JP6427244B2 - Eye drops - Google Patents

Description

  The present invention relates to eye drops.

  Tranilast is clinically used as a therapeutic agent for allergic diseases. For example, in the ophthalmologic field, eye drops containing tranilast as a therapeutic agent for allergic conjunctivitis are clinically used (Non-patent Document 1).

  The cornea is formed of five layers of corneal epithelium, Bowman's membrane, corneal stroma, Descemet's membrane and corneal endothelium in this order from the outside world. In addition, the corneal epithelium is covered with tears, and tears are formed of a mucin layer, tears and oil layer sequentially from the corneal epithelial side. The corneal epithelium functions as a barrier between the external world and the corneal stroma. That is, the homeostasis of the cornea is maintained by controlling the penetration from the corneal epithelium of the stimulant from the outside world such as an allergen and the like, the substance present in the tear fluid, the pathogen and the like from the corneal epithelium to the corneal stroma. The decrease in the barrier function of the corneal epithelium not only increases the risk of allergens or the like entering the corneal parenchyma, but also promotes the penetration of the tear film-derived inflammatory mediator into the corneal parenchyma, causing the development of allergic diseases in the eye, etc. Or it may lead to deterioration.

  For example, in the tears of patients with allergic conjunctivitis, inflammatory cytokines such as IL-4, IL-13 and TNF-α are detected at high concentrations. If the barrier function of the corneal epithelium in patients with allergic conjunctivitis decreases, inflammatory cytokines in the tear fluid penetrate into the corneal parenchyma, thereby stimulating the corneal parenchyma and producing eotaxin, a potent eosinophil migration factor It is induced to promote the aggravation of allergic symptoms.

  Thus, once the barrier function of the corneal epithelium is reduced, the entry of the allergen into the corneal stroma, the enhancement of the permeability of inflammatory mediators, the activation of corneal stroma cells, the expression and secretion of inflammation-related molecules, and the expression in the cornea A vicious cycle occurs that promotes inflammation. That is, maintenance of the barrier function of the corneal epithelium is important from the viewpoint of prevention of suppressing the onset of allergic symptoms.

  As a method of evaluating the barrier function of the corneal epithelium, a method of measuring the electrical resistance value of the corneal epithelial cell layer is known. A corneal epithelial barrier function enhancer containing a PPARγ agonist as an active ingredient has been found using this evaluation method (Patent Document 1).

  However, the action mechanism of tranilast "shows anti-allergic action by suppressing release of chemical mediators (histamine, leukotriene etc.) from mast cells and various inflammatory cells by antigen stimulation" (Non-patent Document 1). Nothing is known about the effect of tranilast on corneal epithelium.

JP, 2009-227668, A

REZABEN (registered trademark) eye drop 0.5% (Kissei Pharmaceutical) package insert

  An object of the present invention is to provide an eye drop that can enhance corneal epithelial barrier function. Another object of the present invention is to provide an eye drop which can prevent allergic symptoms.

  As a result of intensive studies to solve the above problems, the present inventors (A) tranilast or a salt thereof (hereinafter, also referred to as "component (A)"), (B) anti-inflammatory agent, water-soluble vitamin It has been found that the corneal epithelial barrier function is enhanced by combining at least one selected from the group consisting of and a refreshing agent (hereinafter also referred to as "(B) component"), and the present invention has been completed. The

That is, the present invention provides the following [1] to [7].
[1] Wear contact lenses from 1 to 2 weeks before the start of pollen scattering, containing (A) tranilast or a salt thereof and (B) at least one selected from the group consisting of pyridoxine, glycyrrhizinic acid and salts thereof Eye drops for preventing symptoms of allergy to the pollen, wherein at least one selected from the group consisting of chlorpheniramine, pranoprofen and salts thereof, which are used in the form of eye drops without taking Excluding eye drops including
[2] The total content of pyridoxine and its salt is 0.005 to 5 parts by mass, and the total content of glycyrrhizinic acid and its salt is 0.001 to 20 with respect to 1 part by mass of the total content of component (A) The eye drop as described in [1] which is a mass part.
[3] In the eye drop, the content of component (A) is 0.001 to 1 w / v%, the total content of pyridoxine and its salt is 0.005 to 5 w / v%, and the total content of glycyrrhizinic acid and its salt The eyedrops as described in [1] or [2] whose quantity is 0.005-5 w / v%.
[4] The eye drop preparation according to any one of [1] to [3], further containing a thickener.
[5] The eye drop preparation according to any one of [1] to [4], further containing a buffer.
[6] Wear contact lenses from 1 to 2 weeks before the start of pollen scattering, containing (A) tranilast or a salt thereof, and (B) at least one member selected from the group consisting of pyridoxine, glycyrrhizinic acid and salts thereof Eye drops for enhancing the corneal epithelial barrier function against the pollen, wherein the eye drop is used in eye drops in a non-inhaled state (however, at least one selected from the group consisting of chlorpheniramine, pranoprofen and their salts) Excluding eye drops containing one type).
[7] A combination of (A) tranilast or a salt thereof, and (B) at least one selected from the group consisting of pyridoxine, glycyrrhizinic acid and salts thereof, which enhances the corneal epithelial barrier function to pollen, the scattering of the pollen Eyedrops used without wearing contact lenses from 1 to 2 weeks before initiation (except eye drops containing at least one selected from the group consisting of chlorpheniramine, pranoprofen and their salts) How to apply to).

