JP7459508B2 - Mucin degeneration inhibitor and ophthalmic composition - Google Patents

Description

The present invention relates to an ophthalmic composition containing a mucin degeneration inhibitor and phenylephrine.

Lacrimal fluid forms a three-layer structure consisting of an oil layer (approximately 0.1 μm), an aqueous layer (approximately 7 μm), and a mucin layer (approximately 0.4 μm) from the outside. The oil layer is further composed of nonpolar lipids (cholesterol ester, wax ester, etc.) on the outside, and polar lipids (phospholipids, (O-acyl)-omega-hydroxy fatty acid-(OAHFA), etc.) on the inside. It is said that polar lipids have an affinity with the water layer compared to non-polar lipids, which have a high composition ratio. The oil layer plays an important role in (1) lowering the surface tension of the tear fluid, (2) preventing the evaporation of the tear fluid, etc., although it is a small proportion of the tear fluid. The mucin layer is a very high-molecular glycoprotein of several thousand kDa, and countless sugar chains are bound to a core protein called apomucin. Furthermore, mucins are classified into secretory mucins and membrane mucins based on their structure. The mucin layer (1) retains tears, (2) lubricates the ocular surface to enable smooth blinking, (3) forms a smooth spherical surface to maintain good visual acuity, and (4) functions as a barrier to the ocular surface. , (5) It captures pathogens and debris, and plays an important role in the composition of tear fluid, albeit in a small amount, just like the oil layer. However, mucin degeneration occurs due to various factors, and a technology to suppress this has been desired.

Japanese Unexamined Patent Publication No. 63-33327

The present invention has been made in consideration of the above circumstances, and aims to provide a mucin degeneration inhibitor that inhibits mucin degeneration, and an ophthalmic composition that has the effect of inhibiting mucin degeneration.

As a result of intensive studies to achieve the above object, the present inventors found that the components selected from (A) phenylephrine and its salts, and (B) edetic acid, citric acid, trometamol and their salts, and borax, The present invention was based on the discovery that it has the effect of inhibiting mucin degeneration.

Therefore, the present invention provides the following mucin degeneration inhibitor and the following ophthalmic composition.
1. A mucin degeneration inhibitor comprising the following (A) and/or (B):
1. The mucin denaturation inhibitor according to claim 1, wherein the mucin denaturation is caused by (C) one or more selected from quaternary ammonium salts and polyhexanide hydrochloride.
3. (A) one or more selected from phenylephrine and its salts,
An ophthalmic composition comprising (B) one or more selected from edetic acid, citric acid, trometamol and their salts, and borax, and (C) one or more selected from quaternary ammonium salts and polyhexanide hydrochloride.
4. The ophthalmic composition according to 3, wherein the blending amount of component (B) is 0.005 w/v % or more.

According to the present invention, it is possible to provide a mucin denaturation inhibitor that suppresses mucin denaturation and an ophthalmic composition that has a mucin denaturation inhibiting effect.

The present invention will be explained in detail below.
[I] Mucin denaturation inhibitor The mucin denaturation inhibitor of the present invention contains the following (A) and/or (B).
(A) One or more selected from phenylephrine and its salts (B) One or more selected from edetic acid, citric acid, trometamol, salts thereof, and borax

[Component (A)]
The component (A) is one or more selected from phenylephrine and its salts, and may be used alone or in appropriate combination of two or more. For example, the phenylephrine salt may be a medicamentously acceptable salt such as phenylephrine hydrochloride. Phenylephrine or its salt has a tear film stabilizing effect and a meibum secretion promoting effect, and further has a mucin degeneration inhibiting effect.

From the viewpoint of suppressing mucin denaturation, the blending amount of component (A) is 0.01 to 5 w/v% (mass/volume %, g/100mL, hereinafter the same shall apply hereinafter in %) in the mucin denaturation inhibitor. ) is preferable, 0.02 to 5% is more preferable, and even more preferably 0.05 to 5%. Component (A) has a mydriatic effect and may cause a dazzling appearance. Therefore, the component (A) is 0.01 to 0.3 in order to reduce the glare caused by mydriasis while maintaining the tear film stabilizing effect. %, more preferably 0.02 to 0.2%, even more preferably 0.05 to 0.1%.

