WO2013077433A1 - 角結膜保護剤または角結膜障害抑制剤 - Google Patents
角結膜保護剤または角結膜障害抑制剤 Download PDFInfo
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- WO2013077433A1 WO2013077433A1 PCT/JP2012/080391 JP2012080391W WO2013077433A1 WO 2013077433 A1 WO2013077433 A1 WO 2013077433A1 JP 2012080391 W JP2012080391 W JP 2012080391W WO 2013077433 A1 WO2013077433 A1 WO 2013077433A1
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- keratoconjunctival
- keratoconjunctiva
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- glucosylglycerol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Definitions
- the present invention relates to a keratoconjunctiva protective agent or a keratoconjunctival disorder inhibitor, and more particularly to a keratoconjunctiva protector or a keratoconjunctival disorder inhibitor that suppresses keratoconjunctival disorders caused by drying or the like and protects the keratoconjunctiva.
- the lacrimal fluid covers the eyeball surface composed of the cornea and conjunctiva (keratoconjunctiva) and maintains wettability to prevent the eyeball surface from drying.
- tear fluid serves as a lubricant that protects the keratoconjunctiva from irritation caused by blinking, and contributes to maintaining the smoothness of the keratoconjunctival surface.
- Tear fluid also has a bacteriostatic action, protects against infection from bacteria, fungi, viruses, etc., and supplies oxygen and various nutrients to the keratoconjunctiva and removes carbon dioxide and metabolites.
- viscoelastic substances such as hyaluronic acid and instillation of artificial tears containing proteins such as sericin are the mainstream, for example, keratoconjunctiva protective agent containing silk protein sericin as an active ingredient
- a keratoconjunctival disorder improving agent is known (see, for example, Patent Document 1).
- glucosylglycerol (glyceryl glucoside) is a component contained in brewed products such as sake, and has sweetness, heat stability, low Maillard reactivity, moisture retention, non-cariogenicity, indigestibility, etc. In addition, it has a vascular endothelial cell proliferation promoting action, a blood sugar level increase inhibiting action, an antibacterial action and the like, and is used in foods, cosmetics, pharmaceuticals and the like.
- a whitening agent containing ⁇ -D-glucopyranosylglycerol ( ⁇ -glucosylglycerol) as an active ingredient for example, see Patent Document 2
- ⁇ -D-glucopyranosylglycerol ( ⁇ -glucosylglycerol) A dermal matrix production promoter as an active ingredient (for example, see Patent Document 3) is known.
- ⁇ -glucosylglycerol As ⁇ -glucosylglycerol has various effects, it has been applied in various ways. However, it is mainly used as an external preparation for the skin, and what effect it has on the keratoconjunctiva of the eyeball. , Not known so far.
- Japanese Unexamined Patent Publication No. 2010-83829 Japanese Unexamined Patent Publication No. 2004-331581 Japanese Unexamined Patent Publication No. 2004-331579
- the present invention suppresses keratoconjunctival damage caused by drying or the like. It is an object of the present invention to provide a keratoconjunctiva protective agent or a keratoconjunctival disorder inhibitor excellent in the effect of protecting the keratoconjunctiva.
- the present invention provides the following (1) to (6) in order to solve the above problems.
- Keratoconjunctival protection or keratoconjunctiva protection against intrinsic diseases such as Sjogren's syndrome, Stevens-Johnson syndrome or dry eye syndrome (dry eye), or after surgery, drug-related, trauma, or contact lens wearing
- the keratoconjunctival protective agent or the keratoconjunctival disorder inhibitor according to (1) which is used for suppressing conjunctival disorder.
- a method of protecting the keratoconjunctiva or suppressing keratoconjunctival disorder comprising administering glucosylglycerol.
- (6) protect the keratoconjunctiva against Sjogren's syndrome, Stevens-Johnson syndrome or dry eye syndrome, or postoperatively, drug-related, trauma, or extrinsic disease caused by wearing contact lenses.
- a keratoconjunctival protective agent and a keratoconjunctival disorder inhibitor having an excellent effect of suppressing keratoconjunctival disorder.
- FIG. 1 is a graph showing the measurement results of absorbance measured in the examples of the present invention.