  The eye drop preparation of the present invention has an enhancing action on the corneal epithelial barrier function, and can be used for the prevention of allergic symptoms. Specifically, the eye drop preparation of the present invention is effective for preventing allergic symptoms such as eye redness, itchy eyes, naked eyes and foreign body feeling of eyes.

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

  The eye drop according to this embodiment contains (A) tranilast or a salt thereof, and (B) at least one selected from the group consisting of an anti-inflammatory agent, a water-soluble vitamin, and a refreshing agent.

Component (A) Tranilast is a known compound also referred to as N- (3,4-dimethoxycinnamoyl) anthranilic acid, and may be synthesized by a known method or obtained as a commercially available product.

  The salt of tranilast is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Such salts include, for example, organic acid salts [eg, monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polyvalent carboxylates (fumarate) Maleate, succinate, malonate, etc., Oxycarboxylate (lactate, tartrate, citrate etc.), Organic sulfonate (methane sulfonate, toluene sulfonate, tosylate) Etc.), inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, etc.) Salts with organic amines such as pyrrolidine, tripyridine and picoline), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium etc.), alkaline earth metals Calcium, magnesium, etc.), include various salts of salt], etc. with a metal such as aluminum.

  These salts of tranilast may be used alone or in any combination of two or more. Tranilast is preferable as the component (A) from the viewpoint of the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function.

  The content of the component (A) in the eye drop according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (A), the type and content of the component (B) to be used in combination, and the like. As content of (A) component, it is preferable that total content of (A) component is 0.0001-5 w / v% on the basis of the total amount of the eyedrops which concern on this embodiment, for example, 0 It is more preferable that it is .001 to 1 w / v%, still more preferably 0.01 to 0.5 w / v%, and particularly preferably 0.05 to 0.5 w / v%. The content of the component (A) is preferable from the viewpoint of the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function.

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

  The anti-inflammatory agent is not particularly limited as long as it is a substance having an anti-inflammatory action. Anti-inflammatory agents include, for example, ε-aminocaproic acid, allantoin, berberine sulfate, berberine chloride, glycyrrhizinic acid, azulene sulfonic acid, zinc sulfate, zinc lactate, salicylic acid, tranexamic acid, lysozyme, licorice and pranoprofen. The anti-inflammatory agent may be in the form of a salt and is exemplified by dipotassium glycyrrhizinate, sodium azulene sulfonate, lysozyme chloride and the like. Ε-aminocaproic acid, allantoin, berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme chloride and azulene sulfonate sodium from the viewpoint of the effect of preventing allergic symptoms and / or enhancing corneal epithelial barrier function Are preferred, with .epsilon.-aminocaproic acid, allantoin, berberine sulfate, berberine chloride being particularly preferred.

  The content of the anti-inflammatory agent in the eye drop preparation according to the present embodiment is not particularly limited, and is appropriately set according to the type of the anti-inflammatory agent, the type and the content of the component (A) to be used in combination, and the like. The content of the anti-inflammatory agent is, for example, preferably the total content of the anti-inflammatory agent is 0.001 to 7.5 w / v%, based on the total amount of the eyedrops according to the present embodiment, 0 The content is more preferably from .005 to 5 w / v%, further preferably from 0.01 to 1 w / v%, and particularly preferably from 0.02 to 0.5 w / v%. The content of the anti-inflammatory agent is preferable from the viewpoint of the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function.

  Further, the content ratio of the anti-inflammatory agent to the component (A) in the eye drop preparation according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (A) and the anti-inflammatory agent. The content ratio of the antiinflammatory agent to the component (A) is, for example, the total content of the antiinflammatory agent relative to 1 part by mass of the total content of the component (A) contained in the eyedrops according to the present embodiment, It is preferable that it is 0.001-20 mass parts, It is more preferable that it is 0.01-10 mass parts, It is still more preferable that it is 0.02-5 mass parts, It is 0.04-1 mass part Is particularly preferred. The content ratio of the anti-inflammatory agent to the component (A) is preferable from the viewpoint of the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function.

