JP4969052B2 - Ophthalmic composition - Google Patents

Description

  The present invention relates to a cornea protective agent and an ophthalmic composition.

  Corneal cells, which are mucosal tissues, are originally protected by a tear film. However, when the dry eye condition is caused by a change in the amount or quality of tears, this protective effect is reduced, and the cornea is easily damaged by external stimulation. For example, when a physical stimulus such as rubbing eyes at the onset of allergy is applied, the cornea cells are damaged by this stimulus. In addition, the cornea of a contact lens wearer is likely to be damaged by physical stimulation due to lens attachment / detachment. In addition, wearing a contact lens tends to cause corneal cells to become deficient in oxygen and inhibits cell metabolism, so that when they are injured, their healing slows down. Especially in the case of soft contact lenses, the sensitivity to stimulation becomes dull once worn, so wearing continues without realizing that corneal cells are damaged, corneal epithelial injury progresses, corneal infiltration, corneal ulcer It may become serious.

  Repairing damaged corneal epithelial cells is the most important step in dealing with such serious diseases. Conventional methods of dealing with corneal epithelial injury include, for example, passive methods such as the use of artificial eye drops that prevent infection and drying and waiting for natural healing, or eye drops that contain sodium hyaluronate or fibronectin. Examples thereof include a method for promoting injury healing (see, for example, Patent Documents 1 and 2).

However, conventional eye drops are not sufficient in the healing effect of corneal epithelial injury, and there are further problems in terms of stability, antigenicity, raw material costs and the like. Therefore, there is a demand for an inexpensive corneal protective agent that has a high repair effect on corneal epithelial injury.
JP-A-1-238530 JP-A-5-310592

  A main object of the present invention is to provide a corneal protective agent which is inexpensive and has a high repair effect on corneal injury, and an ophthalmic composition containing the same.

  The present inventors have found that hydroxypropylmethylcellulose (hereinafter sometimes abbreviated as HPMC), in particular HPMC having a specific amount of methoxyl group and hydroxypropoxyl group, has a corneal epithelial cell proliferation and repair action. Conventionally, HPMC has been frequently used in ophthalmic drugs as a thickening agent, but it is not known that HPMC itself has a corneal epithelial cell proliferation effect and a repair effect. Furthermore, the present inventors have found that this corneal epithelial cell proliferation action is enhanced by the combined use with chondroitin sulfate or a salt thereof. The present invention has been completed as a result of further research based on the above findings.

The present invention provides the following corneal protective agent and ophthalmic composition.
Item 1. A corneal protective agent comprising hydroxypropylmethylcellulose as an active ingredient.
Item 2. The corneal protective agent according to claim 1, wherein the hydroxypropylmethylcellulose contains 19 to 24% of methoxyl groups and 1 to 12% of hydroxypropoxyl groups.
Item 3. Item 3. The cornea protective agent according to Item 1 or 2, further comprising chondroitin sulfate or a salt thereof.
Item 4. Item 4. The cornea protective agent according to Item 3, wherein the chondroitin sulfate salt is sodium chondroitin sulfate.
Item 5. Item 5. An ophthalmic composition containing the corneal protective agent according to any one of Items 1 to 4.
Item 6. An ophthalmic composition comprising hydroxypropyl methylcellulose containing 19 to 24% methoxyl group and 1 to 12% hydroxypropoxyl group and chondroitin sulfate or a salt thereof.
Item 7. Item 7. The ophthalmic composition according to Item 6, wherein the chondroitin sulfate salt is sodium chondroitin sulfate.

Hereinafter, the cornea protecting agent and the ophthalmic composition of the present invention will be described in detail.
(1) Corneal Protective Agent Hydroxypropylmethylcellulose (HPMC) used as an active ingredient in the corneal protective agent of the present invention has the following structure.

