TWI848171B - Aqueous ophthalmic composition containing DIQUAFOSOL or its salt and polyvinyl pyrrolidone - Google Patents

Abstract

The present invention is an aqueous ophthalmic composition containing diquafosol or its salt, and polyvinyl pyrrolidone. The aqueous ophthalmic composition for preventing or treating dry eye of the present invention contains 3% (w/v) sodium diquafosol, polyvinyl pyrrolidone with a K value of 90, and silver nitrate, and is characterized in that it is used in the form of 1 to 2 drops per time, 2 to 4 times a day. The aqueous ophthalmic composition for preventing or treating dry eye of the present invention contains 3% (w/v) sodium diquafosol, polyvinyl pyrrolidone, and silver nitrate, and has a viscosity of 3 to 30 mPa·s at 25°C. It is characterized in that it is used in the form of 1 to 2 drops per time, 2 to 4 times a day.

Description

Aqueous ophthalmic composition containing DIQUAFOSOL or its salt and polyvinyl pyrrolidone

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

Diquafosol is a purine receptor agonist also called P ¹ , P ⁴ -di(uridine-5')tetraphosphate or Up4U, and has a tear secretion promoting effect. Diquafosol sodium as its salt is used as "DIQUAS ^{( registered trademark )} eye drops 3%" (hereinafter, also referred to as "DIQUAS ^{( registered trademark )} eye drops") for the treatment of dry eye (Japanese Patent No. 3652707 (Patent Document 1), DIQUAS ^{( registered trademark )} eye drops 3% attachment (Non-patent Document 1)). The dosage of DIQUAS ^{( registered trademark )} eye drops is usually 1 drop per time, 6 times per day (non-patent document 1), but there are patients with severe dry eye who cannot obtain sufficient therapeutic effects even with the prescribed dosage. Furthermore, in daily life, it is difficult to regularly and frequently apply eye drops every day, so there are patients who cannot obtain the expected effects due to poor eye drop compliance. In addition, there are patients who complain of side effects such as eye irritation due to the use of DIQUAS ^{( registered trademark )} eye drops even at a low frequency (non-Japanese patent document 1).

As an attempt to explore a novel dry eye treatment agent with a higher tear volume increasing effect, it is known to use diquafosol or its salt in combination with an existing dry eye treatment agent. Japanese Patent Publication No. 2012-077080 (Patent Document 2) discloses that by using diquafosol or its salt in combination with hyaluronic acid as a dry eye treatment agent, tear secretion is synergistically promoted. Japanese Patent Publication No. 2015-160826 (Patent Document 3) discloses that by using diquafosol or its salt in combination with rebamipide as a dry eye treatment agent, tear secretion is synergistically promoted. [Prior Art Document] [Patent Document]

[Patent Document 1] Japanese Patent Publication No. 3652707 [Patent Document 2] Japanese Patent Publication No. 2012-077080 [Patent Document 3] Japanese Patent Publication No. 2015-160826 [Non-Patent Document]

[Non-patent document 1] DIQUAS (registered trademark) eye drops 3% Accessories

[The problem the invention is trying to solve]

Providing an aqueous ophthalmic composition that can enhance the efficacy of diquafosol or its salt and reduce side effects such as eye irritation is an interesting topic. [Technical means to solve the problem]

The inventors and others conducted intensive research and found that the aqueous ophthalmic composition containing diquafosol or its salt and polyvinyl pyrrolidone (hereinafter, also referred to as "the present composition") showed a significant improvement in the fluorescein staining score, that is, it showed a significant improvement in corneal epithelial damage, thereby clarifying that polyvinyl pyrrolidone enhances the efficacy of diquafosol or its salt. In addition, the inventors and others also found that the present composition having a certain viscosity by containing polyvinyl pyrrolidone with a certain K value can exert a therapeutic effect equal to or greater than that of the existing DIQUAS ^{( registered trademark )} eye drops with fewer eye drops than the existing DIQUAS ^{( registered trademark )} eye drops. In addition, it was also found that the present composition showed high viable cell activity and was safer for the corneal and conjunctival epithelium. In addition, it was found that the present composition does not show nerve irritation and can further improve the comfort of eye drops. Furthermore, it was found that even if the present composition contains silver salt, the silver salt is stable and the present composition containing silver salt shows excellent preservation effect.

That is, the present invention relates to the following contents. (1) An aqueous ophthalmic composition containing diquatol or a salt thereof, and polyvinyl pyrrolidone.

(2) The aqueous ophthalmic composition as described in (1), further comprising a silver salt. (3) The aqueous ophthalmic composition as described in (2), wherein the silver salt comprises silver nitrate.

(4) The aqueous ophthalmic composition according to any one of (1) to (3), which is used for preventing or treating dry eye.

(5) The aqueous ophthalmic composition as described in (4), which contains dequafosol sodium at a concentration of 1 to 5% (w/v) and polyvinyl pyrrolidone having a K value of more than 30 and less than 120.

(6) The aqueous ophthalmic composition as described in (4), which contains dequafosol sodium at a concentration of 3% (w/v) and polyvinyl pyrrolidone having a K value of more than 30 and less than 120.

(7) The aqueous ophthalmic composition as described in (4), which contains sodium dequasofrosol 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 as described in (4), which contains sodium dequasofrosol 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 eye drops 2 to 4 times a day.

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

(11) The aqueous ophthalmic composition according to (9) or (10), which is administered into the eye in the form of 1 to 2 drops at a time.

(12) An ophthalmic pharmaceutical product characterized in that a single-dose eye drop container is filled with 0.1 to 1 mL of the aqueous ophthalmic composition described in (1).

(13) An ophthalmic pharmaceutical product characterized in that a single-dose eye drop container is filled with 0.3 to 0.5 mL of the aqueous ophthalmic composition described in (1).

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

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

(16) An ophthalmic pharmaceutical product characterized in that a PFMD (Preservative Free Multi Dose) container is filled with 1 to 10 mL of the aqueous ophthalmic composition described in (1).

(17) An ophthalmic pharmaceutical product, characterized in that: a PFMD container is filled with 5 mL of the aqueous ophthalmic composition described in (1).

(18) An ophthalmic pharmaceutical product as described in any one of (12) to (17), which is used for preventing or treating dry eye.

(19) An ophthalmic pharmaceutical product as described in (18), wherein the aqueous ophthalmic composition contains sodium dequafrolate at a concentration of 1 to 5% (w/v) and polyvinyl pyrrolidone having a K value of more than 30 and less than 120.

(20) An ophthalmic pharmaceutical product as described in (18), wherein the aqueous ophthalmic composition contains dequafroceeding sodium at a concentration of 3% (w/v) and polyvinyl pyrrolidone having a K value greater than 30 and less than 120.

(21) An ophthalmic pharmaceutical preparation as described in (18), wherein the aqueous composition contains sodium dequaminate at a concentration of 1 to 5% (w/v) and has a viscosity of 1.5 to 30 mPa·s at 25°C.

(22) An ophthalmic pharmaceutical preparation as described in (18), wherein the aqueous composition contains sodium dequaminate at a concentration of 3% (w/v) and has a viscosity of 1.5 to 30 mPa·s at 25°C.

(23) An ophthalmic pharmaceutical product as described in any one of (19) to (22), which is administered as eye drops 2 to 4 times a day.

(24) An ophthalmic pharmaceutical product as described in any one of (19) to (22), which is administered as eye drops three times a day.

(25) An ophthalmic pharmaceutical product as described in (23) or (24), which is administered into the eye in the form of 1 to 2 drops at a time.

(26) The aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinyl pyrrolidone having a K value of 17 or more.

(27) The aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinyl pyrrolidone having a K value of 17 to 120.

(28) The aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinyl pyrrolidone 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), comprising polyvinyl pyrrolidone having a K value of 90.

(30) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the concentration of the polyvinyl pyrrolidone 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 diquatsol or a salt thereof 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 diquatsol 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 diquatsol 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 diquatsol or its salt is 3% (w/v).

(35) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the pH value 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 value 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) The 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 dequafosol is dequafosol sodium.

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

(42) An aqueous ophthalmic composition for preventing or treating dry eye, comprising 3% (w/v) diquatsol sodium, polyvinyl pyrrolidone and silver nitrate, and having a viscosity of 3 to 30 mPa·s at 25°C. The composition is characterized in that it is administered in the form of 1 to 2 drops at a time, 2 to 4 times a day.

(43) The aqueous ophthalmic composition as described in (41) or (42), which is administered by eye drops three times a day.

(44) An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, wherein a single-dose eye drop container is filled with 0.1 to 1 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone with a K value of 90, and the aqueous ophthalmic composition is administered into the eye 1 to 2 drops at a time, 2 to 4 times a day.

(45) An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, wherein a single-dose eye drop container is filled with 0.1 to 1 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone, the aqueous ophthalmic composition having a viscosity of 3 to 30 mPa·s at 25°C, and is used in the form of 1 to 2 drops per time, 2 to 4 times a day.

(46) An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, wherein a multi-dose eye drop container is filled with 1 to 10 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone with a K value of 90, and the aqueous ophthalmic composition is administered into the eye 1 to 2 drops at a time, 2 to 4 times a day.

(47) An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, wherein a multi-dose eye drop container is filled with 1 to 10 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone, the aqueous ophthalmic composition having a viscosity of 3 to 30 mPa·s at 25°C, and is used in the form of 1 to 2 drops per time, 2 to 4 times a day.

(48) An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, wherein 1 to 10 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone with a K value of 90 is filled in a PFMD container, and the aqueous ophthalmic composition is administered into the eye 1 to 2 drops at a time and 2 to 4 times a day.

(49) An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, wherein 1 to 10 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone 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 in the form of 1 to 2 drops per time, 2 to 4 times a day, for eye administration.

(50) An ophthalmic pharmaceutical product as described in any one of (44) to (49), which is administered as eye drops three times a day.

(51) An ophthalmic pharmaceutical product as described in any one of (46) or (47), which further contains silver nitrate.

In addition, the present invention also relates to the following contents. (A-1) A method for treating dry eye disease, comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a single-dose eye drop container once, 2 to 4 times a day, wherein the aqueous ophthalmic composition contains 3% (w/v) diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and the single-dose eye drop container is filled with 0.1 to 1 mL of the aqueous ophthalmic composition.