[(B) Component]
Component (B) is one or more selected from edetic acid, citric acid, trometamol, salts thereof, and borax, and can be used alone or in an appropriate combination of two or more. Examples of edetate salts include sodium edetate, disodium edetate, tetrasodium edetate, sodium edetate hydrate, and examples of citrates include sodium citrate. Component (B) has the effect of suppressing mucin denaturation.

When using edetic acid or its salt, the amount of component (B) is preferably 0.005 to 1% in the mucin denaturation inhibitor, more preferably 0.01 to 0.5%, and 0.05 to 0. .2% is more preferred.
When citric acid or a salt thereof is used, it is preferably 0.001 to 2%, more preferably 0.005 to 1%, even more preferably 0.01 to 0.5% in the mucin denaturation inhibitor.
When using trometamol or a salt thereof, the mucin denaturation inhibitor is preferably 0.005 to 5%, more preferably 0.01 to 2%, and even more preferably 0.05 to 1%.
When using borax, it is preferably 0.001 to 2%, more preferably 0.005 to 1%, even more preferably 0.01 to 0.5% in the mucin denaturation inhibitor.

The above components (A) and (B) both have the effect of inhibiting mucin degeneration, but by using them together, the effect of inhibiting mucin degeneration can be further enhanced.

Mucin degeneration is known to occur due to the effects of active ingredients and additives in eye drops, immune diseases, and the like. On the other hand, (C) quaternary ammonium salts such as benzalkonium chloride are used as preservatives in ophthalmic compositions. It was found that nitric acid and polyhexanide hydrochloride denature mucin. Furthermore, both of the above components (A) and (B) suppress mucin denaturation, particularly against mucin denaturation caused by one or more selected from the above (C) quaternary ammonium salts and polyhexanide hydrochloride. The effect is demonstrated.

[II] Ophthalmic Composition The ophthalmic composition of the present invention comprises: (A) one or more selected from phenylephrine and salts thereof;
(B) one or more selected from edetic acid, citric acid, trometamol and their salts, and borax, and (C) one or more selected from quaternary ammonium salts and polyhexanide hydrochloride.

As described above, both of the above components (A) and (B) exhibit a mucin denaturation inhibitory effect against mucin denaturation caused by one or more selected from the above (C) quaternary ammonium salts and polyhexanide hydrochloride. Therefore, even if one or more selected from (C) quaternary ammonium salts and polyhexanide hydrochloride are incorporated into an ophthalmic composition, mucin denaturation is inhibited, and an ophthalmic composition that can maintain the tear film stabilizing effect of phenylephrine or a salt thereof can be obtained.

Regarding components (A) and (B), suitable components are the same as above. The blending amount in each ophthalmic composition is the same as the blending amount in the mucin denaturation inhibitor. That is, the blending amount of component (A) in the ophthalmic composition is preferably 0.01 to 5%, more preferably 0.02 to 5%, and even more preferably 0.05 to 5%.
When using edetic acid or its salt, the blending amount of component (B) is preferably 0.005 to 1% in the ophthalmic composition, more preferably 0.01 to 0.5%, and 0.05 to 0. .2% is more preferred.
When using citric acid or a salt thereof, it is preferably 0.001 to 2%, more preferably 0.005 to 1%, even more preferably 0.01 to 0.5% in the ophthalmic composition.
When using trometamol or a salt thereof, it is preferably 0.005 to 5%, more preferably 0.01 to 2%, even more preferably 0.05 to 1%.
When using borax, it is preferably 0.001 to 2%, more preferably 0.005 to 1%, even more preferably 0.01 to 0.5% in the ophthalmic composition.

[Component (C)]
The component (C) is one or more selected from quaternary ammonium salts and polyhexanide hydrochloride, and may be used alone or in combination of two or more. The component (B) is mainly used as a preservative. Examples of the quaternary ammonium salt include benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride.

From the viewpoint of preservative effect, the amount of component (C) in the ophthalmic composition is preferably 0.0001 to 0.05%, more preferably 0.0005 to 0.02%, and even more preferably 0.001 to 0.01%.

The blending mass ratio of component (B) and component (C), expressed as (B)/(C), is preferably 0.01 to 20,000 from the viewpoint of reducing the influence of component (C) on mucin. More preferably 1 to 10,000, even more preferably 2 to 2,000. Specifically, the following ranges are preferred. Note that although the above ratio is a w/v% ratio, it has the same value as the mass ratio.

The blending mass ratio of component (A) to component (C), represented by (A)/(C), is preferably 0.1 to 10,000, more preferably 1 to 5,000, and even more preferably 10 to 2,000.

The blending mass ratio of components (A), (B), and (C), represented by ((A)+(B))/(C), is preferably 0.1 to 50,000, more preferably 0.5 to 20,000, and even more preferably 1 to 10,000.

When component (C) is a quaternary ammonium salt, the blending mass ratio of component (A) to component (C), represented by (A)/(C), is preferably 0.1 to 1,000, more preferably 1 to 500, and even more preferably 10 to 200.
The preferred blending mass ratio of the component (B) to the component (C), represented by (B)/(C), is as follows:
Edetic acid or a salt thereof: 0.5 to 100 is preferred, 1 to 50 is more preferred, and 2 to 40 is even more preferred.
Citric acid or a salt thereof: 0.01 to 1,000 is preferable, 1 to 400 is more preferable, and 10 to 200 is even more preferable.
Trometamol or a salt thereof: 1 to 2,000 is preferred, 2.5 to 1,000 is more preferred, and 5 to 500 is even more preferred.
Borax: 0.01 to 1,000 is preferable, 1 to 400 is more preferable, and 5 to 200 is even more preferable.

A preferred blending mass ratio of component (A), component (B), and component (C), expressed as ((A)+(B))/(C), is as follows.
Edetic acid or its salt: preferably 0.5 to 200, more preferably 1 to 100, 2 to 80
is even more preferable.
Citric acid or a salt thereof: preferably 0.01 to 2,000, more preferably 1 to 1,000, even more preferably 10 to 200.
Trometamol or a salt thereof: preferably 1 to 5,000, more preferably 2.5 to 2,000, even more preferably 5 to 1,000.
Borax: preferably 0.01 to 2,000, more preferably 1 to 1000, even more preferably 5 to 200.

When component (C) is polyhexanide hydrochloride, the blended mass ratio of component (A) and component (C), expressed as (A)/(C), is preferably 0.1 to 10,000, 1 to 5, 000 is more preferable, and 10 to 2,000 is even more preferable.
A preferred blending mass ratio of component (B) and component (C), expressed as (B)/(C), is as follows.
Edetic acid or a salt thereof: preferably 0.5 to 1,000, more preferably 1 to 500, even more preferably 2 to 400.
Citric acid or a salt thereof: preferably 0.01 to 10,000, more preferably 1 to 4,000, even more preferably 10 to 2,000.
Trometamol or a salt thereof: preferably 1 to 20,000, more preferably 2.5 to 10,000, even more preferably 5 to 5,000.
Borax: preferably 0.01 to 10,000, more preferably 1 to 4,000, even more preferably 5 to 2,000.

A preferred blending mass ratio of component (A), component (B), and component (C), expressed as ((A)+(B))/(C), is as follows.
Edetic acid or a salt thereof: preferably 0.5 to 2,000, more preferably 1 to 1000, even more preferably 2 to 800.
Citric acid or a salt thereof: preferably 0.01 to 20,000, more preferably 1 to 8,000, even more preferably 10 to 4,000.
Trometamol or a salt thereof: preferably 1 to 50,000, more preferably 2.5 to 20,000, even more preferably 5 to 10,000.
Borax: preferably 0.01 to 20,000, more preferably 1 to 8,000, even more preferably 5 to 4,000.

The mucin denaturation inhibitor and ophthalmological composition of the present invention may contain appropriate amounts of other components as long as they do not impair the effects of the present invention. Other ingredients include water, oily ingredients, surfactants, preservatives and antibacterial agents other than component (B), sugars, buffers, pH adjusters, tonicity agents, and stabilizers other than component (C). , refreshing agents, polyhydric alcohols, thickeners, drugs other than component (A), and the like. These components can be blended singly or in an appropriate combination of two or more. The blending amounts of the components shown below are the preferred ranges when blending. Note that the amount of water can be the balance of the ophthalmological composition. Hereinafter, the mucin denaturation inhibitor and the ophthalmological composition may be referred to as "in the composition".

Examples of oily components include liquid paraffin, castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium-chain triglycerides, white petrolatum, mixed tocopherols, lanolin, etc. When an oil component is added, the amount of the oil component is preferably 0.001 to 1.0% of the composition, more preferably 0.001 to 0.5%, and even more preferably 0.001 to 0.25%.

Examples of the surfactant include the following nonionic surfactants.
Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types are known which differ in the average number of moles of ethylene oxide added. The average number of moles of ethylene oxide added in polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified as 5 to 100 moles. Specific examples include polyoxyethylene hydrogenated castor oil 5 (average number of moles of EO added: 5), polyoxyethylene hydrogenated castor oil 10 (average number of moles of EO added: 10), polyoxyethylene hydrogenated castor oil 20 (average number of moles of EO added: 20), polyoxyethylene hydrogenated castor oil 30 (average number of moles of EO added: 30), polyoxyethylene hydrogenated castor oil 40 (average number of moles of EO added: 40), polyoxyethylene hydrogenated castor oil 50 (average number of moles of EO added: 50), polyoxyethylene hydrogenated castor oil 60 (average number of moles of EO added: 60), polyoxyethylene hydrogenated castor oil 80 (average number of moles of EO added: 80), and polyoxyethylene hydrogenated castor oil 100 (average number of moles of EO added: 100). Among these, polyoxyethylene hydrogenated castor oil 60 is preferred.

Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide to castor oil, and several types with different average added moles of ethylene oxide are known. There is no particular limit to the average added moles of ethylene oxide in polyoxyethylene castor oil, but examples include 3 to 60 moles. Specific examples include polyoxyethylene castor oil 3 (the number is the average added moles of ethylene oxide, the same applies below), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, etc.

Examples of polyoxyethylene sorbitan fatty acid esters (POE sorbitan fatty acid esters) include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan tristearate (polysorbate 65), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80). Of these, polyoxyethylene (20) sorbitan monooleate (polysorbate 80) is preferred.

Polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is not particularly limited, and those listed in the Pharmaceutical Excipient Standards (Pharmaceutical Additives Regulations) can be used. The average degree of polymerization of ethylene oxide is preferably 4 to 200, more preferably 20 to 200, and the average degree of polymerization of propylene oxide is preferably 5 to 100, more preferably 20 to 70, and may be a block copolymer or a random polymer. Specifically, polyoxyethylene (200) polyoxypropylene (70) glycol: Lutrol F127 (manufactured by BASF), Unilube 70DP-950B (manufactured by NOF Corporation), polyoxyethylene (120) polyoxypropylene, etc. (40) Glycol: Pluronic F-87 (manufactured by BASF), polyoxyethylene (160) polyoxypropylene (30) Glycol: Pluronic F-68 (manufactured by BASF), Pronon #188P (manufactured by NOF Corporation) etc., polyoxyethylene (42) polyoxypropylene (67) glycol: Pluronic P123 (manufactured by BASF), polyoxyethylene (54) polyoxypropylene (39) glycol: Pluronic P85 (manufactured by BASF), pronon #235P ( (manufactured by NOF Corporation), polyoxyethylene (20) polyoxypropylene (20) glycol: Pluronic L-44, Tetronic (manufactured by BASF), and the like. Among these, polyoxyethylene (200) polyoxypropylene (70) glycol is preferred.

Examples of the polyethylene glycol fatty acid ester include polyethylene glycol-25 stearate and polyethylene glycol-40 stearate, among which polyethylene glycol-40 stearate is preferred.

When a surfactant is added, the amount of the surfactant added is preferably 0.01 to 2.0% of the composition, more preferably 0.05 to 1.5%, and even more preferably 0.1 to 1.2%.

Preservatives and antibacterial agents other than component (C) include preservatives having a hydrophobic portion such as an alkyl chain or a benzene ring, such as thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconate, methyl paraoxybenzoate, and ethyl paraoxybenzoate. Other examples include sorbic acid, sulfurous acid and salts thereof, and chlorobutanol. When a preservative is added, the amount of the preservative may be 0.0001 to 0.5% of the composition, but 0.1% or less is preferable, and 0.01% or less is even more preferable.

Examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc. These may be in the d-, l-, or dl-form. Sugars have moisturizing properties and are effective in increasing the moisture content of the eye when applied, and can also be used as isotonicity agents. When sugars are added, the amount of sugar added is preferably 0.001 to 5.0% of the composition, more preferably 0.001 to 1%, and even more preferably 0.001 to 0.1%.

Examples of the buffer include phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, and sodium hydrogen carbonate. When blending a buffering agent, the blending amount in the composition is preferably 0.001 to 5.0%, more preferably 0.001 to 2%, and even more preferably 0.001 to 1%.

Examples of pH adjusters include inorganic acids and inorganic alkali agents. For example, an example of an inorganic acid is (dilute) hydrochloric acid. Examples of inorganic alkali agents include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. The pH of the composition is preferably 3.5 to 8.0, and more preferably 5.5 to 8.0. The pH is measured at 25°C using a pH meter (HM-25R, DKK-TOA Corporation).

Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. Can be mentioned. In order to further improve the symptoms caused by the destabilization of the tear oil layer, it is preferable that sodium chloride or potassium chloride be added to make the tonicity isotonic. The osmotic pressure ratio of the composition to physiological saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and most preferably 0.83 to 1.20. The osmotic pressure is measured at 25° C. using an automatic osmometer (A2O, Advanced Instruments).

Examples of stabilizers other than component (B) include cyclodextrin, sulfites, dibutylhydroxytoluene, and the like. When blending a stabilizer other than component (B), the blending amount in the composition is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, and 0.001 to 0.1%. is even more preferable.

Examples of the cooling agent include menthol, camphor, borneol, geraniol, cineol, linalool, and the like. Any of the d-form, l-form, or dl-form can be used. When a cooling agent is added, the amount thereof is preferably 0.0001 to 0.2% in the composition.

Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. Polyhydric alcohols have moisturizing properties and can increase the moisturizing effect when applied to the eye, and can also be used as isotonicity agents. When polyhydric alcohols are included, the amount of the composition is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, and even more preferably 0.001 to 0.1%.

Examples of the thickening agent include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, and the like. When blending a thickening agent, the blending amount in the composition is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, even more preferably 0.001 to 0.1%.

Drugs (pharmaceutical active ingredients) other than component (A) include, for example, congestion relief ingredients (e.g., epinephrine, methylnorepinephrine, norepinephrine, epinephrine hydrochloride, ephedrine, methylephedrine, pseudoephedrine, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, dl-methylephedrine hydrochloride, oxymetazoline, methoxamine, phenylpropanol, etc. amine, etilefrine, midodrine, tramazoline, synephrine, cirazoline, xylometazoline and pharma- ceutical acceptable salts thereof, etc.), anti-inflammatory/astringent agents (e.g., neostigmine methylsulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), antihistamines Examples of the composition include steroids (e.g., diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.), fat-soluble vitamins (retinol acetate, retinol palmitate, tocopherol acetate, etc.), amino acids (e.g., potassium L-aspartate, magnesium L-aspartate, potassium magnesium L-aspartate (mixture of equal amounts), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), and sulfa drugs. When drugs are added, the amount of each drug can be selected based on the effective amount of the drug, but is preferably 0.001 to 5% of the composition, more preferably 0.001 to 1%, and even more preferably 0.001 to 0.1%.

[Production method]
The method for producing the mucin denaturation inhibitor and ophthalmological composition of the present invention is not particularly limited, but, for example, they can be obtained by dissolving the aqueous component in purified water, adjusting the pH, and then adjusting the total volume with purified water. . The mixing method may be a general method, and may be carried out appropriately using a pulsator, propeller blade, paddle blade, turbine blade, etc., but the rotation speed is not particularly limited, and is preferably set to a level that does not cause excessive foaming. The mixing temperature of each liquid is not particularly limited, but is specifically selected as appropriate from the range of 20 to 95°C.

The mucin denaturation inhibitor and ophthalmological composition of the present invention are preferably liquids from the viewpoint of easy adaptation to the eyes, and the viscosity at 20°C is 20 mPa·s or less from the viewpoint of facilitating mixing with lachrymal fluid. It is preferably 10 mPa·s or less, more preferably 5 mPa·s or less, particularly preferably 2 mPa·s or less. The viscosity is measured using a cone plate viscometer (DV2T, manufactured by Hideko Seiki Co., Ltd.). Although the lower limit is not particularly limited, it can also be set to 1 mPa·s.

The ophthalmological composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye washes, etc., but from the viewpoint of preventive or therapeutic effects on dry eye, eye drops, eye drops for contact lenses (contact lens wearable), etc. It can be suitably used as eye drops such as eye drops for people. Contact lenses include hard contact lenses, soft contact lenses, specifically silicone hydrogel soft contact lenses, O ₂ hard contact lenses, color contact lenses, and the like, but are not particularly limited.

When used as eye drops or contact lens eye drops, it is preferable to instill 10-100 μL, 1-3 drops, 1-6 times per day, more preferably 10-50 μL, 1-3 drops, 1-6 times per day, and even more preferably 10-30 μL, 1-3 drops, 1-6 times per day. When used as an eyewash, it is preferable to wash the eyes with 3-6 mL, 3-6 times per day.

The obtained ophthalmic composition may be filled into a resin container, which is then sealed with a package, and an inert gas such as nitrogen may be enclosed in the space formed between the container and the package. Alternatively, the composition may be filled into a resin container, which is then sealed with a package together with an oxygen scavenger.

Since the ophthalmic composition has the effect of suppressing mucin degeneration, it is also suitable as an ophthalmic composition for suppressing mucin degeneration.

<Tear film stabilization>
Since phenylephrine or a salt thereof has a tear film stabilizing effect, the ophthalmic composition of the present invention has a tear film stabilizing effect and is suitable as a tear film stabilizer. The tear film stabilizing effect can be measured, for example, by NI (Non-invasive) BUT (Non-invasive Tear Film Breakup Time).

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples and Comparative Examples, but the present invention is not limited to the Examples below. In the examples below, unless otherwise specified, "%" in the composition indicates w/v % (g/100 mL), and ratio indicates mass ratio (same value as w/v % ratio).

Each component in Table 1 below was added and dissolved in a predetermined amount of purified water, and then stirred well. After pH adjustment, the total volume was made up to 100 mL with purified water. In addition, the pH of the obtained ophthalmic composition at 25° C. is 7. The viscosity of the composition at 25° C. was in the range of 1 to 20 mPa·s. The obtained test liquid was evaluated as follows. The results are also listed in the table.

<Mucin degeneration>
A model tear fluid (0.1% mucin, 0.9% sodium chloride, 0.3% potassium chloride, 0.0147% calcium chloride dihydrate, pH 7) was prepared.
9 mL of a test solution containing component (C) in Table 1 was added to 1 mL of model tear fluid. The transmittance at 600 nm of the model tear fluid after addition was measured, and the rate of change in transmittance (reduction in transmittance) was calculated based on the following formula. A higher rate of variation indicates greater mucin degeneration. In addition, as a comparison, the transmittance was measured when physiological saline was added instead of component (C).
Fluctuation rate of transmittance (decrease in transmittance) = (A2-A1)/A1×100 (%)
A1 = Transmittance of "model tear + physiological saline" A2 = Transmittance of "model tear + (A) component"

Benzalkonium chloride, polyhexanide hydrochloride, and benzethonium chloride all reduced permeability, confirming that they have an effect on mucin denaturation.

[Examples and Comparative Examples]
Each component in Tables 2 to 6 below was dissolved in a predetermined amount of purified water and then thoroughly stirred. After adjusting the pH, the total volume was adjusted to 100 mL with purified water. The pH of the obtained ophthalmic composition at 25°C is shown in the table. The viscosity of the composition at 25°C was in the range of 1 to 20 mPa·s. The obtained mucin denaturation inhibitor (Example I) or ophthalmic composition (Example II) was evaluated as follows. The results are also shown in the table.

<Suppression of mucin degeneration>
9 mL of a test solution containing component (A) and/or component (B) and component (C) adjusted to the concentration shown in the table below is added to 1 mL of model tear fluid. The transmittance was measured and the recovery rate (transmittance recovery) was calculated based on the following formula.
Recovery rate (recovery of transmittance) = (A3-A2)/(A1-A2) x 100 (%)
A1 = Transmittance of "model tear + physiological saline" A2 = Transmittance of "model tear + (A) component" A3 = "Model tear + (A) component + (B) and/or (C)" Transmittance of component

As is clear from the above results, both of the above components (A) and (B) inhibit mucin denaturation by one or more selected from the above (C) quaternary ammonium salts and polyhexanide hydrochloride. It was effective. (C) Ophthalmology in which mucin denaturation is suppressed and the tear film stabilizing effect of phenylephrine or its salt can be maintained even when one or more selected from quaternary ammonium salts and polyhexanide hydrochloride is blended into the ophthalmic composition. A composition for use was obtained.

A composition having the following composition was prepared in the same manner as in the above example.

The raw materials used in the above examples are shown below. Unless otherwise specified, the amounts of each component in the table are calculated as pure amounts.
Mucin: Mucin, derived from porcine stomach (FUJIFILM Wako Pure Chemical Industries, Ltd.)
Benzalkonium chloride: Diamitol disinfectant solution 10 w/v% (Maruishi Pharmaceutical Co., Ltd.)
Benzethonium chloride: (FUJIFILM Wako Pure Chemical Industries, Ltd.)
Polyhexamethylene biguanide hydrochloride (BOC Sciences)
EDTA: Crewat N (Nagase Chemtex)
Borax: Borax "Kozakai M" 500g crystals (Kozakai Pharmaceutical Co., Ltd.)
Sodium citrate hydrate: (Komatsuya Co., Ltd.)
Trometamol: (Kanto Chemical Co., Ltd.)

Claims (6)

A mucin denaturation inhibitor containing the following (A) and/or (B) and inhibiting mucin denaturation caused by one or more selected from (C) quaternary ammonium salts and polyhexanide hydrochloride .
(A) One or more selected from phenylephrine and its salts (B) One or more selected from edetic acid, citric acid, trometamol, salts thereof, and borax (A) one or more selected from phenylephrine and its salts,
(B) one or more selected from edetic acid, citric acid, trometamol and their salts, and borax, and (C) one or more selected from quaternary ammonium salts and polyhexanide hydrochloride,
An ophthalmic composition in which the blending mass ratio of component (A), component (B), and component (C), represented by ((A)+(B))/(C), is 20 to 2,000 ( excluding those containing ashitazanolast or a salt thereof, azelastine, or a pharma- ceutically acceptable salt or ester thereof) . 3. The ophthalmic composition according to claim 2 , wherein the blending amount of component (B) is 0.005 to 1 w/v % . The ophthalmic composition according to claim 2 or 3, wherein the quaternary ammonium salt is one or more selected from benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride. Phenylephrine hydrochloride 0.1 w/v% or 0.003 w/v%
Boric acid 1.4 w/v%,
Trometamol 0.1 w/v%,
Sodium chloride 0.2 w/v%,
Sodium edetate 0.1 w/v%,
Sodium hydroxide,
Dilute hydrochloric acid, and
purified water
The ophthalmic composition according to any one of claims 2 to 4, except for those containing: The ophthalmic composition according to any one of claims 2 to 5, wherein component (B) is one or more selected from edetic acid, trometamol and salts thereof, and borax.