JP7192489B2 - Ophthalmic composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to an ophthalmic composition containing an adrenergic α1 receptor agonist.

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

Destruction (destabilization) of the tear film is caused by an abnormality in the tear lipid layer, a decrease in the water content of the tear film, an abnormality in the secretory mucin, or a decrease in the wettability of the epithelium. Currently, in Japan, there are new dry eye diagnosis and treatment concepts (respectively: TFOD (tear film oriented diagnosis: stratified diagnosis of the ocular surface) and TFOT (tear film oriented therapy: stratified treatment of the ocular surface) were born, and are said to be extremely useful for dry eye treatment.

As a remedy for dry eye, artificial tears containing inorganic salts such as sodium chloride and potassium chloride have been widely used in medical and over-the-counter drug treatments. It was only a temporary effect. In recent years, eye drops containing active ingredients for dry eye, such as diquafosol sodium and rebamipide, have begun to be marketed. While these ingredients promote the expression of mucin and water and have the effect of stabilizing the tear film, diquafosol sodium causes eye discharge and eye pain, and rebamipide causes dysgeusia as side effects peculiar to the ingredients. It has been reported that this occurs (see Patent Documents 1 and 2).
As described above, there are few types of active ingredients for dry eye, and side effects may be a problem.

Japanese Patent No. 6267003 Japanese Patent No. 6060168

In view of the above situation, the present inventors have found that adrenergic α1 receptor agonists are excellent in liquid layer stabilizing effect and meibum secretion promoting effect. Adrenergic α1 receptor agonists are excellent in liquid layer stabilizing effect and meibum secretion promoting effect, and are useful as dry eye prophylactic or therapeutic agents. Further, ophthalmic compositions with high effects are desired.

The present inventors have made intensive studies to achieve the above object, and found that (A) one or more selected from adrenergic α1 receptor agonists and (B) one selected from hyaluronic acids, vitamin A and pantothenic acids. The inventors have found that a remarkable liquid layer stabilizing effect and meibum secretion-promoting effect can be obtained by using the above seeds in combination, and have completed the present invention.

Accordingly, the present invention provides the following ophthalmic compositions.
1. (A) one or more selected from adrenergic α1 receptor agonists; and (B) one or more selected from hyaluron and its salts, panthenol, pantothenic acid and pantothenate, and vitamin A. Composition.
2. 2. The ophthalmic composition according to 1, wherein component (A) is one or more selected from phenylephrine and salts thereof.
3. 3. The ophthalmic composition according to 1 or 2, wherein component (B) is hyaluron or a salt thereof, and the amount thereof is 0.1 w/v % or more in the ophthalmic composition.
4. 3. The ophthalmic composition according to 1 or 2, wherein component (B) is panthenol, pantothenic acid or pantothenate, and the amount thereof is 0.05 w/v% or more in the ophthalmic composition.
5. 3. The ophthalmic composition according to 1 or 2, wherein the component (B) is vitamin A and the amount thereof is 10,000 units/100 mL or more in the ophthalmic composition.
6. 6. The ophthalmic composition according to any one of 1 to 5, which is a tear film stabilizer.
7. 6. The ophthalmic composition according to any one of 1 to 5, which is a meibum secretagogue.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an ophthalmic composition having a remarkable liquid layer stabilizing effect and a meibum secretion promoting effect.

4 is a graph showing the results of Test 1; 4 is a graph showing the results of Test 2;

The present invention will be described in detail below.
[(A) component]
Component (A) is an adrenergic α1 receptor agonist, which can be used singly or in combination of two or more. Agonists, adrenergic β1 receptor agonists, adrenergic β2 receptor agonists, and adrenergic β3 receptor agonists. Among these, α1 adrenergic receptor agonists function as vasoconstrictors. The present invention uses adrenergic α1 receptor agonists, such as phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline, methoxamine, phenylpropanolamine, etilephrine, midodrine, tramazoline, synephrine, and sirazoline. , xylometazoline and pharmaceutically acceptable salts thereof; α1 and β1 receptor agonists such as epinephrine, methylnorepinephrine, norepinephrine and their pharmaceutically acceptable salts; ephedrine, Examples include α1, β2 and β3 receptor agonists such as methylephedrine, pseudoephedrine and salts thereof (pharmaceutically acceptable salts).
Among them, phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline, epinephrine, ephedrine, methylephedrine and salts thereof are preferred, phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline and salts thereof are more preferred, and phenylephrine and salts thereof are more preferred.