Water-soluble vitamins are vitamins that are soluble in water. Examples of water-soluble vitamins include vitamin C and vitamin B group. Examples of vitamin B group include vitamin B ₁ , vitamin B ₂ (flavin adenine dinucleotide sodium), niacin (nicotinic acid and nicotinic acid amide), pantothenic acid, panthenol, vitamin B ₆ (pyridoxine, pyridoxal and pyridoxamine), Biotin, folic acid and vitamin B ₁₂ (cyanocobalamin, hydroxocobalamin, methylcobalamin and adenosyl cobalamin). The water-soluble vitamin may be in the form of a salt, and is exemplified by pyridoxine hydrochloride, calcium pantothenate, sodium pantothenate and the like. From the viewpoint of the effect of preventing allergic symptoms and / or enhancing corneal epithelial barrier function, pyridoxine hydrochloride, cyanocobalamin, flavin adenine dinucleotide sodium, panthenol, calcium pantothenate and pantothenate sodium are preferred, and pyridoxine hydrochloride and cyanocobalamin are preferred. Particularly preferred.

  The content of the water-soluble vitamin in the eyedrops according to the present embodiment is not particularly limited, and is appropriately set according to the type of the water-soluble vitamin, the type and the content of the component (A) used in combination, and the like. As the content of the water-soluble vitamin, for example, the total content of the water-soluble vitamin is preferably 0.001 to 0.5 w / v%, based on the total amount of the eye drops according to the present embodiment, 0 .005 to 0.3 w / v% is more preferable, 0.01 to 0.2 w / v% is more preferable, and 0.02 to 0.1 w / v% is particularly preferable . The content of the water-soluble vitamin is preferable from the viewpoint of the prevention of allergic symptoms and / or the enhancement of the corneal epithelial barrier function.

  Further, the content ratio of the water-soluble vitamin to the component (A) in the eye drop according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (A) and 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 1 part by mass of the total content of the component (A) contained in the eyedrops according to the present embodiment, The amount is preferably 0.005 to 5 parts by mass, more preferably 0.01 to 1 parts by mass, still more preferably 0.02 to 0.4 parts by mass, and 0.04 to 0.2 It is particularly preferred that it is part by weight. The content ratio of the water-soluble vitamin to the component (A) is suitable from the viewpoint of the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function.

  The refreshing agent is not particularly limited as long as it is a substance that imparts a refreshing sensation to the eye drop. As the refreshing agent, for example, terpenoids, essential oils containing terpenoids (for example, eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, caffeine oil, spearmint oil, camphor oil, cool mint and mint oil) are mentioned Be Terpenoids include, for example, menthol, menthon, camphor, borneol (Lunou), geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, and linalyl acetate. The terpenoid may be any of d-form, l-form and dl-form, and is exemplified by l-menthol, d-menthol, dl-menthol, dl-camphor, d-camphor, dl-borneol and d-borneol. However, some terpenoids, such as geraniol and cineole, may not have optical isomers. From the viewpoint of the effect of preventing allergic symptoms and / or enhancing corneal epithelial barrier function, menthol, camphor, borneol, geraniol and peppermint oil are preferred, and l-menthol, dl-camphor, d-borneol are particularly preferred .

  The content of the refreshing agent in the eyedrops according to the present embodiment is not particularly limited, and is appropriately set according to the type of the refreshing agent, the type and the content of the component (A) to be used in combination, and the like. The content of the refreshing agent can be measured as a terpenoid. For example, the total content of the refreshing agent (as a terpenoid) is 0.00005 to 0 based on the total amount of the eyedrops according to the present embodiment. .5 w / v% is preferable, 0.0005 to 0.1 w / v% is more preferable, 0.001 to 0.05 w / v% is more preferable, 0.004 to 0 Particularly preferred is .02 w / v%. The content of the above-mentioned refreshing agent is suitable from the viewpoint of the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function.

  Further, the content ratio of the refreshing agent to the component (A) in the eye drop according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (A) and the refreshing agent. As the content ratio of the refreshing agent to the component (A), for example, the total content of the refreshing agent is 1 part by mass of the total content of the component (A) contained in the eyedrops according to the present embodiment, The content is preferably 0.0001 to 2 parts by mass, more preferably 0.0005 to 1 parts by mass, still more preferably 0.001 to 0.2 parts by mass, and 0.005 to 0.1 It is particularly preferred that it is part by weight. The content ratio of the refreshing agent to the component (A) is preferable from the viewpoint of the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function.