- keratoconjunctival protection refers to protection of keratoconjunctival tissue from keratoconjunctival damage that may occur due to various factors.
- “keratoconjunctival protection” can be broadly classified into protection from keratoconjunctival disorders due to external factors and protection from keratoconjunctival disorders due to internal factors.
- External factors include, for example, trauma, burns, chemical substances, drugs, ultraviolet rays, contact lens wear, foreign matter, eyelashes, dry air, infection, and the like.
- external factors include those caused by surgical invasion of the cornea such as corneal refractive surgery and cataract surgery.
- internal factors include Sjogren's syndrome, dry eye syndrome (dry eye), diabetic keratopathy and the like.
- cornea conjunctiva refers to the cornea and the conjunctiva.
- the cornea is composed of the corneal epithelial layer, Bowman's membrane, corneal parenchymal layer, Descemet's membrane, and corneal endothelium layer. Consists of layers.
- the corneal epithelial layer and the conjunctival epithelial layer are a series of epithelial cell layers that are located on the outermost surfaces of the cornea and the conjunctiva and migrate to each other, and are easily damaged by the influence of the outside world.
- the keratoconjunctiva in “keratoconjunctival protection” is the keratoconjunctival epithelium (corneal epithelium and conjunctival epithelium).
- “suppression of keratoconjunctival disorder” means improvement of keratoconjunctival disorder that can be caused by the above-mentioned factors, symptom reduction, symptom reduction, symptom relief, treatment, healing and promotion of healing, etc. It is a meaning including.
- the keratoconjunctival protective agent and the keratoconjunctival disorder inhibitor (hereinafter sometimes collectively referred to as a preparation) of the present invention contain glucosylglycerol as an active ingredient.
- Glucosylglycerol used as an active ingredient includes 1- ⁇ -glyceryl glucoside (Formula 1), 2- ⁇ -glyceryl glucoside (Formula 2) and 1- ⁇ -glyceryl glucoside (Formula 1) represented by the following formulas (1) to (4). 3) 2- ⁇ -glyceryl glucoside (Formula 4) is known, and one of these can be used alone or a mixture of two or more.
- the method for obtaining glucosylglycerol is not particularly limited.
- glycerin derived from palm is allowed to act on a saccharide substrate derived from corn, ⁇ -glucosidase of molds, cyclodextrin glucanotransferase, or sucrose phosphorylase is converted into glycerol.
- a method of acting on a saccharide substrate in solution a method of extracting and purifying from brewed products such as sake, miso, mirin, etc., and cleaving glycol such as isomaltose and maltitol with lead tetraacetate or periodate Examples include a method of reducing, or a method of hydrolyzing ⁇ -glucoside with ⁇ -glucosidase after anomerizing ⁇ -glucoside synthesized by Koening-Knorr reaction.
- Adopted as substrate A method of allowing cyclodextrin glucanotransferase to act on a carbohydrate substrate in a glycerol solution (see, for example, Japanese Patent Application Laid-Open No.
- sucrose phosphorylase on a carbohydrate substrate in a glycerol solution.
- the method (for example, refer to International Publication No. WO2008 / 034158) is particularly preferable from the viewpoint of cost and safety.
- Glucosylglycerol can be used as is, but diluted with water or a polar solvent, decolorized and deodorized in a range that does not undergo denaturation or decomposition, or fractionated by column chromatography, etc. It may be used later. It can also be used by encapsulating in vesicles such as liposomes or microcapsules.
- the amount of glucosylglycerol in the keratoconjunctival protective agent or keratoconjunctive disorder inhibitor according to the present invention varies depending on the dosage form, type, degree of corneal disorder, etc. of the formulation and cannot be uniformly defined.
- the content is preferably 0.01 to 80% by mass, more preferably 0.05 to 50% by mass, and still more preferably 0.01 to 10% by mass.
- glucosylglycerol is 0.01% by mass or more, the desired effect of the present invention can be sufficiently obtained, and if it is 80% by mass or less, the viscosity increase of the preparation by glucosylglycerol is in a desired range. Therefore, it is preferable.