Although the reason why the adrenergic α1 receptor agonist has the effect of stabilizing the tear film and promoting the meibum secretion is unknown, it can be presumed, for example, as follows. Adrenergic α1 receptor agonists generally act on smooth muscle to constrict blood vessels. As a specific example, phenylephrine acts to stabilize the tear film without increasing tear volume. From this, it is predicted that there is a meibum secretion action from the meibomian glands. Meibomian glands are a type of sebaceous gland, but unlike general sebaceous glands, they do not have smooth muscle. presumed to be involved.

The amount of component (A) is preferably 0.00005 to 20 w/v% (mass/volume %, g/100 mL, hereinafter the same, expressed in %) in the ophthalmic composition, and is preferably 0.00015 to 0.00015. 10% is more preferred.

Specifically, the following range is preferable. The amounts of these pharmaceutically acceptable salts are also as follows.
Phenylephrine is preferably 0.0025 to 20%, more preferably 0.005 to 10%. The lower limit is more preferably 0.01% or more, preferably 0.01 to 5%, 0.05 to 1%, 0.1 to 0.5%, and 0.1 to 0.2% in that order.
Methoxamine, etilephrine and midodrine are preferably 0.0025 to 20%, more preferably 0.005 to 10%, even more preferably 0.01 to 0.2%.
Epinephrine, methylnorepinephrine and norepinephrine are preferably 0.00005 to 1%, more preferably 0.00015 to 0.012%, even more preferably 0.0003 to 0.006%.
Ephedrine, methylephedrine and pseudoephedrine are preferably 0.0025 to 1%, more preferably 0.005 to 0.4%, even more preferably 0.01 to 0.2%.
Tetrahydrozoline and oxymetazoline are preferably 0.001 to 1%, more preferably 0.0025 to 0.2%, even more preferably 0.005 to 0.1%.
Naphazoline, synephrine, cirazoline, xylometazoline, phenylpropanolamine and tramazoline are preferably 0.00005 to 1%, more preferably 0.00015 to 0.1%, even more preferably 0.0003 to 0.006%.

[(B) component]
Component (B) is one or more selected from hyaluron and its salts, panthenol, pantothenic acid and pantothenate, and vitamin A, and can be used singly or in combination of two or more. Hyaluronic acid salts include sodium hyaluronate and the like. Pantothenate includes calcium pantothenate, sodium pantothenate and the like. Vitamin A includes not only vitamin A itself, but also vitamin A-containing mixtures such as vitamin A oil and vitamin A derivatives such as vitamin A fatty acid esters. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Among them, retinol palmitate, retinol acetate, and retinoic acid are preferable. Retinol palmitate esters are commercially available at 1,000,000 to 1,800,000 international units/g (hereinafter sometimes abbreviated as IU/g). Specifically, DSM Nutrition Japan Co., Ltd. retinol palmitate (1,740,000 IU/g) manufactured by Sigma-Aldrich, and retinol palmitate manufactured by Sigma-Aldrich.

The amount of the component (B) in the ophthalmic composition is preferably within the following range from the viewpoint of the effect of stabilizing the liquid layer and the effect of promoting meibum secretion.
When blending hyaluron or a salt thereof, preferably 0.01 to 1%, more preferably 0.05 to 0.5%, the lower limit is more preferably 0.1% or more, 0.1 to 0.3% Especially preferred.
When panthenol, pantothenic acid or pantothenate is blended, it is preferably 0.005 to 1%, more preferably 0.01 to 0.5 % , and the lower limit is more preferably 0.05% or more, and 0.05 to 0.1% is particularly preferred.
When vitamin A is blended, the international unit is preferably 1,000 units to 500,000 units/100 mL, more preferably 5,000 units to 100,000 units/100 mL, and the lower limit is more preferably 10,000 units/100 mL or more. 10,000 units to 50,000 units/100 mL are particularly preferred. When vitamin A is 1,740,000 units, it is preferably 0.0005 to 0.3%, more preferably 0.002 to 0.06%, still more preferably 0.005% or more, and 0.005 to 0.03% Especially preferred.

