WO2020138135A1

WO2020138135A1 - Composition for ophthalmic use

Info

Publication number: WO2020138135A1
Application number: PCT/JP2019/050751
Authority: WO
Inventors: 草太渡部; 圭祐渡邊
Original assignee: ライオン株式会社
Priority date: 2018-12-26
Filing date: 2019-12-25
Publication date: 2020-07-02
Also published as: CN112839641A; KR20210107607A; TW202033186A; JPWO2020138135A1

Abstract

This composition for ophthalmic use contains (A) one or more selected from phenylephrine and salts thereof and (B) one or more selected from terpenoids, and, as a result, exhibits an enhanced tear film-stabilizing effect, and is capable of suppressing mydriasis while maintaining the tear film-stabilizing effect of the phenylephrine, even when frequently administered at short intervals.

Description

Ophthalmic composition

The present invention relates to an ophthalmic composition containing phenylephrine.

Dry eye is a disease or condition with a high prevalence. In addition, the prevalence in Asia, including Japan, has been reported to be higher than in the West. Furthermore, it is expected that the number of suspects due to age factors, “wearing contact lenses”, and “long computer work”, which are risk factors for dry eye, will continue to increase in the future.

Destruction (instability) of the tear film is caused by an abnormality of the tear oil layer, a decrease in the water content of the fluid layer, an abnormality of secretory mucin, or a decrease in the wettability of the epithelium. At present, in Japan, a new concept for diagnosis and treatment of dry eye, in which the cause of the tear film destruction that causes dry eye is sought from the lacking component of the eye surface, and by supplementing it, the dry eye is diagnosed and treated (respectively, TFOD (tear film oriented diagnosis) and TFOT (tear film oriented therapy) are born, and they are said to be extremely useful for dry eye diagnosis.

Conventionally, 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 intended for the replacement of 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 released. While these ingredients have the effect of promoting the expression of mucin and water and stabilizing the tear film, diquafosol sodium causes ocular oil development and eye pain, and rebamipide has dysgeusia as a side effect unique to the ingredients. It has been reported to occur (see Patent Documents 1 and 2).
As described above, since there are few kinds of active ingredients for dry eye and side effects may be a problem, the development of a new therapeutic drug for dry eye has been awaited.

Japanese Patent No. 6267003 Patent No. 6060168

In view of the above situation, the present inventors have found that phenylephrine is excellent in the tear layer stabilizing effect and the meibam secretion promoting effect. Phenylephrine is excellent in tear layer stabilizing effect and meibam secretion promoting effect, and is useful as a preventive or therapeutic agent for dry eye. Phenylephrine is used for medical purposes with 5 w/v% (mass/volume %, g/100 mL, the same applies hereinafter, and will be described as %) of eye drops for the purpose of mydriasis during fundus examination. On the other hand, for over-the-counter drugs, the maximum concentration for approval standard is 0.1%, and mydriasis hardly occurs in normal usage. However, it was revealed that weak mydriasis occurs when frequent instillation is performed for a short time. From the above, it is possible to provide an ophthalmic composition capable of suppressing mydriasis while enhancing the tear layer stabilizing effect and further maintaining the tear layer stabilizing effect of phenylephrine even by frequent eye drops in a short time. The purpose is to

The present inventors have conducted extensive studies to achieve the above object, and as a result, (A) one or more selected from phenylephrine and salts thereof, (B) one or more selected from terpenoids, and preferably (C) It was found that the above problems can be solved by using in combination with one or more selected from quaternary ammonium salt, sorbic acid and its salt, polyhexanide and its salt, and paraoxybenzoic acid ester, and the present invention has been accomplished. It is a thing.

