Aqueous ophthalmic composition containing diquafosol or its salts, and polyvinylpyrrolidone.

Abstract

To provide an aqueous ophthalmic composition capable of reducing side effects, such as eye irritation, while enhancing the medicinal effect of diquafosol or a salt thereof.SOLUTION: Specifically, the aqueous ophthalmic composition for the prevention or treatment of dry eye comprises diquafosol sodium at a concentration of 3% (w / v), polyvinylpyrrolidone with a K value of 90, and silver nitrate and is given 1 to 2 drops at a time, 2 to 4 times a day. The aqueous ophthalmic composition for the prevention or treatment of dry eye comprises diquafosol sodium at a concentration of 3% (w / v), polyvinylpyrrolidone, and silver nitrate, has a viscosity of 3-30 mPa-s at 25°C, and is given 1 to 2 drops at a time, 2 to 4 times a day.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to an aqueous ophthalmic composition containing diquafosol or a salt thereof, and polyvinylpyrrolidone. [Background technology]

[0002] Zikuahosol is P 1 ,P 4 Diquafosol sodium, also known as di(uridine-5')tetraphosphate or Up4U, is a purine receptor agonist that promotes tear secretion, and its salt, diquafosol sodium, is called "Diquafosol". (登録商標) 3% eye drops (hereinafter referred to as "Diquas") (登録商標) It is used to treat dry eye as an eye drop solution (also known as "eye drops") (Japanese Patent Publication No. 3652707 (Patent Document 1), Diquas) (登録商標) 3% ophthalmic solution package insert (Non-patent document 1). Diquas (登録商標) The usual dosage and administration of eye drops is one drop six times a day (Non-Patent Literature 1), but there are patients with severe dry eye who do not achieve sufficient therapeutic effect even when using the prescribed dosage and administration. Furthermore, there are patients who do not achieve the expected effect due to poor adherence to eye drop administration, as it is difficult to administer eye drops regularly and frequently in daily life. In addition, although infrequent, Diquas (登録商標) Some patients experience side effects such as eye irritation when using eye drops (Non-Patent Document 1).

[0003] As an attempt to search for new dry eye treatments with a higher tear volume increasing effect, it is known that diquafosol or a salt thereof is used in combination with existing dry eye treatments. Japanese Patent Publication No. 2012-077080 (Patent Document 2) discloses that tear secretion is synergistically promoted by using diquafosol or a salt thereof in combination with hyaluronic acid, a dry eye treatment. Japanese Patent Publication No. 2015-160826 (Patent Document 3) discloses that tear secretion is synergistically promoted by using diquafosol or a salt thereof in combination with rebamipide, a dry eye treatment. [Prior art documents]

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Non - Patent Documents

[0005]

Non - Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] It is an interesting problem to provide an aqueous ophthalmic composition that can enhance the medicinal effects of diclofasol or its salt while reducing side effects such as eye irritation.

Means for Solving the Problems

[0007] As a result of intensive research, the inventors have found that an aqueous ophthalmic composition containing diclofasol or its salt and polyvinylpyrrolidone (hereinafter also referred to as "this composition") shows a remarkable improvement in the fluorescein staining score, that is, a remarkable corneal epithelial disorder improving effect, and have clarified that polyvinylpyrrolidone enhances the medicinal effects of diclofasol or its salt. In addition, the inventors have found that this composition, which has reached a certain viscosity by containing polyvinylpyrrolidone having a certain K value, has fewer (登録商標) eye drop instillation times than the existing Dicuas eye drops and the same (登録商標)It has also been found that it exhibits a therapeutic effect equal to or higher than that of eye drops. Further, it has been found that this composition exhibits high viability of living cells and high safety for the corneal and conjunctival epithelium. Further, it has been found that this composition does not exhibit nerve irritation and can further improve the feel of eye drops. Furthermore, even when a silver salt is contained in this composition, the silver salt is stable and the composition containing the silver salt exhibits excellent preservative efficacy.

[0008] That is, the present invention relates to the following.

[0009] (1) An aqueous ophthalmic composition containing diclofasol or a salt thereof, and polyvinylpyrrolidone.

[0010] (2) The aqueous ophthalmic composition according to (1), further containing a silver salt.

[0011] (3) The aqueous ophthalmic composition according to (2), wherein the silver salt contains silver nitrate.

[0012] (4) The aqueous ophthalmic composition according to any one of (1) to (3) for the prevention or treatment of dry eye.

[0013] (5) The aqueous ophthalmic composition according to (4), containing diclofasol sodium at a concentration of 1 to 5% (w / v) and polyvinylpyrrolidone having a K value of more than 30 and not more than 120.

[0014] (6) The aqueous ophthalmic composition according to (4), containing diclofasol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of more than 30 and not more than 120.

[0015] (7) The aqueous ophthalmic composition according to (4), containing diclofasol sodium at a concentration of 1 to 5% (w / v) and having a viscosity of 1.5 to 30 mPa·s at 25°C.

[0016] (8) The aqueous ophthalmic composition according to (4), containing diclofasol sodium at a concentration of 3% (w / v) and having a viscosity of 1.5 to 30 mPa·s at 25°C.

[0017] (9) An aqueous ophthalmic composition according to any one of (5) to (8), characterized in that it is used to be administered as eye drops two to four times a day.

[0018] (10) An aqueous ophthalmic composition according to any one of (5) to (8), characterized in that it is used to be administered as eye drops three times a day.

[0019] (11) The aqueous ophthalmic composition according to (9) or (10), characterized in that it is used to be administered by instilling 1 to 2 drops at a time.

[0020] (12) An ophthalmic drug product characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition described in (1) is filled into a unit dose type eye drop container.

[0021] (13)(1) An ophthalmic drug product characterized in that 0.3 to 0.5 mL of the aqueous ophthalmic composition described in (1) is filled into a unit dose type eye drop container.

[0022] (14) An ophthalmic drug product characterized in that 1 to 10 mL of the aqueous ophthalmic composition described in any one of (1) to (3) is filled into a multi-dose eye drop container.

[0023] (15) An ophthalmic drug product characterized in that 5 mL of the aqueous ophthalmic composition described in any one of (1) to (3) is filled into a multi-dose eye drop container.

[0024] (16)(1) An ophthalmic medicinal product characterized in that 1 to 10 mL of the aqueous ophthalmic composition described in (16)(1) is filled into a PFMD container.

[0025] (17)(1) An ophthalmic drug product characterized in that 5 mL of the aqueous ophthalmic composition described in (1) is filled into a PFMD container.

[0026] (18) An ophthalmic medicinal product described in any one of (12) to (17) for the prevention or treatment of dry eye.

[0027] (19) The ophthalmic medicinal product according to (18), wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 1-5% (w / v) and polyvinylpyrrolidone with a K value greater than 30 and less than or equal to 120.

[0028] (20) The ophthalmic medicinal product according to (18), wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value greater than 30 and less than or equal to 120.

[0029] (21) The ophthalmic drug product according to (18), wherein the aqueous composition contains diquafosol sodium at a concentration of 1-5% (w / v) and has a viscosity of 1.5-30 mPa·s at 25°C.

[0030] (22) The ophthalmic drug product according to (18), wherein the aqueous composition contains diquafosol sodium at a concentration of 3% (w / v) and has a viscosity of 1.5 to 30 mPa·s at 25°C.

[0031] (23) An ophthalmic drug product according to any one of (19) to (22), characterized in that it is used to be administered as eye drops two to four times a day.

[0032] (24) An ophthalmic drug product according to any one of (19) to (22), characterized in that it is used to be administered as eye drops three times a day.

[0033] (25) The ophthalmic drug product according to (23) or (24), characterized in that it is used by administering 1 to 2 drops as eye drops at a time.

[0034] (26) An aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinylpyrrolidone with a K value of 17 or higher.

[0035] (27) An aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinylpyrrolidone having a K value of 17 to 120.

[0036] (28) An aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinylpyrrolidone with a K value greater than 30 and less than or equal to 120.

[0037] (29) An aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinylpyrrolidone with a K value of 90.

[0038] (30) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the concentration of polyvinylpyrrolidone is 0.001% (w / v) or more.

[0039] (31) The concentration of the diquafosol or its salt is 0.0001 to 10% (w / v) An aqueous ophthalmic composition according to any one of (1) to (4).

[0040] (32) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of the diquafosol or a salt thereof is 0.01 to 5% (w / v).

[0041] (33) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of the diquafosol or a salt thereof is 1 to 5% (w / v).

[0042] (34) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of the diquafosol or a salt thereof is 3% (w / v).

[0043] (35) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the pH of the aqueous ophthalmic composition is in the range of 6 to 8.

[0044] (36) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the pH of the aqueous ophthalmic composition is in the range of 7 to 8.

[0045] (37) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the aqueous ophthalmic composition is a sterile aqueous eye drop solution.

[0046] (38) An aqueous ophthalmic composition according to any one of (1) to (11), which can be stored at room temperature.