The blending mass ratio represented by (B)/(A) is preferably within the following range. Although the above ratio is a w/v% ratio, it has the same value as the mass ratio.
When hyaluron or a salt thereof is added, it is preferably from 0.05 to 5, more preferably from 0.1 to 3, and even more preferably from 0.2 to 2.
When panthenol, pantothenic acid or pantothenate is added, it is preferably from 0.005 to 5, more preferably from 0.01 to 3, and even more preferably from 0.05 to 2.
When vitamin A is blended, it is preferably 0.005 to 2, more preferably 0.01 to 1, even more preferably 0.05 to 0.6.

[Other ingredients]
The ophthalmic composition of the present invention may contain appropriate amounts of other ingredients as long as the effects of the present invention are not impaired. Other ingredients include water, oily ingredients, surfactants, preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, cooling agents, polyhydric alcohols, thickening agents, (A ) component, drugs other than the (B) component, and the like. These components can be blended singly or in combination of two or more. The blending amount of the components shown below is a preferable range when blending. The amount of water to be blended can be the balance of the composition.

Oily ingredients include, for example, liquid paraffin, castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglycerides, white petrolatum, mixed tocopherol, lanolin and the like. The blending amount of the oil component in the ophthalmic composition is preferably 0.001 to 1.0%, more preferably 0.001 to 0.5%, even more preferably 0.001 to 0.25%. .

Examples of surfactants 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 with different average number of added 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 from 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. be done. Among them, 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 mole numbers of ethylene oxide added are known. The average number of added moles of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but is exemplified from 3 to 60 moles. Specifically, polyoxyethylene castor oil 3 (the numerical value is the average number of added moles of ethylene oxide, the same shall apply hereinafter), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60 and the like.

Polyoxyethylene sorbitan fatty acid esters (POE sorbitan fatty acid esters) include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), and polyoxyethylene monostearate. (20) Sorbitan (polysorbate 60), polyoxyethylene tristearate (20) sorbitan (polysorbate 65), polyoxyethylene monooleate (20) sorbitan (polysorbate 80). Among them, polyoxyethylene (20) sorbitan monooleate (polysorbate 80) is preferred.

Polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is not particularly limited, and those listed in the Japanese Pharmaceutical Excipients Standards 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. Block copolymers or random polymers may be used. Specifically, polyoxyethylene (200) polyoxypropylene (70) glycol: Lutrol F127 (manufactured by BASF), Unilube 70DP-950B (manufactured by NOF Corporation), 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 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 ( NOF Co., Ltd.), polyoxyethylene (20) polyoxypropylene (20) glycol: Pluronic L-44, Tetronic (manufactured by BASF) and the like. Among them, polyoxyethylene (200) polyoxypropylene (70) glycol is preferred.

Examples of the polyethylene glycol fatty acid ester include polyethylene glycol-25 stearate, polyethylene glycol-40 stearate, etc. Among them, polyethylene glycol-40 stearate is preferred.

When a surfactant is blended, the blending amount in the ophthalmic composition is preferably 0.01 to 2.0%, more preferably 0.05 to 1.5%, and further 0.1 to 1.2%. preferable.

Examples of antiseptics include thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconate, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzalkonium chloride, etc. quaternary ammonium salts, sorbic acid or salts thereof, and the like. When a preservative is added, the amount in the ophthalmic composition is preferably 0.0001 to 0.5%, preferably 0.1% or less, more preferably 0.01% or less, and 0.001% or less. Especially preferred.

Sugars include, for example, glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. These may be d-, l-, or dl-isomers. When a saccharide is blended, the blending amount 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 buffering agents 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 a buffering agent is added, the amount is preferably 0.001 to 5.0%, more preferably 0.001 to 2%, and even more preferably 0.001 to 1% in the ophthalmic composition.

Examples of pH adjusters include inorganic acids and inorganic alkaline agents. For example, inorganic acids include (dilute) hydrochloric acid. Examples of inorganic alkaline agents include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. The pH of the ophthalmic composition is preferably 3.5-8.0, more preferably 5.5-8.0. The pH is measured at 25° C. using a pH meter (HM-25R, Toa DKK Co., Ltd.).

Examples of isotonizing 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 and the like. mentioned. From the viewpoint of further improving various symptoms caused by destabilization of the lacrimal lipid layer, it is preferable to blend sodium chloride or potassium chloride to make 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).

