JPWO2020138135A1 - Ophthalmic composition - Google Patents

Abstract

By preparing an ophthalmic composition containing (A) one or more selected from phenylephrine and its salt and (B) one or more selected from terpenoid, the tear layer stabilizing effect is enhanced, and further, it is short. Even with frequent instillation over time, mydriasis can be suppressed while maintaining the tear layer stabilizing effect of phenylephrine.

Description

The present invention relates to an ophthalmic composition containing phenylephrine.

Dry eye is a disease or symptom with a high prevalence. In addition, the prevalence in Asia, including Japan, has been reported to be higher than in Europe and the United States. Furthermore, the number of complainants due to the risk factors of dry eye such as "aging", "wearing contact lenses", and "long computer work" is expected to continue to increase in the future.

Destruction (destabilization) of the tear film is caused by abnormalities in the tear oil layer, decreased water content in the fluid layer, abnormal secretory mucin, or decreased epithelial wettability. Currently, in Japan, a new concept of diagnosis and treatment of dry eye is to seek the cause of tear film destruction that causes dry eye from the deficient component of the eye surface and treat the dry eye by supplementing it (each, respectively). TFOD (tear film oriented therapy) and TFOT (tear film oriented therapy) are born, and it is said to be extremely useful for dry eye medical treatment.

As a therapeutic agent for dry eye, artificial tears containing inorganic salts such as sodium chloride and potassium chloride have been widely used in the treatment of medical and over-the-counter drugs, but these are for the purpose of replenishing tears. It was only a temporary effect. In recent years, eye drops containing ingredients effective against dry eye, such as sodium hyaluronate, sodium diquafosol, and rebamipide, have begun to be marketed. While these ingredients promote the expression of mucin and water and stabilize the tear film, diquafosol sodium causes eye oil and eye pain, and rebamipide causes dysgeusia as side effects specific to the ingredients. It has been reported to occur (see Patent Documents 1 and 2).
As described above, since there are few types of active ingredients for dry eye and side effects may be a problem, the development of a new therapeutic agent for dry eye has been awaited.

Japanese Patent No. 6267003 Japanese Patent No. 60060168

In view of the above circumstances, the present inventors have found that phenylephrine is excellent in the tear film stabilizing effect and the mybum secretion promoting effect. Phenylephrine is excellent in the tear film stabilizing effect and the mybum secretion promoting effect, and is useful as a dry eye preventive agent or a therapeutic agent. Phenylephrine is used for medical purposes in which 5 w / v% (similar to mass / volume%, g / 100 mL or less, hereinafter referred to as%) ophthalmic solution is used for the purpose of mydriasis during fundus examination. On the other hand, in over-the-counter drugs, the maximum compounding concentration of the approval standard is 0.1%, and mydriasis rarely occurs in normal usage. However, it was clarified that weak mydriasis occurred when the eye drops were instilled frequently in a short time. Based on the above, we provide an ophthalmic composition that enhances the tear film stabilizing effect and can suppress mydriasis while maintaining the tear layer stabilizing effect of phenylephrine even by frequent instillation in a short time. The purpose is.

As a result of diligent studies to achieve the above object, the present inventors have selected one or more species selected from (A) phenilefurin and a salt thereof, and one or more species selected from (B) terpenoids, preferably (C) first. It has been found that the above problems can be solved by using a quaternary ammonium salt, a sorbic acid and a salt thereof, a polyhexanide and a salt thereof, and one or more selected from a paraoxybenzoic acid ester in combination, and the present invention has been made. It is a thing.

Therefore, the present invention provides the following ophthalmic compositions.
1. 1. An ophthalmic composition containing (A) one or more selected from phenylephrine and a salt thereof, and (B) one or more selected from terpenoids.
2. The ophthalmic composition according to 1 above, which further comprises (C) a quaternary ammonium salt, sorbic acid and a salt thereof, polyhexanide and a salt thereof, and one or more selected from paraoxybenzoic acid esters.
3. 3. Further, (D) polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol, chlorophenylamine maleate, epsilon aminocaproic acid, aspartic acid and its salt, and edetonic acid and its salt. The ophthalmic composition according to 1 or 2, which contains at least one selected from.
4. (B) The ophthalmic composition according to any one of 1 to 3, wherein the component is one or more selected from menthol, borneol, camphor, geraniol, peppermint oil, spearmint oil and eucalyptus oil.

