Ophthalmic composition

Abstract

To solve the problem of emulsion coalescence and clouding which occurs upon preservation under heated conditions followed by storage at low temperatures in ophthalmic compositions containing (A) vitamin A, (B) polyoxyethylene polyoxypropylene glycol, and (C) one or more kinds selected from berberine or salts thereof, and to improve the storage stability of such compositions.SOLUTION: An ophthalmic composition comprises (A) vitamin A, (B) polyoxyethylene polyoxypropylene glycol, (C) one or more kinds selected from berberine and salts thereof, (D) boric acid, (E) disodium edetate hydrate, and (F) trometamol, where the total content of the components (D)+(E)+(F) is 1.4 w / v% or more.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition containing vitamin A. [Background technology]

[0002] Vitamin A, a fat-soluble vitamin, is known as an essential substance for the proliferation and differentiation of epithelial cells, and is known to promote mucin production and heal corneal wounds. Since vitamin A is fat-soluble, it is required to have a uniform appearance, especially when it is mixed at a high concentration. In addition, preservative efficacy is also required for ophthalmic compositions. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2013 / 183778 Summary of the Invention [Problem to be solved by the invention]

[0004] Combining vitamin A with polyoxyethylene polyoxypropylene glycol can enhance the mucin production promoting effect and corneal repair ability of vitamin A. The present inventors have found that when berberine and its salts, which have anti-inflammatory and high antibacterial effects, are contained in an ophthalmic composition for the purpose of treating various ocular symptoms such as blurred vision, itching, and congestion, the emulsion coalesces and becomes cloudy when stored at low temperature after storage under heated conditions. This problem does not occur with surfactants used in ophthalmic compositions such as polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester, but occurs when vitamin A, polyoxyethylene polyoxypropylene glycol, and berberine and its salts are combined. In addition, the preservative effect of the above-mentioned configuration is insufficient. Therefore, the present invention aims to solve the above-mentioned problem in an ophthalmic composition containing (A) vitamin A, (B) polyoxyethylene polyoxypropylene glycol, and (C) berberine and its salts. [Means for solving the problem]

[0005] As a result of intensive research into achieving the above-mentioned object, the inventors have discovered that the above-mentioned problems can be solved by incorporating specific amounts or more of (D) boric acid, (E) sodium edetate hydrate, and (F) trometamol into an ophthalmic composition containing one or more selected from (A) vitamin A, (B) polyoxyethylene polyoxypropylene glycol, and (C) berberine and its salts, and have thus completed the present invention.

[0006] Accordingly, the present invention provides the following ophthalmic compositions. 1. (A) Vitamin A, (B) polyoxyethylene polyoxypropylene glycol, (C) one or more selected from berberine and its salts, (D) boric acid, (E) edetate sodium hydrate, and (F) Contains trometamol, An ophthalmic composition, wherein the total amount of the above components (D), (E) and (F) is 1.4 w / v % or more. 2. The ophthalmic composition according to 1, wherein the mass ratio represented by ((D)+(E)) / (F) is 4 to 20. 3. The ophthalmic composition according to 1 or 2, wherein the content of component (A) is 40,000 to 80,000 units / 100 mL. 4. The ophthalmic composition according to any one of 1 to 3, wherein the content of component (C) is 0.001 to 0.1 w / v %. 5. The ophthalmic composition according to any one of 1 to 4, wherein the content of component (B) is 0.2 to 1 w / v %. 6. The ophthalmic composition according to any one of 1 to 5, having a pH of 5.0 to 7.5. Effect of the Invention

[0007] According to the present invention, in an ophthalmic composition containing one or more selected from (A) vitamin A, (B) polyoxyethylene polyoxypropylene glycol, and (C) berberine and its salts, by storing the composition under heated conditions and then at low temperatures, the problem of the emulsion coalescing and becoming cloudy can be solved, and sufficient preservative efficacy can be obtained. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention will be described in detail below. [Component (A)] The component (A) of the present invention is vitamin A, and in addition to vitamin A itself, examples thereof include vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters, etc. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, retinoids, etc., which can be used alone or in combination of two or more. Among them, retinol palmitate, retinol acetate, and retinoic acid are preferred from the viewpoint of the stability of vitamin A. Retinol palmitate is usually commercially available in the range of 1,000,000 to 1,800,000 international units (hereinafter abbreviated as IU), and specific examples thereof include retinol palmitate (1,740,000 IU) manufactured by DSM Co., Ltd.