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

(A-3) A method for treating dry eye disease, 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) diquatsol sodium and polyvinylpyrrolidone with 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 disease, 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) of sodium diquat 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.

(A-5) A method for treating dry eye disease, 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, wherein the aqueous ophthalmic composition contains 3% (w/v) dequafosol sodium and polyvinylpyrrolidone with a K value of 90, and the PFMD container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

(A-6) A method for treating dry eye disease, 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) of sodium diquat and polyvinylpyrrolidone and 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) The method for treating dry eye as described in any one of (A-1) to (A-6), comprising administering 1 to 2 drops of the aqueous ophthalmic composition to the patient three times a day.

(B-1) An ophthalmic pharmaceutical product, characterized in that: it is used to prevent or treat dry eye syndrome, and is prepared by filling a single-dose eye drop container with 0.1 to 1 mL of an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition contains 3% (w/v) diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and is used in the form of 1 to 2 drops per time, 2 to 4 times a day.

(B-2) An ophthalmic pharmaceutical product, characterized in that: it is used to prevent or treat dry eye syndrome, and is prepared by filling a single-dose eye drop container with 0.1 to 1 mL of an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition contains 3% (w/v) of sodium diquat and polyvinyl pyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and is used in the form of 1 to 2 drops per time, 2 to 4 times a day.

(B-3) An ophthalmic pharmaceutical product, characterized in that: it is used to prevent or treat dry eye syndrome, and is prepared by filling a multi-dose eye drop container with 1 to 10 mL of an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition contains 3% (w/v) diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and is used in the form of 1 to 2 drops per time, 2 to 4 times a day.

(B-4) An ophthalmic pharmaceutical product, characterized in that: it is used to prevent or treat dry eye syndrome, and is prepared by filling a multi-dose eye drop container with 1 to 10 mL of an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition contains 3% (w/v) of sodium diquat and polyvinylpyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and is used in the form of 1 to 2 drops per time, 2 to 4 times a day.

(B-5) An ophthalmic pharmaceutical product, characterized in that: it is used for preventing or treating dry eye syndrome, and is prepared by filling a PFMD container with 1 to 10 mL of an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition contains 3% (w/v) diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and is used in the form of 1 to 2 drops per time, 2 to 4 times a day.

(B-6) An ophthalmic pharmaceutical product, characterized in that: it is used for preventing or treating dry eye syndrome, and is prepared by filling a PFMD container with 1 to 10 mL of an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition contains 3% (w/v) of sodium diquat and polyvinyl pyrrolidone and has a viscosity of 3 to 30 mPa·s at 25°C, and is used in the form of 1 to 2 drops per time and 2 to 4 times per day.

(B-7) The ophthalmic pharmaceutical product as described in any one of (B-1) to (B-6), which is used in the form of an aqueous ophthalmic composition administered in the eye 1 to 2 drops once, 3 times a day.

(C-1) A use of an aqueous ophthalmic composition, characterized in that it is used to manufacture a medicine for preventing or treating dry eye disease, the aqueous ophthalmic composition contains 3% (w/v) diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and is filled with 0.1 to 1 mL of the aqueous ophthalmic composition in a single-dose eye drop container, and is used in the form of 1 to 2 drops per time and 2 to 4 times a day.

(C-2) A use of an aqueous ophthalmic composition, characterized in that: it is used to manufacture a medicine for preventing or treating dry eye disease, the aqueous ophthalmic composition contains sodium diquat and polyvinylpyrrolidone at a concentration of 3% (w/v) and has a viscosity of 3 to 30 mPa·s at 25°C, and is filled with 0.1 to 1 mL of the aqueous ophthalmic composition in a single-dose eye drop container and is used in the form of 1 to 2 drops per time and 2 to 4 times a day.

(C-3) A use of an aqueous ophthalmic composition, characterized in that it is used to manufacture a medicine for preventing or treating dry eye disease, the aqueous ophthalmic composition contains 3% (w/v) diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and is filled with 1 to 10 mL of the aqueous ophthalmic composition in a multi-dose eye drop container, and is used in the form of 1 to 2 drops per time and 2 to 4 times a day.

(C-4) A use of an aqueous ophthalmic composition, characterized in that: it is used to manufacture a medicine for preventing or treating dry eye syndrome, the aqueous ophthalmic composition contains 3% (w/v) of sodium diquat and polyvinyl pyrrolidone, and has a viscosity of 3 to 30 mPa·s at 25°C, and is filled with 1 to 10 mL of the aqueous ophthalmic composition in a multi-dose eye drop container, and is used in the form of 1 to 2 drops per time and 2 to 4 times a day.

(C-5) A use of an aqueous ophthalmic composition, characterized in that: it is used to manufacture a medicine for preventing or treating dry eye syndrome, the aqueous ophthalmic composition contains 3% (w/v) diquafosol sodium and polyvinylpyrrolidone with a K value of 90, 1 to 10 mL of the aqueous ophthalmic composition is filled in a PFMD container, and the composition is administered in the form of 1 to 2 drops per time and 2 to 4 times a day.

(C-6) A use of an aqueous ophthalmic composition, characterized in that: it is used to manufacture a medicine for preventing or treating dry eye syndrome, the aqueous ophthalmic composition contains 3% (w/v) of sodium diquat and polyvinyl pyrrolidone, and has a viscosity of 3 to 30 mPa·s at 25°C, and is filled with 1 to 10 mL of the aqueous ophthalmic composition in a PFMD container, and is used in the form of 1 to 2 drops per time and 2 to 4 times a day for eye administration.

(C-7) The use of the aqueous ophthalmic composition as described in any one of (C-1) to (C-6), wherein the aqueous ophthalmic composition is administered in the form of 1 to 2 drops once, 3 times a day.

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

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

Furthermore, any two or more of the above-mentioned components of the present invention may be selected and combined. [Effect of the invention]

Since the present composition has a higher tear volume increasing effect, it is expected that the present composition has a stronger dry eye treatment effect than the existing DIQUAS ^{( registered trademark )} eye drops. Therefore, it is also expected that the present composition can exert the same or higher dry eye treatment effect at a lower concentration than the existing DIQUAS ^{( registered trademark )} eye drops. In addition, the existing DIQUAS ^{( registered trademark )} eye drops require eye drops 6 times a day, and there are patients who cannot obtain the expected effect due to poor eye drop compliance. However, the present composition having a certain viscosity and containing polyvinyl pyrrolidone having a certain K value can exert a therapeutic effect equal to or greater than that of the existing DIQUAS ^{( registered trademark )} eye drops with a fewer number of eye drops than the existing DIQUAS ^{( registered trademark )} eye drops, so it is expected that the eye drop compliance will be improved.

Furthermore, it is expected that the composition will exhibit high viable cell activity, be safer for the corneal and conjunctival epithelium, and not exhibit nerve irritation, thereby improving the comfort of eye drops.

Furthermore, even if the present composition contains silver salt, the silver salt is stable and exhibits excellent preservation effect.

The present invention is further described in detail. In this specification, "(w/v)%" means the mass (g) of the target ingredient contained in 100 mL of the aqueous ophthalmic composition of the present invention.

In this specification, "PVP" means polyvinyl pyrrolidone. In this specification, "HEC" means hydroxyethyl cellulose.

In this specification, "CMC-Na" means sodium carboxymethyl cellulose.

In this specification, "HPMC" means hydroxypropyl methylcellulose.

In this specification, "CVP" means carboxyvinyl polymer. In this specification, "Diquafosol eye drops" means aqueous eye drops containing diquafosol or its salt.

In this specification, "decubital sodium eye drops" refers to aqueous eye drops containing decubital sodium.

"Diquafuso" is a compound represented by the following chemical structure.

[Chemistry 1]

As for the "salt of diquafuso", there is no special restriction as long as it is a salt permitted in medicine, and examples thereof include: salts of metals such as lithium, sodium, potassium, calcium, magnesium, and zinc; salts of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts of acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, hydroxyethanesulfonic acid, lactobionic acid, oleic acid, penic acid, polygalacturonic acid, stearic acid, tannic acid, tris(III) acid, and tartrate. Salts of organic acids such as fluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; salts of quaternary ammonium such as methyl bromide and methyl iodide; salts of halogen ions such as bromine ion, chloride ion, and iodine ion; salts of ammonia; salts of organic amines such as triethylenediamine, 2-aminoethanol, 2,2-imidobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethylenediamine, etc.

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

In the case where "Diquafosol or its salt" has polymorphs and polymorph groups (polymorph systems), such polymorphs and polymorph groups (polymorph systems) are also included in the scope of the present invention. Here, the polymorph group (polymorph system) means each crystal form in each stage and the entire process thereof when the crystal form changes according to the conditions and states of the production, crystallization, storage, etc. of the crystals.

The "diquat or its salt" of the present invention is preferably diquat sodium salt, and more preferably diquat tetrasodium salt (also referred to as "diquat sodium" in this specification) represented by the following chemical structure.

[Chemistry 2]

Dequafuso or its salt can be produced by the method disclosed in Japanese Patent Publication No. 2001-510484.

The present composition may contain active ingredients other than diquafosol or its salt, or may contain diquafosol or its salt as the only active ingredient.

In the present invention, the concentration of diquatsol or its salt is not particularly limited, for example, preferably 0.0001-10% (w/v), more preferably 0.001-5% (w/v), further preferably 0.01-5% (w/v), further preferably 0.1-5% (w/v), further preferably 1-5% (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) , 0.08%(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).

In the present invention, "polyvinyl pyrrolidone" is a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone, and is usually used as a thickener. Polyvinyl pyrrolidone is also called povidone. The K value of the polyvinyl pyrrolidone used in the present invention is preferably 17 or more, more preferably 17 to 120, further preferably 25 to 120, further preferably 30 to 120, further preferably more than 30 and less than 120, further preferably 40 to 120, particularly preferably 60 to 120, particularly preferably 60 to 90, and further preferably 90. For example, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K40, polyvinyl pyrrolidone K50, polyvinyl pyrrolidone K60, polyvinyl pyrrolidone K70, polyvinyl pyrrolidone K80, polyvinyl pyrrolidone K85, polyvinyl pyrrolidone K90, polyvinyl pyrrolidone K120, etc. In addition, the K value of polyvinyl pyrrolidone is a viscosity characteristic value related to the molecular weight, which is a value calculated by applying the relative viscosity value (25°C) measured by a capillary viscometer to the following Fikentscher formula (1).

