Ophthalmic composition housed in container

Abstract

To provide a contained ophthalmic composition with improved preservative efficacy.SOLUTION: An ophthalmic composition housed in a container contains boric acid. The filling amount of the ophthalmic composition into the container is 3 mL or more and less than 5 mL. Part or all of a portion of the container in contact with the ophthalmic composition is formed of at least one resin selected from the group consisting of polyolefin-based resins and polyester-based resins.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an ophthalmic composition contained in a container. [Background technology]

[0002] Generally, multi-dose eye drops contain preservatives that inhibit the growth of microorganisms in case the eye drops are contaminated with bacteria, fungi, etc. However, preservatives also contain cytotoxic components, and frequent or long-term use of eye drops containing preservatives has been reported to cause corneal epithelial damage.

[0003] As a preservative-free eye drop solution, a unit dose eye drop solution that is a single-use eye drop solution is known (for example, Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Molding and Processing, 2003, Vol. 15, No. 10, pp. 679-682 Summary of the Invention [Problem to be solved by the invention]

[0005] Unit-dose eye drops cannot be recapped, so any remaining drops must be discarded, and frequent use requires carrying multiple bottles. This creates a demand for multi-dose eye drops that do not contain preservatives but have a long shelf life after opening.

[0006] Preservative-free multi-dose eye drops often need to be used up within a short period of time after opening in terms of preservative effectiveness. However, it is often difficult for consumers to use up the eye drops within the consumption period, and there is a demand for extending this consumption period. On the other hand, in order to extend the consumption period after opening, it is necessary to improve the preservative effectiveness of the ophthalmic composition.

[0007] In view of the above circumstances, an object of the present invention is to provide a method for improving the preservative effectiveness of an ophthalmic composition contained in a container (a container-packaged ophthalmic composition), and a container-packaged ophthalmic composition having improved preservative effectiveness. [Means for solving the problem]

[0008] The present inventors have found that filling a container with a specific amount of an ophthalmic composition containing boric acid enhances preservative effectiveness, and the present invention is based on this novel finding.

[0009] The present invention provides, for example, the following inventions. [1] An ophthalmic composition contained in a container, The ophthalmic composition contains boric acid, the amount of the ophthalmic composition filled in the container is 3 mL or more and less than 5 mL; An ophthalmic composition, wherein a part or all of the part of the container that comes into contact with the ophthalmic composition is formed from at least one resin selected from the group consisting of polyolefin-based resins and polyester-based resins. [2] The ophthalmic composition according to [1], wherein the expiration date after opening the container is 11 days or more. [3] The ophthalmic composition according to [1] or [2], wherein the resin is polyethylene. [4] The ophthalmic composition according to any one of [1] to [3], which is substantially free of preservatives. [5] The ophthalmic composition according to any one of [1] to [4], further comprising a salt of boric acid. [6] The ophthalmic composition according to any one of [1] to [5], further comprising cyanocobalamin or a salt thereof. [7] A product containing 2 to 6 bottles of the ophthalmic composition according to any one of [1] to [6] per package. [8] 1. A method for inhibiting microbial growth in an ophthalmic composition, comprising: The ophthalmic composition contains boric acid, The method includes filling the ophthalmic composition into a container, the part of which contacts the ophthalmic composition being formed entirely or partially from at least one resin selected from the group consisting of polyolefin-based resins and polyester-based resins, A method in which the amount of the ophthalmic composition filled into the container is 3 mL or more but less than 5 mL. [9] [8] The method according to [8], wherein the expiration date after opening the container is 11 days or more.

[10] The method according to [8] or [9], wherein the resin is polyethylene.

[11] The method according to any one of [8] to

[10] , wherein the ophthalmic composition is substantially free of preservatives.

[12] The method according to any one of [8] to

[11] , wherein the ophthalmic composition further contains a salt of boric acid.

[13] The method according to any one of [8] to

[12] , wherein the ophthalmic composition further contains cyanocobalamin or a salt thereof. [Effects of the Invention]

[0010] According to the present invention, it is possible to provide a method for improving the preservative effectiveness of an ophthalmic composition contained in a container (a container-packaged ophthalmic composition), and a container-packaged ophthalmic composition having improved preservative effectiveness. DETAILED DESCRIPTION OF THE INVENTION

[0011] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0012] [Ophthalmic composition] The ophthalmic composition according to this embodiment contains boric acid. The ophthalmic composition is filled in a container in which a part or all of the portion that comes into contact with the ophthalmic composition is formed of at least one resin selected from the group consisting of polyolefin-based resins and polyester-based resins, and the filled volume of the container is 3 mL or more but less than 5 mL.