  The eye drop according to this embodiment preferably further contains a buffer. Thereby, the pH of the eye drop can be adjusted, and the effect of the present invention can be more significantly exhibited. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, tris buffer, aspartic acid, aspartate and the like. These buffers may be used alone or in any combination of two or more. The boric acid buffer includes boric acid or boric acid salts such as alkaline metal salts of boric acid and alkaline earth metal salts of boric acid. The phosphate buffer includes phosphates such as phosphoric acid or alkaline metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid or alkali metal citrate, alkaline earth metal citrate and the like. Alternatively, a borate or phosphate hydrate may be used as a borate buffer or a phosphate buffer. More specifically, boric acid or its salt (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a borate buffer; phosphoric acid or its as a phosphate buffer Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate etc.); carbonated buffer, carbonated 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 citric acid buffer 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 the like. Among these buffers, borate buffers (for example, a combination of boric acid and borax and the like) and phosphate buffers (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate and the like) are preferable, and a borate Acid buffers are further preferred.

  When the eyedrops according to the present embodiment contains a buffer, the content thereof is appropriately set according to the type of the buffer, the type and the content of the other components, and the like. As a content of the buffer, for example, the total content of the buffer is preferably 0.01 to 15 w / v%, preferably 0.05 to 10 w / v% based on the total amount of eye drops Is more preferably 0.1 to 7.5 w / v%, particularly preferably 0.5 to 5 w / v%.

  The eye drop according to this embodiment preferably further contains a thickener. Thereby, the viscosity of the eyedrop preparation which concerns on this embodiment can be adjusted, and the effect of this application can be exhibited much more notably. As a thickener, for example, polyvinyl alcohol (completely or partially saponified), polyvinyl pyrrolidone (K25, K30, K90 etc.), carboxyvinyl polymer, cellulose derivative [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910 etc.), carboxymethylcellulose, carboxyethyl cellulose, nitrocellulose or their salts etc.], 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 include sucrose, sorbitol and the like, preferably polyvinyl alcohol (completely or partially saponified), polyvinyl pyrrolidone (K25, K30, K90), carboxyvinyl polymer, cellulose derivative (methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (2208, 2906, 2910), carboxymethylcellulose or salts thereof, polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, Macrogol 6000, etc.), dextran (70), more preferably polyvinyl alcohol Complete or partial saponification), polyvinyl pyrrolidone (K25, K30, K90), carboxyvinyl polymer, methyl cellulose, hydride Carboxymethyl cellulose, hydroxypropyl methylcellulose (2208, 2906, 2910), carboxymethyl cellulose or a salt thereof, polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, Macrogol 6000), dextran (70). From the viewpoint of the effect of preventing allergic symptoms and / or enhancing corneal epithelial barrier function, polyvinyl pyrrolidone, hydroxyethyl cellulose and hydroxypropyl methyl cellulose are more preferable, and polyvinyl pyrrolidone is particularly preferable. These thickeners may be used alone or in any combination of two or more.

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

  Moreover, the eye drop concerning this embodiment can contain an isotonicity agent further. The tonicity agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such tonicity agents include, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium bisulfite, sodium sulfite, sodium chloride, potassium chloride, calcium chloride, sodium chloride, magnesium chloride And potassium acetate, sodium acetate, sodium hydrogencarbonate, 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 is preferable, sodium chloride, potassium chloride or propylene glycol is more preferable, and sodium chloride is particularly preferable. preferable. These tonicity agents may be used alone or in any combination of two or more.

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

  The pH of the eyedrops according to the present embodiment is not particularly limited as long as it is in a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. The pH of the eye drop is, for example, preferably 4.0 to 9.5, more preferably 5.0 to 9.0, and still more preferably 5.5 to 8.5.

  Moreover, about the osmotic pressure of the eyedrops which concern on this embodiment, if it is in the range accept | permitted by the biological body, it will not be restrict | limited in particular. 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 still more preferably 0.7 to 2.0. And particularly preferably 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, a sugar or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia, and the osmotic pressure is the osmotic pressure measurement method described in Japanese Pharmacopoeia Measure with reference to (Freezing point 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) for 40 to 50 minutes at 500 to 650 ° C., in a desiccator (silica gel) The solution is allowed to cool, and its 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be used .

  The viscosity of the eyedrops according to the present embodiment is not particularly limited as long as it is in a range that is acceptable to the living body. The viscosity at 25 ° C. measured with a rotational viscometer (RE 550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ x R 24) is preferably, for example, 0.1 to 1000 mPa · s, 0.5 The viscosity is more preferably 100 mPa · s, further preferably 1 to 10 mPa · s.

