JP7614069B2 - Aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone - Google Patents

Description

The present invention relates to an aqueous ophthalmic composition containing diquafosol or a salt thereof, and polyvinylpyrrolidone.

Diquafosol is a purine receptor agonist also called P ¹ ,P ⁴ -di(uridine-5′)tetraphosphate or Up4U, and has a lacrimal secretion promoting effect. Its salt, diquafosol sodium, is used as “Diquas ^{(registered trademark)} ophthalmic solution 3%” (hereinafter also referred to as “Diquas ^{(registered trademark)} ophthalmic solution”) for the treatment of dry eye (Japanese Patent No. 3652707 (Patent Document 1), Diquas ^{(registered trademark)} ophthalmic solution 3% package insert (Non-Patent Document 1)). The dosage of Diquas ^{(registered trademark)} ophthalmic solution is usually one drop at a time, six times a day (Non-Patent Document 1), but there are some severe dry eye patients who do not obtain sufficient therapeutic effects even when using the prescribed dosage. Furthermore, there are situations in daily life where it is difficult to regularly and frequently apply eye drops every day, and there are also patients who do not obtain the expected effects due to poor adherence to eye drops. In addition, although the frequency is low, some patients complain of side effects such as eye irritation due to the use of Diquas ^{(registered trademark)} eye drops (Non-Patent Document 1).

In an attempt to find a new dry eye treatment with a higher tear volume increasing effect, it is known to use diquafosol or a salt thereof in combination with an existing dry eye treatment. JP 2012-077080 A (Patent Document 2) discloses that the combined use of diquafosol or a salt thereof and hyaluronic acid, a dry eye treatment, synergistically promotes tear secretion. JP 2015-160826 A (Patent Document 3) discloses that the combined use of diquafosol or a salt thereof and rebamipide, a dry eye treatment, synergistically promotes tear secretion.

Patent No. 3652707 JP 2012-077080 A JP 2015-160826 A

Diquas (registered trademark) eye drops 3% package insert

It is an interesting task to provide an aqueous ophthalmic composition that can enhance the efficacy of diquafosol or its salt while reducing side effects such as eye irritation.

As a result of intensive research, the inventors have found that an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone (hereinafter also referred to as "the composition") exhibits a significant improvement in fluorescein staining score, i.e., a significant effect of improving corneal epithelial damage, and have clarified that polyvinylpyrrolidone enhances the efficacy of diquafosol or a salt thereof. In addition, the inventors have also found that the composition, which has a certain viscosity due to the inclusion of polyvinylpyrrolidone having a certain K value, exhibits a therapeutic effect equivalent to or greater than that of existing Diquas ^{(registered trademark)} ophthalmic solutions with fewer instillations than existing Diquas ^{(registered trademark)} ophthalmic solutions. It has also been found that the composition exhibits high viable cell activity and is highly safe for the corneal and conjunctival epithelium. It has also been found that the composition does not exhibit nerve irritation and can further improve the feeling of application of the ophthalmic solution. Furthermore, it has also been found that even if a silver salt is contained in the composition, the silver salt is stable, and the composition containing a silver salt exhibits excellent preservative efficacy.

That is, the present invention relates to the following:

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

(2) The aqueous ophthalmic composition according to (1), further comprising a silver salt.

(3) The aqueous ophthalmic composition according to (2), wherein the silver salt comprises silver nitrate.

(4) An aqueous ophthalmic composition according to any one of (1) to (3) for preventing or treating dry eye.

(5) The aqueous ophthalmic composition according to (4), which contains diquafosol 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.

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

(7) The aqueous ophthalmic composition according to (4), which 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.

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

(9) The aqueous ophthalmic composition according to any one of (5) to (8), which is administered by instillation two to four times a day.

(10) The aqueous ophthalmic composition according to any one of (5) to (8), which is administered by eye drop administration three times a day.

(11) The aqueous ophthalmic composition according to (9) or (10), which is administered by instillation at a rate of 1 to 2 drops at a time.

(12) An ophthalmologist's medicinal product, characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition described in (1) is filled in a unit dose eye drop container.

(13) An ophthalmologist's medicinal product, characterized in that 0.3 to 0.5 mL of the aqueous ophthalmic composition described in (1) is filled in a unit dose eye drop container.

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

(15) An ophthalmologist's medicinal product, characterized in that 5 mL of the aqueous ophthalmic composition described in any one of (1) to (3) is filled in a multi-dose eye drop container.

(16) An ophthalmologist's medicinal product, characterized in that 1 to 10 mL of the aqueous ophthalmic composition described in (1) is filled in a PFMD container.

(17) An ophthalmologist's medicinal product, characterized in that 5 mL of the aqueous ophthalmic composition described in (1) is filled in a PFMD container.

(18) An ophthalmologist's medicinal product according to any one of (12) to (17) for preventing or treating dry eye.

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

(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 having a K value of more than 30 and less than or equal to 120.

(21) The ophthalmic medicinal product according to (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 (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 medicinal product according to any one of (19) to (22), which is administered by eye drop administration two to four times a day.

(24) An ophthalmic medicinal product according to any one of (19) to (22), which is administered by eye drop administration three times a day.

(25) An ophthalmic medicinal product according to (23) or (24), characterized in that it is administered by instillation at a rate of 1 to 2 drops at a time.

(26) The aqueous ophthalmic composition according to any one of (1) to (4), which contains polyvinylpyrrolidone having a K value of 17 or more.

(27) The aqueous ophthalmic composition according to any one of (1) to (4), which contains polyvinylpyrrolidone having a K value of 17 to 120.

(28) The aqueous ophthalmic composition according to any one of (1) to (4), which contains polyvinylpyrrolidone having a K value of more than 30 and not more than 120.

(29) The aqueous ophthalmic composition according to any one of (1) to (4), which contains polyvinylpyrrolidone having a K value of 90.

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

(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).

(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).

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

(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.

(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.

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

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

(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.

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

(41) An aqueous ophthalmic composition for preventing or treating dry eye, comprising diquafosol sodium at a concentration of 3% (w/v), polyvinylpyrrolidone having a K value of 90, and silver nitrate, characterized in that the composition is administered in the form of 1 to 2 drops at a time, 2 to 4 times a day.

(42) An aqueous ophthalmic composition for preventing or treating dry eye, which contains diquafosol sodium at a concentration of 3% (w/v), polyvinylpyrrolidone, and silver nitrate, and is administered by instillation at a rate of 1 to 2 drops at a time, 2 to 4 times a day, and has a viscosity of 3 to 30 mPa·s at 25°C.

(43) The aqueous ophthalmic composition according to (41) or (42), which is administered by eye drop administration three times a day.

(44) An ophthalmologist's medicinal product for preventing or treating dry eye, which is a unit-dose eye dropper filled with 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, and is characterized in that the aqueous ophthalmic composition is administered by instillation in an amount of 1 to 2 drops at a time, 2 to 4 times a day.