- the pH and osmotic pressure thereof are not particularly limited as long as they are acceptable as a topical ophthalmic preparation.
- the pH is preferably 5 to 9.5, more preferably 6 to 9, and still more preferably 7 to 9.
- the osmotic pressure ratio of the preparation (other than eye ointment) to physiological saline is, for example, 0.3 to 4.3, preferably 0.3 to 2.2, particularly preferably 0.5 to 1. About 5.
- 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.
- various components used in the ophthalmic topical preparation as necessary, as long as the effects of the present invention are not hindered.
- Components and physiologically active ingredients include, for example, a decongestant component, an eye regulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, and antibacterial agents.
- bactericidal components Ingredients, bactericidal components, saccharides, polysaccharides or derivatives thereof, cellulose or derivatives thereof or salts thereof, water-soluble polymers other than those described above, local anesthetic components, steroid components, glaucoma treatment components, cataract treatment components, etc. .
- These components may be used individually by 1 type, and may be used in combination of 2 or more type.
- Decongestants include, for example, ⁇ -adrenergic agonists such as imidazoline derivatives (such as naphazoline and tetrahydrozoline), ⁇ -phenylethylamine derivatives (such as phenylephrine, epinephrine, ephedrine, and methylephedrine), and their pharmacological or physiological properties.
- imidazoline derivatives such as naphazoline and tetrahydrozoline
- ⁇ -phenylethylamine derivatives such as phenylephrine, epinephrine, ephedrine, and methylephedrine
- inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride; and organic acid salts such as epinephrine hydrogen tartrate).
- inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride
- organic acid salts such as epinephrine hydrogen tartrate
- ocular muscle modulator component examples include cholinesterase inhibitors having an active center similar to acetylcholine, quaternary ammonium compounds such as neostigmine methyl sulfate, and salts thereof.
- Anti-inflammatory or astringent components include, for example, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemetacin, ibuprofen, thiaprofenic acid, loxoprofen sodium, cyronamide hydrochloride, Aminocaproic acid, berberine and pharmacologically acceptable salts (eg berberine chloride, berberine sulfate), azulene sulfonic acid and pharmacologically acceptable salts (eg sodium azulene sulfonate), zinc salts (eg , Zinc sulfate, zinc lactate, etc.), lysozyme, lysozyme chloride, methyl salicylate, allantoin, glycyrrhizi
- antihistamine component or the antiallergic agent component examples include chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglycic acid, tranilast, amlexanox, mequitazine, loratadine, fetolidine, , Ibudilast, suplatast, pemirolast, repirinast, tazanolast, oxatomide, terfenadine, epinastine, astemizole, ebastine or a salt thereof (for example, chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, Azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydro
- vitamins include 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 [thiamine, dicetiamine, thiamine hydrochloride, thiamine nitrate, bistiamine nitrate, thiamine disulfide, thiamine dicetyl nitrate ester salt, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, chicotiamine, bisibutiamine, bisbenchamine, fursul Thiamine, prosultiamine, benfotiamine, riboflavin, flavin adenine dinucleotide, flavin adenine dinucleotide sodium, riboflavin, riboflavin sodium phosphate, riboflavin butyrate
- amino acids examples include leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline. , Hydroxylysine, glycylglycine, aminoethylsulfonic acid (taurine) or a salt thereof (for example, potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.).
- Antibacterial or bactericidal components include, for example, sulfonamides (eg, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, Isomidine sodium, etc.), acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium, and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetyl bromide) Pyridinium, etc.), alkylpolyaminoethylglycine, new quinolones (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), berberine or a salt
- sugars examples include monosaccharides (eg, glucose), disaccharides (eg, trehalose, lactose, fructose, etc.), oligosaccharides (eg, lactulose, raffinose, pullulan, etc.), sugar alcohols (eg, mannitol, xylitol, etc.). Sorbitol, etc.).
- monosaccharides eg, glucose
- disaccharides eg, trehalose, lactose, fructose, etc.
- oligosaccharides eg, lactulose, raffinose, pullulan, etc.
- sugar alcohols eg, mannitol, xylitol, etc.
- Sorbitol, etc. examples include sugar alcohols (eg, mannitol, xylitol, etc.). Sorbitol, etc.).
