Ophthalmic composition containing diquafosol or its salt, vinyl polymer and cellulose polymer

Abstract

To provide a novel ophthalmic composition containing diquafosol or a salt thereof, which has a higher tear volume increasing effect and enables improvement of eye drop adherence.SOLUTION: Provided is an ophthalmic composition containing diquafosol or a salt thereof, a vinyl polymer, and a cellulose polymer. Provided is a preventive or therapeutic agent for dry eye containing diquafosol or a salt thereof, a vinyl polymer, and a cellulose polymer. Provided is a soluble, aqueous eye drop for treating dry eye, containing diquafosol sodium with a concentration of 3% (w / v), hydroxyethylcellulose, and polyvinylpyrrolidone having a K value of 30, characterized in that the eye drop for treating dry eye is administered in an amount of 1 to 2 drops, 3 times a day.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Jikuahosol is P 1 ,P 4 -Di(uridine-5')tetraphosphate or Up4U is a purinergic receptor agonist that promotes lacrimation. Its salt, diquafosol sodium, is also known as "Diquafosol." (登録商標) 3% eye drops (hereinafter referred to as "Dixas" (登録商標) It is used to treat dry eyes as an eye drop (Patent No. 3652707 (Patent Document 1), Diquas (登録商標) 3% eye drops package insert (Non-patent document 1). (登録商標) The usual dosage of eye drops is one drop per dose, six times a day (Non-Patent Document 1). However, in daily life, it can be difficult to administer eye drops regularly and frequently, and some patients do not achieve the expected results due to poor adherence to eye drops.

[0003] In an attempt to find a new dry eye treatment agent with a higher tear volume-increasing effect, it is known to use diquafosol or a salt thereof in combination with an existing dry eye treatment agent. JP 2012-077080 A (Patent Document 2) discloses that the combined use of diquafosol or a salt thereof and hyaluronic acid, a dry eye treatment agent, synergistically promotes tear secretion. JP 2015-160826 A (Patent Document 3) discloses that the combined use of diquafosol or a salt thereof and rebamipide, a dry eye treatment agent, synergistically promotes tear secretion. [Prior art documents] [Patent documents]

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

[0005] [Non-Patent Document 1] Diquas (registered trademark) eye drops 3% package insert Summary of the Invention [Problem to be solved by the invention]

[0006] It is an interesting problem to provide a novel ophthalmic composition containing diquafosol or a salt thereof that has a higher tear flow-increasing effect and enables improvement in eye drop adherence. [Means for solving the problem]

[0007] As a result of extensive research, the present inventors have found that an ophthalmic composition containing diquafosol or a salt thereof, a vinyl polymer, and a cellulose polymer (hereinafter also referred to as "the composition") has a high tear flow increasing effect, and (登録商標) It has been found that the composition has the same therapeutic effect as eye drops even when administered less frequently than eye drops. Furthermore, it has been found that the composition does not cause nerve irritation and can further improve the sensation of application of eye drops.

[0008] (1) An ophthalmic composition containing diquafosol or a salt thereof, a vinyl polymer, and a cellulose 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 comprises 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 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 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 diquafosol or a salt thereof is 0.0001 to 10% (w / v).

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

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

[0019] (12) The ophthalmic composition according to any one of (1) to (11), wherein the concentration of diquafosol or a salt thereof is 3% (w / v).

[0020] (13) The ophthalmic composition according to any one of (1) to (12), which is an eye drop. (14) The ophthalmic composition according to any one of (1) to (13), which is aqueous.

[0021] (15) The ophthalmic composition according to any one of (1) to (14), which is in a dissolvable form. (16) The ophthalmic composition according to any one of (1) to (15), which has a viscosity of 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) The ophthalmic composition according to any one of (1) to (17) for preventing or treating dry eye.

[0024] (19) The ophthalmic composition according to any one of (1) to (18), which is administered by instillation into the eye in the amount of 1 to 5 drops at a time, 1 to 6 times a day.

[0025] (20) The ophthalmic composition according to any one of (1) to (19), which is administered by instillation into the eye in the amount of 1 to 2 drops at a time, 2 to 4 times a day.

[0026] (21) The ophthalmic composition according to any one of (1) to (20), which is administered by instillation into the eye in the amount of 1 to 2 drops at a time, 3 or 4 times a day.

