JP7404658B2 - Tear film stabilizer and meibum secretion promoter - Google Patents

Description

The present invention relates to a tear film stabilizer and a meibum secretion promoter.

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 America. Furthermore, the number of people with complaints due to dry eye risk factors such as aging, wearing contact lenses, and long hours of computer work is expected to continue to increase in the future.

Traditionally, a decrease in tear secretion has been considered an important factor in dry eye, but in recent years this view has been changing. In fact, in the Japanese dry eye diagnostic criteria revised in 2016, the item regarding tear secretion using the Schirmer test, which had been used up until now, was deleted. This is because it has been recognized that there are cases of dry eye even when the amount of lacrimal secretion determined by the Schirmer test is normal. In other words, it is thought that, except in severe cases such as Sjögren's syndrome, where tear secretion is reduced due to lacrimal gland secretion dysfunction, there is a high possibility that increased tear secretion and improvement in dry eye will not be linked ( (See Non-Patent Document 1).

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

Conventionally, artificial tears containing inorganic salts such as sodium chloride and potassium chloride have been widely used in medical and over-the-counter medicine treatments for dry eye, but these are intended to replenish tear fluid. It was only a temporary effect. In recent years, eye drops containing ingredients effective against dry eyes, such as sodium hyaluronate, diquafosol sodium, 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 eye discharge and eye pain, and rebamipide causes taste disturbance as side effects specific to these ingredients. It has been reported that this phenomenon occurs (see Patent Documents 1 and 2).
As mentioned above, there are only a few types of active ingredients for dry eye, and side effects can be a problem, so the development of a new dry eye treatment has been eagerly awaited.

Patent No. 6267003 Patent No. 6060168 “Read to understand! Understand to change! Dry eye diagnosis”, October 1, 2017, p2-7

The present invention was made in view of the above circumstances, and provides a tear film stabilizer and a meibum secretion promoter that have excellent tear film stabilizing effects and meibum secretion promoting effects and are useful as dry eye preventive or therapeutic agents. The purpose is to

As a result of intensive studies to achieve the above object, the present inventors found that adrenergic α1 receptor agonists have excellent tear film stabilizing effects and meibum secretion promoting effects, and are useful as dry eye preventive or therapeutic agents. This knowledge led to the present invention.

Therefore, the present invention provides the following agent.
1. A tear film stabilizer containing an adrenergic α1 receptor agonist.
2. A meibum secretagogue containing an adrenergic α1 receptor agonist.
3. The agent according to 1 or 2, which is a dry eye preventive or therapeutic agent.
4. 3. The agent according to 3, which is a BUT-shortening dry eye preventive or therapeutic agent.
5. Eye fatigue, dry eyes, discomfort when wearing contact lenses and blurred vision, foreign body sensation, eye pain, dazzling eyes, heavy eyes, eye discomfort due to tear film instability 2. The agent according to 1, which is a preventive or therapeutic agent for a disease or symptom selected from , eye discharge, and lacrimation.
6. Eye fatigue, dry eyes, discomfort when wearing contact lenses, blurred vision, foreign body sensation, eye pain, dazzling eyes, heavy eyes, eye discomfort, eye discharge due to decreased meibum secretion. 2. The agent according to 2, which is a preventive or therapeutic agent for a disease or symptom selected from , epiphora, stye, and chalazion.
7. 7. The agent according to any one of 1 to 6, which is an eye drop.
8. The adrenergic α1 receptor agonist is a group consisting of phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline, methoxamine, phenylpropanolamine, etilefrine, midodrine, tramazoline, synephrine, cilazoline, xylometazoline, and pharmacologically acceptable salts thereof. 8. The agent according to any one of 1 to 7, which is one or more selected from.

According to the present invention, it is possible to provide a tear film stabilizer and a meibum secretion promoter that have excellent tear film stabilizing effects and meibum secretion promoting effects and are useful as dry eye preventive or therapeutic agents.