(45) An ophthalmologist's medicinal product for preventing or treating dry eye, comprising a unit-dose eye drop container filled with 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone, the aqueous ophthalmic composition having a viscosity of 3 to 30 mPa·s at 25°C and being administered as 1 to 2 drops at a time, 2 to 4 times a day.

(46) An ophthalmologist's medicinal product for preventing or treating dry eye, which is a multi-dose eye dropper filled with 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, and is characterized in that the aqueous ophthalmic composition is administered by instillation in an amount of 1 to 2 drops at a time, 2 to 4 times a day.

(47) An ophthalmologist's medicinal product for preventing or treating dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone filled in a multi-dose eye dropper container, the aqueous ophthalmic composition having a viscosity of 3 to 30 mPa·s at 25°C, and being administered as 1 to 2 drops at a time, 2 to 4 times a day.

(48) An ophthalmologist's medicinal product for preventing or treating dry eye, in which 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 is filled in a PFMD container, and the aqueous ophthalmic composition is administered by instillation in an amount of 1 to 2 drops at a time, 2 to 4 times a day.

(49) An ophthalmologist's medicinal product for preventing or treating dry eye, in which 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone is filled in a PFMD container, the aqueous ophthalmic composition having a viscosity of 3 to 30 mPa·s at 25°C, and is used by instilling 1 to 2 drops at a time, 2 to 4 times a day.

(50) An ophthalmic medicinal product according to any one of (44) to (49), which is administered by eye drop administration three times a day.

(51) An ophthalmic medicinal product according to any one of (46) or (47), further comprising silver nitrate.

The present invention also relates to the following:

(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, the aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and the unit-dose eye drop container being filled with 0.1 to 1 mL of the aqueous ophthalmic composition.

(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, the aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v), having a viscosity of 3 to 30 mPa·s at 25°C, and the unit-dose eye drop container being filled with 0.1 to 1 mL of the aqueous ophthalmic composition.

(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 at a time, 2 to 4 times a day, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and the multi-dose eye drop container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

(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 at a time, 2 to 4 times a day, the aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v), having a viscosity of 3 to 30 mPa·s at 25°C, and the multi-dose eye drop container being filled with 1 to 10 mL of the aqueous ophthalmic composition.

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

(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 at a time, 2 to 4 times a day, 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 the PFMD container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

(A-7) A method for treating dry eye according to any one of (A-1) to (A-6), comprising administering 1 to 2 drops of the aqueous ophthalmic composition to a patient three times a day.

(B-1) An ophthalmologist's medicinal product used for preventing or treating dry eye, in which 0.1 to 1 mL of an aqueous ophthalmic composition is filled in a unit-dose eye dropper container, the aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90, and is administered by instillation in the form of 1 to 2 drops at a time, 2 to 4 times a day.

(B-2) An ophthalmologist's medicinal product used for preventing or treating dry eye, in which 0.1 to 1 mL of an aqueous ophthalmic composition is filled in a unit-dose eye dropper container, the aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v), having a viscosity of 3 to 30 mPa·s at 25°C, and being administered by instillation in the form of 1 to 2 drops at a time, 2 to 4 times a day.

(B-3) An ophthalmologist's medicinal product used for the prevention or treatment of dry eye, in which 1 to 10 mL of an aqueous ophthalmic composition is filled in a multi-dose eye dropper container, the aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90, and is administered by instillation in the form of 1 to 2 drops at a time, 2 to 4 times a day.

(B-4) An ophthalmologist's medicinal product used for preventing or treating dry eye, in which 1 to 10 mL of an aqueous ophthalmic composition is filled in a multi-dose eye dropper container, the aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v), having a viscosity of 3 to 30 mPa·s at 25°C, and being administered by instillation in the form of 1 to 2 drops at a time, 2 to 4 times a day.

(B-5) An ophthalmologist's medicinal product used for preventing or treating dry eye, in which 1 to 10 mL of an aqueous ophthalmic composition is filled in a PFMD container, the aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90, and is used by instilling 1 to 2 drops at a time, 2 to 4 times a day.

(B-6) An ophthalmologist's medicinal product used for the prevention or treatment of dry eye, in which 1 to 10 mL of an aqueous ophthalmic composition is filled in a PFMD container, the aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v), having a viscosity of 3 to 30 mPa·s at 25°C, and being administered by instillation in the form of 1 to 2 drops at a time, 2 to 4 times a day.

(B-7) An ophthalmic medicinal product according to any one of (B-1) to (B-6), characterized in that the aqueous ophthalmic composition is administered by instillation in the form of 1 to 2 drops at a time, three times a day.

(C-1) Use of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 for producing a medicine for preventing or treating dry eye, characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition is filled into a unit-dose eye dropper container and is administered by instillation at 1 to 2 drops at a time, 2 to 4 times a day.

(C-2) Use of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone and having a viscosity of 3 to 30 mPa·s at 25°C for producing a medicine for preventing or treating dry eye, characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition is filled into a unit-dose eye dropper container and is administered by instillation, 1 to 2 drops at a time, 2 to 4 times a day.

(C-3) Use of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 for the manufacture of a medicine for preventing or treating dry eye, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled into a multi-dose eye dropper container and is administered by instillation at 1 to 2 drops at a time, 2 to 4 times a day.

(C-4) Use of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone and having a viscosity of 3 to 30 mPa·s at 25°C for producing a medicine for preventing or treating dry eye, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled into a multi-dose eye dropper container and administered as 1 to 2 drops at a time, 2 to 4 times a day.

(C-5) Use of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 for producing a medicine for preventing or treating dry eye, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled into a PFMD container and administered as 1 to 2 drops at a time, 2 to 4 times a day.

(C-6) Use of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) and having a viscosity of 3 to 30 mPa·s at 25°C for producing a medicine for preventing or treating dry eye, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled into a PFMD container and administered as 1 to 2 drops at a time, 2 to 4 times a day.

(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 instillation in the form of 1 to 2 drops at a time, three times a day.

(D-1) A method for imparting preservative effect to an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone, the method comprising adding a silver salt to the aqueous ophthalmic composition.

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

Note that any two or more of the above configurations of the present invention may be selected and combined.

Since the composition has a high tear volume increasing effect, it is expected to have a stronger dry eye treatment effect than the existing Diquas ^{(registered trademark) ophthalmic} solution administered by instillation. Therefore, the composition is expected to have the same or better dry eye treatment effect at a lower concentration than the existing Diquas ^{(registered trademark)} ophthalmic solution. In addition, the existing Diquas (registered trademark) ophthalmic solution needs to be instilled six times a day, and there are patients who do not achieve the expected effect due to poor eye drop adherence, but the composition contains polyvinylpyrrolidone with a certain K value and has a certain viscosity, so that it has the same or better treatment effect as the existing Diquas ^{(registered trademark)} ophthalmic solution with fewer instillations than the existing Diquas ^{(registered trademark)} ophthalmic solution, and is expected to improve eye drop adherence.

In addition, this composition is expected to exhibit high viability, be highly safe for the corneal and conjunctival epithelium, exhibit no nerve irritation, and improve the comfort of applying eye drops.

