Ophthalmic composition containing diquafosol and cationic polymer

Abstract

To provide a new ophthalmic composition containing diquafosol or its salt.SOLUTION: An ophthalmic composition comprising squafosol or a salt thereof, and a cationic polymer, wherein the cationic polymer is at least one selected from the group consisting of chitosan, a chitosan derivative, a cationic (meth) acrylate copolymer, a cationic silicone polymer, a diallyl quaternary ammonium salt / acrylamide copolymer, cationic hydrolyzed keratin, cationic hydrolyzed silk, cationic hydrolyzed collagen, cationic hydrolyzed casein, cationic hydrolyzed soybean protein, a cationic vinylpyrrolidone copolymer, polyvinylpyrrolidone, a dimethyldiallylammonium chloride homopolymer, an adipic acid / dimethylaminohydroxypropyldiethylenetriamine copolymer, an adipic acid / epoxypropyldiethylenetriamine copolymer, and an acrylamide / β - methacryloyloxyethyltrimethylammonium methyl sulfate copolymer. Ophthalmic Compositions.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Jikuahosol is P 1 ,P 4 - Di(uridine-5')tetraphosphate or Up4U is a purinergic receptor agonist that promotes tear secretion. It is an eye drop containing diquafosol tetrasodium salt at a concentration of 3% (w / v) (product name: Diquafosol). (登録商標) It is used as a 3% eye drop solution to treat dry eyes (Patent Document 1, Non-Patent Document 1). Diquafosol tetrasodium salt is highly soluble in water and is (登録商標) The 3% eye drops are clear, colorless, and sterile aqueous eye drops (Non-Patent Document 1).

[0003] On the other hand, cationic polymers refer to polymers containing one or more substituents that become cations when dissolved in water, and are used in a variety of applications. For example, Japanese Patent Application Laid-Open No. 2006-321757 (Patent Document 2) describes that cationic polymers exhibit the effect of preventing roughness, stickiness, and tangles from occurring in the wet hair stage from the time when a hair styling detergent is rinsed off to the time when the hair is dried after shampooing, and also contribute to the effect of imparting gloss, softness, smoothness, moist feeling, ease of management, etc. to the dry hair.

[0004] Furthermore, polyvinylpyrrolidone, a type of cationic polymer, is used in the field of ophthalmic compositions, for example, as a suspending agent or a solubilizing agent for poorly soluble compounds (Patent Document 3). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 3652707 [Patent Document 2] Japanese Patent Application Laid-Open No. 2006-321757 [Patent Document 3] Japanese Patent Application Publication No. 1-294620 [Non-patent literature]

[0006] [Non-Patent Document 1] Diquas (registered trademark) eye drops 3% package insert Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to find a novel ophthalmic composition containing diquafosol or a salt thereof. [Means for solving the problem]

[0008] As a result of intensive research, the present inventors have found that an ophthalmic composition containing diquafosol or a salt thereof and a cationic polymer, wherein the cationic polymer is at least one selected from the group consisting of chitosan, chitosan derivatives, cationic (meth)acrylate copolymers, cationic silicone polymers, diallyl quaternary ammonium salt-acrylamide copolymers, cationic hydrolyzed keratin, cationic hydrolyzed silk, cationic hydrolyzed collagen, cationic hydrolyzed casein, cationic hydrolyzed soy protein, cationic vinylpyrrolidone copolymers, polyvinylpyrrolidone, dimethyldiacrylammonium chloride homopolymers, adipic acid-dimethylaminohydroxypropyldiethylenetriamine copolymers, adipic acid-epoxypropyldiethylenetriamine copolymers, and acrylamide-β-methacryloyloxyethyltrimethylammonium methylsulfate copolymers, has a high tear flow-increasing effect, and the cationic polymer has an effect of stabilizing the metabolism of diquafosol or a salt thereof. Furthermore, the present inventors have found that an ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone, a type of cationic polymer, does not exhibit nerve irritation, can improve the application sensation of eye drops, and has a high tear flow-increasing effect. Hereinafter, these ophthalmic compositions will also be referred to as "the present composition." That is, the present invention relates to the following:

