Ophthalmic composition and method for improving preservative effectiveness of ophthalmic composition

Abstract

To provide an ophthalmic composition that contains (A) at least one selected from an anti-hyperemia agent and an anti-histamine agent and (B) glycyrrhizinic acid or a salt thereof and has a pH of 5.0-5.5, wherein the ophthalmic composition has reduced eye irritation.SOLUTION: An ophthalmic composition contains (A) at least one selected from an anti-hyperemia agent and an anti-histamine agent, (B) glycyrrhizinic acid or a salt thereof, and (C) hyaluronic acid or a salt thereof of 0.001-0.02 mass% and has a pH of 5.0-5.5.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition and a method for improving the preservative effectiveness of an ophthalmic composition. [Background technology]

[0002] Glycyrrhizic acid or its salts can form a complex with a coexisting drug, and are expected to promote the absorption of the coexisting drug. In order to form a complex with a coexisting drug, it is important to adjust the pH. For example, a technique has been proposed for improving the absorbability of the glycyrrhizic acid or its salts from the mucous membrane by adjusting the concentration of glycyrrhizic acids to the critical micelle concentration or higher and adjusting the pH of the composition to 4 to 6 (Patent Document 1: JP-A-11-147825). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 11-147825 [Patent Document 2] JP 2009-161456 A Summary of the Invention [Problem to be solved by the invention]

[0004] It has been found that, in a composition containing a drug and glycyrrhizinic acid or a salt thereof, when a drug selected from (A) antihypertensives and antihistamines is added and the pH is set to 5.5 or less, the sensation of use, such as eye irritation, is deteriorated. As a technique for improving eye irritation, it is known to add 1-menthol or the like to an ophthalmic composition (Patent Document 2: JP 2009-161456 A), but the effect is insufficient as it is merely a masking effect by the cooling agent. In view of the above, the present invention aims to provide an ophthalmic composition containing (A) one or more selected from antihypertensives and antihistamines and (B) glycyrrhizinic acid or a salt thereof and having a pH of 5.0 to 5.5, in which eye irritation is alleviated. [Means for solving the problem]

[0005] As a result of intensive research into achieving the above-mentioned object, the inventors discovered that the above-mentioned problems could be solved by incorporating 0.001 to 0.02 mass % of (C) hyaluronic acid or a salt thereof in an ophthalmic composition containing (A) one or more selected from antihyperemia agents and antihistamines, and (B) glycyrrhizinic acid or a salt thereof, and having a pH of 5.0 to 5.5, and thus completed the present invention.

[0006] Therefore, the present invention provides the following inventions. 1. (A) one or more selected from anticongestive heart drugs and antihistamines; (B) glycyrrhizinic acid or a salt thereof, and (C) hyaluronic acid or a salt thereof 0.001 to 0.02% by mass and having a pH of 5.0 to 5.5. 2. The ophthalmic composition according to 1, wherein the component (A) is one or more selected from tetrahydrozoline hydrochloride and phenylephrine hydrochloride. 3. The ophthalmic composition according to 1 or 2, wherein the content mass ratio represented by (C) / (A) is 0.01 to 2, and the content mass ratio represented by (C) / (B) is 0.004 to 0.4. 4. The ophthalmic composition according to any one of 1 to 3, further comprising (D) one or more types selected from amino acids and water-soluble vitamins. 5. The ophthalmic composition according to any one of 1 to 4, further comprising (E) a terpenoid. 6. The ophthalmic composition according to any one of 1 to 5, further comprising boric acid, trometamol, and edetic acid or a salt thereof. 7. The ophthalmic composition according to 6, wherein the preservative content is 0.001% by mass or less. 8. (A) one or more selected from anticongestive heart drugs and antihistamines; (B) glycyrrhizinic acid or a salt thereof, and (C) hyaluronic acid or a salt thereof 0.001 to 0.02% by mass 2. A method for improving the preservative effectiveness of an ophthalmic composition comprising the above compound, the method comprising adjusting the pH of the ophthalmic composition to 5.0 to 5.5. Effect of the Invention

[0007] According to the present invention, an ophthalmic composition that reduces eye irritation can be provided, which contains (A) one or more selected from antihypertensives and antihistamines, and (B) glycyrrhizinic acid or a salt thereof and has a pH of 5.0 to 5.5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention will be described in detail below. [Component (A)] The component (A) of the present invention is one or more selected from antihypertensives and antihistamines, and can be used alone or in combination of two or more. Antihypertensives include tetrahydrozoline, naphazoline, phenylephrine, and pharmacologically acceptable salts thereof. Antihistamines include chlorpheniramine maleate, diphenhydramine hydrochloride, etc. Among them, tetrahydrozoline hydrochloride and phenylephrine hydrochloride are preferred.