According to the present invention, an ophthalmic composition that enhances the tear film stabilizing effect of phenylephrine or a salt thereof, and does not cause mydriasis while maintaining the tear layer stabilizing effect even after frequent use for a short period of time. Can provide things.

Hereinafter, the present invention will be described in detail.
[(A) component]
The component (A) is one or more selected from phenylephrine and a salt thereof, and one or more can be used alone or in combination of two or more as appropriate. For example, examples of the phenylephrine salt include pharmaceutically acceptable salts such as phenylephrine hydrochloride. The blending amount of the component (A) is 0.01 to 5%, preferably 0.025 to 5%, more preferably 0.1 to 5% in the ophthalmic composition from the viewpoint of the tear film stabilizing effect. preferable. Further, from the viewpoint of the effect of suppressing mydriasis, 0.01 to 1% is more preferable, and 0.1 to 0.5% is further preferable.

[(B) component]
The component (B) is one or more selected from terpenoids, and one or more can be used alone or in combination of two or more as appropriate. The terpenoid in the present invention has a structure having an isoprene unit as a constituent unit, and examples thereof include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. In addition, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes depending on the number of carbon atoms. Specific examples thereof include monoterpenes such as menthol, menthone, camphor, borneol, ryunou, geraniol, cineole, linalol, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids. Above all, it is preferable to use a monoterpene. These terpenoids can be used in any of d-form, l-form or dl-form. In the present invention, an essential oil containing the above compound may be used as the terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, uikyo oil, rose oil, peppermint oil, peppermint oil, sparemint oil, and essential oils of the family Futabagaki family, rosmarin oil, lavender oil and the like. Of these, menthol, borneol, camphor, geraniol, peppermint oil, spearmint oil, and eucalyptus oil are preferable.

The blending amount of the component (B) is preferably 0.00005 to 0.3%, more preferably 0.0001 to 0.2% in the ophthalmic composition from the viewpoint of the tear film stabilizing effect and the mydriasis suppressing effect. It is preferable, 0.0005 to 0.1 is more preferable. From the viewpoint of the tear layer stabilizing effect, the upper limit is particularly preferably 0.03% or less.

The preferred range of each component in the ophthalmic composition is as follows.
When menthol is blended, 0.00005 to 0.2% is preferable, 0.0001 to 0.1% is more preferable, 0.0005 to 0.03% is further preferable, and 0.001 to 0.03% is preferable. It is particularly preferable, and 0.019 to 0.03% is most preferable.
When borneol is blended, 0.00005 to 0.2% is preferable, 0.0001 to 0.1% is more preferable, 0.0005 to 0.03% is further preferable, and 0.001 to 0.03% is preferable. It is particularly preferable, and 0.009 to 0.03% is most preferable.
When camphor is blended, 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, 0.001 to 0.01% is further preferable, and 0.002 to 0.01% is preferable. Especially preferable.
When geraniol is blended, 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, 0.001 to 0.03% is further preferable, and 0.009 to 0.03% is preferable. Especially preferable.
When peppermint oil and spearmint oil are blended, 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, 0.001 to 0.03% is further preferable, and 0.009 to 0 0.03% is particularly preferable.
When eucalyptus oil is blended, 0.0002 to 0.2% is preferable, 0.001 to 0.1% is more preferable, 0.002 to 0.03% is further preferable, and 0.009 to 0.03% is preferable. Is particularly preferable, and 0.009 to 0.02% is most preferable.

The content mass ratio represented by (B) / (A) is preferably 0.001 to 1 and more preferably 0.005 to 0.5 from the viewpoint of enhancing the tear film stabilizing effect and suppressing mydriasis. It is preferable, and 0.01 to 0.3 is more preferable. Although the above ratio is a w / v% ratio, it is the same value as the mass ratio.

[(C) component]
The component (C) is one or more selected from a quaternary ammonium salt, sorbic acid and its salt, polyhexanide and its salt, and paraoxybenzoic acid ester, and one kind alone or two or more kinds are used as appropriate. be able to. For example, the quaternary ammonium salt is benzalkonium chloride, benzethonium chloride, etc., the sorbate is potassium sorbate, etc., the polyhexanide is polyhexanide hydrochloride, and the paraoxybenzoic acid ester is methyl paraoxybenzoate, paraoxybenzoic acid. Examples thereof include ethyl acid acid. By blending these, the mydriasis suppressing effect is further enhanced, and even when the blending amount of the component (A) is high, the mydriasis suppressing effect can be further obtained.

