JP2021075534A - Aqueous ophthalmic preparation - Google Patents

Abstract

To provide a diquafosol eye drop that does not contain benzalkonium chloride and has improved safety, and provide a diquafosol eye drop that contains a preservative and is physicochemically stable during the preparation of the eye drop and its long-term storage.SOLUTION: An aqueous ophthalmic preparation comprises 0.1-10% (w/v) concentration of diquafosol or a salt thereof and 0.0001-0.1% (w/v) concentration of a chlorhexidine compound.SELECTED DRAWING: None

Description

The present invention is an aqueous ophthalmic solution containing diquafosol at a concentration of 0.1 to 10% (w / v) or a salt thereof (hereinafter, also referred to as diquafosol ophthalmic solution), and 0.0001 to 0.1% (hereinafter, also referred to as diquafosol ophthalmic solution). It relates to an aqueous ophthalmic solution containing chlorhexidines at a concentration of w / v).

In general, there are two types of eye drops: a type that is used many times over a certain period after opening (multi-dose type eye drops) and a single-use type (unit-dose type eye drops). In particular, the multi-dose type eye drops generally contain a preservative in order to prevent product spoilage due to microbial contamination during use and to ensure storage stability of the eye drops.

As a preservative, benzalkonium chloride (hereinafter, also referred to as BAK), which has an excellent preservative effect, is widely used. On the other hand, it is known that the use of BAK at a high concentration may cause corneal damage. It has also been pointed out that if an eye drop containing BAK is instilled while the user is wearing a soft contact lens, the BAK comes into contact with the contact lens and deforms the soft contact lens itself. Therefore, it is usually prohibited to instill BAK-containing eye drops while wearing soft contact lenses.

By the way, diquafosol is ^{a purinergic agonist also called P 1} , P ⁴ -di (uridine-5') _{tetraphosphate, Up 4} U, etc. In Japan, diquafosol has a concentration of 3% (w / v). eye drop containing the Sol sodium: as (product name Jikuasu ^® ophthalmic solution 3%), has been used for dry eye treatment. BAK is contained in the Diquas ^{(registered trademark)} ophthalmic solution 3% for the above reason.

Further, Patent Document 1 contains an aqueous ophthalmic solution containing diquafosol having a concentration of 0.1 to 10% (w / v) or a salt thereof and a chelating agent having a concentration of 0.0001 to 1% (w / v). It is disclosed.

Japanese Unexamined Patent Publication No. 2013-227291

An object of the present invention is to provide a diquafosol ophthalmic solution that does not contain BAK and has higher safety. Furthermore, an object of the present invention is to provide a diquafosol ophthalmic solution containing a preservative that is physicochemically stable even when the ophthalmic solution is prepared and stored for a long period of time.

As a result of diligent research to solve the above problems, the present inventors have conducted diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v), and 0.0001 to 0.1% (w / v). We have found that an aqueous ophthalmic solution containing chlorhexidines at a concentration of v) (hereinafter, also referred to as this ophthalmic solution) has an excellent preservative effect, and have reached the present invention. Furthermore, the present inventors have found that the present ophthalmic solution suppresses the deformation of soft contact lenses. In addition, the present inventors have higher viable cell activity in cultured immortalized human corneal epithelial cells than the eye drops containing BAK and chlorhexidines containing diquafosol or salts thereof. Found to show. In addition, the present inventors remarkably increase NIBUT (non-invasive tear film destruction time) in an eye wearing a soft contact lens, that is, stabilize the tear film in an eye wearing a soft contact lens. I found that it would be transformed. On the other hand, no such effect was observed with artificial tears. Since the occurrence / exacerbation 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 by this ophthalmic solution is dry in the eyes wearing soft contact lenses. Useful for the prevention and / or treatment of eye. This ophthalmic solution is also useful for the prevention and / or treatment of dry eye and / or eye discomfort in eyes wearing soft contact lenses. Furthermore, we have found that diquafosol ophthalmic solution containing chlorhexidines in a specific concentration range, that is, a concentration of 0.001 to 0.005% (w / v), has a high residual rate of chlorhexidines at the time of ophthalmic solution preparation. It was found that chlorhexidines in the ophthalmic solution have excellent long-term stability.

That is, the present invention provides the following aqueous eye drops.
(1) An aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines at a concentration of 0.0001 to 0.1% (w / v).
(2) The aqueous eye drop according to (1), wherein the chlorhexidines are chlorhexidine gluconate.
(3) The aqueous eye drop according to (1) or (2), wherein the concentration of chlorhexidine in the eye drop is 0.0005 to 0.05% (w / v).
(4) The aqueous eye drop according to (1) or (2), wherein the concentration of chlorhexidines in the eye drop is 0.001 to 0.005% (w / v).
(5) The aqueous ophthalmic solution according to (1) or (2), wherein the concentration of chlorhexidines in the ophthalmic solution is more than 0.001% (w / v) to 0.005% (w / v) or less. ..
(6) The aqueous eye drop according to (1) or (2), wherein the concentration of chlorhexidines in the eye drop is 0.0015 to 0.005% (w / v).
(7) The aqueous eye drop according to (1) or (2), wherein the concentration of chlorhexidines in the eye drop is 0.002 to 0.005% (w / v).
(8) The aqueous eye drop according to any one of (1) to (7), wherein the concentration of diquafosol or a salt thereof in the eye drop is 3% (w / v).
(9) The aqueous eye drop according to any one of (1) to (8), further containing a chelating agent.
(10) The aqueous eye drop according to (9), wherein the chelating agent is edetic acid or a salt thereof.
(11) The aqueous eye drop according to any one of (1) to (10), which is for soft contact lenses.
(12) The aqueous eye drop according to (11), wherein the soft contact lens is a silicone hydrogel contact lens.