[0009] The content of the (A) component is preferably 0.0001 w / v% (mass / volume%, g / 100 mL, hereinafter the same) or more in the ophthalmic composition from the viewpoint of the pharmaceutical effect of the component, and is preferably 1 w / v% or less from the viewpoint of suppressing eye irritation. 0.001 to 0.3 w / v% is more preferable, 0.01 to 0.2 w / v% is even more preferable, and 0.03 to 0.1 w / v% is particularly preferable. In the case of an antihyperemic drug, 0.0001 to 0.5 w / v% is preferably, 0.001 to 0.3 w / v% is more preferable, 0.01 to 0.2 w / v% is even more preferable, and 0.05 to 0.1% w / v% is particularly preferable. In the case of an antihistamine, 0.001 to 1 w / v% is preferably, 0.01 to 0.1 w / v% is more preferable, and 0.03 to 0.05 w / v% is even more preferable.

[0010] [(B) Component] The component (B) is glycyrrhizinic acid or a salt thereof, which may be used alone or in combination of two or more, and is expected to promote the mobility and absorption of the drug component to the cornea. Examples of the salt include pharmacologically acceptable salts. Examples of the component (B) include glycyrrhizinic acid itself, as well as disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc., with dipotassium glycyrrhizinate being preferred.

[0011] The content of the (B) component in the ophthalmic composition is preferably 0.01 w / v% or more from the viewpoint of mobility of the drug component to the cornea and promotion of absorption, and is preferably 0.5 w / v% or less from the viewpoint of suppressing eye irritation, more preferably 0.03 to 0.4 w / v%, and even more preferably 0.05 to 0.3 w / v%.

[0012] [(C) component] The hyaluronic acid or its salt of the present invention is not particularly limited, and any hyaluronic acid generally used in mucosal application preparations in the ophthalmic field can be used. By incorporating component (C), eye irritation can be significantly alleviated in an ophthalmic composition containing (A) one or more selected from antihyperemia drugs and antihistamine drugs, and (B) dipotassium glycyrrhizinate, and having a pH of 5.0 to 5.5.

[0013] Examples of hyaluronic acid or its salts include hyaluronic acid, its derivatives, and their pharma- ceutical and physiologically acceptable salts. These can be obtained by extraction from cockscomb, fermentation with microorganisms, etc., and their origin and manufacturing method are not particularly limited. Hyaluronic acid or its salts can be used alone or in appropriate combination of two or more. Specific examples of component (C) include hyaluronic acid, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, etc. Among them, sodium hyaluronate is preferred. As component (A), commercially available products can be used, such as purified sodium hyaluronate (manufactured by Seikagaku Corporation, Shiseido Co., Ltd., Kewpie Corporation, Kikkoman Biochemifa Corporation, Iwaki Pharmaceutical Co., Ltd., and Bloomage Biotechnology Co., Ltd.).

[0014] The viscosity average molecular weight of the (C) component is preferably 50 to 5,000,000, more preferably 50 to 4,000,000, even more preferably 50 to 2,500,000, particularly preferably 50 to 2,000,000, and most preferably 500,000 to 1,490,000. The viscosity average molecular weight of the (C) component is measured by the method for measuring viscosity average molecular weight described in "purified sodium hyaluronate" in the Japanese Pharmacopoeia, 17th Edition, Pharmaceuticals. The viscosity average molecular weight of hyaluronic acid or its salt in the eye drop is measured by the method for measuring viscosity average molecular weight described in "purified sodium hyaluronate eye drop" in the Japanese Pharmacopoeia, 17th Edition. Note that multiple types of hyaluronic acid and / or salts with different viscosity average molecular weights can be used.