[0009] The composition is an ophthalmic composition containing diquafosol or a salt thereof, and a cationic polymer, wherein the cationic polymer is at least one selected from the group consisting of chitosan, chitosan derivatives, cationic (meth)acrylate copolymers, cationic silicone polymers, diallyl quaternary ammonium salt-acrylamide copolymers, cationic hydrolyzed keratin, cationic hydrolyzed silk, cationic hydrolyzed collagen, cationic hydrolyzed casein, cationic hydrolyzed soy protein, cationic vinylpyrrolidone copolymers, polyvinylpyrrolidone, dimethyldiacrylammonium chloride homopolymers, adipic acid-dimethylaminohydroxypropyldiethylenetriamine copolymers, adipic acid-epoxypropyldiethylenetriamine copolymers, and acrylamide-β-methacryloyloxyethyltrimethylammonium methylsulfate copolymers.

[0010] In the present composition, the cationic polymer is preferably at least one selected from the group consisting of chitosan, chitosan derivatives, diallyl quaternary ammonium salt-acrylamide copolymers, and polyvinylpyrrolidone.

[0011] In the present composition, the cationic polymer is preferably polyvinylpyrrolidone.

[0012] The composition preferably comprises polyvinylpyrrolidone having a K value of 17 or greater. The present composition preferably contains polyvinylpyrrolidone having a K value of 17-90.

[0013] The composition preferably comprises polyvinylpyrrolidone with a K value of 30. The composition preferably comprises polyvinylpyrrolidone with a K value of 90.

[0014] In the present composition, the cationic polymer is more preferably at least one selected from the group consisting of chitosan and chitosan derivatives.

[0015] In the present composition, the concentration of the cationic polymer is preferably 0.00001 to 10% (w / v).

[0016] In the present composition, the concentration of diquafosol or a salt thereof is preferably 0.0001 to 10% (w / v).

[0017] In the present composition, the concentration of diquafosol or a salt thereof is more preferably 0.01 to 5% (w / v).

[0018] In the present composition, the concentration of diquafosol or a salt thereof is more preferably 1 to 5% (w / v).

[0019] In the present composition, the concentration of diquafosol or a salt thereof is even more preferably 3% (w / v).

[0020] The composition is preferably an eye drop. The composition is preferably aqueous.

[0021] The composition is preferably in a suspended or dissolved form. The viscosity of the present composition is preferably 1 to 500 mPa·s at 25°C.

[0022] The viscosity of the present composition is more preferably 1 to 100 mPa·s at 25°C. In the present composition, the salt of diquafosol is preferably diquafosol sodium.

[0023] The present composition is preferably a composition for preventing or treating dry eye. The composition is preferably administered by instillation into the eyes in an amount of 1 to 5 drops at a time, 1 to 6 times a day.

[0024] More preferably, the composition is administered by instillation into the eyes, 1 to 2 drops at a time, 2 to 4 times a day. More preferably, the composition is administered by instillation into the eyes in the form of 1 to 2 drops at a time, 3 or 4 times a day.

[0025] The present invention also provides an ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone.

[0026] The composition preferably comprises polyvinylpyrrolidone having a K value of 17 or greater. The present composition preferably contains polyvinylpyrrolidone having a K value of 17-90.

[0027] The composition preferably comprises polyvinylpyrrolidone with a K value of 30. The composition preferably comprises polyvinylpyrrolidone with a K value of 90.

[0028] The present invention also provides a therapeutic agent for dry eye comprising diquafosol or a salt thereof and a cationic polymer, wherein the cationic polymer is at least one selected from the group consisting of chitosan, chitosan derivatives, cationic (meth)acrylate copolymers, cationic silicone polymers, diallyl quaternary ammonium salt-acrylamide copolymers, cationic hydrolyzed keratin, cationic hydrolyzed silk, cationic hydrolyzed collagen, cationic hydrolyzed casein, cationic hydrolyzed soy protein, cationic vinylpyrrolidone copolymers, polyvinylpyrrolidone, dimethyldiacrylammonium chloride homopolymers, adipic acid-dimethylaminohydroxypropyldiethylenetriamine copolymers, adipic acid-epoxypropyldiethylenetriamine copolymers, and acrylamide-β-methacryloyloxyethyltrimethylammonium methylsulfate copolymers.