Therefore, the present invention provides the following ophthalmic composition.
1. An ophthalmic composition containing (A) one or more selected from phenylephrine and a salt thereof, and (B) one or more selected from a terpenoid.
2. The ophthalmic composition according to 1, further comprising (C) one or more selected from quaternary ammonium salts, sorbic acid and salts thereof, polyhexanide and salts thereof, and paraoxybenzoic acid ester.
3. Further, (D) polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol, chlorpheniramine maleate, epsilon aminocaproic acid, aspartic acid and its salts, and edetic acid and its salts. The ophthalmic composition according to 1 or 2, containing at least one selected from the group consisting of:
4. The ophthalmic composition according to any one of 1 to 3, wherein the component (B) 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 further maintains the tear film stabilizing effect even with frequent use for a short time without causing mydriasis. You 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 salts thereof, and may be used alone or in combination of two or more. For example, phenylephrine salts include pharmaceutically acceptable salts such as phenylephrine hydrochloride. From the viewpoint of the effect of stabilizing the tear film, the amount of the component (A) is 0.01 to 5% in the ophthalmic composition, preferably 0.025 to 5%, more preferably 0.1 to 5%. preferable. Further, from the viewpoint of the mydriasis suppressing effect, 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 may be used alone or in combination of two or more. The terpenoid in the present invention has a structure having an isoprene unit as a constitutional unit, and examples thereof include terpene hydrocarbon, terpene alcohol, terpene aldehyde, terpene ketone and the like. Further, depending on the carbon number, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes. Specific examples thereof include monoterpenes such as menthol, menthone, camphor, borneol, leno, geraniol, cineol, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids. Of these, it is preferable to use monoterpenes. These terpenoids can be used in any of d-form, l-form and dl-form. In addition, 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, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, and dipterocarp essential oil, rosmarinic oil, lavender oil, and the like. Of these, menthol, borneol, camphor, geraniol, peppermint oil, spearmint oil, and eucalyptus oil are preferable.

The 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 viewpoints of the tear layer stabilizing effect and the mydriasis suppressing effect. The range of 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, it is preferably 0.00005 to 0.2%, more preferably 0.0001 to 0.1%, further preferably 0.0005 to 0.03%, and 0.001 to 0.03%. Particularly preferred, 0.019 to 0.03% is most preferred.
When borneol is added, it is preferably 0.00005 to 0.2%, more preferably 0.0001 to 0.1%, further preferably 0.0005 to 0.03%, and 0.001 to 0.03%. Particularly preferred, 0.009 to 0.03% is most preferred.
When camphor is added, 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. Particularly preferred.
When blending geraniol, 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 Particularly preferred.
When blending peppermint oil and spearmint oil, 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 adding eucalyptus oil, 0.0002 to 0.2% is preferable, 0.001 to 0.1% is more preferable, 0.002 to 0.03% is further preferable, 0.009 to 0.03% 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 layer stabilizing effect and suppressing the mydriasis. The range of 0.01 to 0.3 is more preferable. The above ratio is the w/v% ratio, but it is the same value as the mass ratio.

[(C) component]
The component (C) is one or more selected from quaternary ammonium salts, sorbic acid and its salts, polyhexanide and its salts, and paraoxybenzoic acid esters, and they are used alone or in combination of two or more. be able to. For example, as quaternary ammonium salts, benzalkonium chloride, benzethonium chloride, etc., as sorbates, potassium sorbate, etc., as polyhexanides, polyhexanide hydrochloride, and as paraoxybenzoic acid esters, methyl paraoxybenzoate, paraoxybenzoate, etc. Ethyl acid and the like can be mentioned. By mixing these, the mydriasis suppressing effect is further enhanced, and the mydriasis suppressing effect can be further obtained even when the blending amount of the component (A) is high.

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

The preferred range of each component in the ophthalmic composition is as follows.
When a quaternary ammonium salt is added, 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 its salt 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 its salt 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 the mydriasis suppressing effect and the eye irritation suppressing effect. It is preferably 0.01 to 1, more preferably 0.02 to 0.7. The above ratio is the w/v% ratio, but it is the same value as the mass ratio.

[(D) component]
Component (D) is polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol, chlorpheniramine maleate, epsilon aminocaproic acid, aspartic acid and its salts, and edetic acid and its salts. One or more selected from salts can be used alone or in appropriate combination of two or more. By mixing these, the mydriasis suppressing effect is further enhanced, and the mydriasis suppressing effect can be further obtained even when the blending amount of the component (A) is high. Among them, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene polyoxypropylene glycol are preferable.

Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition-polymerizing ethylene oxide to hydrogenated castor oil, and several types with different average addition mole numbers of ethylene oxide are known. ing. The average number of moles of added ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, but may be 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (EO average addition mole number 5), polyoxyethylene hydrogenated castor oil 10 (EO average addition mole number 10), polyoxyethylene hydrogenated castor oil 20 (EO average addition mole number 20) ), polyoxyethylene hydrogenated castor oil 30 (EO average addition mole number 30), polyoxyethylene hydrogenated castor oil 40 (EO average addition mole number 40), polyoxyethylene hydrogenated castor oil 50 (EO average addition mole number 50), Polyoxyethylene hydrogenated castor oil 60 (EO average addition mole number 60), polyoxyethylene hydrogenated castor oil 80 (EO average addition mole number 80), polyoxyethylene hydrogenated castor oil 100 (EO average addition mole number 100), etc. To be Among them, polyoxyethylene hydrogenated castor oil 60 is preferable.

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

The polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is not particularly limited, and those described in the pharmaceutical additive standard (medical additive regulation) 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), Pronone #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), Pronone #235P ( Polyoxyethylene (20) polyoxypropylene (20) glycol: Pluronic L-44, Tetronic (manufactured by BASF) and the like, such as NOF CORPORATION. Among them, 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 aspartic acid salt of aspartic acid and its salt include potassium aspartate. Examples of edetic acid and edetate salts thereof include sodium edetate and sodium edetate hydrate.

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

The preferred range of each component in the ophthalmic composition is as follows.
When blending polyoxyethylene hydrogenated castor oil, 0.001 to 1% is preferable, 0.005 to 0.5% is more preferable, and 0.01 to 0.2% is further preferable.
When blending the polyoxyethylene sorbitan fatty acid ester, 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 blending polyoxyethylene polyoxypropylene glycol, 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 added, 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 added, it is preferably 0.01 to 5%, more preferably 0.05 to 4%, still more preferably 0.1 to 2%.
When aspartic acid or a salt thereof is added, it is preferably 0.01 to 3%, more preferably 0.03 to 2%, still more preferably 0.05 to 1%.
When adding edetic acid or a salt thereof, 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 other components in appropriate amounts within a range that does not impair the effects of the present invention. Other components include water, oily components, surfactants other than component (D), preservatives other than component (C), sugars, buffers, pH adjusters, tonicity agents, other than component (D). Examples include stabilizers, polyhydric alcohols, thickeners, drugs other than the component (A) and the component (D), and the like. These components may be blended alone or in an appropriate combination of two or more. The blending amounts of the components shown below are preferable ranges when blended. The water content may be the balance of the ophthalmic composition.

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

Examples of the surfactant include the following nonionic surfactants.
Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition-polymerizing ethylene oxide to castor oil, and several types of ethylene oxide having different average addition mole numbers are known. The average number of moles of ethylene oxide added to the polyoxyethylene castor oil is not particularly limited, but may be 3 to 60 moles. Specifically, polyoxyethylene castor oil 3 (numerical value is 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 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, etc. are mentioned.

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

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

As the preservatives other than the component (C), thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconic acid and the like can be mentioned as preservatives having a hydrophobic portion such as an alkyl chain or a benzene ring. When the preservative is added, its 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 sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. It should be noted that these may be any of d body, l body and dl body. When the saccharide is added, the amount of the saccharide added is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, even more preferably 0.001 to 0.1% in the ophthalmic composition.

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

As the pH adjusting agent, an inorganic acid or an inorganic alkaline agent can be mentioned. For example, the inorganic acid may be (dilute) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate 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, Toa DKK Co., Ltd.).

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 improving various symptoms caused by 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 osmometer (A2O, Advanced Instruments Co.).