[0015] As the component (C), commercially available products can be used, for example, "Sodium Hyaluronate "Seikagaku"" (viscosity average molecular weight 500,000 to 1,200,000) and "Cosmetic Sodium Hyaluronate (HC)" (viscosity average molecular weight 530,000 to 1,330,000) manufactured by Seikagaku Corporation, "Bio Sodium Hyaluronate SZE" (viscosity average molecular weight 1,100,000 to 1,600,000) manufactured by Shiseido Co., Ltd., "Bio Sodium Hyaluronate HA9N" (viscosity average molecular weight 800,000 to 1,770,000) and "Bio Sodium Hyaluronate HA12N" (viscosity average molecular weight 1,100,000 to 1,600,000) and "Bio Sodium Hyaluronate" (viscosity average molecular weight 1,100,000 to 1,600,000) manufactured by Shiseido Co., Ltd. "HA20N" (viscosity average molecular weight 1.9 million to 2.7 million), "Bio-hyaluronate sodium 1% aqueous solution (MP-PE) N" (viscosity average molecular weight 1.37 million to 1.53 million), "Bio-hyaluronate sodium 1% aqueous solution (PE) N" (viscosity average molecular weight 1.37 million to 1.57 million), Kikkoman Biochemifa's "Hyaluronic acid FCH-60" (viscosity average molecular weight 500,000 to 700,000), "Hyaluronic acid FCH-80" (viscosity average molecular weight 600,000 to 1 million), "Hyaluronic acid FCH-120" (viscosity average molecular weight 1 million to 1.4 million), "Hyaluronic acid FCH-150" (viscosity average molecular weight 1.4 million to 1.8 million), "Hyaluronic acid FCH-151C" (viscosity average molecular weight 1.4 million to 1.8 million), "Hyaluronic acid FCH-200" (viscosity average molecular weight 1.8 million to 2.2 million), "Hyaluronic acid FCH-201C" (viscosity average molecular weight 1.8 million to 2.2 million), "Hyaluronic acid FCH-80LE" (viscosity average molecular weight 600,000 to 1.2 million), "Hyaluronic acid GS-100" (viscosity average molecular weight 500,000 to 1.49 million), Kewpie's "Hyaluronic acid HA-QA" (viscosity average molecular weight 600,000 to 1.2 million), "Hyaluronic acid HA-AM" (viscosity average molecular weight 600,000 to 1.2 million), "Hyaluronic Acid HA-Q" (viscosity average molecular weight 530,000 to 1.13 million), "Hyaluronic Acid M5070" (viscosity average molecular weight 500,000 to 700,000), "Hyaluronic Acid HA-LQ" (viscosity average molecular weight 850,000 to 1.6 million), "Hyaluronic Acid HA-LQH" (viscosity average molecular weight 1.2 million to 2.2 million), "Hyaluronic Acid HA-AML" (viscosity average molecular weight 500,000 to 1.2 million), "Hyaluronic Acid HA-SHL" (viscosity average molecular weight 1.6 million to 2.4 million), Iwaki Pharmaceutical's "Hyaluronic Acid IW90" (viscosity average molecular weight 800,000 to 1.17 million),Examples include "Hyaluronic Acid IW120" (viscosity average molecular weight 1.1 million to 1.6 million), and "Hyaluronic Acid IW200" (viscosity average molecular weight 1.9 million to 2.7 million).

[0016] From the viewpoint of the irritation suppression effect, the content of component (C) in the ophthalmic composition is 0.001 to 0.02 w / v%, preferably 0.002 to 0.02 w / v%, and more preferably 0.005 to 0.02 w / v%. If the content of component (C) is too low, the irritation suppression effect is insufficient, and if it is too high, the retention of the ophthalmic composition increases, making eye irritation due to component (A) etc. more likely to occur.

[0017] In the ophthalmic composition of the present invention, the content mass ratio of the (A) component to the (C) component, represented by (C) / (A), is preferably 0.01 to 2, more preferably 0.1 to 2.0, and even more preferably 0.2 to 2.0. The content mass ratio of the (B) component to the (C) component, represented by (C) / (B), is preferably 0.004 to 0.4, more preferably 0.02 to 0.2, and even more preferably 0.04 to 0.2. By setting the (C) / (A) ratio and the (C) / (B) ratio within the above range, the effect of alleviating eye irritation is enhanced. Note that the above ratio is a w / v% ratio, but is the same value as the mass ratio.