3 is a graph showing the results of Test Example 1. 3 is a graph showing the results of Test Example 1. 3 is a graph showing the results of Test Example 1. 3 is a graph showing the results of Test Example 1. 3 is a graph showing the results of Test Example 2. 3 is a graph showing the results of Test Example 3. 3 is a graph showing the results of Test Example 3. 3 is a graph showing the results of Test Example 3. 3 is a graph showing the results of Test Example 3.

The present invention will be explained in detail below.
[Adrenergic α1 receptor agonist]
Examples of adrenergic receptor agonists include adrenergic α1 receptor agonists, adrenergic α2 receptor agonists, adrenergic β1 receptor agonists, adrenergic β2 receptor agonists, and adrenergic β3 receptor agonists. Among these, some function as vasoconstrictors. The present invention uses an adrenergic α1 receptor agonist. As the adrenergic α1 receptor agonist, selections include phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline, methoxamine, phenylpropanolamine, etilefrine, midodrine, tramazoline, synephrine, cilazoline, xylometazoline, and pharmaceutically acceptable salts thereof. α1 receptor agonists; α1 and β1 receptor agonists such as epinephrine, methylnorepinephrine, norepinephrine and pharmaceutically acceptable salts thereof; ephedrine, methylephedrine, pseudoephedrine and pharmaceutically acceptable salts thereof α1, β2 and β3 receptor agonists such as agonists and the like. Among these, selective α1 receptor agonists are preferred, and phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline, and pharmaceutically acceptable salts thereof are more preferred.

The reason why adrenergic α1 receptor agonists have a tear film stabilizing effect and a meibum secretion promoting effect is unknown, but it can be speculated as follows, for example. Adrenergic α1 receptor agonists generally act on smooth muscle and constrict blood vessels. As a specific example, phenylephrine has the effect of stabilizing the tear film without increasing tear volume. From this, it is predicted that meibum secretes from the meibomian glands. Meibomian glands are a type of sebaceous gland, but unlike general sebaceous glands, they do not have smooth muscle, so they are not thought to be directly affected by vasoconstrictors, but they may be affected indirectly, such as by acting on Muller's muscle around the meibomian glands. It is presumed that they are involved.

The dosage of the adrenergic α1 receptor agonist in the agent of the present invention is 0.00005 to 20 w/v% (mass/volume%, g/v%) as the amount in the ophthalmic composition. 100 mL (the same applies hereinafter) is preferable, and 0.00015 to 10 w/v% is more preferable. As for such dosage, for example, 1 to 3 drops of 10 to 100 μL of the above-mentioned ophthalmic composition may be used 1 to 6 times per day.

Specifically, the following ranges are preferable. In addition, the amounts of components in these pharmaceutically acceptable salts are also as follows.
Phenylephrine, methoxamine, etilefrine, and midodrine are preferably 0.0025 to 20 w/v%, more preferably 0.003 to 10 w/v%, even more preferably 0.005 to 10 w/v%, and 0.01 to 0. 2 w/v% is particularly preferred, and 0.05-0.2 w/v% is most preferred.
Epinephrine, methylnorepinephrine, and norepinephrine are preferably 0.00005 to 1 w/v%, more preferably 0.00015 to 0.012 w/v%, and even more preferably 0.0003 to 0.006 w/v%.
Ephedrine, methylephedrine, and pseudoephedrine are preferably 0.0025 to 1 w/v%, more preferably 0.005 to 0.4 w/v%, and even more preferably 0.01 to 0.2 w/v%.
Tetrahydrozoline and oxymetazoline are preferably 0.001 to 1 w/v%, more preferably 0.0025 to 0.2 w/v%, even more preferably 0.003 to 0.1 w/v%, and 0.005 to 0.1 w/v% is particularly preferred.
Naphazoline, synephrine, cilazoline, xylometazoline, phenylpropanolamine, and tramazoline are preferably 0.00005 to 1 w/v%, more preferably 0.00015 to 0.1 w/v%, and 0.0003 to 0.006 w/v % is more preferable, and 0.001 to 0.005 w/v% is particularly preferable.

