JP2019218369A - Eye drops for alleviating foreign body sensation - Google Patents

Abstract

To provide eye drops capable of alleviating a foreign body sensation in the eye by suppressing adsorption of the foreign body to a cornea.SOLUTION: The invention provides eye drops for alleviating a foreign body sensation containing (A) pranoprofen or a salt thereof, and (B) at least one compound selected from the group consisting of an antiallergic agent, an anti-inflammatory agent, and a water soluble vitamin. The sensation is a foreign body sensation as an allergic symptom.SELECTED DRAWING: None

Description

  The present invention relates to eye drops.

  The cornea is a tissue composed of five layers of a corneal epithelium, Bowman's membrane, corneal stroma, Descemet's membrane, and corneal endothelium in order from the outside world, and constituted on the outermost surface of the eyeball. Due to anatomical characteristics that are in direct contact with the outside world, various foreign substances such as antigens, microorganisms, and dust are likely to enter. On the other hand, most of the sensory nerves distributed in the cornea are trigeminal nerves. The corneal perception is considered to be one of the most sensitive among the human body's pain perception, and the degree of the pain is extremely sharp. That is, the nerve ending ends immediately below the corneal epithelium, and even a slight defect or detachment of the corneal epithelium is exposed and stimulated by the nerve ending just below the corneal epithelium. Patent Document 1).

  In this way, since the cornea is extremely painful, foreign substances such as dust, pollen, and excessive amounts of protein adhere to the corneal epithelium. Occasionally, lacrimation may occur to discharge foreign objects. In other words, it is important to improve the adhesion of foreign substances such as protein stains to the surface of the eyeball and the sensation of foreign substances resulting therefrom, from the viewpoint of removing indefinite complaints and improving the quality of life.

  In recent years, not only dusts, pollens, and protein stains, but also eyes caused by adhesion of cosmetics (mascara, eyeliner, eyeshadow, lotion, milky lotion, eye cream, glitter cosmetics, scrub facial cleanser, etc.) The foreign body sensation and eye disorders are also serious problems. In order to wash and remove cosmetics or pollen adhering to the eyeballs and eyelids, an eyewash containing a monoterpene in a carboxyvinyl polymer and having a contact amount of 500 μL with a portion to be washed at once has been found (Patent) Reference 1).

  The foreign body sensation of the eye is one of the subjective symptoms that are particularly prone to occur as one of the allergic symptoms. When external allergens such as pollen and house dust come into direct contact with the cornea, when proteins such as the skin stratum corneum or proteins secreted from the eyes are mixed into the conjunctiva of the eye by rubbing the eyes during pruritus, the Oxidation and adsorption to the cornea increase. Also, at the onset of allergic conjunctival disease, the conjunctival papillae, which is a change in the thickness of the conjunctival epithelium, is formed, and many conjunctival papillae come into contact with the cornea at the time of blinking. Patent Document 2). The protein adsorbed on the cornea not only gives a foreign body feeling but also may damage the cornea.

  Pranoprofen and / or its salt are known as propionic acid-based non-steroidal anti-inflammatory drugs having excellent anti-inflammatory action, analgesic action and antipyretic action, and are highly safe. Widely used as an agent.

  However, at present, the effect on the foreign body sensation of the eye when pranoprofen is used in combination with an anti-allergic agent, an anti-inflammatory agent or a water-soluble vitamin cannot be predicted at all.

JP 2011-93889 A

Takehisa Kondo: Corneal nerves, monthly ophthalmic practice 72:30, 2001 Japanese Society of Ophthalmology Allergy: Guidelines for the Treatment of Allergic Conjunctivitis Diseases (2nd edition), Journal of the Japanese Ophthalmology Society, Vol. 114, No. 10: 839-846, 2010

  An object of the present invention is to provide an ophthalmic solution that can alleviate the foreign-body sensation of the eye by suppressing foreign-body adsorption to the cornea.

  The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, (A) pranoprofen or a salt thereof (hereinafter also referred to as “component (A)”), (B) an antiallergic agent, an antiallergic agent, It has been found that a combination of at least one member selected from the group consisting of an inflammatory agent and a water-soluble vitamin (hereinafter, also referred to as “component (B)”) reduces the foreign body sensation of the eye. In addition, the present inventors have found that the combination of a cooling agent (C) remarkably alleviates the feeling of foreign substances. Based on these findings, the present inventors have completed the present invention.