Stabilizers include, for example, sodium edetate, sodium edetate hydrate, cyclodextrin, sulfites, dibutylhydroxytoluene and the like. When a stabilizer is blended, the blending amount 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.

Cooling agents include, for example, menthol, camphor, borneol, geraniol, cineol, linalool and the like. Any of d-, l-, or dl-forms can be used. When the cooling agent is blended, the blending amount is preferably 0.0001 to 0.2% in the ophthalmic composition.

Polyhydric alcohols include, for example, 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%, even more preferably 0.001 to 0.1% in the ophthalmic composition.

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

Drugs (active pharmaceutical ingredients) other than components (A) and (B) include, for example, antiphlogistic/astringent agents (e.g., epsilon aminocaproic acid, neostigmine methyl sulfate, allantoin, berberine chloride hydrate, berberine sulfate, salt hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), antihistamines (e.g., chlorpheniramine maleate, diphenhydramine hydrochloride, etc.), water-soluble vitamins (flavin adenine Dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, etc.), fat-soluble vitamins (tocopherol acetate, etc.), amino acids (e.g., potassium L-aspartate, magnesium L-aspartate, potassium/magnesium L-aspartate (equal mixture) ), aminoethylsulfonic acid, etc.), sulfa drugs, and the like. When a drug is blended, the amount of the drug to be blended can be selected to be an effective and appropriate amount of each drug. , 0.001 to 0.1% is more preferred.

[Production method]
Although the method for producing the ophthalmic composition of the present invention is not particularly limited, it can be obtained, for example, by dissolving the aqueous components in purified water, adjusting the pH, and adjusting the total volume with purified water. The mixing method may be a general method, and it is appropriately performed using a pulsator, propeller blades, paddle blades, turbine blades, etc., but the number of revolutions is not particularly limited, and it is preferable to set it to the extent that it does not foam violently. The mixing temperature of each liquid is not particularly limited, but is specifically selected appropriately 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 application to the eyes, and the viscosity at 20° C. is preferably 20 mPa·s or less, more preferably 10 mPa·s, from the viewpoint of facilitating mixing with lacrimal fluid. The following is more preferable, 5 mPa·s or less is more preferable, and 2 mPa·s or less is particularly preferable. The viscosity is measured using a cone-plate viscometer (DV2T, Eiko Seiki Co., Ltd.). Although the lower limit is not particularly limited, it may be 1 mPa·s.

The ophthalmic composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye washes and the like. It can be suitably used as eye drops such as eye drops for human use. The contact lenses are not particularly limited, and include hard contact lenses, soft contact lenses, more specifically silicon hydrogel soft contact lenses, O ₂ hard contact lenses, color contact lenses, and the like. It has been reported that contact lenses affect morphological changes in meibomian glands and contribute to dry eye, and are particularly suitable as eye drops for contact lenses.

When the ophthalmic composition is used as eye drops or eye drops for contact lenses, it is preferable to apply 1 to 3 drops of 10 to 100 μL each time, preferably 1 to 6 times a day, and 10 to 50 μL each time. More preferably 1 to 3 drops, 1 to 6 times a day, more preferably 1 to 3 drops of 10 to 30 μL each time, 1 to 6 times a day. When used as an eye wash, it is preferable to wash the eyes 3 to 6 times a day, 3 to 6 mL each time.

Alternatively, after the obtained ophthalmic composition is filled in a resin container, it 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. After the composition is filled in a resin container, it may be sealed with a package together with an oxygen scavenger.

<Tear Film Stabilizer>
The ophthalmic composition of the present invention has a tear film stabilizing effect and is suitable as a tear film stabilizing agent. The tear film stabilizing effect can be measured, for example, by NI (Non-invasive) BUT (non-invasive tear film break-up time). Specifically, it is the method of the below-mentioned Example.

If the tear film stabilizing effect is obtained, it can be suitably used as a dry eye prophylactic or therapeutic agent. Dry eye is defined as "a disease or condition in which tear film stability is compromised by a variety of factors, resulting in ocular discomfort and visual dysfunction, and may be associated with ocular surface impairment." The diagnostic criteria are two items: subjective symptoms and fluorescein BUT (tear breakup time) of 5 seconds or less. Fluorescein is generally used to measure BUT, but it is necessary to administer a staining reagent into the eye, which may cause a slight change in the amount of tear fluid and the possibility that the staining reagent will stick to the face or clothes. There is also a widely known method for non-invasively examining the time to breakdown of the tear film (non-invasive breakup time: NIBUT). NIBUT is generally considered to be longer than fluorescein BUT.