(In the formula, —OR ₁ to —OR ₆ are the same or different and represent a hydroxyl group, a methoxyl group or a hydroxypropoxyl group. However, at least one of n —OR ₁ to —OR ₆ is A methoxyl group and one is a hydroxypropoxyl group.)
As HPMC used in the present invention, for example, those synthesized by methylating or hydroxypropylating cellulose according to a conventionally known chemical synthesis method can be used. Moreover, you may use what was obtained commercially. Commercially available products include, for example, HPMC 2910, HPMC 2906, and HPMC 2208 (Metros 60SH, Metros 65SH, Metros 90SH, TC-5, etc., manufactured by Shin-Etsu Chemical Co., Ltd.); Methocel E, Methocel F, Methocel K, etc.); Marporose (Matsumoto Yushi Seiyaku Co., Ltd. Marporose 60MP, Marporose 65MP, Marporose 90MP, etc.) can be used. Of these HPMCs, HPMC 2208 is preferably used in the present invention.

  The HPMC used in the present invention contains about 15 to 32%, preferably about 15 to 30%, more preferably about 19 to 24% of methoxyl groups, and about 1 to 15% of hydroxypropoxyl groups, preferably 1 About 14%, more preferably about 1-12% is included.

  HPMC 2910 contains about 28-30% of methoxyl groups and about 7-12% of hydroxypropoxyl groups.

  HPMC 2906 contains about 27 to 30% of methoxyl groups and about 4 to 7.5% of hydroxypropoxyl groups.

  HPMC 2208 contains about 19 to 24% of methoxyl groups and about 4 to 12% of hydroxypropoxyl groups.

  Here, the methoxyl group and the hydroxypropoxyl group contained in HPMC are expressed in percentage as a ratio of molecular weight, and are obtained as follows.

  The molecular weight excluding the three hydroxyl groups per glucose ring unit of cellulose is about 111, the molecular weight of the methoxyl group is about 31, the molecular weight of the hydroxypropoxyl group is about 75, and the molecular weight of the hydroxyl group is about 17. When the average number of hydroxyl groups substituted with methoxyl groups is x and the average number of hydroxyl groups substituted with hydroxypropoxyl groups is y per glucose ring unit of cellulose, the apparent molecular weight per glucose ring unit is 111 + 31 × x + 75 × y + 17 × (3-xy). Therefore, the methoxyl group content can be determined from 31 × x / (111 + 31 × x + 75 × y + 17 × (3-xy)) × 100 (%). Similarly, a hydroxypropoxyl group content is calculated | required from 75 * y / (111 + 31 * x + 75 * y + 17 * (3-xy)) * 100 (%).

  The range of the average molecular weight of HPMC used in the present invention is about 1 to 1 million, preferably about 7 to 1 million, more preferably about 100 to 300,000.

  Such HPMC itself has a corneal epithelial cell proliferating action and can be used alone for the purpose of protecting the cornea. In particular, HPMC 2208 has a remarkable effect. Two or more of the above HPMCs may be used in combination.

  In the present invention, a higher corneal protective effect can be obtained by using these HPMCs together with chondroitin sulfate or salts thereof.

  Examples of chondroitin sulfate or salts thereof used in the present invention include chondroitin sulfate and organic acid salts of chondroitin sulfate; alkali metal salts; alkaline earth metal salts and the like. For example, sodium chondroitin sulfate can be used. . Sodium chondroitin sulfate can be obtained commercially, for example, for injection of sodium chondroitin sulfate “Biochemical” manufactured by Seikagaku Corporation. In the present invention, chondroitin sulfate salts may be used alone or in combination of two or more.

  The corneal protective agent of the present invention further includes preservatives, antioxidants, buffers, isotonic agents, chelating agents, stabilizers, surfactants, pH adjusters commonly used in the field of ophthalmic drugs. Various components such as fragrances may be optionally contained. Specific examples of these components will be described in detail in (2) below. Moreover, the compounding quantity of these components should just follow the quantity normally used in the said field | area, unless the effect of this invention is impaired.