That is, the present invention provides the following [1] to [10].
[1] A foreign body sensation ophthalmic solution containing (A) pranoprofen or a salt thereof and (B) at least one compound selected from the group consisting of antiallergic agents, antiinflammatory agents and water-soluble vitamins. ;
[2] The ophthalmic solution for reducing foreign body sensation according to [1], wherein the foreign body sensation is a foreign body sensation as an allergic symptom;
[3] The foreign body sensation according to [1] or [2], wherein the (B) component comprises at least one antiallergic agent selected from the group consisting of cromoglycic acid, pemirolast, tranilast, olopatadine, and salts thereof. Relief eye drops;
[4] As the component (B), at least one selected from the group consisting of ε-aminocaproic acid, allantoin, berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, sodium azulene sulfonate, zinc sulfate, zinc lactate and lysozyme chloride The eye drops for reducing foreign body sensation according to any of [1] to [3], comprising:
[5] As a component (B), it contains at least one water-soluble vitamin selected from the group consisting of pyridoxine hydrochloride, cyanocobalamin, sodium flavin adenine dinucleotide, panthenol, calcium pantothenate, and sodium pantothenate, [1] The ophthalmic solution for reducing foreign body sensation according to any one of to [4];
[6] When the anti-allergic agent is contained as the component (B) with respect to 1 part by mass of the total content of the component (A), the total content of the anti-allergic agent is 0.05 to 200 parts by mass, When the anti-inflammatory agent is contained as a component, the total content of the anti-inflammatory agent is 0.02 to 200 parts by weight, and when the water-soluble vitamin is contained as the component (B), the total content of the water-soluble vitamin is 0.002. The eye drop according to any one of [1] to [5], which is from 20 to 20 parts by mass.
[7] The ophthalmic solution for reducing foreign body sensation according to any one of [1] to [6], further comprising (C) a cooling agent;
[8] The ophthalmic solution for alleviating foreign-substance sensation according to [7], comprising, as a component (C), at least one type of refreshing agent selected from the group consisting of menthol, camphor, borneol, geraniol, and mint oil;
[9] The eye drop according to [7] or [8], wherein the total content of the (C) cooling agent is 0.0002 to 5 parts by mass with respect to 1 part by mass of the total content of the component (A). Agent.
[10] The ophthalmic solution for reducing foreign body sensation according to any one of [1] to [9], which is applied without a silicone hydrogel contact lens.
[11] A foreign substance characterized by combining (A) pranoprofen or a salt thereof and (B) at least one compound selected from the group consisting of an antiallergic agent, an antiinflammatory agent and a water-soluble vitamin. A method of imparting a relaxing effect to eye drops.
[12] The method of [11], further comprising (C) a cooling agent.

  ADVANTAGE OF THE INVENTION According to the foreign substance sensation relief eye drop which concerns on this invention, (A) pranoprofen or its salt, and (B) at least 1 type compound selected from the group which consists of an antiallergic agent, an anti-inflammatory agent, and a water-soluble vitamin. By suppressing the adsorption of foreign substances to the cornea, it is possible to alleviate the foreign-body sensation of the eye caused by allergy or the like. Furthermore, by further containing (C) a cooling agent in the combination of the above components (A) and (B), the adsorption of foreign substances to the cornea can be further suppressed, thereby reducing the foreign substance sensation of the eye caused by allergy or the like. It is possible to relax more.

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

  As used herein, the term “foreign body sensation” means a subjective symptom that is caused by dry eyes, inappropriate use of contact lenses, pollen, allergic conjunctivitis due to adhesion of foreign matter such as house dust, etc. I do. Therefore, the present inventors have focused on suppressing adhesion of a foreign substance and improving a subjective symptom itself in order to alleviate a foreign substance sensation. In particular, suppressing the attachment of foreign substances has a preventive effect on the foreign-body sensation of the eyes.

  The ophthalmic solution for alleviating foreign body sensation according to the present embodiment (hereinafter, also simply referred to as the ophthalmic solution according to the present embodiment) comprises (A) pranoprofen or a salt thereof, (B) an antiallergic agent, an anti-inflammatory agent and a water-soluble agent. At least one compound selected from the group consisting of vitamins.

(A) Component Pranoprofen is (2RS) -2- (10H-9-oxa-1-azaanthracen-6-yl) -propanoic acid or α-methyl-5H- [1] benzopyrano [2,3 -B] A known compound also referred to as pyridine-7-acetic acid, which may be synthesized by a known method or may be obtained as a commercial product.

  The salt of pranoprofen is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As such salts, specifically, salts with inorganic bases [eg, ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.] And salts with organic bases [eg, salts with organic amines such as methylamine, triethylamine, diethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline and the like]. Pranoprofen or a salt thereof includes those in the form of a hydrate.

  As the component (A) used in the aqueous composition according to the present embodiment, among pranoprofen or a salt thereof, one type may be used alone, or two or more types may be used in any combination. good. Among these, pranoprofen is preferable as the component (A).

  The content of the component (A) in the eye drops according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (A), the type and the content of the component (B) used in combination, and the like. As the content of the component (A), for example, the content of the component (A) is preferably 0.001 to 0.5 w / v% based on the total amount of the eye drops according to the present embodiment, It is more preferably 0.002 to 0.2 w / v%, further preferably 0.005 to 0.1 w / v%, and particularly preferably 0.01 to 0.1 w / v%. . The content of the component (A) is preferable from the viewpoint of the effect of alleviating the feeling of foreign matter.

(B) Component The (B) component is at least one compound selected from the group consisting of antiallergic agents, antiinflammatory agents, and water-soluble vitamins. As the component (B), one type may be used alone, or two or more types may be used in optional combination.