[0013] The ophthalmic composition according to this embodiment contains boric acid and is filled in a specific amount in a specific container, thereby enhancing preservative effectiveness.

[0014] The ophthalmic composition according to this embodiment may further contain a salt of boric acid in addition to boric acid.

[0015] Boric acid and its salts are not particularly limited as long as they are medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable. Examples of boric acid salts include alkali metal borate salts and alkaline earth metal borate salts. Specific examples include sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. Boric acid and its salts may be hydrated. When the ophthalmic composition according to this embodiment contains a combination of boric acid and a salt thereof, a combination of boric acid and borax is preferred as the boric acid and its salt.

[0016] The content of boric acid in the ophthalmic composition according to this embodiment is not particularly limited, and for example, based on the total amount of the ophthalmic composition, the content of boric acid per 100 mL may be 0.01 g or more, 0.1 g or more, 0.3 g or more, 0.5 g or more, 0.7 g or more, or 0.9 g or more, or 3 g or less, 2 g or less, 1.8 g or less, 1.5 g or less, 1.2 g or less, or 1 g or less.

[0017] When the ophthalmic composition of this embodiment contains a combination of boric acid and a salt thereof, the content of boric acid and a salt thereof in the ophthalmic composition of this embodiment is not particularly limited, and for example, based on the total amount of the ophthalmic composition, the content of boric acid and a salt thereof in 100 mL may be 0.01 g or more, 0.1 g or more, 0.3 g or more, 0.5 g or more, 0.7 g or more, or 0.9 g or more, or 3 g or less, 2 g or less, 1.8 g or less, 1.5 g or less, 1.2 g or less, or 1 g or less.

[0018] The ophthalmic composition according to this embodiment may further contain an inorganic salt. When the ophthalmic composition further contains an inorganic salt, the effects of the present invention are more pronounced. The inorganic salt is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

[0019] Examples of inorganic salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. One type of inorganic salt may be used alone, or two or more types may be used in combination. Preferred inorganic salts are sodium chloride and potassium chloride.

[0020] The content of inorganic salts in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of inorganic salt, the type and content of other blended ingredients, the intended use and formulation of the ophthalmic composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of inorganic salts may be, for example, based on the total amount of the aqueous composition, such that the total content of inorganic salts per 100 mL is 0.0001 g or more, 0.001 g or more, 0.01 g or more, 0.1 g or more, 0.3 g or more, 0.4 g or more, or 0.5 g or more, or may be 1.7 g or less, 1.5 g or less, 1 g or less, 0.8 g or less, 0.6 g or less, or 0.5 g or less.

[0021] The content of potassium chloride in the ophthalmic composition according to this embodiment is not particularly limited, but from the viewpoint of more significantly exhibiting the effects of the present invention, the content of potassium chloride may be, for example, based on the total amount of the aqueous composition, 0.0001 g or more, 0.001 g or more, 0.01 g or more, 0.02 g or more, 0.05 g or more, or 0.1 g or more, or 0.5 g or less, 0.3 g or less, 0.25 g or less, 0.2 g or less, 0.15 g or less, or 0.1 g or less, or even 0.1 g, per 100 mL.

[0022] The content of sodium chloride in the ophthalmic composition according to this embodiment is not particularly limited, but from the viewpoint of more significantly achieving the effects of the present invention, the content of sodium chloride may be, for example, 0.0001 g or more, 0.001 g or more, 0.01 g or more, 0.05 g or more, 0.1 g or more, 0.2 g or more, 0.3 g or more, or 0.4 g or more, based on the total amount of the aqueous composition, or 1.2 g or less, 1 g or less, 0.7 g or less, 0.5 g or less, or 0.4 g or less.

