TWI806829B - Emulsion Eye Drops Containing Vitamin A - Google Patents

Abstract

The present invention relates to a pharmaceutically stable milky eye drop at a wide temperature, which is a milky eye drop containing 50,000 units/100mL or more of vitamin A, and at least one component selected from the group consisting of (A) 0.5% (w/v) or more chondroitin sulfate or its salt and a surfactant, (B) 0.5% (w/v) or more of an amino acid or its salt and a surfactant, and (C) a thickener and a polyhydric alcohol. 6.0~8.0.

Description

Emulsion Eye Drops Containing Vitamin A

This invention relates to an emulsion eye drop containing vitamin A which is pharmaceutically stable over a wide temperature range.

It is well known that vitamin A has preventive or therapeutic effects on dry eye symptoms such as corneal-conjunctival xerosis, and corneal-conjunctival keratosis. In addition, vitamin A is easily decomposed by air, light, heat, acid, metal ions, etc., and is especially unstable in water, so it is difficult to mix it stably in eye drops. Furthermore, it is known that vitamin A is stabilized as the content of vitamin A is higher, for example, more than 50,000 units/100 mL, the more obvious the instability will be (Patent Document 1: Japanese Patent Laid-Open No. 2015-101582).

As a technology for stabilizing unstable vitamin A in eye drops, there is known a method of stabilizing the eye drops by blending a nonionic surfactant such as polyoxyethylene hardened castor oil (Patent Document 2: JP-A-5-331056, Patent Document 3: JP-A-6-40907).

Chondroitin sulfate is one of the mucopolysaccharides present in animal tissues or body fluids, especially in cartilage in large quantities. When mixed with eye drops, it is known to have protection and water retention for the cornea and conjunctiva, and is useful for relieving dry eye symptoms such as corneal and conjunctival xerosthesia.

Surfactants such as polysorbate 80, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 60, and PEG-40 stearate are a general term for compounds having a hydrophilic group and a hydrophobic group in the molecule. They are known to be used as solvents for dissolving active ingredients in solvents or dispersion media in eye drops.

Amino acids or salts represented by potassium L-aspartate and ethylamine sulfonic acid (taurine) are classified as amino acids in eye drops. Potassium L-aspartate or ethylsulfonic acid (taurine) are widely known as ingredients for improving eye fatigue because they can promote the metabolism of eye tissue.

Thickeners such as polyvinylpyrrolidone K30, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polydextrose 70, sodium hyaluronate, and alginic acid are widely known as ingredients mixed to increase the viscosity of eye drops.

Polyhydric alcohols such as propylene glycol, mannitol, glycerin, and tris are widely known as components blended as isotonic agents for adjusting the osmotic pressure of liquids such as eye drops.

On the other hand, in milky eye drops, when properties change due to freeze-and-thaw occurs, the milky eye drops become cloudy or the oil phase and the water phase separate, etc., and the appearance is greatly damaged. In addition, it is also considered that the release behavior of the drug is greatly changed due to the change in properties.

prior art literature patent documents

Patent Document 1 Japanese Patent Application Laid-Open No. 2015-101582

Patent Document 2 Japanese Patent Application Laid-Open No. 5-331056

Patent Document 3 Japanese Patent Application Laid-Open No. 6-40907

The inventors of the present case discovered that when the emulsion eye drops in which more than 50,000 units/100 mL of vitamin A and 0.5% (w/v) or more of chondroitin sulfate or its salt coexisted were stored under strict test conditions (70°C, 1 week), the amount of vitamin A in the milk eye drops decreased significantly.

In addition, the inventors of the present case found that in milky eye drops containing more than 50,000 units/100 mL of vitamin A and 0.5% (w/v) or more of amino acids such as L-aspartate potassium or etethanesulfonic acid or their salts, when the eye drops are stored under strict tests (70°C, 1 week), the amount of vitamin A in the milky eye drops will be significantly reduced.

Furthermore, the inventors of the present case discovered that when freezing and thawing the milky eye drops containing more than 50,000 units/100mL of vitamin A and thickeners such as hydroxyethyl cellulose and polydextrose, the properties of the milky eye drops will change before freezing and after freezing and thawing; moreover, the particle size of the emulsion will change significantly before freezing and after freezing and thawing.

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

Then, as a result of the inventors of the present application who have devoted themselves to research in order to solve the above-mentioned problems, they have found that the combination of 50,000 units/100mL or more of vitamin A and 0.5% (w/v) or more of chondroitin sulfate or its salt The co-existing milky eye drops are mixed with less than 0.3% (w/v) surfactant, and the pH is adjusted to 6.0~8.0, especially when 0.3% (w/v) of polyoxyethylene hardened castor oil 60 is mixed as a surfactant, and the pH is adjusted to 6.0 or 8.0, it will inhibit the significant reduction of the amount of vitamin A in the milky eye drops.

In addition, the inventors of the present application have made efforts to solve the above-mentioned problems. As a result of research, they have found that a surfactant of less than 0.3% (w/v) is mixed with an emulsion eye drop containing more than 50,000 units/100 mL of vitamin A and more than 0.5% (w/v) of amino acid salts such as L-aspartate potassium or ethanol, and the pH is adjusted to 6.0 to 8.0. Blending polyoxyethylene hardened castor oil 60 at a content of 0.3% (w/v) and adjusting its pH to 6.0 or 8.0 can inhibit the significant reduction of the amount of vitamin A in the milky eye drops.

Furthermore, the inventors of the present case have worked hard to solve the above-mentioned problems. As a result of research, they have found a milky eye drop that suppresses the change in properties caused by freezing and thawing by blending polyols, especially propylene glycol at a content of 0.5% (w/v) as a polyol, to the milky eye drops containing more than 50,000 units/100 mL of vitamin A, thickeners such as hydroxyethyl cellulose, and polydextrose. 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 controlled at 0~50nm, and the property change caused by freezing and thawing will be suppressed.

As described above, the inventors of the present case have worked hard to solve the above-mentioned problems. As a result, they found the above-mentioned knowledge, and found a pharmaceutically stable milky eye drop of vitamin A with 50,000 units/100 mL or more that is not easily affected by temperature and is stable in a wide temperature range, and has excellent safety, and finally completed the present invention.

That is, the present invention is as follows:

<The first milky eye drop of the present invention>

(1) A pharmaceutically stable milky eye drop at a wide temperature, which is a milky eye drop containing 50,000 units/100mL or more of vitamin A and at least one component selected from the group consisting of the following (A) to (C), and has a pH of 6.0 to 8.0; (A) 0.5% (w/v) or more chondroitin sulfate or its salt and surfactant; A surfactant, and (C) a thickener and a polyol.

(2) The milky eye drop as in (1), which is pharmaceutically stable in the range of -80°C to 100°C.

(3) Emulsion eye drops as in (1) or (2), which are (i) strict test (fill 10 mL of milk eye drops into 10 mL glass ampoules and seal them, store at 70°C for 7 days), the residual rate of vitamin A is more than 50%, and/or (ii) freeze-thaw test (fill the emulsion eye drops into eye drops containers made of polyethylene terephthalate, and freeze the milk eye drops at -20°C for 12~16 hours Place the frozen milky eye drops at room temperature until completely thawed, and measure the particle size of the emulsion of the milky eye drops before freezing and the particle size of the emulsion of the milky eye drops after freeze-thawing by JIS Z 8826 dynamic light scattering method (photon correlation method).

(4) Milky eye drops as in (1) to (3), wherein the vitamin A content is 50,000 units/100mL.

(5) The milky eye drops as in (1) to (4), wherein vitamin A is vitamin A fatty acid ester.

(6) The milky eye drop as in (5), wherein the vitamin A fatty acid ester is retinyl palmitate.

(7) The milky eye drops as described in (1) to (6), wherein the chondroitin sulfate or its salt is sodium chondroitin sulfate.

(8) The milky eye drops as described in (1) to (7), wherein the amino acid or its salt is potassium L-aspartate and/or ethanol.