[0047] (39) The aqueous ophthalmic composition according to any one of (1) to (6), wherein the viscosity of the aqueous ophthalmic composition is 1.5 to 30 mPa·s at 25°C.

[0048] (40) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the salt of diquafosol is diquafosol sodium.

[0049] (41) An aqueous ophthalmic composition for the prevention or treatment of dry eye, characterized by being administered as eye drops of 1 to 2 drops at a time, 2 to 4 times a day, containing 3% (w / v) diquafosol sodium, polyvinylpyrrolidone with a K value of 90, and silver nitrate.

[0050] (42) An aqueous ophthalmic composition for the prevention or treatment of dry eye, characterized in that it is used by administering 1 to 2 drops at a time, 2 to 4 times a day, containing a 3% (w / v) concentration of diquafosol sodium, polyvinylpyrrolidone, and silver nitrate, wherein the viscosity is 3 to 30 mPa·s at 25°C.

[0051] (43) The aqueous ophthalmic composition according to (41) or (42), characterized in that it is used to be administered as eye drops three times a day.

[0052] (44) An ophthalmic medicated product for the prevention or treatment of dry eye, comprising 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value of 90, filled in a unit-dose type eye drop container, characterized in that the aqueous ophthalmic composition is administered by instillation at a dose of 1 to 2 drops 2 to 4 times a day.

[0053] (45) An ophthalmic medicinal product for the prevention or treatment of dry eye, wherein 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v) is filled into a unit-dose type eye drop container, wherein the aqueous ophthalmic composition An ophthalmic medicated product characterized by having a viscosity of 3 to 30 mPa·s at 25℃ and being used as eye drops, 1 to 2 drops at a time, 2 to 4 times a day.

[0054] (46) An ophthalmic medicated product for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value of 90, filled in a multi-dose eye drop container, characterized in that the aqueous ophthalmic composition is administered by instillation at a dose of 1 to 2 drops 2 to 4 times a day.

[0055] (47) An ophthalmic medicated product for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v) in a multi-dose eye drop container, characterized in that the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25°C and is used to be administered as eye drops of 1 to 2 drops at a time, 2 to 4 times a day.

[0056] (48) An ophthalmic medicated product for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value of 90, filled in a PFMD container, characterized in that the aqueous ophthalmic composition is administered as eye drops at a dose of 1 to 2 drops, 2 to 4 times a day.

[0057] (49) An ophthalmic medicated product for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v) filled in a PFMD container, characterized in that the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25°C and is used to be administered as eye drops of 1 to 2 drops at a time, 2 to 4 times a day.

[0058] (50) An ophthalmic drug product according to any one of (44) to (49), characterized in that it is used to be administered as eye drops three times a day.

[0059] (51) The ophthalmic drug product according to either (46) or (47), further comprising silver nitrate.

[0060] Furthermore, the present invention also relates to the following:

[0061] (A-1) A method for treating dry eye, comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a unit-dose eye drop container 2 to 4 times a day, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value of 90, and the unit-dose eye drop container is filled with 0.1 to 1 mL of the aqueous ophthalmic composition.

[0062] (A-2) A method for treating dry eye, comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a unit-dose eye drop container 2 to 4 times a day, wherein the aqueous ophthalmic composition contains 3% (w / v) diquafosol sodium and polyvinylpyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and the unit-dose eye drop container is filled with 0.1 to 1 mL of the aqueous ophthalmic composition.

[0063] (A-3) A method for treating dry eye comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a multi-dose eye drop container to the eye 2 to 4 times a day, wherein the aqueous ophthalmic A method for treating dry eye, comprising: a composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value of 90, wherein 1 to 10 mL of the aqueous ophthalmic composition is filled into the multi-dose eye drop container.

[0064] (A-4) A method for treating dry eye, comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a multi-dose eye drop container 2 to 4 times a day, wherein the aqueous ophthalmic composition contains 3% (w / v) diquafosol sodium and polyvinylpyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and the multi-dose eye drop container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

[0065] (A-5) A method for treating dry eye, comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a PFMD container 2 to 4 times a day, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value of 90, and the PFMD container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

[0066] (A-6) A method for treating dry eye, comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a PFMD container 2 to 4 times a day, wherein the aqueous ophthalmic composition contains 3% (w / v) diquafosol sodium and polyvinylpyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and the PFMD container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

[0067] (A-7) A method for treating dry eye according to any one of (A-1) to (A-6), comprising administering an aqueous ophthalmic composition to the patient in 1 to 2 drops at a time, 3 times a day.

[0068] (B-1) An ophthalmic medicinal product for use in the prevention or treatment of dry eye, comprising an aqueous ophthalmic composition of 0.1 to 1 mL filled in a unit dose type eye drop container, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value of 90, and is used to be administered by instilling 1 to 2 drops at a time, 2 to 4 times a day.

[0069] (B-2) An ophthalmic medicinal product for use in the prevention or treatment of dry eye, comprising an aqueous ophthalmic composition of 0.1 to 1 mL filled in a unit dose type eye drop container, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v), has a viscosity of 3 to 30 mPa·s at 25°C, and is used to administer 1 to 2 drops at a time, 2 to 4 times a day.

[0070] (B-3) An ophthalmic medicinal product for use in the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition filled in a multi-dose eye drop container, wherein the aqueous ophthalmic composition contains 3% (w / v) diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and is used to be administered by instilling 1 to 2 drops at a time, 2 to 4 times a day.

[0071] (B-4) An ophthalmic medicinal product for use in the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition filled in a multi-dose eye drop container, wherein the aqueous ophthalmic composition contains 3% (w / v) diquafosol sodium and polyvinylpyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and is used to administer 1 to 2 drops at a time, 2 to 4 times a day.

[0072] (B-5) Aqueous ophthalmic composition, 1-10 mL, used for the prevention or treatment of dry eye. An ophthalmic medicinal product filled in a PFMD container, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value of 90, and is used to be administered by instilling 1 to 2 drops at a time, 2 to 4 times a day.

[0073] (B-6) An ophthalmic medicinal product for use in the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition filled in a PFMD container, wherein the aqueous ophthalmic composition contains 3% (w / v) diquafosol sodium and polyvinylpyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and is used to be administered by instilling 1 to 2 drops at a time, 2 to 4 times a day.

[0074] (B-7) An ophthalmic drug product according to any one of (B-1) to (B-6), characterized in that the aqueous ophthalmic composition is administered by instilling 1 to 2 drops into the eye three times a day.

[0075] (C-1) Use of an aqueous ophthalmic composition containing a 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone with a K value of 90 for the manufacture of a medicament for the prevention or treatment of dry eye, characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition is filled into a unit dose type eye drop container and used to administer 1 to 2 drops at a time, 2 to 4 times a day.

[0076] (C-2) Use of an aqueous ophthalmic composition for the manufacture of a pharmaceutical for the prevention or treatment of dry eye, comprising a 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone and having a viscosity of 3 to 30 mPa·s at 25°C, characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition is filled into a unit dose type eye drop container and used to administer 1 to 2 drops at a time, 2 to 4 times a day.

[0077] (C-3) Use of an aqueous ophthalmic composition containing a 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone with a K value of 90 for the manufacture of a pharmaceutical for the prevention or treatment of dry eye, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled into a multi-dose eye drop container and used to administer 1 to 2 drops at a time, 2 to 4 times a day.

[0078] (C-4) Use of an aqueous ophthalmic composition for manufacturing a pharmaceutical for the prevention or treatment of dry eye, the aqueous ophthalmic composition containing a 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone and having a viscosity of 3 to 30 mPa·s at 25°C, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled into a multi-dose eye drop container and used to administer 1 to 2 drops at a time, 2 to 4 times a day.

[0079] (C-5) Use of an aqueous ophthalmic composition containing a 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone with a K value of 90 for the manufacture of a medicament for the prevention or treatment of dry eye, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled into a PFMD container and used to administer 1 to 2 drops at a time, 2 to 4 times a day.

[0080] (C-6) Use of an aqueous ophthalmic composition for the manufacture of a pharmaceutical for the prevention or treatment of dry eye, comprising a 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone, and having a viscosity of 3 to 30 mPa·s at 25°C, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled into a PFMD container and used to administer 1 to 2 drops at a time, 2 to 4 times a day.

[0081] (C-7) Use of the aqueous ophthalmic composition according to any one of (C-1) to (C-6), characterized in that the aqueous ophthalmic composition is administered by instilling 1 to 2 drops at a time, 3 times a day.

[0082] (D-1) A method for imparting preservative efficacy to an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone, comprising including a silver salt in the aqueous ophthalmic composition.

[0083] (D-2) A method for maintaining the preservative efficacy of an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone, comprising adding a silver salt to the aqueous ophthalmic composition.