Furthermore, even if silver salts are contained in this composition, the silver salts are stable and exhibit excellent preservative properties.

1 is a graph showing corneal fluorescein staining scores. FIG. 1 shows the results of a cytotoxicity test using corneal epithelial cells. FIG. 1 shows maximum fluorescence intensity (RFUmax) after addition of diquafosol sodium.

The present invention will be explained in more detail below.

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

In this specification, "PVP" means polyvinylpyrrolidone.

In this specification, "HEC" means hydroxyethyl cellulose.

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

In this specification, "HPMC" means hydroxypropyl methylcellulose.

As used herein, "CVP" means carboxyvinyl polymer.

In this specification, "Diquafosol ophthalmic solution" means an aqueous ophthalmic solution containing Diquafosol or a salt thereof.

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

"Diquafosol" is a compound represented by the following chemical structure:

There are no particular limitations on the "salt of diquafosol" as long as it is a medicamentously acceptable salt, and examples thereof include 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, etc.; salts with acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic 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, p -Salts with organic acids such as 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 ion, chloride ion, and iodide ion; 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.

In the present invention, "diquafosol or a salt thereof" also includes hydrates and organic solvates of diquafosol (free form) or its salt.

When "diquafosol or a salt thereof" has a crystal polymorph or a crystal polymorphic group (crystal polymorphic system), the crystal polymorph and the crystal polymorphic group (crystal polymorphic system) are also included in the scope of the present invention. Here, the crystal polymorphic group (crystal polymorphic system) refers to the individual crystal forms at each stage and the entire process when the crystal form changes depending on the conditions and states of the production, crystallization, storage, etc. of the crystals.

The "diquafosol or a salt thereof" of the present invention is preferably a sodium salt of diquafosol, and diquafosol tetrasodium salt (also referred to simply as "diquafosol sodium" in this specification) represented by the following chemical structural formula is particularly preferred.

Diquafosol or its salt can be produced by the method disclosed in JP-A-2001-510484.

The composition may contain an active ingredient other than diquafosol or a salt thereof, or may contain diquafosol or a salt thereof as the only active ingredient.

In the present invention, the concentration of diquafosol or a salt thereof is not particularly limited, but is, for example, 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.

In the present invention, "polyvinylpyrrolidone" refers to a polymer compound formed by polymerization of N-vinyl-2-pyrrolidone, and is generally used as a thickening agent. Polyvinylpyrrolidone is also called povidone. The K value of the polyvinylpyrrolidone used in the present invention is preferably 17 or more, more preferably 17 to 120, even more preferably 25 to 120, even more preferably 30 to 120, even more preferably 40 to 120, especially preferably 60 to 120, particularly preferably 60 to 90, and even more especially preferably 90. 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 the molecular weight, and is a value calculated by applying the relative viscosity value (25°C) measured by a capillary viscometer to the following Fikentscher formula (1).

In formula (1), η _rel is the relative viscosity of the aqueous polyvinylpyrrolidone solution to water, and c is the concentration (%) of polyvinylpyrrolidone in the aqueous polyvinylpyrrolidone solution.

The K value here is 90-108% of the indicated K value, in accordance with the description of the K value in the Japanese Pharmacopoeia, 17th Edition, for "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.

In the present invention, polyvinylpyrrolidone may be used alone, or two or more types of polyvinylpyrrolidone having different K values may be used in any combination.

In the present invention, the concentration of polyvinylpyrrolidone is not particularly limited, but may be, for example, 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), particularly preferably 0.1 to 5% (w/v), and particularly preferably 1 to 5% (w/v).

If necessary, the composition may further contain a pharma- ceutically acceptable preservative. 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, polydonium chloride, and polyhexanide hydrochloride.

As is clear from the test results described below, the present composition containing a silver salt has excellent preservative effect, and therefore the preferred preservative in the present invention is a silver salt. 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, with silver nitrate being preferred.

In the present invention, the concentration of the silver salt is not particularly limited, and is not particularly limited, for example, 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, 0.00005% (w/v) or more, 0.00008% (w/v) or more, or 0.0001% (w/v) or more is preferable. The upper limit is preferably, for example, 1% (w/v) or less, 0.5% (w/v) or less, 0.1% (w/v) or less, 0.05% (w/v) or less, 0.01% (w/v) or less, 0.005% (w/v) or less, or 0.001% (w/v) or less.

In addition to the polyvinylpyrrolidone and preservatives, pharma- ceutically acceptable additives may be added to the composition as necessary. For example, buffers such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid; isotonicity 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 polysorbates; antioxidants such as ascorbic acid; thickeners (also called thickeners) such as hydroxyethyl cellulose and hydroxypropyl methylcellulose; and pH regulators such as hydrochloric acid and sodium hydroxide may be selected and added as necessary. These additives may be used alone or in any combination of two or more. The composition may not contain a cellulose polymer, which is a thickener, such as hydroxyethyl cellulose and hydroxypropyl methylcellulose.

The pH of the composition is not limited to any particular value as long as it is within the medicamentously acceptable range. However, the pH of the 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, especially preferably in the range of 7 to 8, and particularly preferably in the vicinity of 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.

In the present invention, the term "ophthalmic composition" refers to a composition used for the prevention and/or treatment of eye diseases and the like. Its dosage form may be, for example, eye drops, eye ointments, injections, ointments (for example, that can be administered to the eyelid skin), etc., with eye drops being preferred. Here, eye drops are synonymous with eye drops or eye drops, and eye drops for contact lenses are also included in the definition of eye drops.

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

The composition may be in the form of a solution-type eye drop or a suspension-type eye drop, depending on the properties and contents of the active ingredient and additives.

The composition is preferably a sterile aqueous ophthalmic solution. Here, "sterile" refers to a state in which microorganisms have been killed or removed, specifically, for example, a state that meets the preservative effectiveness test standards set out in the 17th Revised Edition of the Japanese Pharmacopoeia.

The composition is preferably storable at room temperature.

The viscosity of the composition is not particularly limited as long as it is within a medicamentously acceptable range, but is adjusted, for example, to be preferably within the range of 1 to 500 mPa·s, more preferably within the range of more than 1.4 to 100 mPa·s, even more preferably within the range of 1.5 to 100 mPa·s, still more preferably within the range of 1.5 to 50 mPa·s, even more preferably within the range of 1.5 to 30 mPa·s, still 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 particularly preferably within the range of 2 to 10 mPa·s, particularly preferably within the range of 3 to 10 mPa·s, more particularly preferably within the range of 5 to 10 mPa·s, and even more particularly preferably within the range of 7 to 10 mPa·s. The viscosity of the composition can 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 particularly preferably within the range of 7 to 30 mPa·s. The lower limit of the viscosity of the composition is, 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. The upper limit is, 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 the composition is measured with a rotational viscometer (25°C; shear rate of 50 s ^-1 ).

The osmotic pressure of the composition is not limited to any particular value as long as it is within the medicamentously acceptable range. However, the osmotic pressure of the 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.