  When the corneal protective agent of the present invention uses HPMC alone as an active ingredient, for example, HPMC is about 0.01 to 18% by weight, preferably 0.02 to 17% by weight with respect to 100% by weight of the corneal protective agent. The content is preferably about 0.05 to 15% by weight. According to this blending ratio, the corneal protective agent of the present invention can be prepared by dissolving HPMC in sterilized purified water or the like as necessary.

  Further, when HPMC and chondroitin sulfate or salts thereof are used in combination, HPMC is about 0.01 to 18% by weight, preferably about 0.02 to 17% by weight with respect to 100% by weight of the corneal protective agent of the present invention. More preferably, about 0.05 to 15% by weight; chondroitin sulfate or a salt thereof is about 0.005 to 5% by weight, preferably about 0.005 to 3% by weight, more preferably about 0.01 to 3% by weight. contains.

  The blending ratio (weight ratio) of HPMC and chondroitin sulfate or salts thereof is about 1/800 to 500, preferably about 1/620 to 150, more preferably 1/220 to chondroitin sulfate or salts thereof with respect to HPMC1. About 20.

  According to the above blending ratio, the corneal protective agent of the present invention can be prepared by mixing HPMC and chondroitin sulfate or salts thereof, or by dissolving both components in sterilized purified water or the like as necessary.

  In the present invention, corneal protection refers to treating corneal tissue so as to suppress the progression of corneal injury caused by various factors and prevent the occurrence of corneal injury. The corneal protective agent of the present invention can suppress the progression of corneal injury, preferably cure, by exerting a corneal epithelial cell proliferation action or a corneal repair action. Moreover, it has the effect | action which prevents generation | occurrence | production of a corneal injury in advance.

  Examples of corneal injury include physical stimuli such as dryness (dry eyes, etc.), foreign matter (contact lenses, etc.), rubbing eyes, UV exposure, etc .; chemical factors such as drug cytotoxicity, acid / alkali corrosion, etc .; Examples include corneal epithelial detachment, corneal erosion, corneal infiltration, corneal ulcer and the like caused by bacteria, fungi, viruses, Acanthamoeba infection, and the like.

  Corneal ulcers and the like due to bacterial infections can be prevented by promoting the repair of corneal damage because bacteria enter and develop due to the injury of the cornea. Furthermore, the proliferation of corneal epithelial cells can prevent damage to Bowman's membrane, corneal intrinsic material, Descemet's membrane, and corneal endothelium located under the corneal epithelium.

  The cornea protecting agent of the present invention can be used in combination with other conventionally known active ingredients.

  Examples of other active ingredients that can be used in combination include decongestants such as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride; Neostigmine, ε-aminocaproic acid, allantoin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, sodium azulene sulfonate, sodium cromoglycate Anti-inflammatory and astringent agents such as: iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipentyl hydrochloride, chlorfeni maleate Antihistamines such as min; water-soluble vitamins such as flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate; vitamins A (for example, retinol acetate, retinol palmitate), vitamin E ( Fat-soluble vitamins such as tocopherol acetate (eg, d-α-tocopherol acetate); amino acids such as potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate; sulfamethoxazole, Sulpha drugs such as sulfamethoxazole sodium, sulfisoxazole, sodium sulfisomidine, isopropylmethylphenol, hinokitiol; potassium chloride, calcium chloride, salt Sodium, sodium bicarbonate, sodium carbonate, dried sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and inorganic salts such as potassium dihydrogen phosphate and the like.

  One of these active ingredients may be used alone or in combination with the corneal protective agent of the present invention, or two or more thereof may be used in combination.

(2) Ophthalmic Composition The present invention further provides an ophthalmic composition containing the above corneal protective agent. The ophthalmic composition can be instilled even when wearing an aqueous eye drop, non-aqueous eye drop, suspension eye drop, emulsion eye drop, soft contact lens, hard contact lens, etc. containing the corneal protective agent It can be prepared as eye drops such as eye drops; eye ointments; eye washes; contact lens preparations such as contact lens mounting liquids, cleaning liquids, storage liquids, and bactericidal liquids.

