Therapeutic agent for dry eye characterized by being used to be dropped into eye of dry eye patient wearing soft contact lens

Abstract

To find an agent for treating the onset and / or worsening of dry eye symptoms caused by wearing a soft contact lens.SOLUTION: An ophthalmic solution, which contains diquafosol tetrasodium and is free from benzalkonium chloride, treats the onset and / or worsening of dry eye symptoms caused by wearing a soft contact lens.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a dry eye therapeutic agent that contains diclofasol or a salt thereof as an active ingredient and does not contain benzalkonium chloride, and is characterized by being used for instillation into the eyes of dry eye patients wearing soft contact lenses.

Background Art

[0002] Dry eye starts with symptoms such as a dry and gritty feeling in the eyes, and if it worsens, it is a disease that causes great inconvenience in daily life. The number of dry eye patients is increasing year by year with the advent of an aging society and the increase in VDT (video display terminal) work such as using personal computers. The estimated number of patients in the United States is more than 10 million, and in Japan, it is said to be more than 8 million.

[0003] Although the pathological condition of dry eye has not been completely clarified, it is considered that the main causes are a decrease in tear secretion and an increase in tear evaporation associated with a decrease in the stability of the tear film. That is, these cause pathological symptoms and / or findings such as eye discomfort, a feeling of eye dryness, eye fatigue, congestion, and corneal epithelial damage. If these pathological symptoms and / or findings progress, ultimately visual abnormalities will occur, so it is extremely important to treat dry eye early and appropriately.

[0004] Since wearing soft contact lenses leads to a decrease in the stability of the tear film, wearing soft contact lenses by dry eye patients may lead to worsening of dry eye symptoms. In addition, dry eye may also develop due to wearing soft contact lenses. However, even in such dry eye patients, there are cases where they do not want to discontinue wearing soft contact lenses from the perspective of convenience.

[0005] On the one hand, in Japan, there is no drug that is widely recognized as a treatment for the occurrence / worsening of dry eye symptoms caused by wearing soft contact lenses. Rather, "Diquas (登録商標) Eye Drops 3%", "Hialin (登録商標) Eye Drops 0.1%", and "Hialin (登録商標) Eye Drops 0.3%", which are widely used among dry eye patients in Japan, are contraindicated for use by wearers of soft contact lenses themselves.

[0006] By the way, the above-mentioned "Diquas (登録商標) Eye Drops 3%" contains diclofasol tetrasodium salt at a concentration of 3% (w / v) as an active ingredient, and also contains benzalkonium chloride as a preservative. Diclofasol is a purine receptor agonist also known as P 1 ,P 4 -di(uridine-5') tetraphosphate or Up4U, and as disclosed in Patent Document 1, it is known to have a lacrimal secretion promoting effect. However, it is not known what effect diclofasol has on the occurrence / worsening of dry eye symptoms caused by wearing soft contact lenses.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] Therefore, exploring a drug for treating the occurrence / worsening of dry eye symptoms caused by wearing soft contact lenses is an interesting issue.

Means for Solving the Problems

[0009] The inventors of the present invention conducted intensive research to search for a drug for treating the occurrence / worsening of dry eye symptoms caused by wearing soft contact lenses. As a result, when an eye drop containing diclofasol tetrasodium salt and not containing benzalkonium chloride (hereinafter also referred to as "the present eye drop") was instilled into the eyes of cynomolgus monkeys wearing soft contact lenses, a remarkable increase in NIBUT (non-invasive tear film break-up time), that is, stabilization of the tear film, which was not observed with artificial tears, was found, and the present invention was thus completed. As described in the background art section, since the occurrence / worsening of dry eye symptoms caused by wearing soft contact lenses is due to a decrease in the stability of the tear film, stabilization of the tear film contributes to the treatment of dry eye in wearers of soft contact lenses.

