JP6611444B2 - Ophthalmic composition - Google Patents

Description

  The present invention relates to an ophthalmic composition.

  In recent years, there are an increasing number of people complaining of eye strain as lifestyle changes, and there are a wide range of countermeasures such as eye drops and internal medicines, products that give warmth and coolness, and massage machines around the eyes. The product is being developed.

  Causes of eye fatigue include reading, gazing, and observation due to overuse and mental tension in the eyes. In recent years, VDT (Visual Display Terminal) has increased rapidly with the spread of personal computers. ) Eye fatigue due to work is very high. Patients who complain of tired eyes generally have symptoms such as pain in the back of the eyes, stiff shoulders, and head weight. When the eyestrain is severe, nausea and nausea may occur. It has been pointed out that these symptoms are caused by the ciliary muscles becoming excessively tensioned due to long-term gaze work and the like, and the function of eye regulation being lowered.

  Blurred eyes are a phenomenon in which the focus function of the eye is lowered and the field of view is blurred. Visibility may be blurred due to blurry eyes caused by overuse of eyes, inflammation such as cataracts and conjunctivitis, presbyopia that occurs with aging.

  Conventional ophthalmic solutions for improving eye fatigue contain vitamins such as neostigmine methyl sulfate, vitamin B2, vitamin B6, and panthenol, with a focus on ingredients that can be added to general eye drops. Yes. Furthermore, eye drops for improving eye strain (Patent Document 1) containing taurine and menthol, eye drops for improving eye strain (Patent Document 2) consisting of taurine, menthol, neostigmine methyl sulfate, vitamin E acetate, and caffeine. Eye drops for eye strain formulated as an active ingredient (Patent Document 3) and the like are disclosed.

  Ophthalmic solutions for improving blurred vision contain ingredients that improve the focus control function, vitamins and amino acids, and the like.

JP-A-9-40549 JP-A-9-143064 JP 2000-247885 A

  However, a safer and more effective ophthalmic composition for improving fatigue eyes and / or blurring eyes, and an excellent method for improving fatigue eyes and / or blurring eyes are desired.

  An object of the present invention is to provide a new ophthalmic composition for improving fatigue eyes and / or blurring eyes.

  The inventors of the present invention have conducted research to develop an ophthalmic composition for improving fatigue eyes and / or blurring eyes having excellent effects. The inventors have found that the blur can be effectively improved and have completed the present invention.

  The present invention contains at least one selected from the group consisting of rebamipide, rebamipide salts, rebamipide derivatives, and salts thereof, and is contained in a multi-dose type container for improving fatigue eyes and / or blurred eyes. Ophthalmic compositions for being made.

  The ophthalmic composition may be a liquid agent.

  The ophthalmic composition may be an eye drop.

  The ophthalmic composition may contain at least one selected from the group consisting of rebamipide, rebamipide salts, rebamipide derivatives, and salts thereof in a ratio of 0.0001 to 10 (w / v)%.

  The ophthalmic composition may further contain a surfactant.

  The ophthalmic composition may further contain a buffer.

  The ophthalmic composition may further contain a solubilizing agent.

  The ophthalmic composition may further contain a preservative.

  INDUSTRIAL APPLICABILITY According to the present invention, an ophthalmic composition for improving fatigue eyes and / or blurring eyes corresponding to a multi-dose container while containing rebamipide, a salt of rebamipide, a rebamipide derivative, or a salt thereof is provided.

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

  In the present specification, the unit of content “w / w%” is synonymous with the weight% of “g / 100 g”.

  The ophthalmic composition of the present invention contains at least one selected from the group consisting of rebamipide, a salt of rebamipide, a rebamipide derivative, and salts thereof, and is used for improving fatigue eyes and / or blurring eyes. An ophthalmic composition to be contained in a dose-type container.

  The ophthalmic composition of the present specification is preferably an aqueous ophthalmic composition, and water is used in an amount of 1% by weight or more, preferably 5% by weight or more, more preferably 20% by weight or more, and still more preferably still. Contains 50% by weight or more, more preferably 70% by weight or more, and most preferably 90% by weight or more. The water contained in the ophthalmic composition of the present invention may be anything that is pharmaceutically, pharmacologically or physiologically acceptable. For example, distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like can be used. These definitions are based on the 16th revised Japanese Pharmacopoeia.

In the present specification, rebamipide is 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid (2- (4-Chlorobenzoylamino) -3- ( 2-oxo-1,2-dihydroquinolin-4-yl) propanoic acid)
Also referred to as a compound. Rebamipide may be synthesized by a known method or may be obtained as a commercial product.

  Examples of rebamipide derivatives include, but are not limited to, esterified derivatives, etherified derivatives, amidated derivatives, sulfonated derivatives, nitrated derivatives, nitrosated derivatives, halogenated derivatives, and the like of rebamipide. Preferably, the derivative is an esterified derivative and / or an etherified derivative, more preferably an esterified derivative.

  The salt of rebamipide or rebamipide derivative used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable, and specific examples thereof include organic acid salts and inorganic acids. A salt, an organic base, or an inorganic base is mentioned. Examples of organic acid salts include monocarboxylic acid salts such as acetate, trifluoroacetate, butyrate, palmitate, and stearate; fumarate, maleate, succinate, malonate, and the like. Examples thereof include polyvalent carboxylates; oxycarboxylates such as lactate, tartrate and citrate; and organic sulfonates such as methanesulfonate, toluenesulfonate and tosylate. Examples of the inorganic acid salt include hydrochloride, sulfate, nitrate, hydrobromide, and phosphate. Examples of the salt with an organic base include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, and ethylenediamine. Examples of the salt with an inorganic base include various salts such as an ammonium salt; an alkali metal such as sodium or potassium; an alkaline earth metal such as calcium or magnesium; and a salt with a metal such as aluminum. These rebamipide salts or rebamipide derivative salts may be used alone or in any combination of two or more. “Pharmaceutically or physiologically acceptable salt” may include solvates or hydrates of salts.

  In the ophthalmic composition of the present invention, one kind of rebamipide, rebamipide salt, rebamipide derivatives, or salts thereof may be used alone, or two or more kinds may be arbitrarily combined. May be used. Among these, rebamipide is preferably used from the viewpoint of more prominently achieving the effects of the present invention.

