Ophthalmological products

Abstract

To provide an ophthalmic product that prevents a decrease in the transmittance of an ophthalmic composition and has excellent appearance stability by containing an ophthalmic composition containing a certain amount of hyaluronic acid, vitamin A, vitamin E, and a specific nonionic surfactant in a container body made of polyethylene terephthalate.SOLUTION: An ophthalmic product comprises: an ophthalmic composition containing 0.05 to 0.5 w / v% hyaluronic acid or a salt thereof, vitamin A and vitamin E, a specific surfactant, and one or more selected from the following: (D-1) camphor, borneol; (D-2) allantoin, glycyrrhizinic acid, neostigmine, chlorpheniramine, tetrahydrozoline, or salts thereof; and (D-3) boric acid, borax, ethylenediamine acetic acid, ethylenediamine acetic acid derivatives, or ethylenediamine acetate salts; and a polyethylene terephthalate container having a container body and a cap.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an ophthalmic product in which the decrease in transmittance is suppressed. [Background technology]

[0002] Hyaluronic acid or its salts are effective as moisturizing ingredients for the eyes, and by retaining tears, they have the effect of repairing damage to the surface of the eye. Vitamin A and vitamin E are known to be effective ingredients for improving eye function, and vitamin A in particular has attracted attention as an effective ingredient for preventing and treating keratosis of the cornea, conjunctiva, and skin and mucous membranes. In recent years, it has been found to be effective in treating dry eye, including xerocornea and conjunctiva. These vitamin ingredients are solubilized by adding nonionic surfactants such as polyoxyethylene hydrogenated castor oil. However, if cloudiness occurs due to emulsion coalescence during use, it may lead to problems when applying the eye drops or abnormal appearance, so a formulation with high appearance stability is desired. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2018 / 066651 Summary of the Invention [Problem to be solved by the invention]

[0004] As described above, hyaluronic acid or its salt, vitamin A, and vitamin E are ingredients that are effective for the eyes. However, the present inventors have found that when an ophthalmic composition containing a certain amount of hyaluronic acid or its salt, vitamin A, vitamin E, and a specific nonionic surfactant is contained in a polyethylene terephthalate container, the transmittance of the ophthalmic composition decreases. The present invention has been made in view of the above circumstances, and aims to provide an ophthalmic product that suppresses the transmittance decrease and has excellent appearance stability. [Means for solving the problem]

[0005] As a result of extensive research into achieving the above-mentioned object, the inventors have discovered that the above-mentioned problems can be solved by adding a specific component (D) to an ophthalmic composition containing (A) 0.05 to 0.5 w / v% of one or more selected from hyaluronic acid and its salts, (B) vitamin A and vitamin E, and (C) one or more surfactants selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester, in an ophthalmic product housed in a container body made of polyethylene terephthalate, and thus have completed the present invention.

[0006] Accordingly, the present invention provides the following ophthalmic products: 1. (A) 0.05 to 0.5 w / v% of one or more selected from hyaluronic acid and its salts, (B) Vitamin A and Vitamin E, (C) one or more surfactants selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester, and (D) One or more selected from the following (D-1), (D-2), and (D-3): (D-1) Camphor, Borneol (D-2) Allantoin, glycyrrhizinic acid, neostigmine, chlorpheniramine, tetrahydrozoline, and their salts (D-3) Boric acid, borax, ethylenediamine acetic acid, ethylenediamine acetic acid derivatives, ethylenediamine acetate salts and a container having a container body and a cap in which the ophthalmic composition is accommodated, wherein the container body is made of polyethylene terephthalate. 2. (B) An ophthalmic product according to 1, wherein the vitamin A content is 40,000 to 100,000 units / 100 mL. 3. An ophthalmic product according to 1 or 2, wherein the component (D) comprises one or more of the components (D-1) and one or more of the components (D-2) and (D-3). 4. An ophthalmic product according to any one of 1 to 3, wherein the container body made of polyethylene terephthalate has been sterilized with electron beams or gamma rays. 5. An ophthalmic product according to any one of 1 to 4, wherein component (B) is retinol palmitate and d-α-tocopherol acetate. 6. An ophthalmic product according to any one of 1 to 5, further comprising a fat-soluble antioxidant. [Effects of the Invention]

[0007] According to the present invention, an ophthalmic product containing an ophthalmic composition containing (A) 0.05 to 0.5 w / v% of one or more selected from hyaluronic acid and its salts, (B) vitamin A and vitamin E, and (C) one or more surfactants selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester, in a container body made of polyethylene terephthalate, can be provided in which a decrease in the transmittance of the ophthalmic composition is suppressed and the ophthalmic product has excellent appearance stability. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention will be described in detail below. [Component (A)] The hyaluronic acid or its salt of the present invention is not particularly limited, and any hyaluronic acid commonly used in ophthalmic compositions can be used, including hyaluronic acid and its pharmaceutically and physiologically acceptable salts. Hyaluronic acid obtained by extraction from cockscomb, fermentation using microorganisms, etc. can be used, and the origin and production method are not particularly limited. Hyaluronic acid or its salt can be used alone or in appropriate combination of two or more. Specific examples of component (A) include hyaluronic acid, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, etc. Among these, sodium hyaluronate is preferred.

[0009] The viscosity-average molecular weight of component (A) is preferably 100,000 to 5,000,000, more preferably 200,000 to 4,000,000, even more preferably 300,000 to 2,500,000, particularly preferably 400,000 to 2,000,000, and most preferably 500,000 to 1,490,000. The viscosity-average molecular weight of component (A) is measured using the method for measuring viscosity-average molecular weight described in the "Purified Sodium Hyaluronate" section of the Japanese Pharmacopoeia, 18th Edition, listed in each monograph. The viscosity-average molecular weight of hyaluronic acid or its salt in an ophthalmic composition, particularly eye drops, is measured using the method for measuring viscosity-average molecular weight described in the "Purified Sodium Hyaluronate Eye Drops" section of the Japanese Pharmacopoeia, 18th Edition. Note that multiple types of hyaluronic acid or its salt with different viscosity-average molecular weights can be used.

