Ophthalmic product

Abstract

An ophthalmic product in which an ophthalmic composition containing (A) hyaluronic acid or a salt thereof, (B) chlorhexidine, and (C) [epsilon]-aminocaproic acid or a salt thereof is accommodated in a container sterilized with an electron beam or gamma ray.

Description

Technical Field

[0001] The present invention relates to an ophthalmic product contained in a container sterilized by electron beam or gamma ray. Background Art

[0002] Ophthalmic compositions are required to be kept sterile before opening. Examples of methods for sterilizing ophthalmic compositions include adding a preservative to the ophthalmic composition, but the container thereof is also required to be sterilized, and methods for such methods have been proposed.

[0003] Prior art literature

[0004] Patent Literature

[0005] Patent Document 1: Japanese Patent Application Publication No. 2019-6753 Summary of the invention

[0006] Problem that the invention aims to solve

[0007] Among the components of ophthalmic compositions, (A) hyaluronic acid or its salt can keep moisture on the surface of the eye for a long time due to its high water retention, and in addition, it itself has the effect of repairing wounds on the surface of the eye. (B) chlorhexidine has the effect of being a preservative. The inventors have found that if the ophthalmic composition containing these two components is contained in a container sterilized by electron beam or gamma ray, insoluble matter will be produced after freezing and thawing (returning to room temperature again after freezing), resulting in reduced appearance stability. Therefore, solving this problem is a subject.

[0008] Solutions for solving problems

[0009] The present inventors have found that the above-mentioned technical problems can be solved by adding (C) ε-aminocaproic acid to an ophthalmic composition, thereby completing the present invention.

[0010] Therefore, the present invention provides the following ophthalmic products.

[0011] 1. An ophthalmic product comprising an ophthalmic composition contained in a container sterilized by electron beam or gamma ray, the ophthalmic composition comprising:

[0012] (A) hyaluronic acid or a salt thereof,

[0013] (B) Chlorhexidine, and

[0014] (C) ε-Aminocaproic acid or a salt thereof.

[0015] 2. The ophthalmic product according to 1, wherein the content mass ratio represented by (C) / (B) is 100 to 5000.

[0016] 3. The ophthalmic product according to 1 or 2, wherein the content of the component (A) in the ophthalmic composition is 0.01 to 0.1 w / v%.

[0017] 4. The ophthalmic product according to any one of 1 to 3, wherein the ophthalmic composition further contains (D) propylene glycol.

[0018] 5. The ophthalmic product according to any one of 1 to 4, wherein the ophthalmic composition further contains (E) sodium chloride, and the content of sodium chloride in the ophthalmic composition is 0.1 to 1.0 w / v%.

[0019] 6. The ophthalmic product according to any one of 1 to 5, wherein the material of the container is at least one selected from the group consisting of polyethylene, polyethylene terephthalate, and polypropylene.

[0020] Effects of the Invention

[0021] According to the present invention, an ophthalmic product can be provided, wherein an ophthalmic composition containing (A) hyaluronic acid or a salt thereof and (B) chlorhexidine is contained in a container sterilized by electron beams or gamma rays, wherein the ophthalmic product can suppress the generation of insoluble matter after freeze-thawing and has excellent appearance stability. DETAILED DESCRIPTION

[0022] Hereinafter, the present invention will be described in detail.

[0023] [(A) ingredient]

[0024] The hyaluronic acid or its salt of the present invention is not particularly limited, and any hyaluronic acid in the mucosal preparation commonly used in the field of ophthalmology, etc. can be used. As examples of hyaluronic acids, hyaluronic acid, its derivatives, and their pharmacologically physiologically allowed salts can be listed. The material obtained by the method of extracting from cockscomb, the fermentation method using microorganisms, etc. can be used, and the source and the manufacturing method are not particularly limited. Hyaluronic acid or its salt can be used alone or in combination of two or more. As a specific example of (A) component, hyaluronic acid, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, etc. can be listed. Among them, sodium hyaluronate is preferred. As (A) component, commercially available products can be used, for example, purified sodium hyaluronate (manufactured by Biochemical Industry Co., Ltd., manufactured by Kewpie Co., Ltd., manufactured by Kikkoman Biochemical Co., Ltd., manufactured by Iwaki Pharmaceutical Co., Ltd., and manufactured by Huaxi Biological Co., Ltd.) can be listed.