[0023] The content of sodium chloride relative to potassium chloride in the ophthalmic composition of this embodiment may be 0.0001 parts by mass or more, 0.001 parts by mass or more, 0.01 parts by mass or more, 0.1 parts by mass or more, 1 part by mass or more, 3 parts by mass or more, or 4 parts by mass or more, and may be 10,000 parts by mass or less, 1,000 parts by mass or less, 100 parts by mass or less, 50 parts by mass or less, 10 parts by mass or less, 5 parts by mass or less, or 4 parts by mass or less, or may be 4 parts by mass.

[0024] The content of boric acid relative to the total content of inorganic salts in the ophthalmic composition of this embodiment may be 0.001 parts by mass or more, 0.01 parts by mass or more, 0.1 parts by mass or more, or 0.15 parts by mass or more, and may be 10 parts by mass or less, 5 parts by mass or less, 1 part by mass or less, 0.5 parts by mass or less, or 0.3 parts by mass or less.

[0025] The ophthalmic composition according to this embodiment may further contain cyanocobalamin or a salt thereof. When the ophthalmic composition further contains cyanocobalamin or a salt thereof in addition to boric acid, the effects of the present invention are more pronounced. There are no particular limitations on the cyanocobalamin or a salt thereof, as long as it is pharmaceutically, pharmacologically (pharmaceutical), or physiologically acceptable. Examples of cyanocobalamin salts include cyanocobalamin hydrochloride.

[0026] The content of cyanocobalamin or a salt thereof in the ophthalmic composition of this embodiment is not particularly limited, and for example, based on the total amount of the ophthalmic composition, the content of cyanocobalamin or a salt thereof in 100 mL may be 0.0001 g or more, 0.001 g or more, 0.004 g or more, 0.01 g or more, or 0.02 g or more, or 0.1 g or less, 0.05 g or less, 0.02 g or less, or 0.01 g or less.

[0027] The content of cyanocobalamin or a salt thereof in the ophthalmic composition of this embodiment may be 0.001 parts by mass or more, 0.004 parts by mass or more, 0.01 parts by mass or more, 0.02 parts by mass or more, 0.04 parts by mass or more, or 0.1 parts by mass or more, per 1 part by mass of boric acid, and may be 10 parts by mass or less, 5 parts by mass or less, 1 part by mass or less, 0.5 parts by mass or less, 0.1 parts by mass or less, 0.04 parts by mass or less, or 0.02 parts by mass or less.

[0028] The ophthalmic composition according to this embodiment may further contain a pH adjuster, such as hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, citric acid, sodium carbonate, triethanolamine, monoethanolamine, or diisopropanolamine.

[0029] The ophthalmic composition according to this embodiment may or may not contain a preservative. The ophthalmic composition according to this embodiment has enhanced preservative effectiveness even without the inclusion of a preservative, and therefore may not substantially contain a preservative. As used herein, "preservative" refers to a component that exhibits preservative activity. As used herein, "substantially free of preservative" means that the composition contains no preservative at all, or contains less than the amount of preservative necessary to exhibit preservative activity. As used herein, "exhibits preservative activity" means that an ophthalmic composition containing the substance complies with the standards in the preservative effectiveness test method specified in the Japanese Pharmacopoeia, 18th Edition. As used herein, "high preservative effectiveness" means that the preservative effectiveness is improved according to the preservative effectiveness test method specified in the Japanese Pharmacopoeia, 18th Edition.

[0030] Examples of preservatives include alkylpolyaminoethylglycines, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), polidonium chloride, sodium benzoate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), chlorhexidine gluconate, alexidine, etc.). The ophthalmic composition according to this embodiment preferably does not contain any preservatives.