[0027] (22) A prophylactic or therapeutic agent for dry eye, comprising diquafosol or a salt thereof, a vinyl polymer, and a cellulose polymer.

[0028] (23) The preventive or therapeutic agent for dry eye according to (22), which is administered by instillation into the eyes of 1 to 2 drops at a time, 3 or 4 times a day.

[0029] (24) A soluble, aqueous eye drop for treating dry eye, which contains diquafosol sodium at a concentration of 3% (w / v), hydroxyethylcellulose, and polyvinylpyrrolidone having a K value of 30, and is administered by instillation of 1 to 2 drops at a time, 3 times a day.

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

[0031] (26) Use of an ophthalmic composition containing diquafosol 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 diquafosol or a salt thereof, a vinyl polymer, and a cellulose polymer, which is used for the prevention or treatment of dry eye. [Effects of the Invention]

[0033] As is clear from the test results described below, the present composition has a high tear production increasing effect. (登録商標) Compared to instillation of eye drops, it is expected to have a stronger therapeutic effect on dry eyes. (登録商標) Eye drops need to be instilled six times a day, and there are patients who do not achieve the expected effect due to poor adherence to instillation. However, this composition has sufficient therapeutic effect on dry eye while reducing the number of instillations, and is expected to improve adherence to instillation. (登録商標) The eye drops contain 3% (w / v) diquafosol tetrasodium salt, but this composition is expected to have the same or better dry eye therapeutic effect at a lower concentration. In addition, this composition does not exhibit nerve irritation and can improve the sensation of application of the eye drops. [Brief explanation of the drawings]

[0034] [Figure 1]1 is a graph showing the corneal fluorescein staining scores after instillation of the test drug. [Figure 2] FIG. 1 shows the maximum fluorescence intensity (RFUmax) after the addition of diquafosol sodium. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention will now be described in further detail. As used herein, "(w / v)%" refers to the mass (g) of the target component contained in 100 mL of the ophthalmic composition of the present invention.

[0036] As used herein, "PVP" means polyvinylpyrrolidone. As used herein, "HEC" means hydroxyethyl cellulose.

[0037] As used herein, "MC" means methylcellulose. As used herein, "CMC-Na" means sodium carboxymethylcellulose.

[0038] As used herein, "HPMC" means hydroxypropyl methylcellulose.

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

[0040] [ka]

[0041] The "salt of diquafosol" is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include metal salts with lithium, sodium, potassium, calcium, magnesium, zinc, etc.; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; salts with acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples of salts 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 ion, chloride ion, and iodide ion; salts with ammonia; and salts with organic amines such as triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethanediamine.

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

[0043] When "diquafosol or a salt thereof" has a crystalline polymorph or a crystalline polymorphic group (crystalline polymorphic system), the crystalline polymorph or the crystalline polymorphic group (crystalline polymorphic system) is also included within the scope of the present invention. Here, the crystalline polymorphic group (crystalline polymorphic system) refers to the individual crystalline forms at each stage when the crystalline form changes depending on the conditions and states of the production, crystallization, storage, etc. of the crystals, as well as the entire process.

[0044] The "diquafosol or a salt thereof" of the present invention is preferably a sodium salt of diquafosol, and diquafosol tetrasodium salt (also simply referred to as "diquafosol sodium" in this specification) represented by the following chemical structural formula is particularly preferred.

[0045] [ka]

[0046] Diquafosol or a salt thereof can be produced by the method disclosed in JP-A-2001-510484, for example.

[0047] The composition may contain an active ingredient other than diquafosol or a salt thereof, or may contain diquafosol or a salt thereof as the only active ingredient.

[0048] In the present invention, the concentration of diquafosol or a salt thereof is not particularly limited, but is, for example, preferably 0.0001 to 10% (w / v), more preferably 0.001 to 5% (w / v), even more preferably 0.01 to 5% (w / v), still 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, a "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, and examples thereof 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, the molecular weight of the vinyl polymer is not particularly limited, but for example, one having a weight average molecular weight of 2,500 to 3,000,000, preferably 10,000 to 1,500,000, 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 may be, for example, 0.001% (w / v) or more, preferably 0.001 to 10% (w / v), more preferably 0.01 to 10% (w / v), even more preferably 0.05 to 10% (w / v), still more preferably 0.1 to 10% (w / v), particularly preferably 0.1 to 5% (w / v), and particularly preferably 1 to 5% (w / v).

