JP7230825B2 - Aqueous ophthalmic composition and method for atomizing emulsion particles - Google Patents

Description

TECHNICAL FIELD The present invention relates to an aqueous ophthalmic composition containing liquid paraffin and a method for micronizing emulsion particles thereof.

Liquid paraffin is a hydrocarbon that is liquid at room temperature and is characterized by low polarity. Conventionally, it has been widely used as a base for ophthalmic ointments as an ophthalmic composition. On the other hand, when it is formulated as an aqueous ophthalmic composition, it is necessary to uniformly disperse liquid paraffin in water. It was difficult to raise the rate. In addition, a formulation with a cloudy appearance has the problem that it is difficult to determine whether or not foreign matter is present during manufacture or use. Therefore, conventionally, in order to improve the permeability of an aqueous formulation containing liquid paraffin, a high-pressure emulsification step or a high-concentration blending of a surfactant was required. However, high-pressure emulsification requires the introduction of manufacturing equipment, and there is a problem that when a surfactant is blended at a high concentration, an eye irritation occurs as an ophthalmic composition.

Japanese Patent Publication No. 2004-534732

The present invention has been made in view of the above problems, and by atomizing the emulsion particles in the composition without high-pressure emulsification or high-concentration blending of surfactants, the transmittance of the composition is increased, and the long-term An object of the present invention is to provide an aqueous ophthalmic composition containing liquid paraffin capable of suppressing creaming during storage, having excellent appearance storage stability, and capable of stabilizing the lacrimal oil layer.

The tear lipid layer is composed of lipids secreted by the meibomian glands. It is known that lipid saturation in the oil layer progresses due to aging and changes in hormone balance. It is further known to be aided by contact lens wear. Progression of lipid saturation destabilizes the lacrimal lipid layer, which causes dry eye and further causes asthenopia. The present inventors have found that an aqueous composition containing liquid paraffin is effective in stabilizing the lacrimal lipid layer.

In order to provide an aqueous ophthalmic composition containing the above-mentioned liquid paraffin, the present inventors conducted further studies and found that (A) liquid paraffin, (B) a nonionic surfactant, and (B) )/(A), and 0.00 of (C) a terpenoid is added to an aqueous ophthalmic composition in which the blending weight ratio of components (A) and (B) is 3≦(B)/(A)≦25. By blending 0001 to 0.5 w/v%, the emulsion particles are atomized without high-pressure emulsification or high-concentration blending of surfactants, thereby increasing the transmittance of the composition and creaming during long-term storage. The present inventors have found that it is possible to suppress .

Accordingly, the present invention provides the following inventions.
[1]. (A) liquid paraffin, (B) a nonionic surfactant, and (C) a terpenoid, and the blending mass of components (A) and (B) represented by (B)/(A) An aqueous ophthalmic composition in which the ratio is 3≤(B)/(A)≤25 and the amount of component (C) is 0.0001 to 0.5 w/v%.
[2]. Further, (D) Retinol palmitate, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyloxyethylphosphorylcholine, sesame oil and castor oil. Ophthalmic composition.
[3]. The aqueous ophthalmic composition according to [1] or [2], wherein component (B) contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. .
[4]. The aqueous ophthalmic composition according to any one of [1] to [3], wherein component (C) is one or more selected from menthol, menthone, camphor, borneol, geraniol, cineol and linalool.
[5]. (C) The aqueous ophthalmic composition according to [4], wherein the component is menthol.
[6]. The aqueous ophthalmic composition according to any one of [1] to [5], which has a transmittance of 50% or more.
[7]. (A) contains liquid paraffin and (B) a nonionic surfactant, and the blending mass ratio of component (A) and component (B) represented by (B)/(A) is 3 ≤ (B )/(A) ≤ 25. A method for atomizing emulsion particles in an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition is blended with 0.0001 to 0.5 w/v% of (C) a terpenoid. A method for atomizing emulsion particles.

Even without high-pressure emulsification or a high concentration of surfactants, the emulsion particles in the composition are atomized, increasing the transmittance of the composition, making it possible to suppress creaming during long-term storage, and keeping the appearance stable. It is possible to provide an aqueous ophthalmic composition containing liquid paraffin that has excellent tear lipid layer stability.

