KR20200096900A - Aqueous ophthalmic composition and method for atomizing emulsion particles - Google Patents

Abstract

(A) liquid paraffin, (B) nonionic surfactant, (C) terpenoid is contained, and the compounding mass ratio of (A) component and (B) component represented by (B)/(A) is 3 <(B)/(A)<=25, and the amount of the component (C) is 0.0001 to 0.5w/v%.

Description

Aqueous ophthalmic composition and method for atomizing emulsion particles

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

Liquid paraffin is a liquid hydrocarbon at room temperature and has a low polarity. Conventionally, as an ophthalmic composition, it is widely used as a base for an ophthalmic ointment. On the other hand, when blending as an aqueous ophthalmic composition, it is necessary to uniformly disperse liquid paraffin in water, but because liquid paraffin has a low polarity, it becomes cloudy even when a surfactant or the like is used, making it difficult to increase the transmittance. In addition, a formulation having a cloudy appearance has a problem in that it becomes difficult to determine the presence or absence of foreign matter incorporation at the time of manufacture or use. Therefore, conventionally, in order to improve the transmittance of an aqueous formulation containing liquid paraffin, a high-pressure emulsification step or a high concentration formulation of a surfactant has been required. However, high-pressure emulsification requires the introduction of manufacturing equipment, and there has been a problem of causing eye irritation as an ophthalmic composition when a surfactant is mixed at a high concentration.

Japanese Patent Publication No. 2004-534732

The present invention was made in view of the above problems, and by micronizing the emulsion particles in the composition, even without high pressure emulsification or high concentration blending of surfactants, it is possible to increase the transmittance of the composition and to suppress creaming by long-term storage, An object of the present invention is to provide an aqueous ophthalmic composition containing liquid paraffin capable of stabilizing a tear oil layer having excellent appearance storage stability.

The tear fluid layer is composed of lipids secreted from the meibomian glands. It is known that saturation of the lipids in the oil layer proceeds with age, but with hormonal balance changes. It is also known that it is promoted by wearing contact lenses. As the lipid saturation proceeds, the lacrimal fluid layer becomes unstable, causing dry eye, and furthermore, it is a factor that causes stable fatigue. The present inventors have found that an aqueous composition containing liquid paraffin is effective for stabilizing this tear fluid layer.

In order to provide an aqueous ophthalmic composition containing the liquid paraffin, the inventors of the present invention further studied carefully, and as a result, (A) liquid paraffin and (B) nonionic surfactant were contained, and (B)/(A) By mixing 0.0001 to 0.5 w/v% of (C) terpenoid in an aqueous ophthalmic composition in which the blending mass ratio of component (A) and component (B) represented by 3 ≤ (B)/(A) ≤ 25 , Even without high-pressure emulsification or high concentration blending of surfactants, the emulsion particles are atomized, thereby increasing the transmittance of the composition and inhibiting creaming due to long-term storage.

Accordingly, the present invention provides the following invention.

[One]. (A) liquid paraffin, (B) nonionic surfactant, (C) terpenoid is contained, and the compounding mass ratio of (A) component and (B) component represented by (B)/(A) is 3 <(B)/(A)<=25, and the amount of the component (C) is 0.0001 to 0.5w/v%.

[2]. In addition, (D) retinol palmitic acid ester, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyloxyethylphosphorylcholine, sesame oil, and at least one selected from castor oil. The aqueous ophthalmic composition according to [1].

[3]. The aqueous ophthalmic composition according to [1] or [2], wherein the component (B) contains at least one 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 the component (C) is at least one selected from menthol, menthone, campo, 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] having a transmittance of 50% or more.

[7]. (A) Liquid paraffin and (B) nonionic surfactant are contained, and the compounding mass ratio of the component (A) and the component (B) represented by (B)/(A) is 3 ≤ (B)/(A) A method for atomizing emulsion particles in an aqueous ophthalmic composition of ≤25, wherein (C) terpenoid is blended in an amount of 0.0001 to 0.5 w/v% in the aqueous ophthalmic composition.

