JP2010189442A - Suppressor for corneal disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a prophylactic for corneal disorder which can suppress corneal disorder, particularly corneal disorder caused by an ultraviolet ray. <P>SOLUTION: A suppressor for corneal disorder comprises pranoprofen or its salt as an active ingredient. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a corneal disorder inhibitor. Furthermore, the present invention is a preventive or therapeutic agent for corneal injury caused by ultraviolet rays.

  The cornea is an organ that is prone to various disorders because it is in the outermost layer of the eye and directly affected by the external environment. The etiology of corneal disorders mainly includes exposure to light such as ultraviolet rays, decrease in tears, adhesion of foreign substances and pathogens, and damage during contact lens removal. In particular, due to the destruction of the ozone layer in recent years, the amount of ultraviolet rays in the environment has increased, and there is a concern that corneal damage caused by ultraviolet exposure will increase.

  Typical examples of corneal damage caused by exposure to light such as ultraviolet rays include ultraviolet ophthalmitis (so-called snow blindness, snow eye flames, and snow licking) and electric ophthalmitis. Symptoms include pain, photophobia, lacrimation, etc. It is characterized by being strong. In many cases, strong photophobia, lacrimation, and eye pain occur suddenly around 8 hours after exposure to ultraviolet rays, and the eyelid and conjunctiva are congested and swollen, resulting in diffuse superficial keratitis and corneal epithelial detachment. May cause eyelid spasm due to strong irritation.

  Although the mechanism by which ultraviolet rays cause damage to the cornea has not yet been fully elucidated, it is thought that the exposure to UV rays induces corneal epithelial cell division inhibition, metabolic disorders, or cell death. It has been.

  Conventionally, as a corneal disorder treatment / prevention agent, one having lecithinized superoxide dismutase as an active ingredient is known (Patent Document 1). However, the preparation described in Patent Document 1 uses an enzyme as an active ingredient and is difficult to supply as a stable preparation. In addition, a corneal disorder therapeutic agent containing a phosphoric diester compound of ascorbic acid and tocopherol has also been reported (Patent Document 2). However, the preparation described in Patent Document 2 has a drawback that the effect cannot be stably maintained due to decomposition of active ingredients and adsorption to containers.

  On the other hand, pranoprofen is known as a non-steroidal anti-inflammatory agent and is widely used as a component of ophthalmic compositions. It has already been clarified that the pranoprofen does not contribute to the repair of the corneal epithelium in the corneal epithelial exfoliated eye forcibly exfoliating the corneal epithelium (see Non-Patent Document 1). However, it has not been reported so far that pranoprofen has an action of suppressing corneal damage.

By the way, corneal epithelial disorders are caused by various causes, and their symptoms are various, and prevention and treatment according to each corneal disorder is necessary. In the epithelial disorder in which the corneal epithelium is forcibly detached as in Non-Patent Document 1, the remaining cells are not damaged, so the wound heals relatively early. On the other hand, since damage caused by ultraviolet rays affects the entire ocular surface, proliferation of the remaining epithelial cells may be delayed, or even the most important basal cells for wound healing may be affected. Until now, it has not been known what effect pranoprofen exerts on such corneal damage caused by UV damage.

JP-A-9-124505 Japanese Unexamined Patent Publication No. 7-291870

Keiko Terashima et al., “Effect of non-steroidal anti-inflammatory agent, pranoprofen ophthalmic solution on rabbit corneal wound healing”, Pharmacology and Treatment, June 1988, Vol. 16, No. 6, pp. 131-135

  An object of the present invention is to provide a corneal disorder inhibitor capable of suppressing a corneal disorder, particularly a corneal disorder caused by ultraviolet rays. Furthermore, an object of the present invention is to provide a preventive or therapeutic agent for corneal injury that is effective for the prevention or treatment of corneal injury caused by ultraviolet rays.

  As a result of diligent research, the present inventors have found that pranoprofen or a salt thereof has an action of suppressing corneal damage by increasing the viability of corneal epithelial cells and preventing corneal damage caused by ultraviolet rays. It was found that there is an action to treat. The present invention has been completed by further studies based on this finding.

That is, the present invention is a corneal disorder inhibitor listed below:
Item 1. A corneal disorder inhibitor comprising pranoprofen or a salt thereof as an active ingredient.
Item 2. Item 5. The corneal disorder inhibitor according to Item 1, wherein the corneal disorder is caused by ultraviolet rays.