<Tear film stabilizer>
The present invention is a tear film stabilizer containing an adrenergic α1 receptor agonist, preferably a tear film stabilizer containing an adrenergic α1 receptor agonist as an active ingredient.
In the present invention, the tear film stabilizing effect is measured by NI (Non-invasive) BUT (Non-invasive tear film breakdown time). Specifically, this is the method of the embodiment described later.

If a tear film stabilizing effect is obtained, it can be suitably 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 decreases due to various factors, causing ocular discomfort and abnormal visual function, and may be accompanied by damage to the ocular surface.'' The diagnostic criteria are subjective symptoms and fluorescein BUT (tear film break-up time) of 5 seconds or less. BUT measurement generally uses fluorescein, but it requires administering 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 may get on your face or clothes. There is also a widely known method for non-invasively measuring the time until tear film breakdown (NIBUT). NIBUT is generally considered to be longer than fluorescein BUT.

In particular, adrenergic α1 receptor agonists show remarkable effects on BUT-shortened dry eye. BUT-shortened dry eye is a condition in which tear secretion and corneal and conjunctival epithelium are almost normal, but a shortened BUT is detected, which causes eye fatigue, dryness of the eyes, discomfort when wearing contact lenses, and Dry eye is a condition that causes symptoms such as blurred vision, a sensation of a foreign body, pain in the eyes, dizziness, heaviness of the eyes, discomfort in the eyes, discharge from the eyes, and lacrimation. 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 preventive or therapeutic effects even 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.
aqueous hypolacrimia, age-related dry eye, oliguria, xerophthalmia, Sjögren's syndrome, keratoconjunctivitis sicca, Stevens-Johnson syndrome, ocular pemphigoid, blepharitis, ocular closure insufficiency, sensory nerve palsy, allergic conjunctivitis A disease or symptom selected from dry eye related to dry eye, dry eye after viral conjunctivitis, dry eye after cataract surgery, dry eye related to VDT work, and dry eye related to contact lens wear,
Eye fatigue caused by dry eyes, dry eyes, eye fatigue, discomfort when wearing contact lenses, blurred vision, lid wiper epitheliopathy, corneal and conjunctival epithelial disorders, corneal epithelial abrasion, cornea A disease or symptom selected from epithelial erosion, corneal ulcer, and eye infection.

Furthermore, diseases or symptoms caused by destabilization of the tear film include the following symptoms, and the tear film stabilizing agent 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 and blurred vision when wearing contact lenses, foreign body sensation, eye pain, dazzling eyes, heavy eyes, eye discomfort, eye discharge and tearing.

<Meibum secretion enhancer>
The present invention is a meibum secretion promoter containing an adrenergic α1 receptor agonist, preferably a meibum secretion promoter containing an adrenergic α1 receptor agonist as an active ingredient.
Meibum is a component secreted from the meibomian glands, and the promotion of meibum secretion increases the lachrymal oil layer. The meibum secretion promoting effect is measured by measuring the thickness of the tear oil layer. Specifically, this is the method of the embodiment described later.

Meibomian glands located within the eyelids secrete lipids and are important as a source of the tear oil layer. This tear oil layer is important for stabilizing the tear film as a film, such as by lowering the surface tension of the tear fluid and preventing tear evaporation. However, there are few reports regarding the secretion mechanism of the meibomian glands, and it has not been fully elucidated.

Diseases or symptoms caused by inhibition of meibum secretion from the meibomian glands include, in addition to the above-mentioned dry eye, meibomian gland dysfunction, styes (stye, chalazion), and the like.
Meibomian gland dysfunction (MGD) is defined as tear and ocular surface abnormalities caused by impaired meibomian gland secretion. Diagnosis is based on subjective symptoms, abnormal findings around the meibomian gland opening, and findings of meibomian gland obstruction. MGD patients have a wide variety of subjective symptoms, including a feeling of a foreign body, dryness, eye fatigue, and a burning sensation. In order to improve meibomian gland blockage, treatments include heat therapy, extrusion by applying physical force, and methods used overseas to release the blockage directly with a thin wire-like instrument on the meibomian gland. . In addition, in recent years, the Lipiview/Lipiflow system, a system that evaluates the tear oil layer using interference images and treats the eyelids from the inside with heat and massage effects, has been developed, and its future therapeutic effects are attracting attention. However, all of these methods require treatment within medical institutions, so a simple treatment method has been awaited.

