JP7076183B2 - Emulsion ophthalmic solution containing vitamin A - Google Patents

Description

The present invention relates to a pharmaceutically stable emulsion ophthalmic solution containing vitamin A over a wide range of temperatures.

Vitamin A is known to have preventive and therapeutic effects on dry eye symptoms such as corneal / conjunctival dryness and keratosis of the cornea / conjunctiva. In addition, vitamin A is easily decomposed by air, light, heat, acid, metal ions, etc., and is extremely unstable especially in water, and it is difficult to stably add vitamin A to eye drops and the like. Further, it is known that the stabilization of vitamin A becomes significantly unstable as the content of vitamin A increases, for example, when the content is 50,000 units / 100 mL or more (Patent Document 1: Japanese Patent Application Laid-Open No. 2015-101582). Issue).

As a technique for stabilizing unstable vitamin A in ophthalmic solution, a method of blending a nonionic surfactant such as polyoxyethylene hydrogenated castor oil into the ophthalmic solution to stabilize it is known (Patent Document 2). : JP-A-5-331506, Patent Document 3: JP-A-6-40907).

Chondroitin sulfate ester is a type of mucopolysaccharide present in animal tissues and body fluids, and is particularly abundant in cartilage. When blended in eye drops, it has a protective and water-retaining effect on the cornea and conjunctiva, and the cornea. -It is known to be useful for alleviating dry eye symptoms such as conjunctival dryness.

Surfactants such as polysolvate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and polyoxyl 40 stearate are generic names for compounds having hydrophilic and hydrophobic groups in the molecule, and are used in ophthalmic solutions. , It is known that it is used as a solubilizer for dissolving an active ingredient or the like in a solvent or a dispersion medium.

Amino acids such as potassium L-aspartate and aminoethylsulfonic acid (taurine) or salts thereof are classified as amino acids in ophthalmic solutions, and potassium L-aspartate and aminoethylsulfonic acid (taurine) are classified as amino acids. It is known as a component that improves eye fatigue because it promotes the metabolism of eye tissue.

Viscous agents such as polyvinylpyrrolidone K30, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, dextran 70, sodium hyaluronate and alginic acid are known as components to be added to increase the viscosity of eye drops.

Polyhydric alcohols such as propylene glycol, mannitol, glycerin, and trometamol are known as components to be blended as an isotonic agent for adjusting the osmotic pressure of liquids such as eye drops.

On the other hand, when the properties of the emulsion ophthalmic solution change due to freezing and thawing, the appearance of the emulsion ophthalmic solution is significantly impaired, such as cloudiness of the emulsion ophthalmic solution and separation of the oil phase and the aqueous phase. It is also possible that the drug release behavior changes significantly due to changes in properties.

Japanese Patent Application Laid-Open No. 2015-101582 Japanese Unexamined Patent Publication No. 5-331506 Japanese Unexamined Patent Publication No. 6-40907

The present inventor puts the ophthalmic solution under a severe test in an emulsion ophthalmic solution in which 50,000 units / 100 mL or more of vitamin A and 0.5% (w / v) or more of chondroitin sulfate or a salt thereof coexist. It was found that the amount of vitamin A in the emulsion ophthalmic solution was significantly reduced when stored at 70 ° C. for 1 week).

In addition, the present inventor coexisted 50,000 units / 100 mL or more of vitamin A with 0.5% (w / v) or more of amino acids such as potassium L-aspartate or aminoethylsulfonic acid or salts thereof. It has been found that in the emulsion ophthalmic solution, when the ophthalmic solution is stored under a severe test (70 ° C., 1 week), the amount of vitamin A in the emulsion ophthalmic solution is significantly reduced.

Furthermore, the present inventor freezes and thaw an emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A and a viscous agent such as hydroxyethyl cellulose and dextran, and then instills the emulsion before and after freezing. It was found that the properties of the liquid changed, and that the particle size of the emulsion changed significantly before freezing and after freezing and thawing.

That is, the problem to be solved by the present invention is to obtain 50,000 units / 100 mL or more of vitamin A which is not easily affected by temperature, is stable in a wide temperature range, has excellent safety, and is pharmaceutically stable. It is to provide the emulsion ophthalmic solution containing.

Therefore, as a result of diligent research to solve the above-mentioned problems, the present inventor made 50,000 units / 100 mL or more of vitamin A coexist with 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof. Add 0.3% (w / v) or less of a surfactant to the emulsion ophthalmic solution and adjust the pH to 6.0 to 8.0, especially as a surfactant, 0.3. When the polyoxyethylene hydrogenated castor oil 60 having a% (w / v) content is blended and the pH is adjusted to 6.0 or 8.0, the amount of vitamin A in the emulsion ophthalmic solution is remarkable. It was found to suppress the decrease.

In addition, as a result of diligent research to solve the above problems, the present inventor has 50,000 units / 100 mL or more of vitamin A and 0.5% (w / v) or more of potassium L-aspartate or aminoethyl sulfone. Emulsion in which an amino acid such as an acid or a salt thereof coexists is blended with a surfactant of 0.3% (w / v) or less, and its pH is adjusted to 6.0 to 8.0. In particular, an emulsion when a polyoxyethylene hydrogenated castor oil 60 having a content of 0.3% (w / v) is blended as a surfactant and the pH is adjusted to 6.0 or 8.0. It has been found that it suppresses a significant decrease in the amount of vitamin A in the ophthalmic solution.

Furthermore, as a result of diligent research to solve the above problems, the present inventor has added polyhydric alcohol to an emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A and a viscous agent such as hydroxyethyl cellulose and dextran. Emulsion ophthalmic solution that suppresses the change in properties due to freeze-thaw by blending, especially by blending propylene glycol with a content of 0.5% (w / v) as a polyhydric alcohol, and further, an emulsion before freezing. It was found that by controlling the absolute value of the difference between the particle size of the emulsion and the particle size of the emulsion after freezing and thawing to 0 to 50 nm, the property change due to freezing and thawing can be suppressed.

As described above, the present inventor has found the above findings as a result of diligent research to solve the above problems, is not easily affected by temperature, is stable in a wide temperature range, and is excellent in safety. We have found a pharmaceutically stable vitamin A emulsion ophthalmic solution of 50,000 units / 100 mL or more, and have reached the present invention.