The present invention also provides the following methods for suppressing deformation of soft contact lenses.
(13) A method for suppressing deformation of a soft contact lens due to the aqueous eye drop according to any one of (1) to (12).

Furthermore, the present invention also relates to the following.
(14) Prevention of dry eye and containing diquafosol or salts thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines at a concentration of 0.0001 to 0.1% (w / v). / Or an aqueous ophthalmic solution for treatment.
(15) Dry eye of an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines at a concentration of 0.0001 to 0.1% (w / v). Use in the prevention and / or treatment of.
(16) Administer an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines at a concentration of 0.0001 to 0.1% (w / v). Methods of preventing and / or treating dry eye, including.

The present invention also provides the following aqueous eye drops.
(17) The aqueous eye drop according to any one of (1) to (12) for prevention and / or treatment of dry eye in an eye wearing soft contact lenses.
(18) The aqueous eye drop according to any one of (1) to (12) for improving the stability of the tear film in an eye wearing soft contact lenses.
(19) The aqueous ophthalmic solution according to any one of (1) to (12) for preventing or treating dry eye or eye discomfort in eyes wearing soft contact lenses.
(20) The aqueous eye drop according to any one of (17) to (19), wherein the soft contact lens is a silicone hydrogel contact lens.

The present invention also provides the methods listed below.
(21) In the preparation of an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines, a concentration of 0.0001 to 0.005% (w / v). A method for suppressing a decrease in the residual rate of chlorhexidines in the aqueous ophthalmic solution by using the above-mentioned chlorhexidines.
(22) A method for stabilizing chlorhexidines in an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines, wherein the concentration of the chlorhexidines is high. A method of greater than 0.001% (w / v) to less than or equal to 0.1% (w / v).

As is clear from the results of the test examples described later, this ophthalmic solution has an excellent preservative effect. Further, since this ophthalmic solution suppresses deformation of soft contact lenses, it can be used for soft contact lenses. In addition, this ophthalmic solution shows higher viable cell activity in cultured immortalized human corneal epithelial cells than the ophthalmic solution containing BAK and the ophthalmic solution containing chlorhexidines containing diquafosol or a salt thereof. Therefore, this ophthalmic solution is more safe for living organisms, especially the keratoconjunctival epithelium, and is useful for diseases such as dry eye in which the keratoconjunctival epithelium is unstable. In addition, this ophthalmic solution significantly increases NIBUT in eyes wearing soft contact lenses. On the other hand, artificial tears do not have such an effect. That is, this ophthalmic solution stabilizes the tear film in the eye wearing soft contact lenses. Since the occurrence / exacerbation 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 by this ophthalmic solution is dry in the eyes wearing soft contact lenses. Useful for the prevention and / or treatment of eye. This ophthalmic solution is also useful for the prevention and / or treatment of dry eye and / or eye discomfort in eyes wearing soft contact lenses. Furthermore, diquafosol ophthalmic solution containing chlorhexidines in a specific concentration range, that is, at a concentration of 0.001 to 0.005% (w / v), maintains a high residual rate of chlorhexidines during the preparation of the ophthalmic solution, and said Chlorhexidines in ophthalmic solution have excellent long-term stability.

FIG. 1 is a diagram showing the results of a cytotoxicity test using corneal epithelial cells in Test Example 3. FIG. 2 is a diagram showing the results of the evaluation test 1 of the NIBUT increasing action in Test Example 4. FIG. 3 is a diagram showing the results of the evaluation test 2 of the NIBUT increasing action in Test Example 5.

The present invention will be described in more detail.

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

The "salt of diquafosol" is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a metal salt with lithium, sodium, potassium, calcium, magnesium, zinc, etc .; hydrochloric acid, hydrobromic acid, hydroiodide. , Salts with inorganic acids such as nitrate, sulfuric acid, phosphoric acid; 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, horse uric acid, 1,2-ethanedisulfonic acid, isetionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Salts with organic acids such as lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid; quaternary ammonium salts with methyl bromide, methyl iodide, etc .; with halogen ions such as bromine ions, chlorine ions, iodine ions Salt; Salt with ammonia; Triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) ) -1,3-Propanediol, procaine, salts with organic amines such as N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.

In the present invention, "diquafosol or a salt thereof" also includes a hydrate and an organic solvate of diquafosol (free form) or a salt thereof.