  The antiallergic agent is not particularly limited as long as it can suppress an allergic reaction. For example, cromoglycic acid, amlexanox, ibudilast, supratast, pemirolast, tranilast, olopatadine, acitazanolast, ketotifen and salts thereof (for example, Sodium cromoglycate, pemirolast potassium, olopatadine hydrochloride, ketotifen fumarate), and cromoglycic acid, pemirolast, tranilast, olopatadine and salts thereof are preferable from the viewpoint of the effect of alleviating the foreign body sensation, and tranilast or olopatadine is preferable. Hydrochlorides are particularly preferred.

  When the eye drops according to this embodiment contain an anti-allergic agent, the content of the anti-allergic agent is not particularly limited, and is appropriately set according to the type of the anti-allergic agent, the content of the component (A) used in combination, and the like. You. As the content of the antiallergic agent, for example, the total content of the antiallergic agent is preferably 0.005 to 3 w / v%, based on the total amount of the eye drops according to the present embodiment, and is preferably 0.01 to 3 w / v%. ２2 w / v%, more preferably 0.05-1 w / v%, even more preferably 0.1-1 w / v%. The content of the above antiallergic agent is suitable from the viewpoint of the effect of alleviating the feeling of foreign bodies.

  In the eye drops according to the present embodiment, the content ratio of the antiallergic agent to the component (A) is not particularly limited, and is appropriately set according to the type of the antiallergic agent and the like. As the content ratio of the anti-allergic agent to the component (A), for example, the total content of the anti-allergic agent is 0 with respect to 1 part by mass of the component (A) contained in the eye drops according to the present embodiment. 0.05 to 200 parts by mass, more preferably 0.2 to 50 parts by mass, even more preferably 0.5 to 30 parts by mass, and particularly preferably 1 to 20 parts by mass. preferable. The content ratio of the anti-allergic agent to the component (A) is preferable from the viewpoint of the effect of alleviating foreign body sensation.

  Examples of the anti-inflammatory agent include glycyrrhizic acid, allantoin, berberine sulfate, berberine chloride, azulene sulfonic acid, ε-aminocaproic acid, zinc sulfate, zinc lactate, lysozyme, salicylic acid, tranexamic acid and licorice. Anti-inflammatory agents may be in the form of salts, such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, sulfates , Lactate, hydrochloride, chloride, sodium, potassium and the like. Specific examples include dipotassium glycyrrhizinate, sodium azulene sulfonate, lysozyme chloride and the like. From the viewpoint of the effect of alleviating foreign body sensation, dipotassium glycyrrhizinate, allantoin, berberine sulfate, berberine chloride, sodium azulene sulfonate, ε-aminocaproic acid, zinc sulfate, zinc lactate or lysozyme chloride are preferred, and ε-aminocaproic acid, Allantoin, berberine sulfate or dipotassium glycyrrhizinate are particularly preferred.

  When the eye drops according to this embodiment contain an anti-inflammatory agent, the content of the anti-inflammatory agent is not particularly limited, and is appropriately set according to the type of the anti-inflammatory agent, the content of the component (A) used in combination, and the like. You. As the content of the anti-inflammatory agent, for example, the total content of the anti-inflammatory agent is preferably 0.001 to 7.5 w / v% based on the total amount of the eye drops according to the present embodiment. 0.004 to 5 w / v%, more preferably 0.01 to 1 w / v%, particularly preferably 0.02 to 0.5 w / v%. The content of the above-mentioned anti-inflammatory agent is suitable from the viewpoint of the effect of alleviating the foreign body sensation.

  In the eye drops according to the present embodiment, the content ratio of the anti-inflammatory agent to the component (A) is not particularly limited, and is appropriately set according to the type of the anti-inflammatory agent. The content ratio of the anti-inflammatory agent to the component (A) is, for example, such that the total content of the anti-inflammatory agent is 0 with respect to 1 part by mass of the component (A) contained in the eye drops according to the present embodiment. 0.02 to 200 parts by mass, more preferably 0.05 to 100 parts by mass, even more preferably 0.2 to 20 parts by mass, and 0.5 to 10 parts by mass. Is particularly preferred. The content ratio of the anti-inflammatory agent to the component (A) is preferable from the viewpoint of the effect of alleviating foreign body sensation.

Examples of the water-soluble vitamin include vitamin C and vitamin B group. Examples of the vitamin B group include vitamin B ₁ , vitamin B ₂ (flavin adenine dinucleotide sodium), niacin (nicotinic acid and nicotinamide), pantothenic acid, panthenol, vitamin B ₆ (pyridoxine, pyridoxal and pyridoxamine), Biotin, folic acid and vitamin B ₁₂ (cyanocobalamin, hydroxocobalamin, methylcobalamin and adenosylcobalamin). The water-soluble vitamin may be in the form of a salt, and examples include pyridoxine hydrochloride, calcium pantothenate and sodium pantothenate. From the viewpoint of the effect of alleviating foreign body sensation, pyridoxine hydrochloride, cyanocobalamin, sodium flavin adenine dinucleotide, panthenol, calcium pantothenate or sodium pantothenate are preferred, and pyridoxine hydrochloride or cyanocobalamin is particularly preferred.