[0010] That is, the present invention provides a dry eye therapeutic agent as described below. (1) A dry eye therapeutic agent (hereinafter also referred to as "the present agent") containing diclofasol or a salt thereof as an active ingredient, not containing benzalkonium chloride, and being used for instillation into the eyes of dry eye patients wearing soft contact lenses. (2) The therapeutic agent according to (1), which is of the unit dose type. (3) The therapeutic agent according to (1), which is of the multi-dose type. (4) The therapeutic agent according to (3), which contains a preservative other than benzalkonium chloride. (5) The therapeutic agent according to (4), wherein the preservative other than benzalkonium chloride is at least one selected from the group consisting of chlorhexidines, boric acids, chlorous acids, parabens, sorbic acids, chlorobutanol, and benzethonium chloride. (6) The therapeutic agent according to (4) or (5), wherein the preservative other than benzalkonium chloride is chlorhexidines. (7) The therapeutic agent according to any one of (1) to (6), wherein the concentration of diclofasol or a salt thereof is 0.5 to 5% (w / v). (8) The therapeutic agent according to any one of (1) to (7), wherein the concentration of diclofasol or a salt thereof is 3% (w / v). (9) The therapeutic agent according to (1), which is caused by wearing contact lenses and results in dry eye.

[0011] The present invention also provides the following eye drops. (10) An eye drop for improving the stability of the tear film, which contains diclofasol or a salt thereof as an active ingredient, does not contain benzalkonium chloride, and is characterized by being used for instillation into the eye wearing a soft contact lens. (11) An eye drop for treating the dry eye sensation or eye discomfort associated with wearing a soft contact lens, which contains diclofasol or a salt thereof as an active ingredient, does not contain benzalkonium chloride, and is characterized by being used for instillation into the eye wearing a soft contact lens.

[0012] The present invention also relates to the following. (12) An eye drop containing diclofasol or a salt thereof as an active ingredient, not containing benzalkonium chloride, for use in the treatment of dry eye, including instillation into the eyes of dry eye patients wearing soft contact lenses. (13) An eye drop containing diclofasol or a salt thereof as an active ingredient, not containing benzalkonium chloride, for use in improving the stability of the tear film, including instillation into the eyes wearing a soft contact lens. (14) An eye drop containing diclofasol or a salt thereof as an active ingredient, not containing benzalkonium chloride, for use in the treatment of the dry eye sensation or eye discomfort associated with wearing a soft contact lens, including instillation into the eyes wearing a soft contact lens.

[0013] The present invention also relates to the following. (15) Use of an eye drop containing diclofasol or a salt thereof as an active ingredient, not containing benzalkonium chloride, for manufacturing a medicament for treating dry eye, characterized by being used for instillation into the eyes of dry eye patients wearing soft contact lenses. Use of a eye drop containing diclofasol or a salt thereof as an active ingredient and not containing benzalkonium chloride for manufacturing a medicament for improving the stability of the tear film, which is characterized by being used to be instilled into an eye wearing a soft contact lens. Use of a eye drop containing diclofasol or a salt thereof as an active ingredient and not containing benzalkonium chloride for manufacturing a medicament for treating a dry eye feeling or eye discomfort associated with wearing a soft contact lens, which is characterized by being used to be instilled into an eye wearing a soft contact lens.

[0014] Furthermore, the present invention also relates to the following. A method for treating dry eye, which comprises administering an eye drop containing a therapeutically effective amount of diclofasol or a salt thereof and not containing benzalkonium chloride to the eye of a dry eye patient wearing a soft contact lens. A method for improving the stability of the tear film, which comprises administering an eye drop containing a therapeutically effective amount of diclofasol or a salt thereof and not containing benzalkonium chloride to an eye wearing a soft contact lens. A method for treating a dry eye feeling or eye discomfort associated with wearing a soft contact lens, which comprises administering an eye drop containing a therapeutically effective amount of diclofasol or a salt thereof and not containing benzalkonium chloride to an eye wearing a soft contact lens.