That is, the present invention is as follows.
<First emulsion ophthalmic solution of the present invention>
(1) An emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A and at least one component selected from the group consisting of the following (A) to (C), having a pH of 6.0 to. 8.0, an emulsion ophthalmic solution that is pharmaceutically stable over a wide range of temperatures.
(A) 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof and a surfactant,
(B) 0.5% (w / v) or more of amino acids or salts thereof and surfactants, and (C) thickeners and polyhydric alcohols (2) pharmaceutically stable in the range of -80 ° C to 100 ° C. (1) The emulsion ophthalmic solution according to (1).
(3) (a) Is the residual rate of vitamin A 50% or more after a harsh test (10 mL of emulsion ophthalmic solution is filled in a 10 mL glass ampol, sealed, and stored at 70 ° C. for 7 days) and / or (B) Freeze-thaw test (Emulsion instillation is filled in a polyethylene terephthalate instillation container, the emulsion instillation is frozen at -20 ° C for 12 to 16 hours, and the frozen emulsion instillation is completely thawed at room temperature. Before freezing in the JIS Z 8826 dynamic light scattering method (photon correlation method), the particle size of the emulsion of the emulsion ophthalmic solution before freezing and the particle size of the emulsion of the emulsion ophthalmic solution after freezing and thawing are measured. The emulsion ophthalmic solution according to (1) or (2), wherein the absolute value of the difference between the particle size of the emulsion and the particle size of the emulsion after freezing and thawing is 0 to 50 nm.
(4) The emulsion ophthalmic solution according to (1) to (3), wherein the content of vitamin A is 50,000 units / 100 mL.
(5) The emulsion ophthalmic solution according to (1) to (4), wherein vitamin A is a vitamin A fatty acid ester.
(6) The emulsion ophthalmic solution according to (5), wherein the vitamin A fatty acid ester is a retinol palmitic acid ester.
(7) The emulsion ophthalmic solution according to (1) to (6), wherein the chondroitin sulfate ester or a salt thereof is chondroitin sulfate sodium.
(8) The emulsion ophthalmic solution according to (1) to (7), wherein the amino acid or a salt thereof is potassium L-aspartate and / or aminoethyl sulfonic acid.
(9) The emulsion ophthalmic solution according to (1) to (8), wherein the content of the surfactant is 0.3% (w / v) or less.
(10) The emulsion ophthalmic solution according to (1) to (9), wherein the content of the surfactant is 0.1 to 0.3% (w / v).
(11) The surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and polyoxyl 40 stearate (1) to (10). Emulsion ophthalmic solution.
(12) The emulsion ophthalmic solution according to (1) to (11), wherein the content of the viscous agent is 0.01 to 0.5% (w / v).
(13) The emulsion ophthalmic solution according to (1) to (12), wherein the viscous agent is at least one selected from polyvinylpyrrolidone K30, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, dextran 70, sodium hyaluronate and alginic acid.
(14) The emulsion ophthalmic solution according to (1) to (13), wherein the content of the polyhydric alcohol is 0.1 to 1.8% (w / v).
(15) The emulsion ophthalmic solution according to (1) to (14), wherein the polyhydric alcohol is at least one selected from glycerin, propylene glycol, mannitol and trometamol.
(16) The emulsion ophthalmic solution according to (3) to (15), wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is 0 to 30 nm.
(17) The emulsion ophthalmic solution according to (3) to (16), wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is 0 to 10 nm.
(18) The emulsion ophthalmic solution according to (1) to (17), which does not contain polyoxyethylene polyoxypropylene glycol.
(19) An emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A and at least one component selected from the group consisting of the following (a) to (c), having a pH of 6.0 to. Emulsion ophthalmic solution which is 8.0.
(A) 0.5% (w / v) or more of chondroitin sulfate ester or salt thereof and 0.3% (w / v) or less of surfactant (b) 0.5% (w / v) or more of amino acid Alternatively, the salt thereof and a surfactant of 0.3% (w / v) or less, and (c) a viscous agent and a polyhydric alcohol (20) have a vitamin A content of 50,000 units / 100 mL (19). The emulsion ophthalmic solution described.
(21) The emulsion ophthalmic solution according to (19) or (20), wherein vitamin A is a vitamin A fatty acid ester.
(22) The emulsion ophthalmic solution according to (21), wherein the vitamin A fatty acid ester is a retinol palmitic acid ester.
(23) The emulsion ophthalmic solution according to (19) to (22), wherein the chondroitin sulfate ester or a salt thereof is chondroitin sulfate sodium.
(24) The emulsion ophthalmic solution according to (19) to (23), wherein the amino acid or a salt thereof is potassium L-aspartate and / or aminoethyl sulfonic acid.
(25) The emulsion ophthalmic solution according to (19) to (24), wherein the content of the surfactant is 0.1 to 0.3% (w / v).
(26) The surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and polyoxyl 40 stearate (19) to (25). Emulsion ophthalmic solution.
(27) The emulsion ophthalmic solution according to (19) to (26), wherein the content of the viscous agent is 0.01 to 0.5% (w / v).
(28) The emulsion ophthalmic solution according to (19) to (27), wherein the viscous agent is at least one selected from polyvinylpyrrolidone K30, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, dextran 70, sodium hyaluronate and alginic acid.
(29) The emulsion ophthalmic solution according to (19) to (28), wherein the content of the polyhydric alcohol is 0.1 to 1.8% (w / v).
(30) The emulsion ophthalmic solution according to (19) to (29), wherein the polyhydric alcohol is at least one selected from propylene glycol, mannitol, glycerin and tromethamole.
(31) The emulsion ophthalmic solution according to (19) to (30), which does not contain polyoxyethylene polyoxypropylene glycol.
(32) 50,000 units / 100 mL or more of vitamin A, 0.5% (w / v) or more of chondroitin sulfate ester or salt thereof and / or 0.5% (w / v) or more of amino acid or salt thereof. A method for stabilizing the vitamin A by containing an ester and a surfactant and preparing an emulsion ophthalmic solution having a pH of 6.0 to 8.0.
(33) A method for suppressing a change in properties due to freezing and thawing of an emulsion ophthalmic solution by preparing an emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A, a viscous agent and a polyhydric alcohol.
(34) Suppression of changes in properties due to freezing and thawing of emulsion ophthalmic solution is a freeze-thaw test (the emulsion ophthalmic solution is filled in an ophthalmic container made of polyethylene terephthalate, and the emulsion ophthalmic solution is frozen at −20 ° C. for 12 to 16 hours. The frozen emulsion ophthalmic solution is left at room temperature until it is completely thawed, and the particle size of the emulsion of the emulsion ophthalmic solution before freezing and the particle size of the emulsion of the emulsion ophthalmic solution after freezing and thawing are determined by the JIS Z 8826 dynamic light scattering method. The method according to (33), wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing in (measured by the photon correlation method) is controlled to 0 to 50 nm.
(35) The emulsion ophthalmic solution according to (1) to (31), which has an osmotic pressure ratio of 1.4 to 1.6.
(36) The above-mentioned (1) to (31) or (35), further containing at least one selected from a buffer, a stabilizer, a preservative, a cooling agent, a viscous agent, a pH adjuster and a solubilizing agent. Emulsion ophthalmic solution.
(37)
(I) Vitamin A of 50,000 units / 100 mL or more,
(Ii) At least one component selected from the group consisting of the following (A) to (C) (A) 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof and a surfactant.
(B) 0.5% (w / v) or more of amino acids or salts thereof and surfactants, and (C) thickeners and polyhydric alcohols, and (iii) pharmacologically active ingredients, buffers, stabilizers, preservatives. The emulsion ophthalmic solution according to (1) to (18) or (35), which comprises at least one selected from an agent, a refreshing agent, a viscous agent, a pH adjuster and a solubilizing agent.
(38)
(I) Vitamin A of 50,000 units / 100 mL or more,
(Ii) At least one component selected from the group consisting of the following (a) to (c) (a) 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof and 0.3% (w / v). ) The following surfactants (b) 0.5% (w / v) or more amino acids or salts thereof and 0.3% (w / v) or less surfactants, and (c) thickeners and polyvalents. Consists of only one selected from alcohol and (iii) pharmacologically active ingredients, buffers, stabilizers, preservatives, refreshing agents, thickeners, pH regulators and solubilizers, (19)-(31). ) Or the emulsion ophthalmic solution according to (35).
The above (1) to (38) can be arbitrarily selected and combined or applied mutatis mutandis.

<Second emulsion ophthalmic solution of the present invention>
(1) A pH of 6.0 to 8.0 containing 50,000 units / 100 mL or more of vitamin A, 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof, and a surfactant. Emulsion ophthalmic solution with a residual rate of vitamin A of 50% or more after the rigorous test of the emulsion ophthalmic solution (10 mL of the emulsion ophthalmic solution is filled in a 10 mL glass ampol, sealed, and stored at 70 ° C. for 7 days). An emulsion ophthalmic solution.
(2) The emulsion ophthalmic solution according to (1), wherein the content of vitamin A is 50,000 units / 100 mL.
(3) The emulsion ophthalmic solution according to (1) or (2), wherein vitamin A is a vitamin A fatty acid ester.
(4) The emulsion ophthalmic solution according to (3), wherein the vitamin A fatty acid ester is a retinol palmitic acid ester.
(5) The emulsion ophthalmic solution according to (1) to (4), wherein the chondroitin sulfate ester or a salt thereof is chondroitin sulfate sodium.
(6) The emulsion ophthalmic solution according to (1) to (5), wherein the content of the surfactant is 0.3% (w / v) or less.
(7) The emulsion ophthalmic solution according to (1) to (6), wherein the content of the surfactant is 0.1 to 0.3% (w / v).
(8) The surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and polyoxyl 40 stearate (1) to (7). Emulsion ophthalmic solution.
(9) Emulsion containing 50,000 units / 100 mL or more of vitamin A, 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof, and 0.3% (w / v) or less of a surfactant. An emulsion ophthalmic solution having a pH of 6.0 to 8.0.
(10) The emulsion ophthalmic solution according to (9), wherein the content of vitamin A is 50,000 units / 100 mL.
(11) The emulsion ophthalmic solution according to (9) or (10), wherein vitamin A is a vitamin A fatty acid ester.
(12) The emulsion ophthalmic solution according to (11), wherein the vitamin A fatty acid ester is a retinol palmitic acid ester.
(13) The emulsion ophthalmic solution according to (9) to (12), wherein the chondroitin sulfate ester or a salt thereof is chondroitin sulfate sodium.
(14) The emulsion ophthalmic solution according to (9) to (13), wherein the content of the surfactant is 0.1 to 0.3% (w / v).
(15) The surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and polyoxyl 40 stearate (9) to (14). Emulsion ophthalmic solution.
(16) Emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A, 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof and a surfactant, and having a pH of 6.0 to 8.0. A method for stabilizing the vitamin A by the above method.
(17) The emulsion ophthalmic solution according to (1) to (15), which has an osmotic pressure ratio of 1.4 to 1.6.
(18) The above-mentioned (1) to (15) or (17), further containing at least one selected from a buffer, a stabilizer, a preservative, a cooling agent, a viscous agent, a pH adjuster and a solubilizing agent. Emulsion ophthalmic solution.
(19)
(I) Vitamin A of 50,000 units / 100 mL or more,
(Iii) 0.5% (w / v) or more of chondroitin sulfate ester or salt thereof and surfactant, and (iii) pharmacologically active ingredient, buffer, stabilizer, preservative, refreshing agent, viscous agent, The emulsion ophthalmic solution according to (1) to (8) or (17), which comprises only one selected from a pH adjuster and a solubilizer.
(20)
(I) Vitamin A of 50,000 units / 100 mL or more,
(Ii) 0.5% (w / v) or more of chondroitin sulfate ester or salt thereof and 0.3% (w / v) or less of surfactant, and (iii) pharmacologically active ingredient, buffer, stabilizer, The emulsion ophthalmic solution according to (9) to (15) or (17), which comprises at least one selected from a preservative, a cooling agent, a viscous agent, a pH adjuster and a solubilizing agent.
The above (1) to (20) can be arbitrarily selected and combined or applied mutatis mutandis.