[0029] The present invention also provides a therapeutic agent for dry eye containing diquafosol or a salt thereof and polyvinylpyrrolidone.

[0030] The present invention also provides a method for preventing or treating dry eye, comprising administering to a patient an ophthalmic composition containing diquafosol or a salt thereof and a cationic polymer, wherein the cationic polymer is at least one selected from the group consisting of chitosan, chitosan derivatives, cationic (meth)acrylate copolymers, cationic silicone polymers, diallyl quaternary ammonium salt-acrylamide copolymers, cationic hydrolyzed keratin, cationic hydrolyzed silk, cationic hydrolyzed collagen, cationic hydrolyzed casein, cationic hydrolyzed soy protein, cationic vinylpyrrolidone copolymers, polyvinylpyrrolidone, dimethyldiacrylammonium chloride homopolymers, adipic acid-dimethylaminohydroxypropyldiethylenetriamine copolymers, adipic acid-epoxypropyldiethylenetriamine copolymers, and acrylamide-β-methacryloyloxyethyltrimethylammonium methylsulfate copolymers.

[0031] The present invention also provides a method for preventing or treating dry eye, which comprises administering to a patient an ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone.

[0032] The present invention also provides an ophthalmic composition for use in preventing or treating dry eye, comprising diquafosol or a salt thereof and a cationic polymer, wherein the cationic polymer is at least one selected from the group consisting of chitosan, chitosan derivatives, cationic (meth)acrylate copolymers, cationic silicone polymers, diallyl quaternary ammonium salt-acrylamide copolymers, cationic hydrolyzed keratin, cationic hydrolyzed silk, cationic hydrolyzed collagen, cationic hydrolyzed casein, cationic hydrolyzed soy protein, cationic vinylpyrrolidone copolymers, polyvinylpyrrolidone, dimethyldiacrylammonium chloride homopolymers, adipic acid-dimethylaminohydroxypropyldiethylenetriamine copolymers, adipic acid-epoxypropyldiethylenetriamine copolymers, and acrylamide-β-methacryloyloxyethyltrimethylammonium methylsulfate copolymers.

[0033] The present invention also provides an ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone for use in the prevention or treatment of dry eye.

[0034] The present invention also provides use of an ophthalmic composition containing diquafosol or a salt thereof and a cationic polymer for the manufacture of a medicament for preventing or treating dry eye, wherein the cationic polymer is at least one selected from the group consisting of chitosan, chitosan derivatives, cationic (meth)acrylate copolymers, cationic silicone polymers, diallyl quaternary ammonium salt-acrylamide copolymers, cationic hydrolyzed keratin, cationic hydrolyzed silk, cationic hydrolyzed collagen, cationic hydrolyzed casein, cationic hydrolyzed soy protein, cationic vinylpyrrolidone copolymers, polyvinylpyrrolidone, dimethyldiacrylammonium chloride homopolymers, adipic acid-dimethylaminohydroxypropyldiethylenetriamine copolymers, adipic acid-epoxypropyldiethylenetriamine copolymers, and acrylamide-β-methacryloyloxyethyltrimethylammonium methylsulfate copolymers.

[0035] The present invention also provides use of an ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone for the manufacture of a medicament for preventing or treating dry eye. [Effects of the Invention]

[0036] As is clear from the test results described below, the present composition has a high tear volume increasing effect. Furthermore, the cationic polymer contained in the present composition has the effect of stabilizing the metabolism of diquafosol or its salt. Therefore, the present composition is superior to existing diquafosols. (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 a sufficient therapeutic effect on dry eye while reducing the number of instillations, and is expected to improve adherence to instillation. (登録商標)While the eye drops contain diquafosol tetrasodium salt at a concentration of 3% (w / v), this composition is expected to have the same or better dry eye therapeutic effect at a lower concentration. Furthermore, because ophthalmic compositions containing diquafosol or its salt and polyvinylpyrrolidone, a cationic polymer, have not shown neuroirritation, the application sensation of eye drops may be improved. [Brief explanation of the drawings]

[0037] [Figure 1] FIG. 1 shows the maximum fluorescence intensity (RFUmax) after the addition of diquafosol sodium. DETAILED DESCRIPTION OF THE INVENTION

[0038] 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.