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

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

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

Examples of the drug (pharmaceutically active ingredient) other than the components (A) and (D) include decongestant components (eg, epinephrine, methylnorepinephrine, norepinephrine, epinephrine hydrochloride, ephedrine, methylephedrine, pseudoephedrine, ephedrine hydrochloride). , Tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, dl-methylephedrine hydrochloride, oxymetazoline, methoxamine, phenylpropanolamine, etilefrine, midodrine, tramazoline, synephrine, silazoline, xylometazoline and pharmaceutically acceptable salts thereof Etc.), anti-inflammatory/astringent (for example, neostigmine methyl sulfate, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc. ), antihistamines (for example, diphenhydramine hydrochloride, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.), fat-soluble vitamins (retinol acetate, Examples thereof include retinol palmitate, tocopherol acetate and the like), amino acids (for example, aminoethyl sulfonic acid and the like), sulfa drug and the like. When a drug is compounded, the compounding amount of the drug can be selected as an effective appropriate amount of each drug, but is preferably 0.001 to 5%, more preferably 0.001 to 1% 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. For example, it can be obtained by dissolving an aqueous component in purified water, adjusting the pH, and then adjusting the total volume with the purified water. The mixing method may be a general method, and may be appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, or the like, but the number of revolutions is not particularly limited, and it is preferable to set it so that it does not foam violently. The mixing temperature of each liquid is not particularly limited, but specifically, 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 tear fluid, and 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 preferably used as eye drops, eye drops for contact lenses, eye washes, etc., but from the viewpoint of the preventive or therapeutic effect on dry eye, eye drops, eye drops for contact lenses (contact lens wear) It can be suitably used as an eye drop such as a human eye drop). The contact lens is not particularly limited, such as a hard contact lens and a soft contact lens, specifically, a silicon hydrogel soft contact lens, an O ₂ hard contact lens, and a color contact lens. It has been reported that contact lenses affect 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 (6 or more eye drops (or eye washes) per hour) in a short time, but the use method is not limited. For example, when used as an eye drop or an eye drop for contact lenses, it is preferable to apply 1 to 6 drops (preferably 1 to 3 drops) of 10 to 100 μL each time, and 1 to 6 times per day, preferably once. 10 to 50 μL per 1 to 6 drops (preferably 1 to 3 drops), more preferably 1 to 6 times per day, and 10 to 30 μL per time 1 to 6 drops (preferably 1 to 3 drops), 1 More preferably 1 to 6 times a day. When used as an eye wash, it is preferable to wash 3 to 6 mL once and wash 3 to 6 times per day.

In addition, after filling the obtained ophthalmic composition in a resin container, the container is further sealed with a package, and an inert gas such as nitrogen is sealed in the space formed between the container and the package. Of course, after filling the ophthalmic composition in a resin container, the container may be sealed with a deoxidizer.

<Stabilization of tear film>
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 stabilizing agent. 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.

Once the tear layer stabilizing effect is obtained, it can be preferably used as a dry eye preventive or therapeutic agent. Dry eye is defined as "a disease or symptom in which the stability of the tear film is reduced due to various factors, which may cause eye discomfort or abnormal visual function and may be accompanied by damage to the ocular surface." The diagnostic criteria are two items with subjective symptoms and fluorescein BUT (breakdown time of tear film) of 5 seconds or less. Fluorescein is generally used for the measurement of BUT, but it is necessary to administer a staining reagent into the eye, and the tear volume may change 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 until the tear film is destroyed (non-invasive breakup time: NIBUT). NIBUT is generally considered to be longer than fluorescein BUT.

Especially, phenylephrine or its salt shows a remarkable effect on BUT shortened dry eye. With BUT shortened dry eye, tear secretion and keratoconjunctival epithelium are almost normal, 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, eye pain, dazzling eyes, heavy eyes, eye discomfort, eye oil and tearing. The tear film stabilizing agent of the present invention may or may not be accompanied by an increase in tear production, and may exhibit a prominent dry eye preventive or therapeutic effect even without an increase in tear production. it can.