[0053] In the present invention, polyvinylpyrrolidone refers to 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 more, 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 viscosity characteristic value correlated with molecular weight, and is calculated by applying the relative viscosity value (25°C) measured with a capillary viscometer to the following Fikentscher formula (1):

[0054]

number

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

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

[0057] In the present invention, the concentration of polyvinylpyrrolidone is not particularly limited, but may be, for example, 0.001% (w / v) or more, preferably 0.001 to 10% (w / v), more preferably 0.01 to 10% (w / v), even more preferably 0.05 to 10% (w / v), still 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] The composition further contains a cellulose-based polymer. Cellulose is a fibrous polymer in which D-glucopyranose units are linked together via β1→4 glucoside bonds. In the present invention, the term "cellulose-based polymer" refers to a polymer composed of units of cellulose or its derivatives.

[0059] The cellulose-based polymer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate, with hydroxyethyl cellulose and methyl cellulose being preferred, and hydroxyethyl cellulose being more preferred.

[0060] In the present invention, the cellulose-based polymer may be used alone or in any combination of two or more cellulose-based polymers.

[0061] The concentration of the cellulose polymer in the present 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 even more preferably 0.1 to 1% (w / v).

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

[0063] The amounts of polyvinylpyrrolidone and hydroxyethyl cellulose added to the present composition can also be adjusted so that the viscosity of the present composition falls within the preferred range described below.

[0064] The composition may contain polyvinylpyrrolidone, preferably polyvinylpyrrolidone having a K value of 30, as the only vinyl polymer and hydroxyethyl cellulose as the only cellulosic polymer.

[0065] Pharmaceutically acceptable additives can be added to the composition as needed using commonly used techniques. For example, buffers such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid can be added as needed. Tonicity agents such as calcium chloride, sodium chloride, potassium chloride, and concentrated glycerin can be added. Stabilizers such as sodium edetate and sodium edetate hydrate can be added as needed. Surfactants such as polysorbates can be added as needed. Antioxidants such as ascorbic acid can be added as needed. Preservatives such as benzalkonium chloride and chlorhexidine gluconate can be added as needed. These additives can be added singly or in any combination of two or more.

[0066] As mentioned above, the present composition may contain a preservative such as benzalkonium chloride or chlorhexidine gluconate, but may also be preservative-free or substantially preservative-free.

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

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

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

[0070] The composition may be in the form of a solution-type eye drop or a suspension-type eye drop, depending on the properties and contents of the active ingredients and additives.

[0071] The viscosity of the composition is not particularly limited as long as it is within a pharmaceutically acceptable range, 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 still more preferably 1 to 40 mPa·s. The viscosity of the composition is measured by a rotational viscometer (25°C; 50 s). -1 It is measured at a shear rate of 1 / 2.

[0072] The osmotic pressure of the composition is not limited to a specific value as long as it is within a pharmaceutically acceptable range, but 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, still more preferably in the range of 0.8 to 1.4, and particularly preferably in the range of 0.9 to 1.2.

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

[0074] In the present invention, the term "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, and the cap can be freely opened and resealed. Such a multi-dose eye drop container usually contains multiple doses of eye drops 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 to the mouth of the bottle and is intended to be opened by breaking the fused portion between the cap and the bottle-shaped body when in use. The unit-dose eye drop container contains an amount of eye drop solution for one or several uses. The eye drop solution contained in a unit-dose eye drop container generally does not contain, or is substantially free of, preservatives such as benzalkonium chloride.

[0076] The dosage of the composition can be varied as appropriate depending on the dosage form, the severity of the patient's symptoms, age, body weight, and the physician's judgment, but for example, when eye drops are selected as the dosage form, the composition can be administered at a dose of 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 1 drop, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 1 to 2 times a day, every day to once a week. More specifically, the frequency of administration is preferably 6 times a day, 5 times a day, 4 times a day, 3 times a day, 2 times a day, or once a day, more preferably 6 times a day, 4 times a day, 3 times a day, or twice a day, more preferably 6 times a day, 4 times a day, 3 times a day, or twice a day, even more preferably 4 times a day or 3 times a day, and particularly preferably 3 times a day.