[0010] Commercially available products can be used as component (A), including, for example, "Sodium Hyaluronate "Seikagaku"" (viscosity average molecular weight 500,000 to 1,200,000) and "Cosmetic Sodium Hyaluronate (HC)" (viscosity average molecular weight 530,000 to 1,330,000) manufactured by Seikagaku Corporation, "Hyaluronic Acid FCH-60" (viscosity average molecular weight 500,000 to 700,000), "Hyaluronic Acid FCH-80" (viscosity average molecular weight 600,000 to 1,000,000), "Hyaluronic Acid FCH-120" (viscosity average molecular weight 1,000,000 to 1,400,000) manufactured by Kikkoman Biochemifa Corporation. Hyaluronic acid FCH-150 (viscosity average molecular weight 1.4 million to 1.8 million), "Hyaluronic acid FCH-151C" (viscosity average molecular weight 1.4 million to 1.8 million), "Hyaluronic acid FCH-200" (viscosity average molecular weight 1.8 million to 2.2 million), "Hyaluronic acid FCH-201C" (viscosity average molecular weight 1.8 million to 2.2 million), "Hyaluronic acid FCH-80LE" (viscosity average molecular weight 600,000 to 1.2 million), "Hyaluronic acid GS-100" (viscosity average molecular weight 500,000 to 1.49 million), "Hyaluronic acid HA-QA" manufactured by Kewpie Corporation " (viscosity average molecular weight 600,000 to 1.2 million), "Hyaluronic Acid HA-AM" (viscosity average molecular weight 600,000 to 1.2 million), "Hyaluronic Acid HA-Q" (viscosity average molecular weight 530,000 to 1.13 million), "Hyaluronic Acid M5070" (viscosity average molecular weight 500,000 to 700,000), "Hyaluronic Acid HA-LQ" (viscosity average molecular weight 850,000 to 1.6 million), "Hyaluronic Acid HA-LQH" (viscosity average molecular weight 1.2 million to 2.2 million), "Hyaluronic Acid HA-AML" (viscosity average molecular weight 500,000 to 1.2 million), "Hyaluronic Acid HA-SHL" (viscosity average molecular weight 1.6 million to 2.4 million), Iwaki Pharmaceutical Co., Ltd.'s "Hyaluronic Acid IW90" (viscosity average molecular weight 800,000 to 1.17 million), "Hyaluronic Acid IW120" (viscosity average molecular weight 1.1 million to 1.6 million), "Hyaluronic Acid IW200" (viscosity average molecular weight 1.9 million to 2.7 million), Bloomage Biotechnology Japan Co., Ltd.'s "Purified Sodium Hyaluronate JP-AE" (viscosity average molecular weight 500,000 to 1.49 million), "Purified Sodium Hyaluronate JP-E" (viscosity average molecular weight 500,000 to 1.49 million), "Sodium Hyaluronate MW80 / 110" (viscosity average molecular weight 800,000 to 1.1 million), "Sodium HyaluronateExamples include "Sodium Hyaluronate MW110 / 160" (viscosity average molecular weight 1.1 million to 1.6 million), "Sodium Hyaluronate MW190 / 240" (viscosity average molecular weight 1.9 million to 2.4 million).

[0011] The content of component (A) in the ophthalmic composition is 0.05 w / v% (mass / volume %, g / 100 mL) or more, preferably 0.07 w / v% or more, and more preferably 0.09 w / v% or more. By maintaining the content at or above the lower limit, the corneal wound healing effect of hyaluronic acid and improved usability, such as moisturizing sensation, can be expected. On the other hand, if the content of hyaluronic acid or a salt thereof is 0.05 w / v% or more, when an ophthalmic composition containing hyaluronic acid, vitamin A, and a nonionic surfactant such as polyoxyethylene hydrogenated castor oil is contained in a polyethylene terephthalate container, the transmittance of the ophthalmic composition decreases. Furthermore, the content of component (A) is 0.5 w / v% or less, preferably 0.3 w / v% or less, and more preferably 0.2 w / v% or less. By maintaining the content at or below the upper limit, blurred vision after instillation of the ophthalmic composition is less likely to occur. In addition, the viscosity retention rate of the ophthalmic composition is further improved.

[0012] [(B) Component] Component (B) is vitamin A and vitamin E, and each can be used alone or in combination of two or more. Examples of vitamin A include vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid esters. These can be used alone or in appropriate combination of two or more. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Among these, retinol palmitate, retinol acetate, and retinoic acid are preferred. Retinol palmitate is typically commercially available with a concentration of 1,000,000 to 1,800,000 international units / g (hereinafter abbreviated as IU / g). Specific examples include retinol palmitate [1.74 million IU / g] manufactured by DSM K.K. and retinol palmitate manufactured by Sigma-Aldrich Japan. The component (B) of the present invention has an antioxidant effect, and therefore can also be blended for the purpose of containing an antioxidant (antioxidant component).

[0013] The content of vitamin A in 100 mL of the ophthalmic composition is preferably 40,000 to 100,000 international units (IU), more preferably 44,000 to 80,000 IU, and even more preferably 48,000 to 70,000 IU. For example, in the case of 1,740,000 IU / g, the content in 100 mL of the ophthalmic composition is preferably 0.023 to 0.057 w / v%, more preferably 0.025 to 0.046 w / v%, and even more preferably 0.028 to 0.04 w / v%. By ensuring that the content is equal to or greater than the lower limit, the corneal wound healing effect of vitamin A can be expected to be enhanced. By ensuring that the content is equal to or less than the upper limit, the decrease in transmittance of the ophthalmic composition can be further suppressed, thereby achieving greater stability in appearance. In addition, the viscosity retention rate of the ophthalmic composition is further improved.

[0014] Vitamin E is used as a general term to refer to, for example, tocopherol, tocotrienol, their salts, and derivatives (esters). Specific examples include d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, mixed tocopherol, etc. Derivatives thereof include, for example, vitamin E acetate (tocopherol acetate), vitamin E nicotinate, vitamin E succinate, vitamin E linoleate, etc., and these can be used alone or in appropriate combinations of two or more. Among these, tocopherol acetate (d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.) is preferred. Commercially available products include d-α-tocopherol acetate: Riken E acetate α, manufactured by Riken Vitamin Co., Ltd.