[0025] The average molecular weight of component (A) is preferably 500,000 to 5,000,000, more preferably 500,000 to 4,000,000, further preferably 500,000 to 2,500,000, particularly preferably 500,000 to 2,000,000, and most preferably 500,000 to 1,490,000. The average molecular weight of component (A) can be measured according to the method for measuring the average molecular weight recorded in the "Purified Sodium Hyaluronate" recorded in each article of the 18th revised Japanese Pharmacopoeia. It should be noted that a variety of hyaluronic acids and / or salts having different average molecular weights can be used.

[0026] As the component (A), commercially available products can be used, for example, "Sodium Hyaluronate 'Sei Kagaku'" (average molecular weight 500,000 to 1.2 million), "Sodium Hyaluronate for Cosmetics (HC)" (average molecular weight 530,000 to 1.33 million) manufactured by Seikagaku Kogyo Co., Ltd.; "Hyaluronic Acid FCH-60" (average molecular weight 500,000 to 700,000), "Hyaluronic Acid FCH-80" (average molecular weight 600,000 to 1,000,000), "Hyaluronic Acid FCH-120" (average molecular weight 1,000,000 to 1,400,000), and "Hyaluronic Acid FCH-200" (average molecular weight 1,000,000 to 1,000,000) manufactured by Kikkoman Biochemical Co., Ltd. Hyaluronic acid FCH-150 (average molecular weight 1.4 million to 1.8 million), Hyaluronic acid FCH-151C (average molecular weight 1.4 million to 1.8 million), Hyaluronic acid FCH-200 (average molecular weight 1.8 million to 2.2 million), Hyaluronic acid FCH-201C (average molecular weight 1.8 million to 2.2 million), Hyaluronic acid FCH-80LE (average molecular weight 0.6 million to 1.2 million), Hyaluronic acid GS-100 (average molecular weight 0.5 million to 1.49 million); Hyaluronic acid FCH-150 (average molecular weight 1.4 million to 1.8 ...) manufactured by Kewpie Co., Ltd. Hyaluronic acid HA-QA" (average molecular weight 600,000 to 1.2 million), "Hyaluronic acid HA-AM" (average molecular weight 600,000 to 1.2 million), "Hyaluronic acid HA-Q" (average molecular weight 530,000 to 1.13 million), "Hyaluronic acid M5070" (average molecular weight 500,000 to 700,000), "Hyaluronic acid HA-LQ" (average molecular weight 850,000 to 1.6 million), "Hyaluronic acid HA-LQH" (average molecular weight 1.2 million to 2.2 million), "Hyaluronic acid HA-AML" (average molecular weight 500,000 to 1.2 million), "Hyaluronic acid H A-SHL" (average molecular weight 1.6 million to 2.4 million); "Hyaluronic acid IW90" (average molecular weight 800,000 to 1.17 million), "Hyaluronic acid IW120" (average molecular weight 1.1 million to 1.6 million), and "Hyaluronic acid IW200" (average molecular weight 1.9 million to 2.7 million) manufactured by Iwaki Pharmaceutical Co., Ltd.; "Purified sodium hyaluronate JP-AE" (average molecular weight 500,000 to 1.49 million), "Purified sodium hyaluronate JP-E" (average molecular weight 500,000 to 1.49 million), "Sodium Hyaluronate MW80 / 110" (average molecular weight 800,000 to 1.1 million), "Sodium Hyaluronate MW110 / 160" (average molecular weight 1.1 million to 1.6 million), and "Sodium Hyaluronate MW190 / 240" (average molecular weight 1.9 million to 2.4 million) manufactured by Bloomage Biotechnology Co., Ltd.