[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] The concentration of diquafosol or a salt thereof in the composition 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, the term "cationic polymer" refers to a polymer containing one or more substituents that become cations when dissolved in water.

[0050] In cationic polymers, the substituents that become cations when dissolved in water are not particularly limited, but examples include primary, secondary, or tertiary amino groups, imino groups, imide groups, amide groups, and quaternary ammonium groups.

[0051] The cationic polymer may be at least one selected from the group consisting of chitosan, chitosan derivatives, cationic (meth)acrylate copolymers, cationic silicone polymers, diallyl quaternary ammonium salt-acrylamide copolymers, cationic hydrolyzed keratin, cationic hydrolyzed silk, cationic hydrolyzed collagen, cationic hydrolyzed casein, cationic hydrolyzed soy protein, cationic vinylpyrrolidone copolymers, polyvinylpyrrolidone, dimethyldiacrylammonium chloride homopolymers, adipic acid-dimethylaminohydroxypropyldiethylenetriamine copolymers, adipic acid-epoxypropyldiethylenetriamine copolymers, and acrylamide-β-methacryloyloxyethyltrimethylammonium methyl sulfate copolymers. The cationic polymer in the composition is preferably at least one selected from the group consisting of chitosan, chitosan derivatives, diallyl quaternary ammonium salt-acrylamide copolymers, and polyvinylpyrrolidone, and more preferably at least one selected from the group consisting of chitosan, chitosan derivatives, and polyvinylpyrrolidone.

[0052] Chitosan is a polysaccharide essentially composed of β(1→4)-D-glucosamine bond units of the (A) monomer and β(1→4)-N-acetyl-D-glucosamine bond units of the (B) monomer. The numerical ratio of (A) to (B) is preferably about 50% to about 99% for (A) and about 1% to about 50% for (B). The numerical ratio of (A) is also referred to as the "degree of deacetylation." The evaluated viscosity of a 1% aqueous solution of chitosan is preferably about 1 to about 3,000 mPa·s.

[0053] Chitosan also includes chitosan salts such as the hydrochloride salt. An example of a chitosan derivative is chitosan-N-acetylcysteine.

[0054] Examples of cationic (meth)acrylate copolymers include vinylpyrrolidone-alkyldialkylamino(meth)acrylate copolymers, quaternized derivatives of vinylpyrrolidone-dimethylaminomethacrylate copolymers and dimethyl sulfate, and aminoethyl acrylate phosphate-(meth)acrylate copolymers.

[0055] Examples of cationic silicone polymers include cationic siloxane derivatives.

[0056] An example of the diallyl quaternary ammonium salt-acrylamide copolymer is dimethyldiallylammonium chloride-acrylamide copolymer.

[0057] Examples of cationic hydrolyzed keratin include N-[2-hydroxy-3(trimethylammonio)propyl] hydrolyzed keratin chloride.

[0058] Examples of cationic hydrolyzed silk include N-[2-hydroxy-3-(coconut oil alkyl dimethyl ammonio) propyl] hydrolyzed silk chloride.

[0059] An example of cationic hydrolyzed collagen is N-[2-hydroxy-3-(cocoalkyldimethylammonio)propyl] hydrolyzed collagen chloride.

[0060] Examples of cationic hydrolyzed casein include N-[2-hydroxy-3-(cocoalkyldimethylammonio)propyl] hydrolyzed casein chloride.

[0061] An example of the cationic hydrolyzed soy protein is N-[2-hydroxy-3-(cocoalkyldimethylammonio)propyl] hydrolyzed soy protein chloride.

[0062] Examples of cationic vinylpyrrolidone copolymers include copolymers of vinylpyrrolidone and imidazole with a quaternary ammonium salt.

[0063] The composition may contain one cationic polymer or two or more cationic polymers, but preferably contains only one cationic polymer.

[0064] The concentration of the cationic polymer in the composition is not particularly limited, but is preferably 0.00001 to 10% (w / v), more preferably 0.0001 to 5% (w / v), even more preferably 0.001 to 5% (w / v), even more preferably 0.01 to 5% (w / v), and particularly preferably 0.01 to 3% (w / v).