  When the eye drop containing the corneal protective agent of the present invention is prepared, when HPMC is used alone as an active ingredient, the blending ratio of HPMC is 0.01 to 18% by weight, preferably 0 with respect to 100% by weight of the eye drop. 0.02 to 17% by weight, more preferably 0.05 to 15% by weight.

  Moreover, when HPMC and chondroitin sulfate or a salt thereof are used in combination as an active ingredient, the blending ratio of HPMC is 0.01 to 18% by weight, preferably 0.02 to 17% by weight, with respect to 100% by weight of eye drops. More preferably 0.05 to 15% by weight, and the compounding ratio of chondroitin sulfate or its salt is 0.05 to 5% by weight, preferably 0.05 to 3% by weight, more preferably 0.1 to 1% by weight. It is. The blending ratio (weight ratio) of HPMC and chondroitin sulfate or a salt thereof in the eye drop of the present invention is about 1/360 to 500, preferably about 1/340 to 150, with respect to HPMC1. Preferably it is about 1 / 150-20, More preferably, it is about 1 / 140-20.

    The dosage of the eye drops is appropriately selected depending on the health condition of the person to be administered, the degree of symptoms, etc. For example, about 50 μl per drop may be instilled by about 1 to 3 drops. This administration can be repeated about 3 to 6 times per day, whereby a corneal epithelial cell proliferation / repair effect can be obtained.

  When preparing an eye ointment containing the corneal protective agent of the present invention, when HPMC is used alone as an active ingredient, the blending ratio of HPMC is 0.01 to 18% by weight with respect to 100% by weight of the eye ointment, Preferably it is 0.02 to 17 weight%, More preferably, it is 0.05 to 15 weight%.

  Further, when HPMC and chondroitin sulfate or salts thereof are used in combination as an active ingredient, the blending ratio of HPMC is 0.01 to 18% by weight, preferably 0.02 to 17% by weight with respect to 100% by weight of the eye ointment. %, More preferably 0.05 to 15% by weight, and the mixing ratio of chondroitin sulfate or a salt thereof is 0.05 to 5% by weight, preferably 0.05 to 3% by weight, more preferably 0.1 to 1% by weight. %. The blending ratio (weight ratio) of HPMC and chondroitin sulfate or a salt thereof in the eye ointment of the present invention is about 1/360 to 500, preferably about 1/340 to 150, with respect to HPMC1. Preferably it is about 1 / 150-20.

  When preparing the eyewash containing the corneal protective agent of the present invention, when HPMC is used alone as an active ingredient, the blending ratio of HPMC is 0.01 to 4% by weight, preferably 100% by weight of the eyewash. It is 0.02 to 3.1% by weight, more preferably 0.05 to 2.2% by weight.

  Further, when HPMC and chondroitin sulfate or salts thereof are used in combination as an active ingredient, the blending ratio of HPMC is 0.01 to 4% by weight, preferably 0.02 to 3.1% with respect to 100% by weight of the eye wash. % By weight, more preferably 0.05 to 2.2% by weight, and the blending ratio of chondroitin sulfate or salts thereof is 0.005 to 0.1% by weight, preferably 0.005 to 0.05% by weight, more preferably 0.01 to 0.05% by weight. The blending ratio (weight ratio) of HPMC and chondroitin sulfate or a salt thereof in the eyewash of the present invention is about 1/800 to 10, preferably about 1/620 to 3, more preferably 1 to chondroitin sulfate or a salt thereof with respect to HPMC1. Is about 1 / 220-1.

  When preparing the contact lens mounting liquid containing the corneal protective agent of the present invention, when HPMC is used alone as an active ingredient, the blending ratio of HPMC is 0.1-4. It is 7% by weight, preferably 0.2 to 4.2% by weight, more preferably 0.25 to 4% by weight.