Even without high-pressure emulsification or high concentration of surfactant, the emulsion particles in the composition are atomized, so that the permeability of the composition is increased, it is possible to suppress creaming by long-term storage, excellent appearance storage stability, and a flow to stabilize the leaky fluid layer. It is possible to provide an aqueous ophthalmic composition containing paraffin.

Hereinafter, the present invention will be described in detail.

[(A) component]

Liquid paraffin is a component having a high effect of stabilizing the tear fluid layer against an unstable tear fluid layer with increased saturated lipids. Liquid paraffin is an oil having a lower polarity compared to squalane having a short carbon chain length among vegetable oils and hydrocarbons containing triglycerides. In addition, liquid paraffin is a mixture of hydrocarbons obtained from crude oil, and is liquid at room temperature. The crude oil is produced by a method of subjecting the raw material to the atmospheric distillation residual oil under reduced pressure distillation and solvent desorption treatment, and then performing a solvent purification method or a hydrocracking method. The liquid paraffin used in the present invention is not particularly limited, and can be used alone or in combination of two or more as appropriate. There is no particular limitation on the length of the carbon chain of the hydrocarbon, but 15 to 45 are suitably used. In addition, there is no particular limitation on the presence or absence of a double bond in the hydrocarbon, but those containing a large amount of saturated hydrocarbons are suitably used. Moreover, as a structure of a hydrocarbon, any of a linear chain, a branched chain, and a cyclic structure may be included, and liquid paraffin of any specific gravity can also be used. In particular, liquid paraffin and hard liquid paraffin listed in Japanese pharmacy rooms are suitable. In other words, tocopherol in an appropriate form may be included as a stabilizer.

The viscosity of the liquid paraffin is correlated with its molecular weight, and in the measurement method of the 16th revised Japanese Pharmacy Act 1 (37.8°C), the kinematic viscosity is preferably 30 to 100 mm 2 /s, and 37 to 88 mm 2 /s. It is more preferable that it is 74-88 mm<2>/s. You may mix two or more types within the said viscosity range. By setting it as the said 30 mm<2>/s or more, the leakage liquid oil layer stabilization effect can be obtained more. It is preferable that it is 74-88 mm<2>/s from the point which raises the effect of stabilizing the leakage fluid layer. Moreover, by setting it as 100 mm<2>/s or less, the transmittance|permeability of an external appearance increases, and eye irritation peculiar to liquid paraffin can be further reduced. In other words, it is preferable that it is 37-88 mm<2>/s from the point of the transmittance|permeability of an external appearance and eye irritation reduction.

The blending amount of the component (A) is preferably 0.001 to 2 w/v% (mass/volume %, g/100 mL) in the aqueous ophthalmic composition (hereinafter, sometimes referred to as a composition) from the viewpoint of stabilizing the tear oil layer. And 0.001 to 1 w/v% is more preferable, 0.01 to 1 w/v% is still more preferable, and 0.05 to 1 W/V% is most preferable.

[(B) component]

(B) It does not specifically limit as a nonionic surfactant, The nonionic surfactant used for the ophthalmic composition can be used individually by 1 type or in combination of 2 or more types suitably. Specifically, (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, (B-3) nonionic surfactants other than (B-1) and (B-2), etc. Can be mentioned. As the component (B), it is preferable to contain at least one 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, and several kinds of different average added moles of ethylene oxide are known. Although there is no restriction|limiting in particular about the average added mole number of ethylene oxide in polyoxyethylene castor oil, 3 to 60 moles are illustrated. Specifically, polyoxyethylene castor oil 3 (EO average added mole number 3), polyoxyethylene castor oil 10 (EO average added mole number 10), polyoxyethylene castor oil 20 (EO average added mole number 20), polyoxyethylene 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) Etc. are mentioned. These polyoxyethylene castor oils can be used alone or in combination of two or more as appropriate. It is preferable to use polyoxyethylene castor oil 35 from the viewpoint of reducing the irritation sensation during 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, and several kinds of different average added moles of ethylene oxide are known. Although there is no restriction|limiting in particular about the average added mole number of ethylene oxide in polyoxyethylene hardened castor oil, 5-100 moles are illustrated. 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), polyoxy Ethylene 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. are mentioned. These polyoxyethylene hydrogenated castor oils can be used alone or in combination of two or more as appropriate. From the viewpoint of reducing irritation during instillation, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.

