KR20240049646A - Diquafosol or salt thereof, and aqueous ophthalmic composition containing polyvinylpyrrolidone - Google Patents

Abstract

An aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone. Diquafosol sodium at a concentration of 3% (w/v), polyvinylpyrrolidone with a K value of 90, and silver nitrate, which are used to be administered by eye drop, 1 to 2 drops at a time, 2 to 4 times a day. An aqueous ophthalmic composition for preventing or treating dry eye, comprising: Dry eye containing diquafosol sodium, polyvinylpyrrolidone and silver nitrate at a concentration of 3% (w/v), characterized in that it is used to be administered by eye drop, 1 to 2 drops at a time, 2 to 4 times a day. An aqueous ophthalmic composition for the prevention or treatment of, having a viscosity of 3 to 30 mPa·s at 25°C.

Description

Aqueous ophthalmic composition containing diquafosol or its salt and polyvinylpyrrolidone {DIQUAFOSOL OR SALT THEREOF, AND AQUEOUS OPHTHALMIC COMPOSITION CONTAINING POLYVINYLPYRROLIDONE}

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

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

In an attempt to explore a new dry eye treatment with a higher effect of increasing the amount of leakage, it is known to use diquafosol or its salt in combination with an existing dry eye treatment. Japanese Patent Application Laid-Open No. 2012-077080 (Patent Document 2) discloses that tear secretion is synergistically promoted by combined use of diquafosol or its salt and hyaluronic acid, a dry eye treatment agent. Japanese Patent Application Laid-Open No. 2015-160826 (Patent Document 3) discloses that tear secretion is synergistically promoted by combined use of diquafosol or its salt and rebamipide, a dry eye treatment agent.

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

[Non-patent Document 1] Diquas (registered trademark) eye drop 3% attached document

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

As a result of extensive research, the present inventors have found that an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone (hereinafter also referred to as “the present composition”) significantly improves the fluorescein staining score, that is, , it was found that it showed a remarkable effect of improving corneal epithelial disorders, and it was found that polyvinylpyrrolidone enhances the medicinal efficacy of diquafosol or its salt. In addition, the inventors believe that this composition, which has achieved a certain viscosity by containing polyvinylpyrrolidone with a certain K value, can be used with the existing Diquas ^{(registered trademark)} ophthalmic solution with a lower number of drops than the existing Diquas ^{(registered trademark)} ophthalmic solution. ⁾ It was also found that it has an equal or greater therapeutic effect than eye drops. In addition, it was found that this composition shows high live cell activity and is highly safe for the corneal conjunctival epithelium. In addition, it was found that this composition does not exhibit nerve irritation and can further improve the feeling of insertion of eye drops. Furthermore, it was also found that even if a silver salt is contained in the present composition, the silver salt is stable, and the present composition containing the silver salt exhibits excellent preservative effect.

That is, the present invention relates to the following.

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

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

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

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

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

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

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

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

(9) The aqueous ophthalmic composition according to any one of (5) to (8), which is used for eye drop administration 2 to 4 times a day.

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

(11) The aqueous ophthalmic composition according to (9) or (10), which is used to administer 1 to 2 drops at a time.

(12) An ophthalmic pharmaceutical product characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition according to (1) is filled in a unit dose type eye drop container.

(13) An ophthalmic pharmaceutical product characterized in that 0.3 to 0.5 mL of the aqueous ophthalmic composition according to (1) is filled in a unit dose type eye drop container.

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

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

(16) An ophthalmic pharmaceutical product characterized in that 1 to 10 mL of the aqueous ophthalmic composition according to (1) is filled in a PFMD container.

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

(18) The ophthalmic pharmaceutical product according to any one of (12) to (17) for the prevention or treatment of dry eye.

(19) The ophthalmic pharmaceutical product according to (18), wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone with a K value of more than 30 and not more than 120. .

(20) The ophthalmic pharmaceutical product according to (18), wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of more than 30 and not more than 120.

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

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

(23) The ophthalmic pharmaceutical product according to any one of (19) to (22), which is used for eye drop administration 2 to 4 times a day.

(24) The ophthalmic pharmaceutical product according to any one of (19) to (22), which is used for eye drop administration three times a day.

(25) The ophthalmic pharmaceutical product according to (23) or (24), which is used to administer 1 to 2 drops at a time.

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

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

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

(29) The aqueous ophthalmic composition according to any one of (1) to (4) containing polyvinylpyrrolidone with a K value of 90.

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

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

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

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

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

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

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

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

(38) 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 aqueous ophthalmic composition has a viscosity of 1.5 to 30 mPa·s at 25°C.

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

(41) Diquafosol sodium at a concentration of 3% (w/v), polyvinylpyrrolidone with a K value of 90, characterized in that it is used as an eye drop, 1 to 2 drops at a time, 2 to 4 times a day. and an aqueous ophthalmic composition for preventing or treating dry eye containing silver nitrate.

(42) Containing diquafosol sodium, polyvinylpyrrolidone and silver nitrate at a concentration of 3% (w/v), characterized in that it is used to be administered by eye drop, 1 to 2 drops at a time, 2 to 4 times a day. An aqueous ophthalmic composition for preventing or treating dry eye, having a viscosity of 3 to 30 mPa·s at 25°C.

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

(44) Dry eye, in which 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 is filled in a unit dose-type eye drop container. An ophthalmic pharmaceutical product for the prevention or treatment of, wherein the aqueous ophthalmic composition is administered by eye drop, 1 to 2 drops at a time, 2 to 4 times a day.

(45) 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a unit dose-type eye drop container for the prevention or treatment of dry eye. An ophthalmic pharmaceutical product for ophthalmology, wherein the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25°C and is used to administer 1 to 2 drops at a time, 2 to 4 times a day. Medicinal products.

(46) Dry eye, in which 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 is filled in a multi-dose eye drop container. An ophthalmic pharmaceutical product for the prevention or treatment of, wherein the aqueous ophthalmic composition is administered by eye drop, 1 to 2 drops at a time, 2 to 4 times a day.

(47) 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a multi-dose eye drop container for the prevention or treatment of dry eye. An ophthalmic pharmaceutical product for ophthalmology, wherein the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25°C and is used to administer 1 to 2 drops at a time, 2 to 4 times a day. Medicinal products.

(48) 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 is filled in a PFMD container for the prevention of dry eye or An ophthalmic pharmaceutical product for treatment, wherein the aqueous ophthalmic composition is used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day.

(49) An ophthalmic medicament for the prevention or treatment of dry eye, wherein 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a PFMD container. A product for use in ophthalmology, wherein the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25°C and is used to administer 1 to 2 drops at a time, 2 to 4 times a day. .

(50) The ophthalmic pharmaceutical product according to any one of (44) to (49), which is used for eye drop administration three times a day.

(51) The ophthalmic pharmaceutical product according to any one of (46) or (47), further containing silver nitrate.

Additionally, the present invention also relates to the following.

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

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

(A-3) A method of treating dry eye comprising administering to a patient an aqueous ophthalmic composition filled in a multi-dose type eye drop container, 1 to 2 drops at a time, 2 to 4 times a day, wherein the aqueous ophthalmic composition is administered The composition contains diquafosol sodium at a concentration of 3% (w/v) 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. How to treat dry eye.

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

(A-5) A method of treating dry eye comprising administering to a patient an aqueous ophthalmic composition filled in a PFMD container, 1 to 2 drops at a time, 2 to 4 times a day, wherein the aqueous ophthalmic composition contains 3 A method for treating dry eye, comprising diquafosol sodium at a % (w/v) concentration 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 of treating dry eye comprising administering to a patient an aqueous ophthalmic composition filled in a PFMD container, 1 to 2 drops at a time, 2 to 4 times a day, wherein the aqueous ophthalmic composition contains 3 % (w/v) concentration of diquafosol sodium and polyvinylpyrrolidone, and has a viscosity of 3 to 30 mPa·s at 25°C, and the PFMD container contains 1 to 10 mL of the aqueous ophthalmic composition. How to treat dry eye filled with .

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

(B-1) An ophthalmic pharmaceutical product used for the prevention or treatment of dry eye, filled with 0.1 to 1 mL of an aqueous ophthalmic composition in a unit dose-type eye drop container, wherein the aqueous ophthalmic composition contains 3% (w/v) ) An ophthalmic pharmaceutical product containing a high concentration of diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day.

(B-2) An ophthalmic pharmaceutical product used for the prevention or treatment of dry eye, in which 0.1 to 1 mL of an aqueous ophthalmic composition is filled in a unit dose-type eye drop container, wherein the aqueous ophthalmic composition contains 3% (w/v) ) Contains high concentrations of diquafosol sodium and polyvinylpyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and is used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day. Ophthalmic pharmaceutical products characterized by:

(B-3) An ophthalmic pharmaceutical product filled in a multi-dose type eye drop container with 1 to 10 mL of an aqueous ophthalmic composition used for the prevention or treatment of dry eye, wherein the aqueous ophthalmic composition contains 3% (w/v) ) An ophthalmic pharmaceutical product containing a high concentration of diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day.

(B-4) An ophthalmic pharmaceutical product filled in a multi-dose type eye drop container with 1 to 10 mL of an aqueous ophthalmic composition used for the prevention or treatment of dry eye, wherein the aqueous ophthalmic composition contains 3% (w/v) ) Contains high concentrations of diquafosol sodium and polyvinylpyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and is used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day. Ophthalmic pharmaceutical products characterized by:

(B-5) An ophthalmic pharmaceutical product filled in a PFMD container with 1 to 10 mL of an aqueous ophthalmic composition used for the prevention or treatment of dry eye, wherein the aqueous ophthalmic composition has a concentration of 3% (w/v). An ophthalmic pharmaceutical product containing diquafosol sodium and polyvinylpyrrolidone with a K value of 90, and used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day.

(B-6) An ophthalmic pharmaceutical product filled in a PFMD container with 1 to 10 mL of an aqueous ophthalmic composition used for the prevention or treatment of dry eye, wherein the aqueous ophthalmic composition has a concentration of 3% (w/v). It contains diquafosol sodium and polyvinylpyrrolidone, has a viscosity of 3 to 30 mPa·s at 25°C, and is used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day. Ophthalmic medicinal products.

(B-7) An ophthalmic medicinal product according to any one of (B-1) to (B-6), wherein the aqueous ophthalmic composition is used to administer 1 to 2 drops at a time, 3 times a day. product.

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

(C-2) Contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) for producing a medicine for the prevention or treatment of dry eye, and has a temperature of 3 to 30 mPa at 25°C. When using an aqueous ophthalmic composition having a viscosity of s, 0.1 to 1 mL of the aqueous ophthalmic composition is filled into a unit dose type eye drop container and administered 1 to 2 drops at a time, 2 to 4 times a day. Use of an aqueous ophthalmic composition characterized by:

(C-3) An aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 for preparing a medicament for the prevention or treatment of dry eye. For use, 1 to 10 mL of the aqueous ophthalmic composition is filled into a multi-dose type ophthalmic container and used to administer 1 to 2 drops at a time, 2 to 4 times a day. use.

(C-4) Contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) for producing a medicine for the prevention or treatment of dry eye, and has a temperature of 3 to 30 mPa at 25°C. When using an aqueous ophthalmic composition having a viscosity of s, 1 to 10 mL of the aqueous ophthalmic composition is filled into a multi-dose eye drop container and administered 1 to 2 drops at a time, 2 to 4 times a day. Use of an aqueous ophthalmic composition characterized by:

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

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

(C-7) The aqueous ophthalmic composition according to any one of (C-1) to (C-6), wherein the aqueous ophthalmic composition is used to administer 1 to 2 drops at a time, three times a day. Use of the composition.

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

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

Additionally, each of the components of the present invention can be combined by arbitrarily selecting two or more.

Since this composition has a high effect of increasing the amount of leakage, a stronger dry eye treatment effect is expected compared to the case of administering existing Diquas ^{(registered trademark)} eye drops. Therefore, the present composition is expected to exhibit the same or greater 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 need to be instilled 6 times a day, and there are patients who do not obtain the expected effect due to poor eye apheresis, but polyvinyl chloride solution with a certain K value This composition, which has achieved a certain viscosity by containing pyrrolidone, exhibits a therapeutic effect equal to or greater than that of the existing Diquas ^{(registered trademark)} eye drops with a lower number of drops than the existing Diquas ^{(registered trademark)} eye drops. Therefore, improvement in eye drop adherance is expected.

Furthermore, this composition is expected to show high live cell activity, have high safety for the corneal conjunctival epithelium, show no nerve irritation, and be able to improve the feeling of insertion of eye drops.

In addition, even if silver salt is contained in this composition, the silver salt is stable and shows excellent preservation effect.

[Figure 1] A graph showing the fluorescein staining score of the cornea.
[Figure 2] A diagram showing the results of a cytotoxicity test on corneal epithelial cells.
[Figure 3] A diagram showing the maximum fluorescence intensity (RFUmax) after addition of diquafosol sodium.

The present invention will be described in more detail.

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

In this specification, “PVP” means polyvinylpyrrolidone.

In this specification, “HEC” means hydroxyethylcellulose.

In this specification, “CMC-Na” means sodium carboxymethylcellulose.

In this specification, “HPMC” means hydroxypropylmethylcellulose.

In this specification, “CVP” means carboxyvinyl polymer.

In this specification, “Diquafosol ophthalmic solution” refers to an aqueous ophthalmic solution containing Diquafosol or a salt thereof.

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

“Diquafosol” is a compound represented by the following chemical structural formula.

The “salt of diquafosol” is not particularly limited as long as it is a salt acceptable as a medicine, and includes metal salts with lithium, sodium, potassium, calcium, magnesium, zinc, etc.; Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; Acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, manic acid, 1,2-ethanedisulfonic acid, isethionic acid, Salts with organic acids such as lactobionic acid, oleic acid, palm acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid. ; Quaternary ammonium salts such as methyl bromide and methyl iodide; Salts with halogen ions such as bromine ions, chlorine ions, and iodine ions; salts with ammonia; Triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1 , salts with organic amines such as 3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethanediamine.

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

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

Preferred as “Diquafosol or a salt thereof” of the present invention is the sodium salt of Diquafosol, and especially Diquafosol tetrasodium salt (also simply referred to herein as “Diquafosol sodium”) represented by the following chemical structural formula: desirable.

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

The 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 diquafosol or its salt is not particularly limited, but for example, it is preferably 0.0001 to 10% (w/v), more preferably 0.001 to 5% (w/v), It is more preferably 0.01 to 5% (w/v), even more preferably 0.1 to 5% (w/v), even more preferably 1 to 5% (w/v), and 3% (w/v). /v) is particularly preferable. 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) is preferred.

In the present invention, “polyvinylpyrrolidone” is a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone, and is generally used as a viscosity softening agent. Polyvinylpyrrolidone is also called povidone. The K value of the polyvinylpyrrolidone used in the present invention is preferably 17 or more, more preferably 17 to 120, more preferably 25 to 120, even more preferably 30 to 120, and more than 30 to 120 or less. is more preferable, 40 to 120 is even more preferable, 60 to 120 is even more preferable, 60 to 90 is especially preferable, and 90 is especially preferable. For example, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K40, polyvinylpyrrolidone K50, polyvinylpyrrolidone K60, polyvinylpyrrolidone K70, Examples include polyvinylpyrrolidone K80, polyvinylpyrrolidone K85, polyvinylpyrrolidone K90, and polyvinylpyrrolidone K120. In addition, the K value of polyvinylpyrrolidone is a viscosity characteristic value correlated with molecular weight, and is a value calculated by applying the relative viscosity value (25°C) measured by a capillary viscometer to Fikentscher's equation (1) below.

[Equation 1]

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

Here, the K value is 90 to 108% of the indicated K value in accordance with the description of the K value in the 17th revised Japanese Pharmacopoeia for “Povidone,” so, for example, “K90” applies to the above formula (1). This means that the viscosity characteristic value (K value) calculated is in the range of 81 to 97.2.

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

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

This composition may additionally add pharmaceutically acceptable preservatives as needed. For example, silver salts such as silver nitrate, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, boric acid, borax, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, polydronium chloride, and polyhexanide hydrochloride.

As is clear from the test results described later, the present composition containing a silver salt has excellent preservative effect, and therefore the preferred preservative in the present invention is a silver salt. Silver salts include, for example, 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., but silver nitrate is preferred. .

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). Specifically, the lower limit is, for example, 0.00000001% (w/v) or more, 0.0000001% (w/v) or more, 0.000001% (w/v) or more, 0.0000025% (w/v) or more, 0.000004% (w/v) or more. or more, 0.000005% (w/v) or more, 0.000008% (w/v) or more, 0.00001% (w/v) or more, 0.000016% (w/v) or more, 0.000025% (w/v) or more, 0.00004% ( w/v) or more, 0.00005% (w/v) or more, 0.00008% (w/v) or more, or 0.0001% (w/v) or more is preferable. Additionally, the upper limit is, 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. Below, 0.005% (w/v) or less or 0.001% (w/v) or less is preferable.

In addition to the polyvinylpyrrolidone and preservatives described above, pharmaceutically acceptable additives may be added to the present composition as needed. Buffering agents such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid; Isotonic agents such as calcium chloride, sodium chloride, potassium chloride, and concentrated glycerin; Stabilizers such as sodium edetate, sodium edetate hydrate, citric acid hydrate, and sodium citrate hydrate; Surfactants such as polysorbate; Antioxidants such as ascorbic acid; Viscosity-intensifying agents (also called thickeners) such as hydroxyethylcellulose and hydroxypropylmethylcellulose; pH adjusters such as hydrochloric acid and sodium hydroxide can be selected and added as needed. These additives may be used individually, or two or more types may be used in arbitrary combination. Additionally, the composition does not need to contain a cellulose-based polymer that is a thickening agent such as hydroxyethylcellulose or hydroxypropylmethylcellulose.

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

In the present invention, “ophthalmic composition” refers to a composition for use in the prevention and/or treatment of eye diseases and the like. The dosage form includes, for example, eye drops, eye ointment, injection, ointment (for example, which can be administered to the eyelid skin), etc., and eye drops are preferable. Here, eye drops are synonymous with eye drops or eye drops, and eye drops for contact lenses are also included in the definition of eye drops.

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

This composition may be a dissolved eye drop or a suspension type eye drop depending on the nature and content of the active ingredient or additive.

The composition is preferably a sterile aqueous eye drop. Here, sterility refers to a state in which microorganisms have been killed or removed, and specifically refers to a state that satisfies the preservation efficacy test standards described in the 17th revised Japanese Pharmacopoeia, for example.

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

The viscosity of the present composition is not particularly limited as long as it is within a pharmaceutically acceptable range, but for example, it is preferably in the range of 1 to 500 mPa·s, more preferably in the range of more than 1.4 to 100 mPa·s or less. Preferably within the range of 1.5 to 100 mPa·s, more preferably within the range of 1.5 to 50 mPa·s, more preferably within the range of 1.5 to 30 mPa·s, even more preferably within the range of 1.5 to 20 mPa. ·s, more preferably within the range of 1.5 to 10 mPa·s, even more preferably within the range of 2 to 10 mPa·s, particularly preferably within the range of 3 to 10 mPa·s. It is particularly preferably adjusted to be within the range of 5 to 10 mPa·s, and even more preferably within the range of 7 to 10 mPa·s. In addition, the viscosity of this composition is 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, and even more preferably 5. It can also be adjusted to be within the range of -30 mPa·s, particularly preferably within the range of 7 to 30 mPa·s. The lower limit of the viscosity of this composition is preferably, for example, 1 mPa·s or more, 1.5 mPa·s or more, 2 mPa·s or more, 3 mPa·s or more, 5 mPa·s or more, or 7 mPa·s or more. Additionally, the upper limit is preferably, for example, 500 mPa·s or less, 100 mPa·s or less, 50 mPa·s or less, 30 mPa·s or less, 20 mPa·s or less, or 10 mPa·s or less. Additionally, the viscosity of the composition is measured with 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 a pharmaceutically acceptable range. However, the osmotic pressure of the present composition is preferably 2 or less, more preferably 0.5 to 2, even more preferably 0.7 to 1.6, even more preferably 0.8 to 1.4, particularly preferably 0.9. It is ~1.2.

The composition can be stored by being filled in an airtight container, specifically an eye drop container. Examples of the eye drop container filled with the composition include a “multi-dose eye drop container” or a “unit-dose eye drop container.”

In the present invention, “ophthalmic pharmaceutical product” refers to an ophthalmic pharmaceutical product in which the present composition is filled in an eye drop container. Here, “ophthalmic pharmaceutical products” include, for example, eye drop products. In addition, the definition of each term in the “ophthalmic pharmaceutical product” of the present invention is the same as the definition of each term in the “present composition.”

In the present invention, the “multi-dose eye drop container” refers to an eye drop container equipped with a container body and a cap that can be attached to the container body, and the cap can be freely opened and sewn. says This multi-dose eye drop container usually contains multiple doses of eye drop solution for use over a certain period of time. Additionally, if the composition does not contain a preservative such as benzalkonium chloride, the composition may be contained in a PFMD (Preservative Free Multi Dose) container. In addition, the amount of the present composition filled in the multi-dose eye drop container or PFMD container is preferably, for example, 1 to 20 mL, more preferably 1 to 15 mL, further preferably 1 to 10 mL, and 2.5 to 10 mL. is more preferable, and 5 mL is particularly preferable.

On the other hand, the “unit dose type eye drop container” refers to an eye drop container in which a cap is fused and sealed at the bottle mouth, and the fused portion of the cap and the bottle-shaped body is broken open during use. This unit dose type eye drop container contains eye drops for one or multiple uses. Additionally, eye drops contained in unit-dose eye drops containers generally do not contain preservatives such as benzalkonium chloride. In addition, the amount of the present composition filled in the unit dose type eye drop container is preferably, for example, 0.1 to 1 mL, more preferably 0.1 to 0.5 mL, further preferably 0.3 mL to 0.5 mL, and 0.3 mL or 0.4 mL. Particularly desirable.

The dosage of this composition can be appropriately changed depending on the dosage form, severity of symptoms of the patient to be administered, age, weight, doctor's judgment, etc. For example, when eye drops are selected as the dosage form, the dosage is preferably 1 to 5 drops per dose. 1 to 3 drops, more preferably 1 to 2 drops, especially preferably 1 drop, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 2 to 4 times a day, More preferably, it can be administered by eye drop three times a day, every day to a week. Here, the number of 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, and 6 times a day, 1 day. More preferably 4 times a day, 3 times a day or 2 times a day, more preferably 4 times a day, 3 times a day or 2 times a day, and especially preferably 3 times a day.

In addition, when the concentration of diquafosol or its salt in the present composition is 3% (w/v), 1 to 5 drops per dose, preferably 1 to 3 drops, more preferably 1 to 2 drops, especially preferably. is 1 drop, 6 times a day, 5 times a day, 4 times a day, 3 times a day, 2 times a day or once a day, preferably 6 times a day, 4 times a day, 3 times a day. It can be administered by eye drop once or twice a day, more preferably 4 times a day or 3 times a day, and especially preferably 3 times a day.

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

This composition is used for the prevention or treatment of dry eye, and is effective as a prevention or treatment for dry eye. Dry eye is defined as “a chronic disease of lacrimal fluid and corneal conjunctival epithelium caused by various factors, and is accompanied by eye discomfort or visual abnormalities.” Keratoconjunctivitis sicca (KCS: keratoconjunctivitis sicca) is included in dry eye. In the present invention, the occurrence of dry eye symptoms caused by wearing soft contact lenses is also considered to be included in dry eye.

Symptoms of dry eye include subjective symptoms such as dry eye, eye discomfort, eye fatigue, dullness, dullness, eye pain, and blurred vision, as well as noticeable symptoms such as redness and corneal conjunctival epithelial disorders. Opinions are also included. In addition, in the present invention, “prevention or treatment of dry eye” also includes improvement of the above-mentioned subjective symptoms and/or objective findings.

There are many uncertainties regarding the etiology of dry eye, including Sjögren's syndrome; Congenital lacrimal gland disease; sarcoidosis; Graft Versus Host Disease (GVHD) caused by bone marrow transplantation; Pemphigus vulgaris; Stevens-Johnson syndrome; Lacrimal obstruction caused by trachoma, etc.; diabetes; Decreased reflex secretion due to corneal refractive correction surgery (LASIK: Laser(-assisted) in Situ Keratomileusis); Meibomian gland dysfunction; Reduction of oil layer caused by blepharitis, etc.; Labial neck dysfunction (瞬目不全) or closed eye dysfunction (closed eyelid failure) caused by eye protrusion, rabbit eyes, etc.; Decreased mucin secretion from goblet cells; It is reported that VDT (Visual Display Terminals) work is the cause.

Additionally, this composition can be instilled in the eyes of dry eye patients wearing soft contact lenses. Here, instilling drops into the eyes of a patient with dry eye wearing a soft contact lens means instilling eye drops on the cornea of a patient with dry eye while wearing a soft contact lens.

Example

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

[Test 1]

Using a normal male white rabbit, the change over time in the amount of tear fluid after instillation of the present composition was evaluated.

(Sample preparation method)

Eye Drop 1:

Eye drops 1 were prepared according to the prescription table shown in Table 1. That is, dissolve diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) in sterilized purified water to make 50 mL, and make a 6-fold concentrated solution. got it Additionally, after mixing 10 mL of the 6-fold concentrated solution and 5 mL of sterilized purified water, the pH was adjusted to 7 by adding a pH adjuster as appropriate, and the volume was adjusted to 20 mL by adding sterilized purified water to obtain a 3-fold concentrated solution. PVP K90 (4 g) was dissolved in sterilized purified water, the total amount was adjusted to 100 g, and then sterilized under high pressure steam (121°C for 20 minutes) to obtain a 4.00% (w/w) PVP K90 solution. Add 4 mL of 3-fold concentrated solution to 6.0 g of 4.00% (w/w) PVP K90 solution, adjust the total amount to 12 mL by adding sterilized purified water, and then add a pH adjuster appropriately to adjust the pH to 7 to prepare eye drops. 1 was prepared.

Eye Drops 2:

Eye drops 2 were prepared according to the prescription table shown in Table 1. That is, dissolve diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) in sterilized purified water to make 50 mL, and make a 6-fold concentrated solution. got it In addition, after mixing 10 mL of 6-fold concentrated solution and 5 mL of sterilized purified water, dissolve PVP K30 (1.2 g), add a pH adjuster appropriately to adjust the pH to 7, and add sterilized purified water to make 20 mL. , a 3-fold concentrated solution was obtained. Ophthalmic solution 2 was prepared by adding sterilized purified water to 4 mL of the 3-fold concentrated solution to adjust the total amount to 12 mL, and then adjusting the pH to 7 by adding a pH adjuster as appropriate.

Eye Drops 3:

Eye drop 3 was prepared according to the prescription table shown in Table 1. That is, dissolve diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) in sterilized purified water to make 50 mL, and make a 6-fold concentrated solution. got it In addition, after mixing 10 mL of the 6-fold concentrated solution and 5 mL of sterilized purified water, the pH was adjusted to 7 by adding a pH adjuster as appropriate, and the volume was adjusted to 20 mL by adding sterilized purified water to obtain a 3-fold concentrated solution. Hydroxyethylcellulose (15 g) was dissolved in 1500 mL of sterilized purified water and sterilized under high pressure steam (121°C for 20 minutes) to obtain a 1.00% (w/w) hydroxyethylcellulose solution. Add 4 mL of 3 times concentrated solution to 3.6 g of 1.00% (w/w) hydroxyethyl cellulose solution, adjust the total amount to 12 mL by adding sterilized purified water, and then adjust the pH to 7 by adding a pH adjuster as appropriate. , eye drops 3 were prepared.

Eye Drops 4:

Eye drops 4 were prepared according to the prescription table shown in Table 1. That is, dissolve diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) in sterilized purified water to make 50 mL, and make a 6-fold concentrated solution. got it In addition, after mixing 10 mL of the 6-fold concentrated solution and 5 mL of sterilized purified water, the pH was adjusted to 7 by adding a pH adjuster as appropriate, and the volume was adjusted to 20 mL by adding sterilized purified water to obtain a 3-fold concentrated solution. Ophthalmic solution 4 was prepared by adding sterilized purified water to 4 mL of the 3-fold concentrated solution to adjust the total amount to 12 mL, and then adjusting the pH to 7 by adding a pH adjuster as appropriate.

Eye drops 5:

*Ophthalmic solution 5 was prepared according to the prescription table shown in Table 1. That is, diquafosol sodium (18 g), sodium hydrogen phosphate hydrate (1.2 g), and sodium edetate hydrate (0.06 g) were dissolved in sterilized purified water to make 100 mL to obtain a 6-fold concentrated solution. In addition, after mixing 2.5 mL of 6-fold concentrated solution and 5 mL of sterilized purified water, dissolve PVP K60 45% aqueous solution (0.67 g) and sodium chloride (0.068 g), then add a pH adjuster appropriately to adjust the pH to 7. , and sterilized purified water was added to make 15 mL, thereby preparing eye drop 5.

In addition, the viscosity of the prepared eye drops 1 to 5 was measured according to the method described in the 17th revised Japanese Pharmacopoeia, 2.53 Viscosity measurement method, 2nd method rotational viscometer method, and 2.1.3 Cone-plate rotational viscometer (cone plate type viscometer) did. Specifically, Kinexus pro+ (manufactured by Malvern) was used, and measurement conditions were set as follows.

(Measuring conditions)

Rotor angle: 1°

Rotor diameter: 50 mm

Sample volume: 0.57 mL

Measurement temperature: 25℃

Shear rate: 50s ^-1

Measurement time: Viscosity was measured every 2 seconds, and the average value over 1 minute was taken as the viscosity.

(Test method and drug administration method)

Benoxyl ^{(registered trademark)} ophthalmic solution 0.4% (manufactured by Santenseiyaku Co., Ltd.) was instilled in normal male white rabbits (total of 32 eyes of 16 animals), and local anesthesia was administered. After 3 minutes, a Schirmer test strip (manufactured by Ayumi Seiyaku Co., Ltd.) was inserted into the lower eyelid, removed 1 minute after insertion, and the length of the wet portion (amount of leakage) was read. This was done as a transposition. Next, each eye drop solution 1 to 5 was applied once (8 eyes of 4 animals in 1 group, 24 eyes of 40,001 12 eye drops). 3 minutes before inserting the Schirmer test strip (manufactured by Ayumi Seiyaku Co., Ltd.) into the lower eyelid, Benoxyl ^{(registered trademark)} ophthalmic solution 0.4% (manufactured by Santenseiyaku Co., Ltd.) was instilled and local anesthesia was administered. . 60 minutes after instilling each eye drop, a Schirmer test strip (manufactured by Ayumi Seiyaku Co., Ltd.) was inserted into the lower eyelid, removed 1 minute after insertion, and the length of the wet portion (amount of tear fluid) was read.

(Assessment Methods)

The change in the amount of tear fluid before and after instillation of the eye drops was calculated as Δtear amount (mm/min).

(Test result)

The Δ leakage amount (mm/min) at 60 minutes after instillation is shown in Tables 1 and 2 (each value is the average value of 8 eyes. However, the average value of 40,024 eyes with eye drops). Additionally, the effect of this composition to increase the amount of leakage was evaluated according to the following criteria.

+++: Δ leakage amount (mm/min) 60 minutes after instillation is 4 mm/min or more

++: Δ leakage amount (mm/min) 60 minutes after instillation is 1 mm/min or more but less than 4 mm/min

+: Δ leakage amount (mm/min) at 60 minutes after instillation is greater than 0 mm/min to less than 1 mm/min

-: Δ leakage amount (mm/min) 60 minutes after instillation is 0 mm/min or less

As shown in the results in Table 1 above, the eye drop containing PVP K30 (eye drop 2), like the eye drop not containing PVP K30 (eye drop 4), was not recognized to have the effect of increasing the amount of tear fluid 60 minutes after instillation. In addition, HEC is generally used as a thickener, but although the eye drop containing HEC (eye drop 3) has a relatively high viscosity, the effect of increasing the amount of tear fluid 60 minutes after instillation was not recognized, as was the case with eye drop 4. . In contrast, the eye drop containing PVP K90 (eye drop 1) showed a much higher effect of increasing the amount of leakage than the eye drops 2 to 4.

As shown in the results in Table 2 above, even if the K value of PVP was 60, the eye drop containing PVP (eye drop 5) had a high effect of increasing the amount of leakage fluid.

(Review)

Polyvinylpyrrolidone increases the viscosity of the aqueous composition containing diquafosol or its salt, thereby enhancing the medicinal efficacy of diquafosol or its salt, especially when polyvinylpyrrolidone with a K value exceeding 30 is added. In this case, or when the viscosity of the aqueous composition exceeds 1.4 due to the addition of polyvinylpyrrolidone, it has been revealed that the medicinal efficacy of diquafosol or its salt is significantly enhanced.

[Test 2]

The rat extraorbital lacrimal gland extraction model is widely used as a model to evaluate the therapeutic effect of corneal epithelial disorders caused by dry eye, and is also used as a model to evaluate the therapeutic effect of P2Y ₂ receptor agonists (Invest. Ophthalmol Vis. Sci., 42(1), 96-100 (2001). Using the above-mentioned dry eye model, it was examined whether the effect of improving corneal epithelial damage could be obtained by instilling the present composition.

(How to make a dry eye model)

Using male SD rats, a rat extraorbital lacrimal gland extraction model was created according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). That is, after general anesthesia was administered by administering somnopentyl, the extraorbital lacrimal gland was removed to induce corneal epithelial damage.

(Sample preparation method)

Eye Drops A:

Sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), diquafosol sodium (3 g). Dissolve in sterilized purified water to make 100 mL, and add pH adjuster (q.s.) to adjust pH to 7.5.

Eye Drops B:

Dissolve sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), and polyvinylpyrrolidone K90 (4 g) in sterilized purified water to make 100 mL. , a pH adjuster (q.s.) was added to adjust the pH to 7.5.

Eye Drops

As eye ^drops Eye drops

In addition, the viscosity of the prepared eye drops A, B and Therefore, it was measured. Specifically, Kinexus pro+ (manufactured by Malvern) was used, and measurement conditions were set as follows.

(Measuring conditions)

Rotor angle: 1°

Rotor diameter: 50 mm

Sample volume: 0.57 mL

Measurement temperature: 25℃

Shear rate: 50s ^-1

Measurement time: Viscosity was measured every 2 seconds, and the average value over 1 minute was taken as the viscosity.

The measured viscosity of each eye drop was 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)

To the rats in which the corneal epithelial lesion was induced, eye drops A, eye drops B, and eye drops X were administered as follows.

· Eye drop A, 3 times a day administration group: Eye drop A was administered to both eyes 3 times a day for 4 weeks. (12 eyes of 6 animals per group)

· Eye drop B, 3 times a day administration group: Eye drop B was instilled in both eyes 3 times a day for 4 weeks. (12 eyes of 6 animals per group)

· Eye drops X, 6 times a day administration group: Eye drops (12 eyes of 6 animals per group)

In addition, the rats that did not cause the above corneal epithelial lesions and had eye drop-free for 4 weeks were designated as the drop-free eye group (8 eyes of 4 animals in group 1).

Four weeks after starting the instillation, the damaged portion of the cornea was stained with fluorescein, and corneal epithelial damage was determined according to the method of Murakami et al. (New Ophthalmology, 21(1), 87-90 (2004)). That is, for each of the upper, middle, and lower parts of the cornea, the degree of staining with fluorescein was scored according to the following criteria, and the average value of the sum of these scores was calculated. Additionally, 0.5 was set as the midpoint between each score of 0, 1, 2, and 3.

(Criteria)

0: not dyed,

1: The dyeing is sparse, and each dot-shaped dyed part is separated.

2: Staining is moderate, and some of the dot-shaped staining areas are adjacent.

3: The dyeing is dense, and each dot-shaped dyeing part is adjacent.

(result)

A graph of the calculated fluorescein staining scores of each group is shown in Figure 1. Here, the score is the average value + standard error of each of 8 or 12 cases.

As is clear from Figure 1, in the group administered ophthalmic solution A three times a day, an improvement in the fluorescein staining score was recognized compared to the group administered ophthalmic solution B 3 times a day after 2 weeks of starting the instillation. In the group administered ophthalmic solution After 4 weeks of instillation, the group administered eye drop A three times a day and the group administered eye drop X six times a day showed the same degree of effect.

(Review)

Eye ^drops Regarding the present composition containing polyvinylpyrrolidone K90, it is clear that it has a sufficient therapeutic effect on dry eye when instilled three times a day, especially after 2 weeks of starting instillation. "Diquas ^{(registered trademark)} eye drops It was recognized that the treatment effect surpasses that of 3% of eye drops 6 times a day. Accordingly, it was revealed that the present composition exerts a therapeutic effect equal to or greater than that of the existing Diquas ^{(registered trademark)} eye drops with a lower number of drops than the existing Diquas ^{(registered trademark)} eye drops. In particular, considering the test results of Test 1, the composition containing polyvinylpyrrolidone with a K value exceeding 30 or the composition having a viscosity exceeding 1.4 due to the addition of polyvinylpyrrolidone is used 2 to 4 times a day. It has been suggested that eye drops have a therapeutic effect equal to or greater than that of the existing “Diquas ^{(registered trademark)} ophthalmic solution 3%” applied six times a day.

[Test 3]

In order to examine the effect of this composition on corneal epithelial cells, the cytotoxicity of corneal epithelial cells was tested.

(Sample preparation method)

Eye drops Y, C, and D were prepared according to the prescriptions shown in Table 3.

Eye drops Y:

Eye drops Y were prepared according to the prescription shown in Table 3. Specifically, dissolve sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), and diquafosol sodium (3 g) in sterilized purified water to make 100 mL. Then, a pH adjuster (q.s.) was added to adjust the pH to 7.5.

Eye drops C and D:

Eye drops C and D were prepared in the same manner as eye drop Y according to the prescription shown in Table 3.

In addition, the viscosity of the prepared eye drops Y, C and D was determined by the method described in the 17th revised Japanese Pharmacopoeia, 2.53 Viscosity measurement method, 2nd method rotational viscometer method, and 2.1.3 Cone-plate rotational viscometer (cone plate type viscometer). Therefore, it was measured. Specifically, Kinexus pro+ (manufactured by Malvern) was used, and measurement conditions were set as follows.

(Measuring conditions)

Rotor angle: 1°

Rotor diameter: 50 mm

Sample volume: 0.57 mL

Measurement temperature: 25℃

Shear rate: 50s ^-1

Measurement time: Viscosity was measured every 2 seconds, and the average value over 1 minute was taken as the viscosity.

(Test Methods)

SV40 immortalized human corneal epithelial cells (HCE-T: Rikka Genkyusho, Bioresource Center, Cell No.: RCB2280) were seeded (1 × 10 ⁴ cells/well) in a 96-well plate and incubated with D- containing 10% FBS. Cultured for 1 day in MEM/F12 medium. The next day, the medium was replaced with eye drop Y, eye drop C, or eye drop D, and the corneal epithelial cells were cultured for 5, 10, and 15 minutes. Viable cell activity (equivalent to absorbance at 490 nm) was measured using the Cell Proliferation Assay Kit (manufactured by Promega, catalog number: G3580).

(result)

The test results are shown in Figure 2.

As is clear from Figure 2, Diquafosol ophthalmic solutions containing polyvinylpyrrolidone (eye drops C and D) maintained a high survival rate in immortalized human corneal epithelial cells even after 15 minutes of incubation. On the other hand, the survival rate of Diquafosol eye drops (eye drops Y) that did not contain polyvinylpyrrolidone decreased over time.

(Review)

Diquafosol ophthalmic solution containing polyvinylpyrrolidone shows high viable cell activity in cultured immortalized human corneal epithelial cells, so it has higher safety against the corneal conjunctival epithelium and is suitable for diseases such as dry eye where the corneal conjunctival epithelium is unstable. It is useful for use in

[Test 4]

The irritant effect of diquafosol sodium on peripheral nerves in the presence of PVP was examined.

(Sample preparation method)

Prescription amount 1:

Prescription solution 1 was prepared according to the prescription table shown in Table 4. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterilized purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total amount was adjusted to 100 mL to obtain a 10-fold buffer solution. PVP K30 (16 g) was dissolved in sterilized purified water, and the total amount was adjusted to 200 mL to obtain an 8% PVP K30 aqueous solution. Measure 2 mL of 10x buffer solution and 5 mL of 8% PVP K30 aqueous solution, adjust the total amount to 20 mL with sterilized purified water, and adjust the pH to 7.5 using a pH adjuster to obtain prescription solution 1.

Prescription amount 2:

Prescription solution 2 was prepared according to the prescription table shown in Table 4. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterilized purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total amount was adjusted to 100 mL to obtain a 10-fold buffer solution. 2 mL of 10x buffer solution and PVP K90 (0.4 g) were dissolved in sterilized purified water, the pH was adjusted to 7.5 using a pH adjuster, and the total amount was adjusted to 20 mL to obtain prescription solution 2.

Prescription amount 3:

Prescription solution 3 was prepared according to the prescription table shown in Table 4. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterilized purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total amount was adjusted to 100 mL to obtain a 10-fold buffer solution. 2 mL of 10x buffer solution and sodium chondroitin sulfate (0.06 g) were added to sterilized purified water, the pH was adjusted to 7.5 using a pH adjuster, and dissolution was confirmed and the total amount was adjusted to 20 mL to obtain prescription solution 3.

Prescription amount 4-6:

Prescription solutions 4 to 6 were prepared in the same manner as prescription solution 3 according to the prescription table shown in Table 4.

(Test Methods)

Cultured peripheral nerve cells (rat dorsal root ganglion neurons, purchased from Lonza Japan) were incubated in a buffer containing an intracellular calcium indicator fluorescent dye (FLIPR Calcium 6 Assay Kit, Molecular Devices). 40% of the total amount of buffer was replaced with each of the above-mentioned prescription solutions. Additionally, the non-stimulation group and the stimulation control group were treated with a buffer solution in the same manner instead of the prescribed solution. After standing at room temperature, time-dependent fluorescence measurement of the calcium indicator dye was started using a fluorescence plate reader. Diquafosol sodium (final concentration: 0.3%) was added 60 seconds after the start, and measurement of fluorescence intensity was continued.

(Assessment Methods)

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

(Test result)

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

(Review)

Peripheral nerve cells that receive a certain stimulus generate an action potential and become excited, and the stimulus signal converted into an action potential is then transmitted to the central nervous system. An action potential is a change in cell membrane potential caused by the influx of positive ions, including calcium ions, into the cell. Therefore, the increase in calcium ion concentration within nerve cells is widely used experimentally as an indicator of the excited state of nerve cells. When peripheral nerve cells were exposed to diquafosol sodium, the fluorescence intensity of intracellular calcium ions rapidly increased, and it was revealed that the nerve cells received diquafosol sodium as a stimulus and became excited. As a comparative example, the same stimulation response was recognized in each group of polymer prescription solutions 3 to 6 not containing PVP, and each polymer of sodium chondroitin sulfate, HPMC, CVP, and CMC-Na showed no effect on the nerve irritant effect of diquafosol sodium. It had no effect whatsoever. In contrast, under prescription solutions 1 and 2 containing PVP, no increase in calcium ion signals in nerve cells was observed after addition of diquafosol sodium. In other words, it was suggested that diquafosol sodium coexisted with PVP did not show nerve irritation, and that the insertion sensation of diquafosol sodium ophthalmic solution was improved by the addition of PVP.

[Test 5]

The effect of this composition on the stability of preservatives was examined.

(Sample preparation method)

Eye Drops 6:

Eye drop 6 was prepared according to the prescription shown in Table 5. Specifically, diquafosol sodium (3 g), chlorhexidine gluconate (0.0025 g), hydroxyethyl cellulose (0.2 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride ( 0.45 g) was 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:

Ophthalmic solutions 7 to 10 were prepared in the same manner as ophthalmic solution 6 according to the prescriptions shown in Table 5.

(Test Methods)

When eye drops 6 and 7 were stored at 60°C for up to 4 weeks, the content of chlorhexidine gluconate was quantified using high-performance liquid chromatography (HPLC), and the residual percentage (%) was calculated. When eye drops 8 and 9 were stored at 60°C for up to 2 weeks, the content of chlorhexidine gluconate was quantified using high-performance liquid chromatography (HPLC), and the residual percentage (%) was calculated. When eye drop 10 was stored at 60°C for up to 4 weeks, the content of silver nitrate was quantified using high-frequency inductively coupled plasma emission spectroscopy (ICP-AES), and the residual percentage (%) was calculated.

(Test result)

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

(Review)

In the aqueous ophthalmic composition containing diquafosol or its salt and polyvinylpyrrolidone (this composition), when chlorhexidine gluconate was added as a preservative, the residual rate was significantly reduced (eye drops 7 to 9). . On the other hand, when silver nitrate, a silver salt, was contained as a preservative, the residual rate was high (eye drop 10). From the above, it was revealed that the present composition destabilizes chlorhexidine gluconate and stabilizes the silver salt.

[Test 6]

The preservation effect of this composition containing silver salt was examined.

(Sample preparation method)

Eye Drops 11:

Eye drop 11 was prepared according to the prescription shown in Table 7. Specifically, diquafosol sodium (3 g), silver nitrate (0.00008 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K30 (2 g), concentrated glycerin ( 1.2 g) and hydroxyethyl cellulose (0.25 g) were dissolved in sterilized 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:

Each of the eye drops 12 to 15 was prepared in the same manner as the eye drop 11 according to the prescription shown in Table 7.

(Test Methods)

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

(Test result)

The test results are shown in Table 8.

In addition, the test results in Table 8 indicate the extent to which the number of viable bacteria at the time of testing has decreased compared to the number of inoculated bacteria in log reduction. For example, in the case of "1", the number of viable bacteria at the time of testing decreases to 10% of the number of inoculated bacteria. It shows that it was done.

As shown in Table 8, it was found that this composition containing a silver salt complies with the preservation efficacy test standards of the Japanese Pharmacopoeia.

(Review)

From the above results, it was revealed that the present composition containing a silver salt has excellent preservative effect.

[Test 7]

Using a normal male white rabbit, changes over time in the amount of tear fluid 90 minutes after instillation of the present composition were evaluated.

(Sample preparation method)

Eye Drops 16:

As eye drop 16, sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), diquafosol sodium ( 3 g) was dissolved in sterilized 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 drop 17, “Diquas ^{(registered trademark)} eye drop 3%” (manufactured by Santen Seiyaku Co., Ltd.), which is used as a dry eye treatment drug, was used. Eye drop 17 contains 30 mg of diquafosol sodium as an active ingredient in 1 mL of water, and contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium edetate hydrate, and a pH adjuster as additives.

(Test method and drug administration method)

Normal male white rabbits (24 eyes of 12 chickens) were instilled with Benoxyl ^{(registered trademark)} ophthalmic solution 0.4% (manufactured by Santenseiyaku Co., Ltd.), and local anesthesia was administered. After 3 minutes, a Schirmer test strip (manufactured by Ayumi Seiyaku Co., Ltd.) was inserted into the lower eyelid, removed 1 minute after insertion, and the length of the wet portion (amount of leaked fluid) was read. This was transposed. Next, each eye drop 16 or 17 was applied once (12 eyes of 6 animals in 1 group). 3 minutes before inserting the Schirmer test strip (manufactured by Ayumi Seiyaku Co., Ltd.) into the lower eyelid, local anesthesia was administered by instilling Benoxyl ^{(registered trademark)} ophthalmic solution 0.4% (manufactured by Santenseiyaku Co., Ltd.). . 90 minutes after instillation of each eye drop, a Schirmer test strip (manufactured by Ayumi Seiyaku Co., Ltd.) was inserted into the lower eyelid, removed 1 minute after insertion, and the length of the wet portion (amount of tear fluid) was read.

(Assessment Methods)

The change in the amount of tear fluid before and after instillation of the eye drops was calculated as Δtear amount (mm/min).

(Test result)

The Δ leakage amount (mm/min) at 90 minutes after instillation is shown in Table 9 (each value is the average of 12 eyes). Additionally, the effect of this composition to increase the amount of leakage was evaluated according to the following criteria.

+++: Δ leakage amount (mm/min) 90 minutes after instillation is 4 mm/min or more

++: Δ leakage amount (mm/min) 90 minutes after instillation is 1 mm/min or more but less than 4 mm/min

+: Δ leakage amount (mm/min) 90 minutes after instillation is greater than 0 mm/min to less than 1 mm/min

-: Δ leakage amount (mm/min) 90 minutes after instillation is 0 mm/min or less

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

[Test 8]

The preservation effect of this composition containing silver salt was examined.

(Sample preparation method)

Eye Drops 18:

Eye drop 18 was prepared according to the prescription shown in Table 10. Specifically, sodium diquafosol (3 g), silver nitrate (0.00003 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K90 (2 g), sodium chloride (0.45 g) g) was dissolved in sterilized purified water to make 100 mL, and a pH adjuster (q.s.) was added to adjust pH to 7.0.

Eye drops 19:

Ophthalmic solution 19 was prepared in the same manner as ophthalmic solution 18 according to the prescription shown in Table 10.

(Test Methods)

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

(Test result)

The test results are shown in Table 11.

In addition, the test results in Table 11 indicate the extent to which the number of viable bacteria at the time of testing has decreased compared to the number of inoculated bacteria in log reduction. For example, in the case of "1", the number of viable bacteria at the time of testing decreases to 10% of the number of inoculated bacteria. It shows that it was done.

As shown in Table 11, it was found that the composition containing silver salt, regardless of the presence or absence of EDTA, complied with the preservative efficacy test standards of the Japanese Pharmacopoeia.

(Review)

From the above results, it was revealed that the present composition containing silver salt has excellent preservative effect.

[Test 9]

The preservation effect of this composition containing silver salt was examined.

(Sample preparation method)

Eye Drops 20:

Eye drops 20 were prepared according to the prescription shown in Table 12. Specifically, sodium diquafosol (3 g), silver nitrate (0.00004 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K90 (2 g), sodium chloride (0.45 g) g) was dissolved in sterilized purified water to make 100 mL, and a pH adjuster (q.s.) was added to adjust the pH to 7.5.

Eye drops 21-23:

Each of the eye drops 21 to 23 was prepared in the same manner as the eye drop 20 according to the prescription shown in Table 12.

(Test Methods)

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

(Test result)

The test results are shown in Table 13.

In addition, the test results in Table 13 indicate the extent to which the number of viable bacteria at the time of testing has decreased compared to the number of inoculated bacteria in log reduction. For example, in the case of "1", the number of viable bacteria at the time of testing decreases to 10% of the number of inoculated bacteria. It shows that it was done.

As shown in Table 13, it was found that the present composition containing silver salt, regardless of the presence or absence of EDTA, complied with the preservative efficacy test standards of the Japanese Pharmacopoeia. In addition, it was revealed that eye drops containing silver phosphate or silver chloride as silver salts in addition to silver nitrate also meet the preservation efficacy test standards of the Japanese Pharmacopoeia.

(Review)

From the above results, it was revealed that the present composition containing silver salt has excellent preservative effect.

[Test 10]

The effect of this composition on the stability of preservatives was examined.

(Sample preparation method)

Eye Drops 24:

Diquafosol sodium (3 g), sodium edetate hydrate (0.01 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.45 g), polyvinylpyrrolidone K90 (2 g), and silver nitrate (0.00004 g). It was 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 drop 24.

(Test Methods)

When eye drop 24 was stored at 40°C for up to 6 months, the content of silver nitrate was quantified using high-frequency inductively coupled plasma emission spectroscopy (ICP-AES), and the residual percentage (%) was calculated.

(Test result)

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

(Review)

When silver nitrate, a silver salt, was contained as a preservative, the residual rate was high. From the above, it was revealed that the silver salt in this composition was stable.

[jejeye]

The drug of the present invention will be described in more detail using formulation examples, but the present invention is not limited to these formulation examples.

(Prescription Example 1: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Sodium edetate hydrate 0.0001∼0.1 g

Polyvinylpyrrolidone K90 0.0001∼10 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container or PFMD container. Additionally, 0.1 to 1 mL of the eye drop solution can be filled into a unit dose type eye drop container to manufacture an ophthalmic pharmaceutical product. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 2: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Sodium edetate hydrate 0.0001∼0.1 g

Polyvinylpyrrolidone K60 0.0001∼10 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container or PFMD container. Additionally, 0.1 to 1 mL of the eye drop solution can be filled into a unit dose type eye drop container to manufacture an ophthalmic pharmaceutical product. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 3: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Sodium edetate hydrate 0.0001∼0.1 g

Polyvinylpyrrolidone K40 0.0001∼10 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container or PFMD container. Additionally, ophthalmic pharmaceutical products can be manufactured by filling 0.1 to 1 mL of the eye drop solution into a unit dose type eye drop container. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 4: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Sodium edetate hydrate 0.0001∼0.1 g

Polyvinylpyrrolidone K90 0.0001∼10 g

lunar caustic 0.00000001∼1 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 5: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Sodium edetate hydrate 0.0001∼0.1 g

Polyvinylpyrrolidone K60 0.0001∼10 g

lunar caustic 0.00000001∼1 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 6: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Sodium edetate hydrate 0.0001∼0.1 g

Polyvinylpyrrolidone K40 0.0001∼10 g

lunar caustic 0.00000001∼1 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 7: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Polyvinylpyrrolidone K90 0.0001∼10 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to the sterilized purified solution and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container or PFMD container. Additionally, 0.1 to 1 mL of the eye drop solution can be filled into a unit dose type eye drop container to manufacture an ophthalmic pharmaceutical product. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 8: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Polyvinylpyrrolidone K60 0.0001∼10 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container or PFMD container. Additionally, 0.1 to 1 mL of the eye drop solution can be filled into a unit dose type eye drop container to manufacture an ophthalmic pharmaceutical product. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 9: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Polyvinylpyrrolidone K40 0.0001∼10 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container or PFMD container. Additionally, 0.1 to 1 mL of the eye drop solution can be filled into a unit dose type eye drop container to manufacture an ophthalmic pharmaceutical product. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 10: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Polyvinylpyrrolidone K90 0.0001∼10 g

lunar caustic 0.00000001∼1 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 11: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Polyvinylpyrrolidone K60 0.0001∼10 g

lunar caustic 0.00000001∼1 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 12: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

Polyvinylpyrrolidone K40 0.0001∼10 g

lunar caustic 0.00000001∼1 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 13: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

citric acid monohydrate 0.0001∼0.1 g

Polyvinylpyrrolidone K90 0.0001∼10 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container or PFMD container. Additionally, 0.1 to 1 mL of the eye drop solution can be filled into a unit dose type eye drop container to manufacture an ophthalmic pharmaceutical product. Additionally, the eye drops can be stored at room temperature.