  Further, when HPMC and chondroitin sulfate or salts thereof are used in combination as an active ingredient, the blending ratio of HPMC is 0.1 to 4.7% by weight, preferably 0.2% with respect to 100% by weight of the contact lens mounting solution. To 4.2 wt%, more preferably 0.25 to 4 wt%, chondroitin sulfate or salts thereof, 0.05 to 5 wt%, preferably 0.05 to 3 wt%, more preferably 0.1 to 0.1 wt% 1% by weight. The blending ratio (weight ratio) of HPMC and chondroitin sulfate or a salt thereof in the contact lens mounting liquid of the present invention is about 1/94 to 50, preferably about 1/84 to 15, chondroitin sulfate or a salt thereof with respect to HPMC1. More preferably, it is about 1 / 40-4.

  When preparing as a contact lens cleaning liquid, when HPMC is used alone as an active ingredient, the blending ratio of HPMC is 0.01 to 3.1% by weight, preferably 0.02 to 3% with respect to 100% by weight of the contact lens cleaning liquid. % By weight, more preferably 0.05 to 2.2% by weight.

  Further, when HPMC and chondroitin sulfate or salts thereof are used in combination as an active ingredient, the blending ratio of HPMC is 0.01 to 3.1% by weight, preferably 0.02 to 100% by weight of the contact lens cleaning solution. 3 wt%, more preferably 0.05 to 2.2 wt%, chondroitin sulfate or salts thereof as 0.005 to 0.5 wt%, preferably 0.005 to 0.3 wt%, more preferably 0 0.01 to 0.1% by weight. The blending ratio (weight ratio) of HPMC and chondroitin sulfate or a salt thereof in the contact lens cleaning liquid of the present invention is about 1/620 to 50, preferably about 1/600 to 50, more than chondroitin sulfate or a salt thereof with respect to HPMC1. Preferably it is about 1 / 220-2.

  The ophthalmic composition of the present invention further includes various additive components commonly used in ordinary ophthalmic compositions, such as carriers, thickeners, surfactants, sugars, preservatives, isotonic agents, Inorganic salts, chelating agents, pH adjusters, buffers, fragrances, antioxidants, local anesthetics, and the like can be blended. Hereinafter, although the example of each additive is given, the various additives used in this invention are not limited to these.

  Examples of the carrier include aqueous solvents such as sterilized purified water and physiological saline; vegetable oils such as cottonseed oil, soybean oil, and peanut oil as non-aqueous solvents.

  As thickening agents, gum arabic, karaya gum, xanthan gum, casein, agar, alginic acid, α-cyclodextrin, dextrin, dextran, carrageenan, gelatin, collagen, pectin, starch, chitin and its derivatives, chitosan and its derivatives, elastin, Polysaccharides such as heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, methylcellulose, hydroxyethylcellulose or derivatives thereof, ceramide, macrogol, glycerin, popidone, polyvinyl methacrylate, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymer, polyethylene Imine and the like.

  As surfactant, higher fatty acid ester such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid ester such as polysorbate 80 and polyoxyethylene sorbine monooleate, sucrose fatty acid ester, polyoxyethylene polyoxypropylene block copolymer Nonionic surfactants such as glycine type such as alkyldiaminoethylglycine, amphoteric surfactants such as betaine acetate type such as lauryldimethylaminoacetic acid betaine, and imidazoline type; POE such as POE (10) sodium lauryl ether phosphate N-acyl amino acid salts such as alkyl ether phosphoric acid and its salts, sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl such as sodium N-cocoylmethyl taurate Anionic interfaces such as urine salts, sulfonates such as sodium tetradecene sulfonate, alkyl sulfates such as sodium lauryl sulfate, POE alkyl ether sulfates such as POE (3) sodium lauryl ether sulfate, α-olefin sulfonates Activating agents: Cationic surfactants such as alkylamine salts, alkyl quaternary ammonium salts (such as benzalkonium chloride and benzethonium chloride), and alkylpyridinium salts (such as cetylpyridinium chloride and cetylpyridinium bromide). The numbers in parentheses indicate the number of added moles.