[0031] The ophthalmic composition according to this embodiment may contain, in addition to the above-mentioned components, an appropriate amount of a combination of components selected from various pharmacologically active components and physiologically active components, as long as the effects of the present invention are not impaired. The components are not particularly limited, and examples thereof include active ingredients in ophthalmic drugs listed in the 2017 edition of the OTC Drug Manufacturing and Marketing Approval Standards (supervised by the Japan Society of Regulatory Science). Specific examples of components used in ophthalmic drugs include the following: Antiallergic agents: for example, cromoglycic acid or a salt thereof (for example, sodium cromoglycate), tranilast, pemirolast potassium, ashitazanolast, amlexanox, ibudilast, etc. Antihistamines: for example, chlorpheniramine or a salt thereof, diphenhydramine or a salt thereof (e.g., diphenhydramine hydrochloride), iproheptine or a salt thereof (e.g., iproheptine hydrochloride), levocabastine or a salt thereof (e.g., levocabastine hydrochloride), ketotifen or a salt thereof (e.g., ketotifen fumarate), pemirolast potassium, olopatadine or a salt thereof (e.g., olopatadine hydrochloride), epinastine or a salt thereof (e.g., epinastine hydrochloride), etc. Steroids: for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc. Decongestants: for example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc. Ocular muscle regulating agents: for example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methylsulfate, tropicamide, Helenien, atropine sulfate, pilocarpine hydrochloride, etc. Anti-inflammatory agents: for example, azulene sulfonic acid or a salt thereof, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, glycyrrhizic acid or a salt thereof (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), zinc sulfate, zinc lactate, etc. Vitamins: for example, retinol or its derivatives, tocopherol or its derivatives, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, panthenol, calcium pantothenate, ascorbic acid, sodium ascorbate, etc. Amino acids: for example, L-arginine, glutamic acid, glycine, alanine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, trimethylglycine, taurine, aspartic acid, or salts thereof. Astringents: for example, zinc oxide. Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine and their salts.

[0032] The ophthalmic composition according to this embodiment may contain various additives appropriately selected according to the formulation, in accordance with conventional methods, in an appropriate amount in combination of one or more types, as long as the effects of the present invention are not impaired. Examples of such additives include those listed in the Pharmaceutical Additives Encyclopedia 2021 (edited by the Japan Pharmaceutical Additives Association). Representative components include the following additives. Carrier: For example, an aqueous solvent such as water or aqueous ethanol. Chelating agents: for example, ethylenediaminetetraacetic acid (EDTA, edetic acid), ethylenediaminetriacetic acid, ethylenediaminediacetic acid (EDDA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc. Bases: for example, octyldodecanol, titanium oxide, potassium bromide, plastibase, etc. Surfactants: for example, nonionic surfactants such as polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, tyloxapol, polyoxyethylene sorbitan fatty acid esters, polyoxyl stearate, etc.; anionic surfactants such as polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, alkyl sulfates, N-acyltaurine salts, etc.; zwitterionic surfactants such as lauryl dimethylaminoacetate betaine, etc. Thickeners: for example, cellulose-based polymer compounds such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose sodium; guar gum; hydroxypropyl guar gum; gum arabic; karaya gum; xanthan gum; agar; alginic acid and its salts (sodium salt, etc.); mucopolysaccharides such as heparin-like substances, heparin, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and its salts (sodium salt, etc.), and chondroitin sulfate and its salts (sodium salt, etc.); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan; monosaccharides such as glucose, etc. Stabilizers: for example, dibutylhydroxytoluene, butylhydroxyanisole, sodium formaldehyde sulfoxylate (Rongalit), aluminum monostearate, glycerin monostearate, cyclodextrin, monoethanolamine, sodium metabisulfite, sodium sulfite, sodium hydrogensulfite, sodium thiosulfate, potassium iodide, etc. Sugar alcohols: for example, xylitol, sorbitol, mannitol, glycerin, etc. Glycols: for example, propylene glycol, ethylene glycol, etc. Oils: for example, vegetable oils such as sesame oil, castor oil, soybean oil, olive oil, etc.; animal oils such as squalane, etc.; mineral oils such as liquid paraffin, Vaseline, etc.

[0033] The ophthalmic composition according to this embodiment can be used, for example, as eye drops (also called eye drops or eye drops; eye drops include artificial tears. Furthermore, eye drops include eye drops that can be applied while wearing contact lenses), eyewash (also called eyewash or eyewash; eyewashes include eyewashes that can be applied while wearing contact lenses), and contact lens compositions (contact lens wetting solution, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaners, contact lens cleaning and preservatives), contact lens wetting solution that can be used both as a contact lens wetting solution and as an eye drop while wearing contact lenses, etc.). The term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic contact lenses, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses). Suitable examples of the ophthalmic composition according to this embodiment include eye drops, eyewashes, and contact lens compositions, and more suitable examples include eye drops, especially artificial tears.

