JP2019048799A - Ophthalmologic composition and tear fluid oil layer stabilizer - Google Patents

Abstract

To provide ophthalmologic compositions having a high transmissivity, containing cholesterol, and having tear fluid oil layer stabilizing effect, and to provide tear fluid oil layer stabilizer containing cholesterol as an active ingredient.SOLUTION: Provided is an ophthalmologic composition containing one or more nonionic surfactants selected from (A) cholesterol, (B-1) polyoxyethylene castor oil, and (B-2) polyoxyethylene sorbitan fatty acid ester.SELECTED DRAWING: None

Description

  The present invention relates to an ophthalmic composition containing cholesterol and a tear oil phase stabilizer.

  Cholesterol is a type of sterol, is a constituent of biological membranes for animal cells, and is an important compound involved in various life phenomena. In addition, they are used as raw materials for cosmetics, medicines, etc. and liquid crystals.

Japanese Patent Publication No. 2003-517439

  The tear fluid oil layer is a layer composed of oil components such as wax esters, cholesterol esters, cholesterol, and phospholipids that are present on the outermost surface of tears. The main role of this tear fluid oil layer is to prevent evaporation of tear water. In order to play this role, the tear oil layer needs to be stable. The inventors have found that cholesterol contributes to the stabilization of the tear fluid oil layer.

However, as a problem of an ophthalmic composition containing cholesterol, it has been found that solubilization of cholesterol is difficult, and it becomes a cloudy and unstable preparation. In the case of a turbid and unstable preparation, (1) the feeling of use is bad (white in front of eyes, blurred), (2) poor manufacturability, (3) unevenness of ingredients occurs during use, tear fluid There are problems, such as difficulty in exhibiting the effect of oil reservoir stabilization.
From the above, the present invention provides an ophthalmic composition having high permeability, containing cholesterol, and having a tear oil layer stabilizing effect, and a tear oil layer stabilizer containing cholesterol as an active ingredient. With the goal.

  The inventors of the present invention conducted intensive studies to solve the above problems, and as a result of (A) an ophthalmic composition containing cholesterol, (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene sorbitan fatty acid The inventors have found that the transmittance of an ophthalmic composition can be improved by blending one or more nonionic surfactants selected from esters, and the present invention has been achieved.

  Moreover, it is known that the aqueous composition which mix | blended surfactant is easy to foam, and there existed a case where a foam | bubble generate | occur | produced by giving vibration or an impact at the time of manufacture or market distribution. It is better for the product to have less bubbling. In addition, when confirming the dissolution state at the time of production, if bubbles are generated and the bubbles disappear slowly, it is difficult to distinguish between the component or foreign matter and the bubbles, so it is long in the process of dissolution confirmation, foreign matter inspection, etc. It takes time, and the manufacturing can not be performed efficiently. On the other hand, the foaming of the ophthalmic composition was suppressed by blending the polyoxyethylene castor oil, and it was found that the defoaming property was good.

  Furthermore, after instillation, it is easy to transfer cholesterol to the tear fluid oil layer by dilution with tear fluid, and in order to enhance the tear fluid oil layer stabilization effect, the blending mass ratio of the (B-1) component and the nonionic surfactant It was found that it is preferable to set (B-1) / nonionic surfactant ≧ 0.9.

Accordingly, the present invention provides the following invention.
[1]. An ophthalmic composition comprising one or more nonionic surfactants selected from (A) cholesterol, (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene sorbitan fatty acid ester.
[2]. The ophthalmic composition according to [1], wherein the blending mass ratio of (A), (B-1) and (B-2) is ((B-1) + (B-2)) / (A) ≧ 10 object.
[3]. (B-1) The ophthalmic composition according to [1] or [2], which contains polyoxyethylene castor oil as an essential component.
[4]. The ophthalmic composition according to [3], wherein a blending mass ratio of the component (B-1) to the nonionic surfactant is (B-1) / nonionic surfactant ≧ 0.9.
[5]. The ophthalmic composition in any one of [1]-[4] whose transmittance | permeability of wavelength 600nm is 80 to 100%.
[6]. A lacrimal fluid oil layer stabilizer comprising one or more nonionic surfactants selected from (A) cholesterol, (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene sorbitan fatty acid ester.

  According to the present invention, it is possible to provide an ophthalmic composition having a high permeability of an ophthalmic composition, containing cholesterol, and having a tear oil layer stabilizing effect, and a tear oil layer stabilizer.