Stye and chalazion, commonly referred to as styes, are diseases or conditions that occur in the meibomian glands. Stye is an acute purulent inflammation caused by bacterial infection. Treatment includes drug therapy and surgical therapy. For drug therapy, antibiotics are administered if self-destruction or drainage of the pus is observed. For surgical treatment, if the pus point is not in a superficial layer and does not self-destruct or drain, puncture and incision is performed using a needle, etc. to encourage drainage. In other words, treatment requires drainage of the meibomian glands, but until now, the only options were to wait until the glands were drained naturally or to undergo invasive forced drainage. Chalazion is said to be a foreign body reaction to lipids and is not an infectious disease. The basic treatment is surgery. In other words, although it is necessary to drain pus and lipids from the meibomian glands for stye and chalazion, there has been no treatment other than surgery.

The meibum secretion promoter of the present invention can be suitably used as a preventive or therapeutic agent for the same symptoms as the tear film stabilizer described above.
Furthermore, the meibum secretion promoter of the present invention improves meibum secretion, thereby making it possible to prevent or treat MGD, dry eye, stye, and chalazion (sty).

[Other ingredients]
The agent (composition) of the present invention may contain appropriate amounts of other components 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, viscosity agents, and adrenaline α1. Examples include drugs other than receptor agonists. These components can be blended singly or in an appropriate combination of two or more. The blending amounts of the components shown below are the preferred ranges when blending. Note that the amount of water added can be the remainder of the composition.

Examples of oily components include liquid paraffin, castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium chain fatty acid triglyceride, white petrolatum, mixed tocopherol, lanolin, and the like. When blending an oil component, the blending amount is preferably 0.001 to 1.0 w/v%, more preferably 0.001 to 0.5 w/v%, and 0.001 to 0.25 w/v% in the composition. % is more preferred.

Examples of the surfactant include the following nonionic surfactants.
Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerizing ethylene oxide to hydrogenated castor oil, and several types are known that differ in the average number of added moles of ethylene oxide. ing. The average number of moles of ethylene oxide added to polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified as 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (EO average added mole number 5), polyoxyethylene hydrogenated castor oil 10 (EO average added mole number 10), polyoxyethylene hydrogenated castor oil 20 (EO average added mole number 20) ), polyoxyethylene hydrogenated castor oil 30 (EO average added mole number 30), polyoxyethylene hydrogenated castor oil 40 (EO average added mole number 40), polyoxyethylene hydrogenated castor oil 50 (EO average added mole number 50), Polyoxyethylene hydrogenated castor oil 60 (EO average added mole number 60), polyoxyethylene hydrogenated castor oil 80 (EO average added mole number 80), polyoxyethylene hydrogenated castor oil 100 (EO average added mole number 100), etc. It will be done.

Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerizing ethylene oxide to castor oil, and several types are known that differ in the average number of added moles of ethylene oxide. The average number of moles of ethylene oxide added to polyoxyethylene castor oil is not particularly limited, but is exemplified by 3 to 60 moles. Specifically, polyoxyethylene castor oil 3 (the numerical value is the average number of added moles of ethylene oxide, the same applies 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 ester (POE sorbitan fatty acid ester), represented by polysorbate 80 (polyoxyethylene (20) sorbitan oleate ester) (the number in parentheses is the average number of added moles of ethylene oxide, the same applies hereinafter), polyoxyethylene sorbitan fatty acid ester Examples include poloxamers typified by ethylene-polyoxypropylene block copolymer (POEPOP glycol), polyethylene glycol monostearate typified by polyethylene glycol monostearate (10), and the like.