[0084] Furthermore, two or more of the above-mentioned components of the present invention can be arbitrarily selected and combined. [Effects of the Invention]

[0085] This composition has a high tear volume increasing effect, so it is superior to existing diquas (登録商標) Compared to administering eye drops, this composition is expected to have a stronger therapeutic effect on dry eye. Therefore, this composition is expected to have a stronger therapeutic effect on dry eye than existing diquas. (登録商標) It is also expected to exhibit the same or even greater dry eye treatment effect at a lower concentration than eye drops. (登録商標) Eye drops need to be instilled six times a day, and some patients do not achieve the expected effect due to poor adherence to instillation. However, this composition, which has a certain viscosity due to containing polyvinylpyrrolidone with a certain potassium value, is an alternative to the existing Diquas (登録商標) With fewer applications than eye drops, it can be used with the existing Diquas. (登録商標) Because it provides therapeutic effects equivalent to or better than eye drops, improved adherence to eye drop use is expected.

[0086] Furthermore, this composition is expected to exhibit high cell activity, high safety for the corneal and conjunctival epithelium, and be non-irritating to nerves, potentially improving the comfort of eye drops.

[0087] Furthermore, even when silver salts are included in this composition, the silver salts remain stable and exhibit excellent preservative properties. [Brief explanation of the drawing]

[0088] [Figure 1] This graph shows the fluorescein staining score of the cornea. [Figure 2] This figure shows the results of a cytotoxicity test using corneal epithelial cells. [Figure 3] This figure shows the maximum fluorescence intensity (RFUmax) after the addition of diquafosol sodium. [Modes for carrying out the invention]

[0089] The present invention will be described in more detail.

[0090] In this specification, "(w / v)%" means the mass (g) of the target component contained in 100 mL of the aqueous ophthalmic composition of the present invention.

[0091] In this specification, "PVP" means polyvinylpyrrolidone.

[0092] In this specification, "HEC" means hydroxyethylcellulose.

[0093] In this specification, "CMC-Na" means sodium carboxymethylcellulose.

[0094] In this specification, "HPMC" means hydroxypropyl methylcellulose. .

[0095] In this specification, "CVP" means carboxyvinyl polymer.

[0096] In this specification, "diquafosol ophthalmic solution" means an aqueous ophthalmic solution containing diquafosol or a salt thereof.

[0097] In this specification, "diquafosol sodium ophthalmic solution" means an aqueous ophthalmic solution containing diquafosol sodium.

[0098] "Diquafosol" is a compound represented by the following chemical structure.

[0099] [ka]

[0100] As for "diquafosol salts," there are no particular restrictions as long as they are salts that are permitted as medicines, including metal salts with lithium, sodium, potassium, calcium, magnesium, zinc, etc.; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples include salts with organic acids such as p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; quaternary ammonium salts with methyl bromide and methyl iodide; salts with halogen ions such as bromide, chloride, and iodide; salts with ammonia; and salts with organic amines such as triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethanediamine.

[0101] In the present invention, "diquafosol or its salt" also includes diquafosol (free form) or hydrates and organic solvent hydrates of its salt.

[0102] If "diquafosol or its salts" have crystalline polymorphs and groups of crystalline polymorphs (polymorphic systems), then those crystalline polymorphs and groups of crystalline polymorphs (polymorphic systems) are also included in the scope of the present invention. Here, a group of crystalline polymorphs (polymorphic systems) refers to the manufacturing process of those crystals. This refers to the individual crystal forms at each stage and the entire process when the crystal form changes due to conditions and states such as crystallization and storage.

[0103] The preferred "diquafosol or its salt" of the present invention is the sodium salt of diquafosol, and the tetrasodium diquafosol salt (hereinafter also simply referred to as "sodium diquafosol") shown in the following chemical structural formula is particularly preferred.

[0104] [ka]

[0105] Diquafosol or its salts can be produced by methods such as those disclosed in Japanese Patent Publication No. 2001-510484.

[0106] This composition may contain active ingredients other than diquafosol or its salts, or it may contain diquafosol or its salts as the sole active ingredient.

[0107] In the present invention, the concentration of diquafosol or its salt is not particularly limited, but is preferably 0.0001 to 10% (w / v), more preferably 0.001 to 5% (w / v), even more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 5% (w / v), even more preferably 1 to 5% (w / v), and particularly preferably 3% (w / v). More specifically, 0.001%(w / v), 0.002%(w / v), 0.003%(w / v), 0.004%(w / v), 0.005%(w / v), 0.006%(w / v), 0.007%(w / v), 0.008% (w / v), 0.009%(w / v), 0.01%(w / v), 0.02%(w / v), 0.03%(w / v), 0.04%(w / v), 0.05%(w / v), 0.06%(w / v), 0.07%(w / v), 0.0 8%(w / v), 0.09%(w / v), 0.1%(w / v), 0.2%(w / v), 0.3%(w / v), 0.4%(w / v), 0.5%(w / v), 0.6%(w / v), 0.7%(w / v), 0.8%(w / v) , 0.9% (w / v), 1% (w / v), 1.5% (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v) or 5% (w / v) are preferred.

[0108] In this invention, "polyvinylpyrrolidone" is a polymer compound formed by the polymerization of N-vinyl-2-pyrrolidone and is generally used as a viscosity-reducing agent. Polyvinylpyrrolidone is also called povidone. The K value of the polyvinylpyrrolidone used in this invention is preferably 17 or higher, more preferably 17 to 120, even more preferably 25 to 120, and preferably 30 to 120. More preferably, values ​​between 30 and 120 are preferred, 40 to 120 are even more preferred, 60 to 120 are particularly preferred, 60 to 90 are especially preferred, and 90 is especially preferred. Examples include polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K40, polyvinylpyrrolidone K50, polyvinylpyrrolidone K60, polyvinylpyrrolidone K70, polyvinylpyrrolidone K80, polyvinylpyrrolidone K85, polyvinylpyrrolidone K90, and polyvinylpyrrolidone K120. The K value of polyvinylpyrrolidone is a viscosity characteristic value that correlates with molecular weight, and is a numerical value calculated by applying the relative viscosity value (25°C) measured by a capillary viscometer to Fikentscher's formula (1) below.

[0109]

number

[0110] In formula (1), η rel is the relative viscosity of the polyvinylpyrrolidone aqueous solution with respect to water, and c is the concentration (%) of polyvinylpyrrolidone in the polyvinylpyrrolidone aqueous solution.

[0111] Here, the K value is 90-108% of the indicated K value, in accordance with the description of the K value in the 17th edition of the Japanese Pharmacopoeia "Povidone". For example, "K90" refers to a viscosity characteristic value (K value) calculated by applying the above formula (1) in the range of 81-97.2.

[0112] In the present invention, polyvinylpyrrolidone may be used alone, or two or more polyvinylpyrrolidones with different K values ​​may be used in any combination.

[0113] In the present invention, the concentration of polyvinylpyrrolidone is not particularly limited, but for example, it may be 0.001% (w / v) or more, preferably 0.001 to 10% (w / v), more preferably 0.01 to 10% (w / v), even more preferably 0.05 to 10% (w / v), even more preferably 0.1 to 10% (w / v), especially preferably 0.1 to 5% (w / v), and particularly preferably 1 to 5% (w / v).

[0114] This composition may be further enriched with pharmaceutically acceptable preservatives as needed. Examples include silver salts such as silver nitrate, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, boric acid, borax, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, polydronium chloride, and polyhexanide hydrochloride.

[0115] As is clear from the test results described later, this composition containing silver salts has excellent preservative properties, and therefore, silver salts are preferred preservatives in the present invention. Examples of silver salts include silver nitrate, silver sulfate, silver chloride, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, and silver protein, but silver nitrate is preferred.

[0116] In this invention, the concentration of the silver salt is not particularly limited, and is not particularly limited as long as it is within the range of 0.00000001 to 1% (w / v). Specifically, the lower limit is, for example, 0.00000001% (w / v) or more, 0.0000001% (w / v) or more, 0.000001% (w / v) or more, 0.0000025% (w / v) or more, 0.000004% (w / v) or more, 0.000005% (w / v) or more, 0.000008% (w / v) or more, 0.00001% (w / v) or more, 0.000016% (w / v) or more, 0.000025% (w / v) or more, 0.00004% (w / v) or more, 0. Preferably, the w / v is 0.00005% or higher, 0.00008% or higher, or 0.0001% or higher. Furthermore, preferred upper limits include, for example, 1% or less, 0.5% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.005% or less, or 0.001% or less.

[0117] In addition to the aforementioned polyvinylpyrrolidone and preservatives, this composition may contain further pharmaceutically acceptable additives as needed. For example, buffering agents such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid; isotonic agents such as calcium chloride, sodium chloride, potassium chloride, and concentrated glycerin; stabilizers such as sodium edetate, sodium edetate hydrate, citric acid hydrate, and sodium citrate hydrate; surfactants such as polysorbate; antioxidants such as ascorbic acid; thickening agents (also called viscosity enhancers) such as hydroxyethylcellulose and hydroxypropyl methylcellulose; and pH adjusters such as hydrochloric acid and sodium hydroxide may be selected and added as needed. These additives may be used individually or in any combination of two or more. Note that this composition does not necessarily have to contain cellulosic polymers such as hydroxyethylcellulose and hydroxypropyl methylcellulose, which are thickening agents.

