate buffer solution is added, and a fluorescent plate reader (Fluoroskan Ascent CF (Manufactured by Labsystems), the fluorescence value at an excitation wavelength of 485 nm / an emission wavelength of 527 nm was measured. The obtained fluorescence value was converted into the amount of foreign matter (albumin) based on a calibration curve of the amount of foreign matter and the fluorescence value. From the amount of foreign matter obtained, the foreign matter adsorption suppression rate (%) was calculated based on the formula (I). In Examples 6 and 7 and Comparative Example 3, “control” refers to a culture medium (control 2) containing neither component (A) nor component (B). The results are summarized in Table 3.

  As shown in Table 3, in the corneal epithelial cells, when pyridoxine hydrochloride was added (Example 6), compared with the case where no active ingredient was added (Control 2), foreign substances (FITC-labeled albumin) to the corneal epithelial cells were reduced. An increase in the adsorption inhibition rate was observed. On the other hand, when chondroitin sulfate sodium was added, the adsorption inhibition rate rather decreased (Comparative Example 3). Nevertheless, surprisingly, when chondroitin sulfate sodium was added together with pyridoxine hydrochloride, an increase in the foreign matter adsorption rate was remarkably observed (Example 7).

Formulation Examples Eye drops (Formulation Example 1-7) and eyewash (Formulation Example 8) are prepared according to the formulations shown in Tables 4 and 5. The ophthalmic compositions described in Tables 4 and 5 all have an effect of improving the feeling of foreign matter in the eyes.

Claims (6)

(A) It contains at least one selected from the group consisting of pyridoxine and its salt as an active ingredient, and the total content of component (A) is 0.05 to 0.1 w / v%, and hay fever or house Eye drops that are applied without wearing contact lenses to improve the feeling of foreign objects associated with allergies caused by dust (however,
(1) an eye drop containing 0.01-99.9 w / v% naphazoline hydrochloride,
(2) eye drops containing at least one antiallergic agent selected from the group consisting of sodium cromoglycate, amlexanox, pemirolast potassium, ibudilast, acitazanolast, tranilast, ketotifen fumarate and levocabastine hydrochloride ,
(3) eye drops containing at least one anti-inflammatory agent selected from the group consisting of epsilon-aminocaproic acid and dipotassium glycyrrhizinate , and
(4) Excluding eye drops containing chlorpheniramine maleate ).   The eye drop according to claim 1, further comprising (B) an amino acid as an active ingredient.   The eye drop according to claim 2, wherein the amino acid (B) is at least one selected from the group consisting of aminoethylsulfonic acid, chondroitin sulfate and salts thereof.   The eye drop according to claim 2 or 3, wherein the total content of component (B) is 0.001 to 5 w / v%.   The eye drop according to any one of claims 2 to 4, wherein the total content of the component (B) is 0.01 to 10000 parts by mass with respect to 1 part by mass of the total content of the component (A). . Eye drops applied without wearing contact lenses (however,
(1) an eye drop containing 0.01-99.9 w / v% naphazoline hydrochloride,
(2) eye drops containing at least one antiallergic agent selected from the group consisting of sodium cromoglycate, amlexanox, pemirolast potassium, ibudilast, acitazanolast, tranilast, ketotifen fumarate and levocabastine hydrochloride ,
(3) eye drops containing at least one anti-inflammatory agent selected from the group consisting of epsilon-aminocaproic acid and dipotassium glycyrrhizinate , and
(4) Excluding eye drops containing chlorpheniramine maleate )
A method for imparting an effect of improving foreign body sensation associated with allergies caused by hay fever or house dust, wherein (A) at least one selected from the group consisting of pyridoxine and a salt thereof has a total content of component (A) of 0 A method comprising blending in an eye drop so as to be 0.05 to 0.1 w / v%.