Ophthalmic composition, and external appearance stabilization method

Abstract

To provide an ophthalmic composition containing liquid paraffin and vitamin A or vitamin E which can maintain appearance stability even if the composition suffers vibration or the like during a production process or transportation.SOLUTION: An ophthalmic composition contains: (A-1) liquid paraffin; (A-2) one or more kinds selected from vitamin A and vitamin E; (B) nonionic surfactant; (C) one or more kinds selected from hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone, chondroitin sulfuric acid and salt thereof, tetrahydrozoline and salt thereof, berberine and salt thereof, glycyrrhizinic acid and salt thereof, pyridoxine and salt thereof, epsilon aminocaproic acid, allantoin, glucose and propylene glycol, where the transmittance is 70% or more.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition containing liquid paraffin and a method for stabilizing the appearance of the same. [Background technology]

[0002] The tear oil layer is composed of lipids secreted from the meibomian gland. It is known that saturation of lipids in the oil layer progresses due to aging and changes in hormone balance. It is further known that this is promoted by wearing contact lenses. As the saturation of lipids progresses, the tear oil layer becomes unstable, which leads to the development of dry eye and further causes eye fatigue. The present inventors have found that an aqueous composition containing liquid paraffin is effective in stabilizing this tear oil layer (Patent Document 1). On the other hand, fat-soluble vitamins such as vitamins A and E are known to be effective ingredients in improving eye function, and vitamin A in particular is known to be effective in treating dry eye, such as keratosis of the cornea, conjunctiva, and skin and mucous membranes. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2017-186266 A Summary of the Invention [Problem to be solved by the invention]

[0004] On the other hand, it has been found that in an ophthalmic composition in which liquid paraffin and fat-soluble vitamins such as vitamins A and E are solubilized with a nonionic surfactant, the coalescence of emulsions is promoted by vibration during the manufacturing process or transportation, resulting in a deterioration in appearance (a decrease in transmittance). The present invention has been made in view of the above problem, and aims to provide an ophthalmic composition containing liquid paraffin and vitamin A or vitamin E, which can maintain a stable appearance even when subjected to vibration during the manufacturing process or transportation, and a method for stabilizing the appearance of the composition. [Means for solving the problem]

[0005] As a result of intensive research into achieving the above-mentioned object, the inventors discovered that the above-mentioned problems could be solved by blending a nonionic surfactant and a specific component with an ophthalmic composition containing liquid paraffin and vitamin A or vitamin E, and thus completed the present invention.

[0006] Accordingly, the present invention provides the following ophthalmic composition and method for stabilizing the appearance of an ophthalmic composition. 1. (A-1) Liquid paraffin, (A-2) one or more selected from vitamin A and vitamin E; (B) a nonionic surfactant; (C) An ophthalmic composition containing one or more selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, chondroitin sulfate and its salts, tetrahydrozoline and its salts, berberine and its salts, glycyrrhizic acid and its salts, pyridoxine and its salts, epsilon aminocaproic acid, allantoin, glucose, and propylene glycol, and having a transmittance of 70% or more. 2. The ophthalmic composition according to 1, wherein component (B) is one or more selected from polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil and polyoxyethylene polyoxypropylene glycol. 3. The ophthalmic composition according to 1 or 2, wherein (B) / (A) is 2 to 10 and (A-1) / (A-2) is 0.1 to 5. 4. (A-1) Liquid paraffin, (A-2) one or more selected from vitamin A and vitamin E; A method for stabilizing the appearance of an ophthalmic composition, comprising blending (C) one or more members selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, tetrahydrozoline and its salts, berberine and its salts, glycyrrhizic acid and its salts, chondroitin sulfate and its salts, pyridoxine and its salts, epsilon-aminocaproic acid, allantoin, glucose, and propylene glycol into an ophthalmic composition containing (B) a nonionic surfactant. Effect of the Invention

[0007] According to the present invention, it is possible to provide an ophthalmic composition containing liquid paraffin and vitamin A or vitamin E, which can maintain its appearance stability even when subjected to vibrations during the manufacturing process or transportation, and a method for stabilizing the appearance of the same. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention will be described in detail below. [Component (A-1)] Liquid paraffin is a component that has a high tear oil layer stabilizing effect against an unstable tear oil layer with increased saturated lipids. Liquid paraffin is composed of hydrocarbons that are liquid at room temperature, and is an oil with low polarity compared to vegetable oils composed of triglycerides and squalane, which has a short carbon chain among hydrocarbons. Liquid paraffin is a mixture of hydrocarbons obtained from crude oil, has a specific gravity of 0.860 to 0.890 (Japanese Pharmacopoeia 20 / 20°C), and is liquid at room temperature. It is produced by a method in which the atmospheric distillation residue of crude oil is used as a raw material, subjected to reduced pressure distillation and solvent deasphalting treatment, and then subjected to a solvent refining method or hydrocracking treatment. There is no particular restriction on the liquid paraffin used in the present invention, and one type alone or two or more types can be used in appropriate combination. There is no particular restriction on the carbon chain length of the hydrocarbon, but one with a carbon chain length of 15 to 45, preferably 22 to 39, is preferably used. There is no particular restriction on the presence or absence of double bonds in the hydrocarbon, but one containing a large amount of saturated hydrocarbons is preferably used. Furthermore, the hydrocarbon structure may be any of straight chain, branched chain, and cyclic structures, and liquid paraffin of any specific gravity may be used. In particular, liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia are suitable. An appropriate type of tocopherol may be included as a stabilizer.