[0118] The pH of this composition is not limited to a specific value as long as it is within a pharmaceutically acceptable range. However, the pH of this composition is preferably 8 or less, more preferably in the range of 4 to 8, even more preferably in the range of 5 to 8, even more preferably in the range of 6 to 8, particularly preferably in the range of 7 to 8, and especially preferably near 7. More specifically, for example, pH 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0 are preferred, and 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0 are more preferred.

[0119] In the present invention, "ophthalmic composition" refers to a composition used for the prevention and / or treatment of eye diseases. Examples of dosage forms include eye drops, eye ointments, injections, and ointments (for example, those that can be administered to the eyelid skin), with eye drops being preferred. Here, "eye drops" is synonymous with "eye solution" or "eye medicine," and contact lens eye drops are also included in the definition of eye drops.

[0120] In the present invention, the "aqueous ophthalmic composition" is an aqueous ophthalmic composition using water as a solvent (base), and is more preferably an aqueous eye drop.

[0121] Depending on the properties and content of the active ingredients and additives, this composition may be a dissolving eye drop or a suspension eye drop.

[0122] The composition is preferably a sterile aqueous eye drop solution. Here, "sterile" means a state in which microorganisms have been killed or removed, and specifically, for example, a state that conforms to the preservative efficacy test standards described in the 17th edition of the Japanese Pharmacopoeia.

[0123] It is preferable that this composition can be stored at room temperature.

[0124] The viscosity of this composition is not particularly limited as long as it is within a range acceptable for pharmaceutical use, but for example, preferably in the range of 1 to 500 mPa·s, more preferably in the range of more than 1.4 to 100 mPa·s or less, even more preferably in the range of 1.5 to 100 mPa·s, even more preferably in the range of 1.5 to 50 mPa·s, and even more preferably in the range of 1.5 to 30 mPa·s. The viscosity of the composition is adjusted to be within the range of Pa·s, more preferably within the range of 1.5 to 20 mPa·s, particularly preferably within the range of 1.5 to 10 mPa·s, even more preferably within the range of 2 to 10 mPa·s, especially preferably within the range of 3 to 10 mPa·s, even more preferably within the range of 5 to 10 mPa·s, and still most preferably within the range of 7 to 10 mPa·s. The viscosity of the composition can also be adjusted to be within the range of 1.5 to 30 mPa·s, preferably within the range of 2 to 30 mPa·s, more preferably within the range of 3 to 30 mPa·s, even more preferably within the range of 5 to 30 mPa·s, and especially preferably within the range of 7 to 30 mPa·s. The lower limit of the viscosity of the composition is preferably, for example, 1 mPa·s or more, 1.5 mPa·s or more, 2 mPa·s or more, 3 mPa·s or more, 5 mPa·s or more, or 7 mPa·s or more. Furthermore, the upper limit is preferably, for example, 500 mPa·s or less, 100 mPa·s or less, 50 mPa·s or less, 30 mPa·s or less, 20 mPa·s or less, or 10 mPa·s or less. The viscosity of this composition is measured using a rotational viscometer (25°C; 50s). -1 It is measured by the shear rate.

[0125] The osmotic pressure of this composition is not limited to a specific value as long as it is within a range acceptable for pharmaceutical use. However, the osmotic pressure of this composition is preferably 2 or less, more preferably in the range of 0.5 to 2, even more preferably in the range of 0.7 to 1.6, even more preferably in the range of 0.8 to 1.4, and particularly preferably in the range of 0.9 to 1.2.

[0126] This composition can be stored in an airtight container, specifically in an eye drop container. Examples of eye drop containers in which this composition is filled include "multi-dose eye drop containers" or "unit-dose eye drop containers."

[0127] In the present invention, "ophthalmic medicinal product" refers to an ophthalmic medicinal product in which the composition is filled into an eye drop container. Here, "ophthalmic medicinal product" can refer to, for example, an eye drop product. The definitions of each term in "ophthalmic medicinal product" in the present invention are the same as the definitions of each term in "the composition".

[0128] In the present invention, "multi-dose eye drop container" refers to an eye drop container comprising a container body and a cap that can be attached to the container body, wherein the cap can be freely opened and resealed. The multi-dose eye drop container usually contains multiple doses of eye drop solution for use over a certain period of time. Furthermore, if the composition does not contain preservatives such as benzalkonium chloride, the composition may be contained in a PFMD (Preservative Free Multi Dose) container. The amount of the composition to be filled into the multi-dose eye drop container or PFMD container is preferably, for example, 1 to 20 mL, more preferably 1 to 15 mL, even more preferably 1 to 10 mL, even more preferably 2.5 to 10 mL, and particularly preferably 5 mL.

[0129] On the other hand, a "unit-dose eye drop container" refers to an eye drop container in which a cap is fused and sealed to the neck of the bottle, and which is intended to be opened by breaking the fused portion between the cap and the bottle body when in use. The unit-dose eye drop container contains eye drops for one or several uses. Generally, the eye drops contained in a unit-dose eye drop container do not contain preservatives such as benzalkonium chloride. Furthermore, the amount of this composition to be filled into a unit-dose eye drop container is preferably 0.1 to 1 mL, more preferably 0.1 to 0.5 mL, even more preferably 0.3 mL to 0.5 mL, and particularly preferably 0.3 mL or 0.4 mL.

[0130] The method of use of this composition can be appropriately changed depending on the dosage form, the severity of the patient's symptoms, age, weight, and the doctor's judgment. For example, if eye drops are selected as the dosage form, the single dose should be 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and especially preferably 1 drop. The eye drops can be administered 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 2 to 4 times a day, and even more preferably 3 times a day, daily to weekly. More specifically, the number of times to administer the eye drops is preferably 6 times a day, 5 times a day, 4 times a day, 3 times a day, 2 times a day, or 1 time a day; more preferably 6 times a day, 4 times a day, 3 times a day, or 2 times a day; even more preferably 4 times a day, 3 times a day, or 2 times a day; and particularly preferably 3 times a day.

[0131] Furthermore, if the concentration of diquafosol or its salt in this composition is 3% (w / v), a single dose of 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and especially preferably 1 drop, can be administered by eye instillation 6 times, 5 times, 4 times, 3 times, 2 times, or once a day, preferably 6 times, 4 times, 3 times, or 2 times a day, more preferably 4 times or 3 times a day, and especially preferably 3 times a day.

[0132] Furthermore, one drop is preferably 10 to 50 μL, more preferably 20 to 50 μL, and particularly preferably 40 to 50 μL.

[0133] This composition is used for the prevention or treatment of dry eye and is effective as a preventive or therapeutic agent for dry eye. Dry eye is defined as "a chronic disease of the tear film and corneal and conjunctival epithelium caused by various factors, accompanied by eye discomfort and visual abnormalities," and keratoconjunctivitis sicca (KCS) is included in dry eye. In this invention, the occurrence of dry eye symptoms caused by wearing soft contact lenses is also included in dry eye.

[0134] Dry eye symptoms include subjective symptoms such as dryness of the eyes, eye discomfort, eye fatigue, heaviness, photophobia, eye pain, and blurred vision, as well as objective findings such as redness and corneal and conjunctival epithelial damage. In this invention, "prevention or treatment of dry eye" also includes improvement of the aforementioned subjective symptoms and / or objective findings.

[0135] While many aspects of the etiology of dry eye remain unclear, several factors have been reported to be contributing to it, including Sjögren's syndrome; congenital anelacoa; sarcoidosis; graft-versus-host disease (GVHD) following bone marrow transplantation; ocular pemphigoid; Stevens-Johnson syndrome; lacrimal duct obstruction due to trachoma, etc.; diabetes mellitus; decreased reflex secretion due to corneal refractive surgery (LASIK: Laser(-assisted) in situ keratomileusis), etc.; meibomian gland dysfunction; decreased oil layer due to blepharitis, etc.; incomplete blinking or eyelid closure due to proptosis, lagophthalmos, etc.; decreased mucin secretion from germ cells; and VDT (Visual Display Terminal) work.

[0136] Furthermore, this composition can be instilled into the eyes of dry eye patients wearing soft contact lenses. Here, instilling into the eyes of dry eye patients wearing soft contact lenses means that the eye drops are instilled while the soft contact lenses are being worn on the cornea of ​​the dry eye patient. [Examples]

[0137] The results of pharmacological tests and examples of formulations are shown below, but these are for the purpose of better understanding the present invention and do not limit the scope of the present invention.

[0138] [Test 1] The time-dependent changes in tear volume after instillation of this composition were evaluated using normal male white rabbits.

[0139] (Sample preparation method) Eye drops 1: Ophthalmic solution 1 was prepared according to the prescription shown in Table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL of a 6-fold concentrated solution. Alternatively, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, a pH adjuster was added as needed to adjust the pH to 7, and sterile purified water was added to make 20 mL of a 3-fold concentrated solution. PVP K90 (4 g) was dissolved in sterile purified water to make a total volume of 100 g, which was then autoclaved (121 °C for 20 minutes) to obtain a 4.00% (w / w) PVP K90 solution. To prepare eye drops 1, 6.0 g of 4.00% (w / w) PVP K90 solution was mixed with 4 mL of a 3x concentrated solution, sterile purified water was added to adjust the total volume to 12 mL, and then a pH adjuster was added as needed to adjust the pH to 7.