[0015] The content of vitamin E in the ophthalmic composition is preferably 0.005 to 0.5 w / v%, more preferably 0.01 to 0.1 w / v%, and even more preferably 0.03 to 0.06 w / v%. Within the above range, the decrease in transmittance of the ophthalmic composition is further suppressed, and the appearance stability can be further improved. In addition, the viscosity retention rate of the ophthalmic composition is further improved.

[0016] [(C) component] Component (C) is a nonionic surfactant, and is selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester. These components (C) can be used singly or in combination of two or more. Polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester are particularly preferred because they further suppress the decrease in transmittance of the ophthalmic composition, provide better appearance stability, improve the viscosity retention rate of the ophthalmic composition, and provide superior vitamin A stability.

[0017] The polyoxyethylene castor oil is preferably a polyoxyethylene castor oil having an average number of moles of ethylene oxide added within the range of 3 to 60 moles, and examples include polyoxyethylene castor oil 3 (the numerical value is the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, and polyoxyethylene castor oil 60. The number of moles of ethylene oxide added is more preferably 10 to 50, and even more preferably 20 to 40. Note that polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil are different components.

[0018] Polyoxyethylene hydrogenated castor oil is a compound obtained by addition polymerization of hydrogenated castor oil with ethylene oxide, and several types with different average molar numbers of ethylene oxide added are known. The average molar number of ethylene oxide added in polyoxyethylene hydrogenated castor oil is not particularly limited, but is preferably 5 to 100 moles. Specific examples include polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average molar number of ethylene oxide added, 5; the same applies below), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 30, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, and polyoxyethylene hydrogenated castor oil 100. These polyoxyethylene hydrogenated castor oils can be used alone or in appropriate combinations of two or more. Among these, polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 are preferred. Those that comply with the Pharmaceutical Additives Standards 2018 are preferred, and examples of commercially available products include polyoxyethylene hydrogenated castor oil 60:HCO-60, manufactured by Nippon Surfactant Kogyo Co., Ltd.

[0019] Specific examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20, where the numerical value indicates the average number of moles of ethylene oxide added; the same applies below), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan tristearate (polysorbate 65), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80). These polyoxyethylene sorbitan fatty acid esters can be used alone or in combination of two or more. Among these, polyoxyethylene (20) sorbitan monooleate (polysorbate 80) is preferred. Commercially available products include, for example, Polysorbate 80 (Rheodor TW-O120V, manufactured by Kao Corporation). Examples of polyethylene glycol fatty acid esters include polyoxyl 10 stearate (polyethylene glycol (10) monostearate, the numerical value is the average number of moles of ethylene glycol added, the same applies hereinafter), polyoxyl 40 stearate, polyoxyl 45 stearate, and polyoxyl 55 stearate, and among these, polyoxyl 40 stearate is preferred. Furthermore, in order to further exert the effects of the present invention, it is preferable to use polyoxyethylene hydrogenated castor oil 40 or polyoxyethylene hydrogenated castor oil 60 in combination with polyoxyethylene (20) sorbitan monooleate.

[0020] The content of component (C) in the ophthalmic composition is preferably 0.01 to 0.5 w / v%, more preferably 0.05 to 0.5 w / v%, and even more preferably 0.1 to 0.4 w / v%. By ensuring that the content is equal to or greater than the lower limit, the stability of the vitamin A content and appearance (transmittance) of the ophthalmic composition can be improved, while by ensuring that the content is equal to or less than the upper limit, irritation upon application to the eye is less likely to occur.

[0021] [(D) component] The component (D) of the present invention is one or more selected from the following (D-1), (D-2), and (D-3), and can be used alone or in combination of two or more. (D-1) Camphor, Borneol (D-2) Allantoin, glycyrrhizinic acid, neostigmine, chlorpheniramine, tetrahydrozoline, and their salts (D-3) Boric acid, borax, ethylenediamine acetic acid, ethylenediamine acetic acid derivatives, ethylenediamine acetate salts Among these, from the viewpoint of suppressing a decrease in transmittance, it is preferable to use one or more of the (D-1) component in combination with one or more of the (D-2) component and the (D-3) component, it is more preferable to use one or more of the (D-1) component in combination with one or more of the (D-2) component, and it is even more preferable to use one or more of the (D-1) component in combination with one or more of the (D-2) component and one or more of the (D-3) component.

[0022] (D-1) Camphor, Borneol The component (D-1) may be any of the d-, l-, or dl-isomers, with dl-camphor and d-borneol being preferred. The component (D-1) may be used singly or in combination of two or more. The content of the component (D-1) in the ophthalmic composition is preferably 0.0001 to 1 w / v%, more preferably 0.0005 to 0.1 w / v%, and even more preferably 0.001 to 0.05 w / v%. By ensuring that the content is equal to or greater than the lower limit, the decrease in transmittance of the ophthalmic composition is further suppressed, the viscosity retention rate of the ophthalmic composition is improved, the appearance stability is further improved, and an appropriate cooling sensation is more easily achieved upon application. By ensuring that the content is equal to or less than the upper limit, irritation upon application can be further reduced.

[0023] [(D-2)] The component (D-2) is (D-2) allantoin, glycyrrhizinic acid, neostigmine, chlorpheniramine, tetrahydrozoline, or a salt thereof, and can be used alone or in combination of two or more. Examples of the salt of the component (D-2) include sodium salt, potassium salt, ammonium salt, hydrochloride, maleate, and methyl sulfate. Among these components (D-2), allantoin, dipotassium glycyrrhizinate, neostigmine methyl sulfate, chlorpheniramine maleate, and tetrahydrozoline hydrochloride are preferred, and allantoin, dipotassium glycyrrhizinate, neostigmine methyl sulfate, and tetrahydrozoline hydrochloride are more preferred, in terms of further suppressing the decrease in transmittance of the ophthalmic composition and achieving more stable appearance.