  When the eye drops according to this embodiment contain a water-soluble vitamin, the content of the water-soluble vitamin is not particularly limited, and is appropriately set according to the type of the water-soluble vitamin, the content of the component (A) used in combination, and the like. You. As the content of the water-soluble vitamin, for example, the total content of the water-soluble vitamin is preferably 0.001 to 1 w / v%, based on the total amount of the eye drops according to the present embodiment. It is more preferable to be 0.5 to 0.5 w / v%, still more preferable to be 0.003 to 0.3 w / v%, and particularly preferable to be 0.01 to 0.2 w / v%. The content of the water-soluble vitamin is suitable from the viewpoint of the effect of alleviating the feeling of foreign matter.

  In the eye drops according to the present embodiment, the content ratio of the water-soluble vitamin to the component (A) is not particularly limited, and is appropriately set according to the type of the water-soluble vitamin. As the content ratio of the water-soluble vitamin to the component (A), for example, the total content of the water-soluble vitamin is 0 with respect to 1 part by mass of the component (A) contained in the eye drops according to the present embodiment. 0.002 to 20 parts by mass, more preferably 0.01 to 10 parts by mass, still more preferably 0.03 to 6 parts by mass, and 0.1 to 4 parts by mass. Is particularly preferred. The content ratio of the water-soluble vitamin to the component (A) is preferable from the viewpoint of the effect of alleviating the feeling of foreign matter.

(C) Component The eye drop according to the present embodiment may further contain (C) a cooling agent. By containing the component (C), the action of reducing the foreign-body sensation of the eye drops is increased.

  The cooling agent used in the eye drops for relaxing foreign body sensation according to the present embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of the cooling agent include terpenoids, essential oils containing terpenoids (eg, eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, cinnamon oil, spearmint oil, camphor oil, cool mint oil, and mint oil). No. Examples of terpenoids include menthol, menthol, camphor (also referred to as "camphor" or "camphor"), borneol (also referred to as "ryuno" or "crown"), geraniol, nerol, cineol, citronellol, carvone, anethole, eugenol, Limonene, linalool and linalyl acetate. The terpenoid may be any of d-form, l-form and dl-form, and examples thereof include l-menthol, d-menthol, dl-menthol, dl-camphor, d-camphor, dl-borneol and d-borneol. However, some terpenoids such as geraniol, nerol, and cineol do not have optical isomers in some cases. From the viewpoint of the effect of alleviating the foreign-body sensation, menthol, camphor, borneol, geraniol or peppermint oil is preferred, and l-menthol, dl-camphor or d-borneol is particularly preferred.

  The content of the cooling agent in the eye drops according to the embodiment is not particularly limited, and is appropriately set according to the type of the cooling agent, the type and the content of the component (A) and the component (B) used together, and the like. . The content of the cooling agent can be measured as a terpenoid. For example, based on the total amount of the eye drops according to the present embodiment, the total content of the cooling agent (as a terpenoid) is 0.00002 to 0. 0.3 w / v%, more preferably 0.0001 to 0.1 w / v%, even more preferably 0.0005 to 0.05 w / v%, and 0.001 to 0 w / v%. It is particularly preferable that it is 0.02 w / v%. The content of the above-mentioned cooling agent is suitable from the viewpoint of the effect of alleviating the feeling of foreign matter.

  In the eye drops according to the present embodiment, the content ratio of the cooling agent to the component (A) is not particularly limited, and is appropriately set according to the type of the cooling agent. As the content ratio of the cooling agent to the component (A), for example, the total content of the cooling agent is 0 with respect to 1 part by mass of the component (A) contained in the eye drops according to the present embodiment. 0.0002 to 5 parts by mass, more preferably 0.002 to 2 parts by mass, even more preferably 0.005 to 1 part by mass, and 0.02 to 0.5 part by mass. It is particularly preferred that there is. The content ratio of the water-soluble vitamin to the component (A) is preferable from the viewpoint of the effect of alleviating the feeling of foreign matter.

  The eye drops according to the present embodiment can further contain a surfactant. Surfactants, depending on the purpose of use of the ophthalmic solution according to the present embodiment, when blending various pharmacologically active ingredients, physiologically active ingredients, additives, and the like described below, a solubilizing agent that improves their solubility. Is effective as

  The surfactant that can be contained in the ophthalmic solution according to the present embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Any of an agent and an ionic (amphoteric, negative, positive) surfactant may be used.

  As the nonionic surfactant which can be contained in the eye drops according to the present embodiment, specifically, POE (20) sorbitan monourarate (polysorbate 20), POE (20) monopalmitate sorbitan (polysorbate 40) POE sorbitan fatty acid esters such as POE (20) sorbitan monostearate (polysorbate 60), sorbitan tristearate (polysorbate 65), POE (20) sorbitan monooleate (polysorbate 80); POE (40) POE hardened castor oil such as hardened castor oil (polyoxyethylene hardened castor oil 40), POE (60) hardened castor oil (polyoxyethylene hardened castor oil 60); POE (10) castor oil (polyoxyethylene castor oil 10) , POE (35) castor POE castor oil such as (Polyoxyethylene castor oil 35); POE (9) POE alkyl ether such as lauryl ether; POE (20) POP (4) POE-POP alkyl ether such as cetyl ether; POE (196) POP ( 67) Glycols (poloxamer 407, Pluronic F127), polyoxyethylene / polyoxypropylene block copolymers such as POE (200) POP (70) glycol; and polyethylene glycol monostearate such as polyoxyl 40 stearate. In the compounds exemplified above, the numbers in parentheses indicate the number of moles added.