Hereinafter, the present invention will be described in detail.
[(A) component]
(A) Cholesterol has a tear oil layer stabilizing effect, but it causes a problem of clouding of an ophthalmic composition (hereinafter sometimes referred to as a composition). 0.001-0.5 W / V% (mass / volume%, g / 100 mL) in a composition is preferable, and, as for the compounding quantity of (A) component, 0.01-0.2 W / V% is more preferable. By setting it as 0.001 W / V% or more, a tear oil layer stabilization effect is high, and when it is 0.5 W / V% or less, a composition with a higher transmittance | permeability can be obtained.

[(B) component]
The component (B) is at least one nonionic surfactant selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene sorbitan fatty acid ester. These can be used singly or in appropriate combination of two or more. By using these specific nonionic surfactants, it is possible to obtain the effect that the transmittance of the ophthalmic composition, which is the object of the present invention, is high, contains cholesterol, and has the effect of stabilizing the tear oil layer. .

(B-1) Polyoxyethylene castor oil (POE castor oil)
Polyoxyethylene castor oil is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and several types different in the average addition mole number of ethylene oxide are known. The average added mole number of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles are exemplified. Specifically, polyoxyethylene castor oil 3 (EO average addition mole number 3), polyoxyethylene castor oil 10 (EO average addition mole number 10), polyoxyethylene castor oil 20 (EO average addition mole number 20), poly Oxyethylene castor oil 35 (EO average added mole number 35), polyoxyethylene castor oil 40 (EO average added mole number 40), polyoxyethylene castor oil 50 (EO average added mole number 50), polyoxyethylene castor oil 60 (EO average added mole number 60) and the like. Among them, it is preferable to use polyoxyethylene castor oil 35 from the viewpoint of feeling in use.

  0.01-25 W / V% in a composition is preferable, as for the compounding quantity of (B-1), 0.015-15 W / V% is more preferable, 0.2-10 W / V% is more preferable. By setting it as 0.01 W / V% or more, a thing with a higher transmittance | permeability can be obtained, and decelerating property can be made higher by setting it as 25 W / V% or less. In addition, when the ophthalmic composition is diluted in tears after instillation, the cholesterol and the surfactant are separated, and by promoting the unity of the cholesterol, the cholesterol is released to the water surface (hereinafter referred to as It may be said that dilution release) may be higher. The higher the dilution release property, the tear oil layer stabilization effect is further improved.

(B-2) Polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester)
Examples of polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester) include polyoxyethylene monolaurate (20) sorbitan (polysorbate 20), monopalmitate polyoxyethylene (20) sorbitan (polysorbate 40), and monostearate polyoxyethylene (20) Sorbitan (polysorbate 60), polyoxyethylene tristearate (20) sorbitan (polysorbate 65), polyoxyethylene monooleate (20) sorbitan (polysorbate 80). Among them, polyoxyethylene (20) sorbitan (polysorbate 80) monooleate is preferable from the viewpoint of feeling in use.

  0.01-25 W / V% in a composition is preferable, as for the compounding quantity of (B-2), 0.015-15 W / V% is more preferable, 0.1-5 W / V% is more preferable. By setting it as 0.01 W / V% or more, a thing with a higher transmittance | permeability can be obtained, and defoaming property and dilution release property can be made higher by setting it as 25 W / V% or less.

  Above all, it is preferable to contain (B-1) polyoxyethylene castor oil as an essential component from the point of antifoaming property.

  0.01-25 W / V% in a composition is preferable, and, as for the total compounding quantity of (B-1) component and (B-2) component, 0.015-15 W / V% is more preferable, 0.2-10 W More preferred is / V%. By setting it as 0.01 W / V% or more, a thing with a higher transmittance | permeability can be obtained, and defoaming property and dilution release property can be made higher by setting it as 25 W / V% or less.

  In the range which does not impair the effect of the present invention, nonionic surfactant (B-3) other than the (B-1) ingredient and the (B-2) ingredient can be blended. As such surfactant, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymer represented by poloxamer, polyethylene glycol monostearate represented by polyethylene glycol monostearate (10), etc. It can be mentioned.

  Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition-polymerizing ethylene oxide to hydrogenated castor oil, and several types having different average addition mole number of ethylene oxide are known. ing. Although there is no limitation in particular about the average added mole number of ethylene oxide in polyoxyethylene hydrogenated castor oil, 5-100 moles are illustrated. 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), Examples include polyoxyethylene hydrogenated castor oil 60 (EO average added mole number 60), polyoxyethylene cured castor oil 80 (EO average added mole number 80), polyoxyethylene cured castor oil 100 (EO average added mole number 100), etc. Be

  A polyoxyethylene-polyoxypropylene block copolymer (POEPOP glycol) is a block copolymer consisting of a polyoxyethylene chain (POE) and a polyoxypropylene chain (POP), and ethylene oxide (EO) and propylene oxide (PO) Several types are known in which the average addition mole number of is different. The average addition mole number of ethylene oxide and propylene oxide in the polyoxyethylene-polyoxypropylene block copolymer is not particularly limited, but an average addition mole number of 5 to 200 moles is exemplified. Specifically, polyoxyethylene (200) polyoxypropylene (70) glycol (average EOL addition mole number 200, PO average addition mole number 70), polyoxyethylene (196) polyoxypropylene (67) glycol (EO average addition Mol number 196, PO average addition mol number 67), polyoxyethylene (160) polyoxypropylene (30) glycol (EO average addition mol number 160, PO average addition mol number 30), polyoxyethylene (120) polyoxypropylene (40) Glycol (EO average addition mole number 120, PO average addition mole number 40), polyoxyethylene (42) polyoxypropylene (67) glycol (EO average addition mole number 42, PO average addition mole number 67), poly Oxyethylene (54) Polyoxypropylene (39) Glyco Le (EO average addition mole number 54, PO average addition mole number 39), polyoxyethylene (20) polyoxypropylene (20) glycol (EO average addition mole number of 20, PO average addition mole number of 20), and the like.

  Polyethylene glycol monostearate is a compound obtained by addition polymerization of ethylene oxide to stearic acid, and several types having different average addition mole number of ethylene oxide are known. The average added mole number of ethylene oxide in polyethylene glycol monostearate is not particularly limited, and may be 5 to 100 moles. Specifically, polyethylene glycol monostearate 10 (average added mole number of EO 10), polyethylene glycol monostearate 25 (average number added mole of EO 25), polyethylene glycol monostearate 40 (average number added mole of EO 40), mono Examples thereof include polyethylene glycol stearate 45 (average added mole number of EO 45), polyethylene glycol monostearate 55 (average mole number added of EO 55), polyethylene glycol monostearate 100 (average mole number added of EO 100) and the like.

  In order to enhance the release of cholesterol to the water surface by lacrimal fluid dilution and to enhance the lacrimal fluid layer stabilization effect, the (B-1) component and the nonionic surfactant ((B-1) + (B-2) The compounding mass ratio of (A) + (B-3)) is preferably (B-1) / nonionic surfactant ≧ 0.9, more preferably 0.90.95, 1.0 is More preferable. In addition, although the said compounding mass ratio is W / V% ratio, it is the same as mass ratio. In addition, 0.01-25 W / V% in a composition is preferable, as for the total amount of nonionic surfactant, 0.015-15 W / V% is more preferable, and 0.2-10 W / V% is more preferable.

  From the viewpoint of obtaining high transmittance, the blending mass ratio of (A), (B-1) and (B-2) is preferably ((B-1) + (B-2)) / (A) ≧ 10 , ≧ 15 is more preferable. From the point of antifoaming property and dilution release property, ≦ 50 is preferable, ≦ 30 is preferable, and ≦ 25 is more preferable.

[Other ingredients]
In the composition of the present invention, other components can be blended in appropriate amounts as long as the effects of the present invention are not impaired. Examples of other components include oily components, preservatives, saccharides, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, refreshing agents, drugs and the like. These components may be blended singly or in appropriate combination of two or more.

  As oil components other than cholesterol, olive oil, sesame oil, castor oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, camel oil, corn oil, rapeseed oil, vegetable oil such as sunflower oil, coconut oil, cotton seed oil, medium chain Examples include fatty acid triglycerides, liquid paraffin, mineral oils such as light liquid paraffin, petrolatum, lanolin, mixed tocopherols, d-α-tocopherol acetate, retinol palmitate, and the like. When the oil component is blended, the blending amount in the composition is preferably 0.1 W / V% or less, more preferably 0.01 W / V% or less, still more preferably 0.001 W / V% or less, substantially It is particularly preferred not to contain.

  Examples of the preservative include benzalkonium chloride, benzethonium chloride, thimerosal, phenylethyl alcohol, alkylaminoethyl glycine, chlorhexidine gluconic acid, methyl paraoxenobenzoate, ethyl parahydroxybenzoate, sodium benzoate and the like. As cholesterol is less likely to be transferred to the tear fluid oil layer, when a preservative is blended, the blending amount thereof is preferably 1.0 W / V% or less in the composition, more preferably 0.01 W / V% or less, 0. 001 W / V% or less is more preferable, and it is especially preferable not to contain substantially.