Moreover, the eyedrops according to the present embodiment may contain various pharmacologically active ingredients and physiologically active ingredients in appropriate amounts in addition to the above components as long as the effects of the present invention are not impaired. Such ingredients are not particularly limited, and may be, for example, active ingredients in various medicines described in the non-prescription drug manufacturing and marketing approval criteria 2012 edition (general incorporated corporation regulatory science society supervision). Specifically, as components used in ophthalmic drugs, the following components may be mentioned.
Antihistamines or antiallergic agents: for example, ketotifen fumarate, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate, pemirolast potassium, sodium cromoglycate, acetazanolast, anlexanox, ibudilast and the like.
Decongestants: Tetrahydrozoline hydrochloride, Tetrahydrozoline hydrochloride, Naphazoline hydrochloride, Naphazoline nitrate, Epinephrine, Epinephrine hydrochloride, Epinephrine hydrochloride, Ephedrine hydrochloride, Phenylephrine hydrochloride, dl-methylephedrine hydrochloride etc.
Ocular muscle modulating agent: for example, a cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methylsulfate, tropicamide, helenicene atropine etc.
Bactericidal agents: for example, acrinol, cetyl pyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine, polyhexamethylene biguanide, alkyldiaminoethylglycine hydrochloride and the like.
Vitamins: Retinol acetate, retinol palmitate, tocopherol acetate, etc.
Amino acids: potassium aspartate, magnesium aspartate, magnesium and potassium aspartate (equal mixture), aminoethyl sulfonic acid and the like.
Others: for example, sodium hyaluronate, sulfamethoxazole, sulfamethoxazole sodium and salts thereof and the like.

In addition, according to the conventional method, various additives are appropriately selected according to the conventional method according to the application and the form of the preparation, as long as the effects of the invention are not impaired. In an appropriate amount. As those additives, for example, various additives described in Pharmaceutical Additives Dictionary 2007 (edited by Japan Pharmaceutical Additives Association) can be exemplified. The following additives are mentioned as a typical component.
Carrier: For example, an aqueous carrier such as water or water-containing ethanol.
Sugars: 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, germicides or antimicrobials: for example zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, dehydroacetic acid Sodium, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sulfuric acid oxyquinoline, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, polyhexanide hydrochloride etc.), Glokill (brand name made by Rhodia) etc.
Stabilizers: trometamol, sodium formaldehyde sulfoxylate (long gallite), tocopherol, sodium metabisulfite, monoethanolamine, aluminum monostearate, glycerin monostearate and the like.

  The eye drop according to the present embodiment is prepared by adding the above components (A) and (B) and, if necessary, other components to a desired content of the carrier. Specifically, for example, the above components can be dissolved or suspended in purified water, adjusted to a predetermined pH and osmotic pressure, and sterilized by filtration sterilization or the like.

  In the eye drop preparation according to the present embodiment, the water content is 85 w / v% or more, preferably 90 w / v% or more, and 92 w / v% or more based on the total amount of the eye drops Is more preferably 94 w / v% or more, and particularly preferably 96 w / v% or more. As water used for the eyedrops according to the present embodiment, water that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable may be used, and as such water, specifically, Distilled water, normal water, purified water, sterile purified water, water for injection, distilled water for injection, etc. are exemplified.

  The eye drop according to the present embodiment is provided by being contained in any container. The container for containing the eyedrops according to the present embodiment is not particularly limited, and may be made of, for example, glass or plastic. Preferably it is 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 of these. Preferably, it is polyethylene terephthalate. Moreover, the container which accommodates the eyedrops which concerns on this embodiment may be a transparent container which can visually recognize the inside of a container, and the opaque container whose visual recognition of container inside is difficult may be sufficient as it. Preferably it is a transparent container. Here, "a transparent container" includes both a colorless transparent container and a colored transparent container. The eyedrops according to this embodiment can be used, for example, in a form of multi-dose that can be repeatedly used in a colored transparent plastic container or the like.

  The eye drop preparation according to this embodiment can be applied in the state of wearing any contact lenses including hard contact lenses and soft contact lenses, but it has the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function. From the point of view, it is preferable to apply the contact lens, in particular, the soft contact lens, in particular, the silicone hydrogel contact lens without wearing it. Although silicone hydrogel contact lenses are included in soft contact lenses and are both ionic and non-ionic, it is known that ionic silicone contact lenses have the property of adsorbing a protein to be an allergen. In addition, silicone hydrogel contact lenses are harder in material than other soft contact lenses, and physical damage is easily caused to the corneal epithelium, so that the effect of preventing allergic symptoms and / or enhancing the corneal epithelial barrier function can be obtained. The impact is immeasurable. However, the eyedrops according to the present embodiment is not recommended to be instilled during wearing of the silicone hydrogel contact lens.