The present invention will be described in detail below.
[(A) component]
Liquid paraffin is a component that has a high tear lipid layer stabilizing effect on an unstable lacrimal lipid layer with increased saturated lipids. Liquid paraffin is an oil having a low polarity compared to vegetable oils composed of triglycerides and hydrocarbons such as squalane having a short carbon chain length. Liquid paraffin is a mixture of hydrocarbons obtained from crude oil and is liquid at room temperature. It is produced by a method in which atmospheric distillation residue of crude oil is used as a raw material, subjected to vacuum distillation and solvent deasphalting treatment, and then subjected to solvent refining or hydrocracking treatment. The liquid paraffin used in the present invention is not particularly limited, and may be used singly or in combination of two or more. Although the carbon chain length of the hydrocarbon is not particularly limited, those with a carbon chain length of 15 to 45 are preferably used. There is no particular restriction on the presence or absence of double bonds in hydrocarbons, but hydrocarbons containing a large amount of saturated hydrocarbons are preferably used. Furthermore, the hydrocarbon structure may include any of linear, branched and cyclic structures, and liquid paraffin of any specific gravity can be used. Particularly preferred are liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia. Appropriate forms of tocopherol may also be included as stabilizers.

The viscosity of liquid paraffin is correlated with its molecular weight, and kinematic viscosity is preferably 30 to 100 mm ² /s, preferably 37 to 88 mm, according to the 16th revision of the Japanese Pharmacopoeia, Method 1 (37.8 ° C.). ² /s is more preferred, and 74 to 88 mm ² /s is even more preferred. You may mix two or more types in the said viscosity range. By setting it to 30 mm ² /s or more, the lacrimal oil layer stabilizing effect can be further obtained. From the point of view of further enhancing the effect of stabilizing the lacrimal oil layer, it is preferably from 74 to 88 mm ² /s. In addition, by setting it to 100 mm ² /s or less, the transmittance of the appearance can be enhanced, and at the same time, eye irritation peculiar to liquid paraffin can be further reduced. From the viewpoint of the transmittance of the appearance and the reduction of eye irritation, those of 37 to 88 mm ² /s are preferable.

From the viewpoint of stabilizing the lacrimal oil layer, the amount of component (A) is 0.001 to 2 w/v% (mass/volume % , g/100 mL), more preferably 0.001 to 1 w/v%, even more preferably 0.01 to 1 w/v%, most preferably 0.05 to 1 W/V%.

[(B) component]
(B) Nonionic surfactants are not particularly limited, and nonionic surfactants used in ophthalmic compositions can be used singly or in combination of two or more. Specifically, (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, (B-3) nonionic surfactants other than (B-1) and (B-2) agents and the like. Component (B) preferably contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil.

(B-1) Polyoxyethylene castor oil Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil. Several different types 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 (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 (average number of EO addition moles 35), polyoxyethylene castor oil 40 (average number of EO addition moles 40), polyoxyethylene castor oil 50 (average number of EO addition moles 50), polyoxyethylene castor oil 60 (EO average added mole number 60) and the like. These polyoxyethylene castor oils can be used singly or in combination of two or more. It is preferable to use polyoxyethylene castor oil 35 from the viewpoint of reducing irritation at the time of instillation.

(B-2) Polyoxyethylene hydrogenated castor oil Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil. Several types with different number of moles are known. 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. These polyoxyethylene hydrogenated castor oils can be used singly or in combination of two or more. Polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 are preferably used from the viewpoint of reducing irritation when instilled.

(B-3) Nonionic surfactants other than (B-1) and (B-2) Polyoxyethylene sorbitan fatty acid ester (POE sorbitan) represented by polysorbate 80 (polyoxyethylene (20) sorbitan oleate) fatty acid ester), polyoxyethylene polyoxypropylene glycol (POEPOP glycol) typified by poloxamer, polyethylene glycol monostearate (10), polyethylene glycol monostearate typified by polyethylene glycol monostearate (40), and the like. be done.

The blending amount of component (B) is appropriately selected according to the blending mass ratio with component (A), and the blending mass ratio between component (A) and component (B) represented by (B)/(A) is 3 ≤ (B)/(A)≦25. If this ratio is less than 3, the emulsion particles will not be sufficiently atomized, and if it exceeds 25, there will be an excessive amount of surfactant that does not form an emulsion, and foaming will easily occur. The mixing mass ratio is preferably 4≦(B)/(A), more preferably 5≦(B)/(A). By setting the blending mass ratio to 4 or more, the transmittance of the composition becomes 50% or more, depending on the component (C). By setting the blending mass ratio to 5 or more, the composition has a transmittance of 70% or more. From the viewpoint of suppressing foaming of the composition, (B)/(A) ≤ 20 is preferable, and (B)/(A) ≤ 15 is more preferable. Although the above ratio is a w/v% ratio, it has the same value as the mass ratio.