[0009] The viscosity of liquid paraffin is correlated with its molecular weight. In the measurement method of the 17th revised Japanese Pharmacopoeia, Method 1 (37.8°C), the kinetic viscosity is 30 to 100 mm. 2 / s is preferable, 37 to 88 mm 2 / s is more preferable, 74 to 88 mm 2 / s is more preferable. Two or more kinds within the above viscosity range may be mixed. 2 / s or more, the tear film lipid layer stabilization effect can be further improved. 2 / s is preferable. Also, 100mm 2 By keeping the thickness below 37-88 mm / s, the external transmittance can be increased and the eye irritation specific to liquid paraffin can be reduced. 2 / s is preferred.

[0010] From the viewpoint of stabilizing the tear oil layer, the content of the (A-1) component in the ophthalmic composition (hereinafter sometimes referred to as the composition) is preferably 0.001 to 1 w / v% (mass / volume%, g / 100 mL), more preferably 0.005 to 0.5 w / v%, and even more preferably 0.01 to 0.2 w / v%. By setting it in this range, a tear oil layer stabilizing effect can be expected, there is no eye irritation, and the transmittance of the composition can be increased.

[0011] [Component (A-2)] The (A-2) component is one or more selected from vitamin A and vitamin E, and 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, and 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 usually commercially available with a concentration of 1 to 1.8 million international units / g (hereinafter abbreviated as IU / g), and specific examples include retinol palmitate [1.74 million IU / g] manufactured by DSM and retinol palmitate manufactured by Sigma-Aldrich.

[0012] Vitamin E is used as a general term for, for example, tocopherol, tocotrienol, their salts, and derivatives (esters).Specific examples include d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and the like, and derivatives thereof include, for example, vitamin E acetate (tocopherol acetate), vitamin E nicotinate, vitamin E succinate, vitamin E linoleate, and the like, and can be used alone or in combination of two or more.Of these, tocopherol acetate (d-α-tocopherol acetate, dl-α-tocopherol acetate, and the like) is preferred.

[0013] The content of the component (A-2) in the composition is preferably 0.010575 to 0.1575 w / v %, more preferably 0.02575 to 0.0874 w / v %, and even more preferably 0.0472 to 0.0787 w / v %.

[0014] When vitamin A is added, its content in the composition is preferably 1,000 units to 100,000 units (0.000575 to 0.0575 w / v%), more preferably 10,000 units to 65,000 units (0.00575 to 0.0374 w / v%), and even more preferably 30,000 units to 50,000 units (0.0172 to 0.0287 w / v%). (Note that the content in parentheses is for 1.74 million IU / g.)

[0015] When vitamin E is included, its content in the composition is preferably 0.01 to 0.1 w / v %, more preferably 0.02 to 0.08 w / v %, and even more preferably 0.03 to 0.05 w / v %.

[0016] The content mass ratio represented by (A-1) / (A-2) is preferably 0.1 to 5, more preferably 0.5 to 4, and further preferably 1 to 3. Although the above ratio is a w / v % ratio, it is the same as the mass ratio.

[0017] [(B) Component] The nonionic surfactant (B) is not particularly limited, and nonionic surfactants used in ophthalmic compositions can be used alone or in appropriate combination of two or more. Specific examples include (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, (B-3) polyoxyethylene polyoxypropylene glycol, and (B-4) nonionic surfactants other than (B-1), (B-2) and (B-3).

[0018] (B-1) Polyoxyethylene castor oil 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). These polyoxyethylene castor oils can be used alone or in appropriate combination of two or more.

[0019] (B-2) Polyoxyethylene hydrogenated castor oil 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 added moles 5), polyoxyethylene hydrogenated castor oil 10 (EO average number of added moles 10), polyoxyethylene hydrogenated castor oil 20 (EO average number of added moles 20), polyoxyethylene hydrogenated castor oil 30 (EO average number of added moles 30), polyoxyethylene hydrogenated castor oil 40 (EO average number of added moles 40), polyoxyethylene hydrogenated castor oil 50 (EO average number of added moles 50), polyoxyethylene hydrogenated castor oil 60 (EO average number of added moles 60), polyoxyethylene hydrogenated castor oil 80 (EO average number of added moles 80), polyoxyethylene hydrogenated castor oil 100 (EO average number of added moles 100), etc. These polyoxyethylene hydrogenated castor oils can be used alone or in appropriate combination of two or more.