(B-3) Nonionic surfactants other than (B-1) and (B-2)

Polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester) represented by polysorbate 80 (polyoxyethylene (20) sorbitanoleic acid ester), polyoxyethylene polyoxypropylene glycol represented by poloxamer (POEPOP glycol) , Polyethylene glycol monostearate (10), polyethylene glycol monostearate typified by polyethylene glycol monostearate (40), and the like.

The blending amount of the component (B) is appropriately selected from the blending mass ratio with the component (A), and the blending mass ratio of the component (A) and the component (B) represented by (B)/(A) is 3≤(B)/( A)≤25. If this ratio is less than 3, the atomization of the emulsion particles is insufficient, and if it exceeds 25, the surfactant which does not form the emulsion is excessively present, and foaming becomes easy. This blending mass ratio is preferably 4≦(B)/(A), and more preferably 5≦(B)/(A). When the blending mass ratio is 4 or more, depending on the component (C), the transmittance of the composition is 50% or more. When the blending mass ratio is 5 or more, the transmittance of the composition becomes 70% or more. From the viewpoint of suppressing foaming of the composition, (B)/(A)≦20 is preferable, and (B)/(A)≦15 is more preferable. In addition, although the ratio is a w/v% ratio, it becomes the same value as the mass ratio.

The blending amount of the component (B) is not particularly limited as long as the above ratio is satisfied, but in the composition, 0.0001 to 10 w/v% is preferable, and 0.0001 to 5 w/v% is more preferable.

(B-1) When blending polyoxyethylene castor oil, in the composition, 0.003 to 10 w/v% is preferable, 0.003 to 5 w/v% is more preferable, and 0.03 to 1 w/v% is still more preferable.

(B-2) When blending polyoxyethylene hydrogenated castor oil, in the composition, 0.003 to 10 w/v% is preferable, 0.003 to 5 w/v% is more preferable, and 0.03 to 1 w/v% is even more preferable. .

(B-3) When blending nonionic surfactants other than (B-1) and (B-2), in the composition, 0.0003 to 1 w/v% is preferable, and 0.0003 to 0.5 w/v% is more preferable. And 0.003 to 0.1 w/v% is more preferable.

[Component (C)]

(C) By blending the terpenoid, the emulsion particles become fine particles without performing high pressure emulsification or an increase in the surfactant, thereby increasing the transmittance of the composition and suppressing creaming by long-term storage. The terpenoid in the present invention has a structure having an isoprene unit as a structural unit, and examples thereof include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. In addition, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes by carbon number. Specifically, monoterpenes such as menthol, menthone, campo, borneol, dragon brain, geraniol, cineol, linalool, citronellol and limonene, diterpenes such as retinol and retinal, tetraterpenes such as carotenoids Etc. are mentioned. Among them, it is preferable to use a monoterpene. Any of d form, l form, or dl form can be used for these terpenoids. Among them, menthol, menthone, campo, borneol, geraniol, cineol, and linalool are preferable, and menthol, campo, borneol, geraniol, cineol, and linalool are more preferable. More preferably, it is menthol in that the effect of atomizing the emulsion particles is large. In other words, in the present invention, an essential oil containing the above compound may be used as the terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, mentha oil, peppermint oil, spearmint oil and essential oils of the Yiwu family plant, rosemary oil, lavender oil, and the like.