The composition can be stored in an airtight container, specifically, an eye drop container. Examples of the eye drop container in which the composition can be stored include a "multi-dose eye drop container" or a "unit-dose eye drop container."

In the present invention, the term "ophthalmic medicinal product" refers to an ophthalmic medicinal product in which the composition is filled in an eye drop container. Here, an example of the "ophthalmic medicinal product" is an eye drop product. The definition of each term in the "ophthalmic medicinal product" of the present invention is the same as the definition of each term in "the composition".

In the present invention, a "multi-dose eye drop container" refers to an eye drop container that includes a container body and a cap that can be attached to the container body, and the cap can be freely opened and resealed. The multi-dose eye drop container usually contains multiple doses of eye drops for use over a certain period of time. In addition, when the composition does not contain a preservative such as benzalkonium chloride, the composition may be contained in a PFMD (Preservative Free Multi Dose) container. The amount of the composition filled in the multi-dose eye drop container or PFMD container is, for example, preferably 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.

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 mouth of the bottle, and which is intended to be used by breaking and opening the fused part between the cap and the bottle-shaped body. The unit dose eye drop container contains an amount of eye drop solution for one or several uses. Note that the eye drop solution contained in the unit dose eye drop container generally does not contain a preservative such as benzalkonium chloride. The amount of the composition filled in the unit dose eye drop container is, for example, preferably 0.1 to 1 mL, more preferably 0.1 to 0.5 mL, even more preferably 0.3 to 0.5 mL, and particularly preferably 0.3 mL or 0.4 mL.

The method of use of the composition can be varied as appropriate depending on the dosage form, the severity of the symptoms of the patient to be administered, the age, body weight, the doctor's judgment, etc. For example, when eye drops are selected as the dosage form, the composition can be administered in a dose of 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 1 drop, 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, every day to once a week. More specifically, the number of times of administration is preferably 6 times a day, 5 times a day, 4 times a day, 3 times a day, 2 times a day, or once a day, more preferably 6 times a day, 4 times a day, 3 times a day, or twice a day, more preferably 4 times a day, 3 times a day, or twice a day, and even more preferably 3 times a day.

When the concentration of diquafosol or a salt thereof in the composition is 3% (w/v), 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 1 drop, can be administered by instillation 6 times a day, 5 times a day, 4 times a day, 3 times a day, 2 times a day or once a day, preferably 6 times a day, 4 times a day, 3 times a day or twice a day, more preferably 4 times a day or 3 times a day, and particularly preferably 3 times a day.

In addition, one drop is preferably 10 to 50 μL, more preferably 20 to 50 μL, and particularly preferably 40 to 50 μL.

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 tears and corneal and conjunctival epithelium caused by various factors, which is accompanied by ocular discomfort and visual abnormalities," and keratoconjunctivitis sicca (KCS) is included in dry eye. In the present invention, the occurrence of dry eye symptoms caused by wearing soft contact lenses is also included in dry eye.

Dry eye symptoms include subjective symptoms such as dry eyes, eye discomfort, eye fatigue, dullness, photophobia, eye pain, and blurred vision, as well as objective findings such as congestion and corneal and conjunctival epithelial disorders. In the present invention, "prevention or treatment of dry eye" also includes improvement of the subjective symptoms and/or objective findings.

Although the etiology of dry eye remains largely unknown, reported causes include Sjögren's syndrome; congenital alacrimal gland deficiency; sarcoidosis; graft-versus-host disease (GVHD) from bone marrow transplantation; ocular pemphigoid; Stevens-Johnson syndrome; lacrimal obstruction due to trachoma; diabetes; reduced reflex secretion due to corneal refractive surgery (LASIK: Laser (-assisted) in situ keratomileusis); meibomian gland dysfunction; reduced oil layer due to blepharitis; insufficient blinking or eyelid closure due to exophthalmos or lagophthalmos; reduced mucin secretion from germ cells; and work at VDTs (visual display terminals).

The composition can also be instilled into the eyes of a dry eye patient wearing a soft contact lens. Here, instilling into the eyes of a dry eye patient wearing a soft contact lens means that the eye drops are instilled into the eyes of the dry eye patient while the soft contact lens is being worn on the cornea of the dry eye patient.

The results of pharmacological tests and formulation examples are shown below for a better understanding of the present invention, but they are not intended to limit the scope of the present invention.

[Test 1]
Using normal male white rabbits, the change in tear volume over time after instillation of the composition was evaluated.

(Sample Preparation Method)
Eye Drops 1:
According to the prescription shown in Table 1, eye drop solution 1 was prepared. That is, 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, to obtain a 6-fold concentrated solution. In addition, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and then a pH adjuster was appropriately added to adjust the pH to 7, and sterile purified water was added to make 20 mL, to obtain a 3-fold concentrated solution. PVP K90 (4 g) was dissolved in sterile purified water to make a total amount of 100 g, and then the solution was sterilized by high-pressure steam (121° C., 20 minutes) to obtain a 4.00% (w/w) PVP K90 solution. To 6.0 g of 4.00% (w/w) PVP K90 solution, 4 mL of the 3x concentrated solution was added, and sterilized purified water was added to adjust the total volume to 12 mL. A pH adjuster was then added appropriately to adjust the pH to 7, thereby preparing ophthalmic solution 1.

Eye Drops 2:
According to the prescription shown in Table 1, eye drop 2 was prepared. That is, 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, to obtain a 6-fold concentrated solution. In addition, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and PVP K30 (1.2 g) was dissolved therein, and then a pH adjuster was appropriately added to adjust the pH to 7, and sterile purified water was added to make 20 mL, to obtain a 3-fold concentrated solution. Sterile purified water was added to 4 mL of the 3-fold concentrated solution to adjust the total volume to 12 mL, and then a pH adjuster was appropriately added to adjust the pH to 7, to prepare eye drop 2.

Eye Drops 3:
According to the prescription shown in Table 1, eye drop 3 was prepared. That is, 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, and a 6-fold concentrated solution was obtained. In addition, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and then a pH adjuster was appropriately added to adjust the pH to 7, and sterile purified water was added to make 20 mL, to obtain a 3-fold concentrated solution. Hydroxyethyl cellulose (15 g) was dissolved in 1500 mL of sterile purified water, and the solution was sterilized by high-pressure steam (121°C for 20 minutes) to obtain a 1.00% (w/w) hydroxyethyl cellulose solution. 4 mL of the 3-fold concentrated solution was added to 3.6 g of 1.00% (w/w) hydroxyethyl cellulose solution, and sterile purified water was added to adjust the total volume to 12 mL, and then a pH adjuster was appropriately added to adjust the pH to 7, to prepare eye drop 3.

Eye Drops 4:
According to the prescription shown in Table 1, eye drop solution 4 was prepared. That is, 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, to obtain a 6-fold concentrated solution. In addition, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and then a pH adjuster was appropriately added to adjust the pH to 7, and sterile purified water was added to make 20 mL, to obtain a 3-fold concentrated solution. Sterile purified water was added to 4 mL of the 3-fold concentrated solution to adjust the total volume to 12 mL, and then a pH adjuster was appropriately added to adjust the pH to 7, to prepare eye drop solution 4.