[0020] (B-3) Polyoxyethylene polyoxypropylene glycol Polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is a block copolymer consisting of polyoxyethylene chains (POE) and polyoxypropylene chains (POP), and several types with different average added moles of ethylene oxide (EO) and propylene oxide (PO) are known. The average added moles of ethylene oxide and propylene oxide in polyoxyethylene polyoxypropylene glycol are not particularly limited, but examples include an average added mole number of 5 to 200 moles. Specific examples include polyoxyethylene (200) polyoxypropylene (70) glycol (average added mole number of EO: 200, average added mole number of PO: 70), polyoxyethylene (196) polyoxypropylene (67) glycol (average added mole number of EO: 196, average added mole number of PO: 67), polyoxyethylene (160) polyoxypropylene (30) glycol (average added mole number of EO: 160, average added mole number of PO: 30), polyoxyethylene (120) polyoxypropylene (40) glycol (average number of moles of EO added: 120, average number of moles of PO added: 40), polyoxyethylene (42) polyoxypropylene (67) glycol (average number of moles of EO added: 42, average number of moles of PO added: 67), polyoxyethylene (54) polyoxypropylene (39) glycol (average number of moles of EO added: 54, average number of moles of PO added: 39), polyoxyethylene (20) polyoxypropylene (20) glycol (average number of moles of EO added: 20, average number of moles of PO added: 20), and the like.

[0021] (B-4) Nonionic surfactants other than (B-1), (B-2) and (B-3) Examples of such polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan fatty acid esters (POE sorbitan fatty acid esters) such as polysorbate 80 (polyoxyethylene (20) sorbitan oleate), polyethylene glycol monostearate (10), and polyethylene glycol monostearate (40), etc. Among these, polysorbate 80 (polyoxyethylene (20) sorbitan oleate) is preferred.

[0022] The (B) surfactant preferably contains one or more selected from polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, and polyoxyethylene polyoxypropylene glycol, and more preferably contains one or more selected from polyoxyethylene hydrogenated castor oil 60 and polyoxyethylene castor oil.

[0023] The content of component (B) is not particularly limited, but is preferably 0.1 to 10 w / v %, more preferably 0.3 to 5 w / v %, and even more preferably 0.6 to 1 w / v % in the composition.

[0024] The content mass ratio represented by (B) / (A) is preferably 2 to 10, more preferably 4 to 8, and further preferably 5 to 7. The effects of the present invention can be particularly enhanced within this range. The content mass ratio is a w / v% ratio, but is the same as the mass ratio (hereinafter the same).

[0025] [(C) component] The component (C) of the present invention is one or more selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, chondroitin sulfate and its salts, tetrahydrozoline and its salts, berberine and its salts, glycyrrhizic acid and its salts, pyridoxine and its salts, epsilon aminocaproic acid, allantoin, glucose and propylene glycol, and can be used alone or in combination of two or more. Among them, one or more selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, chondroitin sulfate and its salts, tetrahydrozoline and its salts, berberine and its salts, pyridoxine and its salts, allantoin and glucose are preferred.

[0026] Although there is no limitation on the hydroxypropyl methylcellulose used in the present invention, it is preferable to use hydroxypropyl methylcellulose (hypromellose) listed in the 17th edition of the Japanese Pharmacopoeia. The substitution degree type may be any of 2910, 2906, 2208, and 1828, and 2910, 2906, and 2208 are preferred.

[0027] Examples of 2910 include those having a viscosity of 40.0 to 60.0 mPa·s in a 2 w / v% aqueous solution (e.g., METLOSE 60SH50 (manufactured by Shin-Etsu Chemical Co., Ltd.)), those having a viscosity of 3,000 to 5,600 mPa·s (e.g., METLOSE 60SH4000 (manufactured by Shin-Etsu Chemical Co., Ltd.)), and those having a viscosity of 7,500 to 14,000 mPa·s (e.g., METLOSE 60SH10000 (manufactured by Shin-Etsu Chemical Co., Ltd.)).

[0028] Examples of 2906 include those with a viscosity of 40.0 to 60.0 mPa·s in a 2 w / v% aqueous solution (e.g., METLOSE 65SH50 (manufactured by Shin-Etsu Chemical Co., Ltd.)), those with a viscosity of 320 to 480 mPa·s (e.g., METLOSE 65SH400 (manufactured by Shin-Etsu Chemical Co., Ltd.)), and those with a viscosity of 3,000 to 5,600 mPa·s (e.g., METLOSE 65SH4000 (manufactured by Shin-Etsu Chemical Co., Ltd.)).