(9) The milky eye drops as described in (1) to (8), wherein the content of the surfactant is 0.3% (w/v) or less.

(10) The milky eye drops as in (1) to (9), wherein the content of the surfactant is 0.1-0.3% (w/v).

(11) The milky eye drops according to (1) to (10), wherein the surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 60, and PEG-40 stearate.

(12) The milky eye drops as in (1) to (11), wherein the content of the thickener is 0.01-0.5% (w/v).

(13) The milky eye drops according to (1) to (12), wherein the thickener is at least one selected from polyvinylpyrrolidone K30, hydroxyethylcellulose, hydroxypropylmethylcellulose, polydextrose 70, sodium hyaluronate and alginic acid.

(14) The milky eye drops as in (1) to (13), wherein the content of polyhydric alcohol is 0.1-1.8% (w/v).

(15) The milky eye drops according to (1) to (14), wherein the polyhydric alcohol is at least one selected from the group consisting of glycerin, propylene glycol, mannitol and tris.

(16) The milky eye drops as in (3) to (15), wherein the absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing is 0 to 30 nm.

(17) The milky eye drops as in (3) to (16), wherein the absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing is 0 to 10 nm.

(18) The milky eye drops as described in (1) to (17), which do not contain polyoxyethylene polyoxypropylene glycol.

(19) A milky eye drop 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), and having a pH of 6.0 to 8.0; (a) 0.5% (w/v) or more of chondroitin sulfate or its salt and 0.3% (w/v) or less of a surfactant, (b) 0.5% (w/v) or more of an amino acid Or its salt and less than 0.3% (w/v) surfactant, and (c) thickener and polyol.

(20) The milky eye drop as in (19), wherein the vitamin A content is 50,000 units/100mL.

(21) The milky eye drop as described in (19) or (20), wherein vitamin A is vitamin A fatty acid ester.

(22) The milky eye drop as in (21), wherein the vitamin A fatty acid ester is retinyl palmitate.

(23) The milky eye drop as described in (19) to (22), wherein the chondroitin sulfate or its salt is sodium chondroitin sulfate.

(24) The milky eye drops as described in (19) to (23), wherein the amino acid or its salt is potassium L-aspartate and/or ethanol.

(25) The milky eye drops as in (19) to (24), wherein the content of the surfactant is 0.1-0.3% (w/v).

(26) The milky eye drops according to (19) to (25), wherein the surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 60, and PEG-40 stearate.

(27) The milky eye drops as in (19) to (26), wherein the content of the thickener is 0.01-0.5% (w/v).

(28) The milky eye drops according to (19) to (27), wherein the thickener is at least one selected from polyvinylpyrrolidone K30, hydroxyethylcellulose, hydroxypropylmethylcellulose, polydextrose 70, sodium hyaluronate and alginic acid.

(29) The milky eye drops as in (19) to (28), wherein the content of polyhydric alcohol is 0.1-1.8% (w/v).

(30) The milky eye drops according to (19) to (29), wherein the polyhydric alcohol is at least one selected from the group consisting of propylene glycol, mannitol, glycerin and tris.

(31) The milky eye drops as described in (19) to (30), which do not contain polyoxyethylene polyoxypropylene glycol.

(32) A method for stabilizing the aforementioned vitamin A by preparing an emulsion eye drop containing 50,000 units/100 mL or more of vitamin A, 0.5% (w/v) or more of chondroitin sulfate or its salt, and/or 0.5% (w/v) or more of an amino acid or its salt, and a surfactant, and having a pH of 6.0 to 8.0.

(33) A method for suppressing the change in properties of an emulsion eye drop caused by freezing and thawing, which is prepared as an emulsion eye drop containing more than 50,000 units/100mL of vitamin A, a thickener, and a polyhydric alcohol.

(34) The method as in (33), wherein the inhibition of the property change caused by freezing and thawing of the milky eye drop is a freeze-thaw test (fill the milky eye drop into an eye drop container made of polyethylene terephthalate, and freeze the milky eye drop at -20°C for 12 to 16 hours, place the frozen milky eye drop at room temperature until it completely melts, and measure the emulsion before freezing by JIS Z 8826 dynamic light scattering method (photon correlation method) The absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing in the particle diameter of the emulsion of the eye drop and the particle diameter of the emulsion of the milky eye drop after freezing and thawing is controlled at 0 ~ 50nm.

(35) Milky eye drops as in (1) to (31), which have an osmotic pressure ratio of 1.4 to 1.6.

(36) The milky eye drop solution according to (1) to (31) or (35), which further contains at least one selected from buffers, stabilizers, preservatives, coolants, thickeners, pH adjusters and dissolving agents.

(37) The milky eye drop solution according to (1) to (18) or (35), which contains only: (i) 50,000 units/100 mL or more of vitamin A, (ii) at least one component selected from the group consisting of the following (A) to (C) (A) 0.5% (w/v) or more chondroitin sulfate or its salt, and a surfactant, (B) 0.5% (w/v) or more of an amino acid or its salt, and a surfactant, and (C) thickeners and polyols, and (iii) At least one selected from pharmacologically active ingredients, buffers, stabilizers, preservatives, coolants, thickeners, pH regulators and dissolving agents.

(38) The milky eye drop according to (19) to (31) or (35), which contains only: (i) 50,000 units/100 mL or more of vitamin A, (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 or its salt, and 0.3% (w/v) or less of a surfactant (b) 0.5% (w/v) or more of a surfactant Amino acids or their salts and less than 0.3% (w/v) of surfactants, (c) thickeners and polyols, and (iii) at least one selected from pharmacologically active ingredients, buffers, stabilizers, preservatives, coolants, thickeners, pH regulators, and dissolving agents.

In addition, the aforementioned (1) to (38) may be arbitrarily selected and combined or used in parallel.

<The second emulsion eye drop of the present invention>

(1) A milky eye drop that contains more than 50,000 units/100mL of vitamin A, more than 0.5% (w/v) of chondroitin sulfate or its salt, and a surfactant, and has a pH of 6.0 to 8.0. The residual vitamin A rate of the aforementioned milky eye drop after rigorous testing (fill 10 mL of the milky eye drop into a 10 mL glass ampoule and seal it, and store at 70°C for 7 days) is More than 50%.

(2) Milky eye drops as in (1), wherein the vitamin A content is 50,000 units/100mL.

(3) The milky eye drop as in (1) or (2), wherein vitamin A is vitamin A fatty acid ester.

(4) The milky eye drop as in (3), wherein the vitamin A fatty acid ester is retinyl palmitate.

(5) The milky eye drops as in (1) to (4), wherein the chondroitin sulfate or its salt is sodium chondroitin sulfate.

(6) The milky eye drops as described in (1) to (5), wherein the content of the surfactant is 0.3% (w/v) or less.

(7) The milky eye drops as in (1) to (6), wherein the content of the surfactant is 0.1-0.3% (w/v).

(8) The milky eye drops according to (1) to (7), wherein the surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 60, and PEG-40 stearate.

(9) A milky eye drop containing 50,000 units/100 mL or more of vitamin A, 0.5% (w/v) or more of chondroitin sulfate or its salt, and 0.3% (w/v) or less of a surfactant, and having a pH of 6.0 to 8.0.

(10) The milky eye drop as in (9), wherein the vitamin A content is 50,000 units/100mL.

(11) The milky eye drop as described in (9) or (10), wherein the vitamin A is a vitamin A fatty acid ester.

(12) The milky eye drop as in (11), wherein the vitamin A fatty acid ester is retinyl palmitate.

(13) The milky eye drop as described in (9) to (12), wherein the chondroitin sulfate or its salt is sodium chondroitin sulfate.

(14) The milky eye drops as in (9) to (13), wherein the content of the surfactant is 0.1-0.3% (w/v).

(15) The milky eye drops according to (9) to (14), wherein the surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 60, and PEG-40 stearate.