  In the ophthalmic composition of the present invention, the total content of rebamipide, a salt of rebamipide, a rebamipide derivative, or a salt thereof relative to the total amount of the ophthalmic composition is the type of other compounding components and their content, or an aqueous composition. It is set appropriately according to the formulation form. The total content of rebamipide, rebamipide salt, rebamipide derivatives, or salts thereof is not limited with respect to the total amount of the ophthalmic composition, but is preferably 0.0001 w / v% or more, more preferably 0. 0.001 w / v% or more, more preferably 0.01 w / v% or more, and particularly preferably 0.05 w / v% or more. The total content of rebamipide, a rebamipide salt, a rebamipide derivative, or a salt thereof with respect to the total amount of the ophthalmic composition is not limited, but is preferably 10 w / v% or less, more preferably 5 w / v. % Or less, more preferably 3 w / v% or less, particularly preferably 2 w / v% or less. The total content of rebamipide, rebamipide salts, rebamipide derivatives, or salts thereof with respect to the total amount of the ophthalmic composition is not limited, but is preferably 0.0001 w / v% to 10 w / v%, more preferably Is 0.001 w / v% to 5 w / v%, more preferably 0.01 w / v% to 3 w / v%, particularly preferably 0.05 w / v% to 2 w / v%.

  The ophthalmic composition of the present invention is preferably in a solubilized state, precipitation of components and the like is suppressed, and even when stored for a long period of time under light irradiation conditions, a good state is obtained. It is preferred that it be retained.

  The ophthalmic composition of the present invention preferably contains a surfactant in addition to rebamipide, a rebamipide salt, a rebamipide derivative, or a salt thereof. The surfactant that can be blended in the ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and is a nonionic surfactant, Any of an amphoteric surfactant, an anionic surfactant, and a cationic surfactant may be used. These surfactants may be used alone or in any combination of two or more.

  As the nonionic surfactant that can be blended in the ophthalmic composition of the present invention, specifically, polyoxyethylene (hereinafter also referred to as POE) -polyoxypropylene (hereinafter also referred to as POP) block copolymer ( For example, poloxamers such as poloxamer 407, poloxamer 235 and poloxamer 188); POE-POP block copolymer adducts of ethylenediamine such as poloxamine; POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate POE sorbitan fatty acid esters such as (Polysorbate 80), POE sorbitan monostearate (Polysorbate 60), POE sorbitan tristearate (Polysorbate 65); POE (5) hydrogenated castor oil, POE (10) hydrogenated castor POE cured castor oils such as deer oil, POE (20) hydrogenated castor oil, POE (40) hydrogenated castor oil, POE (50) hydrogenated castor oil, POE (60) hydrogenated castor oil, POE (100) hydrogenated castor oil; POE castor oil such as POE (3) castor oil, POE (10) castor oil, POE (35) castor oil; POE alkyl ethers such as POE (9) lauryl ether; POE (20) POP (4) cetyl ether POE / POP alkyl ethers such as POE alkyl phenyl ethers such as POE (10) nonylphenyl ether; polyethylene glycol monostearate such as polyoxyl 40 stearate; In addition, the number in a parenthesis shows the average addition mole number of POP or POE.

  Specific examples of the cationic surfactant include benzalkonium chloride and benzethonium chloride.

  Examples of the anionic surfactant that can be blended in the ophthalmic composition of the present invention include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, aliphatic a-sulfomethyl ester, Examples include a-olefin sulfonic acid.

  Examples of amphoteric surfactants include glycine types such as alkyldiaminoethylglycine, betaine acetate types such as lauryldimethylaminoacetic acid betaine, and imidazoline types.

  Anionic surfactants include 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. N-acyl taurine salts such as sodium taurine, sulfonates such as sodium tetradecene sulfonate, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, α-olefin sulfone Examples include acid salts and the like.

  Among these surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants are preferred, nonionic surfactants and cationic surfactants are more preferred, and nonionic surfactants. Agents are more preferred. Suitable examples of the nonionic surfactant include at least selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, poloxamers, and polyethylene glycol monostearate. One kind of nonionic surfactant, more preferably poloxamer 407, poloxamer 188, POE (10) castor oil (polyoxyethylene castor oil 10), POE (35) castor oil (polyoxyethylene castor oil 35) Polysorbate 80, POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60) and polyoxyl 40 stearate, particularly preferably polysorbate 80, It is OE (60) hardened castor oil.

  When a surfactant is blended in the ophthalmic composition of the present invention, the blending ratio of the surfactant is appropriately determined according to the type of surfactant, the type and amount of other components, the use of the ophthalmic composition, etc. Can be set. As an example of the blending ratio of the surfactant, the total amount of the surfactant is preferably 0.001 w / v% or more, more preferably 0.005 w / v% or more, further preferably, with respect to the total amount of the ophthalmic composition. 0.01 w / v% or more, particularly preferably 0.1 w / v% or more, preferably 5 w / v% or less, more preferably 3 w / v% or less, still more preferably 1 w / v% or less. . The total content of the surfactant with respect to the total amount of the ophthalmic composition is not limited, but is preferably 0.001 w / v% to 5 w / v%, more preferably 0.005 w / v% to 3 w / v%, more preferably 0.01 w / v% to 1 w / v%, particularly preferably 0.1 to 1 w / v%.

  In addition to rebamipide, rebamipide salts, rebamipide derivatives, or salts thereof, the ophthalmic composition of the present invention may further contain a buffer. The buffer that can be incorporated into the ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, aspartic acid, aspartate, epsilon-aminocaproic acid, hydrochloric acid, sodium hydroxide, and the like. It is done. The buffer may be synthesized and used by a known method, or a commercially available product may be obtained and used. These buffering agents may be used alone or in any combination of two or more.

  Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, alkali metal citrate, and alkaline earth metal citrate. Moreover, you may use the hydrate of each salt as a buffering agent. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.) Or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, Calcium acetate, sodium dihydrogen citrate, disodium citrate, etc.) Its salt (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); as a Tris buffer, tris (hydroxymethyl) aminomethane or a salt thereof (hydrochloride, acetate, sulfonate, etc.) can be exemplified. These buffering agents may be used alone or in any combination of two or more.

  Among the above-mentioned buffers, borate buffer, phosphate buffer, citrate buffer, and epsilon-aminocaproic acid, particularly borate buffer and epsilon-aminocaproic acid are particularly suitable. Specific examples of the boric acid buffer include boric acid, a combination of boric acid and a salt thereof (for example, boric acid and borax), preferably boric acid, a combination of boric acid and borax, and more preferably Boric acid is exemplified.