[0027] The content of component (A) in the ophthalmic composition is preferably 0.001 w / v% (mass / volume%, g / 100 mL) or more, more preferably 0.005 w / v% or more, and is further preferably in the order of 0.001-0.3 w / v%, 0.005-0.2 w / v%, 0.01-0.15 w / v%, 0.01-0.1 w / v%, and 0.05-0.1 w / v%. When the content of component (A) is too high, the viscosity of the ophthalmic composition is too high, and there is a risk of causing blurring, etc., and in particular, by setting it to 0.1 w / v% or less, the generation of insoluble matter after freeze-thaw can be further suppressed, and the appearance stability can be further improved.

[0028] [(B) ingredient]

[0029] Chlorhexidine is not particularly limited, and any chlorhexidine in the mucous membrane applicable preparations commonly used in ophthalmology fields etc. can be used, and one or more of them can be used alone. Chlorhexidine can be a salt, for example, chlorhexidine gluconate, chlorhexidine acetate, chlorhexidine hydrochloride etc. can be listed. Among them, chlorhexidine gluconate is preferred.

[0030] The content of component (B) in the ophthalmic composition is preferably 0.0001 to 0.01 w / v, more preferably 0.0002 to 0.005 w / v, further preferably 0.0002 to 0.002 w / v, and particularly preferably 0.0002 to 0.0005 w / v%. By making the content of component (B) above the lower limit, the preservation efficacy of the ophthalmic composition can be further improved. By making the content below the upper limit, the generation of insoluble matter after freeze-thaw can be further suppressed, and the appearance stability can be further improved.

[0031] [(C) ingredient]

[0032] In the present invention, by mixing (C) ε-aminocaproic acid or its salt into an ophthalmic composition, the generation of insoluble matter after freezing and thawing, which is a problem unique to ophthalmic products, is suppressed by containing an ophthalmic composition containing (A) hyaluronic acid or its salt and (B) chlorhexidine in a container sterilized by electron beam or gamma ray, thereby improving the appearance stability. ε-aminocaproic acid is a well-known compound as a neutral amino acid also called 6-aminocaproic acid. As a salt of ε-aminocaproic acid used in the present invention, there is no particular limitation as long as it is a salt allowed medically, pharmacologically (pharmaceutically) or physiologically, and one or more kinds can be used alone or in combination. Specific examples of the salt of ε-aminocaproic acid include organic acid salts [e.g., monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polycarboxylates (fumarates, maleates, succinates, malonates, etc.), hydroxycarboxylates (lactates, tartrates, citrates, etc.), organic sulfonates (methanesulfonates, toluenesulfonates, p-toluenesulfonates, etc.)], inorganic acid salts (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, terpyridine, and picoline), and salts with inorganic bases [e.g., ammonium salts; salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.], etc. Among them, ε-aminocaproic acid is preferred. As the component (C), a commercially available item can be used, and examples thereof include "ε-amino-n-caproic acid EKD" manufactured by Sekisui Medical Co., Ltd., and the like.

[0033] The content of component (C) in the ophthalmic composition is preferably 0.005 to 3 w / v, more preferably 0.015 to 2 w / v, further preferably 0.01 to 2 w / v, still more preferably 0.1 to 1 w / v, still more preferably 0.2 to 0.8 w / v, particularly preferably 0.2 to 0.5 w / v, and most preferably 0.3 to 0.5 w / v%. By making the content of component (C) above the lower limit, the generation of insoluble matter after freeze-thaw can be further suppressed, and the appearance stability can be further improved. By making the content below the upper limit, the preservation efficacy of the ophthalmic composition can be further improved.

[0034] [(D) ingredient]

[0035] By further adding (D) propylene glycol to the ophthalmic composition of the present invention, the generation of insoluble matter after freeze-thawing can be further suppressed, and the appearance stability can be further improved.