[0018] [(D) component] From the viewpoint of the irritation suppression effect, it is preferable that the ophthalmic composition of the present invention further contains (D) one or more selected from amino acids and water-soluble vitamins. The component (D) can be used alone or in combination of two or more. Examples of amino acids include potassium L-aspartate, magnesium L-aspartate, and aminoethylsulfonic acid. Examples of water-soluble vitamins include pyridoxine hydrochloride, panthenol, calcium pantothenate, and sodium pantothenate. Among them, aminoethylsulfonic acid and pyridoxine hydrochloride are preferred.

[0019] The content of the component (D) in the ophthalmic composition is preferably 0.005 to 3 w / v %, more preferably 0.01 to 2 w / v %, and even more preferably 0.05 to 1 w / v %, from the viewpoint of the irritation suppression effect.

[0020] [(E) component] In terms of the irritation suppression effect, it is preferable to further blend (E) terpenoid in the ophthalmic composition of the present invention. The (E) component can be used alone or in combination of two or more. The terpenoid in the present invention has a structure in which an isoprene unit is a constituent unit, and examples thereof include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. In addition, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes according to the number of carbon atoms. Specific examples include monoterpenes such as menthol, menthone, camphor, borneol, ryunou, geraniol, cineole, linalool, citronellol, and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids. Among them, it is preferable to use monoterpenes. These terpenoids can be used in any of the d-, l-, or dl-forms. Among them, menthol, menthone, camphor, borneol, geraniol, cineol, and linalool are preferred, and menthol, camphor, borneol, geraniol, cineol, and linalool are more preferred. More preferred are geraniol and menthol. In the present invention, essential oils containing the above-mentioned compounds may be used as terpenoids. Examples of such essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, spearmint oil, and essential oils of dipterocarpaceae plants, rosmarin oil, and lavender oil.

[0021] The content of component (E), when incorporated, in the ophthalmic composition is preferably 0.0001 to 0.1 w / v %, more preferably 0.0005 to 0.05 w / v %, and even more preferably 0.001 to 0.03 w / v %.

[0022] In order to improve the preservative effect, the ophthalmic composition of the present invention is preferably further formulated with boric acid, trometamol, and edetic acid or a salt thereof. Examples of edetate salts include sodium edetate and sodium edetate hydrate. By formulating these salts, preservative effect is obtained, so that the content of the preservative in the ophthalmic composition can be 0.01 w / v% or less, preferably 0.005 w / v% or less, more preferably 0.001 w / v% or less, and even more preferably 0.0001 w / v% or less.

[0023] Examples of preservatives include benzalkonium chloride, benzethonium chloride, thimerosal, phenylethyl alcohol, alkyl polyaminoethyl glycine, alkyl diaminoethyl glycine and / or a salt thereof (e.g., alkyl diaminoethyl glycine hydrochloride), chlorhexidine gluconate, methyl paraoxybenzoate, ethyl paraoxybenzoate, ethyl propyl paraoxybenzoate, sodium benzoate, sorbic acid, boric acid, borax, sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogensulfite, potassium hydrogensulfite and other sulfites, chlorobutanol, oxyquinoline sulfate, benzyl alcohol, polyhexamethylene biguanide, and polydonium chloride.

[0024] The present inventors have found that in an ophthalmic composition containing (A) one or more selected from antihypertensives and antihistamines, and (B) glycyrrhizic acid or its salt, and having a pH of 5.0 to 5.5, when boric acid, trometamol, and edetic acid or its salt are blended and the content of the preservative in the ophthalmic composition is 0.001% by mass or less, the effect of alleviating eye irritation can be more significantly obtained. In this case, it is important that the pH is 5.0 to 5.5 in order to obtain preservative effectiveness.

[0025] [Other ingredients] The composition of the present invention may contain other components to be added to ophthalmic compositions in appropriate amounts, provided that the effects of the present invention are not impaired. Examples of other components include nonionic surfactants, sugars, buffers, isotonicity agents, stabilizers, polyhydric alcohols, oily components, thickeners, drugs, etc. These components may be added alone or in appropriate combination of two or more. The contents of the components shown below are the preferred ranges when added, and are the amounts in the composition.

[0026] The nonionic surfactant is not particularly limited, and the nonionic surfactants used in ophthalmic compositions can be used alone or in appropriate combination of two or more. Specific examples include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and nonionic surfactants other than those mentioned above.