In particular, adrenergic α1 receptor agonists show remarkable effects on BUT truncated dry eye. Shortened BUT dry eye is a condition in which tear secretion and keratoconjunctival epithelium are almost normal, but shortened BUT is detected, which causes eye fatigue, thirst, and discomfort when wearing contact lenses. It is dry eye that causes symptoms such as blurred vision, foreign body sensation, eye pain, dazzling eyes, heavy eyes, eye discomfort, eye discharge, and lacrimation. The tear film stabilizer of the present invention may or may not be accompanied by an increase in the amount of tear secretion, and even without an increase in the amount of tear secretion, it is possible to exhibit a remarkable dry eye preventive or therapeutic effect. 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.
Hypolacrimation, age-related dry eye, oliguria, dry eye, Sjögren's syndrome, keratoconjunctivitis sicca, Stevens-Johnson syndrome, ocular pemphigoid, blepharitis, insufficiency of eye closure, sensory paralysis, allergic conjunctivitis 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 caused by dry eye, thirst, eye fatigue, discomfort while wearing contact lenses, blurred vision, lid wiper epitheliopathy, keratoconjunctival epithelial disorder, corneal epithelial detachment, cornea A disease or condition selected from epithelial erosions, corneal ulcers and eye infections.

Furthermore, diseases or symptoms caused by destabilization of the tear film include the following symptoms, and the tear film stabilizer of the present invention is preferably 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 discharge and tearing.

<Meibum secretagogue>
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 glands, and promotion of meibum secretion increases the lacrimal lipid layer. In the present invention, the meibum secretagogue effect measures the thickness of the tear lipid layer. Specifically, it is the method of the below-mentioned Example.

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

Diseases or symptoms caused by inhibition of meibum secretion from the meibomian gland include meibomian gland dysfunction, stye (hordeolum, chalazion), etc., in addition to the above-mentioned dry eye.
Meibomian gland dysfunction (MGD) is defined as tear and ocular surface abnormalities caused by impaired secretion of the meibomian glands. Diagnosis is based on subjective symptoms, abnormal findings around meibomian gland orifices, and meibomian gland obstruction findings. Subjective symptoms of MGD patients are diverse, and they complain of foreign body sensation, dryness, eye fatigue, burning sensation, and the like. In order to improve meibomian gland blockage, treatments include hyperthermia and expression by applying physical force. . In recent years, a Lipiview/Lipiflow system, a system that evaluates the lacrimal lipid layer with an interference image and treats the eyelid from the inside with heat and massage effects, has also been developed, and its therapeutic effect in the future has attracted attention. However, since these methods are all treatments in medical institutions, a simple treatment method has been eagerly awaited.

Stye and chalazion, commonly called stye, are diseases or conditions that occur in the meibomian glands. Stye is an acute suppurative inflammation caused by bacterial infection. Treatment includes drug therapy and surgical therapy. For pharmacotherapy, antibacterial agents are administered when self-destruction and drainage of pus points are observed. In surgical therapy, if the pus point is not in the superficial layer and does not self-destruct or drain, puncture/incision is performed using an injection needle or the like to promote pus drainage. In other words, treatment requires drainage from the meibomian glands, but until now, the only options were to wait until the pus drains spontaneously or to undergo invasive forced drainage. Chalazion is said to be a foreign body reaction to lipids and is not an infectious disease. Surgery is the basic treatment. Although hordeolum and chalazion require drainage of pus and lipids from the meibomian glands, there has been no treatment other than surgery.

The meibum secretagogue of the present invention can be suitably used as a prophylactic or therapeutic agent for symptoms similar to those of the tear film stabilizer.
Furthermore, the meibum secretagogue of the present invention can prevent or treat MGD, dry eye, hordeolum and chalazion (stye) by enhancing meibum secretion.

EXAMPLES 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, "%" in composition indicates w/v%, and ratio indicates mass ratio (same value as w/v% ratio).