[0077] Furthermore, when the concentration of diquafosol or a salt thereof in the composition is 3% (w / v), the composition can be administered by instillation at a single dose of 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 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, or twice a day, more preferably 4 times a day or 3 times a day, and particularly 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 lacrimal fluid and corneal and conjunctival epithelium caused by various factors, accompanied by ocular discomfort and visual abnormalities," and keratoconjunctivitis sicca (KCS) is included in dry eye. In the present invention, dry eye also includes the occurrence of dry eye symptoms caused by wearing soft contact lenses.

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

[0081] Although there is still much unknown about the etiology of dry eye, reported causes include Sjögren's syndrome; congenital alacrimal gland deficiency; sarcoidosis; graft-versus-host disease (GVHD) due to bone marrow transplantation; ocular pemphigoid; Stevens-Johnson syndrome; lacrimal obstruction due to trachoma; diabetes; decreased reflex secretion due to corneal refractive surgery (LASIK: Laser(-assisted) in situ keratomileusis); meibomian gland dysfunction; decreased oil layer due to blepharitis; incomplete blinking or eyelid closure due to exophthalmos or lagophthalmos; decreased mucin secretion from germ cells; and working on visual display terminals (VDTs).

[0082] The present composition can also be instilled into the eyes of a dry eye patient wearing a soft contact lens. Here, instillation into the eyes of a dry eye patient wearing a soft contact lens means that the eye drops are instilled into the eyes of the dry eye patient while the soft contact lens is still being worn on the cornea. [Example]

[0083] The results of pharmacological tests and formulation examples are shown below for a better understanding of the present invention, but are not intended to limit the scope of the present invention.

[0084] [Test 1] Using normal male white rabbits, the change in tear volume over time after instillation of this composition was evaluated.

[0085] (Drug Preparation Method) Eye drops 1: Ophthalmic Solution 1 was prepared according to the formulation shown in Table 1 (units are g / 100 mL 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, yielding a 6x concentrate. Furthermore, 10 mL of the 6x concentrate was mixed with 5 mL of sterile purified water, and PVP K30 (1.2 g) was dissolved therein. A pH adjuster was added appropriately to adjust the pH to 7, and sterile purified water was added to make 20 mL, yielding a 3x concentrate. Hydroxyethyl cellulose (15 g) was dissolved in sterile purified water to make a total volume of 1500 g, followed by autoclaving (121°C, 20 minutes) to obtain a 1.00% (w / w) hydroxyethyl cellulose solution. Ophthalmic Solution 1 was prepared by adding 4 mL of a 3x concentrated solution to 3.6 g of a 1.00% (w / w) hydroxyethyl cellulose solution, adjusting the total volume to 12 mL with sterile purified water, and then adding an appropriate pH adjuster to adjust the pH to 7.

[0086] Eye drops 2: Ophthalmic solution 2 was prepared according to the formulation 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 6x concentrate. Furthermore, 10 mL of the 6x concentrate was mixed with 5 mL of sterile purified water, and the pH was adjusted to 7 with an appropriate pH adjuster. Sterile purified water was then added to make 20 mL of a 3x concentrate. PVP K90 (4 g) was dissolved in sterile purified water to make a total volume of 100 g, and the solution was then autoclaved (121°C for 20 minutes) to obtain a 4.00% (w / w) PVP K90 solution. Ophthalmic Solution 2 was prepared by adding 4 mL of the 3x concentrated solution to 6.0 g of 4.00% (w / w) PVP K90 solution, adjusting the total volume to 12 mL with sterile purified water, and then adjusting the pH to 7 by adding a pH adjuster as needed.

[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 make 50 mL, yielding a 6x concentrate. Furthermore, 10 mL of the 6x concentrate was mixed with 5 mL of sterile purified water, and PVP K30 (1.2 g) was dissolved therein. A pH adjuster was added appropriately to adjust the pH to 7, and sterile purified water was added to make 20 mL, yielding a 3x concentrate. Ophthalmic solution 3 was prepared by adding sterile purified water to 4 mL of the 3x concentrate to make a total volume of 12 mL, and then adding a pH adjuster appropriately to adjust the pH to 7.