[0036] The content of component (D) is preferably 0.01 to 1 w / v%, more preferably 0.03 to 0.5 w / v%, and further preferably 0.05 to 0.4 w / v% in the ophthalmic composition. By making the content of component (D) above the lower limit, the generation of insoluble matter after freezing and thawing can be further suppressed, and the appearance stability can be further improved. By making the content below the upper limit, blurring is less likely to occur during eye drops.

[0037] [(E) ingredient]

[0038] By further adding (E) sodium chloride to the ophthalmic composition of the present invention, the generation of insoluble matter after freeze-thawing can be further suppressed, and the appearance stability can be further improved.

[0039] The content of component (E) is preferably 1.0 w / v% or less, more preferably 0.9 w / v% or less, and further preferably 0.7 w / v% or less in the ophthalmic composition. More specifically, it is preferably 0.1 to 1.0 w / v%, more preferably 0.2 to 0.9 w / v%, and further preferably 0.3 to 0.7 w / v%. By making the content of component (E) above the lower limit, the generation of insoluble matter after freeze-thaw can be further suppressed, and the appearance stability can be further improved. By making the content below the upper limit, it is easier to obtain the viscosity of the ophthalmic composition and the moist feeling when dropping the eye.

[0040] The preferred range of the mass ratio of each component in the ophthalmic composition is as follows. It should be noted that this ratio is a w / v% ratio, but it is the same value as the mass ratio. (C) / (B) is preferably 100 or more, and more preferably 200 or more. More specifically, (C) / (B) is preferably 100-5000, more preferably 150-3000, more preferably 200-2000, particularly preferably 350-2000, and most preferably 400-2000. By making the above ratio above the lower limit, the appearance stability after freeze-thaw can be further improved, and by making it below the upper limit, the generation of insoluble matter after freeze-thaw can be further suppressed, and the preservation efficacy of the ophthalmic composition can be further improved.

[0041] (D) / (C) is preferably 0.01 to 3.0, more preferably 0.1 to 2.0, further preferably 0.2 to 1.2, and particularly preferably 0.3 to 1.0. By setting the ratio to the above, the appearance stability after freeze-thaw can be further improved.

[0042] (A) / (E) is preferably 0.05 to 0.70, more preferably 0.10 to 0.50, and even more preferably 0.13 to 0.30. When the ratio is equal to or greater than the lower limit, the appearance stability after freeze-thaw can be further improved, and when the ratio is equal to or less than the upper limit, blurring can be further suppressed.

[0043] ((C) + (D)) / (B) is preferably 100 to 5000, more preferably 150 to 4000, and even more preferably 200 to 3000. When the above ratio is equal to or greater than the lower limit, the appearance stability after freeze-thaw can be further improved, and when it is equal to or less than the upper limit, the preservation efficacy of the ophthalmic composition can be further improved.

[0044] [Other ingredients]

[0045] In the ophthalmic composition of the present invention, other ingredients can be mixed in appropriate amounts within the scope of not damaging the effects of the present invention. As other ingredients, drugs, surfactants, buffers, local anesthetics or analgesics, pH adjusters, stabilizers, sugars, polyols, thickeners, cooling agents, other inorganic compounds, oily components, etc. can be listed. These ingredients can be used alone or in appropriate combinations of two or more for mixing. The content of the ingredients shown below is the preferred range when mixing, which is the amount in the composition.