  In particular, when the ophthalmic composition of the present invention is prepared as a cleaning solution for contact lenses, the cleaning solution has a cleaning action, and can efficiently emulsify and remove dispersion of proteins, lipids, polysaccharides and the like. Is preferably blended. Examples of such surfactants include polyoxyethylene (5) nonylphenyl ether, polyoxyethylene (10) nonylphenyl ether, polyoxyethylene (10) octylphenyl ether, and polyoxyethylene (15) octylphenyl ether. , Sodium lauryl sulfate, potassium lauryl sulfate, triethanolamine lauryl sulfate, ammonium lauryl sulfate, sodium cetyl sulfate, sodium stearyl sulfate, sodium myristyl sulfate, hydrogenated coconut oil fatty acid sodium glyceryl sulfate, polyoxyethylene (4) nonylphenyl ether sulfate triethanol Amine, polyoxyethylene (4) sodium nonylphenyl ether sulfate, polyoxyethylene (3) sodium alkyl ether sulfate, polyoxyethylene (3) Alkyl ether sulfate triethanolamine, polyoxyethylene (2) ammonium lauryl ether sulfate, polyoxyethylene (3) sodium lauryl ether sulfate, polyoxyethylene (4) sodium lauryl ether sulfate, polyoxyethylene (3) lauryl ether Triethanolamine sulfate, polyoxyethylene (3) sodium cetyl ether sulfate, glyceryl monostearate, decaglyceryl monomyristate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (60) hydrogenated castor oil, lauroyl sarcosine Examples include sodium, sodium N-cocoylmethyl taurate, sodium polyoxyethylene (6) alkyl ether acetate, and the like. These surfactants may be used alone or in combination of two or more in the contact lens cleaning solution of the present invention. The amount is usually about 0.1 to 20% by weight.

  Examples of sugars include glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol, and the like. Examples include acceptable salts.

  Preservatives include paraoxybenzoates (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), acrinol, methyl rosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, odor Cetylpyridinium chloride, chlorhexidine, polyhexamethylene biguanide, alkylpolyaminoethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, zirconium phosphate silver, zinc, zinc oxide and other supports, silver zinc aluminosilicate Salt, thimerosal, dehydroacetic acid, chlorxylenol, chlorophene, resorcin, thymol, hinokitiol, sulfamine, lysine Team, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid, propionic acid, sorbic acid, potassium sorbate, sodium sorbate, triclocarban sorbate, halocarban, thiabendazole, polylysine Examples thereof include hydrogen oxide and polydronium chloride.

  Examples of the tonicity agent include polyhydric alcohols such as glycerin and propylene glycol, and sugars (such as butter sugar, mannitol, and sorbitol).

  If necessary, it is desirable to adjust the ophthalmic composition of the invention to a physiologically acceptable range of osmotic pressure using the isotonic agent described above. The osmotic pressure is about 150 to 600 mOsm, preferably about 170 to 550 mOsm, more preferably about 200 to 430 mOsm. The osmotic pressure ratio with respect to physiological saline is usually about 0.55 to 2.2, preferably Is about 0.6 to 2.0, particularly preferably about 0.7 to 1.5.

  Examples of inorganic salts include 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 and the like. It is done.

  As chelating agents, edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), N- (2-hydroxyethyl) ) Iminodiacetic acid (HIDA), citric acid, tartaric acid, phosphoric acids (polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid), succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid or These salts are mentioned.

  As pH adjusters, 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, hydroxide) Calcium, magnesium hydroxide, etc.) and organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.).

Examples of the buffer include a borate buffer, a phosphate buffer, a carbonate buffer, a citrate buffer, an acetic acid buffer, etc. It is desirable to adjust the ophthalmic composition to a physiologically acceptable pH. The pH of the ophthalmic composition of the present invention is usually adjusted within the range of about 4 to 10, preferably about 4.5 to 9, particularly preferably about 5 to 8.