The present invention also provides the following corneal protective agents:
Item 3. A corneal protective agent comprising pranoprofen or a salt thereof as an active ingredient.
Item 4. Item 4. The cornea protective agent according to Item 3, which is used for protecting the cornea against exposure to ultraviolet rays.

Furthermore, the present invention is a preventive or therapeutic agent for corneal disorders listed below:
Item 5. A preventive or therapeutic agent for corneal damage caused by ultraviolet rays, comprising pranoprofen or a salt thereof as an active ingredient.

The invention is described in detail below.
(I) Corneal disorder inhibitor The corneal disorder inhibitor of the present invention comprises pranoprofen or a salt thereof as an active ingredient.

  The corneal disorder to be suppressed in the present invention is not particularly limited. For example, exposure to various rays such as ultraviolet rays, sunlight, welding light, germicidal lamp, laser beam, reduction of tears, adhesion of foreign substances and pathogens, contact lenses Mention may be made of corneal damage caused by causes such as damage during desorption. Among them, examples of corneal disorders that are suitable for suppression include corneal disorders caused by exposure to various light rays, particularly ultraviolet exposure.

  Specific examples of the corneal disorder to be suppressed by the present invention include corneal ulcer, corneal epithelial detachment, keratitis, diffuse superficial keratitis, punctate superficial keratitis, and xerophthalmia. Among these, corneal disorders that are easily induced by UV exposure, specifically, corneal epithelial detachment and diffuse superficial keratitis are suitable suppression targets of the corneal disorder inhibitor of the present invention.

  Although not particularly limited, corneal epithelial disorders can be mentioned as preferable corneal disorders to be suppressed in view of the action of pranoprofen or a salt thereof for enhancing the viability of corneal epithelial cells. The term “viability of corneal epithelial cells” as used in the present invention means the ability to maintain the proliferative ability of the cells and continue to survive even if the corneal epithelial cells are adversely affected by the outside world.

  Planoprofen, that is, 2- (5 H- [1] benzopyrano [2,3-b] pyridin-7-yl) propionic acid, which is an active ingredient of the corneal injury inhibitor of the present invention, is a propionic acid-based acid non-acidic compound. It is a compound already known as a steroidal anti-inflammatory agent.

  In the present invention, a salt of pranoprofen may be used in place of or in combination with the above-described planoprofen. The salt of pranoprofen is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such salts include metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts, and salts with organic bases such as triethylamine, diethylamine, morpholine, and piperazine. These pranoprofen salts may be used alone or in any combination of two or more.

  In the present invention, the above pranoprofen or a salt thereof may be synthesized by a known method, or a commercially available product may be used conveniently.

  The corneal injury inhibitor of the present invention can be formulated into an arbitrary form used for ophthalmic preparations by blending a known base, carrier or other components described later. As an example of the preparation form of the corneal disorder inhibitor of the present invention, topical ophthalmic preparations such as eye drops, eyewashes, eye ointments, contact lens mounting liquids, contact lens preparations; liquids, capsules, tablets, powders, granules And other external preparations. Here, the “contact lens agent” is a composition for storing, cleaning, and disinfecting a contact lens. The corneal disorder inhibitor of the present invention is preferably used as an ophthalmic topical preparation, particularly an eye drop or eye wash.

  The ratio of pranoprofen or a salt thereof to be blended in the above-mentioned various preparations varies depending on the dosage form, type, degree of corneal disorder, etc. of the preparation and cannot be defined uniformly. For example, in the case of a topical application for ophthalmology If present, the proportion of pranoprofen or a salt thereof is 0.005 to 2% by weight, preferably 0.005 to 0.5% by weight, based on the total weight of the preparation. More specifically, when preparing a corneal disorder inhibitor as eye drops, eye ointments, eye drops for contact lenses, contact lens mounting liquids, or contact lens agents (preservatives, cleaning agents, bactericides), Planoprofen or a salt thereof is 0.01 to 0.5% by weight, more preferably 0.01 to 0.1% based on the total weight of the preparation; when prepared as an eyewash, pranoprofen or a salt thereof is based on the total weight of the preparation May be 0.005 to 0.05% by weight, more preferably 0.005 to 0.02%. In the case of an internal preparation, pranoprofen or a salt thereof is 0.01 to 10% by weight, preferably 0.1 to 5% by weight, more preferably 0.5 to 3% by weight with respect to the total weight of the preparation if it is a liquid. On the other hand, in the case of a solid preparation, for example, the preparation may be appropriately set so that the dose per day is 10 to 1000 mg, preferably 30 to 300 mg. In the case of an external preparation, the proportion of pranoprofen or a salt thereof is 0.001 to 10% by weight, preferably 0.005 to 5% by weight, more preferably 0.01 to 1% by weight, based on the total weight of the preparation. Can be mentioned.