(16) A method for stabilizing the aforementioned vitamin A by preparing a milky eye drop containing more than 50,000 units/100 mL of vitamin A, more than 0.5% (w/v) of chondroitin sulfate or its salt, and a surfactant, and having a pH of 6.0 to 8.0.

(17) Milky eye drops as in (1) to (15), which have an osmotic pressure ratio of 1.4 to 1.6.

(18) The milky eye drop solution according to (1) to (15) or (17), which further contains at least one selected from buffers, stabilizers, preservatives, coolants, thickeners, pH adjusters and dissolving agents.

(19) The milky eye drop as described in (1) to (8) or (17), which contains only: (i) 50,000 units/100 mL or more of vitamin A, (ii) 0.5% (w/v) or more of chondroitin sulfate or its salt, and a surfactant, and (iii) at least one selected from pharmacologically active ingredients, buffers, stabilizers, preservatives, coolants, thickeners, pH regulators, and dissolving agents.

(20) The milky eye drop as in (9) to (15) or (17), which contains only: (i) 50,000 units/100 mL or more of vitamin A, (ii) 0.5% (w/v) or more of chondroitin sulfate or its salt, and 0.3% (w/v) or less of a surfactant, and (iii) selected from pharmacologically active ingredients, buffers, stabilizers, preservatives, coolants, thickeners, pH regulators, and dissolving agents At least 1 species.

In addition, the aforementioned (1) to (20) may be arbitrarily selected and combined or used in parallel.

<The third emulsion eye drop of the present invention>

(1) A milky eye drop that contains more than 50,000 units/100mL of vitamin A, more than 0.5% (w/v) of chondroitin sulfate or its salt, and a surfactant, and has a pH of 6.0 to 8.0. The residual rate of vitamin A in the aforementioned milky eye drop is 5 after rigorous testing (fill 10 mL of the milky eye drop into a 10 mL glass ampoule, seal it, and store it at 70°C for 7 days). 0% or more.

(2) Milky eye drops as in (1), wherein the vitamin A content is 50,000 units/100mL.

(3) The milky eye drop as in (1) or (2), wherein vitamin A is vitamin A fatty acid ester.

(4) The milky eye drop as in (3), wherein the vitamin A fatty acid ester is retinyl palmitate.

(5) Milky eye drops as described in (1) to (4), wherein the amino acid or its salt is potassium L-aspartate and/or etaminoethanesulfonic acid.

(6) The milky eye drops as described in (1) to (5), wherein the content of the surfactant is 0.3% (w/v) or less.

(7) The milky eye drops as in (1) to (6), wherein the content of the surfactant is 0.1-0.3% (w/v).

(8) The milky eye drops according to (1) to (7), wherein the surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 60, and PEG-40 stearate.

(9) A milky eye drop containing 50,000 units/100 mL or more of vitamin A, 0.5% (w/v) or more of an amino acid or its salt, and 0.3% (w/v) or less of a surfactant, and having a pH of 6.0 to 8.0.

(10) The milky eye drop as in (9), wherein the vitamin A content is 50,000 units/100mL.

(11) The milky eye drop as described in (9) or (10), wherein the vitamin A is a vitamin A fatty acid ester.

(12) The milky eye drop as in (11), wherein the vitamin A fatty acid ester is retinyl palmitate.

(13) The milky eye drops as described in (9) to (12), wherein the amino acid or its salt is potassium L-aspartate and/or ethanol.

(14) The milky eye drops as in (9) to (13), wherein the content of the surfactant is 0.1-0.3% (w/v).

(15) The milky eye drops according to (9) to (14), wherein the surfactant is at least one selected from the group consisting of polysorbate 80, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 60, and PEG-40 stearate.

(16) A method for stabilizing the aforementioned vitamin A by preparing a milky eye drop containing more than 50,000 units/100 mL of vitamin A, more than 0.5% (w/v) of an amino acid or its salt, and a surfactant, and having a pH of 6.0 to 8.0.

(17) Milky eye drops as in (1) to (15), which have an osmotic pressure ratio of 1.4 to 1.6.

(18) The milky eye drop solution according to (1) to (15) or (17), which further contains at least one selected from buffers, stabilizers, preservatives, coolants, thickeners, pH adjusters and dissolving agents.

(19) The milky eye drop solution according to (1) to (8) or (17), which contains only: (i) vitamin A of 50,000 units/100 mL or more, (ii) amino acid or its salt and surfactant of 0.5% (w/v) or more, and (iii) at least one selected from pharmacologically active ingredients, buffers, stabilizers, preservatives, cooling agents, thickeners, pH regulators, and dissolving agents.

(20) The milky eye drop as in (9) to (15) or (17), which contains only: (i) 50,000 units/100mL or more of vitamin A, (ii) 0.5% (w/v) or more of amino acids or their salts and 0.3% (w/v) or less of surfactants, and (iii) selected from pharmacologically active ingredients, buffers, stabilizers, preservatives, coolants, thickeners, pH regulators, and dissolving agents At least 1 species.

In addition, the aforementioned (1) to (20) may be arbitrarily selected and combined or used in parallel.

<The fourth emulsion eye drop of the present invention>

(1) An emulsion eye drop, which is an emulsion eye drop containing more than 50,000 units/100mL of vitamin A, a thickener, and a polyol. The freeze-thaw test (fill the emulsion eye drop into an eye drop container made of polyethylene terephthalate, and freeze the emulsion eye drop at -20°C for 12 to 16 hours, place the frozen emulsion eye drop at room temperature until it completely melts, and is determined by JIS Z 8826 Dynamic light scattering method (photon correlation method) to measure the particle size of the milky eye drop emulsion before freezing and the milky eye drop after freezing and thawing The absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing in the particle diameter of the emulsion) is 0~50nm.

(2) Milky eye drops as in (1), wherein the vitamin A content is 50,000 units/100mL.

(3) The milky eye drop as in (1) or (2), wherein vitamin A is vitamin A fatty acid ester.

(4) The milky eye drop as in (3), wherein the vitamin A fatty acid ester is retinyl palmitate.

(5) Milky eye drops as in (1) to (4), wherein the content of the thickener is 0.01-0.5% (w/v).

(6) The milky eye drops as in (1) to (5), wherein the thickener is at least one selected from polyvinylpyrrolidone K30, hydroxyethylcellulose, hydroxypropylmethylcellulose, polydextrose 70, sodium hyaluronate and alginic acid.

(7) The milky eye drops as in (1) to (6), wherein the content of polyhydric alcohol is 0.1~1.8% (w/v).

(7-1) The milky eye drop as in (7), wherein the content of polyhydric alcohol is 0.5% (w/v).

(8) The milky eye drop as described in (1) to (7) or (7-1), wherein the polyhydric alcohol is at least one selected from glycerin, propylene glycol, mannitol and tris.

(8-1) The milky eye drop as described in (8), wherein the polyhydric alcohol is propylene glycol.

(9) The milky eye drops as in (1) to (8) or (8-1), wherein the absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing is 0 to 30 nm.

(10) The emulsion eye drops as in (1) to (9), wherein the absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing is 0 to 10 nm.

(11) The milky eye drops as described in (1) to (10), which do not contain polyoxyethylene polyoxypropylene glycol.

(12) A milky eye drop containing not less than 50,000 units/100 mL of vitamin A, a thickener, and a polyhydric alcohol.

(13) The milky eye drop as in (12), wherein the vitamin A content is 50,000 units/100mL.

(14) The milky eye drop as described in (12) or (13), wherein the vitamin A is a vitamin A fatty acid ester.

(15) The milky eye drop as in (14), wherein the vitamin A fatty acid ester is retinyl palmitate.

(16) The milky eye drops as in (12) to (15), wherein the content of the thickener is 0.01-0.5% (w/v).

(17) The milky eye drops according to (12) to (16), wherein the thickener is at least one selected from polyvinylpyrrolidone K30, hydroxyethylcellulose, hydroxypropylmethylcellulose, polydextrose 70, sodium hyaluronate and alginic acid.