[0088] Eye drops 4: Ophthalmic Solution 4 was prepared according to the formulation 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 6x concentrate. Furthermore, 10 mL of the 6x concentrate was mixed with 5 mL of sterile purified water, and the pH was adjusted to 7 by adding a pH adjuster. Sterile purified water was added to make a 20 mL solution to obtain a 3x concentrate. Hydroxyethyl cellulose (15 g) was dissolved in 1500 mL of sterile purified water and sterilized under high pressure (121°C, 20 minutes) to obtain a 1.00% (w / w) hydroxyethyl cellulose solution. 4 mL of the 3x concentrate was added to 3.6 g of the 1.00% (w / w) hydroxyethyl cellulose solution, and sterile purified water was added to make a total volume of 12 mL. The pH was then adjusted to 7 by adding a pH adjuster. Ophthalmic Solution 4 was prepared by the following procedure.

[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, yielding a 6x concentrate. Furthermore, 10 mL of the 6x concentrate and 5 mL of sterile purified water were mixed, and then a pH adjuster was added appropriately to adjust the pH to 7. Sterile purified water was then added to make 20 mL, yielding a 3x concentrate. Ophthalmic Solution 5 was prepared by adding sterile purified water to 4 mL of the 3x concentrate to make a total volume of 12 mL, and then adding a pH adjuster appropriately to adjust the pH to 7.

[0090] Eye drops 6: Ophthalmic Solution 6 was prepared according to the formulation shown in Table 2 (units are g / 100 mL 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, yielding a 6x concentrate. 5 mL of the 6x concentrate and 5 mL of sterile purified water were mixed, followed by dissolving PVP K25 (0.9 g) and sodium chloride (0.135 g). The pH was adjusted to 7 with an appropriate pH adjuster, and sterile purified water was added to make 15 mL, yielding a 2x concentrate. Hydroxyethyl cellulose (15 g) was dissolved in sterile purified water to make a total volume of 1500 g, followed by autoclaving (121°C, 20 minutes) to obtain a 1.00% (w / w) hydroxyethyl cellulose solution. Ophthalmic Solution 6 was prepared by adding 7.5 mL of the double concentrate to 3.75 g of 1.00% (w / w) hydroxyethyl cellulose solution, adjusting the total volume to 15 mL with sterile purified water, and then adjusting the pH to 7 by adding a pH adjuster as needed.

[0091] Eye drops 7: Ophthalmic Solution 7 was prepared according to the formulation 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, yielding a 6x concentrate. After mixing 20 mL of the 6x concentrate with 20 mL of sterile purified water, PVP K30 (2.4 g) and sodium chloride (0.54 g) were dissolved therein, and the pH was adjusted to 7 with an appropriate pH adjuster. Sterile purified water was added to make 60 mL, yielding a 2x concentrate. Hydroxyethyl cellulose (15 g) was dissolved in sterile purified water to make a total volume of 1500 g, followed by autoclaving (121°C, 20 minutes) to obtain a 1.00% (w / w) hydroxyethyl cellulose solution. 50 mL of the double concentrate was added to 25 g of 1.00% (w / w) hydroxyethyl cellulose solution, and sterilized purified water was added to bring the total volume to 100 mL. After that, a pH adjuster was added appropriately to adjust the pH to 7, thereby preparing eye drops 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, yielding a 6x concentrated solution. Additionally, 2.5 mL of the 6x concentrated solution was mixed with 5 mL of sterile purified water, and then 45% aqueous solution of PVP K60 (0.67 g) and sodium chloride (0.068 g) were dissolved therein. The pH was adjusted to 7 by adding a pH adjuster as needed, and sterile purified water was added to make a total volume of 15 mL, thereby preparing ophthalmic solution 8.

[0093] Eye drops 9-11: Ophthalmic Solution 9 was prepared according to the formulation shown in Table 3 (units are g / 100 mL in Table 3). 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, yielding a 6x concentrate. Furthermore, 10 mL of the 6x concentrate was mixed with 5 mL of sterile purified water, and PVP K30 (1.2 g) was dissolved therein. The pH was adjusted to 7 with an appropriate pH adjuster, and sterile purified water was added to make 20 mL, yielding a 3x concentrate. Methylcellulose (2 g) was dissolved in sterile purified water to make a total volume of 100 g, and the mixture was then autoclaved (121°C, 20 minutes) to obtain a 2.00% (w / w) methylcellulose solution. Ophthalmic Solution 9 was prepared by adding 4 mL of a 3x concentrated solution to 3.0 g of a 2.00% (w / w) methylcellulose solution, adjusting the total volume to 12 mL with sterile purified water, and then adding a pH adjuster appropriately 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 to 11 was measured using a rotational viscometer Kinexus pro+ at a temperature of 25°C and a shear rate of 50 s -1 was measured.