<Third emulsion ophthalmic solution of the present invention>
(1) Emulsion ophthalmic solution having a pH of 6.0 to 8.0 containing 50,000 units / 100 mL or more of vitamin A, 0.5% (w / v) or more of amino acids or salts thereof, and a surfactant. Emulsion eye drops having a residual ratio of vitamin A of 50% or more after the harsh test of the emulsion eye drops (10 mL of the emulsion eye drops are filled in a 10 mL glass ampol, sealed, and stored at 70 ° C. for 7 days). liquid.
(2) The emulsion ophthalmic solution according to (1), wherein the content of vitamin A is 50,000 units / 100 mL.
(3) The emulsion ophthalmic solution according to (1) or (2), wherein vitamin A is a vitamin A fatty acid ester.
(4) The emulsion ophthalmic solution according to (3), wherein the vitamin A fatty acid ester is a retinol palmitic acid ester.
(5) The emulsion ophthalmic solution according to (1) to (4), wherein the amino acid or a salt thereof is potassium L-aspartate and / or aminoethylsulfonic acid.
(6) The emulsion ophthalmic solution according to (1) to (5), wherein the content of the surfactant is 0.3% (w / v) or less.
(7) The emulsion ophthalmic solution according to (1) to (6), wherein the content of the surfactant is 0.1 to 0.3% (w / v).
(8) The surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and polyoxyl 40 stearate (1) to (7). Emulsion ophthalmic solution.
(9) Emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A, 0.5% (w / v) or more of amino acids or salts thereof, and 0.3% (w / v) or less of a surfactant. An emulsion ophthalmic solution having a pH of 6.0 to 8.0.
(10) The emulsion ophthalmic solution according to (9), wherein the content of vitamin A is 50,000 units / 100 mL.
(11) The emulsion ophthalmic solution according to (9) or (10), wherein vitamin A is a vitamin A fatty acid ester.
(12) The emulsion ophthalmic solution according to (11), wherein the vitamin A fatty acid ester is a retinol palmitic acid ester.
(13) The emulsion ophthalmic solution according to (9) to (12), wherein the amino acid or a salt thereof is potassium L-aspartate and / or aminoethylsulfonic acid.
(14) The emulsion ophthalmic solution according to (9) to (13), wherein the content of the surfactant is 0.1 to 0.3% (w / v).
(15) The surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and polyoxyl 40 stearate (9) to (14). Emulsion ophthalmic solution.
(16) An emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A, 0.5% (w / v) or more of an amino acid or a salt thereof, and a surfactant to prepare an emulsion ophthalmic solution having a pH of 6.0 to 8.0. The method for stabilizing the vitamin A.
(17) The emulsion ophthalmic solution according to (1) to (15), which has an osmotic pressure ratio of 1.4 to 1.6.
(18) The above-mentioned (1) to (15) or (17), further containing at least one selected from a buffer, a stabilizer, a preservative, a cooling agent, a viscous agent, a pH adjuster and a solubilizing agent. Emulsion ophthalmic solution.
(19)
(I) Vitamin A of 50,000 units / 100 mL or more,
(Ii) 0.5% (w / v) or more of amino acids or salts thereof and surfactants, and (iii) pharmacologically active ingredients, buffers, stabilizers, preservatives, refreshing agents, thickeners, pH adjustments. The emulsion ophthalmic solution according to (1) to (8) or (17), which comprises only one selected from an agent and a solubilizer.
(20)
(I) Vitamin A of 50,000 units / 100 mL or more,
(Ii) 0.5% (w / v) or more of amino acids or salts thereof and 0.3% (w / v) or less of surfactants, and (iii) pharmacologically active ingredients, buffers, stabilizers, preservatives. The emulsion ophthalmic solution according to (9) to (15) or (17), which comprises at least one selected from a refreshing agent, a viscous agent, a pH adjuster and a solubilizing agent.
The above (1) to (20) can be arbitrarily selected and combined or applied mutatis mutandis.

<Fourth emulsion ophthalmic solution of the present invention>
(1) An emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A, a viscous agent and a polyhydric alcohol, which is used in a freeze-thaw test (emulsion ophthalmic solution is filled in an ophthalmic container made of polyethylene terephthalate. The emulsion ophthalmic solution is frozen at −20 ° C. for 12 to 16 hours, and the frozen emulsion ophthalmic solution is left at room temperature until it is completely thawed. The absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing in JIS Z 8826 dynamic light scattering method (photon correlation method) is 0 to 0 to the absolute value of the particle size of the emulsion of the ophthalmic solution. Emulsion ophthalmic solution having a diameter of 50 nm.
(2) The emulsion ophthalmic solution of (1) having a vitamin A content of 50,000 units / 100 mL.
(3) The emulsion ophthalmic solution according to (1) or (2), wherein vitamin A is a vitamin A fatty acid ester.
(4) The emulsion ophthalmic solution according to (3), wherein the vitamin A fatty acid ester is a retinol palmitic acid ester.
(5) The emulsion ophthalmic solution according to (1) to (4), wherein the content of the viscous agent is 0.01 to 0.5% (w / v).
(6) The emulsion ophthalmic solution according to (1) to (5), wherein the viscous agent is at least one selected from polyvinylpyrrolidone K30, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, dextran 70, sodium hyaluronate and alginic acid.
(7) The emulsion ophthalmic solution according to (1) to (6), wherein the content of the polyhydric alcohol is 0.1 to 1.8% (w / v).
(7-1) The emulsion ophthalmic solution according to (7), wherein the content of the polyhydric alcohol is 0.5% (w / v).
(8) The emulsion ophthalmic solution according to (1) to (7) or (7-1), wherein the polyhydric alcohol is at least one selected from glycerin, propylene glycol, mannitol and tromethamole.
(8-1) The emulsion ophthalmic solution of (8) in which the polyhydric alcohol is propylene glycol.
(9) The emulsion ophthalmic solution according to (1) to (8) or (8-1), wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is 0 to 30 nm.
(10) The emulsion ophthalmic solution according to (1) to (9), wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is 0 to 10 nm.
(11) The emulsion ophthalmic solution according to (1) to (10), which does not contain polyoxyethylene polyoxypropylene glycol.
(12) Emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A, a thickener and a polyhydric alcohol.
(13) The emulsion ophthalmic solution according to (12), wherein the content of vitamin A is 50,000 units / 100 mL.
(14) The emulsion ophthalmic solution according to (12) or (13), wherein vitamin A is a vitamin A fatty acid ester.
(15) The emulsion ophthalmic solution according to (14), wherein the vitamin A fatty acid ester is a retinol palmitic acid ester.
(16) The emulsion ophthalmic solution according to (12) to (15), wherein the content of the viscous agent is 0.01 to 0.5% (w / v).
(17) The emulsion ophthalmic solution according to (12) to (16), wherein the viscous agent is at least one selected from polyvinylpyrrolidone K30, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, dextran 70, sodium hyaluronate and alginic acid.
(18) The emulsion ophthalmic solution according to (12) to (17), wherein the content of the polyhydric alcohol is 0.1 to 1.8% (w / v).
(18-1) The emulsion ophthalmic solution according to (18), wherein the content of the polyhydric alcohol is 0.5% (w / v).
(19) The emulsion ophthalmic solution according to (12) to (18) or (18-1), wherein the polyhydric alcohol is at least one selected from propylene glycol, mannitol, glycerin and tromethamole.
(19-1) The emulsion ophthalmic solution of (19) in which the polyhydric alcohol is propylene glycol.
(20) The emulsion ophthalmic solution according to (12) to (19) or (19-1), wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is 0 to 30 nm.
(21) The emulsion ophthalmic solution according to (12) to (20), wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is 0 to 10 nm.
(22) The emulsion ophthalmic solution according to (12) to (21), which does not contain polyoxyethylene polyoxypropylene glycol.
(23) A method for suppressing a change in properties due to freezing and thawing of an emulsion ophthalmic solution by preparing an emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A, a viscous agent and a polyhydric alcohol.
(24) Suppression of changes in properties due to freezing and thawing of emulsion ophthalmic solution is a freeze-thaw test (the emulsion ophthalmic solution is filled in an ophthalmic container made of polyethylene terephthalate, and the emulsion ophthalmic solution is frozen at −20 ° C. for 12 to 16 hours. The frozen emulsion ophthalmic solution is left at room temperature until it is completely thawed, and the particle size of the emulsion of the emulsion ophthalmic solution before freezing and the particle size of the emulsion of the emulsion ophthalmic solution after freezing and thawing are determined by the JIS Z 8826 dynamic light scattering method. The method according to (23), wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing in (measured by the photon correlation method) is controlled to 0 to 50 nm.
(25) The emulsion ophthalmic solution according to (1) to (22), which has a pH of 6.0 to 8.0.
(26) The emulsion ophthalmic solution according to (1) to (22), which has an osmotic pressure ratio of 1.4 to 1.6.
(27) The emulsion ophthalmic solution according to (1) to (22), which further contains at least one selected from a buffer, a stabilizer, a preservative, a refreshing agent, a solubilizer, a pH adjuster and a solubilizer.
(28)
(I) Vitamin A of 50,000 units / 100 mL or more,
Only one selected from (ii) viscous and polyhydric alcohols, and (iii) pharmacologically active ingredients, buffers, stabilizers, preservatives, cooling agents, viscous agents, pH regulators and solubilizers. The emulsion ophthalmic solution according to (1) to (11), (25) or (26), which comprises.
(29)
(I) Vitamin A of 50,000 units / 100 mL or more,
Only one selected from (ii) viscous and polyhydric alcohols, and (iii) pharmacologically active ingredients, buffers, stabilizers, preservatives, cooling agents, viscous agents, pH regulators and solubilizers. The emulsion ophthalmic solution according to (11) to (22), (25) or (26), which comprises.
The above (1) to (29) can be arbitrarily selected and combined or applied mutatis mutandis.