[0029] Examples of 2208 include those with a viscosity of 80 to 120 mPa·s in a 2 w / v% aqueous solution (e.g., METLOSE 90SH-SR100 (manufactured by Shin-Etsu Chemical Co., Ltd.)) and those with a viscosity of 3,000 to 5,600 mPa·s (e.g., METLOSE 90SH-SR4000 (manufactured by Shin-Etsu Chemical Co., Ltd.)). The viscosity of component (C) is measured by Method 1 (20°C) of the 17th Edition of the Japanese Pharmacopoeia when it is less than 600 mPa·s, and by Method 2 when it is 600 mPa·s or more.

[0030] There are no limitations on the methylcellulose used in the present invention, but it is preferable to use methylcellulose (methoxy group 26.0 to 33.0%) listed in the 17th Edition of the Japanese Pharmacopoeia. Examples of methylcellulose include methylcellulose having a viscosity of 3.2 to 4.8 mPa·s in a 2 w / v% aqueous solution (e.g., METLOSE SM4 (manufactured by Shin-Etsu Chemical Co., Ltd.)), a viscosity of 12.0 to 18.0 mPa·s (e.g., METLOSE SM15 (manufactured by Shin-Etsu Chemical Co., Ltd.)), a viscosity of 20.0 to 30.0 mPa·s (e.g., METLOSE SM25 (manufactured by Shin-Etsu Chemical Co., Ltd.)), a viscosity of 80 to 120 mPa·s (e.g., METLOSE SM100 (manufactured by Shin-Etsu Chemical Co., Ltd.)), a viscosity of 320 to 480 mPa·s (e.g., METLOSE SM400 (manufactured by Shin-Etsu Chemical Co., Ltd.)), a viscosity of 1,125 to 2,100 mPa·s (e.g., METLOSE SM1500 (manufactured by Shin-Etsu Chemical Co., Ltd.)), a viscosity of 3,000 to 5,600 mPa·s (e.g., METLOSE SM4000 (manufactured by Shin-Etsu Chemical Co., Ltd.) and the like.

[0031] There is no limitation on the hydroxyethyl cellulose used in the present invention, but it is preferable to use hydroxyethyl cellulose (hydroxyethoxyl group 30.0 to 70.0%) listed in the Pharmaceutical Excipients Standards 2018. Examples of hydroxyethyl cellulose include those having a viscosity of 300 to 600 mPa·s in a 2 w / v% aqueous solution (e.g., HEC CF-G (Sumitomo Seika Chemicals)), those having a viscosity of 5,000 to 10,000 mPa·s in a 2 w / v% aqueous solution (e.g., HEC CF-V (Sumitomo Seika Chemicals)), those having a viscosity of 10,000 to 16,000 mPa·s in a 2 w / v% aqueous solution (e.g., HEC CF-W (Sumitomo Seika Chemicals)), those having a viscosity of 1,250 to 1,750 mPa·s in a 1 w / v% aqueous solution (e.g., HEC CF-X (Sumitomo Seika Chemicals)), and those having a viscosity of 2,000 to 3,000 mPa·s in a 1 w / v% aqueous solution (e.g., HEC CF-Y (Sumitomo Seika Chemicals)).

[0032] Although there is no limitation on the polyvinylpyrrolidone used in the present invention, it is preferable to use polyvinylpyrrolidone (povidone) listed in the 17th edition of the Japanese Pharmacopoeia. The K value is preferably 10 to 120, and the K value can be determined by the method described in the 17th edition of the Japanese Pharmacopoeia. Examples of polyvinylpyrrolidone include those having a K value of 11 to 14 (e.g., Kollidon 12PF (manufactured by BASF Japan)), those having a K value of 16 to 18 (e.g., Kollidon 17PF (manufactured by BASF Japan)), those having a K value of 28 to 32 (e.g., Kollidon 30 (manufactured by BASF Japan)), those having a K value of 85 to 95 (e.g., Kollidon 90F (manufactured by BASF Japan)), and the like.

[0033] The total content of the hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose and polyvinylpyrrolidone in the composition is preferably 0.0001 to 10 w / v %, more preferably 0.001 to 2 w / v %, and even more preferably 0.001 to 1 w / v %.