[0065] In the present invention, polyvinylpyrrolidone is a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone and is a type of cationic polymer. 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, and even more preferably 30 to 90. Examples include polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K40, polyvinylpyrrolidone K50, polyvinylpyrrolidone K60, polyvinylpyrrolidone K70, polyvinylpyrrolidone K80, polyvinylpyrrolidone K85, polyvinylpyrrolidone K90, and polyvinylpyrrolidone K120. The K value of polyvinylpyrrolidone is a viscosity characteristic value 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):

[0066]

number

[0067] In equation (1), η relis the relative viscosity of the aqueous polyvinylpyrrolidone solution to water, and c is the concentration (%) of polyvinylpyrrolidone in the aqueous polyvinylpyrrolidone solution.

[0068] 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.

[0069] The concentration of polyvinylpyrrolidone in the composition 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 0.01 to 3% (w / v), and particularly preferably 0.1 to 3% (w / v).

[0070] 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 dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid; isotonicity agents such as calcium chloride, sodium chloride, potassium chloride, and concentrated glycerin; stabilizers such as sodium edetate; surfactants such as polysorbates; antioxidants such as ascorbic acid; preservatives such as benzalkonium chloride and chlorhexidine gluconate; and pH adjusters such as hydrochloric acid and sodium hydroxide can be selected and added as needed. These additives can be used alone or in any combination of two or more.

[0071] 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.

[0072] 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.

[0073] The present composition is preferably an aqueous ophthalmic composition containing water as a solvent (base), and more preferably an aqueous eye drop.

[0074] 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.

[0075] The viscosity of the composition is adjusted to be preferably in the range of 1 to 500 mPa·s, more preferably in the range of 1 to 100 mPa·s, even more preferably in the range of 1 to 50 mPa·s, still more preferably in the range of 1 to 30 mPa·s, and particularly preferably in the range of 1 to 20 mPa·s, and the viscosity is measured by a rotational viscometer (25°C; 50 s -1 It is measured at a shear rate of 1 / 2.

[0076] 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.

[0077] 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."

[0078] In the present invention, a "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 typically contains multiple doses of eye drops for use over a certain period of time. On the other hand, a "unit-dose eye drop container" refers to an eye drop container in which the cap is fused and sealed to the mouth of the bottle, and which is intended to be opened by breaking the fused portion between the cap and the bottle-shaped body when in use. Such a unit-dose eye drop container contains a single dose or multiple doses of eye drops.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] This composition is effective in preventing or treating dry eye. Dry eye is defined as "a chronic disease of the lacrimal 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.

[0083] 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.

[0084] 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).

[0085] 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]

[0086] The results of pharmacological tests and formulation examples are shown below, but these examples are intended to provide a better understanding of the present invention and are not intended to limit the scope of the present invention.

[0087] [Test 1] Using normal male albino rabbits, changes in tear volume over time after instillation of an ophthalmic composition containing diquafosol sodium and a cationic polymer were evaluated.

[0088] (Drug Preparation Method) Eye drops 1: Ophthalmic Solution 1 was prepared according to the prescription shown in Table 1 (units are g / 100 mL in Table 1). Specifically, 3 g of diquafosol sodium, 1 g of calcium chloride (CaCl), and 40 mL of chitosan (70 / 200) solution (Chitosan 70 / 200 (Product No. 24205) from HEPPE MEDICAL CHITOSAN GmbH's Chitoceuticals Product Line) were dissolved in sterile purified water, a pH adjuster was added, and the resulting solution was brought to 100 mL to prepare Ophthalmic Solution 1. The chitosan (70 / 200) solution was prepared by dissolving 1.5 g of chitosan (70 / 200) in sterile purified water acidified with dilute hydrochloric acid under heating, adding a pH adjuster, and bringing the total volume to 100 mL. Here, chitosan (70 / 200) refers to chitosan with a degree of deacetylation of 70% and an estimated viscosity of a 1% aqueous solution of approximately 200 mPa·s.

[0089] Eye drops 2 and 3: According to the prescription shown in Table 1, eye drops 2 and 3 were prepared in the same manner as eye drops 1.

[0090] [Table 1]

[0091] Eye drops 4: Diquas is used as an eye drop4 to treat dry eyes. (登録商標) "Ophthalmic Solution 3%" (Santen Pharmaceutical Co., Ltd.) was used. Ophthalmic Solution 4 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.

