Ophthalmic composition contained in a container

Abstract

To provide a containerized ophthalmic composition having improved preservative effectiveness. [Solution] An ophthalmic composition contained in a container, the ophthalmic composition containing boric acid, the amount of the ophthalmic composition filled into the container is 3 mL or more and less than 5 mL, and some 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.

Description

[Technical field]

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

[0002] Generally, multiple dose (multi-dose) eye drops contain a preservative that acts to inhibit the growth of microorganisms in case the eye drops are contaminated with microorganisms such as bacteria and fungi. On the other hand, preservatives also contain components that are cytotoxic, and it has been reported that frequent or long-term use of eye drops containing preservatives can cause corneal epithelial disorders.

[0003] As a preservative-free eye drop, a unit dose eye drop that is a single-use eye drop 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 and must be discarded if any is left over. In addition, frequent use requires carrying multiple bottles. For these reasons, there is a demand for multi-dose eye drops that do not contain preservatives but have a long shelf life after opening.

[0006] In view of preservative power, multi-dose eye drops that do not contain preservatives must be used up in a short time after opening. 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 preservative effectiveness can be increased by filling a container with a specific amount of an ophthalmic composition containing boric acid. 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 of 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], wherein the ophthalmic composition is substantially free of a preservative. [5] The ophthalmic composition according to any one of [1] to [4], further comprising a salt of boric acid. [6] A product comprising 2 to 6 bottles of the ophthalmic composition according to any one of [1] to [5] per package. [7] 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 or all of which is in contact with the ophthalmic composition and is formed of at least one resin selected from the group consisting of polyolefin-based resins and polyester-based resins, A method, wherein the amount of the ophthalmic composition filled into the container is 3 mL or more and less than 5 mL. [8] The method according to [7], wherein the expiration date after opening of the container is 11 days or more. [9] The method according to [7] or [8], wherein the resin is polyethylene.

[10] The method according to any one of [7] to [9], wherein the ophthalmic composition is substantially free of a preservative.

[11] The method according to any one of [7] to

[10] , wherein the ophthalmic composition further contains a salt of boric acid. Effect 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 PREFERRED EMBODIMENTS

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

[0012] [Ophthalmic composition] The ophthalmic composition according to the present embodiment contains boric acid. The ophthalmic composition is filled in a container in which a part or all of a portion 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, and the filling amount of the container is 3 mL or more and 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 its 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 hydrates. When the ophthalmic composition according to this embodiment contains boric acid and its salts in combination, the combination of boric acid and borax is preferred as boric acid and its salts.

[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 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, and may be 3 g or less, 2 g or less, or 1 g or less, per 100 mL.

[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 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, and may be 3 g or less, 2 g or less, or 1 g or less, per 100 mL.

[0018] The ophthalmic composition according to the present embodiment may further contain an inorganic salt. When the ophthalmic composition further contains an inorganic salt, the effect of the present invention is more remarkable. 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. The inorganic salts may be used alone or in combination of two or more. As inorganic salts, sodium chloride and potassium chloride are preferred.

[0020] The content of inorganic salts in the ophthalmic composition according to this embodiment is not particularly limited, and is appropriately set depending on the type of inorganic salts, the type and content of other blended components, the use and formulation form of the ophthalmic composition, etc. With regard to the content of inorganic salts, from the viewpoint of more significantly exhibiting the effects of the present invention, for example, based on the total amount of the aqueous composition, the total content of inorganic salts in 100 mL may be 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 achieving the effects of the present invention, the content of potassium chloride may be, for example, based on the total amount of the aqueous composition, in 100 mL, 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, and may be 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.

[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, based on the total amount of the aqueous composition, 0.0001 g or more, 0.001 g or more, 0.01 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, and may be 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 a pH adjuster, such as hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, citric acid, sodium carbonate, triethanolamine, monoethanolamine, diisopropanolamine, etc.

[0026] The ophthalmic composition according to the present embodiment may or may not contain a preservative. The ophthalmic composition according to the present embodiment has enhanced preservative effectiveness even without the inclusion of a preservative, and therefore may not substantially contain a preservative. In this specification, "preservative" means a component that exerts a preservative effect. In this specification, "substantially free of preservative" means that no preservative is contained or that a preservative is contained in an amount less than that required for exerting a preservative effect. In this specification, "exerts a preservative effect" means that an ophthalmic composition containing the substance meets the standards in the preservative effectiveness test method defined in the Japanese Pharmacopoeia, 18th Edition. In this specification, "high preservative effectiveness" means that the preservative effectiveness is improved according to the preservative effectiveness test method defined in the Japanese Pharmacopoeia, 18th Edition.

[0027] Examples of preservatives include alkyl polyaminoethyl glycines, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), polydonium chloride, sodium benzoate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), chlorhexidine gluconate, alexidine, etc.). It is preferable that the ophthalmic composition according to this embodiment does not contain any preservatives.