- polysaccharides or derivatives thereof examples include gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac oil, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, Gelatin, collagen, pectin, starch, polygalacturonic acid (alginic acid), chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate or salts thereof (sodium alginate, hyaluronic acid) Acid sodium, chondroitin sodium sulfate, etc.).
- cellulose or a derivative thereof or a salt thereof examples include cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, and nitrocellulose.
- water-soluble polymers other than those described above examples include polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, and the like.
- Examples of the local anesthetic component include lidocaine, oxybuprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilucaine, mepivacaine, bupivacaine, cocaine, and salts thereof (such as lidocaine hydrochloride and oxybuprocaine hydrochloride).
- steroid component examples include hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, parameterzone, betamethasone, and salts thereof.
- glaucoma treatment components include timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, unoprostone, dipivefrine hydrochloride, epinephrine, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide, metazolamide, and salts thereof It is done.
- Examples of the components for treating cataract include pirenoxine, glutathione, salivary gland hormone, thiopronin, dihydro-azapentacene-disulfonate, and salts thereof (for example, sodium 5,12-dihydro-azapentacene-disulfonate) and the like.
- 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
- 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, Various additives such as surfactants, preservatives, bactericides or antibacterial agents, pH adjusters, tonicity agents, fragrances or refreshing agents, chelating agents, and buffering agents can be mentioned.
- polysaccharides or derivatives thereof for example, polysaccharides or derivatives thereof (gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac 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), ceramide, cellulose derivative (Methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl Cellu
- surfactant examples include 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 (polysorbate 20), POE (20) sorbitan (polysorbate 80) monooleate, polysorbate 60, POE (60) hydrogenated castor oil, etc.
- POE polyoxyethylene
- POP polyoxypropylene
- POE hydrogenated castor oil POE alkyl ethers such as POE (9) lauryl ether, POE / POP alkyl ethers such as POE (20) POP (4) cetyl ether,
- Nonionic surfactants such as POE alkylphenyl ethers such as OE (10) nonylphenyl ether, POE alkylphenyl ethers such as POE (10) nonylphenyl ether; glycine types such as alkyldiaminoethylglycine, lauryldimethylamino Amphoteric surfactants such as betaine acetate and imidazoline types such as betaine acetate; POE alkyl ether phosphates such as POE (10) sodium lauryl ether phosphate and salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyls Ether carboxylates, N-acyl taurine salts such as N-cocoy
- antiseptic, bactericidal agent or antibacterial agent examples include sorbic acid or a salt thereof (sorbic acid, potassium sorbate, sodium sorbate, triclocarban sorbate), paraoxybenzoic acid ester (methyl paraoxybenzoate, parahydroxybenzoic acid).
- pH adjusters include inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (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, Calcium hydroxide, magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), borax, and pharmacologically acceptable salts thereof. .
- inorganic acids hydroochloric acid, sulfuric acid,
- the isotonic agent examples include inorganic salts (for example, sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, Sodium thiosulfate, sodium acetate, etc.), polyhydric alcohols (eg, glycerin, propylene glycol, ethylene glycol, 1,3-butyleneglycol, etc.), saccharides (eg, butter sugar, mannitol, sorbitol, etc.), etc. .
- inorganic salts for example, sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, Sodium thiosulfate, sodium acetate, etc.
- polyhydric alcohols eg, glycerin, propylene glycol
- fragrance or the refreshing agent examples include terpenes (for example, menthol, camphor, borneol, geraniol, cineol, anethole, limonene, eugenol, etc. These may be any of d-form, l-form or dl-form).
- terpenes for example, menthol, camphor, borneol, geraniol, cineol, anethole, limonene, eugenol, etc. These may be any of d-form, l-form or dl-form).
- Eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, fennel oil, peppermint oil, cinnamon oil, rose oil, etc. may be any of d-form, l-form or dl-form.
- Eucalyptus oil for example, menthol, camphor, borneol, geraniol, cineol
- chelating agents include edetic acid, citric acid, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, etc. And pharmacologically acceptable salts thereof.
- the buffer examples include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartate and the like.
- 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.