[0015] Furthermore, the present invention also relates to the following. An eye drop for treating dry eye, which is characterized by being used to be instilled into the eye of a dry eye patient wearing a soft contact lens, containing diclofasol or a salt thereof as an active ingredient and not containing benzalkonium chloride. An eye drop for improving the stability of the tear film, which is characterized by being used to be instilled into an eye wearing a soft contact lens, containing diclofasol or a salt thereof as an active ingredient and not containing benzalkonium chloride. An eye drop for treating dry eye sensation or eye discomfort associated with wearing soft contact lenses, which is characterized by being used for instillation into an eye wearing a soft contact lens, containing diclofasol or a salt thereof as an active ingredient and not containing benzalkonium chloride.

Advantages of the Invention

[0016] A dry eye treatment agent containing diclofasol tetrasodium salt and not containing benzalkonium chloride treats the occurrence / worsening of dry eye symptoms caused by wearing soft contact lenses.

Brief Description of the Drawings

[0017]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0018] Diclofasol is a compound represented by the following formula.

[0019]

Chemical Formula

[0020] Diclofasol can be produced according to the usual methods in the field of organic synthetic chemistry, and can also be produced by the method disclosed in Japanese Patent Application Laid-Open No. 2001-510484.

[0021] The salts of dicuahosor are not particularly limited as long as they are pharmaceutically acceptable salts, and include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; quaternary ammonium salts with methyl bromide, methyl iodide, etc.; salts with halogen ions such as bromide ions, chloride ions, and iodide ions; salts with alkali metals such as lithium, sodium, and potassium; salts with alkaline earth metals such as calcium and magnesium; metal salts with iron, zinc, etc.; salts with ammonia; 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, etc.

[0022] Preferred as the "dicuahosor or its salt" in the present invention is the tetrasodium salt of dicuahosor represented by the following formula (hereinafter also simply referred to as "dicuahosor sodium").

[0023]

Chemical formula

[0024] When geometric isomers or optical isomers exist in dicuahosor or its salt, such isomers or their salts are also included in the scope of the present invention. Further, when proton tautomerism exists in dicuahosor or its salt, such tautomers or their salts are also included in the scope of the present invention.

[0025] When the dikua hosol or its salts, hydrates or solvates have crystal polymorphs and crystal polymorph groups (crystal polymorph systems), those crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are also included in the scope of the present invention. Here, the crystal polymorph group (crystal polymorph system) means each individual crystal form and the whole process at each stage when the crystal form changes depending on conditions and states such as the production, crystallization, storage, etc. of those crystals (note that this state also includes the formulated state).

[0026] Benzalkonium chloride is a preservative widely used in eye drops and is represented by the general formula: [C6H5CH2N(CH3)2R]Cl. In the above general formula, R represents an alkyl group, and benzalkonium chloride in which the alkyl group has 12 carbon atoms (hereinafter simply referred to as "BAK-C 12 ") or benzalkonium chloride in which the alkyl group has 14 carbon atoms (hereinafter simply referred to as "BAK-C 14 ") is particularly widely used in eye drops.

[0027] In the present invention, "instilled into the eyes of dry eye patients wearing soft contact lenses" means that the eye drops are instilled in a state where a soft contact lens is worn on the cornea of a dry eye patient.

[0028] Examples of the soft contact lenses include contact lenses mainly composed of hydroxyethyl methacrylate or silicone hydrogel contact lenses.

[0029] The types of soft contact lenses to which the present invention is applicable are not particularly limited, and it does not matter whether they are ionic or non-ionic, hydrophilic or non-hydrophilic. For example, in addition to lenses for repeated use, all currently marketed or future marketed soft contact lenses such as daily disposable lenses, weekly disposable lenses, and bi-weekly disposable lenses are applicable.

[0030] Dry eye is defined as "a chronic disease of the tear fluid and corneal epithelium caused by various factors, and a disease accompanied by eye discomfort and visual abnormalities", and dry keratoconjunctivitis (KCS) is included in dry eye. In the present invention, the occurrence of dry eye symptoms caused by wearing soft contact lenses is also included in dry eye.