When blending a surfactant, the blending amount is preferably 0.01 to 2.0 w/v% in the composition, more preferably 0.05 to 1.5 w/v%, and 0.1 to 1.2 w/v%. v% is more preferred.

Examples of preservatives include thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconate, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzalkonium chloride, etc. as preservatives having hydrophobic parts such as alkyl chains and benzene rings. Examples include quaternary ammonium salts of. When a preservative is added, the amount thereof is preferably 0.0001 to 0.5 w/v%. However, when blending, it is preferably 0.1 w/v% or less in the composition, more preferably 0.01 w/v% or less.

Examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol, and the like. In addition, these may be any of d-form, l-form, or dl-form. When blending saccharides, the blending amount is preferably 0.001 to 5.0 w/v% in the composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%. preferable.

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 blending a buffering agent, the blending amount is preferably 0.001 to 5.0 w/v% in the composition, more preferably 0.001 to 2 w/v%, and even more preferably 0.001 to 1 w/v%. .

Examples of the pH adjuster include inorganic acids and inorganic alkaline agents. For example, the inorganic acid includes (dilute) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate. The pH of the composition is preferably 3.5 to 8.0, more preferably 5.5 to 8.0. Note that pH measurement is carried out at 25° C. using a pH meter (HM-25R, Toa DKK Co., Ltd.).

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

Examples of the stabilizer include sodium edetate, sodium edetate hydrate, cyclodextrin, sulfite, and dibutylhydroxytoluene. When blending a stabilizer, the blending amount is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and 0.001 to 0.1 w/v% in the composition. is even more preferable.

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

Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. When blending polyhydric alcohol, the blending amount is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and 0.001 to 0.1 w/v% in the composition. is even more preferable.

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

Examples of drugs (active pharmaceutical ingredients) other than adrenergic α1 receptor agonists include anti-inflammatory and astringent agents (e.g., neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate) substances, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), antihistamines (such as diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleotide, etc.) sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.), fat-soluble vitamins (retinol acetate, retinol palmitate, tocopherol acetate, etc.), amino acids (e.g. potassium L-aspartate, L - magnesium aspartate, potassium/magnesium L-aspartate (mixture of equal amounts), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), sulfa drugs, etc. When blending drugs, the amount of the drug to be blended can be selected to be an effective and appropriate amount of each drug, but it is preferably 0.001 to 5 w/v%, more preferably 0.001 to 1 w/v%. Preferably, 0.001 to 0.1 w/v% is more preferable.

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

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

The agent of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye washes, etc. However, from the viewpoint of preventing or treating dry eye, eye drops, eye drops for contact lenses (eye drops for contact lens wearers), etc. It can be suitably used as an eye drop. Contact lenses include hard contact lenses, soft contact lenses, silicone hydrogel soft contact lenses, O ₂ hard contact lenses, colored contact lenses, and the like, but are not particularly limited. It has been reported that contact lenses affect the morphological changes of the meibomian glands and contribute to dry eye, and eye drops for contact lenses are particularly suitable.

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

Alternatively, after filling the obtained agent (composition) into a resin container, the container is further sealed with a packaging body, and an inert gas such as nitrogen is filled in the space formed between the container and the packaging body. Alternatively, the composition may be filled into a resin container and then sealed together with an oxygen absorber in a package.

EXAMPLES Hereinafter, the present invention will be specifically explained using test examples, but the present invention is not limited to the following examples.

[Test Example 1]
<Tear film stability: NI (Non-invasive) BUT (Non-invasive tear film breakdown time)>
A phenylephrine preparation (Example 1), an oxymetazoline preparation 1 (Example 2), and a placebo preparation (Comparative Example 1) having the compositions shown in Table 1 below were tested.