The amount of component (B) to be blended is not particularly limited as long as it satisfies the above ratio.
(B-1) When blending polyoxyethylene castor oil, it is preferably 0.003 to 10 w/v%, more preferably 0.003 to 5 w/v%, and 0.03 to 1 w/v% in the composition. is more preferred.
(B-2) When blending polyoxyethylene hydrogenated castor oil, it is preferably 0.003 to 10 w/v% in the composition, more preferably 0.003 to 5 w/v%, and 0.03 to 1 w/v % is more preferred.
(B-3) When a nonionic surfactant other than (B-1) and (B-2) is blended, it is preferably 0.0003 to 1 w/v% in the composition, and 0.0003 to 0.5 w /v% is more preferred, and 0.003 to 0.1w/v% is even more preferred.

[(C) Component]
(C) By blending terpenoids, emulsion particles are atomized without high-pressure emulsification or increasing the amount of surfactant, so that the permeability of the composition is increased, and it is possible to suppress creaming due to long-term storage. . A terpenoid in the present invention has a structure having an isoprene unit as a structural unit, and includes, for example, terpene hydrocarbons, terpene alcohols, terpene aldehydes, terpene ketones, and the like. In addition, there are monoterpene, sesquiterpene, diterpene, triterpene, and tetraterpene depending on the number of carbon atoms. Specific examples include monoterpenes such as menthol, menthone, camphor, borneol, ryuno, geraniol, cineol, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids. Among them, it is preferable to use a monoterpene. These terpenoids can be used in d-, l- or dl-form. Among them, menthol, menthone, camphor, borneol, geraniol, cineol and linalool are preferred, and menthol, camphor, borneol, geraniol, cineol and linalool are more preferred. Menthol is more preferable because it has a large effect of atomizing emulsion particles. In addition, in this invention, you may use the essential oil containing the said compound as a terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, essential oils of Dipterocarpaceae plants, rosemarine oil, and lavender oil.

The blending amount of component (C) is 0.0001 to 0.5 w/v% in the composition, and is appropriately selected from the type of component (C), other blending components such as component (B), and their blending amounts. be done. Preferably, it is 0.0001 to 0.2 w/v%. Within this blending concentration range, there is little possibility that the (C) terpenoid will precipitate regardless of the type or blending amount of the other blended components. From the viewpoint of atomization of emulsion particles, it is preferably 0.0001 w/v% or more, and from the viewpoint of reducing irritation, it is more preferably 0.075 w/v% or less.

From the viewpoint that menthol remarkably increases atomization, when menthol is blended, it is particularly preferably 0.0001 to 0.075 w/v% in the composition, most preferably 0.001 to 0.075 w/v%.

When borneol or camphor is blended, it is preferably 0.001 to 0.075 w/v%, more preferably 0.005 to 0.075 w/v% in the composition from the viewpoint of enhancing the atomization of the composition. When blending cineol, linalool or geraniol, from the viewpoint of enhancing the atomization of the composition, it is preferably 0.0005 to 0.075 w / v%, more preferably 0.0025 to 0.075 w / v%. .

The composition of the present invention contains (D) retinol palmitate, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, and 2-methacryloyl from the viewpoint of further enhancing the atomization of emulsion particles by component (C). It is preferable to blend one or more selected from oxyethylphosphorylcholine, sesame oil and castor oil. These can be used individually by 1 type or in combination of 2 or more types as appropriate. Among them, retinol palmitate, tocopheryl acetate, glycerin, and propylene glycol are preferred.