[0031] Dry eye symptoms include not only subjective symptoms such as a feeling of dryness in the eyes, eye discomfort, eye fatigue, a dull feeling, photophobia, eye pain, and blurred vision, but also objective findings such as congestion and corneal epithelial damage.

[0032] Although there are still many unclear points about the etiology of dry eye, it has been reported that it is caused by Sjogren's syndrome; congenital anacryodia; sarcoidosis; graft-versus-host disease (GVHD) due to bone marrow transplantation; ocular pemphigoid; Stevens-Johnson syndrome; lacrimal duct obstruction caused by trachoma, etc.; diabetes; reduced reflex secretion caused by corneal refractive surgery (LASIK: Laser(-assisted) in Situ Keratomileusis), etc.; meibomian gland dysfunction; reduced oil layer caused by blepharitis, etc.; incomplete blinking or incomplete eyelid closure caused by proptosis, lagophthalmos, etc.; reduced mucin secretion from germ cells; VDT work, etc.

[0033] In the present invention, "dry eye treatment" means improving dry eye symptoms by improving the stability of the tear film in eyes wearing soft contact lenses. Note that the improvement of dry eye symptoms also means the improvement of dry eye symptoms that have deteriorated due to a dry eye patient wearing soft contact lenses, and the improvement of dry eye symptoms that have occurred due to wearing soft contact lenses itself. Further, in the present invention, "dry eye treatment" includes "prevention of dry eye".

[0034] Improving the stability of the tear film means that the tears are improved quantitatively or qualitatively. Note that the stability of the tear film can be confirmed by measuring the BUT (tear film break-up time). Among the BUTs, the measurement that is closer to a more natural state without applying a load such as a staining solution is called NIBUT (non-invasive tear film break-up time).

[0035] In the present invention, the "multi-dose type container" refers to an eye drop container provided with a container body and a cap that can be attached to the container body, and means an eye drop container that can freely open and re-seal the cap. Usually, a plurality of doses of eye drops are contained in the multi-dose type container for use over a certain period of time.

[0036] In the present invention, the "unit-dose type container" refers to an eye drop container in which a cap is fusion-sealed to the bottle mouth portion and is intended to be used by breaking and opening the fusion portion between the cap and the bottle-shaped body during use. Usually, one or several doses of eye drops are contained in the unit-dose type container. Further, the unit-dose type container is a container in which a cap is fusion-sealed to the bottle mouth portion and can be completely re-capped even after breaking the fusion portion between the cap and the bottle-shaped body to open the container during use, and includes an eye drop container that contains several doses of eye drops for use up in one day.

[0037] In addition, this agent may contain a preservative other than benzalkonium chloride and may be a normal multi-dose type.

[0038] In the present invention, the "preservative other than benzalkonium chloride" is not particularly limited as long as it is a compound other than benzalkonium chloride and is known to have a preservative effect, but is preferably chlorhexidines, boric acids, chlorous acids, parabens, sorbic acids, chlorobutanol, or benzethonium chloride, and more preferably chlorhexidines.

[0039] When this agent contains chlorhexidines, the "chlorhexidines" include chlorhexidine and its salts. Chlorhexidine is a compound represented by the following chemical structural formula and is also a compound called 1,1'-hexamethylenebis[5-(4-chlorophenyl)biguanide].

[0040]

Chemical formula

[0041] Among the above chlorhexidines, the "salts of chlorhexidine" are not particularly limited as long as they are pharmaceutically acceptable salts. Specifically, organic acid salts [for example, monocarboxylic acid salts (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylic acid salts (fumarate, maleate, succinate, malonate, etc.), oxycarboxylic acid salts (gluconate, lactate, tartrate, citrate, etc.), organic sulfonate salts (methanesulfonate, toluenesulfonate, tosylate, etc.), etc.], inorganic acid salts (for example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (for example, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [for example, ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.] and the like can be mentioned. Among these salts, organic acid salts and / or inorganic acid salts are preferred, oxycarboxylic acid salts, monocarboxylic acid salts and / or inorganic acid salts are more preferred, gluconate, acetate and / or hydrochloride are still more preferred, and gluconate is particularly preferred. These salts of chlorhexidine may be used alone or in any combination of two or more.