[0140] Eye drops 2: Ophthalmic solution 2 was prepared according to the prescription shown in Table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to obtain a 6-fold concentrated solution of 50 mL. After mixing 10 mL of the 6-fold concentrated solution with 5 mL of sterile purified water, PVP K30 (1.2 g) was dissolved, and the pH was adjusted to 7 by adding a pH adjuster as appropriate. Sterile purified water was then added to make a total volume of 20 mL to obtain a 3-fold concentrated solution. Ophthalmic solution 2 was prepared by adding sterile purified water to 4 mL of the 3-fold concentrated solution to make a total volume of 12 mL, and then adjusting the pH to 7 by adding a pH adjuster as appropriate.

[0141] Eye drops 3: Ophthalmic solution 3 was prepared according to the prescription shown in Table 1. Specifically, diquafosol sodium (9g), sodium hydrogen phosphate hydrate (0.6g), sodium edetate hydrate (0.03g), and sodium chloride (1.35g) were dissolved in sterile purified water to make 50mL of a 6-fold concentrated solution. Alternatively, 10mL of the 6-fold concentrated solution was mixed with 5mL of sterile purified water, and the pH was adjusted to 7 by adding a pH adjuster as needed. Sterile purified water was then added to make 20mL of a 3-fold concentrated solution. Hydroxyethylcellulose (15g) was dissolved in 1500mL of sterile purified water and sterilized by autoclaving (121°C for 20 minutes) to obtain a 1.00% (w / w) hydroxyethylcellulose solution. 3.6g of the 1.00% (w / w) hydroxyethylcellulose solution was mixed with 4mL of the 3-fold concentrated solution, and sterile purified water was added to adjust the total volume to 12mL. Finally, a pH adjuster was added as needed to adjust the pH to 7, thereby preparing ophthalmic solution 3.

[0142] Eye drops 4: Ophthalmic solution 4 was prepared according to the prescription shown in Table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to obtain a 6-fold concentrated solution of 50 mL. Then, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and the pH was adjusted to 7 by adding a pH adjuster as appropriate. Sterile purified water was then added to make a total volume of 20 mL to obtain a 3-fold concentrated solution. Ophthalmic solution 4 was prepared by adding sterile purified water to 4 mL of the 3-fold concentrated solution to make a total volume of 12 mL, and then the pH was adjusted to 7 by adding a pH adjuster as appropriate.

[0143] Eye drops 5: Ophthalmic solution 5 was prepared according to the prescription shown in Table 1. Specifically, diquafosol sodium (18 g), sodium hydrogen phosphate hydrate (1.2 g), and sodium edetate hydrate (0.06 g) were dissolved in sterile purified water to make 100 mL of a 6-fold concentrated solution. Then, 2.5 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and after dissolving PVP K60 45% aqueous solution (0.67 g) and sodium chloride (0.068 g), a pH adjusting agent was added as needed to adjust the pH to 7. Then, sterile purified water was added to make a total volume of 15 mL to prepare eye drop solution 5.

[0144] The viscosity of the prepared eye drops 1-5 was measured according to the method described in the Seventeenth Edition of the Japanese Pharmacopoeia, 2.53 Viscosity Measurement Method, Method 2, Rotational Viscometer Method, 2.1.3 Cone-Plate Rotational Viscometer (Cone-Plate Viscometer). Specifically, a Kinexus pro+ (Malvern) was used, and the measurement conditions were set as follows: (Measurement Conditions) Rotor angle: 1° Rotor diameter: 50mm Sample volume: 0.57 mL Measurement temperature: 25℃ Shear rate: 50s -1 Measurement time: Viscosity was measured every 2 seconds, and the average value over 1 minute was used as the viscosity.

[0145] (Test methods and drug administration methods) Benoxil was administered to 16 normal male white rabbits (32 eyes in total). (登録商標) Eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were instilled, and local anesthesia was administered. Three minutes later, a Silmel test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, removed one minute after insertion, and the length of the wet area (tear volume) was read. This was used as the baseline value. Next, each eye drop 1-5 was instilled once (8 eyes in 4 animals per group, 24 eyes in 12 animals using eye drop 4 only). Three minutes before inserting the Silmel test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid, Benoxil was administered. (登録商標) Eye drops containing 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were administered, followed by local anesthesia. Sixty minutes after administration of each eye drop, a Silmel test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, removed after one minute, and the length of the wet area (tear volume) was read.

[0146] (Evaluation method) The change in tear volume before and after instillation of eye drops was calculated as Δtear volume (mm / min).

[0147] (Test results) Tables 1 and 2 show the Δtear volume (mm / min) 60 minutes after instillation (each value is the average of 8 eyes, except for eye drop solution 4, which is the average of 24 eyes). In addition, the tear volume-increasing effect of this composition was evaluated according to the following criteria. +++: Δtear volume (mm / min) 60 minutes after instillation is 4 mm / min or more ++: Δtear volume (mm / min) 60 minutes after instillation is 1 mm / min or more and less than 4 mm / min. +: Δtear volume (mm / min) 60 minutes after instillation is greater than 0 mm / min but less than 1 mm / min -: Δtear volume (mm / min) 60 minutes after instillation is 0 mm / min or less.

[0148] [Table 1]

[0149] As shown in the results in Table 1 above, the eye drops containing PVP K30 (Eye Drops 2) did not show an increase in tear volume 60 minutes after instillation, similar to the eye drops without PVP K30 (Eye Drops 4). Furthermore, although HEC is generally used as a thickening agent, the eye drops containing HEC (Eye Drops 3), despite having a relatively high viscosity, did not show an increase in tear volume 60 minutes after instillation, similar to Eye Drops 4. In contrast, the eye drops containing PVP K90 (Eye Drops 1) showed a significantly higher tear volume increase than Eye Drops 2-4.

[0150] [Table 2]

[0151] As shown in the results in Table 2 above, even with a PVP K value of 60, the eye drops containing PVP (eye drops 5) had a high tear volume increasing effect.

[0152] (Consideration) Polyvinylpyrrolidone increased the viscosity of aqueous compositions containing diquafosol or its salts, thereby enhancing the efficacy of diquafosol or its salts. In particular, it was shown that the efficacy of diquafosol or its salts was significantly enhanced when polyvinylpyrrolidone with a K value greater than 30 was added, or when the viscosity of the aqueous composition exceeded 1.4 due to the addition of polyvinylpyrrolidone.

[0153] [Exam 2] The rat extraorbital lacrimal gland excision model is widely used to evaluate the therapeutic effects of treatments for corneal epithelial damage caused by dry eye, and is also used to evaluate the therapeutic effects of P2Y2 receptor agonists (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). Using this dry eye model, we investigated whether administering this composition as eye drops would improve corneal epithelial damage.

[0154] (Method for creating a dry eye model) Using male SD rats, a rat extraorbital lacrimal gland excision model was created according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). Specifically, after administering somnopentyl to induce general anesthesia, the extraorbital lacrimal gland was excised to induce corneal epithelial damage.

[0155] (Sample preparation method) Eye drops A: Sodium hydrogen phosphate hydrate (0.2g), sodium edetate hydrate (0.01g), sodium chloride (0.45g), silver nitrate (0.00004g), polyvinylpyrrolidone K90 (2g), and diquafosol sodium (3g) were dissolved in sterile purified water to make 100mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0156] Eye drops B: Sodium hydrogen phosphate hydrate (0.2g), sodium edetate hydrate (0.01g), sodium chloride (0.45g), silver nitrate (0.00004g), and polyvinylpyrrolidone K90 (4g) were dissolved in sterile purified water to make 100mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0157] Eye drops X: Diquas, used as eye drop X, is a treatment for dry eye. (登録商標) "Ophthalmic Solution 3%" (manufactured by Santen Pharmaceutical Co., Ltd.) was used. Ophthalmic Solution X contains 30 mg of diquafosol sodium as the active ingredient in 1 mL of water, and contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium edetate hydrate, and pH adjusters as additives.

[0158] The viscosity of the prepared eye drops A, B, and X was measured according to the method described in the Seventeenth Edition of the Japanese Pharmacopoeia, 2.53 Viscosity Measurement Method, Method 2, Rotational Viscometer Method, 2.1.3 Cone-Plate Rotational Viscometer (Cone-Plate Viscometer). Specifically, a Kinexus pro+ (Malvern) was used, and the measurement conditions were set as follows. (Measurement conditions) Rotor angle: 1° Rotor diameter: 50mm Sample volume: 0.57 mL Measurement temperature: 25℃ Shear rate: 50s -1 Measurement time: Viscosity was measured every 2 seconds, and the average value over 1 minute was used as the viscosity.