If a crystal polymorph and a crystal polymorph group (crystal polymorph system) are present in diquafosol or a salt thereof, the crystal polymorphs and the crystal polymorph group (crystal polymorph system) are also included in the scope of the present invention. Is done. Here, the crystal polymorph group (crystal polymorph system) is an individual crystal form and its process at each stage when the crystal shape changes depending on conditions and conditions such as production, crystallization, and storage of those crystals. Means the whole.

The "diquafosol or salt thereof" of the present invention is preferably a sodium salt of diquafosol, and a diquafosol tetrasodium salt represented by the following chemical structural formula (hereinafter, also simply referred to as "diquafosol sodium") is particularly preferable.

Diquafosol or a salt thereof can be produced by the method disclosed in JP-A-2001-510484.

This ophthalmic solution may contain an active ingredient other than diquafosol or a salt thereof, but preferably contains diquafosol or a salt thereof as the only active ingredient.

The concentration of diquafosol or a salt thereof in the present ophthalmic solution is 0.1 to 10% (w / v), preferably 1 to 10% (w / v), and 3% (w / v). Is particularly preferable.

In the present invention, the "aqueous ophthalmic solution" means an ophthalmic solution using water as a solvent (base).

In the present invention, "chlorhexidines" include chlorhexidine and salts thereof. Chlorhexidine is a compound represented by the following chemical structural formula, and is also called 1,1'-hexamethylenebis [5- (4-chlorophenyl) biguanide].

In the present invention, among the above chlorhexidines, the "salt of chlorhexidine" is not particularly limited as long as it is a pharmaceutically acceptable salt, and specifically, an organic acid salt [for example, a monocarboxylate (acetate salt). , Trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.), oxycarboxylate (gluconic acid) Salts, lactates, tartrates, citrates, etc.), organic sulfonates (methanesulfonates, toluenesulfonates, tosylates, etc.), etc.], inorganic acid salts (eg, hydrochlorides, sulfates, nitrates, etc.) , Hydrobromates, phosphates, etc.), salts with organic bases (eg, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picolin, etc.), inorganic Examples thereof include salts with bases [for example, ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc.] and the like. Among these salts, preferably organic and / or inorganic salts, more preferably oxycarboxylates, monocarboxylates and / or inorganic acid salts, still more preferably gluconate, acetate and / or hydrochloric acid. Salts, particularly preferably gluconate, are mentioned. These salts of chlorhexidine may be used alone or in any combination of two or more.

Chlorhexidine and a salt thereof may be synthesized by a known method, or can be obtained as a commercially available product.

The concentration of chlorhexidines in the present ophthalmic solution is 0.0001 to 0.1%, preferably 0.0005 to 0.05% (w / v), and 0.001 to 0.005%. (W / v) or more than 0.001% (w / v) to 0.005% (w / v) or less, preferably 0.0015 to 0.005% (w / v), 0 More preferably, it is .002 to 0.005% (w / v). More specifically, 0.0015 (w / v)%, 0.0020 (w / v)%, 0.0025 (w / v)%, 0.0030 (w / v)%, 0.0035 ( It is preferably w / v)%, 0.0040 (w / v)%, 0.0045 (w / v)%, and 0.0050 (w / v)%.

In the present invention, the "chelating agent" is not particularly limited as long as it is a compound that chelate metal ions, and for example, citric acid (ethylenediaminetetraacetic acid), monosodium edetate, disodium edetate, and tri-edetate. Edetoic acid or salts thereof such as sodium, tetrasodium edetate, dipotassium edetate, tripotassium edetate, tetrapotassium edetate; citric acid, monosodium citrate, disodium citrate, trisodium citrate, monocitrate Citric acid or salts thereof such as potassium, dipotassium citrate, tripotassium citrate; metaphosphates such as metaphosphate, sodium metaphosphate, potassium metaphosphate or salts thereof; pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, etc. Pyrrolic acid or a salt thereof; citric acid such as polyphosphate, sodium polyphosphate, potassium polyphosphate or a salt thereof; citric acid such as monosodium malate, disodium malate, monopotassium malate, dipotassium citric acid or the like. Salts; citric acid such as sodium tartrate, potassium tartrate, sodium tartrate or salts thereof; phytic acid such as sodium phytate, potassium phytate or salts thereof, and the like. In the present invention, "edetonic acid, citric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, malic acid, tartaric acid, phytic acid and salts thereof" includes the hydrates of the respective free forms or their salts and the salts thereof. Organic solvent products shall also be included.

In the present invention, the chelating agent includes edetic acid, a salt of edetonic acid (edetate), citric acid, a salt of citric acid (citrate), metaphosphate, a salt of metaphosphate (methaphosphate), polyphosphate, and the like. Salts of polyphosphate (polyphosphates) are preferred, including sodium salts of edetonic acid (including hydrates such as disodium edetate hydrate) and citric acid (including hydrates such as citric acid monohydrate). ), A sodium salt of citric acid (sodium metaphosphate), and a sodium salt of polyphosphate (sodium polyphosphate) are particularly preferable.

In the present invention, the most preferable edetate is disodium edetate hydrate (hereinafter, also simply referred to as "sodium edetate hydrate").

Further, these chelating agents may be used individually by 1 type, or may be used in any combination of 2 or more type.