[0028] The ophthalmic composition according to the present embodiment may contain a suitable amount of a combination of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients, as long as the effects of the present invention are not impaired. The ingredients are not particularly limited, and examples thereof include active ingredients in ophthalmic drugs listed in the 2017 edition of the General Drug Manufacturing and Sales Approval Standards (supervised by the Japan Society of Regulatory Science). Specific examples of ingredients used in ophthalmic drugs include the following ingredients. 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), and the like. 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, and the like. Ocular muscle regulating drugs: 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 (for example, 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, cyanocobalamin, 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.

[0029] In the ophthalmic composition according to this embodiment, various additives may be appropriately selected according to the formulation form, and one or more types may be used in combination in an appropriate amount, as long as the effect of the present invention is not impaired. Examples of such additives include, for example, various additives 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 sodium carboxymethylcellulose; 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 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 pyrosulfite, 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.

[0030] The ophthalmic composition according to the present 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. Eyewash includes eyewash that can be applied while wearing contact lenses.), and a composition for contact lenses [contact lens wetting solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative), contact lens wetting solution used for both contact lens wetting solution and eye drops while wearing contact lenses, etc.]. The term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, and including 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, in particular artificial tears.

[0031] The pH of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a medicamentously, pharmacologically (pharmaceutical) or physiologically acceptable range. The pH of the ophthalmic composition 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.

[0032] The ophthalmic composition according to the present embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary. The appropriate osmotic pressure ratio can be appropriately set depending on the purpose, 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 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) based on the 18th revised Japanese Pharmacopoeia, and the osmotic pressure is measured with reference to the osmometric 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 measuring 0.900 g of it, 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.

[0033] The viscosity of the ophthalmic composition according to the present 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 the present 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, 1 to 5 mPa·s, 1 to 3 mPa·s, or 1 to 1.5 mPa·s at 20°C measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34'×R24).

[0034] (container) The ophthalmic composition according to this embodiment is contained in a container. A part or all of the part of the container 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. The container may be a package having a part that comes into contact with the ophthalmic composition, and may be composed of, for example, a container body part that contains the ophthalmic composition, a part including a discharge part of the container (e.g., a nozzle, an inner plug), a suction tube, a cap, etc.

[0035] The polyolefin resin may be a polymer obtained by polymerizing one kind of olefin alone or a polymer obtained by copolymerizing two or more kinds of olefins. These polymers may contain other monomers that can be polymerized as constituents. Specific examples of polyolefin resins include polyethylene (including low density polyethylene, medium density polyethylene, high density polyethylene, etc.), polypropylene (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene), ethylene-propylene copolymer, polymethylpentene, etc. Among these, polyethylene and polypropylene are preferred, and polyethylene is more preferred, from the viewpoint of usability, such as squeeze force (force required to drip eye drops from an eye drop container) and uniformity of the amount of one drop.

[0036] 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 constituents. Specific examples of polyester resins include polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, and polycarbonate.

[0037] In the container according to the present embodiment, a part or the whole of the part 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. Here, the part of the container that contains the ophthalmic composition that comes into contact with the ophthalmic composition includes, for example, the container body part that contains the ophthalmic composition (when the container has a structure consisting of multiple layers, the innermost layer), the inner plug, and the inner plug with a hole. For example, when the container has a perforated inner plug (nozzle), the container body part that contains the ophthalmic composition other than the perforated inner plug may be formed of the above resin, or the entire container may be formed of the above resin. The container according to the present embodiment may be a container of the above resin molded by the blow-fill-seal (BFS) method.

[0038] The diameter of the hole on the liquid contact surface of the container according to this embodiment may be, for example, φ0.1 to 2 mm, 0.3 to 1.5 mm, or 0.3 to 1 mm.

[0039] 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.

[0040] When the container according to this embodiment is a perforated inner plug (nozzle), the diameter of the tip of the nozzle may be, for example, φ1 to 4 mm, 1.5 to 3 mm, or 2 to 2.5 mm.

[0041] The shape and capacity of the container according to the present embodiment are not particularly limited and may be appropriately set depending on the application. For example, when the container is a container for storing an eye drop, 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.

[0042] The container according to the present 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 exhibiting the effects of the present invention more significantly, the container according to the present embodiment is preferably a multi-dose type.

[0043] The ophthalmic composition according to the present embodiment is filled in a container according to the present embodiment in a filling amount of 3 mL or more and less than 5 mL. This provides the effect of enhancing preservation efficacy. From the viewpoint of more significantly achieving the effects of the present invention, the filling amount 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.

[0044] 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.

[0045] The expiration date of the ophthalmic composition according to the present embodiment after the container is opened is not particularly limited, and may be appropriately set according to the purpose, formulation, method of use, etc. of the ophthalmic composition. Since the ophthalmic composition according to the present embodiment has an effect of increasing the preservative efficacy, 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.