- Examples thereof include carbonic acid or a salt thereof (sodium bicarbonate, sodium carbonate, etc.), citric acid or a salt thereof (sodium citrate, potassium citrate, etc.), and the like.
- the keratoconjunctiva protective agent and keratoconjunctive disorder inhibitor of the present invention can be appropriately manufactured by known methods, for example, eye drops, eye wash, contact lens mounting liquid, or contact lens preparation.
- glucosylglycerol and optional ingredients are mixed in a suitable diluent such as distilled water or purified water, adjusted to the above osmotic pressure and pH, and then sterilized under high pressure steam sterilization or It can be manufactured by sterilizing by filtration and aseptically filling a container that has been cleaned and sterilized.
- ⁇ -glucosylglycerol and an optional component can be mixed in a commonly used eye ointment base and can be prepared aseptically according to a conventional method.
- the keratoconjunctival protective agent and the keratoconjunctival disorder inhibitor of the present invention are intrinsic diseases such as Sjogren's syndrome, Stevens-Johnson syndrome, dry eye syndrome (dry eye), postoperative, pharmaceutical, trauma, contact lens wearing, etc. It can be applied for the purpose of prevention of keratoconjunctival disorder, reduction of keratoconjunctival disorder, reduction / stop of progression of keratoconjunctival disorder, and promotion of healing of keratoconjunctival disorder caused by requirements such as exogenous diseases .
- the application method of the keratoconjunctiva protective agent and the keratoconjunctival disorder inhibitor of the present invention is not particularly limited, and can be applied on a daily basis. You can apply in.
- the application amount may be appropriately adjusted according to the symptoms and the like, usually instilling 1 to 6 times per day, and applying 1 to 3 drops at a time.
- Comparative Example 1 According to the formulation shown in Table 1, a 3% glucosylglycerol solution (Example 1) and a 10% glucosylglycerol solution (Example 2) were prepared. As Comparative Example 1, a 0.1% sodium hyaluronate aqueous solution was used. The present glucosylglycerol is 65.2% glyceryl glucoside ( ⁇ -form 65%, ⁇ -form 35%), glyceryl maltoside 8.1%, glyceryl maltotrioside 0.7%, glycerin 6. It is a composition containing 0% and 20.0% of water (trade name: COSARTE-2G, manufactured by Toyo Sugar Co., Ltd.).
- ⁇ Test method> Six female New Zealand white rabbits with no abnormal eyes were given general anesthesia with urethane, and both eyes were forcibly opened with eyelids. The rabbits were divided into 3 groups of 2 animals, and each rabbit was administered 50 ⁇ l of saline solution to the left eye 4 hours after opening, and the eyes of Examples 1-2 and Comparative Example 1 were administered to the right eye. 50 ⁇ l of each solution was instilled. Thereafter, the eye was further opened for 3 hours, and after 7 hours from the start of the test (opening), a 2% methylene blue solution was instilled to stain the corneal epithelial lesion site caused by forced opening, and the eye was washed with physiological saline.
- the cornea was excised, extracted with 2 ml of an extract (acetone / saturated aqueous sodium sulfate solution 7/3, vol / vol) overnight, and the absorbance at a wavelength of 660 nm was measured the next day.
- the physiological saline solution was treated in the same manner. The average absorbance of each group is shown in FIG. In addition, the physiological saline is an average value of 6 animals.
- FIG. 1 shows the absorbance at a wavelength of 660 nm, and the higher the value, the higher the degree of corneal injury.
- the eye drops of Examples 1 and 2 can greatly reduce corneal damage as compared with the eye drop of Comparative Example 1.
- corneal damage can be reduced as compared with physiological saline, and the eye drop of Example 2 has an effect of reducing corneal damage compared to the eye drop of Example 1, so that the concentration of glucosylglycerol increases. It turned out that a higher effect is acquired as it is.
- the keratoconjunctiva protective agent and the keratoconjunctival disorder inhibitor of the present invention have an excellent keratoconjunctival reduction effect
- the keratoconjunctiva protectant and horn for protecting the keratoconjunctiva by suppressing the keratoconjunctival disorder caused by drying and the like It is useful as a conjunctival disorder inhibitor.