Eye Drops 5:
Ophthalmic solution 5 was prepared according to the prescription shown in Table 1. That is, 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, to obtain a 6-fold concentrated solution. In addition, 2.5 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and then 45% aqueous solution of PVP K60 (0.67 g) and sodium chloride (0.068 g) were dissolved therein, and the pH was adjusted to 7 by adding an appropriate pH adjuster, and sterile purified water was added to make 15 mL, to prepare ophthalmic solution 5.

The viscosity of the prepared eye drops 1 to 5 was measured according to the method described in the 17th Revised Japanese Pharmacopoeia, 2.53 Viscosity Measurement Method, Method 2 Rotational Viscometer Method, and 2.1.3 Cone-Plate Type Rotational Viscometer (Cone-Plate Type Viscometer). Specifically, a Kinexus pro+ (manufactured by 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°C
Shear rate: 50 ^s
Measurement time: The viscosity was measured every 2 seconds, and the average value for 1 minute was recorded as the viscosity.

(Testing Method and Drug Administration Method)
Benoxil ^{(registered trademark)} eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were instilled into normal male white rabbits (total of 16 rabbits, 32 eyes) to administer local anesthesia. After 3 minutes, Schirmer test paper (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, and 1 minute after insertion, it was removed, and the length of the wetted part (tear volume) was read. This was the initial value. Next, each eye drop 1 to 5 was instilled once (4 rabbits, 8 eyes, 12 rabbits for eye drop 4 only). 3 minutes before inserting Schirmer test paper (manufactured by Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid, Benoxil ^{(registered trademark)} eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) was instilled to administer local anesthesia. 60 minutes after instillation of each eye drop, Schirmer test paper (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, and 1 minute after insertion, it was removed, and the length of the wetted part (tear volume) was read.

(Evaluation Method)
The change in tear volume before and after the instillation of the eye drops was calculated as Δ tear volume (mm/min).

(Test Results)
The Δ tear volume (mm/min) 60 minutes after instillation is shown in Tables 1 and 2 (each value is the average of 8 eyes, except for eye drop 4, which is the average of 24 eyes). The tear volume increasing effect of the composition was evaluated according to the following criteria.
+++: Δ tear volume (mm/min) 60 minutes after instillation is 4 mm/min or more
++: Δ tear volume (mm/min) 60 minutes after instillation is 1 mm/min or more and less than 4 mm/min
+: Δ tear volume (mm/min) 60 minutes after instillation is greater than 0 mm/min or less than 1 mm/min
-: Δ tear volume (mm/min) 0 mm/min or less 60 minutes after instillation

As shown in the results in Table 1 above, the eye drops containing PVP K30 (eye drops 2) did not increase tear volume 60 minutes after application, just like the eye drops not containing PVP K30 (eye drops 4). Furthermore, although HEC is generally used as a thickening agent, the eye drops containing HEC (eye drops 3) did not increase tear volume 60 minutes after application, just like eye drops 4, despite having a relatively high viscosity. In contrast, the eye drops containing PVP K90 (eye drops 1) showed a significantly higher tear volume increase effect than eye drops 2 to 4.

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

(Discussion)
Polyvinylpyrrolidone increased the viscosity of the aqueous composition containing diquafosol or a salt thereof, and enhanced the medicinal efficacy of diquafosol or a salt thereof. In particular, it was shown that the medicinal efficacy of diquafosol or a salt thereof was significantly enhanced when polyvinylpyrrolidone having a K value of more than 30 was added or when the viscosity of the aqueous composition exceeded 1.4 due to the addition of polyvinylpyrrolidone.

[Test 2]
A rat extraorbital lacrimal gland removal model is widely used as a model for evaluating the therapeutic effect of corneal epithelial damage caused by dry eye, and is also used as a model for evaluating the therapeutic effect of _P2Y2 receptor agonists (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). Using this dry eye model, it was examined whether or not the present composition could be administered by instillation to improve corneal epithelial damage.

(Method of preparing a dry eye model)
A rat extraorbital lacrimal gland removal model was prepared using male SD rats according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). That is, after administering Somnopentyl to give general anesthesia, the extraorbital lacrimal gland was removed to induce corneal epithelial damage.

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

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

Eye Drops X:
"Diquas ^{(registered trademark)} Ophthalmic Solution 3%" (manufactured by Santen Pharmaceutical Co., Ltd.), which is used as a dry eye treatment drug, was used as the ophthalmic solution X. Ophthalmic solution X contains 30 mg of diquafosol sodium as an active ingredient per 1 mL of water, and also contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium edetate hydrate, and a pH adjuster as additives.

The viscosities of the prepared ophthalmic solutions A, B and X were measured according to the method described in the 17th Edition of the Japanese Pharmacopoeia, 2.53 Viscosity Measurement Method, Method 2 Rotational Viscometer Method, and 2.1.3 Cone-Plate Type Rotational Viscometer (Cone-Plate Type Viscometer). Specifically, a Kinexus pro+ (manufactured by 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°C
Shear rate: 50 ^s
Measurement time: The viscosity was measured every 2 seconds, and the average value for 1 minute was recorded as the viscosity.

The measured viscosities of each eye drop were as follows:
Eye drops A: 7.9 mPa·s
Eye drops B: 28.0 mPa·s
Eye drops X: 0.9 mPa·s
(Testing Method and Drug Administration Method)
To the rats with corneal epithelial damage induced as described above, eye drops A, B and X were administered as follows.
Group administered eye drops A three times a day: Eye drops A was administered to both eyes three times a day for four weeks (12 eyes, six mice per group).
Group administered eye drops B three times a day: Eye drops B was administered to both eyes three times a day for four weeks (12 eyes, six mice per group).
Eye drops X, administered 6 times a day group: Eye drops X was administered to both eyes 6 times a day for 4 weeks (6 mice, 12 eyes per group).
Rats without corneal epithelial damage and without instillation for 4 weeks were classified as the no-instillation group (4 rats, 8 eyes per group).

Four weeks after the start of eye drops, the damaged areas of the cornea were stained with fluorescein, and corneal epithelial damage was assessed according to the method of Murakami et al. (New Ophthalmology, 21 (1), 87-90 (2004)). That is, the degree of fluorescein staining for the upper, middle, and lower parts of the cornea was scored according to the following criteria, and the average of the total scores was calculated. A midpoint of 0.5 was set between scores of 0, 1, 2, and 3.

(Judgment criteria)
0: not stained,
1: Staining is sparse, and each dot-like stained area is separated.
2: Staining is moderate, and some of the dot-like stained areas are adjacent to each other.
3: Dense staining, with each spot of staining adjacent to each other.

(result)
The calculated fluorescein staining scores for each group are shown in a graph in Figure 1. The scores are the average value + standard error of 8 or 12 cases.