[0159] The measured viscosity of each eye drop was as follows: Eye drops A: 7.9 mPa·s Eye drops B: 28.0 mPa·s Eye drops X: 0.9 mPa·s (Test methods and drug administration methods) To the rats in which the aforementioned corneal epithelial damage was induced, eye drops A, eye drops B, and eye drops X were administered as follows. • Group receiving eye drops A three times a day: Eye drops A were administered to both eyes three times a day for four weeks. (6 animals, 12 eyes per group) • Eye drop solution B, administered 3 times a day: Eye drop solution B was administered to both eyes 3 times a day for 4 weeks. (6 animals, 12 eyes per group) • Group administered eye drops X, 6 times a day: Eye drops X were administered to both eyes 6 times a day for 4 weeks. (6 animals, 12 eyes per group) Furthermore, rats that did not exhibit the aforementioned corneal epithelial damage and were kept without eye drops for 4 weeks were designated as the no-eye drop group (4 rats, 8 eyes per group).

[0160] Four weeks after initiation of eye drops, the damaged area of ​​the cornea was stained with fluorescein, and corneal epithelial damage was assessed according to the method of Murakami et al. (Atarashii Ganka, 21(1), 87-90 (2004)). Specifically, the degree of staining with fluorescein was scored for the upper, middle, and lower parts of the cornea according to the following criteria, and the average of the sum of these scores was calculated. A midpoint of 0.5 was set between scores of 0, 1, 2, and 3.

[0161] (Judgment criteria) 0: Unstained, 1: The staining is sparse, and the individual stained points are separated. 2: The staining is moderate, and some of the dotted stained areas are adjacent to each other. 3: The staining is dense, and the individual stained points are adjacent to each other.

[0162] (result) Figure 1 shows a graph of the calculated fluorescein staining scores for each group. The scores represent the mean value plus standard error for 8 or 12 samples in each group.

[0163] As is clear from Figure 1, the group receiving eye drops A three times a day showed improvement in fluorescein staining scores starting two weeks after the start of eye drops compared to the group receiving eye drops B three times a day. The group receiving eye drops X six times a day showed improvement in fluorescein staining scores four weeks after the start of eye drops compared to the group receiving eye drops B three times a day. After four weeks of eye drops, the group receiving eye drops A three times a day and the group receiving eye drops X six times a day showed similar efficacy.

[0164] (Consideration) Eye drops X is "Diquas" (登録商標) It is used as a 3% eye drop solution for the treatment of dry eye, and the number of times it is administered is six times a day. However, it has been shown that this composition, to which polyvinylpyrrolidone K90 is added, provides sufficient therapeutic effect for dry eye with three administrations per day, and in particular, two weeks after the start of administration, "Diquas" (登録商標) A therapeutic effect superior to that of administering "3% eye drops" six times a day was observed. Therefore, this composition is superior to the existing Diquas. (登録商標) With fewer applications than eye drops, it can be used with the existing Diquas. (登録商標) It was shown to produce therapeutic effects equivalent to or better than eye drops. In particular, considering the results of Test 1, it was shown that instilling this composition with polyvinylpyrrolidone with a K value greater than 30, or this composition with a viscosity greater than 1.4 due to the addition of polyvinylpyrrolidone, 2 to 4 times a day is equivalent to the existing "Diquas" (登録商標) The results suggested that it could produce a therapeutic effect equivalent to or better than administering 3% eye drops six times a day.

[0165] [Exam 3] To investigate the effects of this composition on corneal epithelial cells, a test was conducted to assess its cytotoxicity to corneal epithelial cells.

[0166] (Sample preparation method) Ophthalmic solutions Y, C, and D were prepared according to the prescriptions shown in Table 3.

[0167] Eye drops Y: Ophthalmic solution Y was prepared according to the prescription shown in Table 3. Specifically, sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), and diquafosol sodium (3 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0168] Eye drops C and D: Eye drops C and D were prepared in the same manner as eye drop Y, according to the prescriptions shown in Table 3.

[0169] The viscosity of the prepared eye drops Y, C, and D was measured according to the method described in the Seventeenth Edition of the Japanese Pharmacopoeia, 2.53 Viscosity Measurement Method, Method 2, Rotational Viscometer Method, 2.1.3 Cone-Plate Rotational Viscometer (Cone-Plate Viscometer). Specifically, a Kinexus pro+ (Malvern) was used, and the measurement conditions were set as follows. (Measurement conditions) Rotor angle: 1° Rotor diameter: 50mm Sample volume: 0.57 mL Measurement temperature: 25℃ Shear rate: 50s -1 Measurement time: Viscosity was measured every 2 seconds, and the average value over 1 minute was used as the viscosity.

[0170] [Table 3]

[0171] (Test method) SV40 immortalized human corneal epithelial cells (HCE-T: RIKEN, BioResource Center, Cell No.: RCB2280) were seeded in a 96-well plate (1 × 10⁶). 4 Cells were placed in wells and cultured for 1 day in D-MEM / F12 medium containing 10% FBS. The following day, the medium was replaced with eye drops Y, eye drops C, or eye drops D, and the corneal epithelial cells were cultured for 5, 10, and 15 minutes. Cell activity (corresponding to absorbance at 490 nm) was measured using the Cell Proliferation Assay Kit (Promega, catalog number: G3580).

[0172] (result) The test results are shown in Figure 2.

[0173] As is clear from Figure 2, diquafosol eye drops containing polyvinylpyrrolidone (eye drops C and D) maintained a high survival rate in immortalized human corneal epithelial cells even after 15 minutes of culture. On the other hand, diquafosol eye drops without polyvinylpyrrolidone (eye drop Y) showed a decrease in survival rate over time.

[0174] (Consideration) Diquafosol eye drops containing polyvinylpyrrolidone exhibit high viable cell activity in cultured immortalized human corneal epithelial cells, making them safer for the corneal and conjunctival epithelium and useful for treating diseases where the corneal and conjunctival epithelium is unstable, such as dry eye.

[0175] [Exam 4] The irritant effect of diquafosol sodium on peripheral nerves in the presence of PVP was investigated.

[0176] (Sample preparation method) Prescription solution 1: Formula 1 was prepared according to the formulation table shown in Table 4. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100 mL to obtain a 10-fold buffer solution. PVP K30 (16 g) was dissolved in sterile purified water, the total volume was adjusted to 200 mL to obtain an 8% PVP K30 aqueous solution. 2 mL of the 10-fold buffer solution and 5 mL of the 8% PVP K30 aqueous solution were measured out, the total volume was adjusted to 20 mL with sterile purified water, and the pH was adjusted to 7.5 using a pH adjuster to obtain Formula 1.

[0177] Prescription solution 2: Formula 2 was prepared according to the formulation table shown in Table 4. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjusting agent was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100 mL to obtain a 10-fold buffer solution. 2 mL of the 10-fold buffer solution and PVP K90 (0.4 g) were dissolved in sterile purified water, the pH was adjusted to 7.5 using a pH adjusting agent, and the total volume was adjusted to 20 mL to obtain Formula 2.

[0178] Prescription solution 3: Formula 3 was prepared according to the formulation table shown in Table 4. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100 mL to obtain a 10-fold buffer solution. 2 mL of the 10-fold buffer solution and sodium chondroitin sulfate (0.06 g) were added to sterile purified water, the pH was adjusted to 7.5 using a pH adjuster, dissolution was confirmed, and the total volume was adjusted to 20 mL to obtain Formula 3.

[0179] Prescription solutions 4-6: Preparations 4-6 were prepared in the same manner as preparation 3, according to the prescription table shown in Table 4.

[0180] [Table 4]

[0181] (Test method) Cultured peripheral nerve cells (rat dorsal root ganglion neurons, purchased from Lonza Japan) were incubated in a buffer solution containing an intracellular calcium-indicating fluorescent dye (FLIPR Calcium 6 Assay Kit, Molecular Devices). 40% of the total buffer volume was replaced with the above-mentioned formulation solutions. The unstimulated group and the stimulated control group were treated similarly with buffer instead of the formulation solutions. After standing at room temperature, time-course fluorescence measurements of the calcium-indicating dye were started using a fluorescence plate reader. Diquafosol sodium (final concentration: 0.3%) was added 60 seconds after the start, and fluorescence intensity measurements were continued.

[0182] (Evaluation method) The fluorescence intensity (RFU) immediately before the addition of diquafosol sodium was set to 100%, and the maximum fluorescence intensity (RFUmax) after addition was calculated.

[0183] (Test results) The results are shown in Figure 3. In the stimulating control group and formulations 3-6, RFU increased after the addition of diquafosol sodium, recording an RFUmax of 103.5% or higher. On the other hand, in formulations 1 and 2, which contained PVP, the RFUmax was less than 101% in all groups.