[0042] Chlorhexidine and its salts may be synthesized by known methods or can be obtained as commercial products.

[0043] When the agent contains chlorhexidines, the concentration thereof is 0.0001 to 0.1%, preferably 0.0005 to 0.05% (w / v), and particularly preferably 0.001 to 0.005% (w / v).

[0044] When the agent contains boric acids, the "boric acids" include boric acid and its salts. Among the above boric acids, the "salt of boric acid" is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc. may be mentioned, and preferably borax.

[0045] When the agent contains chlorous acids, the "chlorous acids" include chlorous acid and its salts. Among the above chlorous acids, the "salt of chlorous acid" is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, sodium chlorite, potassium chlorite, calcium chlorite, magnesium chlorite, etc. may be mentioned.

[0046] When the agent contains parabens, the "parabens" include paraben and its salts. Among the above parabens, the "salt of paraben" is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, ethyl paraben, methyl paraben, propyl paraben, isopropyl paraben, butyl paraben, isobutyl paraben, etc. may be mentioned, and preferably methyl paraben and ethyl paraben.

[0047] When the agent contains sorbic acids, the "sorbic acids" include sorbic acid and its salts. Among the above sorbic acids, the "salt of sorbic acid" is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, potassium sorbate, etc. may be mentioned.

[0048] The dosage form of the agent is eye drops. This agent can also contain an active ingredient other than diclofasol or its salt, but preferably contains only diclofasol or its salt as the sole active ingredient.

[0049] This agent preferably contains diclofasol or its salt at a concentration of 0.5 to 5% (w / v), more preferably 1, 2, 3 or 4% (w / v), and even more preferably 3% (w / v).

[0050] This agent can be prepared by selecting and using isotonic agents such as sodium chloride, potassium chloride, and concentrated glycerin; buffering agents such as sodium phosphate, sodium acetate, and epsilon-aminocaproic acid; surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, and polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and sodium edetate. The pH may be within the range acceptable for ophthalmic preparations, but is usually preferably within the range of 4 to 8. A pH adjuster such as hydrochloric acid or sodium hydroxide can be appropriately added to this agent.

[0051] This agent can be instilled into the eyes 1 to 10 times a day, preferably 2 to 8 times a day, more preferably 4 to 6 times a day, and even more preferably 6 times a day.

[0052] The results of pharmacological tests and formulation examples are shown below. These examples are for better understanding of the present invention and do not limit the scope of the present invention.

Example

[0053] [Pharmacological Test 1] Evaluation Test of NIBUT Increase Effect The NIBUT of diclofasol eye drops was examined in eyes with reduced stability of the tear film due to wearing soft contact lenses.

[0054] (Sample Preparation) As diclofasol eye drops, the following Eye Drop 1 was prepared and used in the test.

[0055] Eye Drop 1: Sodium diclofenac (3 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.39 g), potassium chloride (0.15 g), sodium edetate hydrate (0.01 g) and chlorhexidine gluconate (0.0025 g) were dissolved in water to make 100 mL, and a pH adjuster was added to adjust the pH to 7.5.

[0056] (Test method) For the eyes of cynomolgus monkeys wearing soft contact lenses (product name: Menicon Soft MA (登録商標) ), before instilling eye drops 1 (20 μL / eye) and at 15, 30, 45, and 60 minutes after instillation, NIBUT was measured with a dry eye observation device (DR-1, Kowa). As a control drug, artificial tears (product name: Soft Santia (登録商標) ) were used (N = 10 - 11 eyes).

[0057] (Results) The test results are shown in Figure 1. As is clear from Figure 1, when eye drops 1 were instilled into the eyes of monkeys wearing soft contact lenses, a significant increase in NIBUT was observed at all measurement points up to 60 minutes after instillation compared with before instillation. On the other hand, no increase in NIBUT was observed with the instillation of artificial tears.