The blending amount of the component (C) is 0.0001 to 0.5 w/v% in the composition, and is appropriately selected from the kind of component (C), other blending components such as component (B), and the blending amount thereof. Preferably, it is 0.0001 to 0.2w/v%. In this blending concentration range, there is little risk of precipitation of (C) terpenoids regardless of the kind or blending amount of other blending components. Further, from the viewpoint of atomization of the emulsion particles, 0.0001 w/v% or more is preferable, and from the viewpoint of reducing the irritation sensation, 0.075 w/v% or less is more preferable.

Menthol is particularly preferably 0.0001 to 0.075 w/v%, and most preferably 0.001 to 0.075 w/v% in the composition when menthol is blended from the viewpoint of remarkably increasing atomization.

In the case of blending borneol or camphor, from the viewpoint of enhancing the atomization of the composition, 0.001 to 0.075 w/v% of the composition is preferable, and 0.005 to 0.075 w/v% is more preferable. In the case of blending cineol, linalool, or geraniol, from the viewpoint of enhancing the atomization of the composition, 0.0005 to 0.075 w/v% of the composition is preferable, and 0.0025 to 0.075 w/v% is more preferable.

In the composition of the present invention, (D) retinol palmitic acid ester, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacrylo, from the viewpoint of further enhancing the atomization of the emulsion particles by the component (C). It is preferable to blend at least one selected from monooxyethylphosphorylcholine, sesame oil and castor oil. These may be used alone or in combination of two or more as appropriate. Among them, retinol palmitic acid ester, tocopherol acetate, glycerin, and propylene glycol are preferable.

The blending amount in the composition of the component (D) is preferably in the following ranges from the viewpoint of enhancing the atomization of the composition. When blending retinol palmitic acid ester and tocopherol acetate, 0.001 to 5.0 w/v% is preferable, 0.01 to 3.0 w/v% is more preferable, and 0.01 to 1.0 w/v% is still more preferable. When glycerin, propylene glycol, benzododecinium bromide, sesame oil, and castor oil are blended, 0.005 to 5.0 w/v% is preferable, 0.05 to 3.0 w/v% is more preferable, and 0.1 to 1.0 w/v % Is more preferred. In the case of blending 2-methacryloyloxyethylphosphorylcholine, 0.01 to 5.0 w/v% is preferable, 0.03 to 2.0 w/v% is more preferable, and 0.05 to 1.0 w/v% is even more preferable. Do.

[Other ingredients]

In the composition of the present invention, other components to be blended in the ophthalmic composition can be blended in an appropriate amount within a range not impairing the effects of the present invention. Examples of other components include preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, viscous agents, and drugs. These components can be blended individually by 1 type or by combining 2 or more types as appropriate. The blending amount of the components shown below is a preferable range when blending, and is an amount in the composition.

Among the preservatives, thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconic acid, methyl paraoxybenzoate, ethyl paraoxybenzoate, etc. are mentioned as preservatives having a hydrophobic part such as an alkyl chain or a benzene ring, but liquid paraffin leaks Since it becomes difficult to migrate to the oil layer, the composition 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 more preferably not substantially contained. Do.

Examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, and mannitol. In other words, these may be any of a D body, an L body, or a DL body. When a saccharide is blended, the blending amount thereof is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and still more preferably 0.001 to 0.1 w/v% in the composition.

As a buffering agent, citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, tromethamol, sodium hydrogen carbonate, etc. are mentioned, for example. In the case of blending a buffering agent, the blending amount is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 2 w/v%, and still more preferably 0.001 to 1 w/v% in the composition.