[0009] The content of component (A) in the ophthalmic composition is preferably 40,000 to 80,000 units / 100 mL (0.023 to 0.046 w / v% (mass / volume%, the same applies below)), and more preferably 50,000 to 70,000 units / 100 mL (0.029 to 0.040 w / v%). (VA is calculated in units of 1.74 million). By setting the content to be equal to or greater than the above lower limit, the mucin production promoting effect and corneal repair effect of component (A) can be further enhanced, and by setting the content to be equal to or less than the above upper limit, the clouding suppression effect can be more easily obtained.

[0010] [(B) Component] The component (B) of the present invention is polyoxyethylene polyoxypropylene glycol, which can be used alone or in combination of two or more. As the polyoxyethylene polyoxypropylene glycol, those described in the Pharmaceutical Excipients Standards (2018) can be suitably used. The average degree of polymerization of ethylene oxide is preferably 3 to 200, more preferably 20 to 200, and the average degree of polymerization of propylene oxide is preferably 5 to 100, more preferably 17 to 70. It may be a block copolymer or a random polymer, but a block copolymer is preferred. Specifically, polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol may be mentioned, and one kind may be used alone or two or more kinds may be appropriately combined. Among them, polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (120) polyoxypropylene (40) glycol are preferred because they are more likely to provide stability of vitamin A and corneal repair ability due to vitamin A. Examples of commercially available products include polyoxyethylene (196) polyoxypropylene (67) glycol under the trade name: Kolliphor P407 [BASF Japan Ltd.] and trade name: Pronon #407P [NOF Corp.]; polyoxyethylene (120) polyoxypropylene (40) glycol under the trade name: Kolliphor P237 [BASF Japan Ltd.], as well as commercially available products listed in the Pharmaceutical Additives Encyclopedia 2021 (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nipposha).

[0011] The content of component (B) in the ophthalmic composition is preferably 0.2 to 1 w / v%, more preferably 0.4 to 1 w / v%, and even more preferably 0.4 to 0.8 w / v%. By making the content equal to or greater than the lower limit, the effect of inhibiting clouding can be more easily obtained, and the stability of component (A) and the mucin production promoting effect and corneal repair effect of component (A) can be further improved, while by making the content equal to or less than the upper limit, the stability of component (A) can be further improved.

[0012] [(C) component] The component (C) of the present invention is one or more selected from berberine and its salts, which are known to have anti-inflammatory effects and high antibacterial properties against bacteria. The component (C) can be used alone or in combination of two or more. Examples of the component (C) include sulfates and hydrochlorides such as berberine sulfide and berberine chloride. Hydrates may also be used. Among them, berberine chloride and berberine chloride hydrate are preferred because they are more likely to provide preservative effectiveness.

[0013] The content of component (C) in the ophthalmic composition is preferably 0.001 to 0.1 w / v%, more preferably 0.005 to 0.05 w / v%, and even more preferably 0.01 to 0.03 w / v%. By making the content equal to or greater than the lower limit, the preservative effect and the anti-inflammatory effect are further improved, and by making the content equal to or less than the upper limit, the effect of suppressing clouding is more easily obtained.

[0014] [(D), (E), (F) components] The ophthalmic composition of the present invention contains (D) boric acid, (E) sodium edetate hydrate, and (F) trometamol, and the total amount of these is 1.4 w / v% or more in the ophthalmic composition, and by using this amount, it is possible to obtain a clouding suppression effect and a preservative effect. The total amount is preferably 1.6 w / v% or more, more preferably 1.8 w / v% or more, and even more preferably 2 w / v% or more, from the viewpoint of obtaining a better clouding suppression effect and a better preservative effect. In addition, it is preferably 5 w / v% or less, more preferably 4.1 w / v% or less, even more preferably 3 w / v% or less, and particularly preferably 2.55 w / v% or less. By keeping it below the above upper limit, irritation is less likely to occur when instilled, and the usability of the ophthalmic composition is further improved.