  When the corneal disorder inhibitor of the present invention is prepared as a topical ophthalmic preparation, its pH and osmotic pressure are not particularly limited as long as it is acceptable as a topical ophthalmic preparation. Examples of the pH of the agent include pH 5 to 9.5, preferably 6 to 9, and particularly preferably 7 to 9. As an osmotic pressure ratio with respect to the physiological saline of this agent (in the case other than eye ointment), for example, 0.3 to 4.3, preferably 0.3 to 2.2, particularly preferably about 0.5 to 1.5 can be exemplified. The pH and osmotic pressure can be adjusted by a method known in the art using a pH adjuster, an isotonic agent, salts and the like described later.

When formulating the corneal injury inhibitor of the present invention, various components (including pharmacologically active components and physiologically active components) in addition to pranoprofen or a salt thereof, as long as the effects of the present invention are not hindered. ) In combination. There are no particular restrictions on the types of such components, for example, decongesting components, ophthalmic modifier components, anti-inflammatory components or astringent components, antihistamine components or antiallergic components, vitamins, amino acids, antibacterial agents Ingredients, bactericidal components, saccharides, polysaccharides or derivatives thereof, cellulose or derivatives or salts thereof, water-soluble polymers other than those described above, local anesthetic components, steroid components, glaucoma treatment components, cataract treatment components, etc. . Examples of suitable components include the following components.

  Decongestant: α-adrenergic drugs such as imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and their pharmaceutically or physiologically acceptable Salts (eg, inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, and methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate).

  Eye muscle modulator component: Cholinesterase inhibitor having an active center similar to acetylcholine, for example, quaternary ammonium compounds such as neostigmine methyl sulfate and salts thereof.

  Anti-inflammatory or astringent ingredients: celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemetacin, ibuprofen sodium, thiaprofen acid , Thiaramide hydrochloride, epsilon-aminocaproic acid, berberine and pharmacologically acceptable salts (eg, berberine chloride, berberine sulfate), azulene sulfonic acid and pharmacologically acceptable salts (eg, sodium azulene sulfonate, etc.) ), Zinc salts (eg, zinc sulfate, zinc lactate, etc.), lysozyme, lysozyme chloride, methyl salicylate, allantoin, glycyrrhizic acid and pharmacologically acceptable Salts (e.g., dipotassium glycyrrhizinate, ammonium glycyrrhizinate, etc.).

  Antihistamine component or antiallergic component: for example, chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglycic acid, tranilast, amlexanox, mequitazine, loratadine (loratadine) fexofenadine), cetirizine, ibudilast, suplatast, pemirolast, repirinast, tazanolast, oxatomide, terfenadine, epinastine, astemizole, ebastine or a salt thereof (e.g., chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptiline fumarate, Emedastine acid, clemastine fumarate, azelastine hydrochloride, levocabasti hydrochloride , Olopatadine hydrochloride, sodium cromoglycate) and the like.

  Vitamins: For example, vitamin A [for example, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (for example, retinol acetate, retinol palmitate, etc.), vitamin B, etc. [Thiamine, dicetiamine, thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl nitrate ester salt, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, chicotiamine, bisibtiamine, bisbenchamine, fursultiamine, Prosultiamine, benfotiamine, riboflavin, flavin adenine dinucleotide, flavin adenine dinucleotide sodium, riboflavin, sodium riboflavin phosphate, riboflavin butyrate, pyridox Syn, pyridoxine hydrochloride, pyridoxal, pyridoxal phosphate, pyridoxal phosphate calcium, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin, hydroxocobalamin, methylcobalamin, deoxyadenocobalamin, folate, tetrahydrofolate, dihydrofolate, nicotinic acid, nicotinamide Nicotinic alcohol, panthenol, pantothenic acid, calcium pantothenate, sodium pantothenate, biotin, choline, inositol, etc.], vitamin C [ascorbic acid and derivatives thereof, erythorbic acid and derivatives thereof and pharmacologically acceptable Salts (eg, sodium ascorbate, sodium erythorbate, etc.)], vitamin D [eg, ergocalciferol, cholecalc Cipherol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaxosterol and pharmacologically acceptable salts thereof, etc.], vitamin E [for example, tocopherol and its derivatives, ubiquinone derivatives and their pharmacologically acceptable Salts such as tocopherol acetate, tocopherol nicotinate, tocopherol succinate, calcium tocopherol succinate, etc.], other vitamins [eg carnitine, ferulic acid, γ-oryzanol, orotic acid, cyanocobalamin, rutin, eriocitrin, Hesperidin and pharmacologically acceptable salts thereof (such as carnitine chloride).