The amount of component (D) to be blended in the composition is preferably within the following range from the viewpoint of increasing the fineness of the composition. When blending retinol palmitate and tocopherol acetate, it is preferably 0.001 to 5.0 w/v%, more preferably 0.01 to 3.0 w/v%, and 0.01 to 1.0 w/v%. is more preferred. When blending glycerin, propylene glycol, benzododecinium bromide, sesame oil, or castor oil, it is preferably 0.005 to 5.0 w/v%, more preferably 0.05 to 3.0 w/v%, and 0 .1 to 1.0 w/v% is more preferred. When blending 2-methacryloyloxyethylphosphorylcholine, it is preferably 0.01 to 5.0 w/v%, more preferably 0.03 to 2.0 w/v%, and 0.05 to 1.0 w/v%. More preferred.

[Other ingredients]
The composition of the present invention may contain appropriate amounts of other ingredients that are commonly used in ophthalmic compositions, as long as the effects of the present invention are not impaired. Other ingredients include preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, drugs 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 the preferred range when blending, and is the amount in the composition.

Among preservatives, preservatives having a hydrophobic moiety such as an alkyl chain or a benzene ring include thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and the like. Paraffin is less likely to be transferred to the lacrimal lipid layer, so it is preferably 0.1 w/v% or less, more preferably 0.01 W/V% or less, more preferably 0.001 W/V% or less, and substantially It is more preferable not to include in

Sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. These may be D-, L-, or DL-isomers. When saccharides are blended, 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. More preferred.

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 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 further 0.001 to 1 w/v%. preferable.

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 composition may have a pH of 3.5 to 13.0, preferably 3.5 to 8.0, more preferably 5.5 to 8, from the viewpoint of further improving various symptoms caused by destabilization of the lacrimal lipid layer. .0 is more preferred. 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 that at least one of sodium chloride and potassium chloride is blended and 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 0.83 from the viewpoint of further improving various symptoms caused by destabilization of the tear lipid layer. ~1.20 is most preferred. The osmotic pressure is measured at 25° C. using an automatic osmometer (A2O, Advanced Instruments).

Stabilizers include, for example, sodium edetate, cyclodextrin, sulfites, dibutylhydroxytoluene and the like. When a stabilizer is blended, the blending amount is preferably 0.001 to 5.0 w/v% in the composition, more preferably 0.001 to 1 w/v%, and 0.001 to 0.1 w/v % is more preferred.

Polyhydric alcohols include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like. When a polyhydric alcohol is blended, the blending amount of the polyhydric alcohol is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, more preferably 0.001 to 0.001 w/v% in the composition. 1 w/v % is more preferred.

Examples of thickening agents 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 more preferred.

(A) Liquid paraffin, and oil components other than (D), such as soybean oil, olive oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglyceride, d-α-tocopherol acetate, retinol palmitate, white petrolatum , purified lanolin, cholesterol, mixed tocopherol and the like. When an oil component other than liquid paraffin is blended, 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%. v% is most preferred.

Drugs (active pharmaceutical ingredients) include, for example, decongestants (e.g., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.), Antiphlogistic/astringent (e.g. 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 (e.g., diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.) , amino acids (eg, potassium L-aspartate, magnesium L-aspartate, potassium/magnesium L-aspartate (equal mixture), aminoethylsulfonic acid, etc.), sulfa drugs, and the like. When a drug is compounded, the compounding amount of the drug can be selected to be an effective and appropriate amount of each drug, but is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v% in the composition. is more preferred, and 0.001 to 0.1 w/v% is even more preferred.

[Production method]
The method for producing the composition of the present invention is not particularly limited, and the composition can be obtained by mixing components (A), (B), (C), and optionally optional components. For example, a mixed solution of oily components such as (A), some or all of (B) and (C) components is mixed with an aqueous solution containing an aqueous component to emulsify, and after adjusting the pH, the total volume is adjusted with water. can be obtained by The method of mixing each liquid may be a general method, and it is appropriately performed using a pulsator, propeller blades, paddle blades, turbine blades, etc., but the rotation speed is not particularly limited, and it should be set to the extent that it does not foam violently. is preferred. Although the mixing temperature of each liquid is not particularly limited, it is preferable that both the oil component and the surfactant component are at a melting temperature or higher, and specifically, it is appropriately selected from the range of 40 to 95°C. In the present invention, even without the high-pressure emulsification step, by atomizing the emulsion particles in the composition, it is possible to increase the transmittance of the composition and suppress creaming due to long-term storage.

Further, after the obtained composition is filled in a resin container, it may be further sealed with a package, and an inert gas may be sealed in the space formed between the container and the package. The substance may be filled in a resin container and sealed with a package together with an oxygen scavenger.