[0046] Examples of the drug (pharmaceutical active ingredient) include decongestants (vasoconstrictors) (e.g., epinephrine, epinephrine hydrochloride, methylnorepinephrine, norepinephrine, ephedrine, methylephedrine, pseudoephedrine, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, oxymetazoline, methoxamine, phenylpropanolamine, etilefrine, midodrine, tramazoline, synephrine, cirazoline, xylometazoline and pharmaceutically acceptable salts thereof), anti-inflammatory agents (ε-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulenesulfonate, dipotassium glycyrrhizinate, lysozyme hydrochloride, pranoprofen, etc.), astringents (e.g., neostigmine methylsulfate (having an eye muscle regulating effect on the ciliary muscle, etc.), zinc sulfate, lactic acid zinc), antihistamines (e.g., diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, olopatadine hydrochloride, etc.), antiallergic agents (e.g., sodium cromoglycate, azalast, ibudilast, tranilast, pemirolast potassium, amlexanox, etc.), water-soluble vitamins (sodium flavin adenine dinucleotide, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, sodium ascorbate, etc.), fat-soluble vitamins (e.g., retinyl palmitate, tocopherol acetate, tocopherol succinate, tocopherol nicotinate), amino acids (e.g., potassium L-aspartate, magnesium L-aspartate, potassium and magnesium L-aspartate (equal amount mixture), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), antibacterial ingredients (e.g., sulfonamides (sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisoxazole sodium, etc.), etc.), etc.

[0047] When the drugs are added, the dosage can be appropriately selected so as to be effective for each drug. In the ophthalmic composition, the dosage 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%.

[0048] Examples of the surfactant include nonionic surfactants (e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene polyoxypropylene glycol, polyethylene glycol monostearate, etc.), amphoteric surfactants (e.g., glycine-type amphoteric surfactants such as alkyldiaminoethylglycine and alkylpolyaminoethylglycine; betaine-type amphoteric surfactants such as lauryldimethylaminoacetic acid betaine and imidazolyl betaine), and cationic surfactants (e.g., benzalkonium chloride and benzethonium chloride).

[0049] When a surfactant is added, the amount in the ophthalmic composition is preferably 0.0001 to 5 w / v%, more preferably 0.0003 to 3 w / v%, and still more preferably 0.003 to 1 w / v%.

[0050] As buffering agents, for example, boric acid or its salts (borax, etc.), trishydroxymethylaminomethane, citric acid or its salts (sodium citrate, etc.), phosphoric acid or its salts (sodium hydrogen phosphate, sodium dihydrogen phosphate, etc.), tartaric acid or its salts (sodium tartrate, etc.), gluconic acid or its salts (sodium gluconate, etc.), acetic acid or its salts (sodium acetate, etc.), glacial acetic acid, carbonic acid or its salts (sodium carbonate, sodium bicarbonate, etc.), various amino acids (potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), etc. can be listed. It should be noted that they can also be hydrates. When the buffering agent is mixed, its amount in the ophthalmic composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 2 w / v%, and further preferably 0.001 to 1 w / v%.

[0051] Examples of the isotonic agent include potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dried sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerol, etc. When the isotonic agent is added, the amount thereof is preferably 0.00001 to 3 w / v%, more preferably 0.0001 to 2 w / v%, and further preferably 0.005 to 1.5 w / v% in the ophthalmic composition.

[0052] Examples of local anesthetics or analgesics include chlorobutanol, oxybuprocaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, lidocaine hydrochloride, etc. When a local anesthetic or analgesic is added, the amount used is preferably 0.001 to 1.0 w / v%, more preferably 0.01 to 0.5 w / v% in the ophthalmic composition.

[0053] As the pH adjuster, for example, inorganic acids or inorganic alkali agents can be listed. Specifically, as the inorganic acid, (dilute) hydrochloric acid can be listed. As the inorganic alkali agent, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc. can be listed. In addition, monoethanolamine, diethanolamine, etc. can be listed. The pH of the composition can also be set to 3.5 to 13.0. From the viewpoint of further improving various symptoms caused by the instability of the tear oil layer, it is preferably 3.5 to 8.0, and more preferably 5.5 to 8.0. It should be noted that the pH is measured at 25°C using a pH meter (HM-25R, manufactured by DKK Toa Co., Ltd.).

[0054] Examples of stabilizers include disodium edetate, disodium edetate hydrate, cyclodextrin, monoethanolamine, etc. Examples of stabilizers (antioxidants) include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and vitamin E (e.g., tocopherol acetate, tocopherol nicotinate, tocopherol succinate, etc.), which are fat-soluble antioxidants.