[0027] Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and several types with different average added moles of ethylene oxide are known. The average added moles of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but is exemplified as 3 to 60 moles. Specific examples include polyoxyethylene castor oil 3 (average added moles of EO: 3), polyoxyethylene castor oil 10 (average added moles of EO: 10), polyoxyethylene castor oil 20 (average added moles of EO: 20), polyoxyethylene castor oil 35 (average added moles of EO: 35), polyoxyethylene castor oil 40 (average added moles of EO: 40), polyoxyethylene castor oil 50 (average added moles of EO: 50), and polyoxyethylene castor oil 60 (average added moles of EO: 60). These polyoxyethylene castor oils can be used alone or in appropriate combination of two or more. From the viewpoint of reducing the irritating sensation when applied to the eyes, it is preferable to use polyoxyethylene castor oil 35.

[0028] Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types with different average added moles of ethylene oxide are known. The average added moles of ethylene oxide in polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified as 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (EO average number of added moles: 5), polyoxyethylene hydrogenated castor oil 10 (EO average number of added moles: 10), polyoxyethylene hydrogenated castor oil 20 (EO average number of added moles: 20), polyoxyethylene hydrogenated castor oil 30 (EO average number of added moles: 30), polyoxyethylene hydrogenated castor oil 40 (EO average number of added moles: 40), polyoxyethylene hydrogenated castor oil 50 (EO average number of added moles: 50), polyoxyethylene hydrogenated castor oil 60 (EO average number of added moles: 60), polyoxyethylene hydrogenated castor oil 80 (EO average number of added moles: 80), polyoxyethylene hydrogenated castor oil 100 (EO average number of added moles: 100), etc. can be mentioned. These polyoxyethylene hydrogenated castor oils can be used alone or in appropriate combination of two or more. From the viewpoint of reducing the irritation when applied to the eye, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.

[0029] Other nonionic surfactants include polyoxyethylene sorbitan fatty acid esters (POE sorbitan fatty acid esters) such as polysorbate 80 (polyoxyethylene (20) sorbitan oleate), polyoxyethylene polyoxypropylene glycols (POEPOP glycols) such as poloxamer, polyethylene glycol monostearate (10) and polyethylene glycol monostearate (40), and the like.

[0030] When a nonionic surfactant is added, its content is not particularly limited as long as the above ratio is satisfied, but it is preferably 0.0001 to 10 w / v %, and more preferably 0.0001 to 5 w / v %, in the composition. When polyoxyethylene castor oil is blended, its amount in the composition is preferably 0.003 to 10 w / v %, more preferably 0.003 to 5 w / v %, and even more preferably 0.03 to 1 w / v %. When polyoxyethylene hydrogenated castor oil is blended, its amount in the composition is preferably 0.003 to 10 w / v %, more preferably 0.003 to 5 w / v %, and even more preferably 0.03 to 1 w / v %. When a nonionic surfactant other than those mentioned above is added, the amount in the composition is preferably 0.0003 to 1 w / v %, more preferably 0.0003 to 0.5 w / v %, and even more preferably 0.003 to 0.1 w / v %.

[0031] Examples of the sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc. These may be in the D-, L- or DL-form. When the sugar is added, the content thereof in the ophthalmic composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0032] Examples of the buffering agent include citric acid, sodium citrate, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, sodium hydrogen carbonate, etc. When a buffering agent is incorporated, the content thereof in the ophthalmic composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 2 w / v%, and even more preferably 0.001 to 1 w / v%.

[0033] Examples of isotonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. The osmotic pressure ratio of the composition to physiological saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and most preferably 0.83 to 1.20. The osmotic pressure is measured at 25°C using an automatic osmometer (A2O, Advanced Instruments).

[0034] Examples of the stabilizer include cyclodextrin, sulfite, dibutylhydroxytoluene, etc. When a stabilizer is added, the content thereof in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0035] Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, polyethylene glycol, etc. When a polyhydric alcohol is incorporated, the content of the polyhydric alcohol in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0036] Examples of oily components include soybean oil, olive oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglyceride, liquid paraffin, vitamin E such as d-α-tocopherol acetate, vitamin A such as retinol palmitate, white petrolatum, purified lanolin, cholesterol, mixed tocopherol, etc. The content is preferably 0.001 to 1.0 w / v%, more preferably 0.001 to 0.5 w / v%, and most preferably 0.001 to 0.25 w / v%.