[Number 1]

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

Here, according to the description related to the K value of "Povidone" in the 17th revised edition of the Japanese Pharmacopoeia, the K value is 90 to 108% of the displayed K value. Therefore, for example, "K90" refers to the range of 81 to 97.2 for the viscosity characteristic value (K value) calculated by the above formula (1).

In the present invention, a single type of polyvinyl pyrrolidone may be used, or two or more types of polyvinyl pyrrolidone having different K values may be used in combination.

In the present invention, the concentration of polyvinyl pyrrolidone is not particularly limited, for example, it is 0.001% (w/v) or more, preferably 0.001-10% (w/v), more preferably 0.01-10% (w/v), further preferably 0.05-10% (w/v), further preferably 0.1-10% (w/v), particularly preferably 0.1-5% (w/v), and particularly preferably 1-5% (w/v).

The present composition may be further added with pharmaceutically acceptable preservatives as needed. Examples include: silver salts such as silver nitrate, benzyl ammonium chloride, benzyl ammonium bromide, benzethonyl ammonium chloride, lohexidine gluconate, boric acid, borax, sorbic acid, potassium sorbate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, chlorobutanol, polychlorinated ammonium, polyhexamethylene biguanide hydrochloride, and the like.

The following test results clearly show that the present composition containing silver salt has excellent preservation effect, so the preferred preservative in the present invention is 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, silver protein, etc., preferably silver nitrate.

In the present invention, the concentration of the silver salt is not particularly limited. For example, as long as it is within the range of 0.00000001 to 1% (w/v), there is no particular limitation. Specifically, the lower limit is preferably, for example, 0.00000001% (w/v) or more, 0.0000001% (w/v) or more, 0.000001% (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. The upper limit thereof 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 above-mentioned polyvinyl pyrrolidone or preservatives, the composition may further contain pharmaceutically acceptable additives as required. For example, the following additives may be selected and added as needed: buffers such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, ε-aminocaproic acid, etc.; tensile agents such as calcium chloride, sodium chloride, potassium chloride, concentrated glycerol, etc.; stabilizers such as sodium ethylenediaminetetraacetate, sodium ethylenediaminetetraacetate hydrate, citric acid hydrate, sodium citrate hydrate, etc.; surfactants such as polysorbate, etc.; antioxidants such as ascorbic acid, etc.; thickeners (also called viscosity enhancers) such as hydroxyethyl cellulose and hydroxypropyl methyl cellulose, etc.; pH adjusters such as hydrochloric acid and sodium hydroxide, etc. These additives may be used alone or in combination of two or more. Furthermore, the composition may not contain cellulose-based polymers such as hydroxyethyl cellulose and hydroxypropyl methyl cellulose as thickeners.

The pH value of the present composition is not limited to a specific value as long as it is within the pharmaceutically acceptable range. However, the pH value of the present composition is preferably 8 or less, more preferably in the range of 4 to 8, further preferably in the range of 5 to 8, further preferably in the range of 6 to 8, particularly preferably in the range of 7 to 8, and particularly preferably about 7. More specifically, for example, the pH value is preferably 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, and more preferably 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.

In the present invention, "ophthalmic composition" refers to a composition used for preventing and/or treating eye diseases, etc. As its dosage form, for example, it can be listed as: eye drops, eye ointments, injections, ointments (for example, can be administered to the eyelid skin), etc., preferably eye drops. Here, eye drops have the same meaning as eye drops or eye drops, and contact lens eye drops are also included in the definition of eye drops.

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

Depending on the properties and content of the active ingredients or additives, the composition can be a dissolving eye drop or a suspension eye drop.

The present composition is preferably a sterile aqueous eye drop. Here, sterility refers to a state in which microorganisms are killed or removed, and specifically, for example, refers to a state that meets the preservation efficacy test criteria described in the 17th revised edition of the Japanese Pharmacopoeia.

The present composition is preferably stored at room temperature. The viscosity of the present composition is not particularly limited as long as it is within a pharmaceutically acceptable range. For example, it is preferably adjusted to be within a range of 1 to 500 mPa·s, more preferably within a range of more than 1.4 and 100 mPa·s or less, further preferably within a range of 1.5 to 100 mPa·s, further preferably within a range of 1.5 to 50 mPa·s, further preferably within a range of 1.5 to 30 mPa·s, further preferably within a range of 1.5 to 20 mPa·s, particularly preferably within a range of 1.5 to 10 mPa·s, further preferably within a range of 2 to 10 mPa·s, particularly preferably within a range of 3 to 10 mPa·s, further preferably within a range of 5 to 10 mPa·s, further preferably within a range of 7 to 10 mPa·s. In addition, the viscosity of the present 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, further preferably within the range of 5 to 30 mPa·s, and particularly preferably within the range of 7 to 30 mPa·s. As the lower limit value of the viscosity of the present composition, for example, it is preferably 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. In addition, as its upper limit value, for example, it is preferably 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 was measured by a rotational viscometer (25°C; shear rate of 50 s ^-1 ).

The osmotic pressure of the present composition is not limited to a specific value as long as it is within the medically acceptable range, but the osmotic pressure of the present composition is preferably 2 or less, more preferably in the range of 0.5 to 2, further preferably in the range of 0.7 to 1.6, further preferably in the range of 0.8 to 1.4, and particularly preferably in the range of 0.9 to 1.2.

The present composition can be stored in an airtight container, specifically, an eye drop container. Examples of the eye drop container filled with the present composition include: a "multi-dose eye drop container" or a "single-dose eye drop container".

In the present invention, "ophthalmic pharmaceutical product" refers to an ophthalmic pharmaceutical product formed by filling the present composition in an eye drop container. Here, as an "ophthalmic pharmaceutical product", for example, eye drops can be listed. Furthermore, the definitions of each term in the "ophthalmic pharmaceutical product" of the present invention are the same as the definitions of each term in the "present composition".

In the present invention, "multi-dose eye drop container" refers to an eye drop container having a container body and a lid that can be installed on the container body, and the lid can be opened and resealed freely. The multi-dose eye drop container usually contains multiple doses of eye drops for use within a certain period of time. In addition, when the present composition does not contain preservatives such as benzyl ammonium chloride, the present composition can also be contained in a PFMD (Preservative Free Multi Dose) container. In addition, the filling amount of the present composition filled into the multi-dose eye drop container or the PFMD container is, for example, preferably 1 to 20 mL, more preferably 1 to 15 mL, further preferably 1 to 10 mL, further preferably 2.5 to 10 mL, and particularly preferably 5 mL.

On the other hand, a "single-dose eye drop container" refers to an eye drop container in which a cap is fused and sealed at the bottle mouth, and the fusion portion between the cap and the bottle body is broken and unsealed for use. The single-dose eye drop container contains eye drops for one or more uses. Furthermore, the eye drops contained in the single-dose eye drop container usually do not contain preservatives such as benzalkonium chloride. In addition, the filling amount of the present composition filled in the single-dose eye drop container is, for example, preferably 0.1 to 1 mL, more preferably 0.1 to 0.5 mL, further preferably 0.3 mL to 0.5 mL, and particularly preferably 0.3 mL or 0.4 mL.

The usage of the composition can be appropriately changed according to the dosage form, the severity of the symptoms of the patient to be administered, the age, weight, the doctor's judgment, etc. For example, when eye drops are selected as the dosage form, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 2 to 4 times a day, and further preferably 3 times a day can be administered in an amount of 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 1 drop. Here, the frequency of eye drops is more specifically, for example, 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 2 times a day, further preferably 4 times a day, 3 times a day or 2 times a day, and particularly preferably 3 times a day.

Furthermore, when the concentration of diquafosol or a salt thereof in the present composition is 3% (w/v), the composition can be administered 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, preferably 6 times a day, 4 times a day, 3 times a day or 2 times a day, more preferably 4 times a day or 3 times a day, and particularly preferably 3 times a day, with 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 1 drop, in the form of eye drops.

Moreover, one drop is preferably 10 to 50 μL, more preferably 20 to 50 μL, and even more preferably 40 to 50 μL.

The composition is used to prevent or treat dry eye disease and is effective as a preventive or therapeutic agent for dry eye disease. Dry eye disease is defined as "a chronic disease of tears and corneal and conjunctival epithelium caused by various factors, accompanied by eye discomfort or visual abnormalities", and keratoconjunctivitis sicca (KCS) is included in dry eye disease. In the present invention, the occurrence of dry eye disease symptoms caused by wearing soft contact lenses is also included in dry eye disease.

Symptoms of dry eye include not only subjective symptoms such as dry eyes, eye discomfort, eye fatigue, dullness, photophobia, eye pain, and foggy vision (blurred vision), but also subjective symptoms such as congestion and corneal and conjunctival epithelial damage. Furthermore, in the present invention, "preventing or treating dry eye" also includes improving the above subjective symptoms and/or subjective symptoms.

There are many unclear aspects about the causes of dry eye. Reported causes include sicca syndrome, congenital alacrimal gland disease, sarcoidosis, graft versus host disease (GVHD) caused by bone marrow transplantation, ocular pemphigoid, Stevens-Johnson syndrome, tear duct obstruction caused by trachoma, diabetes, decreased reflex secretion caused by orthokeratology (LASIK), cataract dysfunction, decreased oil layer caused by blepharitis, incomplete blinking or closure of the eyelids caused by proptosis and lagophthalmos, decreased secretion of mucin from embryonic cells, and VDT (Visual Display Terminals, visual display terminals) operations, etc.

In addition, the present composition can be administered to the eyes of patients with dry eye who wear soft contact lenses. Here, administering the eye drops to the eyes of patients with dry eye who wear soft contact lenses means administering the eye drops while the dry eye patient is wearing soft contact lenses on the cornea. [Example]

The following are the results of pharmacological tests and preparation examples, but they are for better understanding of the present invention and do not limit the scope of the present invention.