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Abstract
Description
(1)グルコシルグリセロールを有効成分として含有する、角結膜保護剤または角結膜障害抑制剤。
(2)シェーグレン症候群、スティーブンス・ジョンソン症候群又は眼球乾燥症候群(ドライアイ)の内因性疾患、或いは、術後、薬剤性、外傷又はコンタクトレンズ装用による外因性疾患に対する角結膜保護または該疾患による角結膜障害の抑制のために使用される、上記(1)に記載の角結膜保護剤または角結膜障害抑制剤。
(3)角結膜保護または角結膜障害抑制のための医薬を製造するためのグルコシルグリセロールの使用。
(4)前記角結膜保護または前記角結膜障害抑制が、シェーグレン症候群、スティーブンス・ジョンソン症候群又は眼球乾燥症候群(ドライアイ)の内因性疾患、或いは、術後、薬剤性、外傷又はコンタクトレンズ装用による外因性疾患に対する角結膜保護または該疾患による角結膜障害の抑制である、上記(3)に記載の使用。
(5)グルコシルグリセロールを投与することを含む、角結膜を保護するまたは角結膜障害を抑制する方法。
(6)シェーグレン症候群、スティーブンス・ジョンソン症候群又は眼球乾燥症候群(ドライアイ)の内因性疾患、或いは、術後、薬剤性、外傷又はコンタクトレンズ装用による外因性疾患に対して角結膜を保護するまたは該疾患による角結膜障害を抑制する、上記(5)に記載の方法。
本発明において、「角結膜保護」とは、種々の要因によって生じうる角結膜障害から、角結膜組織を保護することをいう。具体的には、「角結膜保護」は、外的要因による角結膜障害からの保護と、内的要因による角結膜障害からの保護とに大別することができる。外的要因としては、例えば、外傷、熱傷、化学物質、薬剤、紫外線、コンタクトレンズ装用、異物、睫毛、外気乾燥、感染などが挙げられる。また、角膜屈折矯正手術、白内障手術のような角膜への外科的侵襲によるものも外的要因に包含される。一方、内的要因としては、シェーグレン症候群、眼球乾燥症候群(ドライアイ)、糖尿病性角膜症などが挙げられる。
表1に示す処方に従い、3%グルコシルグリセロール溶液(実施例1)、10%グルコシルグリセロール溶液(実施例2)を調製した。また、比較例1として0.1%ヒアルロン酸ナトリウム水溶液を用いた。なお、本グルコシルグリセロールは、グリセリルグルコシド(α-体65%、β-体35%)を65.2%、グリセリルマルトシドを8.1%、グリセリルマルトトリオシドを0.7%、グリセリン6.0%、水分20.0%を含有する組成物である(商品名;COSARTE-2G、東洋製糖株式会社製)。
眼に異常のないニュージーランドホワイト種ウサギ雌6匹に、ウレタンによる全身麻酔を施し、両眼に開瞼器を装着して強制的に開瞼させた。前記ウサギを2匹ずつ3群に分け、各々のウサギに、開瞼4時間後に左眼には生理食塩液を対象として50μl点眼投与し、右目には実施例1~2、比較例1の点眼液をそれぞれ50μlずつ点眼投与した。その後さらに3時間開瞼させ、試験(開瞼)開始から7時間後に2%メチレンブルー溶液を点眼して、強制開瞼により生じた角膜上皮障害部位を染色し、生理食塩液で洗眼した。麻酔致死後、角膜を切除し、抽出液(アセトン/飽和硫酸ナトリウム水溶液 7/3,vol/vol)2mlにて一晩抽出し、翌日、波長660nmにおける吸光度を測定した。生理食塩液についても、同様に処理した。各群の吸光度の平均値を図1に示す。尚、生理食塩液は6匹の平均値である。
Claims (6)
- グルコシルグリセロールを有効成分として含有する、角結膜保護剤または角結膜障害抑制剤。
- シェーグレン症候群、スティーブンス・ジョンソン症候群又は眼球乾燥症候群(ドライアイ)の内因性疾患、或いは、術後、薬剤性、外傷又はコンタクトレンズ装用による外因性疾患に対する角結膜保護または該疾患による角結膜障害の抑制のために使用される、請求項1に記載の角膜保護剤または角結膜障害抑制剤。
- 角結膜保護または角結膜障害抑制のための医薬を製造するためのグルコシルグリセロールの使用。
- 前記角結膜保護または前記角結膜障害抑制が、シェーグレン症候群、スティーブンス・ジョンソン症候群又は眼球乾燥症候群(ドライアイ)の内因性疾患、或いは、術後、薬剤性、外傷又はコンタクトレンズ装用による外因性疾患に対する角結膜保護または該疾患による角結膜障害の抑制である、請求項3に記載の使用。
- グルコシルグリセロールを投与することを含む、角結膜を保護するまたは角結膜障害を抑制する方法。
- シェーグレン症候群、スティーブンス・ジョンソン症候群又は眼球乾燥症候群(ドライアイ)の内因性疾患、或いは、術後、薬剤性、外傷又はコンタクトレンズ装用による外因性疾患に対して角結膜を保護するまたは該疾患による角結膜障害を抑制する、請求項5に記載の方法。
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
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NZ625350A NZ625350B2 (en) | 2011-11-24 | 2012-11-22 | Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder |
RU2014125426A RU2630581C2 (ru) | 2011-11-24 | 2012-11-22 | Защитное средство для роговицы и конъюнктивы или супрессивное средство при кератоконъюнктивальном нарушении |
EP12851333.0A EP2783689B1 (en) | 2011-11-24 | 2012-11-22 | Keratoconjunctival protecting agent, or keratoconjunctival disorder inhibiting agent |
MX2014006285A MX2014006285A (es) | 2011-11-24 | 2012-11-22 | Agente protector para queratoconjuntiva o agente supresor para el trastorno queratoconjuntival. |