[0034] The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, 5.0 to 9.0, 5.5 to 8.5, 6.0 to 8.0, 6.5 to 7.5, 6.8 to 7.4, 6.9 to 7.3, or 7.0 to 7.2. The pH of the ophthalmic composition according to this embodiment may also be 6.7 to 7.6, 7.0 to 7.5, or 7.2 to 7.4.

[0035] The ophthalmic composition according to this embodiment can be adjusted to have an osmotic pressure ratio within a biologically acceptable range, as needed. The appropriate osmotic pressure ratio can be appropriately determined depending on the intended use, formulation, and method of use of the ophthalmic composition, and may be, for example, 0.5 to 5.0, 0.6 to 3.0, 0.7 to 2.2, 0.8 to 2.0, 0.85 to 1.5, 0.9 to 1.4, 0.9 to 1.3, or 1.0 to 1.2. The osmotic pressure ratio is defined as the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution) in accordance with the Japanese Pharmacopoeia, 18th Edition, and is measured using the osmotic pressure measurement method (freezing-point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, allowing it to cool in a desiccator (silica gel), accurately weighing 0.900 g of the solution, and dissolving it in purified water to make exactly 100 mL; alternatively, a commercially available standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be used.

[0036] The viscosity of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. The viscosity of the ophthalmic composition according to this embodiment may be, for example, 0.5 to 120 mPa·s, 0.6 to 100 mPa·s, 0.7 to 70 mPa·s, 0.8 to 40 mPa·s, 0.9 to 30 mPa·s, 1 to 20 mPa·s, 1 to 10 mPa·s, 1 to 5 mPa·s, 1 to 3 mPa·s, or 1 to 1.5 mPa·s at 20°C as measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34'×R24).

[0037] (container) The ophthalmic composition according to this embodiment is contained in a container. A part or all of the portion of the container that comes into contact with the ophthalmic composition is formed from at least one resin selected from the group consisting of polyolefin-based resins and polyester-based resins. The container may be any packaging having a portion that comes into contact with the ophthalmic composition, and may be composed of, for example, a container body that contains the ophthalmic composition, a portion including a discharge part of the container (e.g., a nozzle, an inner plug), a suction tube, a cap, etc.

[0038] The polyolefin resin may be a polymer obtained by polymerizing one type of olefin alone or a polymer obtained by copolymerizing two or more types of olefins. These polymers may contain other polymerizable monomers as constituent components. Specific examples of polyolefin resins include polyethylene (including low-density polyethylene, medium-density polyethylene, high-density polyethylene, etc.), polypropylene (including isotactic polypropylene, syndiotactic polypropylene, and atactic polypropylene), ethylene-propylene copolymer, polymethylpentene, etc. Among these, polyethylene and polypropylene are preferred, and polyethylene is more preferred, from the viewpoints of usability, such as the squeeze force (the force required to drip eye drops from an eye dropper), and the uniformity of the amount of each drop.

[0039] The polyester resin may be a polymer obtained by condensation polymerization of one or more polycarboxylic acids and one or more polyalcohols. The polymer may contain other polymerizable monomers as constituent components. Specific examples of polyester resins include polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, and polycarbonate.

[0040] In the container according to this embodiment, a part or all of the portion that comes into contact with the ophthalmic composition is formed of at least one resin selected from the group consisting of polyolefin-based resins and polyester-based resins. Here, examples of the portion of the container that comes into contact with the ophthalmic composition include the container body that contains the ophthalmic composition (the innermost layer if the container has a multi-layer structure), the inner stopper, and the perforated inner stopper. For example, if the container has a perforated inner stopper (nozzle), the container body that contains the ophthalmic composition, other than the perforated inner stopper, may be formed of the above-mentioned resin, or the entire container may be formed of the above-mentioned resin. The container according to this embodiment may be a container made of the above-mentioned resin molded by the blow-fill-seal (BFS) method.

[0041] The diameter of the hole on the liquid contact surface of the container according to this embodiment may be, for example, 0.1 to 2 mm, 0.3 to 1.5 mm, or 0.3 to 1 mm.

[0042] The diameter of the tip of the container according to this embodiment may be, for example, φ1 to 4 mm, 1.5 to 3 mm, or 2 to 2.5 mm.

[0043] When the container according to this embodiment is a perforated inner plug (nozzle), the diameter of the nozzle tip may be, for example, φ1 to 4 mm, 1.5 to 3 mm, or 2 to 2.5 mm.