[0058] (Discussion) From the above results, it was shown that this agent improves the decrease in the stability of the tear film caused by wearing soft contact lenses. Therefore, this agent is useful for treating the occurrence / worsening of dry eye symptoms caused by wearing soft contact lenses. That is, this agent can be instilled into the eyes of dry eye patients wearing soft contact lenses to treat dry eye. In addition, it has been reported that wearing soft contact lenses can cause subjective symptoms such as a feeling of dryness and discomfort in the eyes. This is thought to be due to the thinning of the tear film caused by wearing soft contact lenses and the decrease in the stability of the tear film. From the above results, since this agent improves the decrease in the stability of the tear film caused by wearing soft contact lenses, it is useful for treating the feeling of dryness or discomfort in the eyes associated with wearing soft contact lenses.

[0059] [Pharmacological Test 2] Evaluation Test 2 of the NIBUT Increase Effect The NIBUT of diclofasol eye drops was examined in eyes with reduced tear film stability due to wearing soft contact lenses.

[0060] (Sample Preparation) As diclofasol eye drops, Eye Drop 1 was prepared in the same manner as in Pharmacological Test 1 and used in the test.

[0061] (Test Method) In the eyes of cynomolgus monkeys wearing soft contact lenses (product name: Menicon Soft MA (登録商標) ), the NIBUT before instilling Eye Drop 1 (20 μL / eye) and 5, 15, 30, 45, and 60 minutes after instillation was measured with a dry eye observation device (DR-1, Kowa). As a control drug, artificial tears (product name: Soft Santia (登録商標) ), sodium hyaluronate (product name: Hyalaine (登録商標) Mini Eye Drops 0.1%) were used (N = 11 eyes).

[0062] (Results) The test results are shown in Figure 2. As is clear from Figure 2, when Eye Drop 1 was instilled into the eyes of monkeys wearing soft contact lenses, a significant increase in NIBUT was observed at all measurement points up to 60 minutes after instillation compared with before instillation. On the other hand, no increase in NIBUT was observed with instillation of artificial tears. In addition, although an increase in NIBUT was observed 5 minutes after instillation of sodium hyaluronate, the increase effect was lower than that of Eye Drop 1, and no increase in NIBUT was observed after 15 minutes of instillation.

[0063] (Discussion) From the above results, it was shown that this agent improves the reduction in tear film stability due to wearing soft contact lenses more than sodium hyaluronate. These test results indicate that when instilled into the eyes of dry eye patients wearing soft contact lenses, Hyalaine (登録商標)Compared with the mini eye drops, it is shown that this agent has an extremely strong therapeutic effect on dry eye and a therapeutic effect on the dry eye sensation or eye discomfort associated with wearing soft contact lenses.

[0064] [Pharmacological Test 3] Comparative Test of NIBUT Increase Effect In eyes with reduced tear film stability due to wearing soft contact lenses, the NIBUT of this eye drop and an eye drop containing benzalkonium chloride were compared.

[0065] (Sample Preparation) Eye Drop 1: As this eye drop, Eye Drop 1 was prepared in the same manner as in Pharmacological Test 1. Eye Drop 2: As this eye drop, an eye drop 2 without a preservative was prepared. Specifically, diclofasone disodium (3 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.41 g), potassium chloride (0.15 g), and sodium edetate hydrate (0.01 g) were dissolved in water to make 100 mL, and a pH adjuster was added to make the pH 7.5. Eye Drop 3: As a comparative example, an eye drop 3 containing benzalkonium chloride was prepared. Specifically, diclofasone disodium (3 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.41 g), potassium chloride (0.15 g), and benzalkonium chloride (0.0075 g) were dissolved in water to make 100 mL, and a pH adjuster was added to make the pH 7.5. Eye Drops 1, 2, and 3 are all eye drops containing the same concentration of the active ingredient (diclofasone disodium). Also, Eye Drop 1 and Eye Drop 3 both conform to the storage efficacy test criteria of the Japanese Pharmacopoeia and have equivalent storage efficacy.