[0024] The content of the component (D-2) in the ophthalmic composition is preferably 0.0001 to 5 w / v %, more preferably 0.001 to 1 w / v %. The preferred ranges for each component (D-2) are shown below. Allantoin is preferably 0.01 to 1 w / v%, more preferably 0.03 to 0.5 w / v%. Dipotassium glycyrrhizinate is preferably 0.01 to 5 w / v%, more preferably 0.03 to 1 w / v%. Neostigmine methylsulfate is preferably 0.0001 to 0.3 w / v%, more preferably 0.001 to 0.1 w / v%. Chlorpheniramine maleate is preferably 0.001 to 1 w / v%, more preferably 0.01 to 0.5 w / v%. Tetrahydrozoline hydrochloride is preferably 0.001 to 1 w / v %, more preferably 0.01 to 0.5 w / v %. By setting the amount to be equal to or greater than the lower limit, the decrease in transmittance of the ophthalmic composition can be further suppressed, and the appearance stability can be further improved, and by setting the amount to be equal to or less than the upper limit, irritation upon application to the eye is less likely to occur.

[0025] [D-3] The component (D-3) is boric acid, borax, ethylenediamine acetic acid, an ethylenediamine acetic acid derivative, or an ethylenediamine acetate, and can be used alone or in combination of two or more. Examples of ethylenediamine acetic acid, an ethylenediamine acetic acid derivative, or an ethylenediamine acetate include edetic acid (ethylenediaminetetraacetic acid), ethylenediaminediacetic acid, diethylenetriaminepentaacetic acid, N-(2-hydroxyethyl)ethylenediaminetriacetic acid, sodium edetate (sodium ethylenediaminetetraacetate), and disodium ethylenediaminetetraacetate. Among these components (D-3), disodium ethylenediaminetetraacetate (disodium EDTA) is preferred because it can further suppress the decrease in transmittance of the ophthalmic composition and achieve better appearance stability.

[0026] The content of the component (D-3) in the ophthalmic composition is preferably 0.001 to 5 w / v%, more preferably 0.005 to 3 w / v%, and even more preferably 0.01 to 1 w / v%. The preferred ranges for each component (D-3) are shown below. Boric acid and borax are preferably present in an amount of 0.01 to 5 w / v%, more preferably 0.05 to 1 w / v%. Ethylenediamine acetic acid, ethylenediamine acetic acid derivatives, and ethylenediamine acetate salts are preferably present at 0.001 to 0.2 w / v%, more preferably 0.01 to 0.1 w / v%. By setting the amount to be equal to or greater than the lower limit, the decrease in transmittance of the ophthalmic composition can be further suppressed, and the appearance stability can be further improved, and by setting the amount to be equal to or less than the upper limit, irritation upon application to the eye is less likely to occur.

[0027] [Other ingredients] The ophthalmic composition of the present invention (hereinafter sometimes simply referred to as the composition) may contain other ingredients in appropriate amounts within the range that does not impair the effects of the present invention. Examples of other ingredients include drugs (excluding component (A), component (B), and component (D-2)), surfactants (excluding component (C)), buffers (excluding component (D-3)), local anesthetics or soothing agents, pH adjusters, stabilizers, fat-soluble antioxidants, sugars, polyhydric alcohols, thickeners, cooling agents (excluding component (D-1)), preservatives, other inorganic compounds, and oily ingredients. These ingredients may be used alone or in appropriate combinations of two or more. The contents of the ingredients shown below are preferred ranges for the ingredients when used, and are the amounts in the ophthalmic composition.

[0028] Examples of drugs (excluding pharmaceutically active ingredients, component (A), component (B), and component (D-2)) include decongestant ingredients (vasoconstrictors) (e.g., epinephrine, epinephrine hydrochloride, methylnorepinephrine, norepinephrine, ephedrine, methylephedrine, pseudoephedrine, ephedrine hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, oxymetazoline, methoxamine, phenylpropanolamine, etilefrine, mitomycin, dodrine, tramazoline, synephrine, cirazoline, xylometazoline and their pharmaceutically acceptable salts, etc.), anti-inflammatory agents (e.g., berberine chloride hydrate, berberine sulfate hydrate, azulene sodium sulfonate, lysozyme hydrochloride, pranoprofen, etc.), astringents (e.g., zinc sulfate, zinc lactate), antihistamines (e.g., diphenhydramine hydrochloride, ketotifen fumarate, olopatadine hydrochloride, etc.), antiallergic agents (e.g., sodium cromoglycate, azathioprine, thiazolinone ... Examples of suitable anti-inflammatory agents include: citazanolast, ibudilast, tranilast, pemirolast potassium, amlexanox, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, sodium ascorbate, etc.), fat-soluble vitamins, amino acids (e.g., potassium L-aspartate, magnesium L-aspartate, potassium and magnesium L-aspartate (equal mixture), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), antibacterial components (e.g., sulfa drugs (sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, etc.)). When drugs are added, the content can be selected based on the effective amount of each drug, and is preferably 0.001 to 5 w / v % of the ophthalmic composition, more preferably 0.001 to 1 w / v %, and even more preferably 0.001 to 0.1 w / v %.

[0029] Examples of surfactants other than component (C) include amphoteric surfactants (e.g., glycine-type amphoteric surfactants such as alkyldiaminoethylglycine and alkylpolyaminoethylglycine; betaine-type amphoteric surfactants such as lauryldimethylaminoacetic acid betaine and imidazolium betaine), and cationic surfactants (e.g., benzalkonium chloride and benzethonium chloride). When these amphoteric surfactants are incorporated, their content in the ophthalmic composition is preferably 0.01 to 0.5 w / v%, and more preferably 0.05 to 0.4 w / v%. Examples of nonionic surfactants other than component (C) include polyoxyethylene polyoxypropylene glycol. When nonionic surfactants other than component (C) are incorporated, their content in the ophthalmic composition is preferably 0.5 w / v% or less, more preferably 0.1 w / v% or less, and even more preferably substantially none.