The concentration of the chelating agent in the present ophthalmic solution is, for example, 0.0001 to 1% (w / v), preferably 0.0005 to 0.5% (w / v), and 0.001 to 0.1. % (W / v) is particularly preferable.

A nonionic surfactant can be added to the aqueous ophthalmic solution of the present invention, if necessary. The nonionic surfactant is not particularly limited as long as it is within a pharmaceutically acceptable range, and for example, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, and poly. Examples thereof include oxyethylene polyoxypropylene glycol and sucrose fatty acid ester. Examples of the polyoxyethylene fatty acid ester include polyoxyl 40 stearate, and examples of the polyoxyethylene sorbitan fatty acid ester include polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan triolate. Examples thereof include polysolvate 65, and examples of the polyoxyethylene hydrogenation oil derivative include polyoxyethylene hydrogenated bean oil 10, polyoxyethylene hydrogenated bean oil 40, polyoxyethylene hydrogenated bean oil 50, polyoxyethylene hydrogenated bean oil 60, and polyoxyl 5. Examples thereof include castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil. Examples of polyoxyethylene polyoxypropylene glycol include polyoxyethylene (160) polyoxypropylene (30) glycol. , Polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) poly Oxypropylene (20) glycol and the like can be mentioned.

In the present invention, examples of the nonionic surfactant include polyoxyethylene sorbitan fatty acid ester, preferably polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan triolate, and polysorbate. 65 and the like, and particularly preferably polysorbate 80 and the like.

Further, these nonionic surfactants may be used alone or in combination of two or more.

The concentration of the nonionic surfactant in the present ophthalmic solution is, for example, 0.0001 to 10% (w / v), preferably 0.0005 to 1% (w / v), 0.0005 to 0. .1% (w / v) is particularly preferable.

To this ophthalmic solution, a pharmaceutically acceptable additive can be added as needed using a general-purpose technique, for example, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate. , Sodium acetate, epsilon-aminocaproic acid and other buffers; isotonic agents such as sodium chloride, potassium chloride and concentrated glycerin can be selected and added as needed.

The pH of this ophthalmic solution may be within the range acceptable for ophthalmic preparations, but is usually preferably within the range of 4 to 8. A pH regulator such as hydrochloric acid or sodium hydroxide can be appropriately added to the ophthalmic solution.

This ophthalmic solution can be used for soft contact lenses and can also be used when wearing soft contact lenses. Examples of soft contact lenses include contact lenses containing hydroxyethyl methacrylate as a main component or silicone hydrogel contact lenses.

The type of soft contact lens to which this ophthalmic solution is applied is not particularly limited, and it does not matter whether it is ionic or nonionic, water-containing or non-water-containing. For example, it can be applied to all soft contact lenses currently on the market or in the future, such as lenses that are used repeatedly, lenses that are disposable for one day, lenses that are disposable for one week, and lenses that are disposable for two weeks.

The usage of this eye drop and this eye drop can be appropriately changed according to the dosage form, the severity of the patient's symptoms to be administered, the age, the weight, the judgment of the doctor, etc. When selected, it can be administered locally to the eye in 1 to 10 times a day, preferably 2 to 8 times a day, and more preferably 4 to 6 times a day.

Dry eye is defined as "a chronic disease of tear fluid and keratoconjunctival epithelium due to various factors, accompanied by eye discomfort and visual abnormalities", and keratoconjunctivalitis sicca (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.

Dry eye symptoms include subjective symptoms such as dry eyes, discomfort, eye fatigue, dullness, photophobia, eye pain, and blurred vision (blurred vision), as well as other symptoms such as congestion and keratoconjunctival epithelial disorders. Findings are also included.

There are many unclear points about the etiology of dry eye, but Sjogren's syndrome; congenital lacrimal adenopathy; sarcoidosis; transplanted piece-to-host disease (GVHD: Graft Versus Host Disease); blepharitis; Stevens Johnson syndrome Lacrimal obstruction caused by tracoma, etc .; Diabetes; Decreased reflex secretion caused by corneal refraction correction surgery (LASIK: LASIK: Laser (-assisted) in Situ Keratomilisis); It has been reported that the cause is a decrease in the oil layer; a blepharitis or blepharitis caused by eye protrusion, rabbit eye, etc .; a decrease in mutin secretion from embryonic cells; VDT work, etc.

This ophthalmic solution can be used for "prevention and / or treatment of dry eye".

In the present invention, "prevention and / or treatment of dry eye" is defined as preventing and / or treating or ameliorating the pathological symptoms and / or findings associated with dry eye, and the feeling of dry eye associated with dry eye. Not only means prevention and / or treatment or improvement of subjective symptoms such as eye discomfort, eye fatigue, dullness, photophobia, eye pain, blurred vision (blurred vision), but also congestion, horns associated with dry eye. It also includes prevention and / or treatment or amelioration of conjunctival epithelial disorders. "Prevention and / or treatment of dry eye" also includes preventing and / or treating or ameliorating dry eye symptoms by improving the stability of the tear film in the eye wearing soft contact lenses. For prevention and / or treatment or improvement of dry eye symptoms, prevention and / or treatment or improvement of dry eye symptoms that have been exacerbated by wearing soft contact lenses by dry eye patients, or wearing soft contact lenses themselves It also means the prevention and / or treatment or amelioration of the dry eye symptoms that led to the development.