As is clear from Figure 1, in the group administered eye drops A three times a day, an improvement in fluorescein staining score was observed from two weeks after the start of administration, compared to the group administered eye drops B three times a day. In the group administered eye drops X six times a day, an improvement in fluorescein staining score was observed from four weeks after the start of administration, compared to the group administered eye drops B three times a day. Four weeks after administration, the group administered eye drops A three times a day and the group administered eye drops X six times a day showed similar effects.

(Discussion)
Eye drops X is used as "Diquas ^{(registered trademark)} eye drops 3%" for the treatment of dry eye, and is instilled six times a day. It was revealed that the composition containing polyvinylpyrrolidone K90 has a sufficient therapeutic effect on dry eye when instilled three times a day, and in particular, two weeks after the start of instillation, the therapeutic effect was greater than that of "Diquas ^{(registered trademark)} eye drops 3%" six times a day. Therefore, it was shown that the composition has a therapeutic effect equivalent to or greater than that of existing Diquas ^{(registered trademark)} eye drops with a smaller number of instillations than that of existing Diquas ^{(registered trademark)} eye drops. In particular, taking into account the results of Test 1, it was suggested that the composition containing polyvinylpyrrolidone with a K value of more than 30 or the composition having a viscosity of more than 1.4 due to the addition of polyvinylpyrrolidone, instilled two to four times a day, has a therapeutic effect equivalent to or greater than that of existing "Diquas ^{(registered trademark)} eye drops 3%" six times a day.

[Test 3]
In order to examine the effect of this composition on corneal epithelial cells, a test on cytotoxicity to corneal epithelial cells was carried out.

(Sample Preparation Method)
According to the formulations shown in Table 3, eye drops Y, C and D were prepared.

Eye Drops Y:
Ophthalmic solution Y was prepared according to the formulation 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 (q.s.) was added to adjust the pH to 7.5.

Eye drops C and D:
According to the formulations shown in Table 3, eye drops C and D were prepared in the same manner as eye drops Y.

The viscosities of the prepared ophthalmic solutions Y, C and D were measured according to the method described in the 17th Edition of the Japanese Pharmacopoeia, Section 2.53 Viscosity Measurement Method, Section 2 Rotational Viscometer Method, and Section 2.1.3 Cone-Plate Rotational Viscometer (Cone-Plate Viscometer). Specifically, a Kinexus pro+ (manufactured by 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°C
Shear rate: 50 ^s
Measurement time: The viscosity was measured every 2 seconds, and the average value for 1 minute was recorded as the viscosity.

(Test Method)
SV40-immortalized human corneal epithelial cells (HCE-T: RIKEN Bioresource Center, Cell No.: RCB2280) were seeded in a 96-well plate (1 x ¹⁰⁴ cells/well) and cultured in 10% FBS-containing D-MEM/F12 medium for one day. On the following day, the medium was replaced with eye drop solution Y, eye drop solution C, or eye drop solution D, and the corneal epithelial cells were cultured for 5, 10, and 15 minutes. Viable cell activity (corresponding to absorbance at 490 nm) was measured using a Cell Proliferation Assay Kit (Promega, catalog number: G3580).

(result)
The test results are shown in FIG.

As is clear from Figure 2, Diquafosol ophthalmic solution containing polyvinylpyrrolidone (ophthalmic solution C and D) maintained a high viability of immortalized human corneal epithelial cells even after 15 minutes of culture. On the other hand, Diquafosol ophthalmic solution not containing polyvinylpyrrolidone (ophthalmic solution Y) showed a decrease in viability over time.

(Discussion)
Diquafosol ophthalmic solution containing polyvinylpyrrolidone exhibits high viability in cultured immortalized human corneal epithelial cells and is therefore safer for the corneal and conjunctival epithelium and is useful for treating diseases in which the corneal and conjunctival epithelium is unstable, such as dry eye.

[Test 4]
The irritation of peripheral nerves by diquafosol sodium in the presence of PVP was examined.

(Sample Preparation Method)
Formulation 1:
According to the recipe shown in Table 4, formulation solution 1 was prepared. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, and a pH adjuster was added to adjust the pH to 7.5, and the total volume was adjusted to 100 mL to obtain a 10x buffer solution. PVP K30 (16 g) was dissolved in sterile purified water, and the total volume was adjusted to 200 mL to obtain an 8% PVP K30 aqueous solution. 2 mL of the 10x buffer solution and 5 mL of the 8% PVP K30 aqueous solution were weighed out, and 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 formulation solution 1.

Formulation 2:
Formulation solution 2 was prepared according to the recipe shown in Table 4. That is, 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 10x buffer solution. 2 mL of the 10x buffer solution and PVP K90 (0.4 g) were dissolved in sterile purified water, the pH was adjusted to 7.5 using a pH adjuster, and the total volume was adjusted to 20 mL to obtain formulation solution 2.

Formulation 3:
According to the recipe shown in Table 4, formulation solution 3 was prepared. That is, 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 10x buffer solution. 2 mL of the 10x buffer solution and sodium chondroitin sulfate (0.06 g) were added to sterile purified water, the pH was adjusted to 7.5 using the pH adjuster, dissolution was confirmed, and the total volume was adjusted to 20 mL to obtain formulation solution 3.

Prescription solutions 4 to 6:
According to the recipe shown in Table 4, formulations 4 to 6 were prepared in the same manner as formulation 3.

(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 indicator fluorescent dye (FLIPR Calcium 6 Assay Kit, Molecular Devices). 40% of the total volume of the buffer solution was replaced with each of the above-mentioned formulations. The non-stimulated group and the stimulated control group were treated in the same manner with the buffer solution instead of the formulation solution. After standing at room temperature, the time-dependent fluorescence measurement of the calcium indicator dye was started using a fluorescent plate reader. Diquafosol sodium (final concentration: 0.3%) was added 60 seconds after the start, and the measurement of the fluorescence intensity was continued.

(Evaluation Method)
The fluorescence intensity (RFU) immediately before the addition of diquafosol sodium was defined as 100%, and the maximum fluorescence intensity (RFUmax) after the addition was calculated.

(Test Results)
The results are shown in Figure 3. In the stimulation control group and formulations 3 to 6, RFU increased after the addition of diquafosol sodium, and an RFUmax of 103.5% or more was recorded. On the other hand, in each of the groups of formulations 1 and 2 containing PVP, the RFUmax was all less than 101%.

(Discussion)
Peripheral nerve cells that receive some kind of stimulus generate an action potential and become excited, and the stimulus signal converted into the 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 cells. Therefore, an increase in intracellular calcium ion concentration is widely used experimentally as an index of the excited state of nerve cells. When peripheral nerve cells were exposed to diquafosol sodium, an increase in the fluorescence intensity of intracellular calcium ions was observed immediately, indicating that the nerve cells received diquafosol sodium as a stimulus and became excited. A similar stimulus response was observed in each of the groups of polymer formulations 3 to 6 that did not contain PVP as comparative examples, and the polymers of sodium chondroitin sulfate, HPMC, CVP, and CMC-Na had no effect on the nerve irritation of diquafosol sodium. In contrast, in formulations 1 and 2 that contain PVP, no increase in intracellular calcium ion signals was observed after the addition of diquafosol sodium. That is, it was suggested that diquafosol sodium in the presence of PVP did not exhibit nerve irritation, and the addition of PVP improved the application sensation of diquafosol sodium ophthalmic solution.