  As the nonionic surfactant, POE sorbitan fatty acid ester, POE hydrogenated castor oil, POE castor oil, polyethylene glycol monostearate or POE / POP block copolymer are preferable, and polysorbate 80, POE castor oil 10, POE castor oil 35, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, polyoxyl stearate 40 or poloxamer 407 are more preferred.

  As the amphoteric surfactant which can be contained in the ophthalmic solution according to the present embodiment, specifically, N- [2-[[2- (alkylamino) ethyl] amino] ethyl] glycine and a salt thereof (for example, Hydrochloride). N- [2-[[2- (alkylamino) ethyl] amino] ethyl] glycine is also called alkyldiaminoethylglycine or alkylpolyaminoethylglycine.

  Further, as the anionic surfactant which can be contained in the eye drops according to the present embodiment, specifically, alkyl benzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, α-sulfo fatty acid ester salt , Α-olefinsulfonic acid and the like.

  Specific examples of the cationic surfactant that can be contained in the eye drops according to the present embodiment include benzalkonium chloride and benzethonium chloride.

  In the eye drops according to the present embodiment, one type of surfactant may be used alone, or two or more types may be used in combination. Among the surfactants that can be contained in the eye drops according to the present embodiment, nonionic surfactants are preferable.

  When the ophthalmic solution according to the present embodiment contains a surfactant, the content is determined by the type of the surfactant, the type and content of other components, the use of the ophthalmic composition, the formulation, and the use of the ophthalmic composition. It is set appropriately according to the method 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 from 005 to 2 w / v%, further preferably from 0.01 to 1 w / v%, particularly preferably from 0.05 to 1 w / v%.

  The eye drop according to the present embodiment preferably further contains a buffer. Thereby, the pH of the eye drops can be adjusted, and the effects of the present invention can be more remarkably exhibited.

  The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Tris buffer, aspartic acid, aspartate, edetate and the like. These buffers may be used alone or in any combination of two or more. Examples of the borate buffer include boric acid or a salt thereof (such as an alkali metal borate and an alkaline earth metal borate). Examples of the phosphate buffer include phosphoric acid and salts thereof (eg, alkali metal phosphate and alkaline earth metal phosphate). Examples of the carbonate buffer include carbonic acid and salts thereof (eg, alkali metal carbonate and alkaline earth metal carbonate). Examples of the citrate buffer include citric acid and salts thereof (eg, alkali metal citrate, alkaline earth metal citrate). Further, a borate or a phosphate hydrate may be used as the borate buffer or the phosphate buffer. As more specific examples, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a borate buffer; phosphoric acid or a salt thereof as a phosphate buffer Salts (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 hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid) as a citrate buffer Calcium acid, sodium dihydrogen citrate, disodium citrate, etc.); Agents as, acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.), and others. Among these buffers, a borate buffer (for example, a combination of boric acid and borax) or a phosphate buffer (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) is preferable. Acid buffers are more preferred.

  When a buffering agent is blended with the foreign matter sensation-reducing ophthalmic solution according to the present embodiment, the content of the buffering agent depends on the type of the buffering agent, the kind and content of other compounding components, the use of the foreign-body sensation-reducing ophthalmic solution, and the formulation form. , Are appropriately set according to the usage method and the like. As the content of the buffer, for example, the total content of the buffer is preferably 0.01 to 15 w / v%, based on the total amount of the ophthalmic solution for reducing foreign body sensation according to the present invention. It is more preferably from 0.05 to 10 w / v%, further preferably from 0.1 to 7.5 w / v%, and particularly preferably from 0.5 to 5 w / v%.

  The pH of the foreign matter sensation-reducing ophthalmic solution according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. The pH of the foreign matter sensation-reducing eye drop according to the present invention is in the range of 4.0 to 9.5, preferably 5.0 to 9.0, and more preferably 5.5 to 8.5. When the pH is in the above range, there is little irritation to the eyes when the eye drops are used, and the foreign-body sensation tends to be further alleviated.

  The tonicity agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As the tonicity agent, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, acetic acid Examples include sodium, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol and the like. Among these tonicity agents, glycerin, propylene glycol, polyethylene glycol, glucose, sodium chloride, potassium chloride, calcium chloride or magnesium chloride are preferred, sodium chloride, potassium chloride or propylene glycol is more preferred, and sodium chloride is particularly preferred. . These tonicity agents may be used alone or in any combination of two or more.

  When the ophthalmic solution according to the present embodiment contains a tonicity agent, the content is appropriately set according to the type of the tonicity agent, the type and content of the other components, and the like. As the content of the tonicity agent, for example, based on the total amount of the eye drops, the total content of the tonicity agent is preferably 0.01 to 10 w / v%, and 0.05 to 5 w / v%. v%, more preferably 0.1 to 3 w / v%.

  The osmotic pressure of the ophthalmic solution 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 eye drops is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and even more preferably 0.7 to 2.0. , 0.9 to 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 or a sugar. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% aqueous sodium chloride solution) based on the 16th Revised Japanese Pharmacopoeia. (Freezing point descent method). In addition, about the osmotic-pressure-ratio measurement standard solution (0.9 w / v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650 degreeC for 40-50 minutes, the desiccator (silica gel) And weigh accurately 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% aqueous sodium chloride solution). .