  The eye drop preparation according to the present embodiment is effective for preventing various allergic symptoms such as food allergy, animal allergy, hay fever, house dust (room dust) and the like. Above all, it is suitable for the prevention of allergic symptoms of eyes due to pollen and house dust (room dust) etc. Specifically as such allergic symptoms, there are many cases of eye redness, itchy eyes, blurred vision and eyes It is used for the prevention of feeling of eyes, feeling of foreign matter and feeling of foreign matter.

  In addition, the dosage and administration of the eyedrops according to the present embodiment is not particularly limited as long as it exerts effects and has few side effects, but for example, in the case of adults (15 years of age or older) and children of 7 years or older, The method of instillation once or twice a day, four times a day (for example, morning, noon, evening and before going to bed) is preferred.

The suitable start time of use of the eyedrops according to the present embodiment is not particularly limited as long as it is before the onset of allergic symptoms by contact with a certain amount or more of the allergen. For example, when using the eyedrops which concern on this embodiment for prevention of the symptom by allergic substances, such as protein including lysozyme, it is used from one to two weeks before the scheduled date of the contact to those substances. When using the eye drop concerning this embodiment for prevention of the symptom by animal allergy, it is used from 1 to 2 weeks before the scheduled date of the contact to an animal. Animals include dogs, cats, rabbits, guinea pigs, rats and mice. For example, when using the eyedrops according to the present embodiment for the prevention of symptoms due to seasonal allergy such as hay fever, use from several weeks before the start of pollen scattering, preferably from 1 to 2 weeks Is preferred. The pollen includes, for example, cedar, cypress, birch, oak, chestnut, olive, alder, zelkova, ginkgo, red pine, nezu, red-eared moth, tilapia, mugwort and ragweed. Since the scattering start time is known for each type of pollen, it is possible to determine the usage start time (for example, one to two weeks before the pollen scattering start) by the pollen causing the allergy. In particular, cedar pollen begins scattering of the pollen every year around February, and among the pollinosis patients with cedar pollinosis are the most frequent. Therefore, prediction of the pollen scattering start time is performed every year by an organization such as the Ministry of the Environment and the Japan Meteorological Association, and it is possible to determine the usage start timing (for example, one to two weeks before the pollen scattering start) on the basis of the prediction. it can. Therefore, in the present specification, “pollen scattering start” refers to the actual pollen scattering start date defined as the first day when one or more pollens per cm ² are continuously observed for 2 days or more in the pollen measuring instrument. It does not mean, but means the pollen scattering start predicted date or time. The pollen scattering start prediction date or time may be predicted by any organization. In addition, depending on the institution, the pollen scattering start prediction date or time may be announced multiple times, but any prediction date or time may be used. The user can decide on the use start time at his own discretion, and can also make a decision in consultation with a healthcare professional such as a doctor and a pharmacist.

  The eye drop preparation according to this embodiment exerts an effect of enhancing the corneal epithelial barrier function, and therefore, the allergen can be used as the corneal epithelium by using it before the onset of allergic symptoms, in particular, 1 to 2 weeks before contact with the allergen. It is possible to effectively prevent penetration to the corneal stroma, and the onset of allergic symptoms can be effectively prevented.

  This embodiment provides, from another point of view, a method for imparting a preventive action of allergic symptoms to eye drops by combining the (A) component and the (B) component, and further, (B) the component and (B) 2.) provide a method for imparting an action of enhancing corneal epithelial barrier function to eye drops by combining the components.

  The present embodiment provides the agent for preventing eye hyperemia caused by an allergic reaction, which is characterized by containing (A) component and (B) component from the viewpoint of yet another viewpoint, which is characterized by being used in eye drops. is there.

  From the viewpoint of yet another aspect of the present invention, the agent for preventing eye itching caused by an allergic reaction, which is characterized by containing the component (A) and the component (B) and used in eye drops, It is intended to provide a preventive agent for causing excessive eyes, an agent for preventing nausea caused by an allergic reaction, or an agent for preventing foreign body feeling caused by an allergic reaction.

  Component (A) and / or component (B) may be contained as an active ingredient.

  Hereinafter, the present invention will be described in detail by way of examples and test examples, but the present invention is not limited by these examples and the like.

Test Example 1 Measurement of Transcorneal Epithelial Electric Resistance Value TER (1)
Each eye drop was prepared according to Table 1 below, and the corneal barrier function of each eye drop was evaluated.