[0095] (Testing methods and drug administration methods) Benoxil was administered to normal male white rabbits (total of 23 rabbits, 46 eyes). (登録商標)A 0.4% eye drop solution (manufactured by Santen Pharmaceutical Co., Ltd.) was instilled into the eyes, and local anesthesia was administered. After 3 minutes, a Schirmer test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, and after 1 minute it was removed and the length of the wetted area (tear volume) was read. This was used as the baseline value. Next, each eye drop solution 1 to 11 was instilled once (8 eyes of 4 animals per group, and 32 eyes of 16 animals for eye drop solution 5 only). Three minutes before inserting the Schirmer test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid, Benoxil (登録商標) A 0.4% eye drop solution (manufactured by Santen Pharmaceutical Co., Ltd.) was instilled into the eye to administer local anesthesia. Sixty minutes after instillation of each eye drop, a Schirmer test strip (manufactured by Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid and removed one minute later, and the length of the wetted area (tear volume) was measured.

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

[0097] (Test results) The Δ tear volume (mm / min) 60 minutes after instillation is shown in Tables 1 to 3 (each value is the average of 8 eyes, except for eye drops 5, which is the average of 32 eyes). The tear volume-increasing effect of the composition was evaluated according to the following criteria.

[0098] +++: Delta tear flow (mm / min) 60 minutes after instillation is 4mm / min or more ++: Δ tear volume (mm / min) 60 minutes after instillation is 1mm / min or more and less than 4mm / min +: Delta tear volume (mm / min) 60 minutes after instillation is greater than 0 mm / min or less than 1 mm / min -: Delta tear flow (mm / min) 0mm / min or less 60 minutes after instillation

[0099] [Table 1]

[0100] As shown in the results in Table 1 above, the eye drops containing PVP K30 (eye drops 3) did not show any effect of increasing tear production 60 minutes after administration, similar to the eye drops not containing PVP K30 (eye drops 5). Furthermore, although HEC is generally used as a thickener, the eye drops containing HEC (eye drops 4) did not show any effect of increasing tear production 60 minutes after administration, similar to eye drops 5, despite having a relatively high viscosity. In contrast, the eye drops containing PVP K30 and HEC (eye drops 1) surprisingly showed a significantly higher effect of increasing tear production than eye drops 3 to 5.

[0101] [Table 2]

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

[0103] [Table 3]

[0104] As shown in the results in Table 3, the eye drops containing PVP K30 and MC (eye drops 9) had a high tear flow increasing effect, whereas 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 have any tear flow increasing effect.

[0105] [Test 2] The rat extraorbital lacrimal gland removal model is widely used as a model for evaluating the therapeutic effects of corneal epithelial damage caused by dry eye, and is also used as a model for evaluating the therapeutic effects of P2Y2 receptor agonists (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). Using this dry eye model, we investigated whether the ophthalmic administration of the present composition would have an effect of improving corneal epithelial damage.

[0106] (Method for preparing a dry eye model) A rat extraorbital lacrimal gland removal model was established using male SD rats according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). After administering Somnopentyl for general anesthesia, the extraorbital lacrimal gland was removed to induce corneal epithelial damage.

[0107] (Sample preparation method) Eye drops A: Ophthalmic solution A was prepared according to the formulation shown in Table 4 (units are g / 100 mL 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 10x buffer solution. Diquafosol sodium (15 g) was dissolved in sterile purified water to a total volume of 50 g to obtain a 30% diquafosol sodium aqueous solution. Hydroxyethyl cellulose (2 g) was dissolved in sterile purified water to a total volume of 200 g, and the solution was sterilized by high-pressure steam sterilization (121°C, 40 minutes) to obtain a 1.00% (w / w) hydroxyethyl cellulose solution. 50 mL of sterile purified water, 20 mL of 10x buffer solution, 20 mL of 30% diquafosol sodium aqueous solution, and PVP K30 (4 g) were mixed and dissolved, the pH was adjusted to 7 using a pH adjuster, and the total volume was increased to 100 mL to obtain a 2x concentrated solution. Ophthalmic Solution A was prepared by adding 50 mL of the double concentrate to 25 g of 1.00% (w / w) hydroxyethyl cellulose solution, adjusting the total volume to 100 mL with sterile purified water, and then adjusting the pH to 7 by adding a pH adjuster as needed.