[0030] Examples of buffering agents other than component (D-3) include trometamol, citric acid or its salts (e.g., sodium citrate), phosphoric acid or its salts (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate), tartaric acid or its salts (e.g., sodium tartrate), gluconic acid or its salts (e.g., sodium gluconate), acetic acid or its salts (e.g., sodium acetate), glacial acetic acid, carbonic acid or its salts (e.g., sodium carbonate, sodium bicarbonate), and various amino acids (potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate, epsilon-aminocaproic acid). These may also be hydrates. Among these, trometamol is preferred because it can further suppress a decrease in the transmittance of the ophthalmic composition and achieve a more stable appearance. When a buffering agent is incorporated, its content in the ophthalmic composition is preferably 0.001 to 5 w / v%, more preferably 0.005 to 2 w / v%, and even more preferably 0.01 to 1 w / v%.

[0031] Examples of isotonic agents include potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol, etc. When an isotonic agent is added, its content in the ophthalmic composition is preferably 0.00001 to 3 w / v%, more preferably 0.0001 to 2 w / v%, and even more preferably 0.005 to 1.5 w / v%.

[0032] Examples of local anesthetics or soothing agents include chlorobutanol, oxybuprocaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride, etc. When a local anesthetic or soothing agent is added, its content in the ophthalmic composition is preferably 0.001 to 1 w / v %, and more preferably 0.01 to 0.5 w / v %.

[0033] Examples of pH adjusters include inorganic acids and inorganic alkali agents. Specific examples of inorganic acids include (dilute) hydrochloric acid. Examples of inorganic alkali agents include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. Other examples include monoethanolamine and diethanolamine. The pH of the ophthalmic composition can be adjusted to 3.5 to 9.0, and is preferably 3.5 to 8.0, more preferably 5.5 to 8.0, from the viewpoints of a greater expected effect on corneal wound healing and less irritation upon application to the eye. The pH is measured at 25°C using a pH meter (HM-25R, DKK-TOA Corporation).

[0034] Examples of stabilizers include cyclodextrin and monoethanolamine. Examples of fat-soluble antioxidants include dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA). When a fat-soluble antioxidant is incorporated, its content in the ophthalmic composition is preferably 0.001 to 0.05 w / v%. Specifically, when dibutylhydroxytoluene is incorporated, its content in the ophthalmic composition is preferably 0.001 to 0.05 w / v%, more preferably 0.003 to 0.01 w / v%. Within the above ranges, the decrease in transmittance of the ophthalmic composition is further suppressed, the appearance stability can be further improved, and the viscosity retention rate is further improved. Furthermore, the stability of vitamin A is further improved.

[0035] Examples of water-soluble stabilizers (antioxidants) include sulfites such as sodium sulfite, potassium sulfite, dry sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogensulfite, and potassium hydrogensulfite, ascorbic acid, and sodium ascorbate.

[0036] When the ophthalmic composition of the present invention is used as an ophthalmic composition that can be applied to the eye while wearing soft contact lenses, the stabilizer is preferably one that has low lens adsorption and accumulation, and examples thereof include sulfites such as cyclodextrin sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium bisulfite, and potassium bisulfite, ascorbic acid, sodium ascorbate, etc. When a water-soluble stabilizer is incorporated, its content in the ophthalmic composition is preferably 0.001 to 5 w / v %, more preferably 0.003 to 2 w / v %, and even more preferably 0.005 to 1 w / v %.

[0037] Examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, and mannitol. These may be in the d-, l-, or dl-form. Because sugars have moisturizing properties, they have the effect of increasing moisture when applied to the eye, and can also be used as isotonic agents. When sugars are incorporated, their content in the ophthalmic composition is preferably 0.001 to 5 w / v%, more preferably 0.003 to 2 w / v%, and even more preferably 0.005 to 1 w / v%.

[0038] Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. Polyhydric alcohols have moisturizing properties, which increase the moisture content of the eye drops when applied, and they can also be used as isotonic agents. Glycerin and propylene glycol can also be used as solubilizers for cooling agents. When polyhydric alcohols are used, their content in the ophthalmic composition is preferably 0.001 to 5 w / v%, more preferably 0.003 to 1 w / v%, and even more preferably 0.005 to 0.5 w / v%.

[0039] Examples of thickeners include water-soluble polymer compounds, such as polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, dextran, alginic acid, sodium alginate, xanthan gum, etc. When a thickener is added, it can be added to an extent that does not impair the feel during use, such as stickiness or blurring, and the content thereof in the ophthalmic composition is preferably 0.001 to 5 w / v%, more preferably 0.003 to 1 w / v%, and even more preferably 0.005 to 0.5 w / v%.

[0040] Examples of refreshing agents include menthol, geraniol, cineole, linalool, anethole, eugenol, limonene, and rhubarb. They may be in the d-, l-, or dl-isomer. Other examples include essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, eucalyptus oil, rose oil, fennel oil, bergamot oil, and cinnamon oil. These refreshing agents can enhance the perceived effect of sustained moisture. When a refreshing agent or essential oil is incorporated, its content in the ophthalmic composition is preferably 0.0005 to 0.2 w / v %, more preferably 0.001 to 0.1 w / v %.

[0041] Examples of preservatives include chlorhexidine gluconate, chlorobutanol, and benzalkonium chloride. These preservatives can enhance the preservative effectiveness of the ophthalmic composition. When a preservative is added, its content in the ophthalmic composition is preferably 0.00005 to 0.2 w / v%, and more preferably 0.0001 to 0.1 w / v%.

[0042] Examples of other inorganic compounds include sodium thiosulfate, titanium oxide, zinc chloride, etc. When these compounds are added, the content thereof in the ophthalmic composition is preferably 0.001 to 5 w / v%, more preferably 0.003 to 2 w / v%, and even more preferably 0.005 to 1 w / v%.

[0043] [Ophthalmic composition] The composition of the present invention is preferably an "aqueous ophthalmic composition." In the present invention, "aqueous ophthalmic composition" refers to an ophthalmic composition whose medium is water. The content of water in the composition is preferably 90 to 99.5 w / v %, more preferably 95 to 98 w / v %.