[0044] The shape and capacity of the container according to the present embodiment are not particularly limited and may be appropriately determined depending on the application. For example, when the container is a container for storing eye drops, the capacity may be, for example, 5 mL to 20 mL, 6 mL to 15 mL, 7 mL to 12 mL, 7 mL to 10 mL, or 7.5 mL to 9 mL.

[0045] The container according to this embodiment may be a multi-dose type that contains an amount for multiple uses, or a unit-dose type that contains an amount for single use. From the viewpoint of more significantly exhibiting the effects of the present invention, the container according to this embodiment is preferably a multi-dose type.

[0046] The ophthalmic composition according to this embodiment is filled into the container according to this embodiment in a volume of 3 mL or more and less than 5 mL. This provides the effect of enhancing preservative efficacy. From the viewpoint of more significantly achieving the effects of the present invention, the volume may be, for example, 3.2 mL or more and 4.8 mL or less, 3.4 mL or more and 4.6 mL or less, 3.6 mL or more and 4.4 mL or less, 3.8 mL or more and 4.2 mL or less, or 4 mL.

[0047] The filling rate of the ophthalmic composition according to this embodiment may be 30 to 70%, 40 to 60%, or 45 to 55%, from the viewpoint of more significantly exhibiting the effects of the present invention.

[0048] The expiration date of the ophthalmic composition according to this embodiment after opening the container is not particularly limited and can be set appropriately depending on the intended use, formulation, method of use, etc. of the ophthalmic composition. Since the ophthalmic composition according to this embodiment exhibits the effect of enhancing preservative effectiveness, the expiration date may be set longer. The expiration date may be, for example, within a range of 10 to 30 days, 11 to 20 days, 12 to 18 days, 13 to 16 days, 14 to 15 days, or 14 days.

[0049] The ophthalmic composition according to this embodiment may be configured as a product in which, for example, 2 to 6 bottles of the ophthalmic composition (container-packaged ophthalmic composition) are contained per package. The number of bottles per package may be, for example, 2 to 6, 3 to 5, 4 to 5, or 5. The product is usually configured in the form of a paper package containing multiple bottles of the container-packaged ophthalmic composition.

[0050] The present invention as described above can also be understood as a method for inhibiting the growth of microorganisms in an ophthalmic composition, the method comprising filling the ophthalmic composition into a container, the entire or a part of which comes into contact with the ophthalmic composition being formed of at least one resin selected from the group consisting of polyolefin resins and polyester resins, with the ophthalmic composition, and the amount of the ophthalmic composition filled into the container is 3 mL or more but less than 5 mL. Specific embodiments of the method can be applied without particular limitations to the specific embodiments described above. [Example]

[0051] The present invention will be specifically described below based on examples, but the present invention is not limited to these examples.

[0052] [Test Example 1: Preservative Effectiveness Test] Ophthalmic compositions were prepared according to a conventional method using the compositions shown in Table 1. They were then sterilized by filtration through a 0.2 μm membrane filter. [Table 1]

[0053] Each prepared ophthalmic composition was filled into a polyethylene container (volume: 7.8 mL, material: LDPE, body diameter φ20 mm, total height 39.85 mm) at 4 mL or 5 mL. The filling rate for a 4 mL filling volume was 51%, and for a 5 mL filling volume it was 64%. A polyethylene inner stopper (material: LLD-PE, hole diameter φ0.3 mm) was fitted into the container, and a polypropylene cap was attached. The preservative effectiveness of each ophthalmic composition was then tested according to the 18th Revised Japanese Pharmacopoeia. Staphylococcus aureus was inoculated onto the surface of a soybean-casein-digest agar slant medium and cultured at 30-35°C for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile saline to obtain a concentration of approximately 1 × 10 7A bacterial suspension containing viable bacteria at cfu / mL was prepared. The prepared bacterial suspension was inoculated into each ophthalmic composition to the inoculum number shown in Tables 2 and 3, and the mixture was thoroughly stirred to prepare a sample. The bacterial-containing sample was allowed to stand at 20 to 25°C. Three and seven days after inoculation, each sample was collected, adjusted to a concentration appropriate for counting, and inoculated onto a Petrifilm medium. After culturing at 30 to 35°C for two to three days, the number of observed colonies was counted to determine the viable bacterial count. The inoculated bacterial count was compared with the viable bacterial count in the sample after three and seven days, and the reduction in bacterial count was calculated as the bacterial survival rate and Log reduction. The results are shown in Tables 2 and 3.