In the present invention, improving the stability of the tear film means improving the tear fluid quantitatively or qualitatively. The stability of the tear film can be confirmed by measuring the BUT (tear layer destruction time). Among the BUTs, the one measured in a state closer to the natural state without applying a load such as a staining solution is called NIBUT (non-invasive tear layer destruction time).

In the present invention, "prevention or treatment of dry eye or eye discomfort in an eye wearing soft contact lenses" means prevention of dry eye or eye discomfort associated with destabilization of the tear film due to wearing soft contact lenses. Alternatively, it means treatment or prevention or treatment of eye dryness or eye discomfort caused by keratoconjunctival epithelial disorder caused by the instability.

The present invention relates to chlorhexidine at a concentration of 0.005% (w / v) or less in the preparation of an aqueous eye drop containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines. By using the above, a method for suppressing a decrease in the residual rate of chlorhexidines in the aqueous ophthalmic solution is provided. Here, the concentration of chlorhexidines used is preferably 0.005% (w / v) or less, or 0.0001 to 0.005% (w / v).

The present invention provides a method for stabilizing chlorhexidines in an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v), and chlorhexidines. Here, the concentration of the chlorhexidines is preferably more than 0.001% (w / v), or more than 0.001% (w / v) to 0.1% (w / v) or less.

The following are a storage efficacy test, a deformation suppression evaluation test for soft contact lenses, a cytotoxicity test using corneal epithelial cells, an evaluation test for NIBUT-elevating effect, a comparative test for NIBUT-elevating effect, a residual rate measurement test for chlorhexidine gluconate, and chlorhexidine. The results of long-term stability tests of gluconate are shown, but these examples are for a better understanding of the present invention and do not limit the scope of the present invention. CL is an abbreviation for contact lens and SCL is an abbreviation for soft contact lens.

Test example 1. Preservation efficacy test Preservation efficacy tests were performed on the eye drops 1 to 6 of the formulations shown in Table 1.

(Sample preparation)
Eye drops 1:
Ophthalmic solution 1 was prepared according to the formulation shown in Table 1. Specifically, sodium diquafosol (3 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.39 g), potassium chloride (0.15 g), sodium edetate hydrate (0). 0.01 g), polysorbate 80 (0.0005 g) and chlorhexyzingurconate (0.002 g) were dissolved in water to make 100 mL, and a pH adjuster was added to make pH 7.2.

Eye drops 2-6:
According to the prescription shown in Table 1, each ophthalmic solution of ophthalmic solutions 2 to 6 was prepared in the same manner as in ophthalmic solution 1.

(Test method)
The storage efficacy test was conducted in accordance with the 16th revised Japanese Pharmacopoeia Preservation Efficacy Test Law. In this test, Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans) were used as test bacteria. ..

(Test results)
The test results are shown in Table 2.

The test results in Table 2 show how much the viable cell count at the time of the test decreased compared to the number of inoculated bacteria by log reduction. For example, in the case of "1", the viable cell count at the time of the test is shown. Shows that the number of inoculated bacteria has decreased to 10%.

As shown in Table 2, it was shown that the ophthalmic solutions 1 to 6 conformed to the preservation efficacy test standard of the Japanese Pharmacopoeia.

(Discussion)
From the above results, it was shown that this ophthalmic solution has an excellent preservative effect.

Test example 2. Deformation suppression evaluation test of soft contact lenses Using eye drops 4, the effect on soft contact lenses was examined.

(Sample preparation)
An eye drop 4 was prepared in the same manner as the eye drop 1 according to the formulation shown in Table 1.

(Test method)
Of the contact lens classifications by FDA shown in Table 3, contact lenses (2week Acuvue ^{(registered trademark)} ) corresponding to Group IV were immersed in eye drops 4 for 24 hours, and the amount of change in contact lens diameter and base curve before and after. Was calculated, and it was examined whether or not the criteria shown in Table 4 below were satisfied. In addition, the properties of each contact lens after the test were observed. The criteria were set based on the Ministry of Health, Labor and Welfare Notification No. 349, Contact Lens Standards for Visual Acuity Correction (October 5, 2001).

(Criteria)

(result)
The results are shown in Table 5.

As shown in Table 5, the contact lenses after long-term immersion satisfied the criteria. Therefore, it was shown that the eye drop 4 suppresses the deformation of the soft contact lens.

(Discussion)
From the above results, this ophthalmic solution can be used for soft contact lenses because it suppresses deformation of soft contact lenses.

Test example 3. Cytopathic test using corneal epithelial cells In order to investigate the effect of this eye drop on corneal epithelial cells, a cytotoxic test using corneal epithelial cells was performed.

(Sample preparation)
Eye drops 7, 8, 9, and 10 were prepared in the same manner as in eye drops 1 according to the formulation shown in Table 6.