[Test 5]
The effect of this composition on the stability of preservatives was examined.

(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 (q.s.) was added to adjust the pH to 7.5.

Eye drops 7-10:
According to the formulations shown in Table 5, eye drops 7 to 10 were prepared in the same manner as eye drop 6.

(Test Method)
The chlorhexidine gluconate content of each of the eye drops 6 and 7 was quantified using high performance liquid chromatography (HPLC) when the eye drops were stored at 60°C for up to 4 weeks, and the remaining rate (%) was calculated. The chlorhexidine gluconate content of each of the eye drops 8 and 9 was quantified using high performance liquid chromatography (HPLC) when the eye drops were stored at 60°C for up to 2 weeks, and the remaining rate (%) was calculated. The silver nitrate content of the eye drop 10 was quantified using inductively coupled plasma atomic emission spectrometry (ICP-AES) when the eye drops were stored at 60°C for up to 4 weeks, and the remaining rate (%) was calculated.

(Test Results)
The results of the stability test are shown in Table 6.

(Discussion)
In an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone (the present composition), when chlorhexidine gluconate was contained as a preservative, the residual rate was significantly decreased (ophthalmic solutions 7 to 9). On the other hand, when silver nitrate, a silver salt, was contained as a preservative, the residual rate was high (ophthalmic solution 10). From the above, it was demonstrated that the present composition destabilizes chlorhexidine gluconate while stabilizing silver salts.

[Test 6]
The preservative effectiveness of this composition containing a silver salt was investigated.

(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 hydroxyethyl cellulose (0.25 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (q.s.) was added to adjust the pH to 7.5.

Eye drops 12-15:
According to the formulation shown in Table 7, eye drops 12 to 15 were prepared in the same manner as eye drops 11.

(Test Method)
The preservative effectiveness test was performed in accordance with the preservative effectiveness test method of the 17th revised 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.

(Test Results)
The test results are shown in Table 8.

The test results in Table 8 are shown as log reductions, which indicate the degree to which the number of live bacteria at the time of testing had decreased compared to the number of bacteria inoculated. For example, a value of "1" indicates that the number of live bacteria at the time of testing had decreased to 10% of the number of bacteria inoculated.

As shown in Table 8, this composition containing silver salts was shown to meet the preservative effectiveness test standards of the Japanese Pharmacopoeia.

(Discussion)
The above results demonstrate that the composition containing a silver salt has excellent preservative effectiveness.

[Test 7]
Using normal male white rabbits, the change in tear volume over time 90 minutes after instillation of the composition was evaluated.

(Sample Preparation Method)
Eye Drops 16:
Ophthalmic solution 16 was prepared by dissolving sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), and diquafosol sodium (3 g) in sterile purified water to make 100 mL, and adding a pH adjuster (q.s.) to adjust the pH to 7.5.

Eye Drops 17:
"Diquas ^{(registered trademark)} ophthalmic solution 3%" (manufactured by Santen Pharmaceutical Co., Ltd.), which is used as a dry eye treatment drug, was used as the ophthalmic solution 17. Ophthalmic solution 17 contains 30 mg of diquafosol sodium as an active ingredient per 1 mL of water, and also contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium edetate hydrate, and a pH adjuster as additives.

(Testing Method and Drug Administration Method)
Benoxil ^{(registered trademark)} eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were instilled into normal male white rabbits (total of 12 rabbits, 24 eyes) and local anesthesia was administered. After 3 minutes, Schirmer test paper (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, and 1 minute after insertion, it was removed, and the length of the wetted part (tear volume) was read. This was the initial value. Next, each eye drop 16 or 17 was instilled once (12 eyes of 6 rabbits per group). 3 minutes before inserting the Schirmer test paper (manufactured by Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid, Benoxil ^{(registered trademark)} eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were instilled and local anesthesia was administered. 90 minutes after instillation of each eye drop, Schirmer test paper (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, and 1 minute after insertion, it was removed, and the length of the wetted part (tear volume) was read.

(Evaluation Method)
The change in tear volume before and after the instillation of the eye drops was calculated as Δ tear volume (mm/min).

(Test Results)
The Δ tear volume (mm/min) 90 minutes after instillation is shown in Table 9 (each value is the average of 12 eyes). The tear volume increasing effect of the composition was evaluated according to the following criteria.
+++: Δ tear volume (mm/min) 4 mm/min or more 90 minutes after instillation
++: Δ tear volume (mm/min) 90 minutes after instillation is 1 mm/min or more and less than 4 mm/min
+: Δ tear volume (mm/min) 90 minutes after instillation is greater than 0 mm/min or less than 1 mm/min
-: Δ tear volume (mm/min) 0 mm/min or less 90 minutes after instillation

As shown in the results in Table 9 above, this composition showed a high tear volume increasing effect even 90 minutes after instillation.

[Test 8]
The preservative effectiveness of this composition containing a silver salt was investigated.

(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 (q.s.) was added to adjust the pH to 7.0.

Eye Drops 19:
According to the formulation shown in Table 10, eye drops 19 were prepared in the same manner as eye drops 18.

(Test Method)
The preservative effectiveness test was performed in accordance with the preservative effectiveness test method of the 17th revised 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.

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

The test results in Table 11 are shown as log reductions, which indicate the degree to which the number of live bacteria at the time of testing had decreased compared to the number of bacteria inoculated. For example, a value of "1" indicates that the number of live bacteria at the time of testing had decreased to 10% of the number of bacteria inoculated.

As shown in Table 11, this composition containing silver salts, with or without EDTA, was shown to meet the preservative effectiveness test standards of the Japanese Pharmacopoeia.

(Discussion)
The above results demonstrate that the composition containing a silver salt has excellent preservative effectiveness.

[Test 9]
The preservative effectiveness of this composition containing a silver salt was investigated.

(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 (q.s.) was added to adjust the pH to 7.5.

Eye drops 21-23:
According to the formulation shown in Table 12, eye drops 21 to 23 were prepared in the same manner as eye drops 20.

(Test Method)
The preservative effectiveness test was performed in accordance with the preservative effectiveness test method of the 17th revised 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.

(Test Results)
The test results are shown in Table 13.

The test results in Table 13 are shown as log reductions, which indicate the degree to which the number of live bacteria at the time of testing had decreased compared to the number of bacteria inoculated. For example, a value of "1" indicates that the number of live bacteria at the time of testing had decreased to 10% of the number of bacteria inoculated.