The blending amount of the component (C) is preferably 0.00005 to 1%, more preferably 0.0001 to 1%, and 0.0005 to 0.5% in the ophthalmic composition from the viewpoint of the effect of suppressing mydriasis. More preferably, 0.001 to 0.3% is particularly preferable.

The preferred range of each component in the ophthalmic composition is as follows.
When the quaternary ammonium salt is blended, 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, and 0.001 to 0.01% is further preferable.
When sorbic acid and a salt thereof are blended, 0.005 to 1.0% is preferable, 0.01 to 0.5% is more preferable, and 0.05 to 0.3% is further preferable.
When polyhexanide and a salt thereof are blended, 0.00005 to 0.05% is preferable, 0.0001 to 0.02% is more preferable, and 0.0001 to 0.01% is further preferable.
When the paraoxybenzoic acid ester is blended, 0.001 to 0.3% is preferable, 0.005 to 0.2% is more preferable, and 0.01 to 0.1% is further preferable.

The content mass ratio represented by ((B) + (C)) / (A) is preferably 0.001 to 3 and more preferably 0.005 to 2 from the viewpoint of mydriasis suppressing effect and eye irritation suppressing effect. Preferably, 0.01 to 1 is more preferable, and 0.02 to 0.7 is particularly preferable. Although the above ratio is a w / v% ratio, it is the same value as the mass ratio.

[(D) component]
The component (D) is polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol, chlorophenylamine maleate, epsilon aminocaproic acid, aspartic acid and its salt, and edetonic acid and its salts. It is one or more kinds selected from salts, and one kind alone or two or more kinds can be used in combination as appropriate. By blending these, the mydriasis suppressing effect is further enhanced, and even when the blending amount of the component (A) is high, the mydriasis suppressing effect can be further obtained. Of these, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene polyoxypropylene glycol are preferable.

Polyoxyethylene hydrogenated castor oil (POE cured castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types with different average addition moles of ethylene oxide are known. ing. The average number of moles of ethylene oxide added to the polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified by 5 to 100 moles. Specifically, polyoxyethylene cured castor oil 5 (EO average added moles 5), polyoxyethylene cured castor oil 10 (EO average added moles 10), polyoxyethylene cured castor oil 20 (EO average added moles 20). ), Polyoxyethylene cured castor oil 30 (EO average added moles 30), Polyoxyethylene cured castor oil 40 (EO average added moles 40), Polyoxyethylene cured castor oil 50 (EO average added moles 50), Polyoxyethylene cured castor oil 60 (EO average added moles 60), polyoxyethylene cured castor oil 80 (EO average added moles 80), polyoxyethylene cured castor oil 100 (EO average added moles 100), etc. Be done. Of these, polyoxyethylene hydrogenated castor oil 60 is preferable.

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

The polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is not particularly limited, and those described in the pharmaceutical additive standard (pharmaceutical supplementary regulations) can be used. The average degree of polymerization of ethylene oxide is preferably 4 to 200, more preferably 20 to 200, the average degree of polymerization of propylene oxide is preferably 5 to 100, more preferably 20 to 70, and it 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 Nippon Oil & Fats Co., Ltd.), etc. Polyoxyethylene (120) polyoxypropylene (40) Glycol: Pluronic F-87 (manufactured by BASF), Polyoxyethylene (160) Polyoxypropylene (30) Glycol: Pluronic F-68 (manufactured by BASF), Pronon # 188P (manufactured by Nippon Oil & Fats Co., Ltd.) Etc., Polyoxyethylene (42) Polyoxypropylene (67) Glycol: Pluronic P123 (manufactured by BASF), Polyoxyethylene (54) Polyoxypropylene (39) Glycol: Pluronic P85 (manufactured by BASF), Pronon # 235P ( Examples thereof include polyoxyethylene (20) polyoxypropylene (20) glycol: Pluronic L-44, Tetronic (manufactured by BASF) and the like (manufactured by Nippon Oil & Fats Co., Ltd.). Of these, polyoxyethylene (200) polyoxypropylene (70) glycol is preferable.