[0044] The ophthalmic composition of the present invention is preferably a liquid, and its viscosity at 20° C. is preferably 1 to 400 mPa·s, more preferably 1 to 100 mPa·s, even more preferably 1 to 60 mPa·s, and particularly preferably 1 to 30 mPa·s. The viscosity is measured using a B-type viscometer.

[0045] The transmittance of the ophthalmic composition at 600 nm is preferably 96% or more, more preferably 97% or more, and even more preferably 98% or more. By ensuring that the transmittance is 96% or more, the risk of abnormal appearance can be further reduced. The transmittance of the present invention can be measured, for example, using a spectrophotometer (e.g., UV-1800, Shimadzu Corporation).

[0046] The formulation of the ophthalmic composition of the present invention is not particularly limited, and it can be suitably used, for example, as eye drops (including eye drops that can be applied while wearing contact lenses), eyewash, contact lens wetting solution, contact lens removal solution, etc. It is particularly suitable for use as eye drops and contact lens wetting solution, with eye drops being particularly preferred. Among these, it is suitable as an ophthalmic composition for contact lenses used by contact lens wearers, such as eye drops that can be applied while wearing contact lenses, contact lens wetting solution, and contact lens removal solution.

[0047] Contact lenses include, but are not limited to, hard contact lenses (including O2 hard contact lenses), soft contact lenses (including both ionic and non-ionic), silicone hydrogel contact lenses, colored contact lenses, etc. When no preservative is added, the composition is particularly suitable for use with soft contact lenses and silicone hydrogel contact lenses.

[0048] The ophthalmic product of the present invention can be used as an over-the-counter eye drop with efficacy such as dry eyes, foreign body sensation in the eyes (gritty, tingly feeling), eye fatigue, blurred vision (when there is a lot of eye discharge, etc.), discomfort when wearing soft or hard contact lenses, conjunctival congestion, itchy eyes, blepharitis (sore eyelids), prevention of eye diseases (after swimming, when dust or sweat gets into the eyes, etc.), ophthalmitis caused by ultraviolet rays or other light (snow blindness, etc.), etc., or as an artificial tear with efficacy such as discomfort when wearing soft or hard contact lenses, tear supplementation (dry eyes), eye fatigue, blurred vision (when there is a lot of eye discharge, etc.). The dosage is one drop at a time, up to 5 to 6 times a day.

[0049] [Manufacturing method] The method for producing the ophthalmic composition of the present invention is not particularly limited. For example, a mixed solution of components (B) and (C) is pre-dissolved by heating (70-95°C), an aqueous solution containing aqueous components such as component (A) is heated (70-95°C), and then the mixed solution of components (B) and (C) is added and mixed. Then, component (D) is added and mixed, the pH is adjusted, and the total volume is adjusted with water. Component (D-1) may be added to the mixed solution of components (B) and (C) and mixed, or it may be pre-dissolved in a polyhydric alcohol such as propylene glycol and then added immediately before adjusting the pH. The components may be mixed using conventional methods, such as a pulsator, propeller blade, paddle blade, or turbine blade. The rotation speed is not particularly limited, but is preferably set to a level that does not cause vigorous foaming. The mixing temperature of each liquid is not particularly limited, but it is preferably above the melting temperature of both the oily component and the surfactant component, specifically, within the range of 40-95°C.

[0050] [container] The container is an ophthalmic product having a container body in which the ophthalmic composition is contained and a container equipped with a cap, and the container body is made of polyethylene terephthalate. The container comprises a container body (sometimes referred to as a bottle or main body) in which the ophthalmic composition is contained and a cap. More specifically, the main body is provided with an eye dropper and has a cap such as a screw type or one-touch type that seals the main body. The main body may be provided with an inner stopper having an eye dropper, the eye dropper may be provided on the cap, or the cap may be directly attached to the container to seal it. In the present invention, it is preferable that the main body is provided with an inner stopper having an eye dropper. In the present invention, the term "container" refers to a state in which the cap is attached to the main body.

[0051] [Main unit] The main body is made of polyethylene terephthalate. The amount of the ophthalmic composition in the product can be selected appropriately depending on the product and its usage method, and is preferably 2 to 20 mL, more preferably 5 to 20 mL. The container for the ophthalmic composition is not particularly limited, but may be a multi-dose (multi-unit) container or a single-use unit-dose container. Among these, multi-dose (multi-unit) containers are preferred. In addition to polyethylene terephthalate resin, additives used in container manufacturing, such as plasticizers, crosslinking agents, release agents, thickeners, reinforcing agents, flame retardants, light-blocking agents, UV absorbers, colorants, antifogging agents, antistatic agents, polymerization initiators, antioxidants, antifungal agents, lubricants, and fillers, may be contained.

[0052] [Inner stopper, cap] The stopper and cap can be made of materials commonly used for containers of known ophthalmic products. For example, the stopper is preferably made of polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8. The cap is preferably made of polyethylene or polypropylene.

[0053] [Sterilization] Since the ophthalmic composition is a sterile preparation, it is preferable that the polyethylene terephthalate container body be sterilized. Specifically, the sterilization method can be any of ethylene oxide gas sterilization, electron beam sterilization, and gamma ray sterilization. Electron beam sterilization is more preferable because there is no concern about residual gas and the sterilization process can be completed in a short time.

[0054] The method of sterilization using electron beams or gamma rays is not particularly limited and can be carried out according to conventionally known sterilization conditions. For example, from the perspective of sterilization effectiveness, sterilization is preferably carried out at 5 to 80 kGy, more preferably 5 to 50 kGy, and even more preferably 5 to 30 kGy. When the container body is sterilized using electron beams or gamma rays, the presence or absence of sterilization can be confirmed by changes in the polyethylene terephthalate resin monomers and additive components used in the manufacture of the container body (e.g., an increase in dimethyl terephthalate analogues, an increase in 2-ethylhexyl adipate, etc.). These changes in components can be analyzed and evaluated using GC-MS, NMR, etc.

[0055] [Enclosure] The ophthalmic product may have a housing for packaging the container, such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil, aluminum-deposited polyvinyl alcohol or polyamide film, polyvinylidene chloride-coated film or laminate film, or composite or multilayer film thereof.