[0037] Examples of drugs (pharmaceutical active ingredients) include anti-inflammatory and astringent agents (e.g., neostigmine methylsulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), fat-soluble vitamins (vitamin A, vitamin E), sulfa drugs, etc. When drugs are added, the content of the drug can be selected based on the effective amount of each drug, but is preferably 0.001 to 5.0 w / v% in the composition, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0038] Specific examples of vitamin A include retinol palmitate (retinol palmitate ester), retinol acetate, and the like. Specific examples of vitamin E include tocopherol acetate, tocopherol succinate, and tocopherol nicotinate. The content of vitamins is preferably 0.001 to 1 w / v%, more preferably 0.003 to 0.5 w / v%, and even more preferably 0.005 to 0.1 w / v%. When the vitamin is vitamin A, the content of vitamin A is preferably 1000 units / 100mL or more, more preferably 3000 units / 100mL or more, even more preferably 5000 to 100,000 units / 100mL, particularly preferably 10,000 to 80,000 units / 100mL, and most preferably 50,000 to 65,000 units / 100mL. Note that 1 unit of vitamin A content means 1 unit of vitamin A as described in the Vitamin A Quantitative Method of the Japanese Pharmacopoeia, 17th Edition.

[0039] [Manufacturing method] The method for producing the ophthalmic composition is not particularly limited, but for example, the ophthalmic composition can be obtained by mixing the above components (A) to (C) and any optional components as necessary, adjusting the pH, and then adjusting the total volume with water. The liquids can be mixed by a general method, and can be appropriately mixed using a pulsator, propeller blade, paddle blade, turbine blade, etc., but the rotation speed is not particularly limited, and it is preferable to set it to a level that does not cause vigorous foaming.

[0040] [Ophthalmic composition] The ophthalmic composition of the present invention is preferably an "aqueous ophthalmic composition". In the present invention, the "aqueous ophthalmic composition" refers to an ophthalmic composition whose medium is water. The content of water in the composition is preferably 90.0 to 99.5 w / v%, more preferably 95.0 to 99.0 w / v%.

[0041] The pH of the ophthalmic composition of the present invention at 25°C is 5.0 to 5.5, more preferably 5.1 to 5.5, and even more preferably 5.3 to 5.5, from the viewpoints of the mobility of the drug component to the cornea, the promotion of absorption, and the preservative effect. In the present invention, the pH is a value measured at 25°C using a pH meter, for example, HM-25R, manufactured by DKK-TOA Corporation. Preferred examples of the pH adjuster include inorganic acids and inorganic alkali agents. Specifically, examples of the inorganic acid include (dilute) hydrochloric acid. Examples of the inorganic alkali agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, and the like.

[0042] The viscosity of the ophthalmic composition at 25°C is preferably 1 to 2 mPa·s, more preferably 1 to 1.5 mPa·s, and even more preferably 1 to 1.1 mPa·s. Within this range, the feeling of use is good. If the viscosity is too high, the retention will increase and eye irritation will easily occur. In the present invention, the viscosity is a value measured at 20°C using a B-type viscometer, for example, BROOKFIELD DV2T, manufactured by Eiko Seiki Co., Ltd.

[0043] Preferred examples of the viscosity modifier include water-soluble polymer compounds. Examples include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, dextran, alginic acid, sodium alginate, xanthan gum, etc. When a viscosity modifier is added, it can be added within a range that does not cause eye irritation due to increased retention of the ophthalmic composition, and does not impair the feeling of use such as stickiness and blurring. When added, the content is preferably 0.001 to 1.0 w / v% in the ophthalmic composition, more preferably 0.001 to 0.5 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0044] The formulation of the ophthalmic composition of the present invention is not particularly limited, and can be suitably used, for example, as eye drops (including eye drops that can be applied while wearing contact lenses), eyewash, contact lens wetting solution, contact lens removal solution, etc. Contact lenses include, but are not limited to, hard contact lenses (including O2 hard contact lenses), soft contact lenses (including both ionic and non-ionic), silicone hydrogel contact lenses, colored contact lenses, etc. When no preservative is added, the composition is particularly suitable for soft contact lenses and silicone hydrogel contact lenses.