Chlorpheniramine maleate is known as an antihistamine. Epsilon aminocaproic acid is known as an anti-inflammatory astringent. Examples of the aspartate of aspartic acid and its salt include potassium aspartate and the like. Examples of the edetate of edetic acid and its salt include sodium edetate, sodium edetate hydrate and the like.

The blending amount of the component (D) is preferably 0.0001 to 20%, more preferably 0.0005 to 10%, and even more preferably 0.001 to 2% in the ophthalmic composition.

The preferred range of each component in the ophthalmic composition is as follows.
When the polyoxyethylene hydrogenated castor oil is blended, 0.001 to 1% is preferable, 0.005 to 0.5% is more preferable, and 0.01 to 0.2% is further preferable.
When the polyoxyethylene sorbitan fatty acid ester is blended, 0.001 to 0.5% is preferable, 0.005 to 0.4% is more preferable, and 0.01 to 0.2% is further preferable.
When polyoxyethylene polyoxypropylene glycol is blended, 0.01 to 20% is preferable, 0.05 to 10% is more preferable, and 0.1 to 1% is further preferable.
When chlorpheniramine maleate is blended, 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, and 0.001 to 0.03 is further preferable.
When epsilon aminocaproic acid is blended, 0.01 to 5% is preferable, 0.05 to 4% is more preferable, and 0.1 to 2% is further preferable.
When aspartic acid or a salt thereof is blended, 0.01 to 3% is preferable, 0.03 to 2% is more preferable, and 0.05 to 1% is further preferable.
When edetic acid or a salt thereof is blended, 0.0001 to 1.5% is preferable, 0.0005 to 1% is more preferable, and 0.001 to 0.1% is further preferable.

[Other ingredients]
The ophthalmic composition of the present invention may contain an appropriate amount of other ingredients as long as the effects of the present invention are not impaired. Other components include water, oily components, surfactants other than (D) component, preservatives other than (C) component, sugars, buffers, pH adjusters, isotonic agents, and components other than (D) component. Examples thereof include stabilizers, polyhydric alcohols, thickeners, components (A), drugs other than component (D), and the like. These components can be blended individually by 1 type or in combination of 2 or more types as appropriate. The blending amount of the components shown below is a preferable range when blending. The amount of water blended can be the balance of the ophthalmic composition.

Examples of the oily component include liquid paraffin, castor oil, soybean oil, olive oil, sesame oil, corn oil, palm oil, almond oil, medium chain fatty acid triglyceride, white vaseline, mixed tocopherol, lanolin and the like. When the oil component is blended, the blending amount is preferably 0.001 to 1.0%, more preferably 0.001 to 0.5%, still more preferably 0.001 to 0.25% in the ophthalmic composition. ..

Examples of the surfactant include the following nonionic surfactants.
Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide to castor oil, and several types are known in which the average number of moles of ethylene oxide added is different. The average number of moles of ethylene oxide added to the polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles is exemplified. Specifically, polyoxyethylene castor oil 3 (numerical values are the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil. Examples thereof include oil 40, polyoxyethylene castor oil 50, and polyoxyethylene castor oil 60.

Examples of the polyethylene glycol fatty acid ester include polyethylene glycol stearate-25 and polyethylene glycol stearate-40, with polyethylene glycol stearate-40 being preferred.

When a surfactant other than the component (D) is blended, the blending amount is preferably 0.01 to 2.0%, more preferably 0.05 to 1.5%, and 0.1 to 0.1% of the ophthalmic composition. 1.2% is more preferable.

Examples of the preservative other than the component (C) include thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconic acid and the like as preservatives having a hydrophobic portion such as an alkyl chain and a benzene ring. When the preservative is blended, the blending amount is preferably 0.0001 to 0.5% in the ophthalmic composition. However, when blended, it is preferably 0.1% or less, more preferably 0.01% or less in the ophthalmic composition.

Examples of saccharides include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form, or dl-form. When the saccharide is blended, the blending amount is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, still more preferably 0.001 to 0.1% in the ophthalmic composition.