The first to fourth emulsion ophthalmic solutions of the present invention are not easily affected by temperature, are stable over a wide temperature range, and have excellent safety. Emulsion ophthalmic solutions containing 50,000 units / 100 mL or more of vitamin A. A liquid can be provided.

The second emulsion ophthalmic solution of the present invention further contains, for example, 50,000 units or more of vitamin A and 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof and a surfactant. It is possible to provide an emulsion ophthalmic solution having excellent stability of A.

The third emulsion ophthalmic solution of the present invention further contains, for example, 50,000 units or more of vitamin A and 0.5% (w / v) or more of amino acids or salts thereof and a surfactant. It is possible to provide an emulsion ophthalmic solution having excellent stability.

The fourth emulsion ophthalmic solution of the present invention (emulsion ophthalmic solution containing 50,000 units / 100 mL or more of vitamin A, a viscous agent and an isotonic agent) is, for example, further used by a customer in a cold region during transportation (for example). Even if freeze-thaw occurs after it is in the hands of doctors, pharmacists, patients, etc., it does not change the properties that affect the quality of the product, so we provide customers with high-quality emulsion ophthalmic solution. can. In addition, for example, during transportation, after it is in the hands of customers (doctors, pharmacists, patients, etc.) in cold regions, it is not necessary to strictly control the temperature, so a special transportation form / storage form (heat insulating material, heat insulating material, etc.) It does not require a heat insulating device, etc.) and is economical.

Hereinafter, the present invention will be described in detail.

The vitamin A that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of vitamin A include vitamin A-containing mixtures such as vitamin A and vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid ester. More specifically, retinol palmitate ester, retinol acetic acid ester, retinoic acid, retinol, retinoic acid, retinoid and the like can be mentioned, with retinol palmitate ester, retinol acetic acid ester and retinoic acid being preferable, and retinol palmitate ester being particularly preferable. ..

As the vitamin A that can be used in the emulsion ophthalmic solution of the present invention, one of the above vitamin A may be used alone, or two or more of them may be used in any combination.

In the emulsion ophthalmic solution of the present invention, for example, the content of vitamin A is 50, depending on the type of vitamin A, the type and content of other compounding components, the use of the emulsion ophthalmic solution, the formulation form, the method of use, and the like. It can be set appropriately at 000 units / 100 mL or more. Here, the "unit" is an international unit, which is an international unit representing the amount of vitamin A. The method for measuring the amount of vitamin A is not particularly limited, and for example, it can be measured by the method described in "16th revised Japanese Pharmacopoeia general test method vitamin A quantification method".

In the emulsion ophthalmic solution of the present invention, for example, the total content of vitamin A is preferably 50,000 units / 100 mL or more, more preferably 50,000 to 500,000 units / 100 mL, and 50,000 to 300,000 units. / 100 mL is even more preferred, 50,000 to 100,000 units / 100 mL is even more preferred, and 50,000 units / 100 mL is particularly preferred.

The chondroitin sulfate ester or a salt thereof that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the chondroitin sulfate ester or a salt thereof include chondroitin sulfate ester and sodium chondroitin sulfate. Examples of the salt of chondroitin sulfate include alkali metals such as potassium, alkaline earth metals such as calcium and magnesium, and salts with metals such as aluminum. Further, the origin thereof is not particularly limited, and it is preferable to use a commercially available product.

As the chondroitin sulfate ester or a salt thereof that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the chondroitin sulfate ester or its salt can be appropriately set according to the type of the chondroitin sulfate ester or its salt, the type and content of other compounding components, the use of the ophthalmic solution, the formulation form, the method of use and the like. ..

In the emulsion ophthalmic solution of the present invention, for example, the total content of chondroitin sulfate ester or a salt thereof is preferably 0.5% (w / v) or more, more preferably 0.5 to 3.0% (w / v). Preferably, 0.5% to 1.0% (w / v) is more preferable, and 0.5% (w / v) is particularly preferable.

The surfactant (solubilizer) that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the nonionic surfactant include monolaurate POE (20) sorbitan (polysorbate 20), monopalmitate POE (20) sorbitan (polysorbate 40), monostearate POE (20) sorbitan (polysorbate 60), and birds. POE sorbitan fatty acid esters such as POE stearate (20) sorbitan (polysorbate 65), POE monooleic acid (20) sorbitan (polysorbate 80), POE (40) hardened castor oil (polyoxyethylene cured castor oil 40) and POE ( 60) POE cured castor oil such as cured castor oil (polyoxyethylene cured castor oil 60); POE (10) castor oil (polyoxyethylene castor oil 10), POE (35) castor oil (polyoxyethylene castor oil 35) POE castor oil such as POE castor oil, POE alkyl ether such as POE (9) lauryl ether, POE-POP alkyl ether such as POE (20) POP (4) cetyl ether, POE (54) POP (39) glycol, POE (120) Polyoxyethylene polyoxy such as POP (40) glycol, POE (160) POP (30) glycol, POE (196) POP (67) glycol (Poroxummer 407, Pluronic F127), POE (200) POP (70) glycol, etc. Examples thereof include propylene block copolymers, polyethylene glycol monostearate such as polyoxyl 40 stearate, and POE (20) sorbitan (polysorbate 80) monooleate and POE (60) hardened castor oil (polyoxyethylene cured castor oil 60). Especially preferable.

Examples of the amphoteric tenside include N- [2-[[2- (alkylamino) ethyl] amino] ethyl] glycine and salts thereof.

Examples of the anionic surfactant include alkylbenzene sulfonic acid salts, alkyl sulfates, polyoxyethylene alkyl sulfates, α-sulfo fatty acid ester salts, α-olefin sulfonic acid and the like.

Examples of the cationic surfactant include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate and the like.

One of these surfactants may be used alone, or two or more thereof may be used in any combination. Further, the content of the surfactant can be appropriately set according to the type of the surfactant, the type and content of other compounding components, the use of the ophthalmic solution, the pharmaceutical form, the method of use and the like.

In the emulsion ophthalmic solution of the present invention, for example, the total content of the surfactant is preferably 0.3% (w / v) or less, more preferably more than 0 to 0.3% (w / v), and 0. 01 to 0.3% (w / v) is more preferable, and 0.1 to 0.3% (w / v) is particularly preferable.