[0045] [Container, packaging] The obtained ophthalmic composition may be filled into a resin container and then sealed with a packaging material, and an inert gas such as nitrogen may be sealed in the space formed between the container and the packaging material. Alternatively, the ophthalmic composition may be filled into a resin container and then sealed with a packaging material together with an oxygen scavenger.

[0046] The container is preferably a plastic container, and may be made of a material such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, vinyl chloride resin, or a composite of these materials. Polyethylene terephthalate is particularly preferred. The amount of the ophthalmic composition in the product can be appropriately selected depending on the product and its method of use. For example, in the case of eye drops, it is preferably 2 to 20 mL, more preferably 5 to 20 mL. The container for the ophthalmic composition is not particularly limited, but may be a multi-dose (multi-unit) container or a single-use unit-dose container. A multi-dose (multi-unit) container is preferred.

[0047] The obtained ophthalmic composition may be filled into a resin container and then further sealed with a packaging material, and an inert gas may be sealed in the space formed between the container and the packaging material. Alternatively, the ophthalmic composition may be filled into a resin container and then sealed with a packaging material together with an oxygen scavenger.

[0048] The inner stopper and cap can be made of a material used for containers of known ophthalmic products. The inner stopper is preferably made of polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8. The cap is preferably made of polyethylene or polypropylene.

[0049] [Preservative effect method] The present invention relates to a method for treating a chronic obstructive pulmonary disease comprising: (A) one or more selected from antihypertensive drugs and antihistamines; (B) glycyrrhizinic acid or a salt thereof, and (C) hyaluronic acid or a salt thereof 0.001 to 0.02% by mass The present invention provides a method for improving the preservative effectiveness of an ophthalmic composition, comprising adjusting the pH of the ophthalmic composition to 5.0 to 5.5. The preferred components, amounts, etc. are the same as those described above. EXAMPLES

[0050] The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to the following examples. Unless otherwise specified, "%" in the composition is w / v% (mass / volume%, g / 100 mL), and the ratio is w / v% ratio, but is the same as the mass ratio.

[0051] [Examples and Comparative Examples] The components shown in the following table were mixed to prepare an ophthalmic composition (eye drop). The obtained ophthalmic composition was subjected to the following evaluations. The results are also shown in the table.

[0052] [Eye irritation] The ophthalmic composition (eye drops) was filled into an eye drop container (made of polyethylene terephthalate) with a capacity of about 16 mL. One drop of the ophthalmic composition (eye drops) was instilled into each eye of five subjects, and the sensation of irritation (stinging sensation) was evaluated based on the following rating scale for three minutes immediately after instillation. The results are shown according to the following rating scale based on the average score obtained.

[0053] <Score> 0: No irritation (no stinging sensation) 1: Almost no stimulation 2: Slight irritation 3. I feel stimulated <Evaluation criteria> ◎: Average score 0 or more but less than 1 ○: Average score 1 or more but less than 2 ×: Average score 2 or more but less than 3

[0054] [Preservative effect] The preservative effectiveness test was carried out according to the preservative effectiveness test method in the 17th edition of the Japanese Pharmacopoeia, Reference Information. The test strain was Escherichia coli (ATCC8739), and 1 mL of each sample contained 10 5 The bacteria were added so that the number of viable bacteria was 100, and the mixture was allowed to stand at 25° C. After 7 and 14 days, 1 mL of each sample was cultured on an agar medium for 5 days, and the viable cell count was measured. Initial bacterial count (10 5 The remaining rate (%) was calculated based on the total number of cells / mL. Those that met the criteria were deemed conforming, and those that did not were deemed non-conforming. Judgment criteria (residual rate against inoculated bacteria: 7 days later: 10% or less and 14 days later: 0.1% or less

[0055] [Table 1]

[0056] [Table 2]

[0057] [Table 3]

[0058] [Prescription example] An ophthalmic composition (eye drops) was obtained in the same manner as in the above-mentioned Example. Eye irritation was suppressed as in the Example.