As shown in Table 13, this composition containing a silver salt, regardless of the presence or absence of EDTA, was shown to comply with the preservative effectiveness test standards of the Japanese Pharmacopoeia. In addition, eye drops containing silver phosphate and silver chloride, in addition to silver nitrate, were also shown to comply with the preservative effectiveness test standards of the Japanese Pharmacopoeia.

(Discussion)
The above results demonstrate that the composition containing a silver salt has excellent preservative effectiveness.

[Test 10]
The effect of this composition on the stability of preservatives was examined.

(Sample Preparation Method)
Eye Drops 24:
Diquafosol sodium (3 g), sodium edetate hydrate (0.01 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.45 g), polyvinylpyrrolidone K90 (2 g), and silver nitrate (0.00004 g) were dissolved in water to make 100 mL, and a pH adjuster (q.s.) was added to adjust the pH to 7.5 to prepare ophthalmic solution 24.

(Test Method)
The content of silver nitrate in the eye drops 24 after storage at 40° C. for up to 6 months was quantified using inductively coupled plasma atomic emission spectrometry (ICP-AES), and the residual rate (%) was calculated.

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

(Discussion)
When silver nitrate, a silver salt, was added as a preservative, the retention rate was high. From the above, it was demonstrated that the silver salt is stable in this composition.

[Formulation example]
The pharmaceutical agent of the present invention will be explained in more detail with reference to formulation examples, but the present invention is not limited to these formulation examples.

Formulation Example 1: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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-mentioned ophthalmic solution can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and thoroughly mixing them. An ophthalmic medicinal product can be produced by filling 1 to 10 mL of the above-mentioned ophthalmic solution into a multi-dose type ophthalmic container or a PFMD container. In addition, an ophthalmic medicinal product can be produced by filling 0.1 to 1 mL of the above-mentioned ophthalmic solution into a unit-dose type ophthalmic container. The above-mentioned ophthalmic solution can be stored at room temperature.

Formulation Example 2: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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-mentioned ophthalmic solution can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and thoroughly mixing them. An ophthalmic medicinal product can be produced by filling 1 to 10 mL of the above-mentioned ophthalmic solution into a multi-dose type ophthalmic container or a PFMD container. In addition, an ophthalmic medicinal product can be produced by filling 0.1 to 1 mL of the above-mentioned ophthalmic solution into a unit-dose type ophthalmic container. The above-mentioned ophthalmic solution can be stored at room temperature.

Formulation Example 3: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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 Diquafosol sodium and the other components described above are added to sterile purified water and mixed thoroughly to prepare the above eye drop solution. 1 to 10 mL of the above eye drop solution is filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic medicinal product. Also, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to produce an ophthalmic pharmaceutical product. The above eye drop solution can be stored at room temperature.

Formulation Example 4: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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
The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

Formulation Example 5: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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
The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

Formulation Example 6: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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
The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

Formulation Example 7: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K90 0.0001-10g
pH adjuster Appropriate amount Diquafosol sodium and the other components described above are added to the sterile purified liquid, and the mixture is thoroughly mixed to prepare the eye drop. 1-10 mL of the eye drop solution is filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic medicinal product. Also, 0.1-1 mL of the eye drop solution can be filled into a unit-dose eye drop container to produce an ophthalmic medicinal product. The eye drop can be stored at room temperature.

Formulation Example 8: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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 ingredients to sterile purified water and thoroughly mixing them. An ophthalmic medicinal product can be produced by filling 1 to 10 mL of the above eye drop solution into a multi-dose eye drop container or a PFMD container. In addition, an ophthalmic medicinal product can be produced by filling 0.1 to 1 mL of the above eye drop solution into a unit-dose eye drop container. The above eye drop preparation can be stored at room temperature.

Formulation Example 9: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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 ingredients to sterile purified water and thoroughly mixing them. An ophthalmic medicinal product can be produced by filling 1 to 10 mL of the above eye drop solution into a multi-dose eye drop container or a PFMD container. In addition, an ophthalmic medicinal product can be produced by filling 0.1 to 1 mL of the above eye drop solution into a unit-dose eye drop container. The above eye drop preparation can be stored at room temperature.

Formulation Example 10: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K90 0.0001-10g
Silver nitrate 0.00000001~1g
The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

Formulation Example 11: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K60 0.0001-10g
Silver nitrate 0.00000001~1g
The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

Formulation Example 12: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K40 0.0001-10g
Silver nitrate 0.00000001~1g
The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

Formulation Example 13: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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 ingredients to sterile purified water and thoroughly mixing them. An ophthalmic medicinal product can be produced by filling 1 to 10 mL of the above eye drop solution into a multi-dose eye drop container or a PFMD container. In addition, an ophthalmic medicinal product can be produced by filling 0.1 to 1 mL of the above eye drop solution into a unit-dose eye drop container. The above eye drop preparation can be stored at room temperature.

Formulation Example 14: Sterile aqueous ophthalmic solution (3% (w/v))
Diquafosol sodium 3g per 100mL
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
The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

Existing Diquas ^{(registered trademark)} eye drops need to be instilled six times a day, but there are some severe dry eye patients who do not achieve sufficient therapeutic effects even when using the prescribed dosage. Furthermore, there are also patients who do not achieve the expected effects due to poor adherence to instillation. The present composition not only has a stronger dry eye therapeutic effect than existing Diquas ^{(registered trademark)} eye drops, but is also expected to improve instillation adherence by reducing the number of times the eye drops are instilled. In addition, the present composition is expected to have the same or greater dry eye therapeutic effect at a lower concentration than existing Diquas ^{(registered trademark)} eye drops.

In addition, this composition is expected to exhibit high viability, be highly safe for the corneal and conjunctival epithelium, exhibit no nerve irritation, and improve the comfort of applying eye drops.

Furthermore, even if silver salts are contained in this composition, the silver salts are stable and exhibit excellent preservative properties.

Claims (9)

An aqueous eye drop for preventing or treating dry eye, comprising diquafosol sodium at a concentration of 3% (w/v) as an active ingredient, containing polyvinylpyrrolidone and having a viscosity of 3 to 20 mPa·s at 25°C, the aqueous eye drop being administered by instillation one drop at a time, three times a day. The aqueous eye drop according to claim 1, having a viscosity of 3 to 10 mPa·s at 25°C. The aqueous eye drop according to claim 1, having a viscosity of 5 to 10 mPa·s at 25°C. The aqueous eye drop according to claim 1, having a viscosity of 7 to 10 mPa·s at 25°C. The aqueous eye drop according to any one of claims 1 to 4, which contains a thickening agent. The aqueous eye drop according to any one of claims 1 to 5, which contains at least one selected from the group consisting of a preservative, a buffering agent, an isotonicity agent, a stabilizer, a surfactant, an antioxidant, and a pH adjusting agent. The aqueous eye drop according to any one of claims 1 to 6, wherein the aqueous eye drop is filled in a multi-dose eye drop container. The aqueous eye drop according to claim 7, wherein the filling volume of the aqueous eye drop is 1 to 10 mL. The aqueous eye drop according to claim 7, wherein the filling volume of the aqueous eye drop is 5 mL.

Images