  When a buffering agent is blended in the ophthalmic composition of the present invention, the blending ratio of the buffering agent varies depending on the type of buffering agent used, the type and amount of other blending components, the use of the ophthalmic composition, etc. Although not limited, for example, the total amount of the buffer is preferably 0.01 w / v% or more, more preferably 0.05 w / v% or more, and still more preferably 0.00% or more based on the total amount of the ophthalmic composition. 1 w / v% or more, particularly preferably 0.3% or more, preferably 10 w / v% or less, more preferably 5 w / v% or less, further preferably 3 w / v% or less, particularly preferably 2 w / v. % Or less. The total content of the buffer with respect to the total amount of the ophthalmic composition is not limited, but is preferably 0.01 w / v% to 10 w / v%, more preferably 0.05 w / v% to 5 w / v. %, More preferably 0.1 w / v% to 3 w / v%, particularly preferably 0.3 w / v% to 2 w / v%.

  The ophthalmic composition of the present invention preferably further contains a solubilizing agent in addition to rebamipide, a rebamipide salt, a rebamipide derivative, or a salt thereof. The solubilizing agent that can be blended in the ophthalmic composition of the present invention has an action of assisting dissolution of rebamipide and / or a salt thereof, or a rebamipide derivative and / or a salt thereof, which is hardly soluble in water, in an aqueous solution. It may be a component, for example, a vinyl polymer such as polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, carboxyvinyl polymer; trometamol, monoethanolamine, diethanolamine, triethanolamine, meglumine, diisopropanolamine, etc. Amines; Polyhydric alcohols such as glycerin, propylene glycol, and polyethylene glycol; or caffeine. These solubilizing agents may be used singly or in combination of two or more.

  Among these solubilizers, vinyl polymers, amines, and polyhydric alcohols are preferable, vinyl polymers, trometamol, monoethanolamine, meglumine, glycerin, propylene glycol, and polyethylene glycol are more preferable, and polyvinylpyrrolidone and glycerin. Is more preferable, polyvinyl pyrrolidone and glycerol having a K value of 15 to 40 are more preferable, and polyvinyl pyrrolidone K17, K25, polyvinyl pyrrolidone K30, and glycerol are more preferable.

（式中、ｃは溶液１００ｍＬ中の換算した脱水物の質量（ｇ）、η_relは水の動粘度に対する試料溶液の動粘度の比） The “K value” mentioned here is a value calculated from the following Fikentscher viscosity formula, and in the present invention, it refers to a characteristic value of viscosity related to the molecular weight of polyvinylpyrrolidone.

(Where c is the mass (g) of converted dehydrated product in 100 mL of solution, and η _rel is the ratio of the kinematic viscosity of the sample solution to the kinematic viscosity of water)

  When a solubilizing agent is blended in the ophthalmic composition of the present invention, the blending ratio varies depending on the type of solubilizing agent used, the type and blending amount of other components, the use of the ophthalmic composition, and the like. . Although not particularly limited, for example, the total amount of the solubilizing agent is preferably 0.001 w / v% or more, more preferably 0.005 w / v% or more, and still more preferably, with respect to the total amount of the ophthalmic composition. 0.01 w / v% or more, particularly preferably 0.1 w / v% or more, and the total amount of the solubilizing agent is preferably 20 w / v% or less, more preferably 10 w / v% or less, still more preferably 7 w / v% or less, particularly preferably 5 w / v% or less. The total content of the solubilizing agent relative to the total amount of the ophthalmic composition is not limited, but is preferably 0.001 w / v% to 20 w / v%, more preferably 0.005 w / v% to 10 w / It is v%, more preferably 0.01 w / v% to 7 w / v%, particularly preferably 0.1 w / v% to 5 w / v%.

  From the viewpoint of more prominently achieving the effects of the present invention, the ophthalmic composition of the present invention preferably further contains a polysaccharide.

  Specific examples of polysaccharides include cellulose-based polymer compounds such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), carboxymethylcellulose and salts thereof, carboxyethylcellulose and salts thereof, and hyaluron. Examples thereof include at least one selected from the group consisting of acids and salts thereof and glycosaminoglycans such as chondroitin sulfate and salts thereof, dextran, gellan gum, alginic acid and salts thereof. Here, the salt is not particularly limited, but a sodium salt is preferable. A polysaccharide may be used individually by 1 type or may be used in combination of 2 or more type.

In the ophthalmic composition of the present invention, the total content of the polysaccharide relative to the total amount of the ophthalmic composition is appropriately set according to the type of polysaccharide used, the type and amount of other compounding components, and the balance with other components. The
The total polysaccharide content is preferably 0.0001 w / v% or more, more preferably 0.0005 w / v% or more, and still more preferably 0.001 w / v%, based on the total amount of the ophthalmic composition. As mentioned above, it is still more preferably 0.01 w / v% or more, most preferably 0.05 w / v% or more. Further, the total content of the polysaccharide with respect to the total amount of the ophthalmic composition is preferably 5 w / v% or less, more preferably 3 w / v% or less, still more preferably 1 w / v% or less, and even more preferably 0.5 w / v% or less, most preferably 0.3 w / v% or less.

  The total content of polysaccharide is preferably 0.0001 w / v% to 5 w / v%, more preferably 0.0005 w / v% to 3 w / v%, more preferably relative to the total amount of the ophthalmic composition. Is from 0.001 to 1 w / v%, even more preferably from 0.01 w / v% to 0.5 w / v%, most preferably from 0.05 to 0.3 w / v%.

  Among these, when the ophthalmic composition is sodium hyaluronate, the total content of sodium hyaluronate is preferably 0.0001 w / v% to 1 w / v% relative to the total amount of the ophthalmic composition. Preferably, 0.0001 w / v% to 0.5 w / v%, more preferably 0.0001 to 0.1 w / v%, even more preferably 0.0001 w / v% to 0.02 w / v%, Most preferably, it is 0.0001-0.005 w / v%.