[0015] The mass ratio represented by ((D)+(E)) / (F) (the same value as w / v %, hereinafter) is preferably 3 to 20, more preferably 5 to 13, and further preferably 7 to 10. By making it equal to or more than the above lower limit, the effect of suppressing clouding can be further improved, and by making it equal to or less than the above upper limit, the preservative effectiveness can be further improved.

[0016] The blending amount of component (D) in the ophthalmic composition is preferably 0.5 to 3 w / v %, more preferably 1.3 to 2.1 w / v %. By making it equal to or more than the lower limit, the effect of suppressing clouding and preservative efficacy can be more easily obtained, while by making it equal to or less than the upper limit, irritation upon application to the eyes is less likely to occur, and the usability of the ophthalmic composition is further improved.

[0017] The blending amount of the (E) component in the ophthalmic composition is preferably 0.005 to 0.1 w / v %, and more preferably 0.01 to 0.05 w / v %. By making the blending amount equal to or more than the lower limit, the effect of suppressing clouding and preservative efficacy can be more easily obtained, while by making the blending amount equal to or less than the upper limit, irritation upon instillation is less likely to occur, and the usability of the ophthalmic composition is further improved.

[0018] The blending amount of component (F) in the ophthalmic composition is preferably 0.05 to 1 w / v %, more preferably 0.14 to 0.4 w / v %. By making the blending amount equal to or more than the lower limit, the clouding suppression effect and preservative efficacy can be more easily obtained, while by making the blending amount equal to or less than the upper limit, the clouding suppression effect can be more easily obtained, and irritation upon instillation is less likely to occur, thereby improving the usability of the ophthalmic composition.

[0019] [Other ingredients] The ophthalmic composition of the present invention may contain other components to be blended in appropriate amounts within the range that does not impair the effects of the present invention. Examples of other components include the following, which may be used alone or in appropriate combination of two or more.

[0020] [(G) component] From the viewpoint of the stability of the component (A), the ophthalmic composition of the present invention may further contain (G) one or more selected from vitamin E, dibutylhydroxytoluene (BHT) and butylhydroxyanisole. Vitamin E is used as a general term for tocopherol, tocotrienol, their salts and derivatives (esters). Among them, tocopherol acetate is preferred from the viewpoint of the stability of the component (A). The tocopherol acetate may be either d-α-tocopherol acetate or dl-α-tocopherol acetate.

[0021] When component (G) is contained, its content in the ophthalmic composition is preferably 0.001 to 2 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.01 to 0.1%. By making the content equal to or more than the above lower limit, the stability of component (A) can be further improved, and by making the content equal to or less than the above upper limit, the effect of suppressing clouding can be more easily obtained.

[0022] The ophthalmic composition of the present invention can obtain sufficient preservative effectiveness without the incorporation of preservatives such as benzalkonium chloride, benzethonium chloride, sorbic acid, thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconate, methyl paraoxybenzoate, and ethyl paraoxybenzoate, and is preferably substantially free of the above-mentioned components. By substantially not containing the above-mentioned components, an ophthalmic composition can be obtained that is safer for damaged eyes and has excellent storage stability of vitamin A. By substantially not containing the above-mentioned components, it is preferable that the content is 0.001 w / v% or less, more preferably 0.0001 w / v% or less, and even more preferably below the detection limit, and it may not be contained.