[0055] Examples of water-soluble stabilizers (antioxidants) include sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogen sulfite, potassium hydrogen sulfite and other sulfites, ascorbic acid, sodium ascorbate, etc. It should be noted that when a stabilizer is added to the ophthalmic composition for soft contact lenses, a stabilizer having low lens adsorption and deposition properties is preferred, and examples thereof include disodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate hydrate, cyclodextrin, vitamin E, vitamin A, sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogen sulfite, potassium hydrogen sulfite and other sulfites, ascorbic acid, sodium ascorbate and the like.

[0056] When a stabilizer is added, the amount thereof used is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and further preferably 0.001 to 0.1 w / v% in the ophthalmic composition.

[0057] As sugars, glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like can be cited. It should be noted that they can be any of d-type, l-type or dl-type. Sugars have the effect of improving the moistening feeling when dropping the eye due to their wettability, and can also be used as isotonic agents. When sugars are mixed, the amount used is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and further preferably 0.001 to 0.1 w / v% in the ophthalmic composition.

[0058] As polyols, for example, glycerol, butylene glycol, polyethylene glycol, xylitol, mannitol, sorbitol, etc. can be cited. Since polyols have wettability, they have the effect of improving the moist feeling when dropping the eyes, and can also be used as isotonic agents. In addition, glycerol can also be used as a solubilizing agent for cooling agents. When the polyol is mixed, the amount used is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and further preferably 0.001 to 0.1 w / v% in the ophthalmic composition.

[0059] As thickeners, water-soluble polymer compounds can be listed, for example, polyvinyl pyrrolidone, 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. can be listed. When the thickener is mixed, it can be mixed to a degree that does not damage the sense of use such as viscosity and blur. When the thickener is mixed, its amount in the ophthalmic composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and further preferably 0.001 to 0.1 w / v%.

[0060] As a cooling agent, for example, menthol, camphor, borneol, geraniol, eucalyptol, linalool, anethole, eugenol, limonene, borneol, etc. can be listed. It can be any of d type, l type or dl type. In addition, essential oils such as peppermint oil, cooling peppermint oil, spearmint oil, peppermint oil, eucalyptus oil, rose oil, fennel oil, bergamot oil, and cinnamon oil can be listed. The cooling agent can improve the actual effect of continuous moisturizing. When mixing cooling agents and essential oils, the amount used is preferably 0.0001 to 1w / v% in the ophthalmic composition, more preferably 0.0005 to 0.2w / v%, and further preferably 0.001 to 0.1w / v%.

[0061] Examples of other inorganic compounds include sodium thiosulfate, titanium oxide, zinc chloride, etc. When these are added, their usage is preferably 0.001 to 5 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v% in the ophthalmic composition.

[0062] [Ophthalmic composition]

[0063] The ophthalmic composition of the present invention is preferably an "aqueous ophthalmic composition". In the present invention, an "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%, and more preferably 95.0 to 99.0 w / v%.

[0064] The light transmittance of the ophthalmic composition at 600 nm is preferably 98.0 to 100.0%, more preferably 99.0 to 100.0%. The light transmittance of the ophthalmic composition at 600 nm after freeze-thawing is preferably 98.0% or more, more preferably 98.5% or more, and even more preferably 99.0% or more.

[0065] The dosage form of the composition of the present invention is not particularly limited, and for example, it can be suitably used as eye drops (including eye drops that can be instilled when wearing contact lenses), eye washes, contact lens wearing solutions, contact lens removal solutions, etc. In particular, it can be suitably used as eye drops and contact lens wearing solutions, and is particularly suitable for use as eye drops. Among them, it is suitable for use as an ophthalmic composition for contact lenses used by contact lens users such as eye drops that can be instilled when wearing contact lenses, contact lens wearing solutions, and contact lens removal solutions.