  The eye drop according to the present embodiment preferably further contains a thickener. Thereby, the viscosity of the eye drop according to the present embodiment can be adjusted, and the effects of the present application can be more remarkably exhibited.

  Examples of the thickener include polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, cellulose derivative [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910 etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or salts thereof], polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000 etc.), chondroitin Sodium sulfate, sodium hyaluronate, gum arabic, tragacanth, dextran (40, 70 etc.), Examples thereof include sugar, sorbitol and the like, and preferably polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90), carboxyvinyl polymer, cellulose derivative (methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose) (2208, 2906, 2910), carboxymethylcellulose or a salt thereof), polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, Macrogol 6000, etc.) or dextran (70), more preferably polyvinyl alcohol ( Complete or partially saponified), polyvinylpyrrolidone (K25, K30, K90), carboxyvinyl polymer, methylcellulose, Mud carboxymethyl cellulose, hydroxypropyl methylcellulose (2208, 2906, 2910), carboxymethyl cellulose or a salt thereof, polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, Macrogol 6000) or dextran (70). From the viewpoint of the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function, polyvinylpyrrolidone, hydroxyethylcellulose or hydroxypropylmethylcellulose is more preferred, and polyvinylpyrrolidone is particularly preferred. These thickeners may be used alone or in any combination of two or more.

  When the eye drop according to the present embodiment contains a thickener, the content is appropriately set according to the type of the thickener, the type and the content of other components, and the like. As the content of the thickener, for example, based on the total amount of the eye drops, the total content of the thickener is preferably 0.0001 to 5 w / v%, and 0.0005 to 3 w / v%. Is more preferable, 0.001 to 1 w / v% is further preferable, and 0.01 to 0.2 w / v% is particularly preferable.

  The viscosity of the eye drop 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 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × R24) is preferably, for example, 0.1 to 1000 mPa · s, and 0.5 -100 mPa · s, more preferably 1-10 mPa · s.

In addition, the eye drops according to the present embodiment may contain an appropriate amount of various pharmacologically active ingredients or physiologically active ingredients in combination with the above components, as long as the effects of the present invention are not impaired. Such components are not particularly limited, and examples thereof include active ingredients in various pharmaceuticals described in the OTC Pharmaceuticals Manufacturing and Marketing Approval Standards 2012 Edition (supervised by the Society of Regulatory Science). Specifically, the components used in ophthalmic drugs include the following components.
Antihistamines: chlorpheniramine maleate, diphenhydramine hydrochloride, ketotifen fumarate decongestant: tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc. .
Ocular muscle modulators: for example, cholinesterase inhibitors having an active center similar to acetylcholine, such as neostigmine methyl sulfate, tropicamide, helenien, atropine sulfate and the like.
Fungicides: for example, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine, polyhexamethylene biguanide, alkyldiaminoethylglycine hydrochloride and the like.
Amino acids: glycine, alanine, γ-aminobutyric acid, aspartic acid, potassium L-aspartate, glutamic acid, arginine, lysine, aminoethylsulfonic acid (taurine) chondroitin sulfate, sodium chondroitin sulfate, sodium hyaluronate, alginic acid and the like. However, ε-aminocaproic acid is excluded.
Vitamins: retinol acetate, retinol palmitate, tocopherol acetate and the like.
Others: For example, sulfamethoxazole, sulfamethoxazole sodium and the like.

In addition, in the eye drops according to the present embodiment, as long as the effects of the invention are not impaired, various additives are appropriately selected according to a usual method according to the use or the form of the preparation, and one or more kinds of additives are selected. And may be contained in an appropriate amount in combination. Examples of such additives include various additives described in the Pharmaceutical Excipients Dictionary 2007 (edited by the Japan Pharmaceutical Excipients Association). Representative additives include the following additives.
Carrier: Aqueous carrier such as water, hydrous ethanol and the like.
Saccharides: for example, glucose, cyclodextrin 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.
Preservatives, bactericides or antibacterial agents: 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, polyhexanide hydrochloride, etc.), Glow Kill (trade name of Rhodia) and the like.
Stabilizers: trometamol, sodium formaldehyde sulfoxylate (Rongalit), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, dibutylhydroxytoluene, sodium edetate and the like.

  The eye drops according to the present embodiment are prepared by adding the above components (A) and (B) and, if necessary, other components to a carrier so as to have a desired content. Specifically, for example, it can be prepared by dissolving or suspending the above components in purified water, adjusting the pH and osmotic pressure to predetermined values, and sterilizing by filtration sterilization or the like.

  The ophthalmic solution according to the present embodiment has a water content of 85 w / v% or more, preferably 90 w / v% or more, and more preferably 92 w / v% based on the total amount of the eyedrops. Is more preferable, 94 w / v% or more is more preferable, and 96 w / v% or more is particularly preferable. As the water used in the eye drops according to the present embodiment, pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable water may be used. As such water, specifically, Examples include distilled water, ordinary water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like.