[0023] Examples of drugs (pharmaceutical active ingredients) other than the components (A) and (C) include congestion relief ingredients (e.g., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline hydrochloride, etc.), anti-inflammatory / astringent agents (e.g., epsilon aminocaproic acid, allantoin, sodium azulene sulfonate, zinc sulfate, zinc lactate, glycyrrhizic acid, disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, monoammonium glycyrrhizinate, lysozyme, glycyrrhizinate ... Examples of the drug include glycerol hydrochloride, etc.), antihistamines (chlorpheniramine maleate, diphenhydramine hydrochloride), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.), amino acids (e.g., potassium aspartate, magnesium L-aspartate, potassium magnesium aspartate (mixture of equal amounts), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), sodium hyaluronate, and sulfa drugs (sulfamethoxazole, sulfisoxazole, and salts thereof). When these drugs are contained, the content can be selected based on the effective amount of each drug, and is preferably 0.001 to 5 w / v% in the ophthalmic composition, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0024] [Nonionic surfactants other than component (B)] Examples of nonionic surfactants other than component (B) include polyoxyethylene castor oil (POE castor oil), polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil), and polyoxyethylene sorbitan fatty acid esters (POE sorbitan fatty acid esters).

[0025] Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and several types with different average added moles of ethylene oxide are known. The average added moles of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but is exemplified as 3 to 60 moles. Specific examples include polyoxyethylene castor oil 3 (average added moles of EO: 3), polyoxyethylene castor oil 10 (average added moles of EO: 10), polyoxyethylene castor oil 20 (average added moles of EO: 20), polyoxyethylene castor oil 35 (average added moles of EO: 35), polyoxyethylene castor oil 40 (average added moles of EO: 40), polyoxyethylene castor oil 50 (average added moles of EO: 50), and polyoxyethylene castor oil 60 (average added moles of EO: 60). Among them, polyoxyethylene castor oil 35 is preferred.

[0026] Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types with different average added moles of ethylene oxide are known. The average added moles of ethylene oxide in polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified as 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (EO average number of moles added: 5), polyoxyethylene hydrogenated castor oil 10 (EO average number of moles added: 10), polyoxyethylene hydrogenated castor oil 20 (EO average number of moles added: 20), polyoxyethylene hydrogenated castor oil 30 (EO average number of moles added: 30), polyoxyethylene hydrogenated castor oil 40 (EO average number of moles added: 40), polyoxyethylene hydrogenated castor oil 50 (EO average number of moles added: 50), polyoxyethylene hydrogenated castor oil 60 (EO average number of moles added: 60), polyoxyethylene hydrogenated castor oil 80 (EO average number of moles added: 80), polyoxyethylene hydrogenated castor oil 100 (EO average number of moles added: 100), etc. are mentioned. Among them, polyoxyethylene hydrogenated castor oil 60 is preferable.

[0027] Examples of polyoxyethylene sorbitan fatty acid esters (POE sorbitan fatty acid esters) include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), 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). Among these, polyoxyethylene (20) sorbitan monooleate (polysorbate 80) is preferred.

[0028] The content of the nonionic surfactant other than the component (B) in the ophthalmic composition is preferably 0.01 w / v% or less, more preferably 0.005 w / v% or less, and even more preferably below the detection limit. By keeping it below the upper limit, the storage stability of vitamin A can be further improved.

[0029] Examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc. These may be in the d-, l- or dl-form. The amount of sugars to be added is preferably 0.001 to 5 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v% in the ophthalmic composition.

[0030] Examples of buffering agents other than components (D) and (F) include citric acid or its salts (sodium citrate, etc.), phosphoric acid or its salts (sodium hydrogen phosphate, sodium dihydrogen phosphate, etc.), tartaric acid or its salts (sodium tartrate, etc.), gluconic acid or its salts (sodium gluconate, etc.), acetic acid or its salts (sodium acetate, etc.), carbonic acid or its salts (sodium hydrogen carbonate, etc.), various amino acids (aminoethylsulfonic acid, glutamic acid, sodium glutamate), etc. The amount of a buffering agent, when incorporated, is preferably 0.001 to 5 w / v% in the ophthalmic composition, more preferably 0.001 to 2 w / v%, and even more preferably 0.001 to 1 w / v%.