  Amino acids: for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxy Lysine, glycylglycine, aminoethylsulfonic acid (taurine) or a salt thereof (for example, potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.) and the like.

Antibacterial or bactericidal component: Sulfonamides (for example, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.) ), Acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium, and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, etc.), Alkyl polyaminoethylglycine, new quinolone (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), berberine or a salt thereof (eg, berberine sulfate), β-lac Antibiotics (such as sulbenicillin, cefmenoxime), aminoglycoside antibiotics (such as kanamycin, gentamicin, tobramycin, sisomycin, micronomycin), tetracycline antibiotics (such as oxytetracycline), macrolide antibiotics (such as erythromycin), Chloramphenicol antibiotics (such as chloramphenicol), polypeptodo antibiotics (such as colistin), etc. Antiviral drugs (doxuridine, acyclovir, adenine arabinoside, ganciclovir, foscarnet, valacyclovir, trifluoro Thymidine, cidophobia, carbocyclic oxetanocin G, etc.), antifungal drugs (pimaricin, fluconazole, itraconazole, miconazole, flucytosine, amphotericin B) ), And the like.

  Saccharides: monosaccharides (eg glucose), disaccharides (eg trehalose, lactose, fructose etc.), oligosaccharides (eg lactulose, raffinose, pullulan etc.), sugar alcohols (eg mannitol, xylitol, sorbitol etc.) Such.

  Polysaccharides or derivatives thereof: gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac gum, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, Pectin, starch, polygalacturonic acid (alginate), chitin and derivatives thereof, chitosan and derivatives thereof, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate or a salt thereof (sodium alginate, sodium hyaluronate, chondroitin) Such as sodium sulfate).

  Cellulose or a derivative thereof or a salt thereof: cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose, and the like.

  Water-soluble polymers other than those described above: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, and the like.

  Local anesthetic ingredients: lidocaine, oxybuprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilucaine, mepivacaine, bupivacaine, cocaine and their salts (such as lidocaine hydrochloride, oxybuprocaine hydrochloride).

  Steroid component: hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, parameterzone, betamethasone and their salts.

  Glaucoma treatment ingredients: timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, unoprostone, dipivefrine hydrochloride, epinephrine, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide, metazolamide and their salts.

  Cataract treatment ingredients: pirenoxine, glutathione, salivary gland hormone, thiopronin, dihydro azapentacene disulfonate and salts thereof (for example, Sodium 5,12-dihydro azapentacene disulfonate).

The mixing ratio of these components can be selected according to the type of preparation, the type of active ingredient, etc., and the mixing ratios of various components in ophthalmic topical preparations, internal preparations, external preparations and the like are known in the art. . For example, it can be selected from a range of about 0.0001 to 30%, preferably about 0.001 to 10% with respect to the total weight of the preparation. More specifically, each component can be contained in the proportions exemplified below with respect to the total weight of the preparation.
Decongestant component (vasoconstrictor or sympathomimetic drug): for example, 0.0001 to 0.5 wt%, preferably 0.0005 to 0.3 wt%, more preferably 0.001 to 0.1 wt% %.
Ocular muscle modulator component: For example, 0.0001 to 0.5% by weight, preferably 0.0005 to 0.1% by weight, and more preferably 0.0005 to 0.01% by weight.
Anti-inflammatory component or astringent component: for example 0.0001 to 10% by weight, preferably 0.0001 to 5% by weight.
Antihistamine component or antiallergic agent component: for example, 0.0001 to 10% by weight, preferably 0.001 to 5% by weight.
Vitamins: For example, 0.0001 to 1% by weight, preferably 0.0001 to 0.5% by weight.
Amino acids: For example, 0.0001 to 10% by weight, preferably 0.001 to 3% by weight.
Antibacterial component or bactericidal component: for example, 0.00001 to 10% by weight, preferably 0.0001 to 10% by weight.
Sugars: For example, 0.0001 to 5% by weight, preferably 0.001 to 5% by weight, and more preferably 0.01 to 2% by weight.
Polysaccharide or derivative thereof: for example, 0.0001 to 2% by weight, preferably 0.01 to 2% by weight, more preferably 0.01 to 1% by weight.
Cellulose or a derivative thereof or a salt thereof: For example, 0.001 to 5% by weight, preferably 0.01 to 1% by weight.
Water-soluble polymers other than those mentioned above: for example 0.001 to 10% by weight, preferably 0.001 to 5
% By weight, more preferably 0.01 to 3% by weight.
Local anesthetic component: For example, 0.001-1% by weight, preferably 0.01-1% by weight.
Steroid component: For example, 0.001-1% by weight, preferably 0.01-1% by weight.
Glaucoma treatment component: for example, 0.001 to 5% by weight, preferably 0.01 to 1% by weight.
Cataract treatment component: for example, 0.0001 to 10% by weight, preferably 0.001 to 5% by weight.