(Test method)
SV40 immortalized human corneal epithelial cells (HCE-T: RIKEN, Bioresource Center, Cell No .: RCB2280) were seeded in 96-well plates (1 × 10 ⁴ cells / well), and D-MEM containing 10% FBS / The cells were cultured in F12 medium for 1 day. The next day, after exchanging the medium with eye drops 7, eye drops 8, eye drops 9 or eye drops 10, the corneal epithelial cells were cultured for 15 minutes. Live cell activity (corresponding to absorbance at 490 nm) was measured using Cell Proliferation Assay Kit (manufactured by Promega, Catalog No .: G3580).

(result)
The test results are shown in FIG.

As is clear from FIG. 1, diquafosol ophthalmic solution containing chlorhexidine gluconate (ophthalmic solution 7) contains BAK-containing ophthalmic solution (ophthalmic solution 9, ophthalmic solution 10) and chlorhexidine containing diquafosol or a salt thereof. It showed higher viable cell activity in cultured immortalized human chlorhexidine epithelial cells than in eye drops containing.

(Discussion)
Since this ophthalmic solution shows high viable cell activity in cultured immortalized human corneal epithelial cells, it is safer for living organisms, especially the corneal epithelium, and is suitable for diseases such as dry eye in which the corneal epithelium is unstable. Useful to use.

Test example 4. Evaluation test of NIBUT raising effect 1
The NIBUT of diquafosol ophthalmic solution was investigated in the eye in which the stability of the tear film was reduced by wearing soft contact lenses.

(Sample preparation)
An eye drop 4 was prepared in the same manner as the eye drop 1 according to the formulation shown in Table 1.

(Test method)
NIBUT before and after 15, 30, 45, 60 minutes of instillation of ophthalmic solution 4 (20 μL / eye) was applied to the eyes of a crab monkey wearing soft contact lenses (product name: Menicon Soft MA ^{(registered trademark)).} It was measured with a dry eye observation device (DR-1, Kowa). Artificial tears as a control drug were used: (product name software San tier ^{(registered trademark))} (N = ^10~11 eye).

(result)
The test results are shown in FIG. As is clear from FIG. 2, when the eye drops 4 were instilled in the eyes wearing soft contact lenses, a remarkable increase in NIBUT was observed at all the measurement points up to 60 minutes after the instillation as compared with before the instillation. On the other hand, no increase in NIBUT was observed with artificial tears instillation.

(Discussion)
From the above results, it was shown that this ophthalmic solution improves the decrease in the stability of the tear film due to wearing soft contact lenses. Such an effect of this ophthalmic solution was remarkable even when compared with artificial tears generally used for dry eye treatment. Therefore, this ophthalmic solution is useful for the prevention and / or treatment of dry eye in eyes wearing soft contact lenses. This ophthalmic solution is also useful for the prevention and / or treatment of dry eye and / or eye discomfort in eyes wearing soft contact lenses.

Test example 5. Evaluation test of NIBUT raising effect 2
The NIBUT of diquafosol ophthalmic solution was investigated in the eye in which the stability of the tear film was reduced by wearing soft contact lenses.

(Sample preparation)
An eye drop 4 was prepared in the same manner as the eye drop 1 according to the formulation shown in Table 1.

(Test method)
Before instilling eye drops 4 (20 μL / eye) into the eyes of a crab monkey wearing soft contact lenses (product name: Menicon Soft MA ^{(registered trademark)), and after 5, 15, 30, 45, 60 minutes of instillation.} NIBUT was measured with a dry eye observation device (DR-1, Kowa). Artificial tears (product name: Soft Santear ^{(registered trademark)} ) and sodium hyaluronate (product name: Hyalein ^{(registered trademark)} mini ophthalmic solution 0.1%) were used as control agents (N = 11 eyes).

(result)
The test results are shown in FIG. As is clear from FIG. 3, when the eye drops 4 were instilled in the eyes wearing soft contact lenses, a remarkable increase in NIBUT was observed at all the measurement points up to 60 minutes after the instillation as compared with before the instillation. On the other hand, no increase in NIBUT was observed with artificial tears instillation. In addition, although sodium hyaluronate instillation showed an increase in NIBUT 5 minutes after instillation, its increasing effect was lower than that in ophthalmic solution 4, and no increase in NIBUT was observed after 15 minutes after instillation.

(Discussion)
From the above results, it was shown that this ophthalmic solution improves the decrease in the stability of the tear film due to wearing soft contact lenses. Such an effect of this ophthalmic solution was remarkable even when compared with artificial tears and sodium hyaluronate ophthalmic solution generally used for dry eye treatment. Therefore, this ophthalmic solution is useful for the prevention and / or treatment of dry eye in eyes wearing soft contact lenses. This ophthalmic solution is also useful for the prevention and / or treatment of dry eye and / or eye discomfort in eyes wearing soft contact lenses.

Test example 6. Comparative test of NIBUT-elevating effect A comparative study of NIBUT between this eye drop and BAK-containing eye drops (ophthalmic solution containing diquafosol sodium and BAK) in eyes in which the stability of the tear film was reduced by wearing soft contact lenses. did.