Seed 1.0 × 10 ⁵ cells / well (200 μL) of the human corneal epithelial cell line HCE-T (RIKEN BioResource Center, No. RCB 2280) in inserts of Transwell (registered trademark, 24 wells, Corning) (N = 3). In a well on the reservoir side, 600 μL of culture medium was placed and cultured at 37 ° C., 5% CO ₂ for 24 hours. After incubation, the inserts were transferred to wells containing 600 μL of each eye drop and allowed to stand at room temperature for 10 minutes. After treatment, transfer the insert to a well containing 600 μL of phosphate buffer, wash once, and measure transcorneal epithelial electrical resistance (TER) using MILLICELL (registered trademark)-ERS (Millipore). The rate of increase was calculated based on equation (1). The higher the TER increase rate, the tighter the barrier between corneal epithelial cells, which means that the barrier function is enhanced. In addition, in Formula (1), a control refers to the eyedrop which does not contain either (A) component or (B) component.
(Expression 1) TER increase rate (%) = ((TER value of each comparative example or example) / (TER value of control) -1) × 100

  As shown in Table 1, in the eye drops containing only one of tranilast and pyridoxine hydrochloride (Comparative Examples 1 and 2), almost no rise in TER was observed, but the eye drops containing both of them (Example 1) It was confirmed that TER significantly increases TER, and corneal epithelial barrier function is enhanced.

Test Example 2 Measurement of Transcorneal Epithelial Electric Resistance Value TER (2)
Each drug was prepared in culture medium according to Table 2 below, and the corneal barrier function of each drug was evaluated.

Seed 1.0 × 10 ⁵ cells / well (200 μL) of the human corneal epithelial cell line HCE-T (RIKEN BioResource Center, No. RCB 2280) in inserts of Transwell (registered trademark, 24 wells, Corning) (N = 3). 600 μL of each drug was placed in a well on the reservoir side, and cultured at 37 ° C., 5% CO ₂ for 24 hours. After culture, the corneal barrier function of each drug was evaluated in the same manner as in Test Example 1.

  As shown in Table 2, in the drug (comparative examples 3 to 5) containing either tranilast or component (B) (l-menthol, dl-camphor), almost no increase in TER was observed, but both contained It was confirmed that TER was significantly increased and the corneal epithelial barrier function was enhanced in the drugs (Examples 2 and 3).

Test Example 3 Cell Layer Permeability Test Each eye drop was prepared according to Tables 3 and 4 below, and the corneal barrier function of each eye drop was evaluated.

Human corneal epithelial cell line HCE-T was seeded at 1.0 × 10 ⁵ cells / well (200 μL) in inserts of Transwell® (24 wells) (n = 3). The wells were filled with 600 μL of culture medium, and cultured at 37 ° C., 5% CO ₂ for 24 hours. After incubation, the inserts were transferred to wells containing 600 μL of each eye drop and allowed to stand at room temperature for 10 minutes. After treatment, the insert is transferred to a well containing 600 μL of phosphate buffer, washed once, the culture medium in the insert is aspirated off, and 0.01 w / v% fluorescein prepared with phosphate buffer in the insert 100 μL of sodium solution was added. The insert was transferred to a well containing 600 μL of phosphate buffer and allowed to stand at room temperature for 20 minutes. 100 μL of the solution in the wells was transferred to a 96-well microplate, and the fluorescence value at an excitation wavelength of 485 nm / emission wavelength of 527 nm was measured using a fluorescence plate reader (Fluoroskan Ascent CF, manufactured by Labsystems).

The relative fluorescein transmission of each comparative example and example when the fluorescein transmission of the control was 100 was taken as the transmittance, and the permeation suppression enhancement rate of each of the examples was calculated by the following formula (2). The higher the permeation suppression enhancement rate, the tighter the barrier between corneal epithelial cells means that the barrier function is enhanced. Here, the control refers to an eye drop containing neither the (A) component nor the (B) component.
(Formula 2) Permeation suppression enhancement rate (%) = (((permeability of 100-example) / (100-permeability of corresponding comparative example) -1) × 100
Specifically, the corresponding comparative example refers to a comparative example of the same number as in Comparative Example 6 in Example 6 and Comparative Example 7 in Example 7 in the case of Example 6, and the eyedrops of each Example excludes Tranilast. Point to eye drops.

  As shown in Table 4, the eye drops (Examples 6 to 12) in which Tranilast and the component (B) are combined have an enhanced suppression of the transmittance compared to the eye drops (Comparative Examples 6 to 12) not containing Tranilast. It has been confirmed that the corneal epithelial barrier function is enhanced.

Formulation Example An eye drop was prepared according to the following formulation.