  In the present invention, in order to prepare formulations of various desired forms, various components and additives are appropriately selected according to conventional methods according to the use and form within a range not impairing the effects of the present invention. Or you may mix | blend more than it together. As those components or additives, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of topical ophthalmic preparations, semisolid preparations, liquid preparations, thickeners, Examples thereof include various additives such as sugars, surfactants, preservatives, bactericides or antibacterial agents, pH adjusters, tonicity agents, perfumes or refreshing agents, chelating agents, and buffering agents. Although the typical component which can be used is illustrated below, it is not limited to these.

  Thickeners: for example, polysaccharides or derivatives thereof (gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guayac fat, quince seed, dalman gum, tragacanth gum, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, Carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, etc., ceramide, cellulose derivative (methylcellulose) , Ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose , Carboxyethyl cellulose, cellulose, nitrocellulose, etc.), polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, polyethylene oxide, polyethylene glycol, ribo Nucleic acids, deoxyribonucleic acid, methyl vinyl ether / maleic anhydride copolymer, and pharmacologically acceptable salts thereof (for example, sodium alginate).

  Sugars: for example, glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol and the like Acceptable salts.

  Surfactant: For example, polyoxyethylene (POE) -polyoxypropylene (POP) block copolymer (for example, Poloxamer 407, Poloxamer 235, Poloxamer 188, etc.), polyoxyethylene-polyoxypropylene block copolymer adduct of ethylenediamine (for example, , Poloxamine), POE sorbitan fatty acid esters such as POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate (20) sorbitan (polysorbate 80), polysorbate 60, POE such as POE (60) hydrogenated castor oil Hardened castor oil, POE alkyl ethers such as POE (9) lauryl ether, POE / POP alkyl ethers such as POE (20) POP (4) cetyl ether, POE alkyl phenyl ethers such as POE (10) nonylphenyl ether, etc. Nonionic surfactants such as tellurium and POE alkylphenyl ethers such as POE (10) nonylphenyl ether; glycine type such as alkyldiaminoethylglycine, betaine acetate type such as lauryldimethylaminoacetic acid betaine, imidazoline type Amphoteric surfactants; POE alkyl ether phosphates such as POE (10) sodium lauryl ether phosphate and salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-cocoyl methyl taurate sodium, etc. N-acyl taurine salt of sodium, sulfonate such as sodium tetradecene sulfonate, alkyl sulfate such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfate such as sodium lauryl ether sulfate, α-o Anionic surfactants such as fin sulfonates; cations such as alkylamine salts, alkyl quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, etc.), alkyl pyridinium salts (cetylpyridinium chloride, cetylpyridinium bromide, etc.) Surfactant etc. The numbers in parentheses indicate the number of added moles.