Examples of the buffer include citric acid, sodium citrate, boric acid, borosand, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, tromethamole, sodium hydrogen carbonate and the like. When the buffer is blended, the blending amount is preferably 0.001 to 5.0%, more preferably 0.001 to 2%, still more preferably 0.001 to 1% in the ophthalmic composition.

Examples of the pH adjuster include an inorganic acid or an inorganic alkaline agent. For example, examples of the inorganic acid include (dilute) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like. The pH of the ophthalmic composition is preferably 3.5 to 8.0, 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 the tonicity agent 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 and the like. Can be mentioned. From the viewpoint of further improving various symptoms caused by the destabilization of the tear oil layer, it is preferable to add sodium chloride or potassium chloride to make it isotonic. The osmotic pressure ratio of the ophthalmic 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 osmotic pressure gauge (A2O, Advanced Instruments).

Examples of the stabilizer other than the component (D) include cyclodextrin, sulfites, dibutylhydroxytoluene and the like. When the stabilizer is blended, the blending amount is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, still more preferably 0.001 to 0.1% in the ophthalmic composition.

Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like. When the polyhydric alcohol is blended, the blending amount is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, still more preferably 0.001 to 0.1% in the ophthalmic composition.

Examples of the thickener include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, and carboxyvinyl polymer. When the viscous agent is blended, the blending amount is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, still more preferably 0.001 to 0.1% in the ophthalmic composition.

Drugs (pharmaceutical active ingredients) other than the components (A) and (D) include, for example, decongestant components (eg, ephedrine, methylnorepinephrine, norepinephrine, epinephrine hydrochloride, ephedrine, methylephedrine, pseudoephedrine, ephedrine hydrochloride). , Tetrahydrozoline hydrochloride, nafazoline hydrochloride, nafazoline nitrate, dl-methylephedrine hydrochloride, oxymethazoline, methoxamine, phenylpropanolamine, ethyrefrin, middrine, tramazoline, cinefurin, silazoline, xylomezoline and pharmaceutically acceptable salts thereof. Etc.), Anti-inflammatory / astringent agents (eg, neostigmine methyl sulfate, allantin, ephedrine chloride hydrate, ephedrine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc. ), Antihistamines (eg, diphenhydramine hydrochloride, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamine, pyridoxin hydrochloride, pantenol, calcium pantothenate, sodium pantothenate, etc.), fat-soluble vitamins (retinol acetate, etc.) Examples thereof include retinol palmitate, tocopherol acetate, etc.), amino acids (for example, aminoethylsulfonic acid, etc.), sulfa agents, and the like. When a drug is blended, an effective appropriate amount of each drug can be selected as the blending amount of the drug, but 0.001 to 5% is preferable, and 0.001 to 1% is more preferable in the ophthalmic composition. , 0.001 to 0.1% is more preferable.

[Production method]
The method for producing the ophthalmic composition of the present invention is not particularly limited, and can be obtained, for example, by dissolving an 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 is appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, or the like, but the rotation speed is not particularly limited, and it is preferable to set the mixing speed so as not to foam violently. The mixing temperature of each liquid is not particularly limited, but specifically, it is appropriately selected from the range of 20 to 95 ° C.

[Ophthalmic composition]
The ophthalmic composition of the present invention is preferably a liquid from the viewpoint of facilitating adaptation to the eye, and the viscosity at 20 ° C. is preferably 20 mPa · s or less from the viewpoint of facilitating mixing with tears, and is preferably 10 mPa · s. The following is more preferable, 5 mPa · s or less is further preferable, and 2 mPa · s or less is particularly preferable. The viscosity is measured using a cone plate type viscometer (DV2T, Eiko Seiki Co., Ltd.). The lower limit is not particularly limited, but may be 1 mPa · s.

The ophthalmic composition of the present invention can be suitably used as an eye drop, a contact lens eye drop, an eye wash, etc., but from the viewpoint of dry eye prevention or therapeutic effect, an eye drop, a contact lens eye drop (contact lens wearing) It can be suitably used as an eye drop such as eye drops for humans). The contact lens is not particularly limited to a hard contact lens, a soft contact lens, specifically, a silicon hydrogel soft contact lens, an O ₂ hard contact lens, a color contact lens, or the like. It has been reported that contact lenses affect the morphological changes of meibomian glands and contribute to dry eye, and are particularly suitable as eye drops for contact lenses.