[0034] When hydroxypropyl methylcellulose is added, its content in the composition is preferably 0.0001 to 5 w / v %, more preferably 0.001 to 2 w / v %, and even more preferably 0.01 to 0.5 w / v %. When methylcellulose is added, its content in the composition is preferably 0.0001 to 5 w / v %, more preferably 0.001 to 2 w / v %, and even more preferably 0.01 to 0.5 w / v %. When hydroxyethyl cellulose is added, the content thereof in the composition is preferably 0.0001 to 5 w / v %, more preferably 0.001 to 2 w / v %, and even more preferably 0.01 to 0.05 w / v %. When polyvinylpyrrolidone is added, its content in the composition is preferably 0.0001 to 5 w / v %, more preferably 0.001 to 2 w / v %, and even more preferably 0.01 to 0.25 w / v %.

[0035] Examples of chondroitin sulfate or a salt thereof include sodium chondroitin sulfate (manufactured by Maruha Nichiro Co., Ltd.), sodium chondroitin sulfate (manufactured by Seikagaku Corporation), sodium chondroitin sulfate (manufactured by Nippon Biocon Co., Ltd.), etc. When chondroitin sulfate or a salt thereof such as sodium chondroitin sulfate is incorporated, the content thereof in the composition 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%.

[0036] Tetrahydrozoline or its salts such as tetrahydrozoline hydrochloride, berberine or its salts such as berberine chloride hydrate, berberine sulfate hydrate, etc., glycyrrhizic acid or its salts such as dipotassium glycyrrhizinate, pyridoxine or its salts such as pyridoxine hydrochloride, epsilon aminocaproic acid, and allantoin are drugs.

[0037] When tetrahydrozoline or a salt thereof is incorporated, the content in the composition 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 %. When berberine or a salt thereof is added, the content thereof in the composition 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%. When glycyrrhizinic acid or a salt is incorporated, the content in the composition is preferably 0.001 to 5 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.25 w / v%. When pyridoxine or a salt thereof is added, the content in the composition 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 %. When epsilon aminocaproic acid is incorporated, its content in the composition is preferably 0.001 to 5 w / v %, and more preferably 0.001 to 1 w / v %. When allantoin is incorporated, its content in the composition 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 %.

[0038] When glucose is added, its content in the composition is preferably 0.001 to 5 w / v %, more preferably 0.001 to 1 w / v %, and even more preferably 0.001 to 0.2 w / v %.

[0039] When propylene glycol, which is a polyhydric alcohol, is added, its content in the composition is preferably 0.001 to 5 w / v %, and more preferably 0.001 to 1 w / v %.

[0040] The content of component (C) is not particularly limited, but is preferably 0.0001 to 10 w / v %, and more preferably 0.0005 to 2 w / v %, of the composition.

[0041] The content mass ratio represented by (C) / (B) is preferably 0.0001 to 2, more preferably 0.0005 to 2, and even more preferably 0.001 to 2. In particular, when the (B) component is polyoxyethylene hydrogenated castor oil 60 and the (C) component is hydroxypropyl ethyl cellulose, the content mass ratio is preferably 0.0001 to 2, more preferably 0.005 to 1, and even more preferably 0.01 to 0.5.

[0042] When the component (B) is polyoxyethylene hydrogenated castor oil 60 and the component (C) is methylcellulose, the content in the composition is preferably 0.0001 to 2, more preferably 0.005 to 1, and even more preferably 0.01 to 0.5.

[0043] When the component (B) is polyoxyethylene hydrogenated castor oil 60 and the component (C) is hydroxyethyl cellulose, the content in the composition is preferably 0.0001 to 0.5, more preferably 0.005 to 0.1, and even more preferably 0.01 to 0.05.

[0044] When the component (B) is polyoxyethylene hydrogenated castor oil 60 and the component (C) is polyvinylpyrrolidone, the content in the composition is preferably 0.0001 to 1, more preferably 0.005 to 0.5, and even more preferably 0.01 to 0.25.

[0045] [Other ingredients] The composition of the present invention may contain other components to be added to ophthalmic compositions in appropriate amounts, provided that the effects of the present invention are not impaired. Examples of other components include preservatives, sugars, buffers, pH adjusters, isotonicity agents, stabilizers, polyhydric alcohols other than those mentioned above, refreshing agents, thickeners other than component (C), water, oil components, and drugs other than those mentioned above. These components may be added alone or in appropriate combination of two or more. The contents of the components shown below are the preferred ranges when added, and are the amounts in the composition.

[0046] Among preservatives, examples of preservatives having a hydrophobic portion such as an alkyl chain or a benzene ring include thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconate, methyl paraoxybenzoate, and ethyl paraoxybenzoate, but since liquid paraffin is less likely to migrate to the tear oil layer, the content of these preservatives in the composition is preferably 0.1 w / v% or less, more preferably 0.01 w / v% or less, even more preferably 0.001 w / v% or less, and even more preferably substantially free. As preservatives, sorbic acid or its salts, sulfites, and the like are preferred in that they do not prevent liquid paraffin from migrating to the tear oil layer. The content of these preservatives in the composition is preferably 1 w / v% or less, and even more preferably 0.1 w / v% or less.