(18) The milky eye drops as in (12) to (17), wherein the content of polyhydric alcohol is 0.1-1.8% (w/v).

(18-1) The milky eye drop as described in (18), wherein the content of polyhydric alcohol is 0.5% (w/v).

(19) The milky eye drop as described in (12) to (18) or (18-1), wherein the polyhydric alcohol is at least one selected from the group consisting of propylene glycol, mannitol, glycerin and tris.

(19-1) The milky eye drop as described in (19), wherein the polyhydric alcohol is propylene glycol.

(20) The milky eye drops as in (12) to (19) or (19-1), wherein the absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing is 0 to 30 nm.

(21) The emulsion eye drops as in (12) to (20), wherein the absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing is 0 to 10 nm.

(22) The milky eye drops of (12) to (21), which do not contain polyoxyethylene polyoxypropylene glycol.

(23) A method for suppressing changes in properties of an emulsion eye drop caused by freezing and thawing, by preparing an emulsion eye drop containing vitamin A, a thickener, and a polyhydric alcohol at 50,000 units/100 mL or more.

(24) The method as in (23), wherein the inhibition of the property change caused by freezing and thawing of the milky eye drop is a freeze-thaw test (fill the milky eye drop into an eye drop container made of polyethylene terephthalate, and freeze the milky eye drop at -20°C for 12 to 16 hours, place the frozen milky eye drop at room temperature until it completely melts, and measure the emulsion before freezing by JIS Z 8826 dynamic light scattering method (photon correlation method) The absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing in the particle diameter of the emulsion of the eye drop and the particle diameter of the emulsion of the milky eye drop after freezing and thawing is controlled at 0 ~ 50nm.

(25) Milky eye drops as in (1) to (22), which have a pH of 6.0 to 8.0.

(26) Milky eye drops as in (1) to (22), which have an osmotic pressure ratio of 1.4 to 1.6.

(27) The milky eye drops according to (1) to (22), which further contain at least one selected from the group consisting of buffers, stabilizers, preservatives, coolants, solvents, pH adjusters and dissolving agents.

(28) The milky eye drop solution according to (1) to (11), (25) or (26), which contains only: (i) vitamin A of 50,000 units/100mL or more, (ii) thickener and polyhydric alcohol, and (iii) at least one selected from pharmacologically active ingredients, buffers, stabilizers, preservatives, coolants, thickeners, pH regulators and dissolving agents.

(29) The milky eye drop as described in (11) to (22), (25) or (26), which contains only: (i) vitamin A of 50,000 units/100mL or more, (ii) thickener and polyhydric alcohol, and (iii) at least one selected from pharmacologically active ingredients, buffers, stabilizers, preservatives, coolants, thickeners, pH regulators and dissolving agents.

In addition, the aforementioned (1) to (29) can be arbitrarily selected and combined or used in parallel.

The first to fourth milky eye drops of the present invention can provide a milky eye drop containing more than 50,000 units/100mL of vitamin A that is not easily affected by temperature, is stable in a wide temperature range, and has excellent safety.

The second milky eye drop of the present invention, for example, can further provide a milky eye drop with excellent stability of vitamin A, which contains more than 50,000 units of vitamin A, 0.5% (w/v) or more of chondroitin sulfate or its salt, and a surfactant.

The third milky eye drop of the present invention, for example, can further provide a milky eye drop with excellent stability of vitamin A, which contains more than 50,000 units of vitamin A, more than 0.5% (w/v) of amino acid or its salt, and a surfactant.

The fourth emulsion eye drop of the present invention (emulsion eye drop containing more than 50,000 units/100mL of vitamin A, a thickener, and an isotonic pressure agent) is further transported or delivered to customers (physicians, pharmacists, patients, etc.) in cold regions, etc. Even if freezing and thawing occurs, there will be no property changes that affect the quality of the product, so high-quality emulsion eye drops can be provided to customers. Also, for example, when transporting or delivering to customers (doctors, pharmacists, patients, etc.) in cold regions, etc., since strict temperature control is not required, no special transport form and storage form (insulation material, heat preservation device, etc.) are required, so it is economical.

The form of implementing the invention

Hereinafter, the present invention will be described in detail.

Vitamin A that can be used in the milky eye drop of the present invention is not particularly limited as long as it is medically acceptable. Examples of vitamin A include vitamin A, mixtures containing vitamin A such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid esters. More specifically, retinyl palmitate, retinyl acetate, retinoic acid, retinol, retinoic acid, retinoid, etc. are mentioned, Retinyl palmitate, retinyl acetate, and retinoic acid are preferable, Retinyl palmitate is especially preferable.

As the vitamin A that can be used in the milky eye drop of the present invention, one of the above-mentioned vitamin A can be used alone, or two or more can be used in combination arbitrarily.

In the milky eye drop of the present invention, for example, the content of vitamin A can be appropriately set at 50,000 units/100mL or more according to the type of vitamin A, the type and content of other blended ingredients, the use of the milky eye drop, the form of the preparation, and the method of use. Here, the "unit" is an International Unit representing an international unit of the amount of vitamin A. The method for measuring the amount of vitamin A is not particularly limited, and it can be measured, for example, by the method described in "General Test Methods of the Sixteenth Revised Japanese Pharmacopoeia-Vitamin A Quantitative Method".

In the milky eye drop of the present invention, for example, the total content of vitamin A is preferably 50,000 units/100mL or more, more preferably 50,000~500,000 units/100mL, further preferably 50,000~300,000 units/100mL, still more preferably 50,000~100,000 units/100mL, most preferably 50,000 units Unit/100mL.

Chondroitin sulfate or a salt thereof that can be used in the milky eye drop of the present invention is not particularly limited as long as it is medically acceptable. Examples of chondroitin sulfate or salts thereof include chondroitin sulfate and chondroitin sulfate sodium. Moreover, examples of the salt of chondroitin sulfate include salts with alkali metals such as potassium, alkaline earth metals such as calcium and magnesium, and metals such as aluminum. In addition, its source is not particularly limited, and it is preferable to use a commercially available product.

Chondroitin sulfate or a salt thereof that can be used in the milky eye drop of the present invention may be used alone or in combination of two or more. Furthermore, the content of chondroitin sulfate or its salt can be appropriately set according to the type of chondroitin sulfate or its salt, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, the total content of chondroitin sulfate or its salt is preferably at least 0.5% (w/v), more preferably 0.5-3.0% (w/v), further preferably 0.5-1.0% (w/v), and most preferably 0.5% (w/v).

Surfactants (solvents) that can be used in the emulsion eye drops of the present invention are not particularly limited as long as they are medically acceptable. Examples of nonionic surfactants include POE monolaurate (20) sorbitan (polysorbate 20), POE monopalmitate (20) sorbitan (polysorbate 40), POE monostearate (20) sorbitan (polysorbate 60), POE tristearate (20) sorbitan (polysorbate 65), and POE monooleate (20) sorbitan POE sorbitan fatty acid esters such as (polysorbate 80), POE hardened castor oils such as POE (40) hardened castor oil (polyoxyethylene hardened castor oil 40) and POE (60) hardened castor oil (polyoxyethylene hardened castor oil 60); ) POE alkyl ethers such as lauryl ether, POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether, POE (54) POP (39) diol, POE (120) POP (40) diol, POE (160) POP (30) diol, POE (196) POP (67) diol (poloxamer (poloxamer) 407, pluronic (pluronic) F1 27), polyoxyethylene‧polyoxypropylene block copolymers such as POE (200) POP (70) diol, monostearic acid polyethylene glycol such as PEG-40 stearate, etc., particularly preferably monooleic acid POE (20) sorbitan (polysorbate 80) and POE (60) hardened castor oil (polyoxyethylene hardened castor oil 60).

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

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

As a cationic surfactant, benzalkonium chloride, benzolin chloride, loxidine gluconate, etc. are mentioned, for example.