  Examples of saccharides include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. These may be any of d-form, l-form or dl-form. As for the compounding quantity, when mix | blending saccharides, 0.001-1.0 W / V% in a composition is 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. As for the compounding quantity, when mix | blending a buffer, 0.001-1.0 W / V% in a composition is preferable.

  As a pH adjuster, an inorganic acid or an inorganic alkali agent is mentioned. For example, the inorganic acid includes (dilute) hydrochloric acid. As the inorganic alkali agent, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like can be mentioned. The pH of the composition is preferably 3.5 to 8.0. In addition, the measurement of pH is performed using a pH meter (HM-25R, Toa DKK Co., Ltd.) at 25 ° C.

  Examples of tonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium hydrogencarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogenphosphate, sodium dihydrogenphosphate, potassium dihydrogenphosphate and the like. It can be mentioned. The osmotic pressure ratio of the composition to saline is preferably 0.60 to 2.00. 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 the like. When mix | blending a stabilizer, 0.001 to 1.0 W / V% of the compounding quantity in a composition is preferable.

  Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like. When mix | blending a polyhydric alcohol, 0.001-1.0 W / V% in a composition is preferable for the compounding quantity of a polyhydric alcohol.

  Examples of the thickener include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, sodium alginate, gellan gum, carboxyvinyl polymer and the like. When mix | blending a thickener, as for the compounding quantity, 0.001-1.0 W / V% in a composition is preferable.

  As a refreshing agent, menthol, camphor, borneol, geraniol, cineol, linalool etc. are mentioned, for example. It may be d-form, l-form or dl-form. The blending amount in the case of blending the refreshing agent is preferably 0.0001 to 1 W / V% in the composition, more preferably 0.0005 to 0.2 W / V%, 0.001 to 0.1 W / V% Is more preferred.

  Examples of the drug (pharmaceutically active ingredient) include decongestion components (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride etc.), Anti-inflammatory and astringent agents (eg neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride Salts, etc., antihistamines (eg, diphenhydramine hydrochloride, chlorpheniramine maleate etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, bread Nole, calcium pantothenate, sodium pantothenate etc., amino acids (eg, potassium L-aspartate, magnesium L-aspartate, potassium magnesium magnesium L-aspartate (equivalent mixture), aminoethyl sulfonic acid, sodium chondroitin sulfate Etc.), sulfa drugs etc. When a drug is formulated, the content of the drug can be selected as an effective appropriate amount of each drug, but preferably 0.001 to 1.0 W / V% in the composition.

[Production method]
Although the manufacturing method of the ophthalmic composition of this invention is not specifically limited, For example, the following method is mentioned. Prepare small items in which cholesterol and nonionic surfactant are mixed. The preparation temperature is preferably 50 to 90 ° C. A general mixing method can be used for the mixing method, and the method is appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade or the like. The obtained small pieces are added to the aqueous solution in which the aqueous component is dissolved. The temperature at that time is preferably 50 to 90 ° C. The mixing method may be a general mixing method, and pulsator, propeller blades, paddle blades, turbine blades, etc. may be used, or high-pressure homogenizers may be used as appropriate. It will be.

[Ophthalmic composition]
The composition of the present invention is preferably an "aqueous ophthalmic composition". In the present invention, the "aqueous ophthalmic composition" refers to an ophthalmic composition in which the medium is water. In addition, the compounding amount of water makes it easy to mix with tears, and it is transferred to the tears oil layer of cholesterol by dilution of tears, and the effect of stabilizing the tears oil layer of cholesterol is enhanced. 99.5 W / V% is preferable, 90.0 to 99.0 W / V% is more preferable, and 95.0 to 98.0 W / V% is further preferable.

  The transmittance of the ophthalmic composition of the present invention is preferably 80 to 100%, preferably 90 to 100%, at a wavelength of 600 nm measured using a spectrophotometer (UV-1800, Shimadzu Corporation). More preferably, 95 to 100% is more preferable.

  The composition of the present invention is preferably a liquid from the viewpoint of facilitating application to the eye, and the viscosity at 25 ° C. facilitates mixing with tears, prevents cholesterol migration delay, and obtains a tear oil layer stabilizing effect more From the point of view, 20 mPa · s or less is preferable, 10 mPa · s or less is more preferable, and 5 mPa · s or less is more preferable. In addition, the measuring method of a viscosity is performed using a cone-plate viscometer (DV2T, Eiko Seiki Co., Ltd.).