[0046] 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 included 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 a form in which multiple bottles of the container-packaged ophthalmic composition are accommodated in a paper wrapper (package).

[0047] The present invention described above can also be understood as a method for inhibiting the growth of microorganisms in an ophthalmic composition, the ophthalmic composition containing boric acid, the method including filling the ophthalmic composition into a container in which a part or all of a portion in contact with the ophthalmic composition is formed of at least one resin selected from the group consisting of polyolefin resins and polyester resins, and the amount of the ophthalmic composition filled into the container is 3 mL or more and less than 5 mL. Specific aspects of the method can be applied without particular limitations to the specific aspects described above. EXAMPLES

[0048] The present invention will be specifically described below based on examples, but the present invention is not limited to these.

[0049] [Test Example 1: Preservative Effectiveness Test] Ophthalmic compositions were prepared according to a conventional method with the compositions shown in Table 1. Then, the compositions were filtered through a 0.2 μm membrane filter and sterilized. [Table 1]

[0050] Each of the prepared ophthalmic compositions 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 4 mL filling was 51%, and for 5 mL filling 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. Thereafter, a preservative effectiveness test for each ophthalmic composition was performed based on the 18th revised Japanese Pharmacopoeia. Staphylococcus aureus was inoculated onto the surface of a soybean-casein-digest agar slant medium and cultured at 30 to 35°C for 24 hours. The cultured bacteria 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 cfu / mL of live bacteria was prepared. The prepared bacterial suspension was inoculated into each ophthalmic composition so as to obtain the inoculation number of bacteria shown in Tables 2 and 3, and thoroughly stirred to obtain a sample. The sample containing bacteria was left to stand at 20 to 25°C. Three and seven days after inoculation of the bacterial suspension, each sample was collected, adjusted to a concentration appropriate for counting, and inoculated on a petrifilm medium. After culturing at 30 to 35°C for 2 to 3 days, the number of colonies observed was counted to obtain the number of live bacteria. The inoculation number was compared with the number of live bacteria in the sample after 3 and 7 days, and the reduction in the number of bacteria was calculated as the bacterial survival rate and Log reduction. The results are shown in Tables 2 and 3.

[0051] [Table 2]

[0052] [Table 3]

[0053] When 4 mL of the ophthalmic compositions containing boric acid as a buffering agent (Test Examples 1 and 2) was filled into a polyethylene container, a decrease in the bacterial survival rate and an improvement in the log reduction were observed.

[0054] Formulation examples are shown in Tables 4 to 7. The amount of each formulation filled in a container may be 3 mL or more and less than 5 mL. [Table 4] [Table 5] [Table 6] [Table 7]

Claims

1. An ophthalmic composition contained in a container, The ophthalmic composition contains sodium chloride, potassium chloride and boric acid, and is substantially free of preservatives; The amount of the ophthalmic composition filled in the container is 3.8 mL or more and 4.2 mL or less, The container is a multi-dose type ophthalmic composition, a part or all of a portion 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 (excluding the following (i) and / or (ii)). (i) An aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v), a water-soluble polymer, and a first buffering agent, and having a pH in the range of 6 or less, wherein the first buffering agent is at least one selected from the group consisting of a phosphate buffer, an aminocarboxylic acid buffer, a carbonate buffer, an acetate buffer, a tartaric acid buffer, a borate buffer, and trometamol. (ii) an aqueous ophthalmic composition in the form of a solution, comprising 0.005% to 0.18% w / w of hexanoic acid, 6-(nitrooxy)-,(1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester, and 0.5% w / w to 1.5% w / w of macrogol 15 hydroxystearate.

2. The ophthalmic composition according to claim 1 , wherein the expiration date after opening of 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 according to claim 1 or 2, further comprising a salt of boric acid.

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

6. Ophthalmic compositions (excluding the following (i) and / or (ii)). (i) An aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v), a water-soluble polymer, and a first buffering agent, and having a pH in the range of 6 or less, wherein the first buffering agent is at least one selected from the group consisting of a phosphate buffer, an aminocarboxylic acid buffer, a carbonate buffer, an acetate buffer, a tartaric acid buffer, a borate buffer, and trometamol. (ii) A method for inhibiting the growth of microorganisms in an aqueous ophthalmic composition in the form of a solution, comprising 0.005% to 0.18% w / w of hexanoic acid, 6-(nitrooxy)-,(1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester and 0.5% to 1.5% w / w of macrogol 15 hydroxystearate, The ophthalmic composition contains sodium chloride, potassium chloride and boric acid, and is substantially free of preservatives; The method includes filling the ophthalmic composition into a multi-dose container, a part or all of which is in contact with the ophthalmic composition and 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 3.8 mL or more and 4.2 mL or less.

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