  The eye drop according to the present embodiment is provided by being housed in an arbitrary container. The container for containing the eye drops according to the present embodiment is not particularly limited, and may be made of, for example, glass or plastic. It is preferably made of plastic. Examples of the plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, copolymers of monomers constituting these, and mixtures of two or more thereof. Preferably, it is polyethylene terephthalate. Further, the container for storing the eye drops according to the present embodiment may be a transparent container in which the inside of the container can be visually recognized, or may be an opaque container in which the inside of the container is difficult to visually recognize. Preferably, it is a transparent container. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container. The eye drops according to the present embodiment can be used, for example, in a colored transparent plastic container or the like in the form of a multidose that can be used repeatedly.

  The eye drops according to the present embodiment can be used as pharmaceuticals or quasi-drug preparations, and in addition to so-called eye drops [including eye drops that can be instilled while wearing contact lenses], artificial tears , Eyewash [However, the eyewash contains an eyewash that can be washed while wearing the contact lens], a composition for contact lens [contact lens mounting solution, a composition for contact lens care (contact lens disinfectant, contact lens Preservative, contact lens cleaning agent, contact lens cleaning preservative), and the like. Preferred examples of the present invention include eye drops, artificial tears, eyewashes, and contact lens mounting solutions, and particularly preferred examples include eye drops and artificial tears. When used as a composition for contact lenses, the composition can be applied to any contact lenses including hard contact lenses and soft contact lenses.

  The eye drops according to the present embodiment can not only improve the subjective symptoms but also suppress the adhesion of foreign substances in order to alleviate the feeling of foreign substances. The foreign body sensation refers to a subjective symptom that is caused by dry eyes, improper use of a contact lens, allergic conjunctivitis due to adhesion of foreign substances such as pollen and house dust, and the like. Foreign body sensation is further enhanced by inflammation. The eye drops according to the present embodiment can be applied for the purpose of preventing or treating various symptoms accompanied by a foreign body sensation, and are caused by allergic conjunctivitis or the like due to the adhesion of the foreign body, from the viewpoint that the adhesion of the foreign body can be suppressed. It is suitable for foreign body sensation and particularly suitable for foreign body sensation associated with allergy due to hay fever or house dust.

  On the other hand, the eye drops according to the present embodiment can be applied in a state of being worn on all contact lenses including hard contact lenses and soft contact lenses, but from the viewpoint of the effect of alleviating the feeling of foreign substances, It is preferable to apply the contact lens, especially a soft contact lens, especially a silicone hydrogel contact lens without wearing it. The silicone hydrogel contact lens is included in a soft contact lens and has both ionic and nonionic properties. It is known that an ionic silicone contact lens has a property of adsorbing a protein serving as an allergen. Also, silicone hydrogel contact lenses are harder than other soft contact lenses, so they tend to feel a foreign body sensation because they are harder. In addition, they tend to cause physical damage to the corneal epithelium, causing inflammation and causing foreign body sensation as a symptom. The effect on the effect of alleviating the sensation of foreign matter is immense. However, it is not recommended that the eye drops according to the present embodiment be instilled while wearing the silicone hydrogel contact lens.

  In another embodiment of the present invention, (A) pranoprofen or a salt thereof is combined with (B) at least one compound selected from the group consisting of anti-allergic agents, anti-inflammatory agents and water-soluble vitamins. It is intended to provide a method for imparting the effect of alleviating the sensation of foreign matter to an eye drop, and preferably further comprises (C) a cooling agent.

Test Example 1 Measurement of the amount of foreign substances adsorbed on corneal epithelial cells (1)
(1) Test method Each ophthalmic composition was prepared according to Table 1 below, and the effect on foreign substance adsorption to corneal epithelial cells was evaluated. In Table 1, "%" indicating the content means "w / v%" with respect to the whole drug.
The human corneal epithelial cell line HCE-T (RIKEN BioResource Center, No. RCB2280) was added to each well culture medium in a 96-well microplate (manufactured by Corning) at a rate of 1.0 × 10 ⁵ cells / well. , And the cells were cultured at 37 ° C. under 5% CO ₂ for 24 hours. After the culture, the culture medium was removed by suction, 100 μL of each ophthalmic composition containing 0.05% of albumin fluorescently labeled with FITC was added, and the mixture was allowed to stand at room temperature for 10 minutes. After the treatment, the solution in the well was removed by suction, 200 μL of a phosphate buffer was added, and the solution in the well was removed by suction and washed. Then, 100 μL of a phosphate buffer was added, and a fluorescent plate reader (Fluoroskan Ascent CF) was added. , MTX Labsystems) was used to measure the fluorescence value at an excitation wavelength of 485 nm / emission wavelength of 527 nm. The obtained fluorescence value was converted to the amount of foreign matter (albumin) based on the calibration curve of the amount of foreign matter and the fluorescence value. From the obtained foreign matter amount, the foreign matter adsorption suppression rate (%) was calculated based on the equation (1).
Foreign matter adsorption suppression rate (%) = [1− (the amount of foreign matter in each comparative example or example) / (the amount of foreign matter in comparative example 1)] × 100 (1)
(2) Test results The results are shown in Table 1. Corneal epithelial cells were obtained by using Examples 1 to 6 in which (A) pranoprofen and various components (B) were contained in a solution (Comparative Example 1) consisting of a buffer solution containing only boric acid and borax. It was confirmed that the adsorption of the foreign substance (FITC-labeled albumin) to the substrate was significantly suppressed. On the other hand, when (A) a liquid preparation containing only pranoprofen was used (Comparative Example 2), the adsorption of foreign substances was not sufficiently suppressed.