(Sample preparation)
An eye drop 4 was prepared in the same manner as the eye drop 1 according to the formulation shown in Table 1.
Further, as a comparative example, an eye drop 11 containing BAK instead of the chlorhexidine gluconate of the eye drop 4 was prepared. Specifically, sodium diquafosol (3 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.41 g), potassium chloride (0.15 g) and BAK (0.0075 g) are added to water. It was dissolved in 100 mL, and a pH adjuster was added to adjust the pH to 7.5. Both the eye drops 4 and the eye drops 11 are eye drops containing the same concentration of the active ingredient (diquafosol sodium). In addition, both the eye drops 4 and the eye drops 11 are eye drops that meet the preservation efficacy test standards of the Japanese Pharmacopoeia and have the same preservation efficacy.

(Test method)
Dry eye of NIBUT before and 30 minutes after instilling eye drops 4 and 11 (20 μL / eye) into the eyes of a crab monkey wearing soft contact lenses (product name: Menicon Soft MA ^{(registered trademark)).} Measured with an observation device (DR-1, Kowa) (N = 11 eyes).

(result)
The test results are shown in Table 7.

NIBUT 30 minutes after instillation of this ophthalmic solution (eye drops 4) and BAK-containing ophthalmic solution (ophthalmic solution 11), which conforms to the preservation efficacy test standards of the Japanese Pharmacopoeia and has the same preservation efficacy, is measured and compared. As a result, it was shown that this ophthalmic solution has a higher NIBUT-elevating effect than the BAK-containing ophthalmic solution.

(Discussion)
From the above results, it was shown that this ophthalmic solution improves the decrease in the stability of the tear film due to wearing soft contact lenses as compared with the BAK-containing ophthalmic solution.

Test example 7. Residual rate measurement test of chlorhexidine gluconate The effect of the concentration of chlorhexidine gluconate on the residual rate of chlorhexidine gluconate after preparation of diquafosol ophthalmic solution was investigated.

(Sample preparation)
Eye drops 12:
Ophthalmic solution 12 was prepared according to the formulation shown in Table 8. Specifically, it was prepared as follows.
1) A 0.5% (w / v) chlorhexidine gluconate solution was prepared.
2) 0.4% (w / v) sodium hydrogen phosphate hydrate, 0.78% (w / v) sodium chloride, 0.3% (w / v) potassium chloride and 0.02% (w / v) v) An aqueous solution (2-fold concentrated solution) containing sodium edetate hydrate was prepared.
3) The solution prepared in 1) was added to water, and the solution prepared in 2) was further added.
4) After stirring with a magnetic stirrer, sodium diquafosol and a pH adjuster (sodium hydroxide or hydrochloric acid) were added to adjust the pH to 7.5.
4) The total amount was adjusted with water so as to have the concentration shown in Table 8.
5) Ophthalmic solution 12 was prepared by filtering using a 0.22 μm filter.
Eye drops 13, eye drops 14:
The eye drops 13 and the eye drops 14 were prepared in the same manner as the eye drops 12.

(Test method)
The content of chlorhexidine gluconate in the above eye drops 12 to 14 was measured, and the residual rate thereof was calculated.

(result)
The test results are shown in Table 9.

(Discussion)
As shown in Table 9, it is clear that the residual rate of chlorhexidine gluconate decreases in the eye drops 14 using the chlorhexidine gluconate at a concentration of 0.01% (w / v) after the preparation of the eye drops. became. On the other hand, in the eye drops 12 and the eye drops 13 using chlorhexidine gluconate at concentrations of 0.0025% (w / v) and 0.005% (w / v), chlorhexidine gluconic acid is high even after the preparation of the eye drops. The residual rate of salt was maintained. From the above, it was shown that it is preferable to use chlorhexidine gluconate at a concentration of 0.005% (w / v) or less for the preparation of diquafosol ophthalmic solution containing chlorhexidine gluconate.

Test example 8. Long-term stability test of chlorhexidine gluconate The long-term stability of chlorhexidine gluconate in diquafosol ophthalmic solution was investigated.

(Sample preparation)
In the same manner as in Test Example 7, eye drops 15 to 17 were prepared according to the prescription shown in Table 10.

(Test method)
The content of chlorhexidine gluconate when the eye drops 15 to 17 were stored at 40 ° C./20% RH for up to 6 months was quantified using high performance liquid chromatography (HPLC), and the residual rate (%) was determined. ) Was calculated.

(result)
The test results are shown in Table 11.

(Discussion)
The eye drops 16 and the eye drops 17 containing chlorhexidine gluconate at a concentration of 0.0025% (w / v) and 0.01% (w / v) have a concentration of 0.001% (w / v). It was shown that it maintained a high residual rate of chlorhexidine gluconate for 6 months at 40 ° C./20% RH and had excellent long-term stability as compared with ophthalmic solution 15 containing chlorhexidine gluconate. That is, in order to stabilize chlorhexidine gluconate in diquafosol ophthalmic solution, it was shown that the concentration of chlorhexidine gluconate is preferably more than 0.001% (w / v).