[0031] [Transmittance] The transmittance of the ophthalmic composition of the present invention is preferably 85 to 100%, more preferably 90 to 100%. The transmittance of the present invention refers to the transmittance at a wavelength of 600 nm and an optical path length of 10 mm measured using a spectrophotometer (e.g., UV-1800, Shimadzu Corporation).

[0032] Examples of pH adjusters include inorganic acids and inorganic alkali agents. Specifically, examples of inorganic acids include (dilute) hydrochloric acid. Examples of inorganic alkali agents include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate. An appropriate amount is blended to achieve the pH described below.

[0033] Examples of isotonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. In order to further improve various symptoms caused by destabilization of the tear lipid layer, it is preferable to add sodium chloride or potassium chloride to make the composition isotonic. The osmotic pressure ratio of the composition to physiological saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and most preferably 0.83 to 1.20. The osmotic pressure is measured at 25°C using an automatic osmometer (A2O, Advanced Instruments).

[0034] Examples of stabilizers other than the components (D), (E) and (F) include cyclodextrin, sulfites (sodium hydrogensulfite, sodium pyrosulfite, etc.), etc. By including these stabilizers, the stability of vitamin A can be further improved. When a stabilizer is included, the amount of the stabilizer is preferably 0.001 to 5 w / v% in the ophthalmic composition, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0035] Examples of the refreshing agent include menthol, camphor, borneol, geraniol, cineol, linalool, etc. Any of d-, l- or dl-isomers may be used. When a refreshing agent is contained, the content of the refreshing agent in the ophthalmic composition is preferably 0.0001 to 0.2 w / v%.

[0036] Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, polyethylene glycol, etc. When polyhydric alcohols are incorporated, the amount of the polyhydric alcohol is preferably 0.001 to 5 w / v %, more preferably 0.001 to 1 w / v %, and even more preferably 0.001 to 0.1 w / v % in the ophthalmic composition.

[0037] Examples of thickening agents include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethylcellulose (hypromellose), methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, etc. The amount of a thickening agent, when blended, is preferably 0.001 to 5 w / v% in the ophthalmic composition, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0038] Examples of the oil component include liquid paraffin, castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglyceride, white petrolatum, liquid paraffin, wax ester, sterol ester, etc. When an oil component is incorporated, the amount of the oil component is preferably 0.001 to 1 w / v % in the ophthalmic composition.

[0039] As the water, purified water, sterilized water, etc. can be used, and the content of water can be the balance of the composition. Specifically, the content of water in the ophthalmic composition is preferably 90 to 99.9 w / v %, more preferably 93 to 98 w / v %.

[0040] [Manufacturing method] The method for producing the ophthalmic composition of the present invention is not particularly limited, but for example, a mixed solution of oily components such as components (A) and (G) and surfactant components such as component (B) can be mixed with an aqueous solution containing components (D) to (F) to emulsify, then an aqueous component such as component (C) is added, the pH is adjusted, and the total volume is adjusted with water. The mixing method of each component may be a general method, and is appropriately performed using a pulsator, propeller blade, paddle blade, turbine blade, etc., but the rotation speed is not particularly limited, and it is preferable to set it to a level that does not cause vigorous foaming. The mixing temperature of each component is not particularly limited, but it is preferable that both the oily component and the surfactant component are at or above their melting temperatures, and specifically, it is appropriately selected from the range of 40 to 95°C.

[0041] [pH] The pH of the ophthalmic composition of the present invention is preferably 7.3 or less, more preferably 7.1 or less, and even more preferably 7.0 or less. Also, it is preferably 5.0 or more, more preferably 5.5 or more, and even more preferably 6.6 or more. By making it equal to or more than the above lower limit and equal to or less than the above upper limit, the storage stability of vitamin A can be further improved. Also, by making it equal to or less than the above upper limit, the effect of suppressing cloudiness can be more easily obtained. For the above reasons, the pH of the ophthalmic composition is preferably 5.0 to 7.3, more preferably 5.5 to 7.1, and even more preferably 6.6 to 7.0. The pH can be measured at 25°C using a pH meter, for example, HM-25R, manufactured by Toa DKK Corporation.