From the viewpoint of prominently achieving the effects of the present invention, the ophthalmic composition of the present invention preferably further contains amino acids. Examples of amino acids include potassium aspartate, magnesium aspartate, and aminoethylsulfonic acid.
In the ophthalmic composition of the present invention, the total content of amino acids relative to the total amount of the ophthalmic composition is appropriately set depending on the type of amino acid used, the type and amount of other compounding components, and the balance with other components. The total content of amino acids with respect to the total amount of the ophthalmic composition is preferably 0.0001 w / v% or more, more preferably 0.001 w / v% or more, and still more preferably 0.01 w / v% or more. Most preferably, it is 0.05 w / v% or more. Further, the total content of amino acids with respect to the total amount of the ophthalmic composition is preferably 5 w / v% or less, more preferably 3 w / v% or less, still more preferably 2 w / v% or less, most preferably 1 w. / V% or less. The total content of amino acids with respect to the total amount of the ophthalmic composition is preferably 0.0001 w / v% to 5 w / v%, more preferably 0.001 w / v% to 3 w / v%, more preferably 0.01 w / v% to 2 w / v%, more preferably 0.05 w / v% to 1 w / v%.

  From the viewpoint of more prominently achieving the effects of the present invention, the ophthalmic composition of the present invention preferably further contains a preservative. Examples of preservatives include sodium benzoate, ethanol, chlorhexidine gluconate, sodium edetate, zinc chloride, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid Examples thereof include propyl, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), etc.), glowkill (trade name, manufactured by Rhodia), and the like.

  Among the preservatives, ethanol, chlorhexidine gluconate, sodium edetate, zinc chloride, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoic acid At least one selected from the group consisting of butyl, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), etc.) is preferable, ethanol, chlorhexidine gluconate, chloride Zinc, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, para More preferred are butyl xybenzoate, oxyquinoline sulfate and biguanide compounds, chlorhexidine gluconate, zinc chloride, chlorobutanol, sorbic acid, potassium sorbate, polyhexanide hydrochloride (polyhexamethylene biguanide), even more preferred, chlorhexidine gluconate, chloride Zinc hydrochloride polyhexanide (polyhexamethylene biguanide) is particularly preferred.

  In addition, from the viewpoint of more prominently achieving the effects of the present invention, the ophthalmic composition of the present invention preferably contains a terpenoid. Terpenoids are known compounds that have a structure having isoprene units as structural units and are widely used as cooling agents. The terpenoid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of terpenoids include menthol, menthone, camphor, borneol, geraniol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymene, terpineol, pinene, camphene, isoborneol, fenchen. , Nerol, myrcene, myrsenol, linalool acetate, lavandulol, and at least one selected from the group consisting of these derivatives. Here, examples of the “derivative” include, but are not limited to, esterified derivatives, etherified derivatives, amidated derivatives, sulfonated derivatives, nitrated derivatives, nitrosated derivatives, and halogenated derivatives. . Preferably, the derivative is an esterified derivative and / or an etherified derivative, more preferably an esterified derivative. Examples of esterified derivatives include derivatives esterified with organic acids such as valeric acid, butyric acid, acetic acid, propionic acid and / or furancarboxylic acid, and these compounds are d-form, l-form or dl-form Either of these may be used.

  In the present invention, an essential oil containing the above compound may be used as a terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil and the like. These terpenoids may be used alone or in any combination of two or more.

  Among these terpenoids, at least one selected from the group consisting of menthol, menthone, camphor, borneol and geraniol is preferred, and as essential oils containing these, cool mint oil, peppermint oil, peppermint oil, camphor oil, rose oil, etc. Is exemplified. More preferred are menthol and camphor, more preferably l-menthol, dl-menthol, d-camphor and dl-camphor, particularly preferably l-menthol and d-camphor, and still more preferably l-menthol. Examples of essential oils containing these include cool mint oil, peppermint oil, peppermint oil, camphor oil and the like.

  In the ophthalmic composition of the present invention, the total content of the terpenoid component relative to the total amount of the ophthalmic composition is appropriately set depending on the type of terpenoid used, the type and amount of other compounding components, and the balance with other components. . The total content of terpenoids is preferably 0.00001 w / v% or more, more preferably 0.0001 w / v% or more, further preferably 0.0002 w / v% or more with respect to the total amount of the ophthalmic composition. Most preferably, it is 0.001 w / v% or more. Further, the total content of terpenoids with respect to the total amount of the ophthalmic composition is preferably 1 w / v% or less, more preferably 0.5 w / v% or less, still more preferably 0.1 w / v% or less. Preferably it is 0.08 w / v% or less. The total content of terpenoids is preferably 0.00001 w / v% to 1 w / v%, more preferably 0.0001 w / v% to 0.5 w / v%, more than the total amount of ophthalmic composition Preferably they are 0.0002 w / v%-0.1 w / v%, More preferably, they are 0.001 w / v%-0.08 w / v%. In addition, when using the essential oil containing a terpenoid, it can set so that the terpenoid in the essential oil contained in a composition may satisfy | fill the said content.

  The pH of the ophthalmic composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. 4.0 to 9.5, preferably 5.0 to 9.0, more preferably 6.0 to 8.5, still more preferably 6.5 to 8.5, and particularly preferably 7.0 to 8. 5, More preferably, the range which becomes 7.0-8.0 is mentioned.

  The ophthalmic composition of the present invention can be further adjusted to an osmotic pressure ratio within a range acceptable for a living body, if necessary. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc., but is usually in the range of 0.5 to 5.0, more preferably 0.6 to 3.0, and even more preferably 0.7 to 2.0. It is done. The osmotic pressure can be adjusted by a known method in the technical field using an inorganic salt, a polyhydric alcohol, or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measure according to the freezing point method. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes, and then in a desiccator (silica gel). The mixture is allowed to cool and 0.900 g of the solution is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) is used.

  If the viscosity of the ophthalmic composition of the present invention is within a physiologically or pharmaceutically acceptable range, it depends on the type and content of the ingredients, the use of the ophthalmic composition, the dosage form, the method of use, etc. Is set as appropriate. The viscosity at 20 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toyo Sangyo Co., Ltd., rotor: 1 ° 34 ′ × R24) is preferably 0.01 to 10000 mPa · s, and 0.05 to 8000 mPa · s. s, more preferably 0.5 to 1000 mPa · s, still more preferably 1 to 600 mPa · s, particularly preferably 2 to 100 mPa · s, and 2 to 50 mPa · s. -Most preferably, s.