These surfactants may be used alone or in combination of two or more of them arbitrarily. Furthermore, the content of the surfactant can be appropriately set according to the type of the surfactant, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, the total content of surfactant is preferably less than 0.3% (w/v), more preferably more than 0-0.3% (w/v), further preferably 0.01-0.3% (w/v), especially preferably 0.1-0.3% (w/v).

Amino acids or salts thereof that can be used in the milky eye drops of the present invention are not particularly limited as long as they are medically acceptable. Examples of amino acids or salts thereof include glycine, alanine, γ-aminobutyric acid, aspartic acid, potassium L-aspartate, glutamic acid, arginine, lysine, and taurine. Among them, L-aspartate potassium, L-magnesium aspartate, L-magnesium-potassium aspartate, and aminoethanesulfonic acid (taurine) are particularly preferred in the “Pharmaceuticals Manufacturing and Sales Guide Booklet General Drugs Manufacturing and Sales Certification Criteria 2012” (1) Ophthalmic Drug Manufacturing (Import) Certification Criteria for Amino Acids.

The amino acids or salts thereof that can be used in the milky eye drop of the present invention may be used alone or in combination of two or more of them arbitrarily. Furthermore, the content of the amino acid or its salt can be appropriately set according to the type of the amino acid or its salt, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, the total content of amino acids or their salts is preferably at least 0.5% (w/v), more preferably 0.5-5.0% (w/v), further preferably 0.5-3.0% (w/v), particularly preferably 0.5-2.0% (w/v).

Thickeners that can be used in the milky eye drops of the present invention are not particularly limited as long as they are medically acceptable. Examples of thickeners include polyvinylpyrrolidones such as polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, and polyvinylpyrrolidone K90; cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, nitrocellulose, or their salts; polyethylene glycol 300; polyethylene glycol 4 00, Polyethylene glycol such as polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polydextrose such as polydextrose 40, polydextrose 70, hyaluronic acid derivatives such as sodium hyaluronate (refined sodium hyaluronate, etc.), alginic acid, alginic acid derivatives such as sodium alginate, polyvinyl alcohol, carboxyvinyl polymer, sodium chondroitin sulfate, gum arabic, gellan gum, tragacanth, etc., preferably polyvinylpyrrolidone K25, polyvinylpyrrolidone Polyvinylpyrrolidones such as pyrrolidone K30 and polyvinylpyrrolidone K90, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose derivatives such as polyvinylpyrrolidone K30, hydroxyethylcellulose, hydroxypropylmethylcellulose, polydextrose 70, sodium hyaluronate and alginic acid.

The thickeners that can be used in the milky eye drops of the present invention may be used alone or in combination of two or more. Furthermore, the content of the thickener can be appropriately set according to the type of thickener, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, the total content of the thickener is preferably 0.005-1.0% (w/v), more preferably 0.01-0.5% (w/v), particularly preferably 0.01-0.3% (w/v).

Polyhydric alcohols that can be used in the milky eye drop of the present invention are not particularly limited as long as they are medically acceptable. In terms of polyhydric alcohols, for example, glycerin, propylene glycol, polyethylene glycol, mannitol, sorbitol, xylitol, and tris are preferably glycerin, propylene glycol, polyethylene glycol, mannitol, and tris, and particularly preferred are glycerin, propylene glycol, mannitol, and tris. Also, the polyhydric alcohol may be any of d-body, l-body and dl-body.

The polyhydric alcohols that can be used in the milky eye drop of the present invention may be used alone or in combination of two or more of them arbitrarily. Furthermore, the content of the polyol can be appropriately set according to the type of polyol, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, the total content of polyols is preferably 0.05-5% (w/v), more preferably 0.1-1.8% (w/v), and particularly preferably 0.3-0.7% (w/v).

The pH adjuster that can be used in the milky eye drop of the present invention is not particularly limited as long as it is medically acceptable. Examples thereof include dilute hydrochloric acid, acetic acid, sodium hydroxide, sodium bicarbonate, and sodium carbonate, among which dilute hydrochloric acid and sodium hydroxide are particularly preferred.

The pH adjusters that can be used in the milky eye drops of the present invention may be used alone or in combination of two or more. Furthermore, the content of the pH adjuster can be appropriately set according to the type of the pH adjuster, the type and content of other blended ingredients, the use of the eye drop, the form of the preparation, and the method of use.

The pH of the emulsion ophthalmic drop of the present invention is not particularly limited as long as it is medically acceptable, but is preferably 6.0-8.0.

In the present invention, "medically stable at a wide temperature" refers to a wide temperature range, as long as it is medically acceptable, it is not particularly limited, but it means that the physical and chemical changes of the milky eye drop as medicine are suppressed, for example, the reduction caused by the decomposition of vitamin A contained as an active ingredient is suppressed, and/or the property change of the eye drop, especially the change in the particle size of the emulsion is suppressed.

For the emulsion ophthalmic drops of the present invention, for example, when the rigorous test described below (70°C, 1 week) is carried out, the residual rate of vitamin A is more than 50%, and/or when the freeze-thaw test described below is carried out (frozen at -20°C for 12 to 16 hours, and then completely melted 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 freeze-thawing is 0~ When the particle size is 50nm (the particle size is measured by JIS Z 8826 dynamic light scattering method (photon correlation method)), it can be said to be "medically stable at a wide range of temperatures".

The emulsion ophthalmic drops of the present invention are medically stable at a wide temperature range, for example -80°C to 100°C, preferably -50°C to 80°C, more preferably -20°C to 70°C.

The severe test of the milky eye drops of the present invention means, for example, the following meanings.

10 mL of the test preparation was filled and sealed in a 10 mL glass ampoule, and stored at 70° C. for 7 days.

The freeze-thaw test of the milky eye drops of the present invention means the following meanings.

Freezing and thawing operation: Fill the milky eye drop of the present invention into an eye drop container made of polyethylene terephthalate, freeze the milky eye drop at -20°C for 12 to 16 hours, and place the frozen milky eye drop at room temperature until it completely melts.

Measurement of the diameter of the emulsion: The particle diameter of the emulsion of the milky eye drop of the present invention before freezing and the particle size of the emulsion of the milky eye drop of the present invention after freezing and thawing were measured by JIS Z 8826 dynamic light scattering method (photon correlation method) (zeta potential‧particle size measurement system ELSZ-1000ZS (Otsuka Electronics Co., Ltd.) (set temperature: 25°C)).

Difference in emulsion diameter: The absolute value of the difference between the particle diameter of the emulsion of the milky eye drop of the present invention before freezing and the particle diameter of the emulsion of the milky eye drop of the present invention after freezing and thawing was obtained.

In the milky eye drop of the present invention, the particle size of the emulsion of the milky eye drop of the present invention before freezing is the same as that of the milky eye drop of the present invention after freezing and thawing. The absolute value of the difference in particle size of the emulsion of the eye solution is not particularly limited as long as it is medically acceptable, but is preferably 50 nm or less, more preferably 0-30 nm, further preferably 0-10 nm, and most preferably 0-5 nm.

"At least one kind" in the present invention refers to one kind or two or more kinds. Moreover, if it is 2 or more types, it will not specifically limit as long as it is medically acceptable. For example, preferably 2-30, more preferably 2-12, further preferably 2-8, particularly preferably 2-4.