The amino acid or a salt thereof that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the amino acid or a salt thereof include glycine, alanine, γ-aminobutyric acid, aspartic acid, potassium L-aspartate, glutamic acid, arginine, lysine, aminoethylsulfonic acid (taurine) and the like. Among them, "Pharmaceutical Manufacturing and Sales Guidelines Separate Volume General Pharmaceutical Manufacturing and Marketing Approval Standards 2012" (1) L-magnesium potassium L-aspartate and L-aspartic acid described in those listed as amino acids in the approval standards for manufacturing (importing) ophthalmic drugs. Magnesium, magnesium / potassium L-aspartate, and aminoethylsulfonic acid (taurine) are particularly preferable.

As the amino acid or a salt thereof that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the amino acid or the salt thereof can be appropriately set according to the type of the amino acid or the salt thereof, the type and content of other compounding components, the use of the ophthalmic solution, the pharmaceutical form, the method of use and the like.

In the emulsion ophthalmic solution of the present invention, for example, the total content of amino acids or salts thereof is preferably 0.5% (w / v) or more, more preferably 0.5 to 5.0% (w / v). 0.5 to 3.0% (w / v) is more preferable, and 0.5 to 2.0% (w / v) is particularly preferable.

The viscous agent that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the viscous agent include polyvinylpyrrolidones such as polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, and polyvinylpyrrolidone K90, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose2906, and hydroxypropylmethylcellulose. Cellulose derivatives such as carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose or salts thereof, polyethylene glycols such as macrogol 300, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, and dextrans such as dextran 40 and dextran 70. , Hyaluronic acid derivatives such as sodium hyaluronate (purified sodium hyaluronate, etc.), alginic acid, alginic acid derivatives such as sodium alginate, polyvinyl alcohol, carboxyvinyl polymer, sodium chondroitin sulfate, gum arabic, gellan gum, traganth, etc., and polyvinylpyrrolidone. Polyvinylpyrrolidones such as K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or them. Cellulose derivatives such as the salt of the above are preferable, and polyvinylpyrrolidone K30, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, dextran 70, sodium hyaluronate and alginic acid are particularly preferable.

As the thickener that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the viscous agent can be appropriately set according to the type of the viscous agent, the type and content of other compounding components, the use of the ophthalmic solution, the pharmaceutical form, the method of use and the like.

In the emulsion ophthalmic solution of the present invention, for example, the total content of the viscous agent is preferably 0.005 to 1.0% (w / v), more preferably 0.01 to 0.5% (w / v). It is preferable, and 0.01 to 0.3% (w / v) is particularly preferable.

The polyhydric alcohol that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the polyhydric alcohol include glycerin, propylene glycol, polyethylene glycol, mannitol, sorbitol, xylitol, tromethamole and the like, preferably glycerin, propylene glycol, polyethylene glycol, mannitol and tromethamole, and glycerin, propylene glycol, mannitol and tromethamole. Is particularly preferable. Further, the polyhydric alcohol may be d-form, l-form or dl-form.

As the polyhydric alcohol that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the polyhydric alcohol can be appropriately set according to the type of the polyhydric alcohol, the type and content of other compounding components, the use of the ophthalmic solution, the pharmaceutical form, the method of use and the like.

In the emulsion ophthalmic solution of the present invention, for example, the total content of the polyhydric alcohol is preferably 0.05 to 5% (w / v), more preferably 0.1 to 1.8% (w / v). 0.3 to 0.7% (w / v) is particularly preferable.

The pH adjuster that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, dilute hydrochloric acid, acetic acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate and the like can be mentioned, and dilute hydrochloric acid and sodium hydroxide are particularly preferable.

As the pH adjuster that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the pH adjusting agent can be appropriately set according to the type of the pH adjusting agent, the type and content of other compounding components, the use of the eye drop, the pharmaceutical form, the method of use and the like.

The pH of the emulsion eye drops of the present invention is not particularly limited as long as it is pharmaceutically acceptable, but is preferably 6.0 to 8.0.

In the present invention, "medically stable over a wide range of temperatures" is not particularly limited as long as it is pharmaceutically acceptable in a wide temperature range, but suppresses physicochemical changes in the emulsion ophthalmic solution as a pharmaceutical. For example, the decrease of vitamin A, which is an active ingredient, due to decomposition or the like can be suppressed, and / or the change in the properties of the eye drops, particularly the change in the particle size of the emulsion can be suppressed.

The emulsion eye drops of the present invention have, for example, a residual rate of vitamin A of 50% or more in a severe test (70 ° C., 1 week) described later, and / or a freeze-thaw test (-20 ° C.) described later. When frozen for 12 to 16 hours and then completely thawed at room temperature), the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is 0 to 50 nm (the particle size is JIS). It can be said that it is "medically stable at a wide range of temperatures" when it is measured by the Z 8826 dynamic light scattering method (photon correlation method).

The emulsion eye drops of the present invention are pharmaceutically stable in a wide range of temperatures, for example, −80 ° C. to 100 ° C., preferably −50 ° C. to 80 ° C., more preferably −20 ° C. to 70 ° C.

The rigorous test of the emulsion ophthalmic solution of the present invention means, for example, the following.
Fill 10 mL of the test product in a 10 mL glass ampoule, seal it, and store it at 70 ° C. for 7 days.

The freeze-thaw test of the emulsion ophthalmic solution of the present invention means the following.

Freeze-thaw operation: The emulsion ophthalmic solution of the present invention is filled in an ophthalmic container made of polyethylene terephthalate, the emulsion ophthalmic solution is frozen at -20 ° C for 12 to 16 hours, and the frozen emulsion ophthalmic solution is completely thawed at room temperature. Leave it until you do.

Measurement of emulsion diameter: The particle size of the emulsion of the emulsion ophthalmic solution of the present invention before freezing and the particle size of the emulsion of the emulsion ophthalmic solution after freezing and thawing are measured by JIS Z 8826 dynamic light scattering method (photon correlation method) (zeta potential. Particle size measurement system Measured by ELSZ-1000ZS (Otsuka Denshi Co., Ltd. (set temperature: 25 ° C.)).

Difference in emulsion diameter: The absolute value of the difference between the particle size of the emulsion of the emulsion ophthalmic solution of the present invention before freezing and the particle size of the emulsion of the emulsion ophthalmic solution of the present invention after freezing and thawing is obtained.

In the emulsion ophthalmic solution of the present invention, the absolute value of the difference between the particle size of the emulsion of the emulsion ophthalmic solution of the present invention before freezing and the particle size of the emulsion of the emulsion ophthalmic solution of the present invention after freezing and thawing is acceptable as a medicine. If it is, it is not particularly limited, but is preferably 50 nm or less, more preferably 0 to 30 nm, further preferably 0 to 10 nm, and particularly preferably 0 to 5 nm.

"At least one" in the present invention means one or more. In the case of two or more, there is no particular limitation as long as it is acceptable as a medicine. For example, 2 to 30 is preferable, 2 to 12 is more preferable, 2 to 8 is further preferable, and 2 to 4 is particularly preferable.

The emulsion ophthalmic solution of the present invention can contain various pharmacologically active ingredients (physiologically active ingredients or active ingredients) in an appropriate amount as long as it does not interfere with the effects of the present invention, and is particularly acceptable as long as it is pharmaceutically acceptable. Not limited. Examples of the pharmacologically active ingredient (physiologically active ingredient or active ingredient) include antiallergic agents such as chromoglycate, anlexanox, ibudilast, splatast, pemirolast potassium, tranilast, olopatazine hydrochloride, levocabastine hydrochloride, and asitazanolast. Antihistamines such as chlorpheniramine maleate, diphenhydramine hydrochloride, ketotiphenfumarate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, nafazoline hydrochloride, nafazoline nitrate, epinephrine, epinephrine hydrochloride, efedrin hydrochloride, phenyleffrin hydrochloride, dl-methylephedrine hydrochloride, etc. Shrinkage agent (decontamination agent), planoprofen, glycyrrhizinic acid, dipotassium glycyrrhizinate, allantin, berberine sulfate, berberine chloride, azulene sulfonic acid, ε-aminocaproic acid, zinc sulfate, zinc sulfate hydrate, zinc lactate, lysoteam , Salicylic acid, tranexamic acid, licorice, anti-inflammatory agents such as salts thereof, cholinesterase inhibitors having an active center similar to acetylcholine, specifically, neostigmine methylsulfate, neostigmine methylsulfate, tropicamide, helenien, atropin sulfate, etc. Bactericides such as ocular muscle regulators, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine, polyhexamethylenebiguanide and alkyldiaminoethylglycine hydrochloride, glycine, alanine, γ-aminobutyric acid, aspartic acid, L-asparagine Amino acids such as potassium acid, glutamate, arginine, lysine, aminoethylsulfonic acid (taurine), chondroitin sulfate, sodium chondroitin sulfate, vitamin B ₁ , vitamin B2 ( _{flavinadenine} dinucleotide sodium), niacin (nicotinic acid and nicotine). Acid amide), pantothenic acid, pantenol, vitamin B ₆ (pyridoxin, pyridoxin hydrochloride, pyridoxal and pyridoxamine), biotin, folic acid, vitamin B ₁₂ (cyanocobalamine, hydroxocobalamine, methylcobalamine and adenosylcobalamine), vitamin E (acetic acid) Vitamins such as tocopherol and acetic acid-d-α tocopherol), sulfamethoxazole, sodium sulfamethoxazole, sodium hyaluronate, alginic acid and the like can be mentioned.