The 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 preventive or therapeutic agent for the following diseases or symptoms. Can be used.
Hypoplacia, age-related dry eyes, lacrimal tears, xerophthalmia, Sjogren's syndrome, keratoconjunctivitis sicca, Stevens-Johnson syndrome, ocular cysts, blepharitis, ocular closure, sensory nerve paralysis, allergic conjunctivitis A disease or symptom selected from dry eye associated with, dry eye associated with viral conjunctivitis, dry eye associated with cataract surgery, dry eye associated with VDT work, and dry eye associated with contact lens wear.
Eye fatigue, dry eyes, tired eyes, discomfort when wearing contact lenses, blurred vision, lid wiper epitheliopathy, keratoconjunctival epithelial disorder, corneal epithelial detachment, cornea due to dry eye A disease or condition selected from epithelial erosion, corneal ulcer and eye infection.

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 preferably used as a preventive or therapeutic agent for the following symptoms. be able to.
Eye fatigue, dry eyes, discomfort when wearing contact lenses and blurring of eyes, foreign body sensation, eye pain, dazzling eyes, heavy eyes, discomfort in eyes, eye oil and tearing.

<Mybam secretagogue>
Phenylephrine or a salt thereof has a meibum secretagogue effect, and thus the ophthalmic composition of the present invention has a meibum secretagogue effect and is suitable as a meibum secretagogue. Meibum is a component secreted from the meibomian gland, and the tear oil layer increases by promoting the secretion of meibum. The effect of promoting mybam secretion is measured by measuring the thickness of the tear oil layer.

　The meibomian glands in the eyelids secrete lipids and are important as a source of tear oil layer. This tear fluid layer is important because the tear fluid is stable as a film, such as the reduction of the surface tension of the tear fluid and the prevention of evaporation of the tear fluid. However, there are few reports on the mechanism of secretion of the meibomian gland and it has not been fully clarified.

As a disease or symptom caused by the inhibition of meibom secretion from the meibomian gland, in addition to the above dry eye, meibomian gland dysfunction, stye (hordeolum, chalazion) and the like can be mentioned.
Meibomian gland dysfunction (MGD) is defined as tear and eye surface abnormalities caused by impaired secretion of the meibomian glands. It is diagnosed by subjective symptoms, abnormal findings around the meibomian gland opening, and meibomian gland obstruction. MGD patients have a variety of subjective symptoms, including a foreign body sensation, a feeling of dryness, an eye fatigue, and a burning sensation. In order to improve the obstruction of the meibomian gland, the treatment is performed by hyperthermia or by applying physical force, and overseas, the obstruction of the meibomian gland is directly released with a thin wire-like device. .. Further, in recent years, a Lipiview/Lipiflow system, which is a system for evaluating the tear oil layer with an interference image and treating the eyelid from the inside with heat and a massage effect, has been developed, and attention is paid to the future treatment effect. However, since all of these methods require treatment within a medical institution, a simple therapeutic method has been desired.

Ergot and chalazion, commonly called stye, 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. As for drug therapy, an antibacterial agent is administered when self-destruction or drainage of pus is observed. In surgical treatment, if the pus is not in the superficial layer and does not result in self-destruction or drainage, puncture/incision is performed using an injection needle or the like to promote drainage. That is, the treatment requires drainage from the meibomian glands, but until now, the only option was to wait for spontaneous drainage or forceful drainage. Chalazion is said to be a foreign body reaction to lipids and is not an infectious disease. Treatment is basically surgery. In other words, hordeolum and chalazion have not been available by any method other than surgery, although they require pus and lipid excretion from the meibomian glands.

The meibum secretagogue of the present invention can be preferably used as a preventive or therapeutic agent for the same symptoms as the tear film stabilizer.
Furthermore, the agent for promoting secretion of mybam of the present invention can improve or prevent secretion of mebam, thereby preventing or treating MGD, dry eye, hordeolum and chalazion.