[0108] Eye drops B: Ophthalmic Solution B was prepared according to the formulation 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 10x buffer solution. Hydroxyethyl cellulose (2 g) was dissolved in sterile purified water to a total volume of 200 g, and the solution was sterilized by high-pressure steam sterilization (121°C, 40 minutes) to obtain a 1.00% (w / w) hydroxyethyl cellulose solution. 50 mL of sterile purified water, 20 mL of 10x buffer solution, sodium chloride (0.76 g), and PVP K30 (4 g) were mixed and dissolved. The pH was adjusted to 7 using a pH adjuster, and the total volume was adjusted to 100 mL to obtain a 2x concentrate. Ophthalmic Solution B was prepared by adding 50 mL of the 2x concentrate to 25 g of 1.00% (w / w) hydroxyethyl cellulose solution, adding sterile purified water to a total volume of 100 mL, and then adjusting the pH to 7 using an appropriate pH adjuster. In addition, eye drops B is the base of eye drops A.

[0109] Eye Drops X: Diquas, which is used as an eye drop X to treat dry eyes, (登録商標) "Ophthalmic Solution 3%" (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 also contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium edetate hydrate, and a pH adjuster as additives.

[0110] [Table 4]

[0111] (Testing methods and drug administration methods) To the rats with corneal epithelial damage induced, eye drops A, B, and X were administered as follows.

[0112] Eye drops A, twice daily administration group: Eye drops A was administered to both eyes twice daily for 4 weeks (12 eyes in 6 animals per group). Eye drops A, 3 times a day administration group: Eye drops A was administered to both eyes 3 times a day for 4 weeks (12 eyes in 6 animals per group). Eye drops A, four times a day administration group: Eye drops A was administered to both eyes four times a day for four weeks (12 eyes in 6 animals per group). Eye drops X, 6 times a day administration group: Eye drops A was administered to both eyes 6 times a day for 4 weeks (12 eyes in 6 animals per group). Ophthalmic solution B, four times a day administration group (vehicle administration group): Ophthalmic solution B was instilled into both eyes four times a day for four weeks (12 eyes in 6 animals per group).

[0113] Among the rats with corneal epithelial damage induced, those that had not received any eye drops for 4 weeks were classified as the no-drop group (4 rats, 8 eyes per group).

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

[0115] (Judgment criteria) 0: not stained, 1: Staining is sparse, and each punctate staining area is separated. 2: Staining is moderate, with some punctate stained areas adjacent to each other. 3: Dense staining, with each punctate stained area adjacent to each other.

[0116] (result) The calculated fluorescein staining scores for each group are graphed and shown in Figure 1. The scores are the mean value + standard error of 8 or 12 cases.

[0117] As is clear from Figure 1, the groups receiving eye drops A three times a day and four times a day showed an improvement in fluorescein staining scores compared to the group receiving the vehicle (eye drops B, administered four times a day), and showed an improvement in fluorescein staining scores equivalent to that of the group receiving eye drops X six times a day. (登録商標)It is used to treat dry eye as a 3% eye drop solution, and is instilled six times a day. As a result, some patients do not achieve the expected results due to poor adherence to instillation. However, this composition has sufficient therapeutic effects on dry eye, while reducing the number of instillations to three or four times a day, and is expected to improve adherence.

[0118] [Test 3] The irritation of peripheral nerves by diquafosol sodium in the presence of PVP was investigated.

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

[0120] Formulation 2: Formulation 2 was prepared according to the recipe 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 10x buffer solution. 2 mL of the 10x buffer solution and PVP K90 (0.4 g) were dissolved in sterile purified water, and the pH was adjusted to 7.5 using a pH adjuster to obtain a total volume of 20 mL to obtain Formulation 2.