  Preservatives, bactericides or antibacterial agents: for example, sorbic acid or salts thereof (such as sorbic acid, potassium sorbate, sodium sorbate, triclocarban sorbate), paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, Propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), acrinol, methylrosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, chlorhexidine or its salts, polyhexamethylene biguanide, alkylpolyaminoethylglycine, benzyl Alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, silver zirconium phosphate, mercurochrome, poppyon Supports such as card, thimerosal, dehydroacetic acid, chlorxylenol, chlorophene, resorcin, orthophenylphenol, isopropylmethylphenol, thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid , Propionic acid, benzoic acid, propionic acid, halocarban, thiabendazole, polymyxin B, 5-chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, polylysine, peroxidation Hydrogen, polydronium chloride, Glokill (trade name such as Glokill PQ, manufactured by Rhodia), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio Ethylene dichloride], polyethylene polyamine / dimethylamine epichlorohydrin polycondensate (trade name, for example, Busan 1157, manufactured by Buckman), biguanide compound (cosmosyl CQ (trade name, containing polyhexamethylene biguanide hydrochloride, about 20% by weight, manufactured by Apsia) )) And pharmacologically acceptable salts thereof.

  pH adjuster: For example, inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acid (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid , Propionic acid, acetic acid, aspartic acid, epsilon-aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic base (sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, hydroxide) Calcium, magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), borax, and pharmacologically acceptable salts thereof.

  Isotonizing agents: for example, inorganic salts (eg, sodium chloride, potassium chloride, sodium carbonate, sodium bicarbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, thiosulfuric acid Sodium, sodium acetate, etc.), polyhydric alcohols (eg, glycerin, propylene glycol, ethylene glycol, 1,3-butyleneglycol, etc.), saccharides (eg, buttosugar, mannitol, sorbitol, etc.).

Perfume or refreshing agent: terpenes (for example, menthol, camphor, borneol, geraniol, cineol, anethole, limonene, eugenol, etc. These may be d-form, l-form or dl-form) essential oil (eucalyptus oil, bergamot Oil, peppermint oil, cool mint oil, spearmint oil, fennel oil, mint oil, cinnamon oil, rose oil, etc.)
Such.

  Chelating agents: for example, edetic acid, citric acid, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, and the like Pharmacologically acceptable salts and the like.

Buffer: borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartate and the like. For example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof
(Sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.), carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, etc.), citric acid or a salt thereof (sodium citrate, potassium citrate, etc.), etc. .

What is necessary is just to set suitably the mixture ratio of these various components and additives according to the kind etc. of a formulation. Below, although an example of the mixture ratio of these components or additives with respect to a formulation total weight is shown, it is not restrict | limited to this.
Thickener: for example 0.0005 to 50% by weight, preferably 0.001 to 10% by weight
Saccharides: for example 0.001 to 10% by weight, preferably 0.01 to 5% by weight
Surfactant: For example, 0.0001 to 10% by weight, preferably 0.005 to 5% by weight
Preservative, bactericidal agent or antibacterial agent: for example, 0.00001 to 5% by weight, preferably 0.0001 to 2% by weight
pH adjusting agent: for example, 0.00001-5 wt%, preferably 0.0001-2 wt% isotonic agent: for example, 0.001-10 wt%, preferably 0.01-5 wt%
Perfume or refreshing agent: for example, 0.00001 to 5% by weight, preferably 0.0001 to 2% by weight
Chelating agent: for example 0.00001 to 5% by weight, preferably 0.0001 to 2% by weight Buffering agent: for example 0.001 to 10% by weight, preferably 0.01 to 5% by weight
The preparation of the corneal disorder inhibitor of the present invention can be carried out by a known method according to the form and the like. For example, in the case of eye drops, eyewashes, contact lens mounting solutions, or contact lens preparations, mix pranoprofen and optional ingredients in a suitable diluent such as distilled water or purified water. And it can manufacture by adjusting to said osmotic pressure and pH, carrying out the filter sterilization process in an aseptic environment, and aseptically filling the container after washing | cleaning sterilization. In addition, for example, in the case of an eye ointment, pranoprofen or a salt thereof and an optional compounding component may be mixed in a commonly used eye ointment base and prepared aseptically according to a conventional method. it can. When preparing an eye ointment, it is desirable to add a surfactant in order to increase the solubility of pranoprofen or a salt thereof.

  The corneal disorder inhibitor of the present invention can be applied for the purpose of preventing corneal disorder, reducing corneal disorder, reducing / stopping progression of corneal disorder, and promoting healing of corneal disorder. The corneal disorder inhibitor of the present invention can be preferably applied for the purpose of preventing corneal disorder, reducing corneal disorder and reducing / stopping the progression of corneal disorder, and more preferably preventing corneal disorder.