[Test 1] Using normal male white rabbits, the time-dependent changes in tear volume after eye drops of the present composition were evaluated.

(Sample preparation method) Eye drops 1: Eye drops 1 were prepared according to the formula shown in Table 1. That is, sodium diquat (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium ethylenediaminetetraacetic acid 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. Furthermore, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and 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, and the total amount was adjusted to 100 g, followed by autoclaving (121°C for 20 minutes) to prepare a 4.00% (w/w) PVP K90 solution. 4 mL of the 3-fold concentrated solution was added to 6.0 g of the 4.00% (w/w) PVP K90 solution, and after adding sterile purified water to adjust the total amount to 12 mL, a pH adjuster was appropriately added to adjust the pH to 7, thereby preparing eye drops 1.

Eye drops 2: According to the formula shown in Table 1, eye drops 2 were prepared. That is, sodium diquat (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium ethylenediaminetetraacetic acid 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, PVP K30 (1.2 g) was dissolved, and 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. After adding sterile purified water to 4 mL of the 3-fold concentrated solution to adjust the total volume to 12 mL, an appropriate pH adjuster was added to adjust the pH value to 7 to prepare eye drops 2.

Eye drops 3: According to the formula shown in Table 1, eye drops 3 were prepared. That is, sodium diquat (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium ethylenediaminetetraacetic acid 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. Furthermore, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and 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 sterilized by autoclave (121°C for 20 minutes) to prepare a 1.00% (w/w) hydroxyethyl cellulose solution. 4 mL of the 3-fold concentrated solution was added to 3.6 g of the 1.00% (w/w) hydroxyethyl cellulose solution, and the total volume was adjusted to 12 mL by adding sterile purified water. A pH adjuster was appropriately added to adjust the pH to 7 to prepare eye drops 3.

Eye drops 4: According to the formula shown in Table 1, eye drops 4 were prepared. That is, sodium diquat (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium ethylenediaminetetraacetic acid 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. Furthermore, 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. After sterile purified water was added to 4 mL of the 3-fold concentrated solution to adjust the total amount to 12 mL, a pH adjuster was appropriately added to adjust the pH to 7, thereby preparing eye drops 4.

Eye drops 5: According to the formula shown in Table 1, eye drops 5 were prepared. That is, sodium diquat (18 g), sodium hydrogen phosphate hydrate (1.2 g), and sodium ethylenediaminetetraacetic acid hydrate (0.06 g) were dissolved in sterile purified water to make 100 mL to obtain a 6-fold concentrated solution. Furthermore, 2.5 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and PVP K60 45% aqueous solution (0.67 g) and sodium chloride (0.068 g) were dissolved, and then a pH adjuster was appropriately added to adjust the pH to 7, and sterile purified water was added to make 15 mL to prepare eye drops 5.

Furthermore, the viscosity of the prepared eye drops 1 to 5 was measured according to the method described in the 17th revised edition of the Japanese Pharmacopoeia, 2.53 Viscosity measurement method, Method 2 rotational viscometer method, 2.1.3 Cone-plate type rotational viscometer (cone-plate type viscometer). Specifically, Kinexus pro+ (manufactured by Malvern) was used, and the measurement conditions were set as follows. (Measurement conditions) Rotor angle: 1° Rotor diameter: 50 mm Sample volume: 0.57 mL Measurement temperature: 25°C Shear rate: 50 s ^-1 Measurement time: The viscosity was measured every 2 seconds, and the average value of 1 minute was set as the viscosity.

(Test 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 (a total of 16 rabbits, 32 eyes) to perform local anesthesia. 3 minutes later, Schirmer test strips (manufactured by AYUMI Pharmaceutical Co., Ltd.) were inserted into the lower eyelid, and 1 minute after insertion, the length of the wet part (tear volume) was read. This was set as the previous value. Next, each eye drop 1 to 5 was instilled once (a group of 4 rabbits, 8 eyes, and only eye drop 4 was instilled into 12 rabbits, 24 eyes). Benoxil ^{( registered trademark )} eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) was instilled into the eyes 3 minutes before the Schirmer test strips (manufactured by AYUMI Pharmaceutical Co., Ltd.) were inserted into the lower eyelid to perform local anesthesia. 60 minutes after each eye drop was instilled, a Schirmer test strip (manufactured by AYUMI Pharmaceutical Co., Ltd.) was inserted into the lower eyelid and withdrawn after 1 minute to read the length of the wet portion (tear volume).

(Evaluation method) The change in tear volume before and after the eye drops were applied was calculated as Δ tear volume (mm/min).

(Test results) The Δ tear volume (mm/min) 60 minutes after eye drops are shown in Tables 1 and 2 (each value is the average of 8 eyes. Among them, only Eye Drop 4 is the average of 24 eyes). In addition, the tear volume increasing effect of the present composition was evaluated according to the following criteria. +++: Δ tear volume (mm/min) 60 minutes after eye drops is 4 mm/min or more ++: Δ tear volume (mm/min) 60 minutes after eye drops is 1 mm/min or more and less than 4 mm/min +: Δ tear volume (mm/min) 60 minutes after eye drops exceeds 0 mm/min and does not reach 1 mm/min -: Δ tear volume (mm/min) 60 minutes after eye drops is less than 0 mm/min

[Table 1] (In Table 1, the unit is g/100 mL) Eye drops 1 2 3 4 Dequavosol Sodium 3 3 3 3 PVP K30 - 2 - - PVP K90 2 - - - HEC - - 0.3 - Sodium Hydrogen Phosphate Hydrate 0.2 0.2 0.2 0.2 Sodium EDTA hydrate 0.01 0.01 0.01 0.01 Sodium chloride 0.45 0.45 0.45 0.45 pH Adjuster qs qs qs qs pH 7.0 7.0 7.0 7.0 Viscosity (mPa•s) 7.4 1.4 26.9 1.0 Δ tear volume 60 minutes after eye drops (mm/min) 4.4 0.4 -0.6 0.3 Reviews +++ + - +

As shown in the results of Table 1 above, the eye drops containing PVP K30 (eye drops 2) and the eye drops not containing PVP K30 (eye drops 4) did not confirm the effect of increasing the tear volume 60 minutes after instillation. In addition, HEC is usually used as a thickening agent, but although the eye drops containing HEC (eye drops 3) have a relatively high viscosity, it did not confirm the effect of increasing the tear volume 60 minutes after instillation like eye drops 4. In contrast, the eye drops containing PVP K90 (eye drops 1) showed a very high effect of increasing the tear volume compared to eye drops 2 to 4.

[Table 2] (In Table 2, the unit is g/100 mL) Eye drops 5 Sodium diquat 3 PVP K60 2 Sodium Hydrogen Phosphate Hydrate 0.2 Sodium EDTA hydrate 0.01 Sodium chloride 0.45 pH Adjuster qs pH 7.0 Viscosity (mPa•s) 3.0 Δ tear volume 60 minutes after eye drops (mm/min) 4.4 Reviews +++

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

(Discussion) Polyvinyl pyrrolidone increases the viscosity of aqueous compositions containing diquat or its salts, thereby enhancing the efficacy of diquat or its salts. In particular, when polyvinyl pyrrolidone with a K value exceeding 30 is added, or when the viscosity of the aqueous composition exceeds 1.4 by adding polyvinyl pyrrolidone, the efficacy of diquat or its salts is significantly enhanced.

[Test 2] The rat orbital tear gland removal model is a commonly used model for evaluating the therapeutic effects of corneal epithelial damage caused by dry eye, and is also used as a model for evaluating the therapeutic effects of _P2Y2 receptor agonists (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). Using this dry eye model, whether the present composition can improve corneal epithelial damage by eye drops is studied.

(Method for preparing dry eye model) Male SD rats were used to prepare the rat orbital lacrimal gland removal model according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100(2001)). That is, after general anesthesia with somnopentyl, the orbital lacrimal glands were removed to induce corneal epithelial damage.

(Sample preparation method) Eye drops A: Dissolve sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediaminetetraacetic acid hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), and sodium diquat (3 g) in sterile purified water to make 100 mL, and add a pH adjuster (q.s.) to adjust the pH to 7.5.

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

Eye drops X: As eye drops X, "DIQUAS ^{( registered trademark )} eye drops 3%" (manufactured by Santen Pharmaceutical Co., Ltd.), a dry eye treatment drug, was used. Eye drops X contains 30 mg of diquatsol sodium as an active ingredient in 1 mL of water, and contains potassium chloride, sodium chloride, lohexidine gluconate salt solution, sodium hydrogen phosphate hydrate, sodium ethylenediaminetetraacetic acid hydrate, and a pH adjuster as additives.

Furthermore, the viscosity of the prepared eye drops A, B and X was measured according to the method described in the 17th revised edition of the Japanese Pharmacopoeia, 2.53 Viscosity determination method, Method 2 rotational viscometer method, 2.1.3 Cone-plate type rotational viscometer (cone-plate type viscometer). Specifically, Kinexus pro+ (manufactured by Malvern) was used, and the measurement conditions were set as follows. (Measurement conditions) Rotor angle: 1° Rotor diameter: 50 mm Sample volume: 0.57 mL Measurement temperature: 25°C Shear rate: 50 s ^-1 Measurement time: The viscosity was measured every 2 seconds, and the average value of 1 minute was set as the viscosity.

The measured viscosity of each eye drop is as follows. Eye drop A: 7.9 mPa・s Eye drop B: 28.0 mPa・s Eye drop X: 0.9 mPa・s (Test method and drug administration method) Eye drops A, B, and X were administered to rats induced with the above corneal epithelial damage as follows. ・ Eye drops A, 3 times a day administration group: Eye drops A were administered 3 times a day to both eyes for 4 weeks. (One group of 6 rats, 12 eyes) ・ Eye drops B, 3 times a day administration group: Eye drops B were administered 3 times a day to both eyes for 4 weeks. (One group of 6 rats, 12 eyes) ・ Eye drops X, 6 times a day administration group: Eye drops X were administered 6 times a day to both eyes for 4 weeks. (A group of 6 rats with 12 eyes) In addition, among the rats that did not induce the above corneal epithelial damage, those that did not receive eye drops within 4 weeks were designated as the no-eye drop group (a group of 4 rats with 8 eyes).