BR112014012463A BR112014012463A2 (pt) | 2011-11-24 | 2012-11-22 | agente protetor para ceratoconjuntiva ou agente supressor para distúrbio ceratoconjuntival |
US14/360,070 US20140315836A1 (en) | 2011-11-24 | 2012-11-22 | Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder |
KR1020147016706A KR102107471B1 (ko) | 2011-11-24 | 2012-11-22 | 각결막 보호제 또는 각결막 장해 억제제 |
AU2012341425A AU2012341425B2 (en) | 2011-11-24 | 2012-11-22 | Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder |
ES12851333T ES2751248T3 (es) | 2011-11-24 | 2012-11-22 | Agente protector queratoconjuntival o agente inhibidor de trastornos queratoconjuntivales |
CN201280068002.3A CN104144690B (zh) | 2011-11-24 | 2012-11-22 | 角结膜保护剂或角结膜障碍抑制剂 |
CA2856680A CA2856680C (en) | 2011-11-24 | 2012-11-22 | Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder |
DK12851333.0T DK2783689T3 (da) | 2011-11-24 | 2012-11-22 | Keratoconjunctivitis-beskyttelsesmiddel eller keratoconjunctivitis-lidelse-hæmmende middel |
JP2013545975A JP5960720B2 (ja) | 2011-11-24 | 2012-11-22 | 角結膜保護剤または角結膜障害抑制剤 |
PH12014501140A PH12014501140B1 (en) | 2011-11-24 | 2014-05-21 | Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder |
HK15104144.0A HK1203405A1 (en) | 2011-11-24 | 2015-04-29 | Keratoconjunctival protecting agent, or keratoconjunctival disorder inhibiting agent |
US15/254,655 US12005070B2 (en) | 2011-11-24 | 2016-09-01 | Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder |
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JP2011-256516 | 2011-11-24 | ||
JP2011256516 | 2011-11-24 |
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US14/360,070 A-371-Of-International US20140315836A1 (en) | 2011-11-24 | 2012-11-22 | Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder |
US15/254,655 Division US12005070B2 (en) | 2011-11-24 | 2016-09-01 | Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder |
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WO2013077433A1 true WO2013077433A1 (ja) | 2013-05-30 |
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US (1) | US20140315836A1 (ja) |
EP (1) | EP2783689B1 (ja) |
JP (1) | JP5960720B2 (ja) |
KR (1) | KR102107471B1 (ja) |
CN (2) | CN107550920A (ja) |
AU (1) | AU2012341425B2 (ja) |
BR (1) | BR112014012463A2 (ja) |
CA (1) | CA2856680C (ja) |
DK (1) | DK2783689T3 (ja) |
ES (1) | ES2751248T3 (ja) |
HK (1) | HK1203405A1 (ja) |
MX (1) | MX2014006285A (ja) |
MY (1) | MY172807A (ja) |
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RU2669768C1 (ru) * | 2017-12-26 | 2018-10-16 | Илья Александрович Марков | Гелеобразные капли для лечения воспалительных заболеваний глаз, включая инфекционные, устойчивые к антибиотикам |
JP2020509092A (ja) * | 2017-03-05 | 2020-03-26 | レスデブコ リサーチ アンド ディベロップメント カンパニー リミテッド | 感染によるものではない刺激の治療のための点眼剤 |