As the pharmacologically active ingredient that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the pharmacologically active ingredient can be appropriately set according to the type of the pharmacologically active ingredient, the type and content of other compounded ingredients, the use of the ophthalmic solution, the formulation form, the method of use, etc. It is preferable to set as appropriate based on (1) Ophthalmic drug manufacturing (import) approval criteria described in "Separate volume OTC drug manufacturing and marketing approval criteria 2012".

The buffering agent that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the buffering agent include borate or salts thereof such as boric acid, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borosand, phosphoric acid, disodium hydrogen phosphate, and sodium dihydrogen phosphate. , Potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate and other phosphates or salts thereof, carbonic acid, sodium hydrogencarbonate, sodium carbonate, ammonium carbonate, potassium carbonate , Carbonate such as calcium carbonate, potassium hydrogen carbonate, magnesium carbonate or a salt thereof, citric acid, sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate or the like, citric acid or a salt thereof, Acetic acid such as acetic acid, ammonium acetate, potassium acetate, calcium acetate, sodium acetate or a salt thereof, aspartic acid such as aspartic acid, sodium aspartate, magnesium aspartate, potassium aspartate or a salt thereof, ethylenediamine diacetic acid (EDDA), ethylenediamine Triacetic acid, ethylenediamine tetraacetic acid (edetic acid, EDTA), ethylenediamine tetraacetic acid disodium hydrate (sodium edetate hydrate), N- (2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTPA) ) And other ethylenediamine acetic acids or salts thereof, amino acids such as ε-aminocaproic acid and the like, boric acid, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borate and salts thereof. , Phosphorus, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate and other phosphates or salts thereof. And amino acids such as ε-aminocaproic acid are preferred, and boric acid, borosand, or ε-aminocaproic acid is particularly preferred.

As the buffering agent that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the buffering agent can be appropriately set according to the type of the buffering agent, the type and content of other compounding components, the use of the ophthalmic solution, the pharmaceutical form, the method of use and the like.

In the emulsion ophthalmic solution of the present invention, for example, the total content of the buffer is preferably 0.001 to 5% (w / v), more preferably 0.005 to 3% (w / v), and 0.01. ~ 2% (w / v) is particularly preferable.

The stabilizer that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Stabilizers include, for example, tromethamole, sodium formaldehyde sulfoxylate (longalit), tocopherol, sodium pyrosulfate, monoethanolamine, aluminum monostearate, glycerin monostearate, dibutylhydroxytoluene, sodium edetate, sodium edetate. Examples thereof include hydrates, polyoxyethylene polyoxypropylene glycol and the like, and dibutylhydroxytoluene or sodium edetate hydrate is particularly preferable.

As the stabilizer that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the stabilizer can be appropriately set according to the type of the stabilizer, the type and content of other compounding components, the use of the ophthalmic solution, the pharmaceutical form, the method of use and the like.

In the emulsion ophthalmic solution of the present invention, for example, the total content of the stabilizer is preferably 0.001 to 1% (w / v), more preferably 0.005 to 0.5% (w / v), and 0. 0.01-0.1% (w / v) is particularly preferable.

The preservative that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the preservative include biguanide compounds such as polyhexamethylene biguanide and polyhexanide hydrochloride, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol and sorbin. Acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, glow kill (trade name from Rhodia), hoe Examples thereof include acid, borosand, chloric acid and the like, benzalkonium chloride, chlorhexidine gluconate, sorbic acid, phenethyl alcohol, boric acid, borosand, chloric acid and the like, preferably benzalconium chloride, chlorhexidine gluconate and phenethyl. Alcohol, boric acid, boar sand and chloric acid are particularly preferred.

As the preservative that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the preservative can be appropriately set according to the type of the preservative, the type and content of other compounding components, the use of the eye drop, the form of the formulation, the method of use and the like.

In the emulsion ophthalmic solution of the present invention, for example, the total content of the preservative is preferably 0.0001 to 1% (w / v), more preferably 0.0005 to 0.5% (w / v), and 0. .001 to 0.2% (w / v) is particularly preferable.

The refreshing agent that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the refreshing agent include essential oils containing terpenoids such as eucalyptus oil, bergamot oil, peppermint oil, uikyo oil, rose oil, keihi oil, sparemint oil, cypress oil, cool mint, and peppermint oil, menthol, menthol, and camphor. , Borneol, geraniol, nerol, cineole, citronellol, carboxylic, anator, eugenol, limonene, linalol, linaryl acetate and the like, menthol, camphor, borneol and geraniol are preferred, with menthol and borneol being particularly preferred. Further, the terpenoid may be d-form, l-form or dl-form, and for example, l-menthol, d-menthol, dl-menthol, dl-camphor, d-camphor, dl-borneol, d-borneol and the like. , L-menthol, dl-camphor, d-camphor and d-borneol are preferred.

As the refreshing agent that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the refreshing agent can be appropriately set according to the type of the refreshing agent, the type and content of other compounding components, the use of the eye drops, the pharmaceutical form, the method of use and the like.

In the emulsion ophthalmic solution of the present invention, for example, the total content of the refreshing agent is preferably 0.001 to 0.5% (w / v), more preferably 0.001 to 0.1% (w / v). It is preferably 0.005 to 0.05% (w / v), and particularly preferably 0.005 to 0.05% (w / v).

The tonicity agent that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the tonicity agent include sodium hydrogensulfate, sodium sulfite, sodium chloride, sodium acetate, sodium hydrogencarbonate, sodium carbonate, sodium thiosulfate and the like, potassium chloride, potassium acetate and the like, calcium chloride and the like. Calcium salt, magnesium salt such as magnesium chloride, magnesium sulfate, polyhydric alcohols such as glycerin, propylene glycol, polyethylene glycol, mannitol, sorbitol, xylitol, tromethamole, etc. Is preferred, with glycerin, propylene glycol, mannitol and tromethamol particularly preferred.

As the tonicity agent that can be used in the emulsion ophthalmic solution of the present invention, one type may be used alone, or two or more types may be used in any combination. Further, the content of the tonicity agent can be appropriately set according to the type of the tonicity agent, the type and content of other compounding components, the use of the ophthalmic solution, the pharmaceutical form, the method of use and the like.

In the emulsion ophthalmic solution of the present invention, for example, the total content of the tonicity agent is preferably 0.05 to 5% (w / v), more preferably 0.1 to 1.8% (w / v). , 0.3-0.7% (w / v) is particularly preferable.

The osmotic pressure of the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, the osmotic pressure ratio is preferably 0.2 to 2, more preferably 0.5 to 1.8, still more preferably 1.0 to 1.6, and particularly preferably 1.4 to 1.6.

The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9% (w / v) sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacy, and the osmotic pressure is described in the Japanese Pharmacy. It can be measured with reference to the osmotic pressure measurement method (freezing point drop method), and for the standard solution for measuring osmotic pressure ratio (0.9% (w / v) sodium chloride aqueous solution), sodium chloride (Japanese Pharmacy Standard Reagent). ) Is dried at 500 to 650 ° C. for 40 to 50 minutes, then allowed to cool in a chloride (silica chloride), weigh accurately 0.900 g thereof, dissolve in purified water and prepare as exactly 100 mL, or a commercially available osmotic pressure ratio. A standard solution for measurement (0.9% (w / v) sodium chloride aqueous solution) can be used.

The dissolving agent (solvent and / or dispersion medium) that can be used in the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the solubilizer (solvent and / or dispersion medium) include aqueous solubilizers such as water (distilled water, normal water, purified water, sterile purified water, injection water, distilled water for injection, etc.) and hydrous ethanol. .. Further, the content of the solubilizer can be appropriately set according to the type and content of other compounding components, the use of the ophthalmic solution, the pharmaceutical form, the method of use, and the like.