  The method for applying the corneal disorder inhibitor of the present invention is not particularly limited. For example, in the case of the purpose of preventing corneal injury, the agent may be applied before and after the time when the induction of corneal injury is a concern. More specifically, a method of applying an appropriate amount of a corneal disorder inhibitor at an arbitrary number of times from about 3 days before exposure to ultraviolet rays or the like to about 1 week after the final exposure can be exemplified. Moreover, when there is a concern about the induction of corneal damage on a daily basis, it can also be applied on a daily basis. On the other hand, if the purpose is to treat (relieve or cure) a corneal disorder, the corneal disorder inhibitor may be applied any number of times after the corneal disorder has developed.

In the case of eye drops and eye drops for contact lenses, the applied amount is about 0.2 ml for both eyes in one eye drop; for contact mounting solutions, about 0.05 to 0.2 ml for both eyes in a single use amount In the case of a contact lens preparation, about 0.05 to 10 ml for a binocular lens in a single use; in the case of an eye wash, about 10 ml for both eyes; in the case of an eye ointment, about 0.1 g can be exemplified for both eyes. In addition, in the case of other external preparations and internal preparations, it can be appropriately set according to the symptoms, the age of the application target person, expected effects, and the like. It should be noted that the application time, the number of applications, the application amount, and the like of the corneal disorder inhibitor of the present invention should be appropriately adjusted according to the cause of corneal disorder, the degree of symptoms, the age of the user, etc., and are limited to the above. It is not something.

  In addition, pranoprofen or a salt thereof has an effect of protecting the cornea, particularly protecting the corneal epithelium from adverse effects due to exposure to ultraviolet rays or the like. Therefore, from another viewpoint, the corneal disorder inhibitor of the present invention can also be called a corneal protective agent, a corneal epithelial protective agent, or a corneal epithelial cell protective agent.

(II) Preventive or therapeutic agent for corneal disorder In addition, as shown in the test examples described later, pranoprofen or a salt thereof has an action of preventing or treating corneal disorder caused by ultraviolet rays. Therefore, the present invention further provides a preventive or therapeutic agent for corneal damage caused by ultraviolet rays containing pranoprofen or a salt thereof as an active ingredient.

  The corneal disorder that is the target of the prophylactic or therapeutic agent is not particularly limited as long as it is a corneal disorder caused by exposure to ultraviolet rays. For example, corneal ulcer, corneal epithelial detachment, keratitis, diffuse superficial keratitis, punctate superficial cornea Examples include inflammation and xerophthalmia. Among these, corneal epithelial detachment and diffuse superficial keratitis are suitable corneal disorders for prevention and treatment.

  Further, although not particularly limited, corneal epithelial disorders can be mentioned as preferable corneal disorders to be prevented or treated.

  In addition, pranoprofen or a salt thereof used in the preventive or therapeutic agent for corneal disorders of the present invention, a preparation form of the prophylactic or therapeutic agent, a blending ratio of pranoprofen or a salt thereof in the formulation, any of which is blended The components, the method of applying the prophylactic or therapeutic agent, the application amount, etc. are the same as in the case of the corneal disorder inhibitor.

  According to the corneal injury inhibitor of the present invention, the viability of corneal epithelial cells can be increased, thereby suppressing corneal injury caused by various factors, particularly damage to corneal epithelial cells caused by ultraviolet rays. . Therefore, the corneal disorder inhibitor of the present invention is useful for preventing the development of a corneal disorder when it is likely to develop, or reducing the deterioration of an already developed corneal disorder or promoting healing.

  In addition, since the corneal injury inhibitor of the present invention can be prepared in the form of eye drops, eyewashes, etc., before and after corneal injury is induced, for example, when there is a risk of exposure to ultraviolet rays or early, after exposure to ultraviolet rays, The user himself can apply the agent to the cornea. This makes it possible to more effectively suppress the onset of corneal disorders and the deterioration of symptoms.

  Further, according to the corneal protective agent of the present invention, the cornea, particularly the corneal epithelium, can be protected and the cornea can be kept in a normal state, so that the eyes can be kept healthy by daily application of the agent. Is possible.

Furthermore, according to the preventive or therapeutic agent for corneal injury of the present invention, corneal cell injury caused by ultraviolet irradiation can be prevented and reduced or alleviated, so that the corneal injury caused by ultraviolet rays can be prevented or treated. Useful.

  Hereinafter, the present invention will be described in detail based on test examples and examples, but the present invention is not limited thereto.