The ophthalmic composition of the present invention can suppress mydriasis due to frequent use (eye drops (or eye washing) 6 times or more per hour) in a short time, but the method of use thereof is not limited. For example, when used as an eye drop or an eye drop for contact lenses, it is preferable to instill 1 to 6 drops (preferably 1 to 3 drops) of 10 to 100 μL at a time, preferably 1 to 6 times a day. 1 to 6 drops (preferably 1 to 3 drops) of 10 to 50 μL per day, more preferably 1 to 6 times per day, 1 to 6 drops (preferably 1 to 3 drops) of 10 to 30 μL per time, 1 More preferably 1 to 6 times per day. When used as an eye wash, it is preferable to wash the eyes 3 to 6 mL at a time and 3 to 6 times a day.

Further, even if the obtained ophthalmic composition is filled in a resin container, further sealed with a package, and an inert gas such as nitrogen is sealed in the space formed between the container and the package. Often, the ophthalmic composition may be filled in a resin container and then sealed with a packaging material together with an oxygen scavenger.

<Tear fluid layer stabilization>
Since phenylephrine or a salt thereof has a tear film stabilizing effect, the ophthalmic composition of the present invention has a tear layer stabilizing effect and is suitable as a tear layer stabilizer. The tear layer stabilizing effect can be measured by, for example, NI (Non-invasive) BUT (non-invasive tear layer destruction time). Specifically, it is the method of the embodiment described later.

When the tear layer stabilizing effect is obtained, it can be suitably used as a dry eye preventive agent or a therapeutic agent. Dry eye is defined as "a disease or symptom in which the stability of the lacrimal layer is impaired due to various factors, which may cause eye discomfort and visual dysfunction, and may be accompanied by damage to the surface of the eye." The diagnostic criteria are two items: subjective symptoms and fluorescein BUT (tear layer destruction time) of 5 seconds or less. Although fluorescein is generally used for BUT measurement, it is necessary to administer a staining reagent intraocularly, the amount of tears changes slightly, and the staining reagent may adhere to the face or clothes. There is also a widely known method for non-invasively examining the time to tear layer destruction (non-invasive break-up time: NIBUT). Compared to fluorescein BUT, NIBUT is generally considered to be longer.

In particular, phenylephrine or a salt thereof shows a remarkable effect on BUT shortened dry eye. BUT shortened dry eye has almost normal tear secretion and keratoconjunctival epithelium, but shortened BUT is detected, which causes eye fatigue, dry eyes, discomfort when wearing contact lenses, and Dry eye that causes symptoms such as blurred vision, foreign body sensation, pain in the eyes, dazzling eyes, heavy eyes, discomfort in the eyes, eye oil and tears. The tear film stabilizer of the present invention may or may not be accompanied by an increase in tear secretion and may exhibit significant dry eye prevention or therapeutic effects without an increase in tear secretion. can.

Diseases or symptoms caused by destabilization of the tear film include the following symptoms, and the tear film stabilizer of the present invention is suitable as a prophylactic or therapeutic agent for the following diseases or symptoms. Can be used.
Lacrimal hypoplasia, age-related dry eye, lacrimation, dry eye, Schegren's syndrome, keratoconjunctivitis sicca, Stevens-Johnson's syndrome, vesicular vesicles, palpebral inflammation, ocular insufficiency, sensory nerve palsy, allergic conjunctivitis Diseases or symptoms selected from dry eye associated with, dry eye after viral conjunctivitis, dry eye after cataract surgery, dry eye associated with VDT work and dry eye associated with contact lens wear.
Eye fatigue, dry eyes, eye fatigue, discomfort when wearing contact lenses, blurred vision, lid wiper epitheliopathy, corneal conjunctival epithelial disorders, corneal epithelial detachment, corneal ulcers caused by dry eye Diseases or symptoms selected from epithelial ulcers, corneal ulcers and eye infections.

Further, the diseases or symptoms caused by the destabilization of the tear film include the following symptoms, and the tear film stabilizer of the present invention is suitably used as a prophylactic or therapeutic agent for the following symptoms. be able to.
Eye fatigue, dry eyes, discomfort when wearing contact lenses and blurred vision, foreign body sensation, eye pain, dazzling eyes, heavy eyes, eye discomfort, eye oil and tears.