[0066] As contact lenses, hard contact lenses (including O 2 The invention can be used for hard contact lenses, soft contact lenses (including both ionic and non-ionic contact lenses), silicone hydrogel contact lenses, colored contact lenses, etc., without particular limitation. When no preservative is added, it is particularly suitable for use as soft contact lenses and silicone hydrogel contact lenses.

[0067] [Manufacturing method]

[0068] The method for producing the composition of the present invention is not particularly limited, and for example, the composition can be obtained by pre-dissolving (A), then mixing the solution with a solution containing an aqueous component such as component (B), adjusting the pH, and adjusting the total volume with water. The mixing method of each liquid can be a conventional method, and can be appropriately carried out using an impeller, propeller blades, paddle blades, turbine blades, etc., but the rotation speed is not particularly limited, and is preferably set to a degree that does not foam violently. The mixing temperature of each liquid is not particularly limited, but from the viewpoint of the stability of component (A), it is preferably non-high temperature, and can be appropriately selected from the range of 20 to 60°C.

[0069] [Ophthalmic products]

[0070] The present invention is an ophthalmic product in which the above-mentioned ophthalmic composition is contained in a container sterilized by electron beam or gamma ray.

[0071] [container]

[0072] As a container, a plastic container is preferably used, and materials such as polyethylene (PE), polyethylene terephthalate (PET), polypropylene (PP), polybutene, polycarbonate, polyarylate, vinyl chloride, or containers formed by a composite of these materials can be used. Among them, polyethylene, polyethylene terephthalate, and polypropylene are preferred. The amount of the ophthalmic composition in the product can be appropriately selected according to the product and its method of use. For example, in the case of eye drops, it is preferably 2 to 20 mL, and more preferably 5 to 20 mL. The container of the ophthalmic composition is not particularly limited, and can be a multi-dose (multi-unit) container or a unit dose container that can be used up at one time. It is preferably a multi-dose (multi-unit) container.

[0073] The method of sterilizing by electron beam or gamma ray is not particularly limited and can be carried out according to conventionally known sterilization conditions. For example, from the viewpoint of sterilization effect, it is preferably carried out at 5 to 80 kGy, more preferably at 5 to 50 kGy, and even more preferably at 5 to 30 kGy.

[0074] [Package]

[0075] The ophthalmic composition can be contained in a container sterilized by electron beam or gamma ray, and an inert gas such as nitrogen can be sealed in the space formed between the above container and the above package. The ophthalmic composition can also be filled and contained in the above container, and then sealed with a package together with a deoxidizer. The inner plug and the lid can use a lid made of a material used in a container of a known ophthalmic product. As the material of the inner plug, polyethylene or polypropylene with a melt flow rate of 2.0 or less, preferably 1.2 to 1.8, is preferred. As the material of the lid, polyethylene or polypropylene is preferred.

[0076] [Appearance stabilization method]

[0077] The method of the present invention is a method for stabilizing the appearance of an ophthalmic composition containing (A) hyaluronic acid or a salt thereof and (B) chlorhexidine, which is contained in an ophthalmic product in a container sterilized by electron beam or gamma ray and compounded with (C) ε-aminocaproic acid or a salt thereof. In these methods, the preferred ingredients and dosages are the same as those described above. It should be noted that the appearance stabilization method refers to a method for inhibiting the deterioration of the appearance of the above-mentioned ophthalmic product after freeze-thawing (freezing and returning to room temperature again). Specifically, the appearance stability after freeze-thawing is evaluated by the method described in the examples.

[0078] The light transmittance of the ophthalmic composition product of the present invention at 600 nm is preferably 99.0 to 100.0%, and the light transmittance after repeating the freezing and thawing operation three times is preferably 97.5 to 100.0%, and more preferably 98.0 to 100.0%.

[0079] Example

[0080] The present invention is specifically described below with reference to the Examples and Comparative Examples, but the present invention is not limited to the following Examples. It should be noted that, in the following examples, unless otherwise specified, the "%" of the composition is "w / v% (g / 100mL)", and the ratio is the w / v% ratio, which is the same value as the mass ratio.