唑、磺胺甲異

唑鈉、玻尿酸鈉、海藻酸等。 As long as the effects of the present invention are not hindered, the milky eye drops of the present invention may contain various pharmacologically active ingredients (physiologically active ingredients or active ingredients) in appropriate amounts, and there are no particular limitations as long as they are medically acceptable.就藥理活性成分(生理活性成分或有效成分)而言，可舉出例如色甘酸鹽、氨來佔諾、異丁司特、甲磺司特、吡嘧司特鉀、曲尼司特、鹽酸奧洛他定、鹽酸左卡巴斯汀、阿扎司特等的抗過敏劑、馬來酸氯苯那敏、鹽酸苯海拉明、富馬酸酮替芬等的抗組織胺劑、鹽酸四氫唑啉、硝酸四氫唑啉、鹽酸萘唑啉、硝酸萘唑啉、腎上腺素、鹽酸腎上腺素、鹽酸麻黃鹼、鹽酸去氧腎上腺素、dl-鹽酸甲基麻黃鹼等的血管收縮劑(去充血劑)、普拉洛芬、甘草酸、甘草酸二鉀、尿囊素、硫酸黃連素、氯化黃連素、薁磺酸、ε-胺己酸、硫酸鋅、硫酸鋅水合物、乳酸鋅、溶菌酶、水楊酸、傳明酸、甘草、此等之鹽等的抗發炎劑、具有與乙醯膽鹼類似之活性中心的膽鹼酯酶抑制劑，具體而言為硫酸甲酯新斯狄明、新斯狄明甲基硫酸鹽、托吡卡胺、堆心菊素及硫酸阿托品等的眼肌調節藥劑、黃藥水、十六基吡啶鎓、氯化苄烷銨、氯化本索寧、洛赫西定、聚六亞甲基雙胍及鹽酸烷基二胺乙基甘胺酸等的殺菌劑、甘胺酸、丙胺酸、γ-胺基丁酸、天冬胺酸、L-天冬胺酸鉀、麩胺酸、精胺酸、離胺酸、胺乙磺酸(牛磺酸)、硫酸軟骨素、硫酸軟骨素鈉等的胺基酸類、維他命B ₁ 、維他命B ₂ (黃素腺嘌呤二核苷酸鈉)、菸鹼(菸鹼酸及菸鹼醯胺)、泛酸、泛醇、維他命B ₆ (吡哆醇、吡哆醇鹽酸鹽、吡哆醛及吡哆胺)、生物素、葉酸、維他命B ₁₂ (氰鈷胺素、羥鈷胺素、甲基鈷胺素及腺苷基鈷胺素)、維他命E(乙酸生育酚、乙酸-d-α生育酚)等的維他命類、磺胺甲異

azoles, sulfamethide

Sodium azole, sodium hyaluronate, alginic acid, etc.

The pharmacologically active ingredients that can be used in the milky eye drop of the present invention can be used alone or in combination of two or more. Furthermore, 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 blended ingredients, the use of the eye drop, the form of the preparation, and the method of use.

Buffers that can be used in the milky eye drops of the present invention are not particularly limited as long as they are medically acceptable. Examples of the buffer include boric acid, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, boric acid such as boric acid or salt thereof, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc. Citric acid or its salts, citric acid, sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc., citric acid or its salts, acetic acid, ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc., acetic acid or its salts, aspartic acid, sodium aspartate, magnesium aspartate, potassium aspartate, etc. TA), ethylenediaminetetraacetic acid disodium hydrate (sodium edetate hydrate), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA) and other ethylenediamineacetic acids or their salts, amino acids such as ε-aminocaproic acid, etc., preferably boric acid, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax and other boric acid or its salts, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate Phosphoric acid such as potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, or its salt, and amino acids such as ε-aminocaproic acid, especially boric acid, borax, or ε-aminocaproic acid.

Buffers that can be used in the milky eye drops of the present invention may be used alone or in combination of two or more. Furthermore, the content of the buffering agent can be appropriately set according to the type of the buffering agent, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, the total content of the buffering agent is preferably 0.001-5% (w/v), more preferably 0.005-3% (w/v), and particularly preferably 0.01-2% (w/v).

The stabilizer that can be used in the milky eye drop of the present invention is not particularly limited as long as it is medically acceptable. In terms of stabilizers, for example, trismethylolaminomethane, sodium formaldehyde sulfoxylate ( white powder), tocopherol, sodium metabisulfite, monoethanolamine, aluminum monostearate, glycerol monostearate, dibutyl hydroxytoluene, sodium acetate, sodium acetate hydrate, polyoxyethylene polyoxypropylene glycol, etc., particularly preferably dibutyl hydroxytoluene or sodium acetate hydrate.

The stabilizers that can be used in the milky eye drop of the present invention may be used alone or in combination of two or more. Furthermore, the content of the stabilizer can be appropriately set according to the type of the stabilizer, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, the total content of stabilizers is preferably 0.001-1% (w/v), more preferably 0.005-0.5% (w/v), especially preferably 0.01-0.1% (w/v).

The preservatives that can be used in the milky eye drops of the present invention are not particularly limited as long as they are medically acceptable. Preservatives include, for example, biguanide compounds such as polyhexamethylene biguanide and polyhexamformin hydrochloride, zinc chloride, alkyldiamineethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzionine chloride, lohecidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium tetrahydroacetate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, and hydroxyquinoline sulfate. , phenylethyl alcohol, benzyl alcohol, Gurokiru (trade name manufactured by Rhodia), boric acid, borax, chlorous acid, etc., preferably benzalkonium chloride, lohexidine gluconate, sorbic acid, phenylethyl alcohol, boric acid, borax, chlorous acid, particularly preferably benzalkonium chloride, lohexidine gluconate, phenylethyl alcohol, boric acid, borax, chlorous acid.

The preservatives that can be used in the milky eye drop of the present invention may be used alone or in combination of two or more. Furthermore, the content of the preservative can be appropriately set according to the type of preservative, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drops of the present invention, for example, the total content of preservatives is preferably 0.0001-1% (w/v), more preferably 0.0005-0.5% (w/v), and particularly preferably 0.001-0.2% (w/v).

The coolant that can be used in the milky eye drop of the present invention is not particularly limited as long as it is medically acceptable. Examples of cooling agents include terpenoid-containing essential oils such as eucalyptus oil, bergamot oil, peppermint oil, anise oil, rose oil, cinnamon oil, spearmint oil, camphor oil, peppermint, and peppermint oil; alcohol, camphor, borneol and geraniol, especially menthol and borneol. In addition, the terpenes may be any of the d-body, the l-body, and the dl-body, for example, l-menthol, d-menthol, dl-menthol, dl-camphor, d-camphor, dl-borneol, d-borneol, etc., preferably l-menthol, dl-camphor, d-camphor, and d-borneol.

The coolants that can be used in the milky eye drops of the present invention can be used alone or in combination of two or more. Furthermore, the content of the coolant can be appropriately set according to the type of coolant, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, the total content of coolant is preferably 0.001-0.5% (w/v), more preferably 0.001-0.1% (w/v), especially preferably 0.005-0.05% (w/v).

The isotonic agent that can be used in the milky eye drop of the present invention is not particularly limited as long as it is medically acceptable. Examples of isotonic agents include sodium bisulfite, sodium sulfite, sodium chloride, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate and other sodium salts, potassium chloride and potassium acetate and other potassium salts, calcium salts such as calcium chloride, magnesium chloride and magnesium sulfate and other magnesium salts, glycerin, propylene glycol, polyethylene glycol, mannitol, sorbitol, xylitol, trishydroxymethylaminomethane and other polyhydric alcohols, etc., preferably glycerin, propylene glycol, polyethylene glycol, Mannitol and tris, particularly preferably glycerin, propylene glycol, mannitol and tris.

The isotonic agents that can be used in the milky eye drops of the present invention may be used alone or in combination of two or more. Furthermore, the content of the isotonic agent can be appropriately set according to the type of the isotonic agent, the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, the total content of the isotonic agent is preferably 0.05-5% (w/v), more preferably 0.1-1.8% (w/v), and particularly preferably 0.3-0.7% (w/v).

The osmotic pressure of the milky eye drop of the present invention is not particularly limited as long as it is medically acceptable. For example, the osmotic pressure is preferably 0.2-2, more preferably 0.5-1.8, further preferably 1.0-1.6, particularly preferably 1.4-1.6.