[Ophthalmic composition]
The composition of the present invention is an "aqueous ophthalmic composition". In the present invention, "aqueous ophthalmic composition" refers to an ophthalmic composition whose medium is water. The amount of water to be blended is preferably 90.0 to 99.5 w/v%, more preferably 95.0 to 97%, in the composition from the viewpoint of facilitating mixing with lacrimal fluid and further obtaining the effect of stabilizing the lacrimal oil layer. 0.5 w/v % is more preferred.

The particle size of the emulsion particles (association of component (A) and component (B)) contained in the composition of the present invention can be 800 nm or less, preferably 500 nm or less, and more preferably 300 nm or less. Although the lower limit is not particularly limited, it can be 1 nm. In the present invention, the particle diameter refers to the average diameter (median diameter nm) of the volume-based particle size distribution calculated from the scattered light intensity. The particle size is measured by various measuring devices that apply the principle of light scattering, etc., using a constant temperature bath under constant temperature conditions of 25°C. As such a device, for example, a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.) can be used for measurement.

Specifically, the transmittance of the composition of the present invention is 30 to 100% at a wavelength of 600 nm measured using a spectrophotometer (eg, UV-1800, Shimadzu Corporation). 50 to 100% is preferred, and 70 to 100% is more preferred.

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. is 20 mPa·s from the viewpoint of facilitating mixing with lacrimal fluid and obtaining a greater lacrimal oil layer stabilizing effect. The following is preferable, 10 mPa·s or less is more preferable, and 5 mPa·s or less is even more preferable. The viscosity is measured using a cone-plate viscometer (DV2T, Eiko Seiki Co., Ltd.).

The composition of the present invention can be suitably used as an eye drop, a contact lens eye drop, an eye wash, etc., but it has a high lacrimal fluid dilution rate, promotes the release of the surfactant from liquid paraffin, and is not delivered to liquid paraffin. can be suitably used as eye drops and eye drops for contact lenses (eye drops for contact lens wearers). Examples of contact lenses include hard contact lenses, O ₂ hard contact lenses, soft contact lenses, and silicone hydrogel soft contact lenses, but are not particularly limited.

When used as eye drops or eye drops for contact lenses, it is preferable to instill 1 to 3 drops of 10 to 100 μL each time, 1 to 6 times a day. 1 to 3 drops of 10 to 50 μL each time, 1 to 6 times a day is more preferable. 1 to 3 drops of 10 to 30 μL each time, more preferably 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.

[Atomization method]
The present invention contains (A) liquid paraffin and (B) a nonionic surfactant, and the blending mass ratio of components (A) and (B) represented by (B)/(A) is A method for micronizing emulsion particles in an aqueous ophthalmic composition wherein 3≦(B)/(A)≦25, wherein (C) a terpenoid is added to the aqueous ophthalmic composition at 0.0001 to 0.5 w/w/ Provided is a method for micronizing emulsion particles to be blended by v %. Preferred components and blending amounts are the same as above. In addition, by making the particles fine, the composition can be made transparent, and the appearance storage stability can be improved. The term "appearance storage stability" means that aggregation, creaming, coalescence, floating, etc. of aggregates of components (A) and (B) are suppressed when the composition is stored over time. . In the atomization method, if (B)/(A) is outside the above range, the atomization effect of component (C) cannot be obtained.

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 aqueous component in the table below was dissolved in 90 mL of purified water, and the mixture was heated and mixed at 90° C. for 15 minutes. Separately, a preliminary mixture of (A) liquid paraffin, (B) a nonionic surfactant and (C) a terpenoid was prepared and heated and mixed at 90° C. for 15 minutes. Next, a predetermined amount of the preliminary mixture was added to the aqueous solution, and the mixture was heated and mixed at 90° C. for 15 minutes. Then, it was cooled to room temperature, pH was adjusted, and purified water was added so that the volume became 100 mL. The viscosity of each example was in the range of 0.5 to 2.0 mPa·s. The obtained compositions were evaluated as follows. The results are also shown in the table.