[0092] Eye drop 5: As eye drop 5, the base of eye drop 4 was used.

[0093] The viscosities of the prepared eye drops 1 to 3 were measured using a rotational viscometer Kinexus pro+ at a temperature of 25°C and a shear rate of 50 s -1 and measured.

[0094] (Test method and drug administration method) Benoxil eye drops 0.4% (manufactured by参天製薬株式会社) were instilled into normal male white rabbits (total 44 rabbits, 88 eyes), and local anesthesia was administered. After 3 minutes, a Shirmer test paper (manufactured byあゆみ製薬株式会社) was inserted into the lower eyelid, removed 1 minute after insertion, and the length of the wetted part (tear volume) was read. This was used as the pre-value. Next, each of the eye drops 1 to 5 was instilled once (4 rabbits, 8 eyes per group). Three minutes before inserting the Shirmer test paper (manufactured byあゆみ製薬株式会社) into the lower eyelid, Benoxil (登録商標) eye drops 0.4% (manufactured by参天製薬株式会社) were instilled, and local anesthesia was administered. Thirty minutes after instilling each eye drop, a Shirmer test paper (manufactured byあゆみ製薬株式会社) was inserted into the lower eyelid, removed 1 minute after insertion, and the length of the wetted part (tear volume) was read. (登録商標)

[0095] (Evaluation method) The change in tear volume before and after instilling the eye drops was calculated as Δtear volume (mm / min).

[0096] (Test results) The Δtear volume (mm / min) at each measurement time is shown in Table 2. Each value is the average value of eyes.

[0097] [Table 2]

[0098] (Discussion) When chitosan, a cationic polymer, was used as an additive (eye drops 1 and 2), a high Δ tear volume was observed even 30 minutes after administration, demonstrating that the ophthalmic composition containing diquafosol sodium and a cationic polymer has an excellent tear volume-increasing effect.

[0099] [Test 2] As in Test 1, normal male white rabbits were used to evaluate the tear volume after instillation of an ophthalmic composition containing diquafosol sodium and a cationic polymer.

[0100] (Drug Preparation Method) Eye drops 6: Ophthalmic Solution 6 was prepared according to the prescription shown in Table 3 (units are g / 100 mL in Table 3). Specifically, 3 g of diquafosol sodium, 1 g of chitosan (oligomer) (Chitosan Oligomer (Product No. 44009) from the Chitoceuticals Product Line of HEPPE MEDICAL CHITOSAN GmBH), and 0.51 g of sodium chloride were dissolved in sterile purified water to make 100 mL, and a pH adjuster was added to prepare Ophthalmic Solution 6. The chitosan (oligomer) used in Ophthalmic Solution 6 has a degree of deacetylation of 75% or more, and the viscosity of a 1% aqueous solution of chitosan is evaluated to be approximately 5 mPa s or less.

[0101] Eye drops 7 and 8: According to the prescription shown in Table 3, eye drops 7 and 8 were prepared in the same manner as eye drops 6. The chitosan N-acetylcysteine ​​used in eye drops 7 and 8 (Kitopure N-Acetyl-Cysteine ​​Conjugated Chitosan (Catalog No. KITO-7) from Poly Sci Tech®) has a degree of deacetylation of 75 to 85%, and the viscosity of a 1% aqueous solution is approximately 5 mPa s or less.

[0102] [Table 3]

[0103] Eye drops 4 and 5: Eye drops 4 and 5 shown in Test 1 were also used.

[0104] (Testing methods and drug administration methods) Benoxil was administered to normal male white rabbits (total of 18 rabbits, 36 eyes). (登録商標) 0.4% eye drops (Santen Pharmaceutical Co., Ltd.) were instilled into the eyes to administer local anesthesia. After 3 minutes, a Schirmer test strip (Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid. After 1 minute, it was removed and the length of the wetted area (tear volume) was measured. This was the baseline value.

[0105] Next, each eye drop solution 4 to 8 was instilled once (6 eyes of 3 mice or 8 eyes of 4 mice per group). Benoxil was administered 3 minutes before inserting Schirmer's test paper (manufactured by Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid. (登録商標) Local anesthesia was administered by instilling 0.4% eye drops (manufactured by Santen Pharmaceutical Co., Ltd.). Thirty 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.