[0056] An inert gas such as nitrogen may be sealed in the space formed between the container and the packaging, or the ophthalmic composition may be filled into the container and then sealed in the packaging together with an oxygen scavenger. Examples of the means include (1) injecting an inert gas into the enclosure, (2) packaging an oxygen absorber in the enclosure, (3) a container having oxygen absorbing capacity, or (4) an enclosure having oxygen absorbing capacity. By using such means, the problems of the present invention can be solved, the decrease in transmittance of the ophthalmic composition can be further suppressed, and the appearance stability can be improved. (1) Injection of inert gas into the enclosure Examples of inert gases include nitrogen, helium, neon, and argon. Of these, nitrogen gas is preferred. The concentration of the inert gas is preferably 50% by volume or more, more preferably 80% by volume or more, and even more preferably 90% by volume or more, of the volume of the space formed between the enclosure and the plastic container. There is no particular upper limit, but it is 100% by volume or less. To achieve such a concentration, the space formed between the enclosure and the plastic container may be replaced with the inert gas. (2) Packing oxygen absorbers inside the enclosure Specifically, Ageless (registered trademark) (FX, SP, SS, SPE, ZP, Z-PT, Z-PKC, GLS, GL-M, Z-20PK) manufactured by Mitsubishi Gas Chemical Company, Inc., PharmaKeep, Vitalon manufactured by Tokiwa Sangyo Co., Ltd., Sansoles manufactured by Hakuyo Co., Ltd., WonderKeep manufactured by Powder Tech Co., Ltd., Sansocut manufactured by Iris Fine Products Co., Ltd., etc. can be used. (3) Containers with oxygen absorption capacity Specifically, for example, Oxyblock manufactured by Toyo Seikan Co., Ltd. can be used. (4) Oxygen-absorbing enclosure Specifically, Oxycatch (registered trademark) ICA manufactured by Kyodo Printing Co., Ltd., Cryovac (registered trademark) OS Film manufactured by Sealed Air Japan Co., Ltd., Hyster O2 manufactured by Star Plastics Industries Co., Ltd., Ageless Omac manufactured by Mitsubishi Gas Chemical Company, Inc., Oxydec manufactured by Toyo Seikan Co., Ltd., etc. can be used. The above means can be combined as appropriate, with (2) and (4) being preferred, and (1)+(2) and (1)+(4) being more preferred.

[0057] [Method for suppressing decrease in transmittance of ophthalmic composition] The present invention provides an ophthalmic product in which a container body containing an ophthalmic composition is made of polyethylene terephthalate, (A) 0.05 to 0.5 w / v% of one or more selected from hyaluronic acid and its salts, (B) Vitamin A and Vitamin E, and (C) an ophthalmic composition containing one or more surfactants selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester, (D) One or more selected from the following (D-1), (D-2), and (D-3): (D-1) Camphor, Borneol (D-2) Allantoin, glycyrrhizinic acid, neostigmine, chlorpheniramine, tetrahydrozoline, and their salts (D-3) Boric acid, borax, ethylenediamine acetic acid, ethylenediamine acetic acid derivatives, ethylenediamine acetate salts The present invention also provides a method for suppressing a decrease in transmittance of the ophthalmic composition, which comprises blending the following components. The preferred components and amounts are the same as those described above.

[0058] [Method for improving the appearance stability of an ophthalmic composition] The present invention provides (A) 0.05 to 0.5 w / v% of one or more selected from hyaluronic acid and its salts, (B) Vitamin A and Vitamin E, and (C) an ophthalmic composition containing one or more surfactants selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester, (D) One or more selected from the following (D-1), (D-2), and (D-3) are blended, (D-1) Camphor, Borneol (D-2) Allantoin, glycyrrhizinic acid, neostigmine, chlorpheniramine, tetrahydrozoline, and their salts (D-3) Boric acid, borax, ethylenediamine acetic acid, ethylenediamine acetic acid derivatives, ethylenediamine acetate salts The present invention also provides a method for improving the appearance stability of an ophthalmic composition containing the above-mentioned components (A) to (C), which comprises storing the ophthalmic composition in a container body made of polyethylene terephthalate that has been sterilized by electron beam or gamma ray. The preferred components and amounts are the same as those described above. [Example]

[0059] The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to the following examples. Note that the w / v % of the composition is g / 100 mL.

[0060] [Examples and Comparative Examples] A mixed solution of components (B) and (C) was pre-dissolved by heating (70-95°C). Component (A) and phosphate buffer (a mixed solution of 0.02 w / v% aqueous disodium hydrogen phosphate and 0.11 w / v% aqueous sodium dihydrogen phosphate; adjusted to pH 7) were then heated to 70-95°C and mixed. The mixed solution of components (B) and (C) (also referred to as a (B)(C) mixed solution) was then added and mixed, and the pH was adjusted to 7 with phosphate buffer. Subsequently, component (D) was added and mixed, and the total volume was adjusted with water to obtain an ophthalmic composition. Note that component (D-1) was premixed with a 0.04 w / v% equivalent portion of component (C) and mixed. The obtained ophthalmic composition was filled into a polyethylene terephthalate container or a polyethylene container body to obtain an ophthalmic product (using a polyethylene inner stopper and a polypropylene cap). The ophthalmic products were stored in an environment of 50°C and 75% RH for two weeks.

[0061] [Transmittance] The transmittance at 600 nm of the ophthalmic composition before storage (immediately after production) was measured using a spectrophotometer (UV-1800, Shimadzu Corporation), and the ophthalmic product was stored for two weeks in an environment of 50°C and 75% RH. After storage, the ophthalmic product was returned to room temperature (20°C), and the transmittance was measured in the same manner as before storage. The results are also shown in the table.

[0062] [exterior] The transmittance results are recorded according to the following criteria. ○: Transmittance is 97.0% or more (appearance is clear) △: Transmittance is 96.0% or more but less than 97.0% (indistinguishable from ophthalmic compositions with transmittance of 97.0% or more) ×: Transmittance less than 96.0% (distinguishable by comparison with ophthalmic compositions with transmittance of 97.0% or more) A △ or 〇 will be considered a pass.