In addition, the osmotic pressure ratio is based on the 16th revision of the Japanese Pharmacopoeia, relative to the ratio of the osmotic pressure of a sample of 286mOsm (0.9% (w/v) sodium chloride aqueous solution), and the osmotic pressure can be measured with reference to the osmotic pressure measurement method (freezing point depression method) recorded in the Japanese Pharmacopoeia; In addition, the standard solution (0.9% (w/v) sodium chloride aqueous solution) for the osmotic pressure ratio measurement is sodium chloride (standard reagent of the Japanese Pharmacopoeia) dried at 500 ~ 650 ° C for 4 After 0~50 minutes, place it in a desiccator (silica gel) to cool, accurately measure 0.900g of it, dissolve it in pure water and adjust it to 100mL to prepare it, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9% (w/v) sodium chloride aqueous solution).

The dissolving agent (solvent and/or dispersing vehicle) that can be used in the emulsion eye drop of the present invention is not particularly limited as long as it is medically acceptable. Examples of the solubilizer (solvent and/or dispersion medium) include aqueous solubilizers such as water (distilled water, ordinary water, pure water, sterilized pure water, water for injection, distilled water for injection, etc.), hydrous ethanol, and the like. Furthermore, the content of the dissolving agent can be appropriately set according to the type and content of other blending ingredients, the use of the eye drop, the form of the preparation, and the method of use.

In the milky eye drop of the present invention, for example, when the dissolving agent is water, relative to the total amount of the eye drop, it is preferably 85% (w/v) or more, more preferably 90% (w/v) or more, further preferably 93% (w/v) or more, particularly preferably 96% (w/v) or more.

The milky eye drop of the present invention is preferably an eye drop that does not contain polyoxyethylene polyoxypropylene glycol as a stabilizing component (stabilizer).

The particle size of the emulsion of the milky eye drop of the present invention is preferably less than 120 nm, more preferably 30-120 nm, further preferably 55-110 nm, particularly preferably 80-100 nm.

The particle diameter of the emulsion of the milky eye drop of the present invention refers to the average particle diameter, and can be obtained by the method prescribed in JIS Z 8826 dynamic light scattering method (photon correlation method).

The milky eye drop of the present invention can be prepared by adding vitamin A, sodium chondroitin sulfate, surfactant, amino acid, thickener, polyhydric alcohol, and other ingredients to a solvent or dispersion vehicle in an optional amount. For example, it can be prepared by dissolving or dispersing the above-mentioned compounding components in pure water, adjusting to predetermined pH and osmotic pressure, and performing sterilization treatment by filtration sterilization or the like.

The milky eye drop of the present invention can be accommodated in any container (main body, inner plug, cap) and provided. Moreover, the container for containing this milky eye drop is not particularly limited as long as it is medically acceptable. Examples of containers for containing milky eye drops include glass containers, polyethylene terephthalate, polyacrylate, polyethylene naphthalate, polycarbonate, polyethylene, polytetrafluoroethylene, polypropylene, polybutylene terephthalate, polyimide, polymethylpentene, copolymers of monomers constituting these, and plastic containers made of combinations of two or more of these materials. In addition, the combination referred to here may mix different materials, or make layers of different materials. Furthermore, the aforementioned container may be a multi-dose container that can be used repeatedly, or may be a unit-dose container that can be used only once.

The emulsion eye drop of the present invention can also be used as an eye drop for contact lenses. Furthermore, when the above-mentioned milky eye drops are used as eye drops for contact lenses, it can be applied to products including hard contact lenses and soft contact lenses (ISO18369-1:2006, ISO18369-1, AMENDMENT1). All commercially available contact lenses can be used while wearing contact lenses.

The milky eye drop of the present invention can be used to alleviate, improve, and suppress blurred vision (when there is a lot of eye mucus, etc.), eye fatigue, conjunctival hyperemia, itchy eyes, eye disease prevention (when dust or sweat enters the eyes after swimming, etc.), blepharitis (eyelid ulcers), ophthalmia caused by light other than ultraviolet rays (snow blindness, etc.), discomfort when wearing hard contact lenses, discomfort when wearing soft contact lenses, etc. In addition, it can also be used for corneal protection and water retention.

The usage and dosage of the milky eye drop of the present invention are not particularly limited as long as it is sufficient to exert the desired medicinal effect. For example, the number of eye drops is preferably 1 to 3 drops per eye, more preferably 1 to 2 drops per eye, and most preferably 1 drop per eye. Also, the frequency of eye drops is preferably 1-6 times/day, more preferably 3-6 times/day, particularly preferably 5-6 times/day. Furthermore, the amount of 1 eye drop is preferably 20-60 μL, more preferably 25-50 μL, and most preferably 30-40 μL.

[Example]

The formulation examples and the results of rigorous tests and freeze-thaw tests are shown below, but these are for a better understanding of the present invention rather than limiting the scope of the present invention.

(preparation example)

Table 1 and Table 2 below show typical preparation examples of the present invention. In addition, the compounding quantity of each component in the following formulation example is content in 100 mL of formulations.

In addition, by appropriately adjusting the types or blending amounts of the pharmacologically active ingredients and additives in the aforementioned formulation examples 1 to 10, the desired formulation can be obtained.

<Example 1 and 2> (strict test) 1. Preparation of test formulations

1.74 million units/g of retinyl palmitate (0.29 g, 50,000 units) and polyoxyethylene hardened castor oil 60 (3.0 g) were fully kneaded at 65°C, and 700 mL of water heated to 65°C was added and stirred. After cooling this to room temperature, water was further added to adjust to 800 mL. Take 40 mL of this solution, add sodium chondroitin sulfate (0.25 g), ε-aminocaproic acid (0.25 g), and boric acid (0.25 g) and stir to dissolve, then add dilute hydrochloric acid/sodium hydroxide to adjust the pH to 6.0, add water to make the total amount 50 mL, and prepare the preparation of Example 1.

Preparations of Example 2 and Reference Example 1 were prepared in the same manner as in Example 1.

2. Test method

Strict test operation: 10 mL of the test preparation is filled in a 10 mL glass ampoule and stored at 70°C for 7 days.

Quantification of the residual amount and calculation of the residual rate: Dilute the retinyl palmitate content of the test preparation before and after the rigorous test with 2-propanol so that the retinyl palmitate in the preparation becomes 250-750 units/mL, quantify it by high performance liquid chromatography (the sixteenth revision of the Japanese Pharmacopoeia) using the Japanese Pharmacopoeia "retinyl palmitate standard" as a standard, and calculate the residual rate (%) based on the following formula.

Residual rate of retinyl palmitate (%)={retinyl palmitate content after storage/retinyl palmitate content before storage}×100

High performance liquid chromatography determination conditions

Detector: UV absorbance photometer (measurement wavelength: 325nm)

Column: A stainless steel tube with 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: a certain temperature around 50°C

Mobile Phase: Methanol

Flow rate: about 1.5mL/min

3. Test results and investigation

Table 3 shows the test results.

From Reference Example 1 in Table 3, it can be seen that when the test formulation was mixed with more than 50,000 units/100mL of vitamin A, more than 0.5% (w/v) of chondroitin sulfate or its salt, and 1% (w/v) of polyoxyethylene hardened castor oil 60, and the pH was adjusted to 6.0~8.0, the residual rate of retinyl palmitate (vitamin A) was relatively low.

On the other hand, as can be seen from Examples 1 and 2, when a rigorous test is carried out on a test preparation that is blended with 50,000 units/100 mL or more of vitamin A, 0.5% (w/v) or more of chondroitin sulfate or its salt, and 0.3% (w/v) of polyoxyethylene hardened castor oil 60, and adjusted to a pH of 6.0 to 8.0, the residual rate of retinyl palmitate (vitamin A) is still more than 50%.

These results show that by mixing 50,000 units/100mL or more of vitamin A and 0.5% (w/v) or more of chondroitin sulfate or its salt into the milky eye drops that coexist with less than 0.3% (w/v) of surfactants, and adjusting the pH to 6.0 to 8.0, the residual rate of retinyl palmitate (vitamin A) is still more than 50% in strict tests.