In the emulsion ophthalmic solution of the present invention, for example, when the solubilizer is water, 85% (w / v) or more is preferable, 90% (w / v) or more is more preferable, and 93%, based on the total amount of the ophthalmic solution. (W / v) or more is more preferable, and 96% (w / v) or more is particularly preferable.

The emulsion ophthalmic solution of the present invention is preferably an ophthalmic solution that does not contain polyoxyethylene polyoxypropylene glycol as a stabilizing component (stabilizer).

The particle size of the emulsion of the emulsion ophthalmic solution of the present invention is preferably 120 nm or less, more preferably 30 to 120 nm, further preferably 55 to 110 nm, and particularly preferably 80 to 100 nm.

The particle size of the emulsion of the emulsion ophthalmic solution of the present invention means an average particle size, and can be obtained by a method defined by the JIS Z 8826 dynamic light scattering method (photon correlation method).

The emulsion ophthalmic solution of the present invention contains vitamin A, sodium chondroitin sulfate, a surfactant, an amino acid, a viscous agent, a polyhydric alcohol and other components as required, in a solvent or dispersion so as to have a desired content. Prepared by adding to the medium. For example, it can be prepared by dissolving or dispersing the compounded components in purified water, adjusting the pH and osmotic pressure to a predetermined pH, and sterilizing by filtration sterilization or the like.

The emulsion ophthalmic solution of the present invention can be provided by being contained in any container (main body, inner plug, cap). Further, the container for containing the emulsion ophthalmic solution is not particularly limited as long as it is acceptable as a pharmaceutical product. Examples of the container for containing the emulsion ophthalmic solution include a glass container, polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polytetrafluoroethylene, polypropylene, polybutylene terephthalate, polyimide, and polymethylpentene. Examples thereof include a copolymer of the monomers to be used, a plastic container in which two or more kinds containing these materials are combined, and the like. Here, the combination may be a mixture of different materials, or a combination of different materials may be used as a layered structure. Further, the container may be a multi-dose container that can be used repeatedly or a single-use unit-dose container.

The emulsion ophthalmic solution of the present invention can also be used as an ophthalmic solution for contact lenses. Further, when the emulsion ophthalmic solution is used as an ophthalmic solution for contact lenses, it can be applied to all commercially available contact lenses including hard contact lenses and soft contact lenses (ISO18369-1: 2006, ISO18369-1, AMENDMENT1). It can also be used while wearing contact lenses.

The emulsion ophthalmic solution of the present invention can be used for blurred vision (when there are many eyes and eyes), tired eyes, conjunctival congestion, itching of eyes, prevention of eye diseases (when dust or sweat gets into the eyes after swimming), eyelids. Symptoms such as flames (eyelid soreness), eye inflammation caused by ultraviolet rays and other rays (snow eyes, etc.), discomfort when wearing hard contact lenses, discomfort when wearing soft contact lenses, etc. Can be used for mitigation / improvement / suppression. It can also be used to protect and retain water in the cornea.

The dosage of the emulsion ophthalmic solution of the present invention is not particularly limited as long as it is sufficient to achieve the desired medicinal effect. For example, the number of eye drops is preferably 1 to 3 drops / eye, more preferably 1 to 2 drops / eye, and particularly preferably 1 drop / eye. The number of instillations is preferably 1 to 6 times / day, preferably 3 to 6 times / day, and particularly preferably 5 to 6 times / day. The amount of one drop of eye drops is preferably 20 to 60 μL, more preferably 25 to 50 μL, and particularly preferably 30 to 40 μL.

Examples of the pharmaceutical product and the results of the harsh test and the freeze-thaw test are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

(Formulation example)
Tables 1 and 2 below show typical pharmaceutical examples of the present invention. In the following formulation example, the blending amount of each component is the content in 100 mL of the formulation.

The type and blending amount of the pharmacologically active ingredient and the additive in the above-mentioned preparation examples 1 to 10 can be appropriately adjusted to obtain a preparation having a desired composition.

<Examples 1 and 2>
(Severe test)
1. 1. Preparation of test product 1.74 million units / g of retinol palmitate (0.29 g, 50,000 units) and polyoxyethylene hydrogenated castor oil 60 (3.0 g) were kneaded well at 65 ° C and heated to 65 ° C. 700 mL of water was added to it and stirred. After cooling it to room temperature, water was further added to make 800 mL. Take 40 mL of this solution, add sodium chondroitin sulfate (0.25 g), epsilon-aminocaproic acid (0.25 g), and boric acid (0.25 g), stir and dissolve, and then add dilute hydrochloric acid / sodium hydroxide to pH 6. The preparation of Example 1 was prepared by adjusting to 0 and adding water to make a total volume of 50 mL.

The formulations of Example 2 and Reference Example 1 were prepared by the same method as the preparation method of Example 1.

2. 2. Test method Severe test operation: The test product was filled in 10 mL of a 10 mL glass ampoule and stored at 70 ° C. for 7 days.

Quantification of residual amount and calculation of residual rate: The content of retinol palmitate in the test preparation before and after the severe test was diluted with 2-propanol so that the retinol palmitate in the preparation was 250 to 750 units / mL. , Japanese Pharmacopoeia "Retinol palmitate ester standard product" is used as a standard product and quantified by the high-speed liquid chromatography method (16th revised Japanese Pharmacopoeia) using the absolute calibration curve method, and the residual rate (%) is based on the following formula. ) Was calculated.

Retinol palmitate residual rate (%) = {Retinol palmitate content after storage / Retinol palmitate content before storage} x 100

High Performance Liquid Chromatography Measurement Condition Detector: Ultraviolet Absorption Photometer (Measurement Wavelength: 325nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm is filled with 5 μm octadecylsilylated silica gel for high performance liquid chromatography (YMC-Pack ODS-AM AM12S05-1546WT, YMC).
Column temperature: Constant temperature around 50 ° C Mobile phase: Methanol flow rate: Approximately 1.5 mL / min

3. 3. Test Results and Discussion Table 3 shows the test results.

From Reference Example 1 in Table 3, 50,000 units / 100 mL or more of vitamin A, 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof, and 1% (w / v) of polyoxyethylene hydrogenated castor oil. In the test preparation containing 60 and having a pH of 6.0 to 8.0, a decrease in the residual rate of retinol palmitic acid ester (vitamin A) was observed when a severe test was carried out.

On the other hand, from Examples 1 and 2, 50,000 units / 100 mL or more of vitamin A and 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof and 0.3% (w / v) of polyoxyethylene. In the test preparation containing the cured castor oil 60 and having a pH of 6.0 to 8.0, the residual rate of retinol palmitic acid ester (vitamin A) was 50% or more even when a severe test was carried out. became.

From these results, 0.3% (w / v) or less was added to an emulsion ophthalmic solution in which 50,000 units / 100 mL or more of vitamin A and 0.5% (w / v) or more of chondroitin sulfate ester or a salt thereof coexisted. By blending the above-mentioned surfactant and adjusting its pH to 6.0 to 8.0, the residual rate of retinol palmitate (vitamin A) is 50% even when a severe test is carried out. It was shown that the above was achieved.

<Examples 3 to 6>
(Severe test)
1. 1. Preparation of test product 1.74 million units / g of retinol palmitate (0.29 g, 50,000 units) and polyoxyethylene hydrogenated castor oil 60 (3.0 g) were kneaded well at 65 ° C and added separately to 65 ° C. Warm 700 mL of water was added to it and stirred. After cooling it to room temperature, water was added to make 800 mL. Take 40 mL of this solution, add taurine (aminoethylsulfonic acid: 0.25 g), potassium L-aspartate (0.25 g), epsilon-aminocaproic acid (0.25 g), and boric acid (0.25 g) and stir. -After dissolution, dilute hydrochloric acid / sodium hydroxide was added to adjust the pH to 6.0, and water was added to make the total volume 50 mL, thereby preparing the preparation of Example 3.

The formulations of Reference Examples 2 to 4 and Examples 4 to 6 were prepared by the same method as the preparation method of Example 3.

2. 2. Test method Severe test operation: The test product was filled in 10 mL of a 10 mL glass ampoule and stored at 70 ° C. for 7 days.

Quantification of residual amount and calculation of residual rate: The content of retinol palmitate in the test preparation before and after the severe test was diluted with 2-propanol so that the retinol palmitate in the preparation was 250 to 750 units / mL. , Japan Pharmacopoeia "Retinol palmitate ester standard product" is used as a standard product and quantified using the high-speed liquid chromatography method (16th revised Japanese Pharmacopoeia) using the absolute calibration curve method, and the residual rate is based on the following formula. (%) Was calculated.