[0063] [Table 1]

[0064] [Table 2]

[0065] [Table 3]

[0066] [Table 4]

[0067] [Table 5]

[0068] [Table 6]

[0069] As is clear from the results of Reference Examples 1 to 3 and Comparative Example 1, when an ophthalmic composition containing (A) 0.05 w / v% or more of sodium hyaluronate, (B) vitamin A and vitamin E, and (C) one or more surfactants selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester is placed in a container body made of polyethylene terephthalate, a problem arises in that the transmittance of the ophthalmic composition decreases. From the results of the Examples, it was found that by blending a specific component (D) with an ophthalmic composition containing (A) 0.05-0.5 w / v% of one or more selected from hyaluronic acid and its salts, (B) vitamin A and vitamin E, and (C) one or more surfactants selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester, the decrease in the transmittance of the ophthalmic composition was suppressed even when the ophthalmic composition was contained in a polyethylene terephthalate container body. Furthermore, this effect was more pronounced when one or more components (D-1) were used in combination with one or more components (D-2) and (D-3).

[0070] The raw materials used are listed below. Unless otherwise specified, the amount of each ingredient in the table is the pure equivalent. The terms "JP," "Extra-Pharmacopoeia Standards," and "Pharmaceutical Additive Standards" below refer to raw materials that comply with the 18th Revised Japanese Pharmacopoeia Standards, the Japanese Pharmacopoeia Extra-Pharmacopoeia Standards, and the Pharmaceutical Additive Standards (2018), respectively. Sodium hyaluronate: Trade name "Hyaluronic Acid HA-AML" (JP), manufactured by Kewpie Corporation Retinol palmitate: Trade name "Retinol palmitate 1.74 million IU, BHA / BHT added" (Japanese Pharmacopoeia), manufactured by DSM Co., Ltd. d-α-Tocopherol acetate: Trade name "Riken E Acetate α" (extraneous regulation), manufactured by Riken Vitamin Co., Ltd. Dibutylhydroxytoluene: Trade name "Dibutylhydroxytoluene" (Pharmaceutical Additives Regulations), manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Polyoxyethylene hydrogenated castor oil 60: Product name "NIKKOL HCO-60 (medical use)" (Pharmaceutical Additives Regulations), manufactured by Nippon Surfactant Industries Co., Ltd. Polyoxyethylene (20) sorbitan monooleate, sorbitan polysorbate 80: trade name "Rheodor TW-0120V" (Japan Pharmacopoeia), manufactured by Kao Corporation dl-Camphor: Trade name "Japanese Pharmacopoeia dl-Camphor" (JP), manufactured by Nissei Bayliss Co., Ltd. d-Borneol: Product name "Special Boiling Water (d-Borneol)" (Pharmaceutical Additives Regulations), manufactured by Yanagisawa Masami Shoten Co., Ltd. Allantoin: Product name "Allantoin" (external regulations), manufactured by PermaChem Asia Co., Ltd. Dipotassium glycyrrhizinate: Trade name "Dipotassium glycyrrhizinate" (non-regulated by the Ministry of Health, Labour and Welfare), manufactured by Maruzen Pharmaceutical Co., Ltd. Neostigmine methylsulfate: Trade name "Neostigmine methylsulfate" (JP), manufactured by Tokyo Chemical Industry Co., Ltd. Chlorpheniramine maleate: Trade name "Chlorpheniramine maleate (chlorpheniramine maleate)" (Japanese Pharmacopoeia), manufactured by Kongo Chemical Co., Ltd. Tetrahydrozoline hydrochloride: Trade name "Tetrahydrozoline hydrochloride" (extra-official regulations), manufactured by Nippon Bulk Pharmaceutical Co., Ltd. Boric acid: Trade name "Boric Acid" (Japanese Pharmacopoeia), manufactured by Kanto Chemical Co., Ltd. Disodium ethylenediaminetetraacetic acid (EDTA disodium): Trade name "Sodium edetate hydrate (for manufacturing use only)" (JP), manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Trometamol: Trade name "2-amino-2-hydroxymethyl-1,3-propanediol" (extraneous regulation), manufactured by Kanto Chemical Co., Ltd. Disodium hydrogen phosphate: Trade name "Disodium hydrogen phosphate" (special reagent grade), manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Sodium dihydrogen phosphate: Trade name "Sodium dihydrogen phosphate" (special grade reagent), manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Polyethylene terephthalate container: 10 mL, multi-dose type, manufactured by Shinko Chemical Co., Ltd. Polyethylene container: 5 mL, multi-dose type, manufactured by Taisei Kako Co., Ltd.

Claims

1. (A) 0.05 to 0.5 w / v% of one or more selected from hyaluronic acid and salts thereof; (B) Vitamin A and Vitamin E; (C) one or more surfactants selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester, and (D) One or more selected from the following (D-1), (D-2), and (D-3): (D-1) Camphor, borneol (D-2) Allantoin, glycyrrhizinic acid, neostigmine, chlorpheniramine, tetrahydrozoline, and salts thereof (D-3) Boric acid, borax, ethylenediamine acetic acid, ethylenediamine acetic acid derivatives, ethylenediamine acetate salts and a container having a container body and a cap in which the ophthalmic composition is contained, wherein the container body is made of polyethylene terephthalate.

2. 2. The ophthalmic product according to claim 1, wherein the content of (B) vitamin A is 40,000 to 100,000 units / 100 mL.

3. 3. The ophthalmic product according to claim 1, wherein the component (D) comprises at least one selected from the component (D-1) and at least one selected from the component (D-2) and the component (D-3).

4. 3. The ophthalmic product according to claim 1, wherein the container body made of polyethylene terephthalate has been sterilized by electron beam or gamma ray.

5. 3. The ophthalmic product according to claim 1, wherein component (B) is retinol palmitate and d-α-tocopherol acetate.

6. 3. The ophthalmic product according to claim 1, further comprising a fat-soluble antioxidant.

Images