[0059] [Table 4]

[0060] [Table 5]

[0061] [Table 6]

[0062] The raw materials used in the above examples are shown below. Unless otherwise specified, the amounts of each component in the table are calculated as pure amounts. Tetrahydrozoline hydrochloride: Tetrahydrozoline hydrochloride, manufactured by Okami Chemical Industry Co., Ltd. Phenylephrine hydrochloride: Phenylephrine hydrochloride (crystal), manufactured by Iwaki Pharmaceutical Co., Ltd. Chlorpheniramine maleate: Chlorpheniramine maleate (chlorpheniramine maleate), manufactured by Kongo Chemical Co., Ltd. Dipotassium glycyrrhizinate: Dipotassium glycyrrhizinate, non-regulated by the Ministry of Health, Labour and Welfare, manufactured by Maruzen Pharmaceutical Co., Ltd. Sodium hyaluronate: Hyaluronic acid FCH-80, Viscosity average molecular weight: 500,000 to 1,490,000, Kikkoman Biochemifa Corporation Hypromellose: METLOSE Japanese Pharmacopoeia Hypromellose 60SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd. Bio-sodium hyaluronate (SZE), manufactured by Shiseido Aminoethylsulfonic acid: Taurine, Iwaki Pharmaceutical Co., Ltd. Pyridoxine hydrochloride: Pyridoxine hydrochloride Pyridoxine hydrochloride, manufactured by BASF Japan Ltd. Panthenol: Panthenol, manufactured by DSM Nutrition Japan Boric acid: Boric acid, manufactured by Kanto Chemical Co., Ltd. Trometamol: 2-amino-2-hydroxymethyl-1,3-propanediol, manufactured by Kanto Chemical Co., Ltd. Sodium edetate: Crewat N, manufactured by Nagase Chemtex Corporation l-Menthol: l-Menthol (mint), manufactured by Suzuki Mint Co., Ltd.

Claims

1. (A) one or more selected from anticongestive heart drugs and antihistamines, (B) glycyrrhizinic acid or a salt thereof, (C) 0.001 to 0.02% by mass of hyaluronic acid or a salt thereof, and Boric acid, trometamol, edetic acid or a salt thereof, Contains the content of a preservative selected from benzalkonium chloride, benzethonium chloride, thimerosal, phenylethyl alcohol, alkyl polyaminoethyl glycine, alkyl diaminoethyl glycine and / or a salt thereof, chlorhexidine gluconate, methyl paraoxybenzoate, ethyl paraoxybenzoate, ethyl propyl paraoxybenzoate, sodium benzoate, sorbic acid, sodium sulfite, potassium sulfite, dry sodium sulfite, sodium pyrosulfite, potassium pyrosulfite, sodium hydrogensulfite, potassium hydrogensulfite, chlorobutanol, oxyquinoline sulfate, benzyl alcohol, polyhexamethylene biguanide, and polydronium chloride is 0.001% by mass or less, An ophthalmic composition having a pH of 5.0 to 5.

5.

2. 2. The ophthalmic composition according to claim 1, wherein the component (A) is at least one member selected from the group consisting of tetrahydrozoline hydrochloride and phenylephrine hydrochloride.

3. 3. The ophthalmic composition according to claim 1, wherein the content mass ratio represented by (C) / (A) is 0.01 to 2, and the content mass ratio represented by (C) / (B) is 0.004 to 0.

4.

4. The ophthalmic composition according to any one of claims 1 to 3, further comprising (D) one or more members selected from the group consisting of amino acids and water-soluble vitamins.

5. The ophthalmic composition according to any one of claims 1 to 4, further comprising (E) a terpenoid.

6. (A) one or more selected from anticongestive heart drugs and antihistamines, (B) glycyrrhizinic acid or a salt thereof, (C) 0.001 to 0.02% by mass of hyaluronic acid or a salt thereof, and Boric acid, trometamol, edetic acid or a salt thereof, Contains A method for improving the preservative effectiveness of an ophthalmic composition, comprising: an ophthalmic composition containing 0.001% by mass or less of a preservative selected from benzalkonium chloride, benzethonium chloride, thimerosal, phenylethyl alcohol, alkylpolyaminoethylglycine, alkyldiaminoethylglycine and / or a salt thereof, chlorhexidine gluconate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, ethylpropyl parahydroxybenzoate, sodium benzoate, sorbic acid, sodium sulfite, potassium sulfite, dry sodium sulfite, sodium pyrosulfite, potassium pyrosulfite, sodium hydrogensulfite, potassium hydrogensulfite, chlorobutanol, oxyquinoline sulfate, benzyl alcohol, polyhexamethylene biguanide, and polydonium chloride; and adjusting the pH of the ophthalmic composition to 5.0 to 5.5.

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