<My Bum Secretagogue>
Since phenylephrine or a salt thereof has a mybum secretion promoting effect, the ophthalmic composition of the present invention has a mybam secretagogue effect and is suitable as a mybam secretion promoting agent. Meibomian gland is a component secreted by the meibomian glands, and the tear oil layer increases by promoting meibomian gland secretion. The mybum secretagogue effect measures the thickness of the lacrimal fluid layer.

The meibomian glands present in the eyelid secrete lipids and are important as a source of the lacrimal oil layer. This tear oil layer is important for the tear fluid to be stable as a membrane, such as lowering the surface tension of the tear fluid and preventing evaporation of the tear fluid. However, there are few reports on the secretory mechanism of the meibomian glands, and it has not been fully elucidated.

In addition to the above-mentioned dry eye, diseases or symptoms caused by inhibition of meibomian gland secretion include meibomian gland dysfunction, styes (stye, chalazion) and the like.
Meibomian gland dysfunction (MGD) is defined as tear fluid and ocular surface abnormalities caused by impaired secretion of the meibomian glands. Diagnosis is based on subjective symptoms, abnormal findings around the meibomian gland opening, and meibomian gland obstruction findings. The subjective symptoms of MGD patients are diverse and complain of foreign body feeling, dry feeling, eye fatigue feeling, burning sensation and the like. Treatments include hyperthermia and extrusion by applying physical force to improve the obstruction of the meibomian glands, and overseas, methods such as directly releasing the obstruction of the meibomian glands with a thin wire-like device are performed. .. Further, in recent years, a system for evaluating the tear oil layer with an interference image and treating the eyelids from the inside with a heat and massage effect, a Liveview / Lipiflow system, has been developed, and future therapeutic effects are attracting attention. However, since all of these methods are treatments within medical institutions, a simple treatment method has been long-awaited.

Stye and chalazion, commonly referred to as styes, are diseases or symptoms that occur in the meibomian glands. Stye is an acute purulent inflammation caused by a bacterial infection. Treatment includes drug therapy and surgical therapy. In drug therapy, antibacterial agents are administered when pus spots are self-destructed or drained. In surgical therapy, if the pus point is not in the superficial layer and self-destruction / drainage does not occur, puncture / incision is performed using an injection needle or the like to promote drainage. That is, treatment requires drainage from the meibomian glands, but until now the only options were to wait for spontaneous drainage or invasive forced drainage. Chalazion is said to be a foreign body reaction to lipids and is not an infectious disease. Treatment is based on surgery. That is, although hordeolum and chalazion require excretion of pus and lipids from the meibomian glands, there has been no method other than surgery.

The mybum secretagogue of the present invention can be suitably used as a prophylactic or therapeutic agent for the same symptoms as the tear film stabilizer.
Furthermore, the meibomian gland secretagogue of the present invention can prevent or treat MGD, dry eye, hordeolum and chalazion by improving meibomian gland secretion.

<Mydriasis inhibitor>
According to the present invention, mydriasis due to phenylephrine can be suppressed while maintaining the tear layer stabilizing effect of phenylephrine even by frequent use for a short period of time (eye drops). It is suitable as a mydriasis inhibitor that can suppress mydriasis. Suitable ingredients, blending amounts, etc. are the same as above. In the present invention, frequent use in a short time means instilling (or washing) eyes 6 times or more per hour. The amount of the ophthalmic composition at one time is appropriately selected from the range of 10 to 100 μL, and may be 50 μL.

Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. In the following examples, unless otherwise specified, the "%" of the composition indicates w / v%, and the ratio indicates the mass ratio (the same value as the w / v% ratio).

[Examples, comparative examples]
After the component (B) is mixed with propylene glycol and dissolved in purified water, the components (A) to (D) and other water-soluble components are dissolved in purified water, and after pH adjustment, the total volume is 100 mL with purified water. And said. 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 ophthalmic composition was evaluated as follows. The results are also shown in the table.