[0042] The composition of the present invention is preferably a liquid from the viewpoint of easy application to the eye, and has a viscosity at 25° C. of preferably 20 mPa s or less, more preferably 10 mPa s or less, and even more preferably 5 mPa s or less. The viscosity is measured using a cone-plate viscometer (e.g., DV2T, Eiko Seiki Co., Ltd.).

[0043] The ophthalmic composition of the present invention may be prepared as a liquid formulation or as a gel formulation. Examples of the form of use include eye drops (e.g., general eye drops, contact lens eye drops, etc.), contact lens wetting solution, contact lens removal solution, etc. Among these, eye drops are preferred. The above-mentioned contact lenses are not particularly limited to hard contact lenses, O2 hard contact lenses, soft contact lenses (non-ionic, ionic), silicone hydrogel contact lenses, etc.

[0044] When the ophthalmic composition of the present invention is used as eye drops or eye drops for contact lenses, it is preferable to instill 1 to 3 drops of 10 to 100 μL each time, 1 to 6 times per day, more preferably 1 to 3 drops of 10 to 50 μL each time, 1 to 6 times per day, and even more preferably 1 to 3 drops of 10 to 30 μL each time, 1 to 6 times per day.

[0045] The ophthalmic composition of the present invention can be used as a general eye drop having the effects and efficacy of eye fatigue, blurred vision (when there is a lot of eye discharge, etc.), conjunctival congestion, itchy eyes, blepharitis (sore eyelids), prevention of eye diseases (after swimming, when dust or sweat gets into the eyes, etc.), eye inflammation caused by ultraviolet rays or other light (snow blindness, etc.), discomfort when wearing hard contact lenses, etc., or as an artificial tear having the effects and efficacy of discomfort when wearing soft or hard contact lenses, supplementation of tears (dry eyes), eye fatigue, blurred vision (when there is a lot of eye discharge, etc.) In particular, since it contains component (A), it repairs corneal scratches and corneal damage caused by mild rubbing, and is effective in fatigue (eye fatigue), blurred vision, itchiness, congestion, etc., which are common causes of these.

[0046] [Ophthalmic products] The present invention provides an ophthalmic product comprising an ophthalmic composition, a container filled with the ophthalmic composition, and an enclosure for packaging the container, and using a means for storing the ophthalmic composition in a state in which the oxygen concentration in the ophthalmic composition is reduced, the stabilization of (A) vitamin A can be further improved. Examples of the means include (1) injection of an inert gas into the enclosure, (2) packaging an oxygen absorber in the enclosure, (3) a container having oxygen absorption capacity, or (4) an enclosure having oxygen absorption capacity. It is preferable that the enclosure be capable of sealing the container.

[0047] The container is preferably a plastic container, and may be made of materials such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, polyvinyl chloride, or a composite of these materials. In particular, polyethylene terephthalate is preferred. The oxygen permeability coefficient of the container is 10 cc / (m 2 24hr·atm) or more is preferable. The amount of the ophthalmic composition in the product can be appropriately selected depending on the product and its method of use. For example, in the case of eye drops, it is preferably 2 to 20 mL, more preferably 5 to 20 mL. The capacity of the container is preferably appropriately selected depending on the amount of the ophthalmic composition to be filled, and is preferably 100 to 150% of the amount of the ophthalmic composition to be filled. For example, in the case of eye drops, it is preferably 2 to 30 mL. The eye drops are not particularly limited, and may be multi-dose eye drops or disposable eye drops.

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

[0049] Examples of the enclosure include polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil, polyvinyl alcohol-based or polyamide-based films vapor-deposited with aluminum, polyethylene terephthalate vapor-deposited with alumina, polyethylene terephthalate vapor-deposited with silicon oxide, films or laminate films coated with polyvinylidene chloride, and composite or multilayer films thereof. Among these, polyethylene terephthalate / polyethylene multilayer films and alumina-vapor-deposited polyethylene terephthalate / polyethylene multilayer films are preferred. The oxygen permeability coefficient of the enclosure is 10 cc / (m 2 ·24hr·atm) or less (i.e., 0 to 10cc / (m 2 An oxygen-impermeable enclosure of 24 hr atm is preferred.