  In the ophthalmic composition of the present invention, in addition to rebamipide, a rebamipide salt, a rebamipide derivative, or a salt thereof, any component that can be usually used for an ophthalmic composition can be contained. Such an ingredient is not particularly limited, and examples thereof include the active ingredients described in the over-the-counter drug manufacturing (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee). Specific examples include the following components.

  Antiallergic agents or antihistamines: for example, diphenhydramine hydrochloride, iproheptin, chlorpheniramine maleate, acitazanolast, amlexanox, ibudilast, tranilast, levocabastine hydrochloride, sodium cromoglycate, ketotifen fumarate, potassium pemirolast, olopatadine hydrochloride, etc.

  Decongestant: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, and the like.

  Eye muscle modulating agent: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien.

  Bactericides: for example, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biguanide hydrochloride, etc.

  Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate, etc.

  Anti-inflammatory agents: for example, glycyrrhizic acid, methyl salicylate, glycol salicylate, dipotassium glycyrrhizinate, allantoin, tranexamic acid, berberine, berberine chloride, berberine sulfate, lysozyme, lysozyme chloride, azulene sulfonic acid, sodium azulene sulfonate, indomethacin, pranopro Fen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, etc.

  Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.

  Others: For example, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sodium sulfisomidine, sodium hyaluronate, alginic acid, purple root, horse chestnut, and salts thereof.

  Furthermore, in the ophthalmic composition of the present invention, additives such as carriers, pH adjusters, general sugar alcohols and saccharides, general isotonic agents, chelating agents, stabilizers, preservatives are selected. In addition, an appropriate amount may be contained in combination of at least one. Examples of these additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.

  Carrier: Aqueous carrier such as water or hydrous ethanol.

  Sugars: for example, glucose, cyclodextrin and the like.

  Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.

  Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride and the like.

  pH regulators: for example, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, glucono Lactone, ammonium acetate, etc.

  Stabilizer: For example, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), sodium formaldehyde sulfoxylate (Longalite), sodium pyrosulfite, aluminum monostearate, glyceryl monostearate, tocopherol, cyclodextrin and the like.

  Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), ascorbic acid Edetate tetrasodium, edetate sodium and the like.

  Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil and olive oil, animal oils such as squalane, mineral oils such as liquid paraffin and petrolatum.

  In the present invention, “physiologically or pharmaceutically acceptable salts” include, for example, salts with alkali metal salts, alkaline earth metal salts, organic bases, and the like, such as sodium, potassium, calcium, magnesium, ammonium. Or a salt with diethanolamine, ethylenediamine or the like. These salts can be obtained, for example, by converting a sulfate group or a carboxyl group present in the substance into a salt by a known method. Furthermore, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, Examples include salts of amines such as N-methylglucamine and L-glucamine; and salts with basic amino acids such as lysine, δ-hydroxylysine and arginine. Also, for example, salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, Malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salts with organic acids such as salicylic acid; or aspartic acid, glutamic acid And salts with acidic amino acids such as

  The “physiologically or pharmaceutically acceptable salt” referred to in the present invention may include a solvate or hydrate of a salt.

  The ophthalmic composition of the present invention is prepared by adding a desired amount of rebamipide, a salt of rebamipide, a rebamipide derivative, or a salt thereof, and if necessary, other compounding components to a desired concentration. The ophthalmic composition of the present invention can take various preparation forms depending on the purpose. For example, as a preparation form of the ophthalmic composition of the present invention, a liquid agent, a semi-solid agent (ointment etc.) and the like can be mentioned. A liquid agent is preferable.

  Ophthalmic compositions (compositions for ocular mucosa) include eye drops (including eye drops that can also be used while wearing contact lenses), artificial tears (artificial that can also be used while wearing contact lenses). (Including tears), eye wash, eye ointment, contact lens mounting solution, contact lens care agent (contact lens disinfectant, contact lens preservative, contact lens cleaner, contact lens cleaner, etc.) ) Etc. are included.

  Ophthalmic compositions (compositions for ophthalmic mucosa) cause drops in quality, including safety as a preparation to be applied to the ocular mucosa, when crystals are deposited upon storage. It is required to suppress the generation of foreign matter such as

  The ophthalmic composition of the present invention is preferably a clear and pharmaceutically stable ophthalmic composition containing rebamipide, a salt of rebamipide, a rebamipide derivative, and / or a salt thereof. Among ophthalmic compositions, in particular, eye drops and eye wash products require foreign matter inspection, and therefore it is preferable that the formulation has high clarity. Light absorbance is used as an indicator of clarity. As the light absorbance of the ophthalmic composition according to the present embodiment, for example, the light absorbance at a wavelength of 660 nm may be 0.5 or less, preferably 0.3 or less, and preferably 0.15 or less. Is more preferably 0.12 or less, even more preferably 0.1 or less, particularly preferably 0.07 or less, and most preferably 0.04 or less. Since the ophthalmic composition of the present invention is accommodated in a multi-dose container, it is preferably a preparation with higher transparency.

  The ophthalmic composition of the present invention can be an ophthalmic composition housed in a multi-dose container. Here, the multi-dose refers to a packaging form that is intended to be taken or used multiple times and can be freely opened and resealed such as a cap. The ophthalmic composition of the present invention can be a multi-dose type eye drop as a particularly suitable example. Since the ophthalmic composition of the present invention is used to improve fatigue eyes, the number of instillations per day is large, and it tends to be used continuously over a long period of time. Therefore, an ophthalmic composition that is housed in a multi-dose container is preferable.

When the ophthalmic composition of the present invention is evaluated according to the Japanese Pharmacopoeia (16th revision) reference information “preservation efficacy test” category IA preparation, it preferably satisfies the preparation criteria.
That is, Escherichia coli (ATCC 8739, NBRC3972), Pseudomonas aeruginosa (ATCC 9027, NBRC13275), Staphylococcus aureus (ATCC 6538, NBRC13276), Candida albicans (ATCC 10231, NBRC1594, JCM2085), and Aspergillus brasilienNB (RC16 For 5 bacterial species, inoculate and mix viable bacteria so that the number of viable bacteria is 10 ⁵ to 10 ⁶ per 1 mL of the preparation, and store at 20 to 25 ° C. in the dark, on days 0, 14, and 28. Take 1 mL from the test preparation and measure the number of viable bacteria. When expressed as a percentage with the number of bacteria at the start of the test as 100, the number of viable bacteria after 14 days was 0.1% or less of the number of inoculated bacteria, the fungus was at the same level or less, and 28 It is preferable that the number of viable bacteria after the day is equal to or less than the level after 14 days for bacteria, and the level of the fungus is equal to or less than the number of inoculated bacteria.