Test Example 1 Action of Planoprofen on Rabbit Corneal Epithelial Cells Irradiated with Ultraviolet Ray In order to confirm the action of pranoprofen on corneal damage caused by ultraviolet light, a test was conducted according to the method described below.

(Method)
Rabbit corneal epithelial cells (NRCE2, Kurabo Corp.) are seeded in a 96-well microplate (5000 cells / well) and serum-free medium (RCGM2, Kurabo Corp.) until confluent at 37 ° C, 5% CO ₂ ) Was pre-cultured. To the cells that became 90% confluent, pranoprofen dissolved in PBS (-) [PBS (phosphate buffered saline) without Ca ²⁺ and Mg ²⁺ ] was added to a final concentration of 0.01% (treatment). group). As a control group, diclofenac sodium, which is a nonsteroidal anti-inflammatory agent and is known to suppress the proliferation of corneal epithelial cells, was added to a final concentration of 0.002%. Only PBS (-) was added to the untreated control group. Immediately, 250 mJ / cm ² of UV (UV-B, 302 nm) was irradiated for about 4 minutes, and the culture was further continued for 72 hours. Thereafter, the respiration rate of living cells serving as an index of cell viability was measured by the MTT (3- (4,5-Dimethyl-2-thiazolyl) -2,5-diphenyl-2H tetrazolium bromide) method. MTT (obtained from Wako Pure Chemical Industries, Ltd.) is a substrate for intracellular mitochondrial dehydrogenase, and the more viable cells the more MTT is reduced, and the resulting formazan amount corresponds well with the number of viable cells. MTT solution was added to each well at 0.5 mg / ml, and after incubation for 4 hours, MTT and formazan were dissolved in 2-propanol. Absorbance at 570 nm was measured to determine cell viability.

(result)
The obtained results are shown in Table 1. In Table 1, the percentage of cell viability in each group cultured for 72 hours after UV irradiation, assuming that the viability (respiration rate of living cells) of cells cultured for 72 hours without UV irradiation was 100% (Hereinafter referred to as cell viability (%)). As shown in Table 1, it was confirmed that the cell survival rate was significantly higher in the 0.01% pranoprofen added group than in the non-added group and the 0.002% diclofenac sodium added group.

試験例１の実験結果から、プラノプロフェンには紫外線曝露後の角膜上皮細胞の細胞生存率を向上させる作用があることが確認された。即ち、本結果から、プラノプロフェンはＵＶ等による角膜上皮障害の抑制に有効であることが明らかである。この結果はまた、プラノプロフェンには、紫外線暴露等による悪影響から角膜上皮細胞を保護する作用があることを示している。

From the experimental results of Test Example 1, it was confirmed that pranoprofen has an effect of improving cell viability of corneal epithelial cells after exposure to ultraviolet rays. That is, it is clear from this result that pranoprofen is effective in suppressing corneal epithelial damage by UV or the like. This result also shows that pranoprofen has an effect of protecting corneal epithelial cells from adverse effects caused by ultraviolet exposure or the like.

Furthermore, this result shows that pranoprofen has an action of promoting or reducing the cure of symptoms of corneal disorders caused by UV exposure, and pranoprofen can prevent or prevent corneal disorders caused by UV radiation. It is clear that it is useful as a therapeutic agent.

  In addition, in the group with diclofenac sodium, a non-steroidal anti-inflammatory agent similar to pranoprofen, the cell survival rate was lower than in the no-addition group, whereas pranoprofen was lower than the no-addition group However, since the cell viability was high, it was confirmed that, among anti-inflammatory agents, pranoprofen is particularly useful for the suppression, protection, prevention and treatment of corneal epithelial damage caused by ultraviolet rays.

Example 1-11
According to conventional methods, eye drops, eye wash, contact lens mounting liquid (in the table, referred to as CL mounting liquid), contact lens disinfectant (in the table, referred to as CL disinfectant) of the formulations described in Tables 2 and 3 below, And a contact lens preservative (referred to as CL preservative in the table).

Claims (5)

A corneal disorder inhibitor comprising pranoprofen or a salt thereof as an active ingredient. The corneal disorder inhibitor according to claim 1, wherein the corneal disorder is caused by ultraviolet rays. A corneal protective agent comprising pranoprofen or a salt thereof as an active ingredient. The corneal protective agent according to claim 3, which is used for corneal protection against ultraviolet exposure. A preventive or therapeutic agent for corneal damage caused by ultraviolet rays, comprising pranoprofen or a salt thereof as an active ingredient.