The above samples were instilled into the eyes for one week each, and changes in NIBUT before and after instillation were compared. Eye drops were administered by 3 to 5 people (3 to 10 eyes), and one drop (50 μL) was applied at a time, six times a day.
DR-1 (manufactured by Kowa) was used for NIBUT evaluation. Measurements were taken within 15 minutes after 5 minutes or more had elapsed since the final instillation.
Using DR-1, observe the tear interference image and measure the time (seconds) until the tear film is destroyed (the uniform gray or white interference image disappears) after opening the eyelids. The average value was calculated.
For comparison between groups, Wilcoxon test was performed.
The results are shown in Table 2 and the average values are shown in Figures 1 to 3.

In the phenylephrine formulation 1 eye drop group (Example 1) and the oxymetazoline formulation 1 eye drop group (Example 2), a significant prolongation of NIBUT was observed after the eye drop compared to before the eye drop. In the placebo formulation eye drop group (Comparative Example 1), no significant prolongation of NIBUT was observed after eye drop compared to before eye drop.
Phenylephrine hydrochloride and oxymetazoline hydrochloride had the effect of prolonging NIBUT, and their tear film stabilizing effect was confirmed.

The samples in Table 3 below were evaluated in the same manner as above. The eye drops were administered by 3 people (3 eyes). From the obtained average NIBUT value, the average change in NIBUT after instillation compared to before instillation was calculated using the following formula.
(formula)
Average NIBUT change (seconds) = Average NIBUT value after instillation (seconds) - Average NIBUT value before instillation (seconds)
Dunnett's test was performed to compare each formulation to the placebo formulation.
The results are shown in Table 4 and FIG.

A significant prolongation of NIBUT was observed in the phenylephrine formulation 2-eye drop group (Example 3) and the oxymetazoline formulation 2-eye drop group (Example 6) compared to the placebo formulation eye drop group. Furthermore, in the naphazoline formulation eye drop group (Example 4) and the tetrahydrozoline formulation eye drop group (Example 5), a significant prolongation of NIBUT was observed compared to the placebo formulation eye drop group, confirming the tear film stabilizing effect.

The above results revealed that adrenergic α1 receptor agonists have a tear film stabilizing effect.

[Test Example 2]
<Tear secretion amount)
Similarly to the above, phenylephrine formulation 1 (Example 1) and placebo formulation (Comparative Example 1) were instilled into the eyes for one week each, and changes in tear secretion before and after instillation were compared. The eye drops were applied to 5 people (10 eyes), and 1 drop (50 μL) was applied at a time, 6 times a day. After 5 minutes or more had elapsed since the final instillation, measurements were taken within 15 minutes according to the following procedure.
The lower eyelid was pushed down, and the entire amount of tears accumulated between the cornea and lower eyelid conjunctiva was collected by pressing a pre-weighed filter paper against the lower eyelid conjunctiva without touching the cornea. Thereafter, the weight of the filter paper was measured to determine the amount of tear fluid (mg). The collection method described above was used because contact with the cornea produces irritating secretions.
The amount of change in tear secretion before and after instillation was calculated and compared between groups.
[Formula for calculating amount of change]
Amount of change in tear secretion before and after instillation (mg) = ((Average value (mg) of (filter paper weight after tear collection after eye instillation (mg) - filter paper weight before tear collection (mg)))) - ( (Average value (mg) of filter paper weight (mg) after tear collection before instillation - filter paper weight (mg) before tear collection)))
For comparison between groups, a paired t-test was performed.
The results are shown in Table 5 and FIG.

No significant difference was observed between the phenylephrine formulation 1 eye drop group and the placebo formulation eye drop group.

The results of Test Examples 1 and 2 revealed that phenylephrine stabilizes the tear film without affecting changes in the amount of tear secretion. The five panelists who applied the eye drops felt that their dry eyes improved with the phenylephrine formulation in their eyes compared to the placebo formulation. Therefore, it was confirmed that phenylephrine can prevent or treat dry eye regardless of the amount of lacrimal secretion.