As a pH adjuster, an inorganic acid or an inorganic alkali agent is mentioned. For example, (dilute) hydrochloric acid is mentioned as an inorganic acid. Examples of the inorganic alkali agent include sodium hydroxide, potassium hydroxide, sodium carbonate and sodium hydrogen carbonate. The pH of the composition may be 3.5 to 13.0, and 3.5 to 8.0 are preferable, and 5.5 to 8.0 are more preferable from the viewpoint of further improving various symptoms caused by destabilization of the tear fluid layer. In addition, measurement of pH is performed at 25 degreeC using a pH meter (HM-25R, Toa DKK Co., Ltd.).

Examples of the tonicity agent include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. From the viewpoint of further improving the symptoms caused by the destabilization of the leakage fluid layer, it is preferable that at least one or more sodium chloride and potassium chloride are blended to be isotonic. The penetration pressure ratio of the composition to physiological saline solution is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and most preferably 0.83 to 1.20 from the viewpoint of further improving the symptoms caused by the instability of the tear fluid layer. In addition, the measurement of the permeation pressure is performed at 25°C using an automatic permeation pressure meter (A2O, Advanced Instruments).

As a stabilizer, sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene, etc. are mentioned, for example. When a stabilizer is blended, the blending amount thereof is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and still more preferably 0.001 to 0.1 w/v% in the composition.

As polyhydric alcohol, glycerin, propylene glycol, butylene glycol, polyethylene glycol, etc. are mentioned. When blending a polyhydric alcohol, the blending amount of the polyhydric alcohol is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and still more preferably 0.001 to 0.1 w/v% in the composition.

Examples of the viscosity aid include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, and carboxyvinyl polymer. In the case of blending a viscous agent, the blending amount is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and still more preferably 0.001 to 0.1 w/v% in the composition.

As oil components other than (A) liquid paraffin and (D), soybean oil, olive oil, corn oil, palm oil, almond oil, medium-chain fatty acid triglyceride, acetic acid-d-α-tocopherol, retinol palmitic acid ester, white petrolatum, purified lanolin , Cholesterol, mixed tocopherol, etc. are mentioned. When blending oil components other than liquid paraffin, the blending amount is preferably 0.001 to 1.0 w/v%, more preferably 0.001 to 0.5 w/v%, and most preferably 0.001 to 0.25 w/v%.

As a drug (pharmaceutically active ingredient), for example, a decongestion component (e.g., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, napazoline hydrochloride, napazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine Hydrochloride, etc.), anti-salt/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), antihistamines (e.g., diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavinadenin dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.) , Amino acids (for example, L-aspartate potassium, L-aspartate magnesium, L-aspartate potassium/magnesium (equivalent mixture), aminoethylsulfonic acid, etc.), sulfa agents, and the like. In the case of compounding a drug, the amount of the drug may be selected from the appropriate amount of each drug, but in the composition, 0.001 to 5.0 w/v% is preferable, 0.001 to 1 w/v% is more preferable, and 0.001 to 0.1 w/ v% is more preferred.

[Manufacturing method]

The method for producing the composition of the present invention is not particularly limited, and can be obtained by mixing components (A), (B), and (C) and optional components as necessary. For example, a mixed solution of oily components such as (A), some or all of the components (B) and (C) is emulsified by mixing with an aqueous solution containing an aqueous component, and after adjusting the pH, the total volume is added to water. It can be obtained by adjusting by. The mixing method of each liquid may be a general method, and it is appropriately performed using a pulsator, propeller blade, paddle blade, turbine blade, etc., but the number of rotations is not particularly limited, and it is preferably set to such an extent that it does not cause severe foaming. . The mixing temperature of each liquid is not particularly limited, but it is preferable that both the oily component and the surfactant component be at least the melting temperature, and specifically, it is appropriately selected from the range of 40 to 95°C. In other words, in the present invention, even without a high pressure emulsification step, by micronizing the emulsion particles in the composition, it is possible to increase the transmittance of the composition and to suppress the creaming due to long-term storage.