[0047] Examples of sugars include cyclodextrin, xylitol, sorbitol, mannitol, etc. These may be in D-, L- or DL-form. When sugars are added, the content thereof in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0048] Examples of the buffering agent include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, sodium hydrogen carbonate, etc. When a buffering agent is added, the content thereof in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 2 w / v%, and even more preferably 0.001 to 1 w / v%.

[0049] Examples of pH adjusters include inorganic acids and inorganic alkali agents. For example, an example of an inorganic acid is (dilute) hydrochloric acid. Examples of inorganic alkali agents include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. The pH of the composition can be 3.5 to 13.0, and is preferably 3.5 to 8.0, more preferably 5.5 to 8.0, from the viewpoint of further improving various symptoms caused by destabilization of the tear lipid layer. The pH is measured at 25°C using a pH meter (HM-25R, Toa DKK Corporation).

[0050] 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 symptoms caused by destabilization of the tear lipid layer, it is preferable to incorporate at least one of sodium chloride and potassium chloride to make the composition isotonic. In order to further improve symptoms caused by destabilization of the tear lipid layer, 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).

[0051] Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene, etc. When a stabilizer is added, the content thereof in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0052] Examples of polyhydric alcohols include glycerin, butylene glycol, polyethylene glycol, etc. When a polyhydric alcohol is added, the content of the polyhydric alcohol in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0053] Examples of the refreshing agent include menthol, camphor, borneol, geraniol, cineol, linalool, etc. Any of d-, l- or dl-isomers may be used. The content of the refreshing agent in the composition is preferably 0.0001 to 0.2 w / v%.

[0054] Examples of thickeners other than component (C) include hydroxypropyl cellulose, hydroxymethyl cellulose, ethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, carboxyvinyl polymer, polyvinyl alcohol, sodium hyaluronate, polyacrylic acid, etc. When a thickener is added, the content thereof in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0055] The water is not particularly limited and may be purified water, but is preferably 90.0 to 99.5 w / v % in the composition, and more preferably 95.0 to 99.5 w / v %.

[0056] Examples of oil components include soybean oil, olive oil, corn oil, coconut oil, almond oil, medium chain fatty acid triglyceride, vitamin E such as d-α-tocopherol acetate, vitamin A such as retinol palmitate, white petrolatum, refined lanolin, cholesterol, mixed tocopherol, etc. When oil components other than liquid paraffin are added, the content is preferably 0.001 to 1.0 w / v%, more preferably 0.001 to 0.5 w / v%, and most preferably 0.001 to 0.25 w / v%. Note that oil components other than liquid paraffin may not be added (0 w / v%).

[0057] Examples of drugs (pharmacologically active ingredients) include congestion relief ingredients (e.g., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.), anti-inflammatory / astringent agents (e.g., neostigmine methylsulfate, sodium azulene sulfonate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), antihistamines (e.g., diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (sodium flavin adenine dinucleotide, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, etc.), amino acids (e.g., potassium L-aspartate, magnesium L-aspartate, potassium and magnesium L-aspartate (equal mixture), aminoethylsulfonic acid, etc.), and sulfa drugs. When drugs are incorporated, the content of the drugs can be selected based on the effective amount of each drug, but is preferably 0.001 to 5.0 w / v% in the composition, more preferably 0.001 to 1 w / v%, and even more preferably 0.001 to 0.1 w / v%.

[0058] [Manufacturing method] The method for producing the composition of the present invention may be to mix the essential components and the optional components, but a method of high-pressure emulsification using a high-pressure emulsifier is preferred. By forming a high-pressure emulsion, the transmittance can be increased. More specifically, the following method can be mentioned. The above components (A) and (B) are mixed to obtain an aqueous suspension, which is then placed in a high-pressure emulsifier for high-pressure emulsification. The mixing method may be a general mixing method, and may be appropriately performed using a pulsator, propeller blade, paddle blade, turbine blade, or the like. The rotation speed is not particularly limited, and is preferably set to a level that does not cause vigorous foaming.

[0059] The aqueous suspension before high-pressure emulsification is promptly put into a high-pressure emulsifier. The injection pressure of the high-pressure emulsifier is preferably 80 to 250 MPa, more preferably 150 to 250 MPa, and even more preferably 200 to 250 MPa, from the viewpoint of increasing the transmittance of the composition. By applying a pressure higher than this, the liquid paraffin becomes more uniform. The back pressure is preferably 1 to 10 MPa, more preferably 3 to 10 MPa, from the viewpoint of increasing the transmittance of the composition. In addition, back pressure may not be applied. The number of passes is preferably 3 or more, more preferably 5 or more, 10 or more, and even 20 or more, from the viewpoint of increasing the transmittance of the composition. The temperature of the composition immediately after high-pressure emulsification is preferably 30°C or more, more preferably 40°C or more, and even more preferably 50°C or more, from the viewpoint of increasing the processing efficiency. The high-pressure emulsification time is preferably 10 to 30 minutes, more preferably 10 to 15 minutes, from the start to the end of the suspension introduction into the high-pressure emulsifier. By setting the time to this or more, the added aqueous suspension can be emulsified more uniformly. After the emulsification is completed, the temperature can be left at room temperature.