As described above, from the results of Test Examples 7 and 8, diquafosol ophthalmic solution containing chlorhexidines having a specific concentration range, that is, a concentration of 0.001 to 0.005% (w / v) is high in chlorhexidines at the time of ophthalmic solution preparation. It was shown that chlorhexidines in the ophthalmic solution have excellent long-term stability while maintaining the residual rate of. Therefore, as shown in Test Example 1, the eye drops are also expected to have an excellent storage effect for a long period of time.

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

(Prescription example 1: Eye drops (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.1-0.5g
Sodium chloride 0.01-1g
Potassium chloride 0.01-1g
Sodium edetate hydrate 0.0001-0.1 g
Chlorhexidine gluconate 0.0001-0.1 g
Sterilized purified water The above eye drops can be prepared by adding diquafosol sodium and other above-mentioned components to an appropriate amount of sterilized purified water and mixing them sufficiently.

(Prescription example 2: Eye drops (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.1-0.5g
Sodium chloride 0.01-1g
Potassium chloride 0.01-1g
Sodium edetate hydrate 0.0001-0.1 g
Chlorhexidine gluconate 0.0001-0.1 g
Polysorbate 80 0.0001-0.1g
Sterilized purified water The above eye drops can be prepared by adding diquafosol sodium and other above-mentioned components to an appropriate amount of sterilized purified water and mixing them sufficiently.

This eye drop has an excellent preservative effect. Further, since this ophthalmic solution suppresses deformation of soft contact lenses, it can be used for soft contact lenses. In addition, this ophthalmic solution shows higher viable cell activity in cultured immortalized human corneal epithelial cells than the ophthalmic solution containing BAK and the ophthalmic solution containing chlorhexidines containing diquafosol or a salt thereof. Therefore, this ophthalmic solution is more safe for living organisms, especially the keratoconjunctival epithelium, and is useful for diseases such as dry eye in which the keratoconjunctival epithelium is unstable. In addition, this ophthalmic solution significantly increases NIBUT in eyes wearing soft contact lenses. On the other hand, artificial tears do not have such an effect. That is, this ophthalmic solution stabilizes the tear film in the eye wearing soft contact lenses. Since the occurrence / exacerbation 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 by this ophthalmic solution is dry in the eyes wearing soft contact lenses. Useful for the prevention and / or treatment of eye. This ophthalmic solution is also useful for the prevention and / or treatment of dry eye and / or eye discomfort in eyes wearing soft contact lenses. Furthermore, diquafosol ophthalmic solution containing chlorhexidines in a specific concentration range, that is, at a concentration of 0.001 to 0.005% (w / v), maintains a high residual rate of chlorhexidines during the preparation of the ophthalmic solution, and said Chlorhexidines in ophthalmic solution have excellent long-term stability.

Claims (19)

An aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines at a concentration of 0.0001 to 0.1% (w / v). The aqueous eye drop according to claim 1, wherein the chlorhexidines are chlorhexidine gluconate. The aqueous eye drop according to claim 1 or 2, wherein the concentration of chlorhexidines in the eye drop is 0.0005 to 0.05% (w / v). The aqueous eye drop according to claim 1 or 2, wherein the concentration of chlorhexidines in the eye drop is 0.001 to 0.005% (w / v). The aqueous ophthalmic solution according to claim 1 or 2, wherein the concentration of chlorhexidines in the ophthalmic solution is more than 0.001% (w / v) to 0.005% (w / v) or less. The aqueous eye drop according to claim 1 or 2, wherein the concentration of chlorhexidines in the eye drop is 0.0015 to 0.005% (w / v). The aqueous ophthalmic solution according to claim 1 or 2, wherein the concentration of chlorhexidines in the ophthalmic solution is 0.002 to 0.005% (w / v). The aqueous eye drop according to any one of claims 1 to 7, wherein the concentration of diquafosol or a salt thereof in the eye drop is 3% (w / v). The aqueous eye drop according to any one of claims 1 to 8, further comprising a chelating agent. The aqueous eye drop according to claim 9, wherein the chelating agent is edetic acid or a salt thereof. The aqueous eye drop according to any one of claims 1 to 10, which is for soft contact lenses. The aqueous eye drop according to claim 11, wherein the soft contact lens is a silicone hydrogel contact lens. A method for suppressing deformation of a soft contact lens due to the aqueous eye drop according to any one of claims 1 to 12. The aqueous ophthalmic solution according to any one of claims 1 to 12, for the prevention and / or treatment of dry eye in an eye wearing soft contact lenses. The aqueous eye drop according to any one of claims 1 to 12, for improving the stability of the tear film in an eye wearing soft contact lenses. The aqueous ophthalmic solution according to any one of claims 1 to 12, for the prevention or treatment of dry eye or eye discomfort in an eye wearing soft contact lenses. The aqueous eye drop according to any one of claims 14 to 16, wherein the soft contact lens is a silicone hydrogel contact lens. In the preparation of aqueous eye drops containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines, chlorhexidines at a concentration of 0.0001 to 0.005% (w / v). A method for suppressing a decrease in the residual rate of chlorhexidines in the aqueous ophthalmic solution by using. A method for stabilizing chlorhexidines in an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidines, wherein the concentration of the chlorhexidines is 0.001. A method that is greater than% (w / v) to less than or equal to 0.1% (w / v).

Images