Four weeks after the start of eye drops, corneal epithelial damage was determined by staining the damaged part of the cornea with fluorescein according to the method of Murakami et al. (New Ophthalmology, 21(1), 87-90(2004)). That is, the degree of staining with fluorescein was scored for each of the upper, middle, and lower parts of the cornea according to the following criteria, and the average value of the scores was calculated. In addition, 0.5 was set as the median value between each score of 0, 1, 2, and 3.

(Judgment criteria) 0: No staining; 1: Sparse staining, the staining parts of each dot are separated; 2: Moderate staining, part of the staining parts of the dot are adjacent; 3: Dense staining, the staining parts of each dot are adjacent.

(Results) The calculated fluorescence staining scores of each group are plotted in Figure 1. The scores are the mean + standard error of 8 or 12 cases each.

As shown in Figure 1, in the group that received eye drops A 3 times a day, 2 weeks after the start of eye drops, improvement in the fluorescein staining score was observed compared to the group that received eye drops B 3 times a day. In the group that received eye drops X 6 times a day, 4 weeks after the start of eye drops, improvement in the fluorescein staining score was observed compared to the group that received eye drops B 3 times a day. 4 weeks after the start of eye drops, the group that received eye drops A 3 times a day and the group that received eye drops X 6 times a day showed the same degree of effect.

(Discussion) Eye drops X is used as "DIQUAS ^{( registered trademark )} eye drops 3%" for the treatment of dry eye, and the frequency of eye drops is 6 times a day. Regarding the present composition to which polyvinylpyrrolidone K90 is added, it is clear that eye drops 3 times a day have a sufficient therapeutic effect on dry eye, and in particular, after 2 weeks from the start of eye drops, a therapeutic effect exceeding the 6-times-a-day eye drops of "DIQUAS ^{( registered} trademark ⁾ eye drops 3%" was confirmed. Therefore, it is shown that the present composition exerts a therapeutic effect equal to or greater than that of the existing DIQUAS ^{( registered trademark )} eye drops with a lesser frequency of eye drops than the existing DIQUAS ^{( registered trademark )} eye drops. In particular, if the test results of Test 1 are considered, it is suggested that the present composition to which polyvinyl pyrrolidone having a K value exceeding 30 is added, or the present composition to which the viscosity exceeds 1.4 by adding polyvinyl pyrrolidone, when applied 2 to 4 times a day to the eyes, exerts a therapeutic effect equivalent to or greater than that of the existing "DIQUAS ^{( registered trademark )} eye drops 3%" applied 6 times a day.

[Test 3] In order to study the effect of this composition on corneal epithelial cells, a test on the cell damage of corneal epithelial cells was conducted.

(Sample preparation method) Prepare eye drops Y, C and D according to the formula shown in Table 3.

Eye drops Y: Eye drops Y were prepared according to the formula shown in Table 3. Specifically, sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediaminetetraacetic acid hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), and diquatsol sodium (3 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (q.s.) was added to make the pH value 7.5.

Eye drops C and D: Prepare each of eye drops C and D in the same manner as eye drops Y according to the formulations shown in Table 3.

Furthermore, the viscosity of the prepared eye drops Y, C and D was measured according to the method described in the 17th revised edition of the Japanese Pharmacopoeia, 2.53 Viscosity determination method, Method 2 rotational viscometer method, 2.1.3 Cone-plate type rotational viscometer (cone-plate type viscometer). Specifically, Kinexus pro+ (manufactured by Malvern) was used, and the measurement conditions were set as follows. (Measurement conditions) Rotor angle: 1° Rotor diameter: 50 mm Sample volume: 0.57 mL Measurement temperature: 25°C Shear rate: 50 s ^-1 Measurement time: The viscosity was measured every 2 seconds, and the average value of 1 minute was set as the viscosity.

[table 3] (In Table 3, the unit is g/100 mL) Eye drops Y C D Sodium diquat 3 3 3 PVP K90 - 2 4 Sodium Hydrogen Phosphate Hydrate 0.2 0.2 0.2 Sodium EDTA hydrate 0.01 0.01 0.01 Silver nitrate 0.00004 0.00004 0.00004 Sodium chloride 0.45 0.45 0.45 pH Adjuster qs qs qs pH 7.5 7.5 7.5 Viscosity (mPa・s) 1.0 8.1 27.2

(Test method) SV40 immortalized human corneal epithelial cells (HCE-T: RIKEN, Bio-Resource Center, Cell No.: RCB2280) were inoculated into 96-well culture plates (1×10 ⁴ cells/well) and cultured for 1 day in D-MEM/F12 medium containing 10% FBS. On the second 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. The viability of live cells (equivalent to absorbance at 490 nm) was measured using the Cell Proliferation Assay Kit (produced by Promega, catalog number: G3580).

(Results) The test results are shown in Figure 2.

As shown in Figure 2, the Dequafosol eye drops containing polyvinyl pyrrolidone (eye drops C and D) still maintained a high survival rate in immortalized human corneal epithelial cells after 15 minutes of culture. On the other hand, the survival rate of the Dequafosol eye drops without polyvinyl pyrrolidone (eye drops Y) decreased over time.

(Discussion) Since Diquafosol eye drops containing polyvinyl pyrrolidone show high cell viability in cultured immortalized human corneal epithelial cells, it is highly safe for the corneal and conjunctival epithelium and is useful for diseases such as dry eye syndrome where the corneal and conjunctival epithelium is unstable.

[Test 4] Study the irritation of diquat sodium on peripheral nerves in the presence of PVP.

(Sample preparation method) Formulation 1: Formulation 1 was prepared according to the formula shown in Table 4. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, pH was adjusted to 7.5 by adding a pH adjuster, 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 measured, and the total volume was adjusted to 20 mL with sterile purified water, and the pH was adjusted to 7.5 with a pH adjuster to obtain Formula 1.

Formula 2: Prepare Formula 2 according to the formula shown in Table 4. That is, dissolve sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) in sterile purified water, add a pH adjuster, adjust the pH to 7.5, and adjust the total volume to 100 mL to obtain a 10x buffer. Dissolve 2 mL of the 10x buffer and PVP K90 (0.4 g) in sterile purified water, use a pH adjuster to adjust the pH to 7.5, and adjust the total volume to 20 mL to obtain Formula 2.

Formula 3: Prepare Formula 3 according to the formula shown in Table 4. That is, dissolve sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) in sterile purified water, add a pH adjuster, adjust the pH to 7.5, and adjust the total volume to 100 mL to obtain a 10x buffer solution. Add 2 mL of the 10x buffer solution and chondroitin sodium sulfate (0.06 g) to sterile purified water, adjust the pH to 7.5 with a pH adjuster, confirm dissolution, and adjust the total volume to 20 mL to obtain Formula 3.

Formula 4-6: Prepare Formula 4-6 in the same manner as Formula 3 according to the formula shown in Table 4.

[Table 4] (In Table 4, the unit is g/100 mL) Liquid formula 1 2 3 4 5 6 Sodium chloride 0.85 0.85 0.85 0.85 0.80 0.85 Sodium Hydrogen Phosphate Hydrate 0.20 0.20 0.20 0.20 0.20 0.20 PVP K30 2.00 - - - - - PVP K90 - 2.00 - - - - Chondroitin Sodium Sulfate - - 0.30 - - - HPMC - - - 0.30 - - CVP - - - - 0.30 - CMC-Na - - - - - 0.30 pH Adjuster qs qs qs qs qs qs pH 7.5 7.5 7.5 7.5 7.5 7.5

(Test method) Cultivate peripheral nerve cells (rat dorsal root ganglion neurons, purchased from LONZA Japan) in a buffer solution containing intracellular calcium indicator fluorescent pigment (FLIPR Calcium 6 Assay Kit, Molecular Devices). Replace 40% of the total volume of the buffer solution with the above-mentioned formula solutions. Furthermore, for the non-stimulated group and the stimulated control group, replace the formula solution with the buffer solution and perform the same treatment. After standing at room temperature, use a fluorescent plate reader to start the time-dependent fluorescence measurement of the calcium indicator pigment. 60 seconds after the start, sodium diquat was added (final concentration: 0.3%), and the fluorescence intensity was continued to be measured.

(Evaluation method) The fluorescence intensity (RFU) just before adding diquat sodium was set as 100%, and the maximum fluorescence intensity (RFUmax) after adding was calculated.

(Test results) The results are shown in Figure 3. In the stimulated control group and formula solutions 3 to 6, after adding diquat sodium, RFU increased and recorded RFUmax of more than 103.5%. On the other hand, in each group of formula solutions 1 and 2 containing PVP, RFUmax did not reach 101%.

(Discussion) When peripheral nerve cells receive certain stimuli, they generate action potentials and enter an excited state. The stimulus signal converted into action potential is then transmitted to the central nervous system. Action potentials are changes in cell membrane potentials caused by the influx of cations containing calcium ions into cells. Therefore, the increase in calcium ion concentration in nerve cells is widely used in experiments as an indicator of the excited state of nerve cells. If peripheral nerve cells are exposed to sodium diquat, the fluorescence intensity of calcium ions in the cells will increase rapidly, indicating that the nerve cells receive sodium diquat as a stimulus and enter an excited state. The same stimulation response was also confirmed in each group of polymer formula solutions 3 to 6 that did not contain PVP as a comparative example. Each polymer of chondroitin sulfate sodium, HPMC, CVP and CMC-Na had no effect on the neuroirritation of dexamethasone sodium. In contrast, in formula solutions 1 and 2 containing PVP, no increase in calcium ion signals in nerve cells was observed after adding dexamethasone sodium. In other words, dexamethasone sodium did not show neuroirritation in the presence of PVP, and the comfort of dexamethasone sodium eye drops was improved by adding PVP.

[Test 5] Study the effect of this composition on the stability of preservatives.

(Sample preparation method) Eye drops 6: Eye drops 6 were prepared according to the formula shown in Table 5. Specifically, sodium diquat (3 g), lohexidine gluconate (0.0025 g), hydroxyethyl cellulose (0.2 g), sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediaminetetraacetic acid 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: Prepare eye drops 7-10 in the same manner as eye drops 6 according to the formula shown in Table 5.