Further, after filling the obtained composition into a resin container, it is further sealed with a packaging body, and an inert gas in the space formed between the container and the packaging body may be sealed, and the ophthalmic composition is filled into a resin container, You may seal it with a package body together with an oxygen scavenger.

[Ophthalmic composition]

The composition of the present invention is a "aqueous ophthalmic composition". In the present invention, the "aqueous ophthalmic composition" refers to an ophthalmic composition in which the medium is water. Incidentally, the blending amount of water is preferably 90.0 to 99.5 w/v%, and more preferably 95.0 to 97.5 w/v% in the composition from the viewpoint of facilitating mixing with the tear fluid and further obtaining the effect of stabilizing the tear fluid layer. Do.

The particle diameter of the emulsion particles (the aggregate 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. The lower limit is not particularly limited, but may be 1 nm. In other words, 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 diameter is carried out under a constant temperature condition at 25°C using a constant temperature bath by various measuring devices to which principles such as light scattering are applied. As such an apparatus, it can measure with a particle diameter measuring apparatus (ELSZ-200ZS, Otsuka Electric Corporation make), for example.

The transmittance of the composition of the present invention is specifically, the transmittance at a wavelength of 600 nm measured using a spectrophotometer (for example, UV-1800, Shimadzu Corporation) may be 30 to 100%. And 50 to 100% are preferable, and 70 to 100% are more preferable.

The composition of the present invention is preferably a liquid from the viewpoint of facilitating adaptation to the eye, and the viscosity at 25°C is 20 mPa· in that it facilitates mixing with the tear fluid and further obtains the effect of stabilizing the tear fluid layer. s or less is preferable, 10 mPa·s or less is more preferable, and 5 mPa·s or less is still more preferable. In addition, the measuring method of the viscosity is performed using a cone plate type viscometer (DV2T, Eco Seiki Co., Ltd.).

The composition of the present invention can be suitably used as an eye drop, contact lens eye drop, eye wash, etc. From this point of view, it can be suitably used as an eye drop and an eye drop for a contact lens (eye drop for a person wearing a contact lens). Examples of the contact lenses include hard contact lenses, O ₂ hard contact lenses, soft contact lenses, silicone hydrogel soft contact lenses, and the like, and are not particularly limited.

When using as an eye drop or as an eye drop for contact lenses, it is preferable to instill 1 to 3 drops of 10 to 100 μL per time, 1 to 6 times per day, and there is a possibility that the effect of stabilizing the leakage fluid layer may decrease due to spillage from the eye. 1 to 3 drops of 10 to 50 μL per once, and 1 to 6 times per day are more preferable. 1 to 3 drops of 10 to 30 μL per once, 1 to 6 times per day are more preferable. When used as an eye cleanser, it is preferable to wash the eyes 3 to 6 mL per time and 3 to 6 times per day.

[Atomization method]

The present invention contains (A) liquid paraffin and (B) a nonionic surfactant, and the blending mass ratio of the component (A) and the component (B) represented by (B)/(A) is 3 ≤ (B) As a method for atomizing emulsion particles in an aqueous ophthalmic composition of /(A)≦25, there is provided a method for atomizing emulsion particles in which 0.0001 to 0.5 w/v% of (C) terpenoid is blended in the aqueous ophthalmic composition. Preferred components and blending amounts are the same as above. In other words, by fine-granulation, the composition can be made transparent, and the appearance storage stability can be improved. In other words, "appearance storage stability" means that when the composition is stored over time, aggregation, creaming, coalescence, floating, etc. of the aggregates of the component (A) and the component (B) are suppressed. In the atomization method, when (B)/(A) is outside the above range, the atomization effect by the component (C) cannot be obtained.

Example

Hereinafter, examples and comparative examples are shown to specifically describe the present invention, but the present invention is not limited to the following examples. Incidentally, in the following examples, when there is no special specification, "%" of the composition represents w/v%, and the ratio represents the mass ratio (the same value as the w/v% ratio).

[Examples, