Ophthalmic composition containing diquafosol or its salts, vinyl polymers and cellulosic polymers

Abstract

The present invention provides a novel ophthalmic composition containing diquafosol or a salt thereof, which has a higher tear volume increasing effect and enables improved adherence to eye drop administration. [Solution] An ophthalmic composition containing diquafosol or a salt thereof, a vinyl polymer, and a cellulosic polymer. A preventive or therapeutic agent for dry eye containing diquafosol or a salt thereof, a vinyl polymer, and a cellulosic polymer. A soluble, aqueous eye drop for the treatment of dry eye containing 3% (w / v) diquafosol sodium, hydroxyethylcellulose, and polyvinylpyrrolidone with a K value of 30, characterized in that it is administered by instilling 1 to 2 drops at a time, 3 times a day.

Description

[Technical Field]

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

[0002] Zikuahosol is P 1 ,P 4 Diquafosol sodium, also known as di(uridine-5')tetraphosphate or Up4U, is a purine receptor agonist that promotes tear secretion, and its salt, diquafosol sodium, is called "Diquafosol". (登録商標) 3% eye drops (hereinafter referred to as "Diquas") (登録商標) It is used to treat dry eye as an eye drop solution (also known as "eye drops") (Japanese Patent Publication No. 3652707 (Patent Document 1), Diquas) (登録商標) 3% ophthalmic solution package insert (Non-patent document 1). On the other hand, Diquas (登録商標) The usual dosage and administration of eye drops is one drop six times a day (Non-Patent Literature 1). However, in daily life, it is difficult to administer eye drops regularly and frequently, and some patients do not achieve the expected effects due to poor adherence to eye drop administration.

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

[0004] [Patent Document 1] Patent No. 3652707 [Patent Document 2] Japanese Patent Publication No. 2012-077080 [Patent Document 3] Japanese Patent Publication No. 2015-160826 [Non-patent literature]

[0005] [Non-Patent Document 1] Diquas® Ophthalmic Solution 3% Package Insert [Overview of the project] [Problems that the invention aims to solve]

[0006] Providing a novel ophthalmic composition containing diquafosol or a salt thereof that has a higher tear volume increasing effect and enables improved adherence to eye drop administration is an interesting challenge. [Means for solving the problem]

[0007] As a result of diligent research, the present inventors have found that an ophthalmic composition containing diquafosol or its salt, a vinyl polymer, and a cellulosic polymer (hereinafter also referred to as "this composition") has a high tear volume increasing effect, and that existing diquafosol (登録商標) We found that this composition provides equivalent therapeutic effects even with a reduced number of applications compared to eye drops. Furthermore, we found that this composition does not exhibit nerve irritation and can further improve the comfort of applying eye drops. In other words, the present invention relates to the following:

[0008] (1) An ophthalmic composition containing diquafosol or a salt thereof, a vinyl polymer, and a cellulosic polymer.

[0009] (2) The ophthalmic composition according to (1), wherein the vinyl polymer comprises polyvinylpyrrolidone.

[0010] (3) The ophthalmic composition according to (1) or (2), wherein the cellulose-based polymer contains at least one selected from the group consisting of hydroxyethyl cellulose and methyl cellulose.

[0011] (4) The ophthalmic composition according to any one of (1) to (3), which contains polyvinylpyrrolidone having a K value of 17 or more.

[0012] (5) The ophthalmic composition according to any one of (1) to (4), which contains polyvinylpyrrolidone having a K value of 17 to 90.

[0013] (6) The ophthalmic composition according to any one of (1) to (5), which contains polyvinylpyrrolidone having a K value of 30.

[0014] (7) The ophthalmic composition according to any one of (1) to (6), wherein the concentration of the vinyl-based polymer is 0.001% (w / v) or more.

[0015] (8) The ophthalmic composition according to any one of (1) to (7), wherein the concentration of the cellulose-based polymer is 0.0001 to 5% (w / v).

[0016] (9) The ophthalmic composition according to any one of (1) to (8), wherein the concentration of the diclofasol or its salt is 0.0001 to 10% (w / v). <好

[0017] (10) The ophthalmic composition according to any one of (1) to (9), wherein the concentration of the diclofasol or its salt is 0.01 to 5% (w / v).

[0018] (11) The ophthalmic composition according to any one of (1) to (10), wherein the concentration of the diclofasol or its salt is 1 to 5% (w / v).

[0019] (12) The ophthalmic composition according to any one of (1) to (11), wherein the concentration of the diclofasol or its salt is 3% (w / v). <00好00102> (13) An ophthalmic composition described in any one of (1) to (12), which is an eye drop. (14) An ophthalmic composition according to any one of (1) to (13), which is aqueous.

[0021] (15) An ophthalmic composition according to any one of (1) to (14), which is in a dissolvable form. (16) An ophthalmic composition according to any one of (1) to (15), wherein the viscosity is 1 to 500 mPa·s at 25°C.

[0022] (17) The ophthalmic composition according to any one of (1) to (16), wherein the salt of diquafosol is diquafosol sodium.

[0023] (18) An ophthalmic composition according to any one of (1) to (17) for the prevention or treatment of dry eye.

[0024] (19) An ophthalmic composition according to any one of (1) to (18), characterized by being administered by instilling 1 to 5 drops at a time, 1 to 6 times a day.

[0025] (20) An ophthalmic composition according to any one of (1) to (19), characterized by being administered by instilling 1 to 2 drops at a time, 2 to 4 times a day.

[0026] (21) An ophthalmic composition according to any one of (1) to (20), characterized by being administered by instilling 1 to 2 drops into the eye 3 or 4 times a day.

[0027] (22) A prophylactic or therapeutic agent for dry eye containing diquafosol or a salt thereof, vinyl polymers and cellulosic polymers.

[0028] (23) The preventive or therapeutic agent for dry eye according to (22), characterized by being administered by instilling 1 to 2 drops into the eye 3 or 4 times a day.

[0029] An ophthalmic solution for the treatment of dry eye, which is a dissolving type and aqueous solution containing diclofasone sodium, hydroxyethyl cellulose and polyvinylpyrrolidone with a K value of 30 at a concentration of 3% (w / v), and is characterized by being administered by instilling 1 to 2 drops once and 3 times a day.

[0030] (25) A method for treating dry eye, which comprises administering to a patient an ophthalmic composition containing diclofasone or a salt thereof, a vinyl polymer and a cellulose polymer.

[0031] (26) Use of an ophthalmic composition containing diclofasone or a salt thereof, a vinyl polymer and a cellulose polymer for the manufacture of a medicament for the prevention or treatment of dry eye.

[0032] (27) An ophthalmic composition containing diclofasone or a salt thereof, a vinyl polymer and a cellulose polymer, which is used for the prevention or treatment of dry eye.

Advantages of the Invention

[0033] As is clear from the test results described below, the present composition has a high effect of increasing tear volume. Therefore, the present composition is expected to have a stronger therapeutic effect on dry eye compared to the case of instilling the existing dicuas (登録商標) eye drops. In addition, the existing dicuas (登録商標) eye drops need to be instilled 6 times a day, and there are patients who cannot obtain the expected effect due to poor instillation adherence. However, the present composition has a sufficient therapeutic effect on dry eye while reducing the number of instillations, and an improvement in instillation adherence is expected. Furthermore, the existing dicuas (登録商標) eye drops contain diclofasone tetrasodium salt at a concentration of 3% (w / v), but the present composition is expected to exhibit the same or higher therapeutic effect on dry eye at a lower concentration. In addition, the present composition does not show neurostimulation and can improve the feel of the eye drops.

Brief Description of the Drawings

[0034] [Figure 1]This graph shows the fluorothane staining score of the cornea after administration of the investigational drug eye drops. [Figure 2] This figure shows the maximum fluorescence intensity (RFUmax) after the addition of diquafosol sodium. [Modes for carrying out the invention]

[0035] 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 ophthalmic composition of the present invention.

[0036] In this specification, "PVP" means polyvinylpyrrolidone. In this specification, "HEC" means hydroxyethylcellulose.

[0037] In this specification, "MC" means methylcellulose. In this specification, "CMC-Na" means sodium carboxymethylcellulose.

[0038] In this specification, "HPMC" means hydroxypropyl methylcellulose.

[0039] "Diquafosol" is a compound represented by the following chemical structure.

[0040] [ka]

[0041] As for "diquafosol salts," there are no particular restrictions as long as they are salts that are permitted as medicines, including metal salts with lithium, sodium, potassium, calcium, magnesium, zinc, etc.; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples include salts with organic acids such as p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; quaternary ammonium salts with methyl bromide and methyl iodide; salts with halogen ions such as bromide, chloride, and iodide; salts with ammonia; and salts with organic amines such as triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethanediamine.

[0042] In the present invention, "diquafosol or its salt" also includes diquafosol (free form) or hydrates and organic solvent hydrates of its salt.

[0043] If "diquafosol or its salts" have crystalline polymorphs and groups of crystalline polymorphs (polymorphic systems), then those crystalline polymorphs and groups of crystalline polymorphs (polymorphic systems) are also included in the scope of the present invention. Here, a group of crystalline polymorphs (polymorphic systems) refers to the individual crystalline forms at each stage and the entire process when the crystalline form changes depending on the conditions and states of the production, crystallization, and storage of those crystals.

[0044] The preferred "diquafosol or its salt" of the present invention is the sodium salt of diquafosol, and the tetrasodium diquafosol salt (hereinafter also simply referred to as "sodium diquafosol") shown in the following chemical structural formula is particularly preferred.

[0045] [ka]

[0046] Diquafosol or its salts can be produced by methods such as those disclosed in Japanese Patent Publication No. 2001-510484.

[0047] This composition may contain active ingredients other than diquafosol or its salts, or it may contain diquafosol or its salts as the sole active ingredient.

[0048] In the present invention, the concentration of diquafosol or its salt is not particularly limited, but is preferably 0.0001 to 10% (w / v), more preferably 0.001 to 5% (w / v), even more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 5% (w / v), even more preferably 1 to 5% (w / v), and particularly preferably 3% (w / v). More specifically, 0.001%(w / v), 0.002%(w / v), 0.003%(w / v), 0.004%(w / v), 0.005%(w / v), 0.006%(w / v), 0.007%(w / v), 0.008% (w / v), 0.009%(w / v), 0.01%(w / v), 0.02%(w / v), 0.03%(w / v), 0.04%(w / v), 0.05%(w / v), 0.06%(w / v), 0.07%(w / v), 0.0 8%(w / v), 0.09%(w / v), 0.1%(w / v), 0.2%(w / v), 0.3%(w / v), 0.4%(w / v), 0.5%(w / v), 0.6%(w / v), 0.7%(w / v), 0.8%(w / v) , 0.9% (w / v), 1% (w / v), 1.5% (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v) or 5% (w / v) are preferred.

[0049] In the present invention, "vinyl polymer" refers to a type of synthetic polymer obtained by polymerizing a vinyl compound having a double bond. The vinyl polymer is not particularly limited as long as it is pharmaceutically acceptable, but examples include vinyl alcohol polymers such as polyvinyl alcohol, vinylpyrrolidone polymers such as polyvinylpyrrolidone, and carboxyvinyl polymers. Among these, vinylpyrrolidone polymers such as polyvinylpyrrolidone are preferred.

[0050] Furthermore, while the molecular weight of the vinyl polymer is not particularly limited, for example, a weight-average molecular weight of 25 to 3 million, preferably 10,000 to 1.5 million, more preferably 10,000 to 500,000, and even more preferably 10,000 to 400,000 can be used.

[0051] Furthermore, commercially available vinyl polymers can be used, and one or more of these compounds may be used in combination.

[0052] In the present invention, the concentration of the vinyl polymer is not particularly limited, but for example, it may be 0.001% (w / v) or more, preferably 0.001 to 10% (w / v), more preferably 0.01 to 10% (w / v), even more preferably 0.05 to 10% (w / v), even more preferably 0.1 to 10% (w / v), especially preferably 0.1 to 5% (w / v), and particularly preferably 1 to 5% (w / v).

[0053] In the present invention, polyvinylpyrrolidone is a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone. The K value of the polyvinylpyrrolidone used in the present invention is preferably 17 or higher, more preferably 17 to 90, even more preferably 25 to 90, even more preferably 30 to 90, and particularly preferably 30. Examples include polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K40, polyvinylpyrrolidone K50, polyvinylpyrrolidone K60, polyvinylpyrrolidone K70, polyvinylpyrrolidone K80, polyvinylpyrrolidone K85, polyvinylpyrrolidone K90, and polyvinylpyrrolidone K120. The K value of polyvinylpyrrolidone is a viscous characteristic value that correlates with molecular weight, and is a numerical value calculated by applying the relative viscosity value (25°C) measured by a capillary viscometer to Fikentscher's formula (1) below.

[0054]

number

[0055] In formula (1), η rel is the relative viscosity of the polyvinylpyrrolidone aqueous solution with respect to water, and c is the concentration (%) of polyvinylpyrrolidone in the polyvinylpyrrolidone aqueous solution.

[0056] In the present invention, polyvinylpyrrolidone may be used alone, or two or more types of polyvinylpyrrolidone with different K values ​​may be used in any combination.

[0057] In the present invention, the concentration of polyvinylpyrrolidone is not particularly limited, but for example, it may be 0.001% (w / v) or more, preferably 0.001 to 10% (w / v), more preferably 0.01 to 10% (w / v), even more preferably 0.05 to 10% (w / v), even more preferably 0.1 to 10% (w / v), especially preferably 0.1 to 5% (w / v), and particularly preferably 1 to 5% (w / v).

[0058] This composition further contains a cellulosic polymer. Cellulose is a fibrous polymer in which D-glucopyranose is linked by β1→4 glucosidic bonds. In this invention, "cellulosic polymer" refers to a polymer composed of cellulose or its derivatives as units.

[0059] The cellulosic polymer is not particularly limited as long as it is permissible as a pharmaceutical product, but examples include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, etc. Hydroxyethylcellulose and methylcellulose are preferred, and hydroxyethylcellulose is more preferred.

[0060] In the present invention, a single cellulose polymer may be used, or two or more cellulose polymers may be used in any combination.

[0061] The concentration of the cellulose polymer in this composition is not particularly limited, but is preferably 0.0001 to 5% (w / v), more preferably 0.001 to 3% (w / v), even more preferably 0.01 to 2% (w / v), and still more preferably 0.1 to 1% (w / v).

[0062] The preferred combination of vinyl polymer and cellulosic polymer used in this composition is polyvinylpyrrolidone and hydroxyethylcellulose, with the combination of polyvinylpyrrolidone with a K value of 30 (polyvinylpyrrolidone K30) and hydroxyethylcellulose being more preferred. When using a combination of polyvinylpyrrolidone with a K value of 30 and hydroxyethylcellulose, the concentration of polyvinylpyrrolidone with a K value of 30 is preferably, for example, 0.1 to 5% (w / v), and the concentration of hydroxyethylcellulose is preferably 0.01 to 2% (w / v).

[0063] Furthermore, the amounts of polyvinylpyrrolidone and hydroxyethylcellulose added to this composition can be adjusted so that the viscosity of the composition falls within the preferred range described later.

[0064] This composition may contain polyvinylpyrrolidone, preferably polyvinylpyrrolidone with a K value of 30, as the sole vinyl polymer, and hydroxyethylcellulose as the sole cellulosic polymer.

[0065] This composition may be further enriched with pharmaceutically acceptable additives as needed, using commonly used techniques. For example, buffering agents such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid; isotonic agents such as calcium chloride, sodium chloride, potassium chloride, and concentrated glycerin; stabilizers such as sodium edetate and sodium edetate hydrate; surfactants such as polysorbate; antioxidants such as ascorbic acid; preservatives such as benzalkonium chloride and chlorhexidine gluconate; and pH adjusters such as hydrochloric acid and sodium hydroxide may be selected and added as needed. These additives may be used individually or in any combination of two or more.

[0066] As described above, this composition may contain preservatives such as benzalkonium chloride and chlorhexidine gluconate, but it may also not contain preservatives or may substantially not contain preservatives.

[0067] The pH of this composition is not limited to a specific value as long as it is within a pharmaceutically acceptable range. However, the pH of this composition is preferably 8 or less, more preferably in the range of 4 to 8, even more preferably in the range of 5 to 8, even more preferably in the range of 6 to 8, and particularly preferably near 7.

[0068] In the present invention, "ophthalmic composition" refers to a composition used for the prevention and / or treatment of eye diseases. Examples of dosage forms include eye drops, eye ointments, injections, and ointments (for example, those that can be administered to the eyelid skin), with eye drops being preferred. Here, "eye drops" is synonymous with "eye solution" or "eye medicine," and contact lens eye drops are also included in the definition of eye drops.

[0069] This composition is preferably an aqueous ophthalmic composition using water as a solvent (base), and more preferably an aqueous eye drop.

[0070] Depending on the properties and content of the active ingredients and additives, this composition may be a dissolving eye drop or a suspension eye drop.

[0071] The viscosity of this composition is not particularly limited as long as it is within a range acceptable for pharmaceutical use, but is preferably adjusted to a range of 1 to 500 mPa·s, more preferably 1 to 100 mPa·s, even more preferably 1 to 50 mPa·s, and even more preferably 1 to 40 mPa·s, and measured using a rotational viscometer (25°C; 50s). -1 It is measured by the shear rate.

[0072] The osmotic pressure of this composition is not limited to a specific value as long as it is within a range acceptable for pharmaceutical use. However, the osmotic pressure of this composition is preferably 2 or less, more preferably in the range of 0.5 to 2, even more preferably in the range of 0.7 to 1.6, even more preferably in the range of 0.8 to 1.4, and particularly preferably in the range of 0.9 to 1.2.

[0073] This composition can be stored in containers made of various materials. For example, containers made of polyethylene or polypropylene can be used. If the composition is an eye drop, it is stored in an eye drop container, more specifically in a "multi-dose eye drop container" or a "unit-dose eye drop container."

[0074] In the present invention, "multi-dose eye drop container" refers to an eye drop container comprising a container body and a cap that can be attached to the container body, wherein the cap can be freely opened and resealed. The multi-dose eye drop container typically contains multiple doses of eye drop solution for use over a certain period of time.

[0075] On the other hand, a "unit-dose eye drop container" refers to an eye drop container in which a cap is fused and sealed to the bottle neck, and which is intended to be opened by breaking the fused portion between the cap and the bottle body before use. A unit-dose eye drop container contains enough eye drops for one or several uses. Generally, eye drops contained in unit-dose eye drop containers do not contain or substantially do not contain preservatives such as benzalkonium chloride.

[0076] The method of use of this composition can be appropriately changed depending on the dosage form, the severity of the patient's symptoms, age, weight, and the doctor's judgment. For example, if eye drops are selected as the dosage form, 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and especially preferably 1 drop, can be administered as eye drops 1 to 6 times a day, preferably 1 to 4 times a day, and more preferably 1 to 2 times a day, daily to once a week. More specifically, the number of times to administer the eye drops is preferably 6 times a day, 5 times a day, 4 times a day, 3 times a day, 2 times a day, or 1 time a day; more preferably 6 times a day, 4 times a day, 3 times a day, or 2 times a day; even more preferably 4 times a day or 3 times a day; and especially preferably 3 times a day.

[0077] Furthermore, if the concentration of diquafosol or its salt in this composition is 3% (w / v), a single dose of 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and especially preferably 1 drop, can be administered by eye instillation 6 times, 5 times, 4 times, 3 times, 2 times, or once a day, preferably 6 times, 4 times, 3 times, or 2 times a day, more preferably 4 times or 3 times a day, and especially preferably 3 times a day.

[0078] Furthermore, one drop is preferably about 0.1 to 30 μL, more preferably about 0.5 to 20 μL, and even more preferably about 1 to 15 μL.

[0079] This composition is effective as a preventive or therapeutic agent for dry eye. Dry eye is defined as "a chronic disease of the tear film and corneal and conjunctival epithelium caused by various factors, accompanied by eye discomfort and visual abnormalities," and keratoconjunctivitis sicca (KCS) is included in dry eye. In this invention, the occurrence of dry eye symptoms caused by wearing soft contact lenses is also included in dry eye.

[0080] Dry eye symptoms include subjective symptoms such as dryness of the eyes, eye discomfort, eye fatigue, heaviness, photophobia, eye pain, and blurred vision, as well as objective findings such as redness and corneal and conjunctival epithelial damage.

[0081] While many aspects of the etiology of dry eye remain unclear, several factors have been reported to be contributing to it, including Sjögren's syndrome; congenital anelacoa; sarcoidosis; graft-versus-host disease (GVHD) following bone marrow transplantation; ocular pemphigoid; Stevens-Johnson syndrome; lacrimal duct obstruction due to trachoma, etc.; diabetes mellitus; decreased reflex secretion due to corneal refractive surgery (LASIK: Laser(-assisted) in situ keratomileusis), etc.; meibomian gland dysfunction; decreased oil layer due to blepharitis, etc.; incomplete blinking or eyelid closure due to proptosis, lagophthalmos, etc.; decreased mucin secretion from germ cells; and VDT (Visual Display Terminal) work.

[0082] Furthermore, this composition can be instilled into the eyes of dry eye patients wearing soft contact lenses. Here, instilling into the eyes of dry eye patients wearing soft contact lenses means that the eye drops are instilled while the soft contact lenses are being worn on the cornea of ​​the dry eye patient. [Examples]

[0083] The results of pharmacological tests and examples of formulations are shown below, but these are for the purpose of better understanding the present invention and do not limit the scope of the present invention.

[0084] [Test 1] The time-dependent changes in tear volume after instillation of this composition were evaluated using normal male white rabbits.

[0085] (Method of drug preparation) Eye drops 1: Ophthalmic solution 1 was prepared according to the prescription shown in Table 1 (units in Table 1 are g / 100 mL). Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL of a 6-fold concentrated solution. Alternatively, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, PVP K30 (1.2 g) was dissolved, and a pH adjusting agent was added as needed to adjust the pH to 7. Sterile purified water was then added to make 20 mL of a 3-fold concentrated solution. Hydroxyethylcellulose (15 g) was dissolved in sterile purified water to a total volume of 1500 g, which was then autoclaved (121 °C, 20 mins) to obtain a 1.00% (w / w) hydroxyethylcellulose solution. To prepare eye drops 1, 3.6 g of 1.00% (w / w) hydroxyethylcellulose solution was mixed with 4 mL of a 3x concentrated solution, sterile purified water was added to adjust the total volume to 12 mL, and then a pH adjusting agent was added as needed to adjust the pH to 7.

[0086] Eye drops 2: Ophthalmic solution 2 was prepared according to the prescription shown in Table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL of a 6-fold concentrated solution. Alternatively, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, a pH adjuster was added as needed to adjust the pH to 7, and sterile purified water was added to make 20 mL of a 3-fold concentrated solution. PVP K90 (4 g) was dissolved in sterile purified water to make a total volume of 100 g, which was then autoclaved (121 °C for 20 minutes) to obtain a 4.00% (w / w) PVP K90 solution. To prepare eye drops 2, 6.0 g of 4.00% (w / w) PVP K90 solution was mixed with 4 mL of a 3x concentrated solution, sterile purified water was added to adjust the total volume to 12 mL, and then a pH adjuster was added as needed to adjust the pH to 7.

[0087] Eye drops 3: Ophthalmic solution 3 was prepared according to the prescription shown in Table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to obtain a 6-fold concentrated solution of 50 mL. Then, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, PVP K30 (1.2 g) was dissolved, and the pH was adjusted to 7 by adding a pH adjuster as appropriate. Sterile purified water was then added to make a total volume of 20 mL to obtain a 3-fold concentrated solution. Ophthalmic solution 3 was prepared by adding sterile purified water to 4 mL of the 3-fold concentrated solution to make a total volume of 12 mL, and then adjusting the pH to 7 by adding a pH adjuster as appropriate.

[0088] Eye drops 4: Ophthalmic solution 4 was prepared according to the prescription shown in Table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL of a 6-fold concentrated solution. Alternatively, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and the pH was adjusted to 7 by adding a pH adjuster as appropriate. Sterile purified water was then added to make 20 mL of a 3-fold concentrated solution. Hydroxyethylcellulose (15 g) was dissolved in 1500 mL of sterile purified water and sterilized by autoclaving (121 °C, 20 min) to obtain a 1.00% (w / w) hydroxyethylcellulose solution. 3.6 g of the 1.00% (w / w) hydroxyethylcellulose solution was mixed with 4 mL of the 3-fold concentrated solution, and sterile purified water was added to adjust the total volume to 12 mL. Finally, a pH adjuster was added as appropriate to adjust the pH to 7, thereby preparing ophthalmic solution 4.

[0089] Eye drops 5: Ophthalmic solution 5 was prepared according to the prescription shown in Table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL of a 6-fold concentrated solution. Then, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and the pH was adjusted to 7 by adding a pH adjuster as appropriate. Sterile purified water was then added to make 20 mL of a 3-fold concentrated solution. Ophthalmic solution 5 was prepared by adding sterile purified water to 4 mL of the 3-fold concentrated solution to make a total volume of 12 mL, and then the pH was adjusted to 7 by adding a pH adjuster as appropriate.

[0090] Eye drops 6: Ophthalmic solution 6 was prepared according to the prescription shown in Table 2 (units in Table 2 are g / 100mL). Specifically, diquafosol sodium (18g), sodium hydrogen phosphate hydrate (1.2g), and sodium edetate hydrate (0.06g) were dissolved in sterile purified water to make 100mL to obtain a 6-fold concentrated solution. Alternatively, 5mL of the 6-fold concentrated solution was mixed with 5mL of sterile purified water, PVP K25 (0.9g) and sodium chloride (0.135g) were dissolved, and a pH adjusting agent was added as needed to adjust the pH to 7. Sterile purified water was then added to make 15mL to obtain a 2-fold concentrated solution. Hydroxyethylcellulose (15g) was dissolved in sterile purified water to a total volume of 1500g, and then autoclaved (121°C, 20 minutes) to obtain a 1.00% (w / w) hydroxyethylcellulose solution. To prepare eye drops 6, 3.75 g of 1.00% (w / w) hydroxyethylcellulose solution was mixed with 7.5 mL of a 2x concentrated solution, sterile purified water was added to adjust the total volume to 15 mL, and then a pH adjusting agent was added as needed to adjust the pH to 7.

[0091] Eye drops 7: Ophthalmic solution 7 was prepared according to the prescription shown in Table 2. Specifically, diquafosol sodium (18 g), sodium hydrogen phosphate hydrate (1.2 g), and sodium edetate hydrate (0.06 g) were dissolved in sterile purified water to make 100 mL of a 6-fold concentrated solution. Then, 20 mL of the 6-fold concentrated solution was mixed with 20 mL of sterile purified water, PVP K30 (2.4 g) and sodium chloride (0.54 g) were dissolved, and a pH adjusting agent was added as needed to adjust the pH to 7. Sterile purified water was added to make 60 mL of a 2-fold concentrated solution. Hydroxyethylcellulose (15 g) was dissolved in sterile purified water to make a total volume of 1500 g, and then autoclaved (121 °C, 20 mins) to obtain a 1.00% (w / w) hydroxyethylcellulose solution. Ophthalmic solution 7 was prepared by adding 50 mL of a 2x concentrated solution to 25 g of 1.00% (w / w) hydroxyethylcellulose solution, adding sterile purified water to adjust the total volume to 100 mL, and then adding a pH adjusting agent as appropriate to adjust the pH to 7.

[0092] Eye drops 8: Ophthalmic solution 8 was prepared according to the prescription shown in Table 2. Specifically, diquafosol sodium (18 g), sodium hydrogen phosphate hydrate (1.2 g), and sodium edetate hydrate (0.06 g) were dissolved in sterile purified water to make 100 mL of a 6-fold concentrated solution. Then, 2.5 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and after dissolving PVP K60 45% aqueous solution (0.67 g) and sodium chloride (0.068 g), a pH adjusting agent was added as appropriate to adjust the pH to 7, and sterile purified water was added to make a total volume of 15 mL to prepare ophthalmic solution 8.

[0093] Eye drops 9-11: Ophthalmic solution 9 was prepared according to the prescription shown in Table 3 (units in Table 3 are g / 100 mL). Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL of a 6-fold concentrated solution. Alternatively, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, PVP K30 (1.2 g) was dissolved, and a pH adjusting agent was added as needed to adjust the pH to 7. Sterile purified water was then added to make 20 mL of a 3-fold concentrated solution. Methylcellulose (2 g) was dissolved in sterile purified water to make a total volume of 100 g, and then autoclaved (121 °C, 20 mins) to obtain a 2.00% (w / w) methylcellulose solution. To prepare eye drops 9, 3.0 g of 2.00% (w / w) methylcellulose solution was mixed with 4 mL of a 3x concentrated solution, and sterile purified water was added to adjust the total volume to 12 mL. Then, a pH adjusting agent was added as needed to adjust the pH to 7.

[0094] Eye drops 10 and 11 were prepared in the same manner as eye drops 9. The viscosity of the prepared eye drops 1-11 was measured using a Kinexus pro+ rotational viscometer at a temperature of 25°C and a shear rate of 50s. -1 It was measured using [this method].

[0095] (Test methods and drug administration methods) Benoxil was administered to normal male white rabbits (23 rabbits, 46 eyes in total). (登録商標)Eye drops 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were instilled, and local anesthesia was administered. Three minutes later, a Silmel test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, removed one minute after insertion, and the length of the wet area (tear volume) was read. This was used as the baseline value. Next, each eye drop 1-11 was instilled once (4 animals, 8 eyes per group; eye drop 5 only: 16 animals, 32 eyes). Three minutes before inserting the Silmel test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid, Benoxil was administered. (登録商標) Eye drops containing 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) were administered, followed by local anesthesia. Sixty minutes after administration of each eye drop, a Silmel test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, removed after one minute, and the length of the wet area (tear volume) was read.

[0096] (Evaluation method) The change in tear volume before and after instillation of eye drops was calculated as Δtear volume (mm / min).

[0097] (Test results) Tables 1-3 show the Δtear volume (mm / min) 60 minutes after instillation (each value is the average of 8 eyes, except for eye drop solution 5, which is the average of 32 eyes). In addition, the tear volume increasing effect of this composition was evaluated according to the following criteria.

[0098] +++: Δtear volume (mm / min) 60 minutes after instillation is 4 mm / min or more ++: Δtear volume (mm / min) 60 minutes after instillation is 1 mm / min or more and less than 4 mm / min. +: Δtear volume (mm / min) 60 minutes after instillation is greater than 0 mm / min but less than 1 mm / min -: Δtear volume (mm / min) 60 minutes after instillation is 0 mm / min or less.

[0099] [Table 1]

[0100] As shown in the results in Table 1 above, the eye drop solution containing PVP K30 (eye drop solution 3) did not show an increase in tear volume 60 minutes after instillation, similar to the eye drop solution without PVP K30 (eye drop solution 5). Furthermore, although HEC is generally used as a thickening agent, the eye drop solution containing HEC (eye drop solution 4), despite having a relatively high viscosity, did not show an increase in tear volume 60 minutes after instillation, similar to eye drop solution 5. In contrast, the eye drop solution containing both PVP K30 and HEC (eye drop solution 1) surprisingly showed a significantly higher tear volume increase than eye drops 3-5.

[0101] [Table 2]

[0102] As shown in the results in Table 2 above, even when the K value of PVP was 25, in addition to 30, eye drops containing PVP and HEC (eye drops 6 and 7) had a high tear volume increasing effect.

[0103] [Table 3]

[0104] As shown in the results in Table 3 above, the eye drops containing PVP K30 and MC (eye drops 9) had a high tear volume increasing effect. On the other hand, the eye drops containing PVP K30 and HPMC (eye drops 10) and the eye drops containing PVP K30 and CMC-Na (eye drops 11) did not show a tear volume increasing effect.

[0105] [Exam 2] The rat extraorbital lacrimal gland excision model is widely used to evaluate the therapeutic effects of treatments for corneal epithelial damage caused by dry eye, and is also used to evaluate the therapeutic effects of P2Y2 receptor agonists (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). Using this dry eye model, we investigated whether administering this composition as eye drops would improve corneal epithelial damage.

[0106] (Method for creating a dry eye model) Using male SD rats, a rat extraorbital lacrimal gland excision model was created according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). Specifically, after administering somnopentyl to induce general anesthesia, the extraorbital lacrimal gland was excised to induce corneal epithelial damage.

[0107] (Sample preparation method) Eye drops A: Ophthalmic solution A was prepared according to the prescription shown in Table 4 (units in Table 4 are g / 100mL). Specifically, sodium hydrogen phosphate hydrate (4g) and sodium chloride (9g) were dissolved in sterile purified water to a total volume of 200mL to obtain a 10-fold buffer solution. Diquafosol sodium (15g) was dissolved in sterile purified water to a total volume of 50g to obtain a 30% diquafosol sodium aqueous solution. Hydroxyethylcellulose (2g) was dissolved in sterile purified water to a total volume of 200g, which was then autoclaved (121°C, 40 minutes) to obtain a 1.00% (w / w) hydroxyethylcellulose solution. 50mL of sterile purified water, 20mL of 10-fold buffer solution, 20mL of 30% diquafosol sodium aqueous solution, and PVP K30 (4g) were mixed and dissolved, the pH was adjusted to 7 using a pH adjuster, and the total volume was raised to 100mL to obtain a 2-fold concentrated solution. Ophthalmic solution A was prepared by adding 50 mL of a 2x concentrated solution to 25 g of 1.00% (w / w) hydroxyethylcellulose solution, adding sterile purified water to adjust the total volume to 100 mL, and then adding a pH adjusting agent as needed to adjust the pH to 7.

[0108] Eye drops B: Ophthalmic solution B was prepared according to the prescription shown in Table 4. Specifically, sodium hydrogen phosphate hydrate (4 g) and sodium chloride (9 g) were dissolved in sterile purified water to a total volume of 200 mL to obtain a 10-fold buffer solution. Hydroxyethylcellulose (2 g) was dissolved in sterile purified water to a total volume of 200 g, and then autoclaved (121°C, 40 mins) to obtain a 1.00% (w / w) hydroxyethylcellulose solution. 50 mL of sterile purified water, 20 mL of 10-fold buffer solution, sodium chloride (0.76 g), and PVP K30 (4 g) were mixed and dissolved, and the pH was adjusted to 7 using a pH adjuster. The total volume was then increased to 100 mL to obtain a 2-fold concentrated solution. Ophthalmic solution B was prepared by adding 50 mL of the 2-fold concentrated solution to 25 g of the 1.00% (w / w) hydroxyethylcellulose solution, adding sterile purified water to adjust the total volume to 100 mL, and then adding a pH adjuster as appropriate to adjust the pH to 7. Note that eye drops B are the base for eye drops A.

[0109] Eye drops X: Diquas, used as eye drop X, is a treatment for dry eye. (登録商標) "Ophthalmic Solution 3%" (manufactured by Santen Pharmaceutical Co., Ltd.) was used. Ophthalmic Solution X contains 30 mg of diquafosol sodium as the active ingredient in 1 mL of water, and contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium edetate hydrate, and pH adjusters as additives.

[0110] [Table 4]

[0111] (Test methods and drug administration methods) To the rats in which the aforementioned corneal epithelial damage was induced, eye drops A, eye drops B, and eye drops X were administered as follows.

[0112] • Group receiving eye drops A twice daily: Eye drops A were administered to both eyes twice daily for 4 weeks (6 animals, 12 eyes per group). • Group receiving eye drops A three times a day: Eye drops A were administered to both eyes three times a day for four weeks (6 animals, 12 eyes per group). • Group receiving eye drops A four times a day: Eye drops A were administered to both eyes four times a day for four weeks (6 animals, 12 eyes per group). • Group receiving eye drops X, 6 times a day: Eye drops A were administered to both eyes 6 times a day for 4 weeks (6 animals, 12 eyes per group). • Group administered eye drops B four times a day (base administration group): Eye drops B were administered to both eyes four times a day for four weeks (6 animals, 12 eyes per group).

[0113] Of the rats in which corneal epithelial damage was induced, those that were not treated with eye drops for 4 weeks were designated as the eye drop-free group (4 rats, 8 eyes per group).

[0114] Four weeks after initiation of eye drops, the damaged area of ​​the cornea was stained with fluorescein, and corneal epithelial damage was assessed according to the method of Murakami et al. (Atarashii Ganka, 21(1), 87-90 (2004)). Specifically, the degree of staining with fluorescein was scored for the upper, middle, and lower parts of the cornea according to the following criteria, and the average of the sum of these scores was calculated. A midpoint of 0.5 was set between scores of 0, 1, 2, and 3.

[0115] (Judgment criteria) 0: Unstained, 1: The staining is sparse, and the individual stained points are separated. 2: The staining is moderate, and some of the dotted stained areas are adjacent to each other. 3: The staining is dense, and the individual stained points are adjacent to each other.

[0116] (result) Figure 1 shows a graph of the calculated fluorescein staining scores for each group. The scores represent the mean value plus standard error for 8 or 12 samples in each group.

[0117] As is clear from Figure 1, the groups administered eye drops A three times and four times a day showed improvement in fluorocein staining scores compared to the base administration group (eye drops B, administered four times a day), and showed improvement in fluorocein staining scores comparable to the group administered eye drops X six times a day. Eye drops X is Diquas. (登録商標)This 3% eye drop solution is used to treat dry eye, and is administered six times a day. As a result, some patients do not achieve the expected effect due to poor adherence to the eye drop. However, this composition provides sufficient therapeutic effect against dry eye while reducing the number of eye drops to three or four times a day, and is expected to improve eye drop adherence.

[0118] [Exam 3] The irritant effect of diquafosol sodium on peripheral nerves in the presence of PVP was investigated.

[0119] (Sample preparation method) Prescription solution 1: Formula 1 was prepared according to the formulation table shown in Table 5 (units in Table 5 are g / 100mL). Specifically, sodium chloride (8.5g) and sodium hydrogen phosphate hydrate (2g) were dissolved in sterile purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100mL to obtain a 10-fold buffer solution. PVP K30 (16g) was dissolved in sterile purified water, and the total volume was adjusted to 200mL to obtain an 8% PVP K30 aqueous solution. 2mL of the 10-fold buffer solution and 5mL of the 8% PVP K30 aqueous solution were measured out, the total volume was adjusted to 20mL with sterile purified water, and the pH was adjusted to 7.5 using a pH adjuster to obtain Formula 1.

[0120] Prescription solution 2: Formula 2 was prepared according to the formulation table shown in Table 5. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100 mL to obtain a 10-fold buffer solution. 2 mL of the 10-fold buffer solution and PVP K90 (0.4 g) were dissolved in sterile purified water, the pH was adjusted to 7.5 using a pH adjuster, and the total volume was adjusted to 20 mL to obtain Formula 2.

[0121] Prescription solution 3: Formula 3 was prepared according to the formulation table shown in Table 5. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjuster was added to adjust the pH to 7.5, and the total volume was adjusted to 100 mL to obtain a 10-fold buffer solution. PVP K30 (16 g) was dissolved in sterile purified water, and the total volume was adjusted to 200 mL to obtain an 8% PVP K30 aqueous solution. 4 mL of the 10-fold buffer solution and 10 mL of the 8% PVP K30 aqueous solution were measured out, and the total volume was adjusted to 20 mL with sterile purified water. The pH was then adjusted to 7.5 using a pH adjuster to obtain a 2-fold concentrated solution of Formula 3. Hydroxyethylcellulose (1 g) was dissolved in sterile purified water, and the total volume was adjusted to 100 g. This was then autoclaved (121°C, 25 mins) to obtain a 1.00% (w / w) hydroxyethylcellulose solution. 6 g of 1.00% (w / w) hydroxyethylcellulose solution and 10 mL of formula solution 3 (2x concentrated) were mixed with sterile purified water to adjust the total volume to 20 mL.

[0122] Prescription solution 4: Formula 4 was prepared according to the formulation table shown in Table 5. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100 mL to obtain a 10-fold buffer solution. 2 mL of the 10-fold buffer solution and sodium chondroitin sulfate (0.06 g) were added to sterile purified water, the pH was adjusted to 7.5 using a pH adjuster, dissolution was confirmed, and the total volume was adjusted to 20 mL to obtain Formula 4.

[0123] Prescription solutions 5-7: Preparations 5-7 were prepared in the same manner as preparation 4, according to the prescription table shown in Table 5.

[0124] [Table 5]

[0125] (Test method) Cultured peripheral nerve cells (rat dorsal root ganglion neurons, purchased from Lonza Japan) were incubated in a buffer solution containing an intracellular calcium-indicating fluorescent dye (FLIPR Calcium 6 Assay Kit, Molecular Devices). 40% of the total buffer volume was replaced with the above-mentioned formulation solutions. The unstimulated group and the stimulated control group were treated similarly with buffer instead of the formulation solutions. After standing at room temperature, time-course fluorescence measurements of the calcium-indicating dye were started using a fluorescence plate reader. Diquafosol sodium (final concentration: 0.3%) was added 60 seconds after the start, and fluorescence intensity measurements were continued.

[0126] (Evaluation method) The fluorescence intensity (RFU) immediately before the addition of diquafosol sodium was set to 100%, and the maximum fluorescence intensity (RFUmax) after addition was calculated.

[0127] (Test results) The results are shown in Figure 2. In the stimulating control group and formulations 4-7, RFU increased after the addition of diquafosol sodium, recording an RFUmax of 103.5% or higher. On the other hand, in each of the formulations 1-3 containing PVP, the RFUmax was less than 101%.

[0128] (Consideration) Peripheral nerve cells that receive a stimulus generate an action potential and become excited, and the stimulus signal converted into an action potential is then transmitted to the central nervous system. An action potential is a change in cell membrane potential caused by the influx of cations, including calcium ions, into the cell. Therefore, an increase in intracellular calcium ion concentration in nerve cells is widely used experimentally as an indicator of the excited state of nerve cells. When peripheral nerve cells were exposed to diquafosol sodium, a rapid increase in the fluorescence intensity of intracellular calcium ions was observed, indicating that the nerve cells received diquafosol sodium as a stimulus and became excited. Similar stimulus responses were observed in each of the polymer formulations 4-7, which were used as comparative examples and did not contain PVP, and the polymers chondroitin sulfate sodium, HPMC, CVP, and CMC-Na did not have any effect on the nerve stimulant properties of diquafosol sodium. In contrast, under formulations 1-3 containing PVP, no increase in intracellular calcium ion signaling was observed after the addition of diquafosol sodium. In other words, diquafosol sodium in the presence of PVP did not exhibit nerve irritant effects, suggesting that the addition of PVP or the addition of PVP and HEC improved the comfort of applying eye drops.

[0129] [Examples of formulations] The present invention will be described in more detail with reference to examples of formulations, but the present invention is not limited to these examples.

[0130] (Example prescription 1: Eye drops (3% (w / v))) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Sodium chloride 0.01-1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone 0.0001~10g Hydroxyethylcellulose 0.0001~5g pH adjuster (appropriate amount) The above eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterile purified water and mixing them thoroughly. [Industrial applicability]

[0131] This composition has a high tear volume increasing effect. Therefore, this composition is superior to existing diquas. (登録商標) Compared to administering eye drops, a stronger therapeutic effect on dry eye can be expected. Furthermore, it is expected to provide a greater therapeutic effect on existing products like Diquas. (登録商標) Eye drops need to be administered six times a day, and some patients do not achieve the expected effect due to poor adherence to the eye drop solution. However, this composition is expected to reduce the number of eye drop administrations while providing sufficient therapeutic effect against dry eye, thereby improving eye drop adherence. Furthermore, it is comparable to the existing Diquas (登録商標) While the eye drops contain a 3% (w / v) concentration of diquafosol tetrasodium salt, this composition is expected to exhibit a similar or even greater dry eye treatment effect at a lower concentration. Furthermore, this composition does not exhibit nerve irritation and may improve the comfort of applying the eye drops.

Claims

1. An ophthalmic composition containing diquafosol or a salt thereof as the sole active ingredient, and containing vinyl polymers and cellulosic polymers, The vinyl polymer comprises at least one selected from the group consisting of vinyl alcohol polymers, vinylpyrrolidone polymers (excluding polyvinylpyrrolidone), and carboxyl vinyl polymers. An ophthalmic composition comprising at least one cellulosic polymer selected from the group consisting of hydroxyethylcellulose and methylcellulose.

2. The ophthalmic composition according to claim 1, wherein the vinyl polymer is a vinylpyrrolidone polymer (excluding polyvinylpyrrolidone).

3. The ophthalmic composition according to claim 1, wherein the concentration of the vinyl polymer is 0.001% (w / v) or more.

4. The ophthalmic composition according to claim 1, wherein the concentration of the cellulose polymer is 0.0001 to 5% (w / v).

5. The ophthalmic composition according to claim 1, wherein the concentration of the diquafosol or a salt thereof is 0.0001 to 10% (w / v).

6. The ophthalmic composition according to claim 1, wherein the concentration of the diquafosol or a salt thereof is 0.01 to 5% (w / v).

7. The ophthalmic composition according to claim 1, wherein the concentration of the diquafosol or a salt thereof is 1 to 5% (w / v).

8. The ophthalmic composition according to claim 1, wherein the concentration of the diquafosol or a salt thereof is 3% (w / v).

9. An ophthalmic composition according to any one of claims 1 to 8, which is an eye drop.

10. An ophthalmic composition according to any one of claims 1 to 8, wherein the composition is aqueous.

11. An ophthalmic composition according to any one of claims 1 to 8, which is in a soluble form.

12. An ophthalmic composition according to any one of claims 1 to 8, wherein the viscosity is 1 to 500 mPa·s at 25°C.

13. The ophthalmic composition according to claim 1, wherein the salt of diquafosol is diquafosol sodium.

14. An ophthalmic composition according to any one of claims 1 to 8 for the prevention or treatment of dry eye.

15. An ophthalmic composition according to any one of claims 1 to 8, characterized in that it is administered by instilling 1 to 5 drops at a time, 1 to 6 times a day.

16. An ophthalmic composition according to any one of claims 1 to 8, characterized in that it is administered by instilling 1 to 2 drops into the eye 2 to 4 times a day.

17. An ophthalmic composition according to any one of claims 1 to 8, characterized in that it is administered by instilling one to two drops into the eye three or four times a day.

18. A preventive or therapeutic agent for dry eye containing diquafosol or a salt thereof as the sole active ingredient, and containing vinyl polymers and cellulosic polymers, The vinyl polymer comprises at least one selected from the group consisting of vinyl alcohol polymers, vinylpyrrolidone polymers (excluding polyvinylpyrrolidone), and carboxyl vinyl polymers. A preventive or therapeutic agent for dry eye, wherein the cellulose polymer comprises at least one selected from the group consisting of hydroxyethylcellulose and methylcellulose.

19. The dry eye preventive or therapeutic agent according to claim 18, characterized by being administered by instilling one to two drops into the eye three or four times a day.

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