<Example 3~6> (strict test) 1. Preparation of test formulations

1.74 million units/g of retinyl palmitate (0.29 g, 50,000 units) and polyoxyethylene hardened castor oil 60 (3.0 g) were fully kneaded at 65°C, and 700 mL of water heated to 65°C was added and stirred. After cooling it to room temperature, water was added to make it 800 mL. Take 40 mL of this solution, add taurine (aminoethanesulfonic acid: 0.25 g), potassium L-aspartate (0.25 g), ε-aminocaproic acid (0.25 g), and boric acid (0.25 g) and stir to dissolve. Then add dilute hydrochloric acid/sodium hydroxide to adjust the pH to 6.0, add water to make the total amount 50 mL, and prepare the preparation of Example 3.

In the same manner as the preparation method of Example 3, the preparations of Reference Examples 2-4 and Examples 4-6 were prepared.

2. Test method

Strict test operation: 10 mL of the test preparation is filled in a 10 mL glass ampoule and stored at 70°C for 7 days.

Quantification of the residual amount and calculation of the residual rate: Dilute the retinyl palmitate content of the test preparation before and after the rigorous test with 2-propanol, so that the retinyl palmitate in the preparation becomes 250-750 units/mL, quantify using the high performance liquid chromatography (the sixteenth revised Japanese Pharmacopoeia) using the absolute calibration curve method using the Japanese Pharmacopoeia "retinyl palmitate standard" as a standard, and calculate the residual rate (%) based on the following formula.

Residual rate of retinyl palmitate (%)={retinyl palmitate content after storage/retinyl palmitate content before storage}×100

High performance liquid chromatography determination conditions

Detector: UV absorbance photometer (measurement wavelength: 325nm)

Column: A stainless steel tube with 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: a certain temperature around 50°C

Mobile Phase: Methanol

Flow rate: about 1.5mL/min

3. Test results and investigation

Table 4 shows the test results.

From reference examples 2 to 4 in Table 4, it can be seen that the results of rigorous tests were carried out on the test preparations in which more than 50,000 units/100 mL of vitamin A coexisted with amino acids or their salts, and the content of amino acids or their salts was more than 0.5% (w/v). It can be seen that the residual rate of retinyl palmitate (vitamin A) is relatively low.

On the other hand, as can be seen from Examples 3 to 6, when a rigorous test is carried out for a test preparation that is blended with vitamin A of more than 50,000 units/100 mL, more than 0.5% (w/v) of amino acid or its salt, and 0.3% w/v of polyoxyethylene hardened castor oil 60, and adjusted to a pH of 6.0 to 8.0, the residual rate of retinyl palmitate (vitamin A) is still more than 50%.

These results show that by mixing 0.3% (w/v) or less of a surfactant and adjusting the pH to 6.0 to 8.0 in a milky eye drop containing 50,000 units/100 mL or more of vitamin A and 0.5% (w/v) or more of an amino acid or its salt, the residual rate of retinyl palmitate (vitamin A) is still more than 50% even when a strict test is carried out.

<Example 7> (freeze-thaw test) 1. Preparation of test formulations

1.74 million units/g of retinyl palmitate (0.29 g, 50,000 units), polyoxyethylene hardened castor oil 60 (2.0 g), and polysorbate 80 (1.0 g) were fully kneaded at 65°C, and 700 mL of water heated to 65°C was added and stirred. After cooling this to room temperature, water was further added to adjust to 800 mL. Take 40 mL of this solution, add propylene glycol (0.25 g), hydroxyethyl cellulose (0.05 g), and polydextrose 70 (0.05 g) and stir. After dissolving, add water to make the total amount 50 mL to prepare the preparation of Example 7.

In the same manner as the preparation method of Example 7, the preparations of Reference Examples 5-6 were prepared.

2. Test method

Freezing and thawing operation: Fill the test preparation into an eye drop container made of polyethylene terephthalate, freeze the test preparation at -20°C for 12-16 hours, and place the frozen test preparation at room temperature until it completely thaws.

Determination of emulsion diameter: The particle diameter of the emulsion of the test preparation before freezing and the particle diameter of the emulsion of the test preparation after freezing and thawing were measured by JIS Z 8826 dynamic light scattering method (photon correlation method) (zeta potential‧particle size measurement system ELSZ-1000ZS (Otsuka Electronics Co., Ltd.) (set temperature: 25°C)).

Difference in emulsion diameter: Calculate the absolute value of the difference between the particle diameter of the emulsion of the test preparation before freezing and the particle diameter of the emulsion of the test preparation after freezing and thawing.

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

3. Test results and investigation

Table 5 shows the test results.

From reference examples 5 and 6 in Table 5, it can be seen that when the test preparation containing 50,000 units/100mL or more of vitamin A and hydroxyethyl cellulose and polydextrose as thickeners was freeze-thawed, it was found that the properties of the test preparation changed before freezing and after freezing and thawing, that is, the particle size of the emulsion changed greatly before freezing and after freezing and thawing. Also, with regard to the test preparation of Reference Example 6, clear property changes such as cloudiness can be seen after freezing and thawing.

On the other hand, as shown in Example 7, by mixing propylene glycol, which is a polyhydric alcohol, with a test preparation containing 50,000 units/100 mL or more of vitamin A, hydroxyethyl cellulose and polydextrose as thickeners, Alcohol can inhibit the property change after freezing and thawing, that is, the absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing can be controlled within 0~50nm. Also, with regard to the test formulation of Example 7, no clear property changes such as cloudiness were observed after freezing and thawing.

Claims (10)

A milky eye drop, which is vitamin A containing 50,000 units/100mL, a thickener of 0.01~0.5% (w/v), a polyol of 0.1~1.8% (w/v), and a surfactant of 0.01~0.3% (w/v), and a pH of 6.0~8.0; wherein the thickener is hydroxyethyl cellulose and polydextrose 70, and the polyol is Propylene glycol, the surfactant is polyoxyethylene hardened castor oil 60 and polysorbate 80. The milky eye drop solution as claimed in claim 1 is medically stable in the range from -20°C to room temperature. For example, the milky eye drop of claim 1 is a freeze-thaw test (fill the milky eye drop into an eye drop container made of polyethylene terephthalate, and freeze the milky eye drop at -20°C for 12 to 16 hours, place the frozen milky eye drop at room temperature until it completely melts, and measure the particle size of the emulsion of the milky eye drop before freezing and the milky drop after freeze-thawing by JIS Z 8826 dynamic light scattering method (photon correlation method) The absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing in the liquid emulsion particle diameter) is 0~50nm. As the milky eye drop of claim item 1, wherein vitamin A is vitamin A fatty acid ester. As the milky eye drop of claim 4, wherein the vitamin A fatty acid ester is retinyl palmitate. For example, the milky eye drop of claim 3, the absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing is 0~30nm. For example, the milky eye drop of claim 3, the absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing is 0~10nm. As the milky eye drops of claim 1, it does not contain polyoxyethylene polyoxypropylene glycol. A method for suppressing the property change caused by freezing and thawing of the milky eye drop according to any one of claims 1 to 8, by adjusting the milky eye drop containing 50,000 units/100mL of vitamin A, 0.01~0.5% (w/v) of thickener, 0.1~1.8% (w/v) of polyol, and 0.01~0.3% (w/v) of surfactant, and the pH is 6.0 ~8.0; wherein the thickener is hydroxyethyl cellulose and polydextrose 70, the polyol is propylene glycol, and the surfactant is polyoxyethylene hardened castor oil 60 and polysorbate 80. The method of claim 9, wherein the inhibition of the property change caused by freezing and thawing of the milky eye drop is a freeze-thaw test (filling the milky eye drop into an eye drop container made of polyethylene terephthalate, and freezing the milky eye drop at -20°C for 12 to 16 hours, placing the frozen milky eye drop at room temperature until it completely melts, and measuring the emulsion of the milky eye drop before freezing by JIS Z 8826 dynamic light scattering method (photon correlation method) The absolute value of the difference between the particle diameter of the emulsion before freezing and the particle diameter of the emulsion after freezing and thawing is controlled at 0 ~ 50nm.