Test Example 2. Measurement of the amount of foreign substances adsorbed on corneal epithelial cells (2)
(1) Test method Each ophthalmic composition was prepared according to Table 2 below, and the effect on foreign substance adsorption to corneal epithelial cells was evaluated in the same manner as in Test Example 1. In Table 2, "%" indicating the content means "w / v%" with respect to the whole drug.
(2) Test results The results are shown in Table 2. By combining (A) pranoprofen, (B) tranilast or olopatadine, and (C) l-menthol, dl-camphor or borneol, it is possible to exhibit a more remarkable inhibitory effect on foreign substance adsorption to corneal epithelial cells. It became clear.

Test Example 3 Sensory test: Foreign body sensation improvement effect (1)
(1) Test method Each eye drop was prepared according to a conventional method according to Table 3 below, and filled in a polyethylene terephthalate container. For three subjects conscious of foreign body sensation in the eye, (A) eye drops containing pranoprofen (Comparative Example 3) were applied to the left eye, and (A) pranoprofen and (B) dipotassium glycyrrhizinate were administered to the left eye. The ophthalmic solution containing Example (Example 11) was administered to the right eye in a single dose, or the ophthalmic solution containing (A) pranoprofen (Comparative Example 3) was applied to the left eye with (A) pranoprofen and (B) After a single administration of each eye drop containing pyridoxine hydrochloride and (C) 1-menthol to the right eye (Example 12), the degree of improvement in the foreign body sensation of the eye after eye drop was evaluated. The degree of foreign body sensation of the eyes was evaluated by the Visual Analog Scale method (VAS method), and the state of the strongest symptom was defined as 100%, and the degree of the symptom of each group was described. In Table 3, "%" indicating the content means "w / v%" with respect to the whole drug.

(2) Test results The results are shown in Table 3. When Example 11 containing (A) pranoprofen and (B) dipotassium glycyrrhizinate was used, it was confirmed that a remarkable effect of improving foreign body sensation was exhibited. In addition, when Example 12 further containing (C) l-menthol was used, it was clarified that the effect of improving the feeling of foreign matter was more remarkably exhibited.

Test example 4. Sensory test: Foreign body sensation improvement effect (2)
(1) Test method Each eye drop was prepared according to a conventional method according to Table 4 below, and filled in a polyethylene terephthalate container. Eye drops containing (A) pranoprofen and (B) tranilast for the left eye, (A) pranoprofen containing eye drops (Comparative Example 4) for four subjects who are conscious of foreign body sensation in the eyes The agent (Example 13) was administered once to the right eye, respectively, or (A) eye drops containing pranoprofen (Comparative Example 4) were administered to the left eye with (A) pranoprofen, (B) tranilast and ( C) After a single administration of the ophthalmic solution containing l-menthol (Example 14) to each of the right eyes, the degree of improvement in the foreign body sensation of the eyes after instillation was evaluated. The degree of foreign body sensation of the eyes was evaluated by the Visual Analog Scale method (VAS method), and the state of the strongest symptom was defined as 100%, and the degree of the symptom of each group was described. In Table 4, "%" indicating the content means "w / v%" with respect to the whole drug.
(2) Test results The results are shown in Table 4. When Example 13 containing (A) pranoprofen and (B) tranilast was used, it was confirmed that a remarkable effect of improving foreign body sensation was exhibited. In addition, when Example 14 further containing (C) l-menthol was used, it was clarified that a more remarkable effect of improving foreign-body sensation was exhibited.

Test Example 5. Sensory test: Foreign body feeling improvement effect (3)
(1) Test method Each eye drop was prepared according to a conventional method according to Table 5 below, and filled in a polyethylene terephthalate container. Eye drops containing (A) pranoprofen and (B) cyanocobalamin were added to the left eye of (A) pranoprofen for four subjects who were conscious of the foreign body sensation of the eye. After a single administration of the agent (Example 15) to each of the right eyes, the degree of improvement in the foreign body sensation of the eyes after instillation was evaluated. The degree of foreign body sensation of the eyes was evaluated by the Visual Analog Scale method (VAS method), and the state of the strongest symptom was defined as 100%, and the degree of the symptom of each group was described. In Table 5, "%" indicating the content means "w / v%" with respect to the whole drug.

(2) Test results The results are shown in Table 5. It was confirmed that when Example 15 containing (A) pranoprofen and (B) cyanocobalamin was used, a remarkable effect of improving foreign body sensation was exhibited.

Formulation Examples Eye drops were prepared according to the formulations described in Tables 6 and 7 below. By using these eye drops, it is possible to alleviate the foreign body sensation of the eyes. In Tables 6 and 7, "%" indicating the content means "w / v%" based on the whole drug.

Claims (1)

The invention described in the specification.