[0050] (1) Injection of inert gas into the enclosure Examples of the inert gas include nitrogen, helium, neon, and argon. Among them, 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, in the volume of the space formed between the enclosure and the plastic container. The upper limit is not particularly limited, and 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.

[0051] (2) Packing oxygen absorbers inside the enclosure Specifically, it is possible to use Ageless (registered trademark) (FX, SP, SS, SPE, ZP, Z-PT, Z-PT15, Z-PKC, GLS, GL-M, Z-20PKya) manufactured by Mitsubishi Gas Chemical Co., Ltd., 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. By including these oxygen absorbers in the enclosure, the oxygen concentration inside the enclosure and the container can be reduced to 0.1% or less.

[0052] (3) Containers with oxygen absorbing capacity Specifically, Oxyblock manufactured by Toyo Seikan Co., Ltd., Oxyvanish manufactured by Mitsubishi Gas Chemical Co., Inc., and the like can be used.

[0053] (4) Enclosure with oxygen absorption capacity Specifically, Oxycatch (registered trademark) ICA manufactured by Kyodo Printing Co., Ltd., Cryovac (registered trademark) OS Film manufactured by Sealed Air Corporation, Hystar O2 manufactured by Star Plastics Industries Co., Ltd., Ageless Omac manufactured by Mitsubishi Gas Chemical Company, Inc., and Oxydec manufactured by Toyo Seikan Co., Ltd. can be used.

[0054] The above means can be combined as appropriate. (1), (2), and (4) are preferred, and (1)+(2), (1)+(4), and (2)+(4) are more preferred. EXAMPLES

[0055] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples. "%" in the composition indicates w / v% (g / 100 mL), and the ratio indicates mass ratio (the same value as w / v%).

[0056] [Examples, Comparative Examples, and Reference Examples] A mixed solution of oily components (A) and (G) and surfactant component (B) was heated to 85°C, mixed with an aqueous solution containing components (D), (E) and (F) heated to the same temperature to emulsify, cooled to 40°C or less, aqueous components such as component (C) were added, and the pH was adjusted to 6.6 to 7.0 using dilute hydrochloric acid or sodium hydroxide as appropriate, and the total volume was adjusted with water to prepare an ophthalmic composition (eye drops). The obtained ophthalmic composition (eye drops) was evaluated as follows. The results are shown in the table. Vitamin A 50,000 units / 100mL is 0.029g / 100mL.

[0057] [Preservative effectiveness test] The obtained ophthalmic composition (eye drops) was sterilized by filter and then filled into an eye drop container (materials: cap: polypropylene, inner stopper: polyethylene, bottle: polyethylene terephthalate) and pillow-packaged together with an oxygen scavenger (product name: Ageless Z-20PK, Mitsubishi Gas Chemical Co., Ltd.). A preservative effectiveness test was carried out on the above in accordance with the preservative effectiveness test of the Japanese Pharmacopoeia, 18th Edition, and the viability rate of Staphylococcus aureus was measured after 1 week and 2 weeks. The results are shown according to the following evaluation criteria. <Evaluation criteria> 1 week viable bacteria rate: less than 10%, 2 week viable bacteria rate: less than 0.1% ◎: Meets the criteria for both 1 week and 2 weeks 〇: Either 1 week or 2 weeks meets the criteria ×: Does not meet the criteria for either 1 week or 2 weeks

[0058] [Transmittance] The obtained ophthalmic composition (eye drops) was sterilized by filter, and then filled into an ampoule tube (product name: Ampoule tube (borosilicate glass, manufactured by Nippon Electric Glass Co., Ltd.) AP-20, manufactured by Maruemu Co., Ltd.) and melted. The above was stored at 80°C for one week, and then at -5°C for one week, and the transmittance of the content liquid was measured at a wavelength of 600 nm and an optical path length of 10 mm. A value of 70% or more was considered to be acceptable. (Measurement temperature: 25°C)