RU2766298C2 (ru) * | 2021-11-29 | 2022-03-14 | Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр радиологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ радиологии" Минздрава России) | Способ лечения ожогов роговицы |
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ES2939641T3 (es) * | 2016-02-17 | 2023-04-25 | Seed Co Ltd | Solvente anti-Acanthamoeba para lentes de contacto |
EP3266446B1 (en) * | 2016-07-07 | 2018-11-21 | Laboratorios SALVAT, S.A. | Ophthalmic composition comprising castor oil and medium chain triglyceride |
KR101911377B1 (ko) * | 2016-12-01 | 2018-10-25 | 주식회사 진켐 | 항염 조성물 |
CN112807275B (zh) * | 2019-11-15 | 2022-05-20 | 湖北远大天天明制药有限公司 | 一种眼用组合物及其制备方法与应用 |
RU2736082C1 (ru) * | 2019-12-02 | 2020-11-11 | федеральное государственное бюджетное образовательное учреждение высшего образования "Волгоградский государственный медицинский университет" Министерства здравоохранения Российской Федерации | Фармацевтическая композиция противоаллергического и противовоспалительного действия для интраназального применения |
EP4302767A1 (en) * | 2022-07-04 | 2024-01-10 | Skeye Pharma GmbH | Ophthalmic composition comprising eriocitrin |
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- 2012-11-22 DK DK12851333.0T patent/DK2783689T3/da active
- 2012-11-22 CN CN201710806698.XA patent/CN107550920A/zh active Pending
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RU2766298C2 (ru) * | 2021-11-29 | 2022-03-14 | Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр радиологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ радиологии" Минздрава России) | Способ лечения ожогов роговицы |
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Publication number | Publication date |
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DK2783689T3 (da) | 2019-12-16 |
KR102107471B1 (ko) | 2020-05-07 |
PH12014501140A1 (en) | 2014-07-28 |
EP2783689A4 (en) | 2015-06-24 |
CN104144690A (zh) | 2014-11-12 |
BR112014012463A2 (pt) | 2017-06-06 |
AU2012341425A1 (en) | 2014-06-12 |
EP2783689A1 (en) | 2014-10-01 |
JP5960720B2 (ja) | 2016-08-02 |
RU2014125426A (ru) | 2015-12-27 |
RU2630581C2 (ru) | 2017-09-11 |
PH12014501140B1 (en) | 2014-07-28 |
CN104144690B (zh) | 2017-12-29 |
MY172807A (en) | 2019-12-12 |
CA2856680C (en) | 2020-07-14 |
MX2014006285A (es) | 2014-10-24 |
US20160367584A1 (en) | 2016-12-22 |
HK1203405A1 (en) | 2015-10-30 |
KR20140102701A (ko) | 2014-08-22 |
AU2012341425B2 (en) | 2017-03-02 |
JPWO2013077433A1 (ja) | 2015-04-27 |
ES2751248T3 (es) | 2020-03-30 |
NZ625350A (en) | 2016-02-26 |
CN107550920A (zh) | 2018-01-09 |
EP2783689B1 (en) | 2019-09-25 |
US20140315836A1 (en) | 2014-10-23 |
CA2856680A1 (en) | 2013-05-30 |
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