[0106] (Evaluation method) The change in tear volume before and after instillation of the eye drops was calculated as Δ tear volume (mm / min).

[0107] (Test results) The delta tear volume (mm / min) at each measurement time is shown in Table 4. Each value is the average value of 6 or 8 eyes.

[0108] [Table 4]

[0109] (Consideration) When cationic polymers chitosan or chitosan N-acetylcysteine ​​were used as additives (eye drops 6 and 7), a high Δ tear volume was observed even 30 minutes after administration, demonstrating that the ophthalmic composition containing diquafosol sodium and a cationic polymer has an excellent tear volume-increasing effect.

[0110] [Test 3] The effect of each additive on the metabolic stability of diquafosol sodium was investigated.

[0111] (Sample preparation method) Eye drops 9: Ophthalmic Solution 9 was prepared according to the prescription shown in Table 5 (units are g / 100 mL in Table 5). Specifically, 1 g of diquafosol sodium, 3.22 g of sodium chloride, and 80 mL of chitosan (Chitosan low molecular weight (Catalog No. 448869) from SIGMA ALDRICH) solution were dissolved in sterile purified water, a pH adjuster was added, and the resulting solution was brought to 100 mL to prepare Ophthalmic Solution 9. The chitosan solution was prepared by dissolving 1 g of chitosan in sterile purified water acidified with dilute hydrochloric acid while heating, and adding a pH adjuster to bring the total to 100 mL. The chitosan used in Ophthalmic Solution 9 has a degree of deacetylation of 75 to 85%, and the viscosity of a 1% aqueous solution is estimated to be approximately 20 to 300 mPa·s.

[0112] Eye drops 10-20: According to the prescription shown in Table 5, eye drops 10 to 20 were prepared in the same manner as eye drops 9.

[0113] [Table 5]

[0114] (Test Method) 90 μL of rabbit plasma and 90 μL of purified water were mixed with 10 μL each of eye drops 9-20 in an incubator at 37°C. After 6 hours of reaction, 0.3 mL of 10% formic acid solution was added and vortexed thoroughly. 100 μL of the reaction mixture was then mixed with 900 μL of 800 mM potassium phosphate / methanol solution and filtered through a 0.45 μm filter. The filtrate was analyzed by HPLC.

[0115] (Evaluation method) The residual rate and decomposition inhibition rate of diquafosol sodium were calculated from the HPLC analysis results using the following formulas.

[0116] Residual rate (%) = (concentration of diquafosol sodium in plasma / concentration of diquafosol sodium in water) x 100 Decomposition inhibition rate (%) = (remaining rate of eye drops 9-19 / remaining rate of eye drops 20) x 100 (Test results) The residual rate and decomposition inhibition rate for each ophthalmic solution are shown in Table 6.

[0117] [Table 6]

[0118] (Consideration) When chitosan, a cationic polymer, was used as an additive, the metabolic decomposition of diquafosol sodium was suppressed, indicating that cationic polymers have the effect of stabilizing the metabolism of diquafosol sodium.

[0119] [Test 4] The irritation of diquafosol sodium to peripheral nerves in the presence of PVP, a type of cationic polymer, was investigated. "PVP" refers to polyvinylpyrrolidone. "CMC-Na" refers to sodium carboxymethylcellulose. "HPMC" refers to hydroxypropyl methylcellulose. "CVP" refers to carboxyvinyl polymer.

[0120] (Sample preparation method) Prescription 1: Formulation 1 was prepared according to the formula shown in Table 7 (units are g / 100 mL in Table 7). 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.

[0121] Prescription 2: Formulation 2 was prepared according to the recipe shown in Table 7. 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.

[0122] Formulation 3: Formulation 3 was prepared according to the recipe shown in Table 7. 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 3.

[0123] Prescriptions 4-6: According to the recipe shown in Table 7, formulations 4 to 6 were prepared in the same manner as formulation 3.