[Test Example 3]
<Meibum secretion promotion: tear oil layer thickness>
Similarly to the above, the above phenylephrine preparation 1 (Example 1), oxymetazoline preparation 1 (Example 2), and placebo preparation (Comparative Example 1) were instilled into the eyes for one week each, and the thickness of the tear oil layer before and after the instillation was changed. were compared. Eye drops were administered to 3 to 9 people (3 to 18 eyes), and one drop (50 μL) was applied at a time, six times a day.
Lipiview (manufactured by Tearscience) was used to evaluate the thickness of the tear oil layer. After 5 minutes or more had elapsed since the final instillation, measurements were taken within 15 minutes according to the following procedure.
The tear oil layer thickness was measured using Lipiview, and the average value thereof was determined.
For comparison between groups, Wilcoxon test was performed.
The results are shown in Table 6 and the average values are shown in Figures 6 to 8.

In the phenylephrine formulation 1 eye drop group (Example 1) and the oxymetazoline formulation 1 eye drop group (Example 2), a significant difference was observed in the thickness of the tear oil layer after eye drop compared to before eye drop. In the placebo formulation eye drop group, no significant difference was observed in the thickness of the tear oil layer after eye drop compared to before eye drop.
Phenylephrine hydrochloride and oxymetazoline hydrochloride have the effect of thickening the tear oil layer and were confirmed to have a meibum secretion promoting effect.

In addition, phenylephrine formulation 2 (Example 3), naphazoline formulation (Example 4), tetrahydrozoline formulation (Example 5), and oxymetazoline formulation 2 (Example 6) were evaluated in the same manner as above. The eye drops were administered by 3 people (3 eyes). From the obtained average tear oil layer thickness, the average change in tear oil layer thickness after instillation compared to before instillation was determined from the following formula.
Average change in tear oil layer thickness (nm) = Average tear oil layer thickness after instillation (nm) - Average tear oil layer thickness before eye instillation (nm)
Dunnett's test was performed to compare each formulation to the placebo formulation.
The results are shown in Table 7 and FIG. 9.

There was a significant difference in the tear oil layer thickness between the phenylephrine formulation 2 eye drop group (Example 3) and the oxymetazoline formulation 2 eye drop group (Example 6) compared to the placebo formulation eye drop group (Comparative Example 1). Admitted. Further, significant differences were also observed in the naphazoline formulation eye drop group (Example 4) and the tetrahydrozoline formulation eye drop group (Example 5) compared to the placebo formulation.
Therefore, it was confirmed that the adrenergic α1 receptor agonist has the effect of thickening the tear oil layer and has a meibum secretion promoting effect.

The above results revealed that adrenergic α1 receptor agonists have the effect of promoting meibum secretion. Therefore, it was confirmed that adrenergic α1 receptor agonists can prevent or treat MGD, dry eye, stye, and chalazion (sty).

Claims (6)

A tear film stabilizer containing one or more selected from the group consisting of oxymetazoline and pharmacologically acceptable salts thereof. A tear film stabilizer containing one or more selected from the group consisting of naphazoline, tetrahydrozoline, and pharmacologically acceptable salts thereof (provided that A) acidic mucopolysaccharide, and B) hydroxyethylcellulose, methylcellulose , hydroxypropylmethylcellulose, polyvinylpyrrolidone or polyvinyl alcohol, or carboxymethylcellulose or a salt thereof, and has a viscosity of 15 mPa·s or more and 300 mPa·s or less at 20°C. ) . A meibum secretion promoter containing one or more selected from the group consisting of phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline, and pharmacologically acceptable salts thereof. A BUT-shortening dry eye preventive or therapeutic agent containing one or more selected from the group consisting of phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline, and pharmacologically acceptable salts thereof. Eye fatigue, dry eyes, discomfort when wearing contact lenses, blurred vision, foreign body sensation, eye pain, dazzling eyes, heavy eyes, eye discomfort, eye discharge due to decreased meibum secretion. 4. The meibum secretion promoter according to claim 3 , which is a preventive or therapeutic agent for a disease or symptom selected from , epiphora, stye, and chalazion. The agent according to any one of claims 1 to 5 , which is an eye drop.

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