  The ophthalmic composition of the present invention is provided as a composition for improving fatigue eyes and / or blurring eyes. Here, fatigue eyes are caused by eye overuse and mental tension such as reading, gazing work, observation work, etc., and those caused by VDT work that has increased rapidly with the spread of personal computers, etc. However, as symptoms, for example, symptoms such as pain in the back of the eyes, stiff shoulders, and head weight often accompany. Furthermore, nausea and nausea may occur when eyestrain is severe. It has been pointed out that these symptoms are caused by the ciliary muscles becoming excessively tensioned due to long-term gaze work and the like, and the function of eye regulation being lowered. Although not limited, fatigue eyes can be measured using the HFC-1 value and VAS value measured after 1 hour of VDT work as indicators. The HFC-1 value is a value indicating the frequency of appearance of a high frequency component when a fixed distance is observed with respect to fine adjustment caused when the refraction value of the eye is recorded over time. The high frequency component indicates the vibration of the crystalline lens, that is, the tremor of the ciliary muscle. The higher the frequency of appearance of the high frequency component, the stronger the ciliary muscle, and the higher the HFC-1 value. The ciliary muscles are tense and the eyes are tired.

  The VAS value is on the subjective symptom survey sheet on which a 10 cm line is drawn. When the eye fatigue is not felt, 0 mm, and when the eye fatigue is strongly felt is 100 mm. This length (mm) was measured as the severity of subjective symptoms and calculated as a fatigue eye score. That is, the higher the VAS value, the higher the subjective symptom score of tired eyes.

  Here, the blurred eye refers to a symptom in which the focus function of the eye is lowered and the field of view is blurred, or it takes a long time to focus when looking at the distance and looking at the distance. Blurred eyes can occur due to overuse of the eyes, inflammation such as cataracts and conjunctivitis, presbyopia that occurs with aging.

  The ophthalmic composition of the present invention is provided by being contained in an arbitrary container. The container for storing the ophthalmic composition of the present invention is not particularly limited, and may be made of glass or resin, for example. The container for housing the ophthalmic composition of the present invention may be a resin container in which a resin is further reinforced by containing a reinforcing agent such as glass fiber.

  Specifically, in the ophthalmic composition of the present invention, at least a part, preferably all, of the container is made of polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polypropylene (PP), polyarylate (PAR). ), Polybutylene terephthalate (PBT), polycarbonate (PC), polyethylene (PE). Preferably, PET, PEN, PP, PAR, PBT, PC, PE, more preferably PET, PBT, PP, PE, and even more preferably PET or PP Made of PET, particularly preferably made of PET.

  In this specification, a container mainly means a container (primary container) that directly stores a rebamipide-containing ophthalmic composition. In addition, the container may be integrally molded, and the container main body part may be accompanied by a lid part or a spout part, but a form in which the container main body part is accompanied by a lid part or a spout part is preferable. The above material mainly means the material of the container main body.

  When the container for storing the ophthalmic composition according to the present embodiment is made of resin, the container may be formed from only a single resin, or may be formed by combining a plurality of synthetic resins. . When combining a plurality of synthetic resins, the above-mentioned synthetic resins (PET, PEN, PP, PAR, PBT, PC and PE) may be combined. In addition to the above-mentioned synthetic resins, a synthetic resin container is usually formed. You may combine the synthetic resin used. As such synthetic resins, polyester resins (polyethylene terephthalate resin, polyethylene naphthalate resin, polybutylene terephthalate, etc.), olefin resins (polyethylene, polypropylene, etc.), polyarylate resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins Examples thereof include resins such as resins, polyamide resins, polyimide resins, hard vinyl chloride resins, styrene resins (polystyrene, acrylonitrile-styrene copolymers, etc.), and cellulose acetates. Moreover, when the polymer contained in resin is comprised with a some monomer component, the method of the combination is not limited. Copolymers of these monomer components may be used, homopolymers may be simply mixed, or the copolymers may be mixed. The copolymer may be any of an alternating copolymer, a random copolymer, a block copolymer, and a graft copolymer.

  When the container for storing the ophthalmic composition according to the present embodiment is a synthetic resin container, the total weight of PET, PEN, PP, PAR, PBT, PC, and PE with respect to the weight of the entire constituent material of the container is not particularly limited. However, the total weight of PET, PEN, PP, PAR, PBT, PC and PE is usually 30 w / w% or more, preferably 50 w / w% or more, more preferably with respect to the total weight of the constituent materials of the container. Is 65 w / w% or more, particularly preferably 80 w / w or more. In a more preferred embodiment, the weight of the synthetic resin of any one of PET, PEN, PP, PAR, PBT, PC and PE is 30 w / w% or more and 50 w / w% based on the total weight of the constituent material of the container. As mentioned above, they are 65 w / w% or more or 80 w / w% or more.

  The container for housing the ophthalmic composition of the present invention, particularly the container main body, may be a transparent container that allows the inside of the container to be visually recognized, or may be an opaque container that is difficult to visually recognize inside the container. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container. By being accommodated in the transparent container, foreign matter inspection and the like can be easily performed visually.

  In the present invention, the shape of the container and the capacity that can be accommodated therein are not particularly limited. For example, if the container is used for topical mucosa application such as eye drops or nasal drops, the internal volume is 1 ml to 1000 ml, preferably 1 ml to 100 ml, more preferably 2 ml to 50 ml, and even more preferably. May be a container that can accommodate 3 ml to 25 ml, particularly preferably 3 ml to 20 ml.

The ophthalmic composition of the present invention is provided alone or in the form of a kit accommodated in a resin container.
In the case where the ophthalmic composition of the present invention is an eye drop, the drop amount per drop is usually 5 to 60 μL, preferably 10 to 50 μL, more preferably 15 to 15 from the viewpoint of more prominently achieving the effects of the present application. It is preferably designed to be 45 μL, more preferably 20 to 42 μL.

  The present invention contains at least one selected from the group consisting of rebamipide, rebamipide salts, rebamipide derivatives, and salts thereof, and is contained in a multi-dose type container for improving fatigue eyes and / or blurred eyes. However, the following embodiments are particularly preferable.