[0124] [Table 7]

[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 1. In the stimulation control group and formulations 3 to 6, RFU increased after the addition of diquafosol sodium, recording an RFUmax of 103.5% or more. On the other hand, in the PVP-containing formulations 1 and 2, 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 3 to 6, 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 and 2, which contained PVP, did not show an increase in intracellular calcium ion signals after the addition of diquafosol sodium. In other words, diquafosol sodium in the presence of PVP does not exhibit neuroirritation, suggesting that the addition of PVP improves the sensation of application of diquafosol sodium eye drops.

[0129] [Test 5] Using normal male white rabbits, the change in tear volume over time after instillation of this composition was evaluated.

[0130] (Drug Preparation Method) Eye drops A: Ophthalmic solution A was prepared according to the formulation shown in Table 8 (units are g / 100 mL in Table 8). 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 the pH was adjusted to 7 with an appropriate pH adjuster. Sterile purified water was then added to make 20 mL, yielding a 3x concentrate. PVP K90 (4 g) was dissolved in sterile purified water to make a total volume of 100 g, which was then autoclaved (121°C, 20 minutes) to obtain a 4.00% (w / w) PVP solution. To 6.0 g of 4.00% (w / w) PVP K90 solution was added 4 mL of the 3x concentrated solution, and the mixture was adjusted to a total volume of 12 mL with sterile purified water. An appropriate pH adjuster was then added to adjust the pH to 7, thereby preparing eye drops A.

[0131] Eye drops B: Ophthalmic Solution B was prepared according to the prescription shown in Table 8. 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 B was prepared by adding sterile purified water to 4 mL of the 3x concentrate to make a total volume of 12 mL, and then adjusting the pH to 7 by adding a pH adjuster appropriately.

[0132] Eye drops C: Ophthalmic Solution C was prepared according to the prescription shown in Table 8. 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 added to make a total of 20 mL, yielding a 3x concentrate. Ophthalmic Solution C 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.

[0133] The viscosity of the prepared eye drops A to C was measured using a rotational viscometer Kinexus pro+ at a temperature of 25°C and a shear rate of 50 s -1 was measured.

[0134] (Testing methods and drug administration methods) Benoxil was administered to normal male white rabbits (total of 12 rabbits, 24 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 paper (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 of eye drops A to C was instilled once (8 eyes of 4 animals per group, except for eye drop C, which was administered to 24 eyes of 12 animals). Three minutes before inserting the Schirmer test paper (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.

[0135] (Evaluation method) The change in tear volume before and after instillation of the eye drops was calculated as Δ tear volume (mm / min).

[0136] (Test results) The Δ tear volume (mm / min) 60 minutes after instillation is shown in Table 8 (each value is the average of 8 eyes, except for eye drops C, which was the average of 24 eyes). The tear volume-increasing effect of the composition was evaluated according to the following criteria.

[0137] +++: 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

[0138] [Table 8]

[0139] As shown in the results in Table 8 above, the eye drops containing PVP, which is a type of cationic polymer, and particularly PVP K90 (eye drops A) had a high tear volume increasing effect.

[0140] [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.

[0141] (Formulation Example 1: Eye drops (3% (w / v)) in 100mL Diquafosol sodium 3g Chitosan 0.6g Calcium chloride 1.0g Appropriate amount of sterile purified water The eye drops can be prepared by adding diquafosol sodium and the other ingredients described above to sterile purified water and mixing them thoroughly.

[0142] (Formulation Example 2: Eye drops (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01-0.5g Disodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone 0.0001~10g Sodium chloride 0.01-1g 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]

[0143] The present composition has a high tear flow increasing effect. Furthermore, the cationic polymer contained in the present composition has the effect of stabilizing the metabolism of diquafosol or its salt. Therefore, the present composition is superior to existing diquafosols. (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 a sufficient therapeutic effect on dry eye while reducing the number of instillations, and is expected to improve adherence to instillation.(登録商標) While the eye drops contain diquafosol tetrasodium salt at a concentration of 3% (w / v), this composition is expected to have the same or better dry eye therapeutic effect at a lower concentration. Furthermore, because ophthalmic compositions containing diquafosol or its salt and polyvinylpyrrolidone, a cationic polymer, have not shown neuroirritation, the application sensation of eye drops may be improved.

Claims

[Claim 1] The invention described in the specification.

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