The composition of the present invention can be used for known compositions such as ophthalmic compositions and ophthalmic compositions for contact lenses, and is not particularly limited. Among them, although it can be suitably used as eye drops, eye drops for contact lenses, eye wash, etc., the tear dilution ratio is high, withdrawal of surfactant from cholesterol is further promoted, and delivery of cholesterol to tear oil layer is possible. It can be suitably used particularly as an eye drop, an eye drop for contact lens (eye drop for contact lens wearer) from the viewpoint of efficient operation. The contact lens is not particularly limited, such as a hard contact lens, a soft contact lens, a silicone hydrogel soft contact lens, an O ₂ hard contact lens, a color contact lens, and the like.

  When used as eye drops or eye drops for contact lenses, it is preferable to instill 10 to 60 μL, 1 to 3 drops, and 3 to 6 times per day. 10 to 30 μL instillation at one time is preferable, and 10 to 15 μL instillation at one time is more preferable, in order to increase the dilution rate with tear fluid and efficiently perform cholesterol delivery.

[Tear fluid oil layer stabilizer]
The present invention is characterized in that it has at least one nonionic surfactant selected from (A) cholesterol, (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene sorbitan fatty acid ester from the viewpoint of having the above effects. Provided is a tear fluid oil layer stabilizer. The preferred components, blending amounts and the like are the same as in the above-mentioned ophthalmic composition.

  Cholesterol does not merely supplement the tear fluid oil layer or promote the production of oil components from the meibomian glands. Simply promoting the production of the oil component increases the saturated lipid and causes rather worsening of the condition, and simply replenishing the tear oil layer with oil can not stabilize the destabilized tear oil layer.

  From the above points, for patients with meibomian gland dysfunction, for patients with dry eye, for patients with eye fatigue, in particular for patients with dry eye caused by tear oil layer destabilization or meibomian gland dysfunction, tear oil layer destabilization or meibom It is useful for eye fatigue patients caused by glandular dysfunction. In addition, since the contact lens attachment promotes meibomian gland dysfunction, it is preferable to use it for a contact lens wearer, particularly for a soft contact lens wearer.

  EXAMPLES The present invention will be specifically described below 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% (g / 100 mL), and the ratio indicates a mass ratio.

Example, Comparative Example
An aqueous solution was prepared in advance, in which an aqueous component was dissolved in water at 90 ° C., and an accessory obtained by mixing cholesterol, a nonionic surfactant and an oil component at 90 ° C. Next, small articles were added to the aqueous solution and stirred using a propeller blade to obtain an ophthalmic composition. The following evaluation was performed about the obtained ophthalmic composition. The results are shown in the table. In addition, the pH of 25 degreeC of the ophthalmic composition of an Example and a comparative example was 7.1.

Transmittance
The wavelength 600 nm transmittance of the preparation immediately after manufacture was measured using a spectrophotometer (UV-1800, Shimadzu Corporation). The obtained transmittance is shown by the following evaluation criteria.
<Evaluation criteria>
:: 95% or more ○: 90% or more and less than 95% Δ: 80% or more and less than 90% ×: less than 80%

[Defoaming property]
5 mL of each sample was added to a 15 mL centrifuge tube (12 cm height) and shaken at 180 times / min with an amplitude of about 40 cm. After 5 minutes of shaking, the height (cm) of the foam after 3 hours was measured. The defoaming rate of each sample was measured in accordance with the following formula, and evaluated based on the following evaluation criteria.
Defoaming rate (%) = (1− (height of foam after 3 hours from shaking (cm)) / (height of foam after 5 minutes of shaking (cm)) × 100
<Evaluation criteria>
++ ++: 30% or more + ++: 30% or less 20% or more ++: 20% or less 10% or more +: 10% or less