[table 5] (In Table 5, the unit is g/100 mL) Eye drops 6 7 8 9 10 Dequavosol Sodium 3 3 3 3 3 Lohexidine gluconate salt (preservative) 0.0025 0.0025 0.0025 0.0025 - Silver nitrate (preservative) - - - - 0.00008 PVP K30 - 2 - - 2 PVP K90 - - 2 4 - HEC 0.2 0.2 - - 0.25 Sodium Hydrogen Phosphate Hydrate 0.2 0.2 0.2 0.2 0.2 Sodium EDTA hydrate 0.01 0.01 0.01 0.01 0.01 Sodium chloride 0.45 0.45 0.45 0.45 0.45 Concentrated glycerin - - 1.2 1.2 - pH Adjuster qs qs qs qs qs pH 7.5 7.5 7.5 7.5 7.5

(Test method) The content of lohexidine gluconate in eye drops 6 and 7 stored at 60°C for 4 weeks was quantified using high performance liquid chromatography (HPLC), and the residual rate (%) was calculated. The content of lohexidine gluconate in eye drops 8 and 9 stored at 60°C for 2 weeks was quantified using high performance liquid chromatography (HPLC), and the residual rate (%) was calculated. The content of silver nitrate in eye drops 10 stored at 60°C for 4 weeks was quantified using high frequency inductively coupled plasma emission spectrometry (ICP-AES), and the residual rate (%) was calculated.

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

[Table 6] Eye drops 6 7 8 9 10 Survival rate (%) 90.1 20.4 26.7 8.0 100

(Discussion) In the aqueous ophthalmic composition containing diquafosol or its salt and polyvinyl pyrrolidone (the present composition), when lohexidine gluconate salt was contained as a preservative, its residual rate was significantly reduced (eye drops 7 to 9). On the other hand, when silver nitrate as a silver salt was contained as a preservative, its residual rate was higher (eye drops 10). Based on the above content, it is shown that the present composition destabilizes lohexidine gluconate salt and stabilizes the silver salt.

[Test 6] The preservation effect of the present composition containing silver salt was studied.

(Sample preparation method) Eye drops 11: Eye drops 11 were prepared according to the formula shown in Table 7. Specifically, sodium diquat (3 g), silver nitrate (0.00008 g), sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediaminetetraacetic acid hydrate (0.01 g), polyvinylpyrrolidone K30 (2 g), concentrated glycerol (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 to 15: According to the formula shown in Table 7, prepare each of eye drops 12 to 15 in the same manner as eye drop 11.

[Table 7] (In Table 7, the unit is g/100 mL) Eye drops 11 12 13 14 15 Dequavosol Sodium 3 3 3 3 3 Silver nitrate 0.00008 0.00004 0.000016 0.000008 0.000004 Sodium Hydrogen Phosphate Hydrate 0.2 0.2 0.2 0.2 0.2 Sodium EDTA hydrate 0.01 0.01 0.01 0.01 0.01 PVP K30 2 2 2 2 2 Sodium chloride - 0.45 0.45 0.45 0.45 Concentrated glycerin 1.2 - - - - HEC 0.25 0.25 0.25 0.25 0.25 pH Adjuster qs qs qs qs qs pH 7.5 7.5 7.5 7.5 7.5

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

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

[Table 8] (Unit: logarithmic removal rate) Eye drops 11 12 13 14 15 E. coli 1 week 4.6 4.7 4.7 4.7 4.7 2 weeks 4.6 4.7 4.7 4.7 4.7 4 weeks 4.6 4.7 4.7 4.7 4.7 P.aeruginosa 1 week 4.7 4.7 4.7 4.7 4.7 2 weeks 4.7 4.7 4.7 4.7 4.7 4 weeks 4.7 4.7 4.7 4.7 4.7 S. aureus 1 week 4.7 4.6 3.1 2.3 1.8 2 weeks 4.7 4.6 4.6 4.6 4.6 4 weeks 4.7 4.6 4.6 4.6 4.6 C.albicans 1 week 4.3 3.9 3.1 2.6 2.0 2 weeks 4.6 4.8 4.8 4.8 4.2 4 weeks 4.6 4.8 4.8 4.8 4.8 A. brasiliensis 1 week 3.2 0.5 0.2 0.2 0.2 2 weeks 4.3 0.7 0.3 0.2 0.2 4 weeks 4.3 1.1 0.4 0.4 0.3 determination conform to conform to conform to conform to conform to

Furthermore, the test results in Table 8 use log reduction to indicate the extent to which the number of live bacteria at the time of testing is reduced compared to the number of bacteria at the time of inoculation. For example, when it is "1", it means that the number of live bacteria at the time of testing is reduced to 10% of the number of bacteria at the time of inoculation.

As shown in Table 8, the present composition containing silver salt meets the preservation efficacy test criteria of the Japanese Pharmacopoeia.

(Discussion) The above results show that the present composition containing silver salt has excellent preservation effect.

[Test 7] Using normal male white rabbits, the changes in tear volume over time 90 minutes after the eye drops of the present composition were evaluated.

(Sample preparation method) Eye drops 16: As eye drops 16, sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediaminetetraacetic acid hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), and sodium diquat (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 17: As eye drops 17, "DIQUAS ^{( registered trademark )} eye drops 3%" (manufactured by Santen Pharmaceutical Co., Ltd.), a dry eye treatment drug, was used. Eye drops 17 contains 30 mg of diquatsol sodium as an active ingredient in 1 mL of water, and contains potassium chloride, sodium chloride, lohexidine gluconate salt solution, sodium hydrogen phosphate hydrate, sodium ethylenediaminetetraacetic acid hydrate, and a pH adjuster as additives.

(Test method and drug administration method) Benoxil ^{( registered trademark )} eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were instilled into the eyes of normal male white rabbits (a total of 12 rabbits, 24 eyes) to perform local anesthesia. Three minutes later, a Schirmer test strip (manufactured by AYUMI Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, and after 1 minute of insertion, it was withdrawn to read the length of the wet part (amount of tears). This was set as the previous value. Next, each eye drop 16 and 17 was instilled once (a group of 6 rabbits, 12 eyes). Benoxil ^{( registered trademark )} eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) was instilled into the eyes 3 minutes before the Schirmer test strip (manufactured by AYUMI Pharmaceutical Co., Ltd.) was inserted into the lower eyelid to perform local anesthesia. 90 minutes after each eye drop was instilled, a Schirmer test strip (manufactured by AYUMI Pharmaceutical Co., Ltd.) was inserted into the lower eyelid and withdrawn after 1 minute to read the length of the wet portion (tear volume).

(Evaluation method) The change in tear volume before and after the eye drops were applied was calculated as Δ tear volume (mm/min).

(Test results) The Δ tear volume (mm/min) 90 minutes after eye drops are shown in Table 9 (each value is the average of 12 eyes). In addition, the tear volume increasing effect of the present composition was evaluated according to the following criteria. +++: Δ tear volume (mm/min) 90 minutes after eye drops is 4 mm/min or more ++: Δ tear volume (mm/min) 90 minutes after eye drops is 1 mm/min or more and less than 4 mm/min +: Δ tear volume (mm/min) 90 minutes after eye drops exceeds 0 mm/min and less than 1 mm/min -: Δ tear volume (mm/min) 90 minutes after eye drops is less than 0 mm/min

[Table 9] Eye drops 16 17 ∆ tear volume 90 minutes after eye drops (mm/min) 2.0 -0.3 Reviews ++ -

As shown in the results of Table 9, the present composition showed a high tear volume increasing effect even 90 minutes after eye drop.

[Test 8] The preservation effect of the present composition containing silver salt was studied.

(Sample preparation method) Eye drops 18: Eye drops 18 were prepared according to the formula shown in Table 10. Specifically, sodium diquat (3 g), silver nitrate (0.00003 g), sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediaminetetraacetic acid 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: Prepare eye drops 19 in the same manner as eye drops 18 according to the formulation shown in Table 10.

[Table 10] (In Table 10, the unit is g/100 mL) Eye drops 18 19 Sodium diquat 3 3 Sodium EDTA hydrate 0.01 - Sodium Hydrogen Phosphate Hydrate 0.2 0.2 PVP K90 2 2 Silver nitrate 0.00003 0.00003 Sodium chloride 0.45 0.45 pH Adjuster qs qs pH 7.0 7.0

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

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

[Table 11] (Unit: logarithmic removal rate) Eye drops 18 19 E. coli 1 week 4.1 4.1 2 weeks 4.1 4.1 4 weeks 4.1 4.1 P.aeruginosa 1 week 3.2 4.4 2 weeks 4.4 4.4 4 weeks 4.4 4.4 S. aureus 1 week 4.4 4.4 2 weeks 4.4 4.4 4 weeks 4.4 4.4 C.albicans 1 week 4.2 4.2 2 weeks 4.2 4.2 4 weeks 4.2 4.2 A. brasiliensis 1 week 0.4 0.4 2 weeks 0.3 0.3 4 weeks 0.6 0.8 determination conform to conform to

Furthermore, the test results in Table 11 use log reduction to indicate the extent to which the number of live bacteria at the time of testing is reduced compared to the number of bacteria at the time of inoculation. For example, when it is "1", it means that the number of live bacteria at the time of testing is reduced to 10% of the number of bacteria at the time of inoculation.

As shown in Table 11, the present composition containing silver salts meets the preservation efficacy test criteria of the Japanese Pharmacopoeia regardless of the presence or absence of EDTA.

(Discussion) The above results show that the present composition containing silver salt has excellent preservation effect.

[Test 9] The preservation effect of the present composition containing silver salt was studied.

(Sample preparation method) Eye drops 20: Eye drops 20 were prepared according to the formula shown in Table 12. Specifically, sodium diquat (3 g), silver nitrate (0.00004 g), sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediaminetetraacetic acid 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 to 23: According to the formula shown in Table 12, prepare each of eye drops 21 to 23 in the same manner as eye drop 20.