(Prescription Example 14: Sterile aqueous eye drop (3% (w/v))

In 100 mL

Diquafosol Sodium 3g

Sodium hydrogen phosphate hydrate 0.01∼0.5 g

sodium chloride 0.01∼1 g

citric acid monohydrate 0.0001∼0.1 g

Polyvinylpyrrolidone K90 0.0001∼10 g

lunar caustic 0.00000001∼1 g

pH regulator Appropriate amount

The eye drops can be prepared by adding diquafosol sodium and the other ingredients to sterilized purified water and thoroughly mixing them. An ophthalmic pharmaceutical product can be manufactured by filling 1 to 10 mL of the eye drop solution into a multi-dose eye drop container. Additionally, the eye drops can be stored at room temperature.

The existing Diquas ^{(registered trademark)} eye drops need to be instilled 6 times a day, but there are patients with severe dry eye who do not receive sufficient treatment effect even when used at the prescribed dosage. Additionally, there are patients who do not obtain the expected effect due to poor eye drop apheresis. In addition to demonstrating a stronger dry eye treatment effect than the existing Diquas ^{(registered trademark)} eye drop, this composition is also expected to improve eye drop tolerance by reducing the number of drops. In addition, this composition has a lower concentration than the existing Diquas ^{(registered trademark)} eye drops and is expected to exhibit the same or greater effect in treating dry eye.

Furthermore, this composition is expected to show high live cell activity, have high safety for the corneal conjunctival epithelium, show no nerve irritation, and be able to improve the feeling of insertion of eye drops.

In addition, even if silver salt is contained in this composition, the silver salt is stable and exhibits excellent preservative effect.

Claims (51)

An aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone. The aqueous ophthalmic composition according to claim 1, further comprising a silver salt. 3. The aqueous ophthalmic composition of claim 2, wherein the silver salt comprises silver nitrate. The aqueous ophthalmic composition according to any one of claims 1 to 3 for preventing or treating dry eye. The aqueous ophthalmic composition according to claim 4, containing diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and not more than 120. The aqueous ophthalmic composition according to claim 4, comprising diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and not more than 120. The aqueous ophthalmic composition according to claim 4, which contains diquafosol sodium at a concentration of 1 to 5% (w/v) and has a viscosity of 1.5 to 30 mPa·s at 25°C. The aqueous ophthalmic composition according to claim 4, which contains diquafosol sodium at a concentration of 3% (w/v) and has a viscosity of 1.5 to 30 mPa·s at 25°C. The aqueous ophthalmic composition according to any one of claims 5 to 8, which is used for eye drop administration 2 to 4 times a day. The aqueous ophthalmic composition according to any one of claims 5 to 8, which is used for eye drop administration three times a day. The aqueous ophthalmic composition according to claim 9 or 10, which is used to administer 1 to 2 drops at a time. An ophthalmic pharmaceutical product characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition according to claim 1 is filled in a unit dose type eye drop container. An ophthalmic pharmaceutical product characterized in that 0.3 to 0.5 mL of the aqueous ophthalmic composition according to claim 1 is filled in a unit dose type eye drop container. An ophthalmic pharmaceutical product characterized in that 1 to 10 mL of the aqueous ophthalmic composition according to any one of claims 1 to 3 is filled in a multi-dose eye drop container. An ophthalmic pharmaceutical product characterized in that 5 mL of the aqueous ophthalmic composition according to any one of claims 1 to 3 is filled in a multi-dose eye drop container. An ophthalmic pharmaceutical product characterized in that 1 to 10 mL of the aqueous ophthalmic composition according to claim 1 is filled in a PFMD container. An ophthalmic pharmaceutical product characterized in that 5 mL of the aqueous ophthalmic composition according to claim 1 is filled in a PFMD container. 18. An ophthalmic pharmaceutical product according to any one of claims 12 to 17 for the prevention or treatment of dry eye. 19. The ophthalmic pharmaceutical product according to claim 18, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone having a K value of greater than 30 and not greater than 120. 19. The ophthalmic pharmaceutical product according to claim 18, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of greater than 30 and not greater than 120. 19. The ophthalmic pharmaceutical product according to claim 18, wherein the aqueous composition contains diquafosol sodium at a concentration of 1 to 5% (w/v) and has a viscosity of 1.5 to 30 mPa·s at 25°C. 19. The ophthalmic pharmaceutical product according to claim 18, wherein the aqueous composition contains diquafosol sodium at a concentration of 3% (w/v) and has a viscosity of 1.5 to 30 mPa·s at 25°C. 23. The ophthalmic pharmaceutical product according to any one of claims 19 to 22, which is used for eye drop administration 2 to 4 times a day. 23. The ophthalmic medicinal product according to any one of claims 19 to 22, which is used for eye drop administration three times a day. The ophthalmic pharmaceutical product according to claim 23 or 24, which is used to administer 1 to 2 drops at a time. The aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 17 or more. The aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 17 to 120. The aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of more than 30 and less than or equal to 120. The aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 90. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the concentration of polyvinylpyrrolidone is 0.001% (w/v) or more. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of diquafosol or its salt is 0.0001 to 10% (w/v). The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of diquafosol or its salt is 0.01 to 5% (w/v). The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of diquafosol or its salt is 1 to 5% (w/v). The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of diquafosol or its salt is 3% (w/v). 12. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the pH of the aqueous ophthalmic composition is in the range of 6 to 8. 12. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the pH of the aqueous ophthalmic composition is in the range of 7 to 8. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the aqueous ophthalmic composition is a sterile aqueous eye drop. The aqueous ophthalmic composition according to any one of claims 1 to 11, which can be stored at room temperature. The aqueous ophthalmic composition according to any one of claims 1 to 6, wherein the aqueous ophthalmic composition has a viscosity of 1.5 to 30 mPa·s at 25°C. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the salt of diquafosol is diquafosol sodium. Diquafosol sodium at a concentration of 3% (w/v), polyvinylpyrrolidone with a K value of 90, and silver nitrate, which are used to be administered by eye drop, 1 to 2 drops at a time, 2 to 4 times a day. An aqueous ophthalmic composition for preventing or treating dry eye, comprising: Dry eye containing diquafosol sodium, polyvinylpyrrolidone and silver nitrate at a concentration of 3% (w/v), characterized in that it is used to be administered by eye drop, 1 to 2 drops at a time, 2 to 4 times a day. An aqueous ophthalmic composition for prevention or treatment, having a viscosity of 3 to 30 mPa·s at 25°C. 43. The aqueous ophthalmic composition according to claim 41 or 42, which is used for eye drop administration three times a day. 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 is filled in a unit dose type eye drop container for the prevention of dry eye or An ophthalmic pharmaceutical product for treatment, characterized in that the aqueous ophthalmic composition is used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day. An ophthalmic medicine for the prevention or treatment of dry eye, wherein 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a unit dose-type eye drop container. A product for use in ophthalmic medicine, wherein the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25°C and is used to administer 1 to 2 drops at a time, 2 to 4 times a day. product. 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 is filled in a multi-dose eye drop container for the prevention of dry eye or An ophthalmic pharmaceutical product for treatment, characterized in that the aqueous ophthalmic composition is used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day. An ophthalmic medicine for the prevention or treatment of dry eye, wherein 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a multi-dose eye drop container. A product for use in ophthalmic medicine, wherein the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25°C and is used to administer 1 to 2 drops at a time, 2 to 4 times a day. product. 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone with a K value of 90 is filled in a PFMD container for the prevention or treatment of dry eye. An ophthalmic pharmaceutical product, characterized in that the aqueous ophthalmic composition is used for eye drop administration, 1 to 2 drops at a time, 2 to 4 times a day. An ophthalmic medicinal product for the prevention or treatment of dry eye, wherein 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a PFMD container. , An ophthalmic pharmaceutical product characterized in that the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25°C and is used to be administered by eye drop, 1 to 2 drops at a time, 2 to 4 times a day. 50. The ophthalmic medicinal product according to any one of claims 44 to 49, which is used for eye drop administration three times a day. 48. An ophthalmic pharmaceutical product according to claim 46 or 47, further comprising silver nitrate.