[Atomization of emulsion particles]
The particle size of the emulsion particles in the composition immediately after production was measured using ELSZ-200ZS (manufactured by Otsuka Electronics Co., Ltd.). From the obtained particle size, the micronization of the emulsion particles in the composition is shown by the following evaluation criteria. The particle diameter is the average diameter (median diameter nm) of the volume-based particle size distribution calculated from the scattered light intensity, and the measurement was carried out under a constant temperature condition of 25°C.
[Evaluation criteria]
○: Atomization is observed compared to the comparative example that does not contain the component (C) (and the component (D)) ×: Compared to the comparative example that does not contain the component (C) (and the component (D)) , no atomization is observed

[Transmittance measurement]
The composition immediately after production was measured for transmittance (%) at a wavelength of 600 nm using an ultraviolet-visible-near-infrared spectrophotometer UV-1800 (Shimadzu Corporation).

[Improved transmittance]
○: Transmittance is improved compared to comparative examples that do not contain component (C) (and component (D)) ×: Compared to comparative examples that do not contain component (C) (and component (D)) and transmittance is not improved

[Composition: transmittance (%)]
◎: 70% or more and 100% or less ○: 50% or more and less than 70% △: 30% or more and less than 50% ×: less than 30%

Comparing Samples 1-1 to 1-2 with Comparative Samples 1-1 to 1-2, liquid paraffin as component (A) and POE castor oil as component (B) were mixed to 3≦(B)/ By adding (C) 1-menthol to the aqueous composition containing (A) ≤ 25, the light transmittance at 600 nm increased and the particle size decreased. From the above, by adding (C)l-menthol to the above composition, the emulsion particles were finely divided and the transmittance of the composition was improved. On the other hand, comparing Comparative Sample 1-3 and Comparative Sample 1-3', when (B)/(A) was 1, the particle size and transmittance were almost the same, and the above effect was not obtained.

All of the compositions of Examples were evaluated as "O" in the following appearance storage stability evaluation.
[Appearance Storage Stability]
20 g of the composition was placed in a glass bottle (capacity: 20 mL) and allowed to stand at room temperature for 48 hours. After that, the appearance storage stability of the stored product was visually observed and judged according to the following criteria.
[Evaluation criteria]
○: Appearance does not change immediately after preparation ×: Creaming etc. occur, and changes in the appearance of the emulsion are seen compared to immediately after preparation

All of the compositions of Examples were evaluated as "⊚" or "◯" in the following tear lipid layer stability test.
The results of Examples 3-1 and 3-7 and Comparative Examples A and B are shown below.
[Tear Oil Layer Stability Test]
The stability of the tear lipid layer was evaluated by measuring the BUT (break up time) of the tear lipid layer using a dry eye monitor DR-1 (manufactured by Kowa Company, Ltd.). The DR-1 is a device that can measure interference images of light reflected at the interface between the tear oil layer surface and the tear aqueous layer. In healthy eyes, a uniform gray or white interferogram is observed, and the interferogram disappears when the tear lipid layer breaks down. 30 μL of each composition was instilled into the eyes of the subject, and after 10 minutes, the subject blinked several times, and the time from the blink to the breakdown of the tear lipid layer (oil layer BUT) was measured. Subjects were selected from 13 eyes of 7 people whose oil layer BUT before instillation was 10 seconds or less. The results are shown by the following evaluation criteria based on the average values of 13 eyes of 7 persons. The oil layer BUT, which was 10 seconds or less, does not exceed 10 seconds for intraday and daily fluctuations, and the composition does not contain liquid paraffin, and improvement to 10 seconds or more is acceptable as having sufficient usefulness. It was judged.
[Evaluation criteria]
◎: Oil layer BUT is 60 seconds or more ○: Oil layer BUT is 30 seconds or more and less than 60 seconds ●: Oil layer BUT is 10 seconds or more and less than 30 seconds × (Unacceptable): Oil layer BUT is less than 10 seconds "●" or more is passed.

It was confirmed that the aqueous ophthalmic composition of the present invention has a tear lipid layer stabilizing effect.