[0060] [Ophthalmic composition] The particle size of the emulsion particles (an association of components (A) and (B)) contained in the composition can be 1,000 nm or less, preferably 100 nm or less, and more preferably 50 nm or less. There is no particular restriction on the lower limit, but it can be 1 nm. In the present invention, the particle size refers to the average diameter (median diameter) of the volume-based particle size distribution calculated from the scattered light intensity. The particle size is measured using various measuring devices that apply the principles of light scattering, etc., in a thermostatic bath under a constant temperature condition of 25°C. As such a device, for example, a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.) can be used to measure by the dynamic scattering method.

[0061] Specifically, the transmittance of the composition of the present invention is 70% or more, preferably 80 to 100%, more preferably 90 to 100%, and more preferably 95 to 100%, as measured at a wavelength of 600 nm using a spectrophotometer (e.g., UV-1800, Shimadzu Corporation). After a "shaking test" in the examples described below, the transmittance is preferably 70% or more and less than 80%, more preferably 80% or more and less than 90%, and even more preferably 90% or more and 100%.

[0062] The composition of the present invention is preferably a liquid from the viewpoint of easy application to the eye, and the viscosity at 25° C. is preferably 20 mPa s or less, more preferably 10 mPa s or less, and even more preferably 5 mPa s or less, from the viewpoint of easy mixing with tears and obtaining a greater effect of stabilizing the tear lipid layer. The viscosity is measured using a cone-plate viscometer (DV2T, Eiko Seiki Co., Ltd.).

[0063] The ophthalmic composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eyewashes, etc., and is particularly suitable for use as eye drops and eye drops for contact lenses (eye drops for contact lens wearers). Examples of contact lenses include hard contact lenses, O 2 Examples of such contact lenses include, but are not limited to, hard contact lenses, soft contact lenses, and silicone hydrogel soft contact lenses.

[0064] When used as eye drops or eye drops for contact lenses, it is preferable to instill 10-100μL, 1-3 drops, 1-6 times per day. Because overflow from the eye may reduce the effect of stabilizing the tear lipid layer, it is more preferable to instill 10-50μL, 1-3 drops, 1-6 times per day. It is even more preferable to instill 10-30μL, 1-3 drops, 1-6 times per day. When used as an eyewash, it is preferable to wash the eyes with 3-6mL, 3-6 times per day.

[0065] The obtained composition may be filled into a resin container and then sealed with a packaging material, and an inert gas such as nitrogen may be sealed in the space formed between the container and the packaging material. Alternatively, the composition may be filled into a resin container and then sealed with a packaging material together with an oxygen scavenger.

[0066] [Appearance stabilization method] The present invention provides a method for stabilizing the appearance of an ophthalmic composition, which is characterized by blending (C) one or more selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, tetrahydrozoline and its salts, berberine and its salts, glycyrrhizic acid and its salts, chondroitin sulfate and its salts, pyridoxine and its salts, epsilon aminocaproic acid, allantoin, glucose, and propylene glycol, with an ophthalmic composition containing (A-1) liquid paraffin, (A-2) one or more selected from vitamin A and vitamin E, and (B) a nonionic surfactant. In these methods, the preferred components and amounts are the same as those described above. The appearance stabilization method refers to suppressing the deterioration of appearance (reduction in transmittance) when the ophthalmic composition is subjected to vibration. EXAMPLES

[0067] 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. In the following examples, unless otherwise specified, "%" in the composition indicates "w / v% (g / 100 mL)" and the ratio indicates the mass ratio.

[0068] [Examples and Comparative Examples] Each water-soluble component including component (C) was added to 90 mL of water, and heated and mixed at 90°C for 15 minutes to obtain an aqueous solution of the water-soluble components. Separately, (A) liquid paraffin, (B) vitamin A or vitamin E, and (B) nonionic surfactant were heated and mixed at 90°C for 15 minutes to prepare a preliminary mixture. Next, a predetermined amount of the preliminary mixture was added to the aqueous solution of the water-soluble components, and further heated and mixed at 90°C for 15 minutes. After that, it was cooled to room temperature, and water was added to make the total volume 100 mL. The above was prepared for each example, and further, it was treated using a high-pressure emulsifier (Starburst Mini, Sugino Machine Co., Ltd.) at an injection pressure of 200 Pa, a back pressure of 3 MPa, and five treatments. The composition of the obtained composition is shown in the table. The ophthalmic compositions obtained in the above examples were evaluated as follows. The results are also shown in the table. The pH of the ophthalmic compositions was in the range of 6.9 to 7.9.