[0066] (Test Method) Soft contact lenses (product name: Menicon Soft MA (登録商標) ) were worn on the eyes of cynomolgus monkeys, and the NIBUT before instilling Eye Drops 1 to 3 (20 μL / eye) and 30 minutes after instillation was measured with a dry eye observation device (DR-1, Kowa) (N = 11 eyes).

[0067] (Results) The test results are shown in Table 1.

[0068]

Table 1

[0069] After measuring and comparing the NIBUT 30 minutes after instillation of Eye Drops 1 and Eye Drops 3, which conform to the storage efficacy test criteria of the Japanese Pharmacopoeia and have equivalent storage efficacy, it was shown that Eye Drops 1 have a higher NIBUT increasing effect than Eye Drops 3 containing benzalkonium chloride. In addition, it was shown that the preservative-free eye drops (Eye Drops 2) also have a higher NIBUT increasing effect than Eye Drops 3 containing benzalkonium chloride.

[0070] (Discussion) It was shown that this eye drop improves the reduction in the stability of the tear film caused by wearing soft contact lenses compared to eye drops containing benzalkonium chloride.

[0071] [Formulation Example] The drug of the present invention will be further specifically described by giving formulation examples, but the present invention is not limited only to these formulation examples. (Formulation Example 1: Eye Drops (3% (w / v))) In 100 mL Diclofasone disodium 3 g Sodium hydrogen phosphate hydrate 0.1 - 0.5 g Sodium chloride 0.01 - 1 g Potassium chloride 0.01 - 1 g Sodium edetate hydrate 0.0001 - 0.1 g Chlorhexidine gluconate 0.0001 - 0.1 g Polysorbate 80 0.0001 - 0.1 g Sterile purified water q.s. The above eye drops can be prepared by adding diclofasone disodium and the other above components to sterile purified water and mixing them well.

Industrial Applicability

[0072] An eye drop containing disodium diclofenac and not containing benzalkonium chloride treats the occurrence / worsening of dry eye symptoms caused by wearing soft contact lenses.

Claims

1. A therapeutic agent for dry eye, which is used by being instilled into the eyes of a patient with dry eye who wears soft contact lenses, and which contains diquafosol or a salt thereof as an active ingredient and does not contain benzalkonium chloride.

2. The therapeutic agent according to claim 1 , which is contained in a unit-dose container.

3. The therapeutic agent according to claim 1 , which is contained in a multi-dose container.

4. 4. The therapeutic agent according to claim 3, which contains a preservative other than benzalkonium chloride.

5. 5. The therapeutic agent according to claim 4, wherein the preservative other than benzalkonium chloride is at least one selected from the group consisting of chlorhexidines, borates, chlorites, parabens, sorbates, chlorobutanol and benzethonium chloride.

6. 6. The therapeutic agent according to claim 4 or 5, wherein the preservative other than benzalkonium chloride is a chlorhexidine.

7. The therapeutic agent according to any one of claims 1 to 6, wherein the concentration of diquafosol or a salt thereof is 0.5 to 5% (w / v).

8. The therapeutic agent according to any one of claims 1 to 7, wherein the concentration of diquafosol or a salt thereof is 3% (w / v).

9. The method according to claim 1, wherein the dry eye is caused by contact lens wear.

10. 1. An eye drop for improving the stability of the tear film, comprising diquafosol or a salt thereof as an active ingredient and not containing benzalkonium chloride, the eye drop being characterized in that it is used by being instilled into an eye wearing a soft contact lens.

11. An eye drop for treating dry eye or eye discomfort associated with wearing soft contact lenses, comprising diquafosol or a salt thereof as an active ingredient and not containing benzalkonium chloride, characterized in that the eye drop is used by being instilled into an eye in which a soft contact lens is worn.

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