[0121] Formulation 3: Formulation 3 was prepared according to the recipe shown in Table 5. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, and a pH adjuster was added to adjust the pH to 7.5. The total volume was then adjusted to 100 mL to obtain a 10x buffer solution. PVP K30 (16 g) was dissolved in sterile purified water, and the total volume was adjusted to 200 mL to obtain an 8% PVP K30 aqueous solution. 4 mL of the 10x 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 Formulation 3, a 2x concentrated solution. Hydroxyethyl cellulose (1 g) was dissolved in sterile purified water to a total volume of 100 g, and the solution was then autoclaved (121°C, 25 minutes) to obtain a 1.00% (w / w) hydroxyethyl cellulose solution. Sterile purified water was added to 6 g of 1.00% (w / w) hydroxyethyl cellulose solution and 10 mL of 2x concentrated solution of formulation solution 3 to bring the total volume to 20 mL.

[0122] Formulation 4: Formulation 4 was prepared according to the recipe 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 10x buffer solution. 2 mL of the 10x buffer solution and sodium chondroitin sulfate (0.06 g) were added to sterile purified water, the pH was adjusted to 7.5 using the pH adjuster, dissolution was confirmed, and the total volume was adjusted to 20 mL to obtain Formulation 4.

[0123] Prescriptions 5-7: According to the formulation shown in Table 5, formulations 5 to 7 were prepared in the same manner as formulation 4.

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

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

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

[0128] (Consideration) Upon receiving some kind of stimulus, peripheral neurons generate an action potential, becoming excited. 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 intracellular influx of cations, including calcium ions. Therefore, an increase in intracellular calcium ion concentration is widely used experimentally as an indicator of the excited state of neurons. Exposure of peripheral neurons to diquafosol sodium rapidly increased the fluorescence intensity of intracellular calcium ions, indicating that the neurons received diquafosol sodium as a stimulus and became excited. Similar stimulus responses were observed in the comparative polymer formulations 4 to 7, which did not contain PVP. The polymers chondroitin sulfate, HPMC, CVP, and CMC-Na had no effect on the neuroirritating properties of diquafosol sodium. In contrast, formulations 1 to 3, which contained PVP, did not show an increase in intracellular calcium ion signals after the addition of diquafosol sodium. In other words, it was suggested that diquafosol sodium in the presence of PVP did not exhibit neuroirritating properties, and that the addition of PVP or the addition of PVP and HEC improved the sensation of application of the eye drops.

[0129] [Formulation example] The pharmaceutical agent of the present invention will be explained in more detail with reference to formulation examples, but the present invention is not limited to these formulation examples.

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

[0131] The present composition has a high tear production increasing effect. (登録商標) Compared to instillation of eye drops, it is expected to have a stronger therapeutic effect on dry eyes. (登録商標) Eye drops need to be instilled six times a day, and there are patients who do not achieve the expected effect due to poor adherence to instillation. However, this composition has sufficient therapeutic effect on dry eye while reducing the number of instillations, and is expected to improve adherence to instillation. (登録商標) The eye drops contain 3% (w / v) diquafosol tetrasodium salt, but this composition is expected to have the same or better dry eye therapeutic effect at a lower concentration. In addition, this composition does not exhibit nerve irritation and can improve the sensation of application of the eye drops.

Claims

1. An aqueous ophthalmic composition comprising diquafosol or a salt thereof as the only active ingredient, polyvinylpyrrolidone having a K value of 17 to 30, and one kind of methylcellulose.

2. 10. The aqueous ophthalmic composition of claim 1, comprising polyvinylpyrrolidone having a K value of 30.

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

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

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

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

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

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

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

10. The aqueous ophthalmic composition according to any one of claims 1 to 9, which is in a dissolvable form.

11. The aqueous ophthalmic composition according to any one of claims 1 to 10, which has a viscosity of 1 to 500 mPa·s at 25°C.

12. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the salt of diquafosol is diquafosol sodium.

13. The aqueous ophthalmic composition according to any one of claims 1 to 12, for the prevention or treatment of dry eye.

14. The aqueous ophthalmic composition according to any one of claims 1 to 13, which is administered by instillation into the eye in an amount of 1 to 5 drops at a time, 1 to 6 times a day.

15. The aqueous ophthalmic composition according to any one of claims 1 to 14, which is administered by instillation into the eye in the amount of 1 to 2 drops at a time, 2 to 4 times a day.

16. The aqueous ophthalmic composition according to any one of claims 1 to 15, which is administered by instillation into the eye in the form of 1 to 2 drops at a time, 3 or 4 times a day.

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