Raw materials used in preparing Examples and Comparative Examples are shown below. The amount of each component in the table is the amount converted to pure content.
Liquid paraffin: 16th revision Japanese Pharmacopoeia Law 1 (37.8°C) Kinematic viscosity 76.6 mm ² /s (KAYDOL, manufactured by Shima Boeki Co., Ltd.)
Liquid paraffin: 16th revision Japanese Pharmacopoeia Law 1 (37.8° C.) Kinematic viscosity 34.8 mm ² /s (Hicol M-172, manufactured by Kaneda Corporation)
Polyoxyethylene (POE) castor oil (polyoxyethylene castor oil 35: Uniox C35, manufactured by NOF Corporation)
Polyoxyethylene (POE) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60: HCO60, HCO40, manufactured by Nippon Surfactant Kogyo Co., Ltd.)
PEG monostearate (polyethylene glycol monostearate (10): MYS10V, polyethylene glycol monostearate (40): MYS40MV, manufactured by Nippon Surfactant Kogyo Co., Ltd.)
PEG monostearate (polyethylene glycol (100) monostearate: EMALEX8100, manufactured by Nippon Emulsion Co., Ltd.)
POE sorbitan fatty acid ester (polyoxyethylene (20) sorbitan oleate ester: Rhodol TW-O120V, manufactured by Kao Corporation)
POEPOP glycol (polyoxyethylene (200) polyoxypropylene (70) glycol) (Lutrol F127, manufactured by BASF Japan Ltd.)
l-Menthol (manufactured by Suzuki Minka Co., Ltd.)
dl-camphor (manufactured by Nippon Fine Chemical Co., Ltd.)
d-borneol (manufactured by Masami Yanagisawa Co., Ltd.)
Geraniol (manufactured by Takasago International Corporation)
Cineol (manufactured by Takasago International Corporation)
Linalool (manufactured by Takasago International Corporation)
Boric acid (manufactured by Kanto Chemical Co., Ltd.)
Trometamol (manufactured by Kanto Chemical Co., Ltd.)
Sodium edetate hydrate (Klewat N, manufactured by Nagase ChemteX Corporation)
Sodium chloride (manufactured by Tomita Pharmaceutical Co., Ltd.)
Sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.)
Retinol palmitate (manufactured by DSM Nutrition Japan Co., Ltd., retinol palmitate, 174 units/g)
d-α-Tocopherol Acetate (Riken E Acetate α, manufactured by Riken Vitamin Co., Ltd.)
Glycerin (Japanese Pharmacopoeia Glycerin, manufactured by ADEKA Co., Ltd.)
Propylene glycol (Japanese Pharmacopoeia propylene glycol, manufactured by ADEKA Corporation)
Benzododecinium bromide (benzyldodecyldimethylammonium bromide, manufactured by Wako Pure Chemical Industries, Ltd.)
Sesame oil (Japanese Pharmacopoeia sesame oil, manufactured by Kaneda Corporation)
Castor oil (Japanese Pharmacopoeia castor oil, manufactured by Kaneda Corporation)

Claims (8)

(A) Liquid paraffin having a kinematic viscosity of 74 to 88 mm ² /s according to the method of measurement according to the 16th revision of the Japanese Pharmacopoeia Law (37.8°C) , (B) a nonionic surfactant, ( C) contains a terpenoid, and the blending mass ratio of the component (A) and the component (B) represented by (B)/(A) is 3 ≤ (B)/(A) ≤ 25, and (C) ) is an aqueous ophthalmic composition containing 0.0001 to 0.5 w/v% of components and having a pH of 5.5 to 8.0 . Furthermore, (D) retinol palmitate, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyloxyethylphosphorylcholine, sesame oil and castor oil. Ophthalmic composition. 3. The aqueous ophthalmic composition according to claim 1, wherein component (B) contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. The aqueous ophthalmic composition according to any one of claims 1 to 3, wherein component (C) is one or more selected from menthol, menthone, camphor, borneol, geraniol, cineol and linalool. 5. The aqueous ophthalmic composition according to claim 4, wherein component (C) is menthol. The aqueous ophthalmic composition according to any one of claims 1 to 5, which has a transmittance of 50% or more. (A) Liquid paraffin having a kinematic viscosity of 74 to 88 mm ² /s according to the 16th revision of the Japanese Pharmacopoeia, Method 1 (37.8°C), and (B) a nonionic surfactant. and the mixing mass ratio of component (A) to component (B) represented by (B)/(A) is 3 ≤ (B)/(A) ≤ 25, and the pH is 5.5 to 8. A method for micronizing emulsion particles in an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition is blended with (C) terpenoid in an amount of 0.0001 to 0.5 w/v%. conversion method. The aqueous ophthalmic composition further contains (D) one or more selected from retinol palmitate, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyloxyethylphosphorylcholine, sesame oil and castor oil. The method for atomizing emulsion particles according to claim 7.