[0184] (Consideration) Peripheral nerve cells that receive a stimulus generate an action potential and become excited, and the stimulus signal converted into an action potential is then transmitted to the central nervous system. An action potential is a change in cell membrane potential caused by the influx of cations, including calcium ions, into the cell. Therefore, an increase in intracellular calcium ion concentration in nerve cells is widely used experimentally as an indicator of the excited state of nerve cells. When peripheral nerve cells were exposed to diquafosol sodium, a rapid increase in the fluorescence intensity of intracellular calcium ions was observed, indicating that the nerve cells received diquafosol sodium as a stimulus and became excited. Similar stimulus responses were observed in each of the polymer formulations 3-6, which were used as comparative examples and did not affect the nerve stimulant properties of diquafosol sodium. In contrast, under formulations 1 and 2, which contained PVP, no increase in intracellular calcium ion signaling was observed after the addition of diquafosol sodium. In other words, diquafosol sodium in the presence of PVP did not exhibit nerve irritant effects, suggesting that the addition of PVP improved the comfort level of diquafosol sodium eye drops.

[0185] [Exam 5] The effect of this composition on the stability of preservatives was investigated.

[0186] (Sample preparation method) Eye drops 6: Ophthalmic solution 6 was prepared according to the formulation shown in Table 5. Specifically, diquafosol sodium (3 g), chlorhexidine gluconate (0.0025 g), hydroxyethylcellulose (0.2 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), and sodium chloride (0.45 g) were dissolved in water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0187] Eye drops 7-10: Ophthalmic solutions 7-10 were prepared in the same manner as ophthalmic solution 6, according to the prescriptions shown in Table 5.

[0188] [Table 5]

[0189] (Test method) The chlorhexidine gluconate content of eye drops 6 and 7 was quantified using high-performance liquid chromatography (HPLC) after storage at 60°C for up to 4 weeks, and the remaining percentage (%) was calculated. The chlorhexidine gluconate content of eye drops 8 and 9 was quantified using high-performance liquid chromatography (HPLC) after storage at 60°C for up to 2 weeks, and the remaining percentage (%) was calculated. The silver nitrate content of eye drops 10 was quantified using inductively coupled plasma emission spectroscopy (ICP-AES) after storage at 60°C for up to 4 weeks, and the remaining percentage (%) was calculated.

[0190] (Test results) The results of the stability test are shown in Table 6.

[0191] [Table 6]

[0192] (Consideration) In an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone (the Composition), when chlorhexidine gluconate was included as a preservative, its retention rate decreased significantly (eye drops 7-9). On the other hand, when silver nitrate, a silver salt, was included as a preservative, the retention rate was high (eye drops 10). From the above, it was shown that the Composition destabilizes chlorhexidine gluconate while stabilizing silver salts.

[0193] [Exam 6] The preservative efficacy of this composition containing silver salts was investigated.

[0194] (Sample preparation method) Eye drops 11: Ophthalmic solution 11 was prepared according to the formulation shown in Table 7. Specifically, diquafosol sodium (3 g), silver nitrate (0.00008 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K30 (2 g), concentrated glycerin (1.2 g), and hydroxyethylcellulose (0.25 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0195] Eye drops 12-15: Each of the eye drops 12-15 was prepared in the same manner as eye drop 11, according to the prescriptions shown in Table 7.

[0196] [Table 7]

[0197] (Test method) The preservative efficacy test was conducted in accordance with the preservative efficacy test method of the 17th edition of the Japanese Pharmacopoeia. In this test, Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis) were used as test bacteria.

[0198] (Test results) The test results are shown in Table 8.

[0199] [Table 8]

[0200] Table 8 shows the test results, with log reduction indicating the extent to which the number of viable bacteria at the time of testing decreased compared to the number of inoculated bacteria. For example, a value of "1" indicates that the number of viable bacteria at the time of testing decreased to 10% of the number of inoculated bacteria.

[0201] As shown in Table 8, this composition containing silver salts was shown to conform to the preservative efficacy test standards of the Japanese Pharmacopoeia.

[0202] (Consideration) The results above demonstrate that this composition containing silver salts has excellent preservative properties.

[0203] [Exam 7] The time course of tear volume 90 minutes after instillation of this composition was evaluated using normal male white rabbits.

[0204] (Sample preparation method) Eye drops 16: For eye drops 16, sodium hydrogen phosphate hydrate (0.2g), sodium edetate hydrate (0.01g), sodium chloride (0.45g), silver nitrate (0.00004g), polyvinylpyrrolidone K90 (2g), and diquafosol sodium (3g) were dissolved in sterile purified water to make 100mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0205] Eye drops 17: Diquas, used as eye drop 17 and as a treatment for dry eye. (登録商標) The eye drops used were "3% Ophthalmic Solution" (manufactured by Santen Pharmaceutical Co., Ltd.). Ophthalmic Solution 17 contains 30 mg of diquafosol sodium as the active ingredient in 1 mL of water, and the additives include potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, and sodium edetate. Contains um hydrate and pH adjusters.

[0206] (Test methods and drug administration methods) Benoxil was administered to normal male white rabbits (12 rabbits, 24 eyes in total). (登録商標) Eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were instilled, and local anesthesia was administered. Three minutes later, a Silmel test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, and after one minute it was removed. The length of the wet area (tear volume) was read. This was used as the baseline value. Next, eye drops 16 and 17 were instilled once each (12 eyes in a group of 6 animals). Three minutes before inserting the Silmel test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid, Benoxil was administered. (登録商標) Eye drops containing 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were administered, followed by local anesthesia. Ninety minutes after administration of each eye drop, a Silmel test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, removed after one minute, and the length of the wet area (tear volume) was measured.

[0207] (Evaluation method) The change in tear volume before and after instillation of eye drops was calculated as Δtear volume (mm / min).

[0208] (Test results) Table 9 shows the Δtear volume (mm / min) 90 minutes after instillation (each value is the average value for 12 eyes). Furthermore, the tear volume-increasing effect of this composition was evaluated according to the following criteria. +++: Δtear volume (mm / min) 90 minutes after instillation is 4 mm / min or more ++: Δtear volume (mm / min) 90 minutes after instillation is 1 mm / min or more and less than 4 mm / min +: Δtear volume (mm / min) 90 minutes after instillation is greater than 0 mm / min but less than 1 mm / min -: Δtear volume (mm / min) 90 minutes after instillation is 0 mm / min or less.

[0209] [Table 9]

[0210] As shown in the results in Table 9 above, this composition exhibited a high tear volume-increasing effect even 90 minutes after instillation.

[0211] [Test 8] The preservative efficacy of this composition containing silver salts was investigated.

[0212] (Sample preparation method) Eye drops 18: Ophthalmic solution 18 was prepared according to the formulation shown in Table 10. Specifically, diquafosol sodium (3 g), silver nitrate (0.00003 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K90 (2 g), and sodium chloride (0.45 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.0.

[0213] Eye drops 19: Ophthalmic solution 19 was prepared in the same manner as ophthalmic solution 18, according to the prescription shown in Table 10.

[0214] [Table 10]

[0215] (Test Method) The preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 17th revised Japanese Pharmacopoeia. In this test, Esherichia Coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis) were used as test bacteria.

[0216] (Test Results) The test results are shown in Table 11.

[0217] [Table 11]

[0218] Note that the test results in Table 11 show the degree of reduction of the viable bacteria count at the time of inspection compared to the inoculated bacteria count in terms of log reduction. For example, in the case of "1", it indicates that the viable bacteria count at the time of inspection has decreased to 10% of the inoculated bacteria count. The viable bacteria count has decreased to 10% of the inoculated bacteria count.

[0219] As shown in Table 11, the composition containing the silver salt was shown to meet the preservation efficacy test criteria of the Japanese Pharmacopoeia regardless of the presence or absence of EDTA.

[0220] (Discussion) From the above results, it was shown that the composition containing the silver salt has excellent preservation efficacy.

[0221] [Test 9] The preservation efficacy of the composition containing the silver salt was examined.

[0222] (Sample Preparation Method) Eye drops 20: Ophthalmic solution 20 was prepared according to the formulation shown in Table 12. Specifically, diquafosol sodium (3 g), silver nitrate (0.00004 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K90 (2 g), and sodium chloride (0.45 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0223] Eye drops 21-23: Each of the eye drops, 21-23, was prepared in the same manner as eye drop 20, according to the prescriptions shown in Table 12.

[0224] [Table 12]

[0225] (Test method) The preservative efficacy test was conducted in accordance with the preservative efficacy test method of the 17th edition of the Japanese Pharmacopoeia. In this test, Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis) were used as test bacteria.

[0226] (Test results) The test results are shown in Table 13.

[0227] [Table 13]

[0228] The test results in Table 13 show the log reduction, indicating how much the number of viable bacteria at the time of testing decreased compared to the number of inoculated bacteria. For example, a value of "1" indicates that the number of viable bacteria at the time of testing decreased to 10% of the number of inoculated bacteria.

[0229] As shown in Table 13, the present composition containing a silver salt was shown to comply with the storage efficacy test criteria of the Japanese Pharmacopoeia regardless of the presence or absence of EDTA. Also, as the silver salt, in addition to silver nitrate, in eye drops containing silver phosphate or silver chloride, it was shown to comply with the storage efficacy test criteria of the Japanese Pharmacopoeia.