[Table 12] (In Table 12, the unit is g/100 mL) Eye drops 20 twenty one twenty two twenty three Sodium diquat 3 3 3 3 Sodium EDTA hydrate 0.01 - 0.01 0.01 Sodium Hydrogen Phosphate Hydrate 0.2 0.2 0.2 0.2 PVP K90 2 2 2 2 Silver nitrate 0.00004 0.00004 - - Silver phosphate - - 0.0000328 - Silver chloride - - - 0.0000337 Sodium chloride 0.45 0.45 0.45 0.45 pH Adjuster qs qs qs qs pH 7.5 7.5 7.5 7.5

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

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

[Table 13] (Unit: logarithmic removal rate) Eye drops 20 twenty one twenty two twenty three E. coli 1 week 4.9 4.9 4.9 4.9 2 weeks 4.9 4.9 4.9 4.9 4 weeks 4.9 4.9 4.9 4.9 P.aeruginosa 1 week 4.8 4.8 4.8 4.8 2 weeks 4.8 4.8 4.8 4.8 4 weeks 4.8 4.8 4.8 4.8 S. aureus 1 week 4.8 4.8 4.8 4.8 2 weeks 4.8 4.8 4.8 4.8 4 weeks 4.8 4.8 4.8 4.8 C.albicans 1 week 3.7 3.3 3.6 3.8 2 weeks 4.6 4.6 4.5 4.6 4 weeks 4.6 4.6 4.6 4.6 A. brasiliensis 1 week 0.4 0.3 0.3 0.5 2 weeks 0.5 0.5 0.6 0.8 4 weeks 0.6 0.7 1.0 1.0 determination conform to conform to conform to conform to

Furthermore, the test results in Table 13 use log reduction to indicate the extent to which the number of live bacteria at the time of testing is reduced compared to the number of bacteria at the time of inoculation. For example, when it is "1", it means that the number of live bacteria at the time of testing is reduced to 10% of the number of bacteria at the time of inoculation.

As shown in Table 13, the compositions containing silver salts, whether or not EDTA is present, meet the preservation efficacy test criteria of the Japanese Pharmacopoeia. In addition, eye drops containing silver phosphate or silver chloride as silver salts in addition to silver nitrate also meet the preservation efficacy test criteria of the Japanese Pharmacopoeia.

(Discussion) The above results show that the present composition containing silver salt has excellent preservation effect.

[Test 10] Study the effect of this composition on the stability of preservatives.

(Sample preparation method) Eye drops 24: Sodium diquat (3 g), sodium ethylenediaminetetraacetic acid 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 eye drops 24.

(Test method) The content of silver nitrate in eye drops 24 stored at 40°C for 6 months was quantified using high frequency inductively coupled plasma emission spectrometry (ICP-AES), and its residual rate (%) was calculated.

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

[Table 14] Survival rate (%) 40℃ 6 months 97.0

(Discussion) When silver nitrate as a silver salt is used as a preservative, the residual rate is higher. Based on the above content, it is shown that the silver salt is stable in this composition.

[Preparation Examples] Preparation examples are listed to further specifically describe the pharmaceutical preparation of the present invention, but the present invention is not limited to these preparation examples.

(Formula Example 1: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Sodium ethylenediaminetetraacetic acid hydrate              0.0001～0.1 g Polyvinylpyrrolidone K90                 0.0001～10 g pH adjuster                               Appropriate amount The above eye drops can be prepared by adding sodium diquatsol and the above ingredients other than it to sterile purified water and mixing them thoroughly. 1～10 mL of the above eye drops are filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic pharmaceutical product. Alternatively, 0.1 to 1 mL of the above eye drops can be filled into a single-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the above eye drops can be stored at room temperature.

(Formula Example 2: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Sodium ethylenediaminetetraacetic acid hydrate              0.0001～0.1 g Polyvinylpyrrolidone K60                 0.0001～10 g pH adjuster                               Appropriate amount The above eye drops can be prepared by adding sodium diquatsol and the above ingredients other than it to sterile purified water and mixing them thoroughly. 1～10 mL of the above eye drops are filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic pharmaceutical product. Alternatively, 0.1 to 1 mL of the above eye drops can be filled into a single-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the above eye drops can be stored at room temperature.

(Formula Example 3: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Sodium ethylenediaminetetraacetic acid hydrate              0.0001～0.1 g Polyvinylpyrrolidone K40                 0.0001～10 g pH adjuster                               Appropriate amount The above eye drops can be prepared by adding sodium diquatsol and the above ingredients other than it to sterile purified water and mixing them thoroughly. 1～10 mL of the above eye drops are filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic pharmaceutical product. Alternatively, 0.1 to 1 mL of the above eye drops can be filled into a single-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the above eye drops can be stored at room temperature.

(Formula Example 4: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Sodium ethylenediaminetetraacetic acid hydrate             0.0001～0.1 g Polyvinylpyrrolidone K90                 0.0001～10 g Silver nitrate                                        0.00000001～1 g pH adjuster                                Appropriate amount The above-mentioned eye drops can be prepared by adding diquat sodium and the above-mentioned ingredients other than diquat sodium to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above-mentioned eye drops can be filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the above-mentioned eye drops can be stored at room temperature.

(Formula Example 5: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Sodium ethylenediaminetetraacetic acid hydrate             0.0001～0.1 g Polyvinylpyrrolidone K60                 0.0001～10 g Silver nitrate                                        0.00000001～1 g pH adjuster                                Appropriate amount The above-mentioned eye drops can be prepared by adding diquat sodium and the above-mentioned ingredients other than diquat sodium to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above-mentioned eye drops can be filled into a multi-dose eye drop container to manufacture an ophthalmic pharmaceutical product. Furthermore, the above-mentioned eye drops can be stored at room temperature.

(Formula Example 6: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Sodium ethylenediaminetetraacetic acid hydrate              0.0001～0.1 g Polyvinylpyrrolidone K40                 0.0001～10 g Silver nitrate                                        0.00000001～1 g pH adjuster                                Appropriate amount The above-mentioned eye drops can be prepared by adding diquat sodium and the above-mentioned ingredients other than diquat sodium to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above-mentioned eye drops can be filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the above-mentioned eye drops can be stored at room temperature.

(Formula Example 7: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                               3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Polyvinyl pyrrolidone K90                 0.0001～10 g pH adjuster                               Appropriate amount The above eye drops can be prepared by adding sodium diquatsol and the above ingredients other than it to the sterilized purified solution and mixing them thoroughly. 1～10 mL of the above eye drops can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic pharmaceutical product. In addition, 0.1～1 mL of the eye drops are filled into a single-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the eye drops can be stored at room temperature.

(Formula Example 8: Sterile aqueous eye drops (3% (w/v)) In 100 mL Diquafosol sodium                                    3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Polyvinyl pyrrolidone K60                 0.0001～10 g pH adjuster                               appropriate amount The above eye drops can be prepared by adding diquafosol sodium and the above ingredients other than it to sterile purified water and mixing them thoroughly. 1～10 mL of the above eye drops can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic pharmaceutical product. In addition, 0.1～1 mL of the eye drops are filled into a single-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the eye drops can be stored at room temperature.

(Formula Example 9: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Polyvinyl pyrrolidone K40                 0.0001～10 g pH adjuster                               Appropriate amount The above eye drops can be prepared by adding sodium diquatsol and the above ingredients other than it to sterile purified water and mixing them thoroughly. 1～10 mL of the above eye drops can be filled into a multi-dose eye drop container or a PFMD container to manufacture an ophthalmic pharmaceutical product. In addition, 0.1～1 mL of the eye drops are filled into a single-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the eye drops can be stored at room temperature.

(Formula Example 10: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Polyvinyl pyrrolidone K90                 0.0001～10 g Silver nitrate                                            0.00000001～1 g pH adjuster                                   Appropriate amount The above eye drops can be prepared by adding sodium diquatsol and the above ingredients other than it to sterile purified water and mixing them thoroughly. 1～10 mL of the eye drops are filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the eye drops can be stored at room temperature.

(Formula Example 11: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Polyvinylpyrrolidone K60                 0.0001～10 g Silver nitrate                                            0.00000001～1 g pH adjuster                                   appropriate amount The above eye drops can be prepared by adding sodium diquatsol and the above ingredients other than it to sterile purified water and mixing them thoroughly. 1～10 mL of the eye drops are filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the eye drops can be stored at room temperature.

(Formula Example 12: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Polyvinyl pyrrolidone K40                 0.0001～10 g Silver nitrate                                            0.00000001～1 g pH adjuster                                   appropriate amount The above eye drops can be prepared by adding sodium diquatsol and the above ingredients other than it to sterile purified water and mixing them thoroughly. 1～10 mL of the eye drops are filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the eye drops can be stored at room temperature.

(Formula Example 13: Sterile aqueous eye drops (3% (w/v)) In 100 mL Diquafosol sodium                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Citric acid hydrate                             0.0001～0.1 g Polyvinyl pyrrolidone K90                 0.0001～10 g pH adjuster                                   appropriate amount The above eye drops can be prepared by adding diquafosol sodium and the above ingredients other than diquafosol sodium to sterile purified water and mixing them thoroughly. 1～10 mL of the above eye drops are filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic pharmaceutical product. Alternatively, 0.1 to 1 mL of the above eye drops can be filled into a single-dose eye drop container to produce an ophthalmic pharmaceutical product. Furthermore, the above eye drops can be stored at room temperature.

(Formula Example 14: Sterile aqueous eye drops (3% (w/v)) In 100 mL Sodium diquatsol                                3 g Sodium hydrogen phosphate hydrate                         0.01～0.5 g Sodium chloride                                        0.01～1 g Citric acid hydrate                             0.0001～0.1 g Polyvinyl pyrrolidone K90                 0.0001～10 g Silver nitrate                                       0.00000001～1 g pH adjuster                                Appropriate amount The above-mentioned eye drops can be prepared by adding diquat sodium and the above-mentioned ingredients other than diquat sodium to sterile purified water and mixing them thoroughly. 1 to 10 mL of the above-mentioned eye drops can be filled into a multi-dose eye drop container to manufacture an ophthalmic pharmaceutical product. Furthermore, the above-mentioned eye drops can be stored at room temperature. [Industrial Applicability]

The existing DIQUAS ^{( registered trademark )} eye drops need to be applied 6 times a day, but there are patients with severe dry eye who cannot obtain sufficient therapeutic effects even with the prescribed dosage. Furthermore, there are patients who cannot obtain the expected effects due to poor compliance with eye drops. This composition exerts a stronger effect on the treatment of dry eye than the existing DIQUAS ^{( registered trademark )} eye drops, and in addition, it is expected to improve eye drop compliance by reducing the number of eye drops. In addition, it is also expected that this composition will exert the same or greater effect on the treatment of dry eye at a concentration lower than that of the existing DIQUAS ^{( registered trademark )} eye drops.