[0081] [Examples, Comparative Examples]

[0082] In order to obtain the compounding composition shown in the table, the components other than purified water and pH adjusting agent are dissolved in 90 mL of purified water, and stirred and mixed at room temperature (25°C) for 18 hours. Then, in order to make the pH of the ophthalmic composition at 25°C be 6.5, after adjusting the pH using a pH adjusting agent as needed, the remaining purified water is added in a total amount of 100 mL to obtain an ophthalmic composition. The pH is measured using a pH meter (manufactured by DKK East Asia Co., Ltd., trade name "HM-25R"). The following evaluation is performed on the obtained composition. The results are shown in the table together. It should be noted that the pH of the composition is in the range of 6.0 to 7.0.

[0083] [Appearance stability test method]

[0084] The prepared test ophthalmic composition (10 mL) was filled and contained in an electron beam sterilized container (irradiation dose 18 kGy) and an unsterilized container (10 mL). The obtained ophthalmic product was frozen at -20°C, and after confirming that the ophthalmic composition was frozen, it was taken out to room temperature and thawed. This freezing and thawing operation was repeated 3 times.

[0085] The transmittance at 600 nm was measured using a spectrophotometer (UV-1800, Shimadzu Corporation) for the ophthalmic composition initially and after the freezing and thawing operation was repeated three times.

[0086] The appearance of the ophthalmic product after freezing and thawing was repeated three times was visually observed under a fluorescent light to confirm the presence of particles. The results are shown below.

[0087] ○: No particles observed

[0088] ×: Particles observed

[0089] [Table 1]

[0090]

[0091] [Table 2]

[0092]

[0093] [Table 3]

[0094]

[0095] [Table 4]

[0096]

[0097] [Table 5]

[0098]

[0099] [Table 6]

[0100]

[0101] [Table 7]

[0102]

[0103] [Table 8]

[0104]

[0105] The raw materials used in the preparation of the examples and comparative examples are as follows. It should be noted that, unless otherwise specified, the amounts of the components in the table are based on purity.

[0106] Sodium hyaluronate: Hyaluronic acid HA-AML, manufactured by Kewpie Co., Ltd.

[0107] Chlorhexidine gluconate: 20w / v% MASKIN SOLUTION, manufactured by Maruishi Pharmaceutical Co., Ltd.

[0108] ε-Aminocaproic acid: ε-amino-n-caproic acid EKD, manufactured by Sekisui Medical Co., Ltd.

[0109] Propylene glycol: Japanese Pharmacopoeia Propylene Glycol, manufactured by ADEKA Co., Ltd.

[0110] Sodium chloride: Japanese Pharmacopoeia sodium chloride SG, manufactured by Tomita Pharmaceutical Co., Ltd.

[0111] Disodium EDTA: Disodium EDTA hydrate "for manufacturing only", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.

Claims

1. An ophthalmic product in which an ophthalmic composition is contained in a container sterilized by electron beam or gamma ray, the ophthalmic composition containing: (A) Hyaluronic acid or its salt, (B) Chlorhexidine, and (C) ε-Aminocaproic acid or its salt.

2. The ophthalmic product according to claim 1, wherein the mass ratio of (C) / (B) is 100 to 5000.

3. The ophthalmic product according to claim 1 or 2, wherein the content of component (A) in the ophthalmic composition is 0.01 to 0.1 w / v%.

4. The ophthalmic product according to claim 1 or 2, wherein the ophthalmic composition further contains (D) propylene glycol.

5. The ophthalmic product according to claim 1 or 2, wherein the ophthalmic composition further contains (E) sodium chloride, and its content in the ophthalmic composition is 0.1 to 1.0 w / v%.

6. The ophthalmic product according to claim 1 or 2, wherein the material of the container is one or more selected from polyethylene, polyethylene terephthalate, and polypropylene.

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