[0054] [Table 2]

[0055] [Table 3]

[0056] When 4 mL of the ophthalmic compositions containing boric acid as a buffer (Test Examples 1 and 2) was filled into a polyethylene container, a decrease in bacterial survival rate and an improvement in Log reduction were observed.

[0057] [Test Example 2: Preservative Effectiveness Test] Ophthalmic compositions were prepared according to a conventional method using the compositions shown in Table 4. They were then sterilized by filtration through a 0.2 μm membrane filter. [Table 4]

[0058] Each prepared ophthalmic composition was filled into a polyethylene container (volume: 8.6 mL) at 4 mL or 5 mL. The filling rate for a 4 mL filling volume was 47%, and for a 5 mL filling volume, the filling rate was 58%. A polyethylene inner stopper was fitted into the container, and a polypropylene cap was attached. A preservative effectiveness test for each ophthalmic composition was then conducted in accordance with the 18th Revised Japanese Pharmacopoeia. Escherichia coli was inoculated onto the surface of a soybean-casein-digest agar slant medium and cultured at 30-35°C for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile saline to obtain a concentration of approximately 1 x 10 7 A bacterial suspension containing viable bacteria at cfu / mL was prepared. The prepared bacterial suspension was inoculated into each ophthalmic composition to the inoculum number shown in Table 5, and the mixture was thoroughly stirred to prepare a sample. The samples containing bacteria were allowed to stand at 20 to 25°C. Seven days after inoculation with the bacterial suspension, each sample was collected, adjusted to a concentration appropriate for counting, and plated on a Petrifilm medium. After culturing at 30 to 35°C for 2 to 3 days, the number of observed colonies was counted to determine the viable bacterial count. The bacterial survival rate was calculated using the inoculated bacterial count and the viable bacterial count in the sample after 7 days, according to the following formula. The results are shown in Table 5. Bacterial survival rate (%) = (number of live bacteria after 7 days / number of inoculated bacteria) x 100

[0059] [Table 5]

[0060] When 4 mL of an ophthalmic composition containing boric acid as a buffer (Test Example 4) was filled into a polyethylene container, a lower bacterial survival rate was observed than when 5 mL was filled into the container. Furthermore, when cyanocobalamin was further added in addition to boric acid (Test Example 5), a further decrease in bacterial survival rate was observed.

[0061] Formulation examples are shown in Tables 6 to 9. The amount of each formulation filled into a container may be 3 mL or more and less than 5 mL. [Table 6]

Table 7

Table 8

Table 9

Claims

1. An ophthalmic composition contained in a container, The ophthalmic composition contains boric acid, the amount of the ophthalmic composition filled in the container is 3 mL or more and less than 5 mL; An ophthalmic composition, wherein a part or all of the portion of the container that comes into contact with the ophthalmic composition is formed from at least one resin selected from the group consisting of polyolefin-based resins and polyester-based resins.

2. The ophthalmic composition according to claim 1 , wherein the expiration date after opening the container is 11 days or more.

3. The ophthalmic composition according to claim 1 or 2, wherein the resin is polyethylene.

4. The ophthalmic composition of claim 1 or 2, wherein the ophthalmic composition is substantially free of preservatives.

5. The ophthalmic composition according to claim 1 or 2, further comprising a salt of boric acid.

6. The ophthalmic composition according to claim 1 or 2, further comprising cyanocobalamin or a salt thereof.

7. The ophthalmic composition according to claim 1 or 2, which is a multi-dose type.

8. A product comprising 2 to 6 bottles of the ophthalmic composition according to claim 1 or 2 per package.

9. 1. A method for inhibiting microbial growth in an ophthalmic composition, comprising: The ophthalmic composition contains boric acid, The method includes filling the ophthalmic composition into a container, a part of which or the whole of which comes into contact with the ophthalmic composition is formed of at least one resin selected from the group consisting of polyolefin-based resins and polyester-based resins, The method, wherein the amount of the ophthalmic composition filled into the container is 3 mL or more and less than 5 mL.

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