Furthermore, it is expected that the composition will exhibit high viable cell activity, be safer for the corneal and conjunctival epithelium, and not exhibit nerve irritation, thereby improving the comfort of eye drops.

Furthermore, even if silver salt is contained in the present composition, the silver salt is stable and exhibits excellent preservation effect.

Figure 1 is a graph showing the corneal fluorescence staining score. Figure 2 is a graph showing the results of a cell damage test using corneal epithelial cells. Figure 3 is a graph showing the maximum fluorescence intensity (RFUmax) after adding dequafosol sodium.

Claims (61)

An aqueous ophthalmic composition, which contains diquafosol or its salt and polyvinyl pyrrolidone and is filled in a multi-dose eye drop container, and the filling amount of the aqueous ophthalmic composition is 1~10mL. The aqueous ophthalmic composition of claim 1 further contains silver salt. The aqueous ophthalmic composition of claim 2, wherein the silver salt comprises silver nitrate. An aqueous ophthalmic composition as claimed in any one of claims 1 to 3, which is used for preventing or treating dry eye. The aqueous ophthalmic composition of claim 4 contains sodium dequafosol at a concentration of 1-5% (w/v) and polyvinyl pyrrolidone with a K value exceeding 30 and below 120. The aqueous ophthalmic composition of claim 4 contains 3% (w/v) sodium dequafosol and polyvinyl pyrrolidone with a K value greater than 30 and less than 120. The aqueous ophthalmic composition of claim 4 contains sodium dequafosol at a concentration of 1-5% (w/v) and has a viscosity of 1.5-30 mPa‧s at 25°C. The aqueous ophthalmic composition of claim 4 contains sodium diquat at a concentration of 3% (w/v) and has a viscosity of 1.5-30 mPa‧s at 25°C. For example, the aqueous ophthalmic composition of claim 5 is used by eye drops 2 to 4 times a day. For example, the aqueous ophthalmic composition of claim 6 is used by eye drops 2 to 4 times a day. For example, the aqueous ophthalmic composition of claim 7 is used by eye drops 2 to 4 times a day. For example, the aqueous ophthalmic composition of claim 8 is used by eye drops 2 to 4 times a day. For example, the aqueous ophthalmic composition of claim 5 is used by eye drops three times a day. For example, the aqueous ophthalmic composition of claim 6 is used by eye drops three times a day. For example, the aqueous ophthalmic composition of claim 7 is used by eye drops three times a day. For example, the aqueous ophthalmic composition of claim 8 is used by eye drops three times a day. For example, the aqueous ophthalmic composition of claim 9 is used by administering 1 to 2 drops into the eye at a time. An ophthalmic pharmaceutical product characterized in that: a multi-dose eye drop container is filled with 1 to 10 mL of an aqueous ophthalmic composition as described in any one of claims 1 to 3. An ophthalmic pharmaceutical product characterized in that: a multi-dose eye drop container is filled with 5 mL of an aqueous ophthalmic composition as described in any one of claims 1 to 3. An ophthalmic pharmaceutical product characterized in that: 1 to 10 mL of the aqueous ophthalmic composition as described in claim 1 is filled in a PFMD container. An ophthalmic pharmaceutical product characterized in that: a PFMD container is filled with 5 mL of the aqueous ophthalmic composition as described in claim 1. For ophthalmic medicinal products as claimed in item 20 or 21, they are used to prevent or treat dry eye syndrome. For example, the ophthalmic pharmaceutical product of claim 22, wherein the aqueous ophthalmic composition contains sodium dequafrolate at a concentration of 1-5% (w/v) and polyvinyl pyrrolidone with a K value exceeding 30 and below 120. For example, the ophthalmic pharmaceutical product of claim 22, wherein the aqueous ophthalmic composition contains 3% (w/v) of sodium dequafosol and polyvinyl pyrrolidone with a K value exceeding 30 and below 120. For example, the ophthalmic pharmaceutical product of claim 22, wherein the aqueous composition contains sodium dequasofrosol at a concentration of 1-5% (w/v) and has a viscosity of 1.5-30 mPa‧s at 25°C. For example, the ophthalmic pharmaceutical product of claim 22, wherein the aqueous composition contains 3% (w/v) sodium diquat and has a viscosity of 1.5-30 mPa‧s at 25°C. For example, ophthalmic pharmaceutical products in claim 23 are used by eye drops 2 to 4 times a day. For example, ophthalmic pharmaceutical products in claim 24 are used by eye drops 2 to 4 times a day. For example, ophthalmic pharmaceutical products in claim 25 are used by eye drops 2 to 4 times a day. For example, ophthalmic pharmaceutical products in claim 26 are used by eye drops 2 to 4 times a day. For example, the ophthalmic pharmaceutical product in claim 23 is administered as eye drops three times a day. For example, the ophthalmic pharmaceutical product in claim 24 is administered as eye drops three times a day. For example, the ophthalmic pharmaceutical product in claim 25 is administered as eye drops three times a day. For example, the ophthalmic pharmaceutical product in claim 26 is administered as eye drops three times a day. For example, ophthalmic pharmaceutical products in claim 27 are administered by eye drops of 1 to 2 drops at a time. The aqueous ophthalmic composition of any one of claims 1 to 3, comprising polyvinyl pyrrolidone having a K value of 17 or more. The aqueous ophthalmic composition of any one of claims 1 to 3 comprises polyvinyl pyrrolidone having a K value of 17 to 120. The aqueous ophthalmic composition of any one of claims 1 to 3 contains polyvinyl pyrrolidone having a K value greater than 30 and less than 120. The aqueous ophthalmic composition of any one of claims 1 to 3, comprising polyvinyl pyrrolidone having a K value of 90. The aqueous ophthalmic composition of any one of claims 1 to 3, wherein the concentration of the polyvinyl pyrrolidone is 0.001% (w/v) or more. The aqueous ophthalmic composition of any one of claims 1 to 3, wherein the concentration of the above-mentioned diquafosol or its salt is 0.0001~10% (w/v). The aqueous ophthalmic composition of any one of claims 1 to 3, wherein the concentration of the above-mentioned diquafosol or its salt is 0.01~5% (w/v). The aqueous ophthalmic composition of any one of claims 1 to 3, wherein the concentration of the above-mentioned diquafosol or its salt is 1-5% (w/v). An aqueous ophthalmic composition as claimed in any one of claims 1 to 3, wherein the concentration of the above-mentioned diquafosol or its salt is 3% (w/v). The aqueous ophthalmic composition of any one of claim 1 to 3, wherein the pH value of the aqueous ophthalmic composition is in the range of 6 to 8. The aqueous ophthalmic composition of any one of claim 1 to 3, wherein the pH value of the aqueous ophthalmic composition is in the range of 7 to 8. The aqueous ophthalmic composition of any one of claims 1 to 3, wherein the aqueous ophthalmic composition is a sterile aqueous eye drop. The aqueous ophthalmic composition of any one of claims 1 to 3 can be stored at room temperature. The aqueous ophthalmic composition of any one of claims 1 to 3, wherein the viscosity of the aqueous ophthalmic composition is 1.5-30 mPa‧s at 25°C. The aqueous ophthalmic composition of any one of claims 1 to 3, wherein the above-mentioned salt of diquatsol is diquatsol sodium. An aqueous ophthalmic composition for preventing or treating dry eye syndrome, containing 3% (w/v) sodium diquat, polyvinyl pyrrolidone with a K value of 90, and silver nitrate, and is characterized in that it is used in the form of 1 to 2 drops per time, 2 to 4 times a day. An aqueous ophthalmic composition for preventing or treating dry eye syndrome, containing 3% (w/v) sodium diquat, polyvinyl pyrrolidone and silver nitrate, and having a viscosity of 3-30 mPa‧s at 25°C. It is characterized in that it is used in the form of 1-2 drops per time, 2-4 times a day. For example, the aqueous ophthalmic composition of claim 51 or 52 is administered by eye drops three times a day. An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, which is prepared by filling a single-dose eye drop container with 0.1-1 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone with a K value of 90, and is used by administering the aqueous ophthalmic composition to the eye 1-2 drops at a time and 2-4 times a day. An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, which is formed by filling a single-dose eye drop container with 0.1~1mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone, the aqueous ophthalmic composition having a viscosity of 3~30mPa‧s at 25°C, and is used in the form of 1~2 drops per time, 2~4 times a day. An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, wherein 1 to 10 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone with a K value of 90 is filled in a multi-dose eye drop container, and the aqueous ophthalmic composition is administered to the eye 1 to 2 drops at a time and 2 to 4 times a day. An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, wherein 1 to 10 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquafosol and polyvinyl pyrrolidone is filled in a multi-dose eye drop container, the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa‧s at 25°C, and is used in the form of 1 to 2 drops per time, 2 to 4 times a day. An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye disease, wherein 1-10 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquat and polyvinyl pyrrolidone with a K value of 90 is filled in a PFMD container, and the aqueous ophthalmic composition is administered to the eye 1-2 drops at a time and 2-4 times a day. An ophthalmic pharmaceutical product, characterized in that: it is an ophthalmic pharmaceutical product for preventing or treating dry eye syndrome, which is formed by filling 1-10 mL of an aqueous ophthalmic composition containing 3% (w/v) sodium diquafosol and polyvinyl pyrrolidone in a PFMD container, the aqueous ophthalmic composition having a viscosity of 3-30 mPa‧s at 25°C, and is used in the form of 1-2 drops per time, 2-4 times a day. For example, an ophthalmic pharmaceutical product as claimed in any of claims 54 to 59 is administered by eye drops three times a day. For example, an ophthalmic pharmaceutical product as claimed in claim 56 or 57, which further contains silver nitrate.