[Examples, Comparative Examples]
Each component shown in Table 1 below was added to a predetermined amount of purified water and dissolved, and then thoroughly stirred. When the component (B) was retinol palmitate, it was mixed with a surfactant and stirred well, then added to purified water and stirred well. After that, purified water was added so that the volume became 100 mL. Table 1 shows the pH of the obtained composition at 25°C. The viscosity of the composition at 25°C was in the range of 1 to 20 mPa·s. The obtained compositions were evaluated as follows.

<Test 1: Tear film stability: NI (Non-invasive) BUT (non-invasive tear film breakup time)>
The samples were instilled into the eyes for one week each, and changes in NIBUT before and after instillation were compared. Eye instillation was carried out by 2 persons (4 eyes), 1 drop (50 μL) at a time, 6 times a day.
DR-1 (manufactured by Kowa) was used for evaluation of NIBUT. Measurements were taken after 5 minutes or more from the last instillation.
Using DR-1, observe the tear interference image, measure the time (seconds) until the tear film is destroyed (uniform gray or white interference image disappears) after eyelid opening, An average value was obtained.
Wilcoxon test was performed for comparison between groups. The results are shown in Tables 2 to 4, and the difference before and after instillation is shown in FIG.

<Test 2: Promotion of Meibum Secretion: Tear Oil Layer Thickness>
The samples were instilled into the eyes for one week each, and changes in tear lipid layer thickness before and after instillation were compared. Eye instillation was carried out by 2 persons (4 eyes), 1 drop (50 μL) at a time, 6 times a day.
Lipiview (manufactured by Tearscience) was used to evaluate the thickness of the tear lipid layer. After 5 minutes or more from the final instillation, measurement was performed according to the following procedure.
Using Lipiview, the tear lipid layer thickness was measured and the average value was obtained.
Wilcoxon test was performed for comparison between groups. The results are shown in Tables 5 to 7, and the difference before and after instillation is shown in FIG.

When comparing the difference before and after instillation, in both the tear film stability test and the meibum secretion promotion test, (A) phenylephrine hydrochloride, (B) sodium hyaluronate, (B) retinol palmitate, (B) bread Synergy by (A) phenylephrine hydrochloride + (B) sodium hyaluronate, (A) phenylephrine hydrochloride + (B) retinol palmitate, (A) phenylephrine hydrochloride + (B) panthenol compared to tenol The effect was confirmed.

The raw materials used in the above examples are shown below. In addition, unless otherwise specified, the amount of each component in the table is the amount in terms of pure content.
Phenylephrine Hydrochloride: Phenylephrine Hydrochloride (Crystal) Iwaki Pharmaceutical Co., Ltd.
Sodium hyaluronate: Biosodium hyaluronate (SZE) Shiseido Co., Ltd. Panthenol: Panthenol DSM Co., Ltd.
Retinol palmitate: Retinol palmitate [1,740,000 I.V. U.S.A. / g] DSM Corporation

Claims (8)

An ophthalmic composition containing (A) one or more selected from phenylephrine and salts thereof and (B) one or more selected from hyaluron and salts thereof, panthenol, pantothenic acid and pantothenate, and vitamin A . An ophthalmic composition containing (A) one or more selected from phenylephrine and salts thereof and (B) one or more selected from hyaluron and salts thereof, panthenol, pantothenic acid and pantothenate, and vitamin A (However, vitamin B ₂ Excludes ophthalmic compositions containing ). 3. The ophthalmic composition according to claim 1 or 2, wherein component (B) is hyaluron or a salt thereof, and the content thereof is 0.1 w/v% or more in the ophthalmic composition. 3. The ophthalmic composition according to claim 1 or 2, wherein component (B) is panthenol, pantothenic acid or pantothenate, and the content thereof is 0.05 w/v% or more in the ophthalmic composition. 3. The ophthalmic composition according to claim 1 or 2, wherein the component (B) is vitamin A, and the content thereof is 10,000 units/100 mL or more in the ophthalmic composition. The ophthalmic composition according to any one of claims 1 to 5, which is a tear film stabilizer. The ophthalmic composition according to any one of claims 1 to 5, which is a meibum secretagogue. The ophthalmic composition according to any one of claims 1 to 5, which is used for preventing or treating BUT-shortened dry eye.

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