  Examples of the fragrance (cooling agent) include menthol, camphor, borneol, eucalyptus oil, peppermint oil, bergamot oil, geraniol and the like.

  Examples of the antioxidant include dibutylhydroxytoluene (BHT), tocopherol acetate, ascorbic acid phosphate magnesium salt, and the like.

  Examples of the local anesthetic include chlorobutanol.

  In addition, when the ophthalmic composition of the present invention is prepared as a cleaning solution for contact lenses, the cleaning solution may contain a proteolytic enzyme, a lipolytic enzyme, a polysaccharide-degrading enzyme, etc. in order to further increase the cleaning power. it can. These can also be added separately when using the cleaning liquid of the present invention.

  In addition to the above, conventionally known solubilizers, colorants and the like can be appropriately added to the ophthalmic composition of the present invention as necessary within the range not impairing the effects of the present invention.

  The ophthalmic composition of the present invention can be prepared according to a conventionally known method. Steps such as filtration / sterilization treatment and filling into containers can be added to the resulting composition as necessary.

  ADVANTAGE OF THE INVENTION According to this invention, the corneal protective agent which has the proliferation effect | action of the outstanding corneal epithelial cell can be provided by using HPMC or HPMC, chondroitin sulfate, or its salts as an active ingredient. Further, the corneal protective agent of the present invention can be widely applied to various ophthalmic compositions according to conventionally known methods. Furthermore, since HPMC and chondroitin sulfate or salts thereof can be obtained relatively inexpensively, it is possible to provide a corneal protective agent and an ophthalmic composition having an excellent corneal protective action at a low price.

  HPMC and chondroitin sulfate or salts thereof used as active ingredients in the present invention are highly safe because they are stable. Further, the corneal protective agent and the ophthalmic composition of the present invention are extremely low in irritation when instilled and not only have excellent moisturizing effect, but also have high sustainability for eliminating the dryness of the eyes. . In addition, when a contact lens is mounted, generally the lens tends to stick to the eyeball due to dry eyes, eye pain, eye fatigue, hyperemia, etc., but the corneal protective agent or ophthalmic composition of the present invention is soft. / Because it does not adversely affect the incorporation into hard contact lenses and their quality, there is an advantage that it can be instilled even with various contact lenses attached.

  Thus, the corneal protective agent or ophthalmic composition of the present invention can be used safely and comfortably for a long time because it has high safety and excellent usability.

  Hereinafter, the present invention will be specifically described with reference to formulation examples and test examples, but the present invention is not limited thereto.

  The formulation example of this invention is shown below. In addition, the numerical value in Tables 1-4 represents weight%. In Table 4, the mounting liquid or cleaning liquid is a contact lens mounting liquid or cleaning liquid.

Test example 1

  Using rabbit corneal epithelial cells, the corneal epithelial cell proliferation action of HPMC was confirmed. The culture conditions and measurement method are as follows.

Normal rabbit corneal epithelial cells (NRCE2: manufactured by Kurabo Industries) were seeded at 1 × 10 ⁵ cells / well on a 6-well culture plate. As a culture solution, a serum-free rabbit corneal epithelial cell growth medium (RCGM2: manufactured by Kurabo Industries Co., Ltd.) was used, and the culture was performed under conditions of 37 ° C. and 5% CO ₂ . After 24 hours, the culture broth was removed, and a serum-free rabbit corneal epithelial cell growth medium (control) to which only hydroxyethylcellulose was added or the same medium containing each component so as to have the concentrations shown in Table 5 below was added to each well. In addition, the cells were further cultured for 3 days.

  The viscosity of the medium is determined by the general test method described in the 14th revised Japanese Pharmacopoeia, 45. Viscosity measuring method, second method Rotational viscometer method (2) According to the method described in the section of a single cylindrical rotational viscometer, the viscosity was measured under the following conditions and adjusted with hydroxyethyl cellulose to be 30 mPa · s.