Retinol palmitate residual rate (%) = {Retinol palmitate content after storage / Retinol palmitate content before storage} x 100

High Performance Liquid Chromatography Measurement Condition Detector: Ultraviolet Absorption Photometer (Measurement Wavelength: 325nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm is filled with 5 μm octadecylsilylated silica gel for high performance liquid chromatography (YMC-Pack ODS-AM AM12S05-1546WT, YMC).
Column temperature: Constant temperature around 50 ° C Mobile phase: Methanol flow rate: Approximately 1.5 mL / min

3. 3. Test Results and Discussion Table 4 shows the test results.

From Reference Examples 2 to 4 in Table 4, 50,000 units / 100 mL or more of vitamin A and an amino acid or a salt thereof coexist, and the content of the amino acid or a salt thereof is 0.5% (w / v) or more. As a result of conducting a rigorous test, a decrease in the residual rate of retinol palmitic acid ester (vitamin A) was observed in the test preparation.

On the other hand, from Examples 3 to 6, 50,000 units / 100 mL or more of vitamin A, 0.5% (w / v) or more of amino acid or a salt thereof, and 0.3 w / v% of polyoxyethylene hydrogenated castor oil 60. In the test preparations compounded and having a pH of 6.0 to 8.0, the residual rate of retinol palmitic acid ester (vitamin A) was 50% or more even when a severe test was carried out.

From these results, 0.3% (w / v) or less was added to an emulsion ophthalmic solution in which 50,000 units / 100 mL or more of vitamin A and 0.5% (w / v) or more of amino acids or salts thereof coexisted. By blending a surfactant and adjusting its pH to 6.0 to 8.0, the residual rate of retinol palmitic acid ester (vitamin A) is 50% or more even when a severe test is carried out. Was shown to be.

<Example 7>
(Freezing and thawing test)
1. 1. Preparation of test product 1.74 million units / g of retinol palmitate (0.29 g, 50,000 units), polyoxyethylene hydrogenated castor oil 60 (2.0 g), polysorbate 80 (1.0 g) at 65 ° C. The mixture was kneaded, 700 mL of water heated to 65 ° C. was added thereto, and the mixture was stirred. After cooling it to room temperature, water was further added to make 800 mL. Take 40 mL of this solution, add propylene glycol (0.25 g), hydroxyethyl cellulose (0.05 g), and dextran 70 (0.05 g), stir and dissolve, and then add water to make a total volume of 50 mL. The formulation of Example 7 was prepared.

The formulations of Reference Examples 5 to 6 were prepared by the same method as the preparation method of Example 7.

2. 2. Test method Freezing and thawing operation: The test product was filled in an eye drop container made of polyethylene terephthalate, the test product was frozen at -20 ° C for 12 to 16 hours, and the frozen test product was left to stand until it was completely thawed at room temperature. ..

Measurement of emulsion diameter: Measure the particle size of the emulsion of the test preparation before freezing and the particle size of the emulsion of the test preparation after freezing and thawing. Measured by -1000ZS (Otsuka Denshi Co., Ltd. (set temperature: 25 ° C.)).

Difference in emulsion diameter: The absolute value of the difference between the particle size of the emulsion of the test product before freezing and the particle size of the emulsion of the test product after freezing and thawing was determined.

Difference in emulsion diameter = | (particle size of the emulsion of the test product before freezing)-(particle size of the emulsion of the test product after freezing and thawing) |

3. 3. Test Results and Discussion Table 5 shows the test results.

From Reference Examples 5 and 6 in Table 5, when the test preparation containing 50,000 units / 100 mL or more of Vitamin A and the viscous agents hydroxyethyl cellulose and dextran are freeze-thawed, before and after freezing and thawing. It has been found that the properties of the test product change, that is, the particle size of the emulsion changes significantly before and after freezing and thawing. In addition, in the test product of Reference Example 6, clear changes in properties such as cloudiness were observed after freezing and thawing.

On the other hand, by adding propylene glycol, which is a polyhydric alcohol, to the test product containing Vitamin A of 50,000 units / 100 mL or more and the viscous agent hydroxyethyl cellulose and dextran from Example 7, the properties after freezing and thawing. It was shown that the change can be suppressed, that is, the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing can be controlled to 0 to 50 nm. In addition, in the test product of Example 7, no clear change in properties such as cloudiness was observed even after freezing and thawing.

Claims (18)

An emulsion ophthalmic solution containing 50,000 units / 100 mL of vitamin A, a viscous agent and a polyhydric alcohol, wherein the viscous agent is hydroxyethyl cellulose and dextran 70 , and the polyhydric alcohol is propylene glycol . Emulsion ophthalmic solution that is pharmaceutically stable over a wide range of temperatures and has a pH of 6.0 to 8.0 (but does not contain d-α-tocopherol acetate). The emulsion ophthalmic solution according to claim 1, which is pharmaceutically stable in the range of -80 ° C to 100 ° C. Freeze-thaw test (Emulsion instillation is filled in a polyethylene terephthalate instillation container, the emulsion instillation is frozen at -20 ° C for 12 to 16 hours, and the frozen emulsion instillation is left at room temperature until it is completely thawed. Then, the particle size of the emulsion of the emulsion before freezing and the particle size of the emulsion of the emulsion after freezing and thawing are measured by the JIS Z 8826 dynamic light scattering method (photon correlation method)) of the emulsion before freezing. The emulsion ophthalmic solution according to claim 1 or 2, wherein the absolute value of the difference between the particle size and the particle size of the emulsion after freeze-thaw is 0 to 50 nm. The emulsion ophthalmic solution according to any one of claims 1 to 3, wherein the vitamin A is a vitamin A fatty acid ester. The emulsion ophthalmic solution according to claim 4, wherein the vitamin A fatty acid ester is a retinol palmitic acid ester. The emulsion ophthalmic solution according to any one of claims 1 to 5, wherein the content of the thickener is 0.01 to 0.5% (w / v). The emulsion ophthalmic solution according to any one of claims 1 to 6, wherein the content of the polyhydric alcohol is 0.1 to 1.8% (w / v). The emulsion ophthalmic solution according to any one of claims 3 to 7 , wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is 0 to 30 nm. The emulsion ophthalmic solution according to any one of claims 3 to 8 , wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is 0 to 10 nm. The emulsion ophthalmic solution according to any one of claims 1 to 9 , which does not contain polyoxyethylene polyoxypropylene glycol. An emulsion ophthalmic solution containing 50,000 units / 100 mL of vitamin A, a viscous agent and a polyhydric alcohol, wherein the viscous agent is hydroxyethyl cellulose and dextran 70 , and the polyhydric alcohol is propylene glycol . Emulsion ophthalmic solution having a pH of 6.0 to 8.0 (however, it does not contain d-α-tocopherol acetate). The emulsion ophthalmic solution according to claim 11 , wherein the vitamin A is a vitamin A fatty acid ester. The emulsion ophthalmic solution according to claim 12 , wherein the vitamin A fatty acid ester is a retinol palmitic acid ester. The emulsion ophthalmic solution according to any one of claims 11 to 13 , wherein the content of the viscous agent is 0.01 to 0.5% (w / v). The emulsion ophthalmic solution according to any one of claims 11 to 14 , wherein the content of the polyhydric alcohol is 0.1 to 1.8% (w / v). The emulsion ophthalmic solution according to any one of claims 11 to 15 , which does not contain polyoxyethylene polyoxypropylene glycol. A method for suppressing a change in properties due to freezing and thawing of an emulsion ophthalmic solution by preparing an emulsion ophthalmic solution containing 50,000 units / 100 mL of vitamin A, a viscous agent and a polyhydric alcohol. Hydroxyethyl cellulose and dextran 70 , wherein the polyhydric alcohol is propylene glycol (provided that the emulsion ophthalmic solution does not contain d-α-tocopherol acetate). Suppression of changes in properties due to freezing and thawing of emulsion ophthalmic solution is a freeze-thaw test (the emulsion ophthalmic solution is filled in an ophthalmic container made of polyethylene terephthalate, and the emulsion ophthalmic solution is frozen at -20 ° C for 12 to 16 hours and then frozen. The emulsion ophthalmic solution is left at room temperature until it is completely thawed, and the particle size of the emulsion of the emulsion ophthalmic solution before freezing and the particle size of the emulsion of the emulsion ophthalmic solution after freezing and thawing are determined by the JIS Z 8826 dynamic light scattering method (photon correlation). The method according to claim 17 , wherein the absolute value of the difference between the particle size of the emulsion before freezing and the particle size of the emulsion after freezing and thawing is controlled to 0 to 50 nm in (measured from the method).