[Tear fluid dilution and release (test for release of cholesterol to water surface by dilution)]
Human tear fluid is said to have an average of 7 μL, and when it is instilled in 30 to 60 μL of eye drops, it will be diluted about 1.12 to 1.23 times. In this test, in order to evaluate the release of cholesterol to the water surface by the tear liquid dilution of the ophthalmic composition, physiological saline is used as a model tear liquid and it is on the water surface when diluted at a dilution ratio of about 1.2 times. Cholesterol release was observed. A narrow measuring flask with an opening was used to facilitate observation. Specifically, 10 mL of physiological saline was added to a 50 mL volumetric flask, and the composition to be evaluated was poured to the opening. The area of the opening was 150 mm ² using a measuring flask in which the dilution rate when poured to the opening was 1.2 times. Observation of cholesterol on the water surface was performed by applying light to the liquid surface using a fluorescent lamp as a light source, observing interference light of oil floating on the liquid surface, and evaluating according to the following criteria. When interference light is observed, cholesterol is released from the eye drop by tear solution dilution, and it can be transferred to the tear solution layer to stabilize the tear solution layer. Moreover, it is conceivable that the larger the area of the interference light on the water surface, the higher the stabilization effect. In all of the Examples and Comparative Examples, no interference light of oil was observed in the case of non-dilution.
[Evaluation criteria]
+++: oil interference light observed at 30% or more of water surface area ++: oil interference light observed at 10% to less than 30% of water surface area +: oil interference light at less than 10% of water surface area Is observed

[Tear fluid layer stability test]
Evaluation of tear fluid oil layer stability was performed by measuring BUT (break up time) of tear fluid oil layer using dry eye observation apparatus DR-1 (made by Kowa Co., Ltd.). DR-1 is an apparatus capable of measuring an interference image of light reflected at the interface between the surface of the tear fluid oil layer and the tear fluid water layer. In a normal eye, a uniform gray or white interference image is observed, and when the tear oil layer collapses, the interference image disappears. 30 μL of each eye drop was instilled in a subject, and after 10 minutes, it blinked several times, and measured the time from the blink to the collapse of the tear liquid oil layer (oil layer BUT). The subjects selected 13 eyes of 7 people who had oil reservoir BUT less than 10 seconds before instillation. The oil layer BUT, which was 10 seconds or less, did not fluctuate in the day or day, and it did not exceed 10 seconds in the eye drop without cholesterol, and it was judged that the improvement to 10 seconds or more had sufficient utility.
As a result of conducting the tear fluid layer stability test of the ophthalmic composition of each Example, in all, improvement to 10 seconds or more was seen. The results of Examples 2, 4 and 9 are shown in Table 5.

[Example of prescription]
The ophthalmic composition of the following composition was obtained by the method similar to an Example. The obtained ophthalmologic composition was evaluated in the same manner as in the example, and the same effect as in the example was obtained. The pH at 25 ° C. of the ophthalmic composition of the formulation example was 7.1.

Raw materials used in the above example are shown below. In addition, the amount of each component in the table is a net equivalent amount unless otherwise specified.
Cholesterol (manufactured by Wako Pure Chemical Industries, Ltd.)
Polyoxyethylene castor oil (polyoxyethylene castor oil 35: Uniox C 35, manufactured by NOF Corporation)
Polyoxyethylene sorbitan fatty acid ester (polysorbate 80, Leodol TW-O120V Kao Corporation)
Polyoxyethylene hydrogenated castor oil (Polyoxyethylene hydrogenated castor oil 60: HCO60, manufactured by Nippon Surfactant Industries Co., Ltd.)
Polyethylene glycol monostearate (polyethylene glycol monostearate (10): MYS10V, manufactured by Nippon Surfactant Industries Co., Ltd.)
Boric acid (manufactured by Kojima Pharmaceutical Co., Ltd.)
Trometamol (Kanto Chemical Co., Ltd.)
Edetate sodium hydrate (Crewat N, Nagase ChemteX Co., Ltd.)
Sodium chloride (manufactured by Tomita Pharmaceutical Co., Ltd.)
Sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.)

Claims (6)

  An ophthalmic composition comprising one or more nonionic surfactants selected from (A) cholesterol, (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene sorbitan fatty acid ester.   The ophthalmic composition according to claim 1, wherein the blending mass ratio of (A), (B-1) and (B-2) is ((B-1) + (B-2)) / (A) ≧ 10. object.   The ophthalmic composition according to claim 1, wherein the composition contains (B-1) polyoxyethylene castor oil as an essential component.   The ophthalmic composition according to claim 3, wherein the blending mass ratio of the component (B-1) to the nonionic surfactant is (B-1) / nonionic surfactant 界面 0.9.   The ophthalmic composition according to any one of claims 1 to 4, wherein the transmittance at a wavelength of 600 nm is 80 to 100%.   A lacrimal fluid oil layer stabilizer comprising one or more nonionic surfactants selected from (A) cholesterol, (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene sorbitan fatty acid ester.