[0069] (1) Evaluation of cloudiness suppression (shaking test) The ophthalmic composition was filled into a PET (polyethylene terephthalate) eye drop container (4 mL filled into a 15 mL container) and shaken at 40°C at 360 rpm for 6 hours. The transmittance (%) at a wavelength of 600 nm was measured at 25°C using a UV1800 spectrophotometer (Shimadzu Corporation). The transmittance (%) of the control (preparation of the same composition immediately after production) was measured using the same method, and the transmittance ratio after the shaking test to that immediately after production was calculated using the following formula (N=2 average). Ratio of transmittance after shaking test to immediately after manufacture = transmittance after shaking test (%) / transmittance immediately after manufacture (%) The clouding suppression rate relative to a corresponding comparative example having the same composition except that it did not contain the component (C) was calculated using the following formula. Suppression rate of cloudiness for corresponding comparative example=(transmittance ratio after shaking test to immediately after manufacture−transmittance ratio after shaking test to immediately after manufacture for corresponding comparative example) / (1−transmittance ratio after shaking test to immediately after manufacture for corresponding comparative example)×100

[0070] [Table 1]

[0071] [Table 2]

[0072] [Table 3]

[0073] [Table 4]

[0074] [Table 5]

[0075] The raw materials used in the above examples are shown below. Unless otherwise specified, the amounts of each component in the table are calculated as pure amounts. Liquid paraffin: 17th Revised Japanese Pharmacopoeia Law No. 1 (37.8℃) Viscosity 76.6mm 2 / s (KAYDOL, manufactured by Shima Boeki) Retinol palmitate (DSM) d-α-Tocopherol acetate (Riken E Acetate α, manufactured by Riken Vitamin Co., Ltd.) Polyoxyethylene hydrogenated castor oil 60 (HCO60, manufactured by Nippon Surfactant Co., Ltd.) Polyoxyethylene castor oil (Uniox C35, NOF Corp.) Polyoxyethylene polyoxypropylene glycol (Lutrol F127, manufactured by BASF Japan Ltd.) Hydroxypropyl methylcellulose (METLOSE, Japanese Pharmacopoeia Hypromellose, manufactured by Shin-Etsu Chemical Co., Ltd.), type and viscosity grade: 60SH4000 Methylcellulose (METLOSE, Japanese Pharmacopoeia Methylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.), type and viscosity grade: SM4 Hydroxyethyl cellulose (CF-V, manufactured by Sumitomo Seika Chemicals Co., Ltd.) Polyvinylpyrrolidone (Kollidon 90F, manufactured by BASF Japan) Tetrahydrozoline hydrochloride (Okami Chemical Industry Co., Ltd.) Epsilon-aminocaproic acid (manufactured by Sekisui Medical Co., Ltd.) Allantoin (manufactured by Permakem Asia Co., Ltd.) Berberine chloride hydrate (berberine chloride, manufactured by Alps Pharmaceutical Co., Ltd.) Dipotassium glycyrrhizinate (Maruzen Pharmaceutical Co., Ltd.) Pyridoxine hydrochloride (BASF Japan Ltd.) Sodium chondroitin sulfate (Maruha Nichiro Co., Ltd.) Glucose (FUJIFILM Wako Pure Chemical Industries, Ltd.) Propylene glycol (ADEKA Corporation)

Claims

1. (A-1) liquid paraffin, (A-2) one or more selected from vitamin A and vitamin E; (B) a nonionic surfactant; and (C) An ophthalmic composition containing one or more selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, chondroitin sulfate and its salts, tetrahydrozoline and its salts, berberine and its salts, glycyrrhizic acid and its salts, pyridoxine and its salts, epsilon aminocaproic acid, allantoin, glucose, and propylene glycol, and having a transmittance of 70% or more.

2. 2. The ophthalmic composition according to claim 1, wherein the component (B) is at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil and polyoxyethylene polyoxypropylene glycol.

3. 3. The ophthalmic composition according to claim 1, wherein (B) / (A) is 2 to 10, and (A-1) / (A-2) is 0.1 to 5.

4. (A-1) liquid paraffin, (A-2) one or more selected from vitamin A and vitamin E; A method for stabilizing the appearance of an ophthalmic composition, comprising blending (C) one or more selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, tetrahydrozoline and its salts, berberine and its salts, glycyrrhizic acid and its salts, chondroitin sulfate and its salts, pyridoxine and its salts, epsilon-aminocaproic acid, allantoin, glucose, and propylene glycol into the ophthalmic composition containing (B) a nonionic surfactant.

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