The preferred embodiment of the present invention is as follows.
[1] An eye drop for enhancing corneal epithelial barrier function, comprising (A) tranilast or a salt thereof, and (B) at least one selected from the group consisting of anti-inflammatory agents, water-soluble vitamins and refreshing agents.
[2] The eye drop preparation according to [1], wherein the eye drop preparation for enhancing corneal epithelial barrier function is an eye drop preparation for preventing allergic symptoms.
[3] The eye drop preparation according to [2], wherein the allergic condition is at least one selected from the group consisting of eye redness, itchy eyes, naked eyes and foreign body feeling of the eyes.
[4] The eye drop preparation according to any one of [1] to [3], which is applied 1 to 2 weeks before the onset of pollen scattering.
[5] The eye drop preparation according to any one of [1] to [4], which is applied without wearing a silicone hydrogel contact lens.
[6] The total content of the anti-inflammatory agent is 0.001 to 20 parts by mass, and the total content of water-soluble vitamins is 0.005 to 5 parts by mass with respect to 1 part by mass of the total content of the component (A) The eyedrop preparation in any one of [1]-[5] whose total content of a part and a refreshing agent is 0.0001-2 mass parts.
[7] As component (B), at least one selected from the group consisting of ε-aminocaproic acid, allantoin, berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme chloride and azulene sulfonate sodium The eye drop preparation according to any one of [1] to [6], which comprises an anti-inflammatory agent.
[8] The component (B) contains at least one water-soluble vitamin selected from the group consisting of pyridoxine hydrochloride, cyanocobalamin, flavin adenine sodium disodium, panthenol, calcium pantothenate and sodium pantothenate [1] The eye drop preparation according to any one of [7].
[9] The eye drop according to any one of [1] to [8], which comprises at least one refreshing agent selected from the group consisting of menthol, camphor, borneol, geraniol and peppermint oil as the component (B). Agent.
[10] A combination of (A) tranilast or a salt thereof and (B) at least one selected from the group consisting of an anti-inflammatory agent, a water-soluble vitamin and a refreshing agent, which imparts to the eye drops a preventive action on allergic symptoms Method.
[11] A combination of (A) tranilast or a salt thereof and (B) at least one member selected from the group consisting of anti-inflammatory agents, water-soluble vitamins and refreshing agents, for enhancing corneal epithelial barrier function into eye drops How to give.

Claims (13)

(A) and tranilast or a salt thereof, (B) containing pyridoxine or a salt thereof, characterized in that it is used by pollen started 1-2 weeks before or al point eye, for the prevention of allergic symptoms against the pollen An eye drop (although an eye drop containing at least one member selected from the group consisting of chlorpheniramine, pranoprofen and their salts) and at least one member selected from the group consisting of monoethanolamine and its salts Excluding eye drops ). The eye drop preparation according to claim 1, which is applied without wearing a contact lens. The eye drop preparation according to claim 1, further comprising glycyrrhizinic acid or a salt thereof. The total content of pyridoxine and its salt is 0.005 to 5 parts by mass, and the total content of glycyrrhizinic acid and its salt is 0.001 to 20 parts by mass with respect to 1 part by mass of the total content of component (A) The eye drop preparation according to claim 3 . In the eye drop, the content of component (A) is 0.001 to 1 w / v%, the total content of pyridoxine and its salt is 0.005 to 5 w / v%, and the total content of glycyrrhizinic acid and its salt is 0 The eye drop preparation of Claim 3 or 4 which is .005-5 w / v%. The eye drop preparation according to any one of claims 1 to 5 , further comprising a thickener. The eye drop preparation according to any one of claims 1 to 6 , further comprising a buffer. (A) and tranilast or a salt thereof, (B) containing pyridoxine or a salt thereof, characterized in that it is used by pollen started 1-2 weeks before or al point eyes, corneal epithelial barrier function with respect to the pollen Eyedrops for enhancing use (however, eye drops containing at least one selected from the group consisting of chlorpheniramine, pranoprofen and their salts, and at least one kind selected from the group consisting of monoethanolamine and its salts Excluding eye drops including The eye drop preparation according to claim 8, which is applied without wearing a contact lens. The eye drop preparation according to claim 8, further comprising glycyrrhizinic acid or a salt thereof. And (A) tranilast or a salt thereof, (B) combining pyridoxine or a salt thereof, eye drops the enhancing effect for a scatter started 1-2 weeks before or al use of the pollen of the corneal epithelial barrier function against pollen (however, chlorine Eye drops containing at least one member selected from the group consisting of pheniramine, pranoprofen and their salts, and eye drops containing at least one member selected from the group consisting of monoethanolamine and its salts ) How to give. The eye drop preparation according to claim 11, which is used without wearing a contact lens. The eye drop preparation according to claim 11, further comprising glycyrrhizinic acid or a salt thereof.