[0230] (Discussion) From the above results, it was shown that the present composition containing a silver salt has excellent storage efficacy.

[0231] [Test 10] The effect of the present composition on the stability of the preservative was examined.

[0232] (Sample Preparation Method) Eye Drop 24: Disodium guaiazulene sulfonate (3 g), sodium edetate hydrate (0.01 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.45 g), polyvinylpyrrolidone K90 (2 g), silver nitrate (0.00004 g) were dissolved in water to make 100 mL, and a pH adjuster (q.s.) was added to make the pH 7.5, and Eye Drop 24 was prepared.

[0233] (Test Method) When Eye Drop 24 was stored at 40°C for up to 6 months, the content of silver nitrate was quantified using high-frequency inductively coupled plasma optical emission spectrometry (ICP-AES), and its residual rate (%) was calculated.

[0234] (Test Results) The results of the stability test are shown in Table 14.

[0235] [Table 14]

[0236] (Discussion) When silver nitrate, which is a silver salt, was contained as a preservative, its residual rate was high. From the above, it was shown that the silver salt is stable in the present composition.

[0237] [Examples of formulations] The present invention will be described in more detail with reference to examples of formulations, but the present invention is not limited to these examples.

[0238] (Example prescription 1: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic drug product. Alternatively, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0239] (Example prescription 2: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K60 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic drug product. Alternatively, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0240] (Prescription example 3: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K40 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic drug product. Alternatively, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0241] (Prescription example 4: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0242] (Prescription example 5: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K60 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0243] (Prescription example 6: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K40 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0244] (Prescription example 7: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Polyvinylpyrrolidone K90 0.0001~10g pH adjuster (appropriate amount) The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to a sterile purified solution and mixing them thoroughly. 1 to 10 mL of the above eye drops can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic drug product. Alternatively, 0.1 to 1 mL of the above eye drops can be filled into a unit-dose eye drop container to manufacture an ophthalmic drug product. The above eye drops can be stored at room temperature.

[0245] (Prescription example 8: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Polyvinylpyrrolidone K60 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic drug product. Alternatively, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0246] (Prescription example 9: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Polyvinylpyrrolidone K40 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic drug product. Alternatively, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0247] (Prescription example 10: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution is administered in a multi-dose form. The eye drops can be filled into eye containers to manufacture ophthalmic medicinal products. Furthermore, the above eye drops can be stored at room temperature.

[0248] (Prescription example 11: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Polyvinylpyrrolidone K60 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0249] (Prescription example 12: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Polyvinylpyrrolidone K40 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0250] (Prescription example 13: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Citric acid hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic drug product. Alternatively, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature.

[0251] (Prescription example 14: Sterile aqueous eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Citric acid hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above-mentioned ingredients to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to manufacture an ophthalmic drug product. The above eye drop solution can be stored at room temperature. [Industrial applicability]

[0252] Existing Zikuas (登録商標) While eye drops need to be administered six times a day, some patients with severe dry eye do not achieve sufficient therapeutic effects even when using the prescribed dosage and administration. Furthermore, some patients do not achieve the expected effects due to poor adherence to eye drop administration. This composition addresses the issue of the existing Diquas (登録商標) In addition to providing a stronger dry eye treatment effect than eye drops, it is also expected to improve eye drop adherence by reducing the frequency of application. Furthermore, this composition is based on the existing Diquas (登録商標) It is also expected that this method can produce a similar or even greater therapeutic effect on dry eye at a lower concentration than eye drops.

[0253] Furthermore, this composition is expected to exhibit high cell activity, high safety for the corneal and conjunctival epithelium, and be non-irritating to nerves, potentially improving the comfort of eye drops.

[0254] Furthermore, even when silver salts are included in this composition, the silver salts remain stable and exhibit excellent preservative properties.

Claims

1. An aqueous ophthalmic composition containing diquafosol or a salt thereof, and polyvinylpyrrolidone.

2. Furthermore, the aqueous ophthalmic composition according to claim 1, further containing a silver salt.

3. The aqueous ophthalmic composition according to claim 2, wherein the silver salt contains silver nitrate.

4. An aqueous ophthalmic composition according to any one of claims 1 to 3 for the prevention or treatment of dry eye.

5. The aqueous ophthalmic composition according to claim 4, comprising diquafosol sodium at a concentration of 1-5% (w / v) and polyvinylpyrrolidone with a K value greater than 30 and less than or equal to 120.

6. The aqueous ophthalmic composition according to claim 4, comprising a 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone with a K value greater than 30 and less than or equal to 120.

7. The aqueous ophthalmic composition according to claim 4, comprising diquafosol sodium at a concentration of 1-5% (w / v) and having a viscosity of 1.5-30 mPa·s at 25°C.

8. The aqueous ophthalmic composition according to claim 4, comprising 3% (w / v) diquafosol sodium and having a viscosity of 1.5 to 30 mPa·s at 25°C.

9. An aqueous ophthalmic composition according to any one of claims 5 to 8, characterized in that it is used to be administered as eye drops two to four times a day.

10. An aqueous ophthalmic composition according to any one of claims 5 to 8, characterized in that it is used to be administered as eye drops three times a day.

11. The aqueous ophthalmic composition according to claim 9 or 10, characterized in that it is used to be administered by instilling one to two drops into the eye at a time.

12. An ophthalmic drug product characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition described in claim 1 is filled into a unit dose type eye drop container.

13. An ophthalmic drug product characterized in that 0.3 to 0.5 mL of the aqueous ophthalmic composition described in claim 1 is filled into a unit dose type eye drop container.

14. An ophthalmic drug product characterized in that 1 to 10 mL of the aqueous ophthalmic composition according to any one of claims 1 to 3 is filled into a multi-dose eye drop container.

15. An ophthalmic drug product characterized in that 5 mL of the aqueous ophthalmic composition described in any one of claims 1 to 3 is filled into a multi-dose eye drop container.

16. An ophthalmic medicinal product characterized in that 1 to 10 mL of the aqueous ophthalmic composition described in claim 1 is filled into a PFMD container.

17. An ophthalmic medicinal product characterized in that 5 mL of the aqueous ophthalmic composition described in claim 1 is filled into a PFMD container.

18. An ophthalmic medicinal product according to any one of claims 12 to 17, for the prevention or treatment of dry eye.

19. The ophthalmic medicinal product according to claim 18, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 1-5% (w / v) and polyvinylpyrrolidone with a K value greater than 30 and less than or equal to 120.

20. The ophthalmic medicinal product according to claim 18, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone with a K value greater than 30 and less than or equal to 120.

21. The ophthalmic medicinal product according to claim 18, wherein the aqueous composition contains diquafosol sodium at a concentration of 1 to 5% (w / v) and has a viscosity of 1.5 to 30 mPa·s at 25°C.

22. The ophthalmic medicinal product according to claim 18, wherein the aqueous composition contains diquafosol sodium at a concentration of 3% (w / v) and has a viscosity of 1.5 to 30 mPa·s at 25°C.

23. An ophthalmic drug product according to any one of claims 19 to 22, characterized in that it is used to be administered as eye drops two to four times a day.

24. An ophthalmic drug product according to any one of claims 19 to 22, characterized in that it is used to be administered as eye drops three times a day.

25. The ophthalmic drug product according to claim 23 or 24, characterized in that it is used by administering one to two drops as eye drops at a time.

26. An aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone with a K value of 17 or higher.

27. An aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 17 to 120.

28. An aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone with a K value greater than 30 and less than or equal to 120.

29. An aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone with a K value of 90.

30. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the concentration of the polyvinylpyrrolidone is 0.001% (w / v) or more.

31. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of the diquafosol or a salt thereof is 0.0001 to 10% (w / v).

32. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of the diquafosol or a salt thereof is 0.01 to 5% (w / v).

33. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of the diquafosol or a salt thereof is 1 to 5% (w / v).

34. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of the diquafosol or a salt thereof is 3% (w / v).

35. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the pH of the aqueous ophthalmic composition is in the range of 6 to 8.

36. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the pH of the aqueous ophthalmic composition is in the range of 7 to 8.

37. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the aqueous ophthalmic composition is a sterile aqueous eye drop solution.

38. An aqueous ophthalmic composition according to any one of claims 1 to 11, which can be stored at room temperature.

39. The aqueous ophthalmic composition according to any one of claims 1 to 6, wherein the viscosity of the aqueous ophthalmic composition is 1.5 to 30 mPa·s at 25°C.

40. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the salt of diquafosol is sodium diquafosol.

41. An ophthalmic medicated product for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition containing a 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone with a K value of 90, filled in a multi-dose eye drop container, characterized in that the aqueous ophthalmic composition is administered as eye drops in 1 to 2 drops 2 to 4 times a day.

42. An ophthalmic medicated product for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition containing a 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone, filled in a multi-dose eye drop container, characterized in that the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25°C and is used to be administered as eye drops of 1 to 2 drops 2 to 4 times a day.

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