  Using a digital viscometer (model name: DV-II +, manufactured by Brookfield), which is a B-type viscometer, the spindle was measured for viscosity at 20 ° C. using ULA. The measurement condition is 3 rpm.

  After completion of the culture, the culture solution was removed, the cells were collected with a trypsin / EDTA solution (Kurabo), and the number of cells was measured with a hemocytometer after staining with trypan blue.

  FIG. 1 shows the result of comparing the number of cells in a medium containing each component, assuming that the number of cells measured in a medium (control) containing only HEC was 1.

  In Table 5 and Table 6 shown below, sodium hyaluronate is hyaluronic acid HA-AM manufactured by Kewpie Co., Ltd .; sodium chondroitin sulfate manufactured by Seikagaku Corporation is sodium chondroitin sulfate "Biochemical" for injection; HPMC is Metroise 90SH-4000 (medium 4, 8, 12, 16, 18), 90SH-100 (medium 5, 9), 60SH-4000 (medium 6, 10), 65SH-4000 (medium 7) manufactured by Shin-Etsu Chemical Co., Ltd. 11); Hydroxyethyl cellulose (indicated as HEC in the table) is HEC Daicel SE-900 manufactured by Daicel Chemical Industries, Ltd. The average molecular weights of HPMC are Metroze 90SH-4000: about 300,000, 90SH-100: about 100,000, Metroze 60SH-4000: about 300,000, and Metroze 65SH-4000: about 300,000, respectively.

Test example 2

    The proliferation effect of corneal epithelial cells was observed when HPMC alone or HPMC and chondroitin sulfate or salts thereof were added to the medium so as to have the concentrations shown in Table 6 below (1/5 concentration of Test Example 1). A serum-free rabbit corneal epithelial cell growth medium to which no components were added was used as a control (medium 13). The viscosity was measured according to the method of Test Example 1. However, the measurement condition is 60 rpm. Culture conditions and measurement methods are as described in Test Example 1.

  FIG. 2 shows the result of comparing the number of cells in the medium containing each component, with the number of cells measured by the control being 1.

It represents the proliferation effect of corneal epithelial cells when HPMC alone or HPMC and chondroitin sulfate or salts thereof are used in combination. It represents the proliferation effect of corneal epithelial cells by adding HPMC alone, or by adding HPMC and chondroitin sulfate or salts thereof when prepared to 1/5 concentration of Test Example 1.

Claims (10)

A corneal epithelial cell proliferating agent comprising hydroxypropylmethylcellulose as an active ingredient. The corneal epithelial cell proliferating agent according to claim 1, wherein the hydroxypropylmethylcellulose contains 19 to 24% methoxyl group and 4 to 12% hydroxypropoxyl group. The corneal epithelial cell proliferating agent according to claim 1 or 2, which contains 0.01 to 18% by weight of hydroxypropylmethylcellulose. The corneal epithelial cell proliferating agent according to any one of claims 1 to 3, further containing chondroitin sulfate or a salt thereof. The corneal epithelial cell proliferating agent according to claim 4, wherein the chondroitin sulfate salt is sodium chondroitin sulfate. The corneal epithelial cell proliferating agent according to claim 4 or 5, which contains 0.01 to 18% by weight of hydroxypropylmethylcellulose and 0.005 to 5% by weight of chondroitin sulfate or a salt thereof. An ophthalmic composition for corneal epithelial cell proliferation containing hydroxypropylmethylcellulose as an active ingredient for corneal epithelial cell proliferation. Hydroxypropylmethylcellulose, it is those containing 4-12% of 19-24% and hydroxypropoxyl groups methoxyl group, further containing chondroitin sulfate or a salt thereof, ophthalmic composition of claim 7. The ophthalmic composition according to claim 8 , wherein the chondroitin sulfate salt is sodium chondroitin sulfate. The ophthalmic composition according to claim 8 or 9 , comprising 0.01 to 18% by weight of hydroxypropylmethylcellulose and 0.005 to 5% by weight of chondroitin sulfate or a salt thereof.

Images