  That is, the present invention contains a multidose container that contains at least one selected from the group consisting of rebamipide, a salt of rebamipide, a rebamipide derivative, and salts thereof, and is for improving fatigue eyes and / or blurring eyes. It is preferably a liquid ophthalmic composition to be contained in the eye, and in particular, an eye drop is preferable.

  The ophthalmic composition of the present invention can be used to improve eye fatigue, assistance of tears, blurring of eyes, etc. as an effect and effect, particularly in the case of eye drops.

  The ophthalmic composition of the present invention preferably contains at least one selected from the group consisting of rebamipide, rebamipide salts, rebamipide derivatives, and salts thereof in a ratio of 0.0001 to 10 (w / v)%. contains.

  The ophthalmic composition of the present invention preferably contains either a nonionic surfactant, an amphoteric surfactant, an anionic surfactant or a cationic surfactant.

  The ophthalmic composition of the present invention is particularly preferably a polyoxyethylene (hereinafter also referred to as POE) -polyoxypropylene (hereinafter also referred to as POP) block copolymer, a POE-POP block copolymer adduct, or a POE alkyl ether. At least selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, POE / POP alkyl ethers, POE alkyl phenyl ethers, and polyethylene glycol monostearate Contains one nonionic surfactant.

  The ophthalmic composition of the present invention is preferably from the group consisting of borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, hydrochloric acid, and sodium hydroxide. Contains at least one selected buffer.

  The ophthalmic composition of the present invention preferably contains at least one solubilizing agent selected from the group consisting of polymers, amines, polyhydric alcohols, and caffeine.

  The ophthalmic composition of the present invention is preferably dibutylhydroxytoluene, butylhydroxyanisole, sodium benzoate, ethanol, chlorhexidine gluconate, sodium edetate, zinc chloride, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate At least one selected from the group consisting of methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds, polyhexanide hydrochloride, and glowkill Contains preservatives.

  The ophthalmic composition of the present invention preferably has a pH of 5.5 to 8.0.

  The ophthalmic composition of the present invention is preferably clear.

  More specifically, the following ophthalmic compositions are exemplified.

It contains at least one selected from the group consisting of rebamipide, rebamipide salt, rebamipide derivatives, and salts thereof, and contains polyvinylpyrrolidone K17, 25, or 30 and is for fatigue eye improvement and / or blurred eye improvement. Liquid ophthalmic compositions for storage in multi-dose containers:
Containing at least one selected from the group consisting of rebamipide, a salt of rebamipide, a rebamipide derivative, and salts thereof, polyvinylpyrrolidone K17, 25 or 30, nonionic surfactant, amines, polyhydric alcohol, and buffer A liquid ophthalmic composition for containing in a multi-dose container for improving fatigue eyes and / or blurring, containing an agent and a preservative:
A clear ophthalmic composition containing at least one member selected from the group consisting of rebamipide, a salt of rebamipide, a rebamipide derivative, and salts thereof, for improving fatigue and / or blurred vision:
Multidose containing at least one member selected from the group consisting of rebamipide, rebamipide salts, rebamipide derivatives, and salts thereof, and for improving fatigue eyes and / or blurring eyes having a pH of 5.5 to 8.0. Eye drops for storage in mold containers:
Rebamipide, a salt of rebamipide, a rebamipide derivative, and at least one selected from the group consisting of these salts, for containing in a multi-dose container for improving fatigue eyes and / or blurred eyes Eye drops:
A clear eye drop containing at least one member selected from the group consisting of rebamipide, rebamipide salt, rebamipide derivatives, and salts thereof, for improving fatigue and / or blurring eyes:
It contains at least one member selected from the group consisting of rebamipide, rebamipide salt, rebamipide derivatives, and salts thereof, and is contained in a multidose container made of PET for improving fatigue eyes and / or blurred eyes. Eye drops for:
A multidose type ophthalmic solution made of PET containing at least one member selected from the group consisting of rebamipide, rebamipide salt, rebamipide derivatives, and salts thereof, for improving fatigue eyes and / or blurred eyes .

  In the present invention, the ophthalmic solution containing polyvinylpyrrolidone contains at least one selected from the group consisting of rebamipide, rebamipide salts, rebamipide derivatives, and salts thereof, thereby preventing deterioration of fatigue eye symptoms. It also relates to methods and methods for preventing fatigue eye symptoms.

  From the viewpoint of having rebamipide, the ophthalmic composition according to this embodiment is also useful for prevention, improvement, and treatment of dry eye.

  EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.

Example 1
An aqueous ophthalmic composition having the composition shown in Table 1 was prepared according to a conventional method. Specifically, each component was weighed into a 100 ml glass vial and a required amount of distilled water was added. The mixture was stirred while warming, and the pH was adjusted to obtain a uniform preparation. Then, it filled with the container made from a polyethylene terephthalate with a capacity | capacitance of 13 mL, and the nozzle made from polyethylene was mounted | worn. Here, as rebamipide, rebamipide conforming to the Japanese Pharmacopoeia was used.

(Comparative Example 1)
In the same manner as in Example 1, formulation examples shown in Table 2 were prepared.

Test Example 1: Fatigue eye evaluation test 1
Using the formulation examples shown in Table 1, a fatigue eye test was performed based on the following method.
Specifically, two test subjects who did not wear contact lenses, who were apt to feel tired eyes, placed a load on their eyes by carrying out VDT work (character input work while looking at a personal computer screen) for 1 hour.
Thereafter, the HFC-1 value (pre-dose HFC-1 value) was measured.
Next, the eye drop of Example 1 was instilled into both eyes by 40 μL using Pipetman, and the HFC-1 value was measured 10 minutes after the instillation.

  Here, the HFC-1 value is a value indicating the appearance frequency of a high-frequency component when gazing at a certain distance with respect to shaking generated when the refraction value of the eye is recorded over time, that is, adjustment fine movement. The high frequency component indicates the vibration of the crystalline lens, that is, the tremor of the ciliary muscle. The higher the frequency of appearance of the high frequency component, the stronger the stress is generated in the ciliary muscle. That is, it can be said that the higher the HFC-1 value, the more ciliary muscle is tense and the eye is tired.