<Test 1: Mydriasis suppression effect>
Three panelists instilled the sample 6 times in 1 hour (1 drop (50 μL) at a time). The degree of mydriasis was evaluated before and after instillation according to the following criteria. In order to evaluate the degree of mydriasis, a digital camera was used to set the pre-emission mode, and immediately before shooting, light adaptation (miosis) was induced and the picture was taken. The lower the mydriasis rate, the higher the effect of suppressing mydriasis.
Mydriasis rate (miosis suppression rate) = (D2-D1) / D1 × 100 (%)
D1 = Pupil diameter (mm) before instillation (initial state)
D2 = Pupil diameter after instillation (mm)
From the average value of the mydriasis rate of the three panelists, the mydriasis suppression effect was evaluated based on the following evaluation criteria. Pass "○" and "◎".
[Mydriasis suppression effect]
⊚: Average value of mydriasis rate is less than 10% 〇: Average value of mydriasis rate is 10% or more and less than 20% Δ: Average value of mydriasis rate is 20% or more and less than 30% ×: Average value of mydriasis rate Is over 30%

<Test 2: Evaluation of glare>
Three panelists instilled each sample 6 times in 1 hour (1 drop (50 μL) at a time). After instillation, the degree of glare was evaluated according to the following criteria. The lower the score, the less glare. Pass "○" and "◎".
[Glitter]
0 points: No symptoms at all.
1: Symptoms are not painful, but sometimes. There is almost no problem in daily life.
2: Symptoms are not so painful, but they are always present. There is a slight hindrance to daily life.
3 points: The symptoms are quite painful, but I can manage to put up with them. It interferes with daily life.
4 points: The symptoms are terrible and unbearable. I can't do my daily life.
[No glare]
⊚: less than 0.5 ○: 0.5 or more and less than 1.0 Δ: 1.0 or more and less than 1.5 ×: average value is 1.5 or more

<Test 3: Tear layer stability: NI (Non-invasive) BUT (non-invasive tear layer destruction time)>
Three panelists instilled the sample 6 times in 1 hour (1 drop (50 μL) at a time. Before and after instillation (after 5 minutes or more of the last instillation), the measurement was performed by the following procedure.
DR-1 (manufactured by Kowa) was used for the evaluation of NIBUT.
Using DR-1, observe the tear interference image, and after opening the eyelid, the time (seconds) until the tear layer is destroyed (the uniform gray or white interference image disappears) (NIBUT; non-invasive). The target tear film destruction time) was measured, and the average value was calculated. The longer the NIBUT, the higher the tear layer stability effect.
The NIBUT when the Examples and Comparative Examples were instilled was measured and the average value was calculated.
In addition, the difference in tear layer stability effect between the average value of the examples and the average value of the comparative examples was calculated and evaluated according to the following criteria. When the phenylephrine hydrochloride concentration is 0.1%, it is a difference from Comparative Example 2, and when it is 1%, it is a difference from Comparative Example 3. In the comparative example, NIBUT; non-invasive tear layer destruction time is described. Pass "●", "○", and "◎".
⊚: Difference in average value is 1.5 seconds or more ○: Difference in average value is 1 second or more and less than 1.5 seconds ●: Difference in average value is less than 1 second ×: No tear layer stability effect

The raw materials used in the above example are shown below. Unless otherwise specified, the amount of each component in the table is a net conversion amount.
POE (Polyoxyethylene) Hardened Castor Oil (Polyoxyethylene Hardened Castor Oil 60: HCO-60, manufactured by Nippon Surfactant Industry Co., Ltd.)
POE (polyoxyethylene) sorbitan fatty acid ester (Polysorbate 80, Leodor TW-O120V manufactured by Kao Corporation)
EOPO (Polyoxyethylene (196) Polyoxypropylene (67) Glycol (LutrolF127, manufactured by BASF Japan Ltd.)

Claims (4)

An ophthalmic composition containing (A) one or more selected from phenylephrine and a salt thereof, and (B) one or more selected from terpenoids. The ophthalmic composition according to claim 1, further comprising (C) a quaternary ammonium salt, sorbic acid and a salt thereof, polyhexanide and a salt thereof, and one or more selected from paraoxybenzoic acid esters. Further, (D) polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol, chlorophenylamine maleate, epsilon aminocaproic acid, aspartic acid and its salt, and edetonic acid and its salt. The ophthalmic composition according to claim 1 or 2, which contains one or more selected from the above. The ophthalmic composition according to any one of claims 1 to 3, wherein the component (B) is at least one selected from menthol, borneol, camphor, geraniol, peppermint oil, spearmint oil and eucalyptus oil.