[0059] [Table 1]

[0060] [Table 2]

[0061] [Table 3]

[0062] [Table 4]

[0063] [Table 5]

[0064] [Table 6]

[0065] As is clear from the results of Reference Example 1 and Comparative Example 1, by blending one or more selected from (C) berberine and its salts with an ophthalmic composition containing (A) vitamin A and (B) polyoxyethylene polyoxypropylene glycol, the transmittance is deteriorated and opacity occurs. By blending a total of 1.4 w / v% or more of components (D) to (F) with Comparative Example 1 containing components (A) to (C), it was possible to achieve both preservative efficacy and suppression of opacity.

[0066] The raw materials used in the above example are listed below. Unless otherwise specified, the amount of each component in the table is the pure amount. The terms "JP", "Extra-Pharmacopoeia Regulations", and "Pharmaceutical Excipient Regulations" below refer to raw materials that comply with the 18th Revised Japanese Pharmacopoeia Standards, the Japanese Pharmacopoeia Extra-Pharmacopoeia Pharmaceutical Standards, and the Pharmaceutical Excipients Standards (2018), respectively. Retinol palmitate (Product name: Retinol palmitate 1.74 million IU, with BHA / BHT, DSM Co., Ltd., JP) Polyoxyethylene (196) Polyoxypropylene (67) Glycol (Product name: Kolliphor P407, BASF Japan Ltd., Pharmaceutical Additives Regulations) Polyoxyethylene hydrogenated castor oil 60 (Product name: HCO-60 (medical use), Nippon Surfactant Kogyo Co., Ltd., Pharmaceutical Additives Regulations) Berberine chloride hydrate (Product name: Japanese Pharmacopoeia Berberine Chloride Hydrate, Alps Pharmaceutical Co., Ltd., Japan Pharmacopoeia) Boric Acid (Product Name: Boric Acid, Kanto Chemical Co., Ltd., Japanese Pharmacopoeia) Sodium edetate hydrate (EDTA) (trade name: Sodium edetate hydrate "For manufacturing only", Fujifilm Wako Pure Chemical Industries, Ltd., Japan Pharmacopoeia) Trometamol (trade name: 2-amino-2-hydroxymethyl-1,3-propanediol, Kanto Chemical Co., Ltd., extra-official regulations) d-α-Tocopherol acetate (Product name: Riken E Acetate α, Riken Vitamin Co., Ltd., extra-official regulations) Dibutylhydroxytoluene (BHT) (Product name: Dibutylhydroxytoluene, Fujifilm Wako Pure Chemical Industries, Ltd., Pharmaceutical Additives Regulations) Dilute hydrochloric acid (product name: Dilute hydrochloric acid, Kosakai Pharmaceutical Co., Ltd., Japanese Pharmacopoeia) Sodium hydroxide (trade name: Sodium hydroxide, Kosakai Pharmaceutical Co., Ltd., Japan Pharmacopoeia)

Claims

1. (A) Vitamin A, (B) polyoxyethylene polyoxypropylene glycol, (C) one or more selected from berberine and its salts, (D) boric acid, (E) edetate sodium hydrate, and (F) containing trometamol, An ophthalmic composition, wherein the total amount of the above components (D), (E) and (F) is 1.4 w / v % or more.

2. 2. The ophthalmic composition according to claim 1, wherein the mass ratio represented by ((D)+(E)) / (F) is 4 to 20.

3. 3. The ophthalmic composition according to claim 1, wherein the content of component (A) is 40,000 to 80,000 units / 100 mL.

4. 3. The ophthalmic composition according to claim 1, wherein the content of component (C) is 0.001 to 0.1 w / v %.

5. 3. The ophthalmic composition according to claim 1, wherein the content of component (B) is 0.2 to 1 w / v %.

6. 3. The ophthalmic composition according to claim 1, having a pH of 5.0 to 7.3.

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