In this test, the HFC-1 value was measured according to the attached instruction manual using the following apparatus and conditions.
Device name: Eye adjustment function measurement software AA-1 (made by Nidec Corporation)

  From the measured HFC-1 value, the fatigue eye improvement rate (%) by instillation of Example 1 was determined by the following equation (2).

  The results are also shown in Table 1 below.

In the average value of the two subjects, the tendency to improve the fatigue eye (%) was observed by the instillation of Example 1.

Moreover, when the comparative example 1 shown in Table 2 was instilled, the tendency for the symptoms of tired eyes to be promoted was confirmed.

Test Example 2: Fatigue eye evaluation test 2
Five subjects who did not wear contact lenses, who were likely to feel tired eyes, were subjected to VDT work (character input work while looking at a personal computer screen) for 1 hour. Next, the eye drop of Example 1 was instilled with 40 μL using a Pipetman, and after 10 minutes of instillation, the HFC-1 value was measured by the same procedure as in Test Example 1, and further the VAS (Visual Analogue Scale) was performed by the following procedure. : Visual evaluation scale). Thereafter, Comparative Example 1 was evaluated in the same procedure for the same five subjects.

Here, the VAS value is 0 mm when the eye fatigue is not felt on the subjective symptom survey sheet with a 10 cm line drawn, and 10 mm when the eye fatigue is strongly felt. This length (mm) was measured as the severity of subjective symptoms, and this was calculated as a fatigue eye score. The higher the VAS value, the higher the subjective symptom score of tired eyes.

  From the measured HFC-1 value and the average value of the VAS score, the fatigue eye improvement rate (%) of Example 1 relative to Comparative Example 1 was determined by the following equation (3).

The fatigue eye improvement rate (%) of Example 1 calculated from the average values of the HFC-1 values and VAS scores of five subjects is shown in Table 2.

As a result, in the average value of the five subjects, the improvement of the fatigue eye improvement rate was confirmed by instillation of Example 1 as compared with Comparative Example 1.

From the above results, it was confirmed that the ophthalmic composition of the present invention was excellent in fatigue eye improvement effect and eye fatigue improvement effect and was highly useful as an ophthalmic composition for fatigue eye improvement.

Test Example 3: Usability Test Using Example 1 and Reference Example 1 shown in Table 1 (contents taken out from containers of commercially available Mucosta UD (Otsuka Pharmaceutical)), the clarity of each solution was evaluated. The sensory evaluation after instillation was performed based on the following method.
Evaluation of clarity 1
Each solution was filled in 5 mL in a 10 mL colorless glass vial and mixed by inversion, and then the clarity was evaluated visually according to the following criteria. In addition, Example 1 was evaluated 24 hours after preparation.
<Evaluation criteria for clarity>
There is almost no cloudiness and the back of the vial can be confirmed without any problem.
There is slight cloudiness, but the back of the vial can be confirmed without any problem.
There is white turbidity and it is somewhat difficult to confirm the back of the vial: △
There is white turbidity, and the back of the vial cannot be confirmed at all: ×
Evaluation of clarity 2
The absorbance at 660 nm was measured for each solution.
<Measurement device>
U-3300 Spectrophotometer HITACHI

  Two subjects wearing non-contact lenses, who are easily tired, experienced a strain on their eyes by carrying out VDT work (character input work while looking at a personal computer screen) for 1 hour.

Next, 40 μL of the eye drop of Example 1 was instilled using Pipetteman, and sensory evaluation was performed by VAS immediately after the instillation and 10 minutes after the instillation.
The items evaluated are as follows.
Table 3 shows the evaluation results of irritation, blemishes of eyes, stickiness and sticky transparency, and Table 4 shows the evaluation results of VAS.

From Table 4, compared to Reference Example 1, in Example 1, the VAS score was remarkably reduced in all items, and the sensory characteristics such as “stimulation”, “smear of eyes”, “feeling sticky”, “feeling sticky”, etc. It was confirmed that the surface was remarkably improved.

  Therefore, it was confirmed that the preparation of Example 1 is a preparation having a remarkably excellent usability compared to Reference Example 1 which is a suspension preparation. According to Example 1, it is possible to provide a preparation having an excellent effect on fatigue eyes and a good feeling to use.

Formulation Example Eye drops (Prescription Examples 1 to 19), eyewashes (Prescription Examples 20 and 21), and mounting solutions (Prescription Example 22) were prepared according to the formulations described in Tables 5 and 6 below. Be contained. In the formulation examples in Tables 5 to 6, hydrochloric acid and sodium hydroxide are used for pH adjustment, and the ophthalmic composition is added so as to have the pH described in Tables 5 and 6. Purified water is added so that the total amount of each solution is 100 mL.

Formulation Examples 1-22 are accommodated in PET containers and equipped with PE nozzles. Formulation Examples 1-22; Formulation Examples 1-22 are accommodated in PET containers and equipped with PBT nozzles. 23 to 44; Formulation Examples 1 to 22 were accommodated in a PP container and equipped with a PE nozzle, Formulation Examples 45 to 66; Formulation Examples 1 to 22 were accommodated in a PP container, and a PBT nozzle was mounted. These were made into the formulation examples 67-88.

Claims (8)

At least one selected from the group consisting of rebamipide and a salt of rebamipide; and
Boric acid
An ophthalmic composition (provided to be contained in a multi-dose type container for improving fatigue eyes and / or blurring eyes (excluding those caused by dry eye)) 1) except rebamipide, (2) amino sugar and (3) a pharmaceutical composition containing a buffer and not containing an inorganic cation) .   The ophthalmic composition according to claim 1, which is an eye drop.   The ophthalmic composition according to claim 1, comprising at least one selected from the group consisting of rebamipide and a salt of rebamipide in a proportion of 0.0001 to 10 (w / v)%.   Furthermore, the ophthalmic composition of any one of Claims 1-3 containing either a nonionic surfactant, an amphoteric surfactant, an anionic surfactant, or a cationic surfactant.   Furthermore, the ophthalmic composition of any one of Claims 1-4 containing a solubilizing agent.   The ophthalmic composition according to any one of claims 1 to 5, comprising boric acid in a proportion of 0.01 to 3 (w / v)%.   The ophthalmic composition according to any one of claims 1 to 6, further comprising epsilon-aminocaproic acid.   The ophthalmic composition according to any one of claims 1 to 7, wherein the absorbance of light having a wavelength of 660 nm is 0.5 or less.