<Mydriatic inhibitor>
INDUSTRIAL APPLICABILITY Since the present invention can suppress mydriasis by phenylephrine while maintaining the tear layer stabilizing effect of phenylephrine even by frequent and short-term use (eye drops), the mydriasis by frequent and short-term use can be suppressed. It is suitable as a mydriatic inhibitor that can suppress the Suitable components and blending amounts are the same as above. In addition, in the present invention, frequent use in a short time means to instill (or wash) eyes 6 times or more per hour. The amount of the ophthalmic composition for each administration is appropriately selected from the range of 10 to 100 μL, and may be 50 μL.

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

[Examples and comparative examples]
After mixing the component (B) with propylene glycol and dissolving it in purified water, the components (A) to (D) and other water-soluble components are dissolved in purified water, and after adjusting the pH, the total volume is 100 mL with purified water. And 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 following evaluations were performed on the obtained ophthalmic compositions. The results are also shown in the table.

<Test 1: Mydriasis suppressing effect>
Three panelists instilled the sample 6 times in 1 hour (1 drop (50 μL) each time). The degree of mydriasis before and after the instillation was evaluated according to the following criteria. In order to evaluate the degree of mydriasis, a pre-light emission mode was set using a digital camera, and light adaptation (constriction of eyes) was induced immediately before the shooting, and the shooting was performed. The lower the mydriasis rate, the higher the mydriatic suppression effect.
Mydriasis rate (mydriasis 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 three panelists, the mydriasis suppressing effect was evaluated based on the following evaluation criteria. "○" and "◎" are passed.
[Mydriasis suppressing effect]
⊚: Average value of mydriatic rate is less than 10% ◯: Average value of mydriatic rate is 10% or more and less than 20% △: Average value of mydriatic rate is 20% or more and less than 30% ×: Average value of mydriatic rate Is over 30%

<Test 2: Evaluation of glare>
Three panelists instilled each sample 6 times in 1 hour (1 drop (50 μL) each time). After instillation, the degree of glare was evaluated according to the following criteria. The lower the score, the less glare. "○" and "◎" are passed.
[Glare]
0 points: No symptoms.
1 point: Symptoms are not painful, but sometimes there are. There is almost no obstacle in daily life.
2 points: The symptoms are not so painful, but always. I have some problems in my daily life.
3 points: The symptoms are quite painful, but somehow I can endure it. It is a serious obstacle to daily life.
4 points: The symptoms are so severe that I can't stand them. I can't live my daily life.
[No glare]
◎: Less than 0.5 ○: 0.5 or more and less than 1.0 △: 1.0 or more and less than 1.5 ×: Average value of 1.5 or more

<Test 3: Stability of tear film: NI (Non-invasive) BUT (Non-invasive tear film destruction time)>
Three panelists instilled the sample 6 times in 1 hour (1 drop (50 μL each). Before and after the instillation (5 minutes or more after the last instillation), the sample was measured by the following procedure.
DR-1 (manufactured by Kowa) was used for evaluation of NIBUT.
The tear interference pattern is observed using DR-1, and the time (seconds) until the tear layer is destroyed (the uniform gray or white interference pattern disappears) after opening the eyelid (NIBUT; non-invasive) Tear layer destruction time) was measured and the average value was calculated. The longer NIBUT is, the higher the tear film stability effect is.
NIBUT was measured when the Examples and Comparative Examples were instilled, and the average value was obtained.
Further, the tear layer stability effect was evaluated by the following criteria by calculating the difference between the average value of the examples and the average value of the comparative examples. It should be noted that 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 film destruction time is described. "●", "○", "◎" are passed.
◎: 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 film stability effect

The raw materials used in the above example are shown below. In addition, unless otherwise specified, the amounts of the respective components in the table are amounts converted to pure components.
POE (polyoxyethylene) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60: HCO-60, manufactured by Nippon Surfactant Industry Co., Ltd.)
POE (polyoxyethylene) sorbitan fatty acid ester (Polysorbate 80, Leodol TW-O120V manufactured by Kao Corporation)
EOPO (polyoxyethylene (196) polyoxypropylene (67) glycol (Lutrol F127, manufactured by BASF Japan Ltd.)

Claims

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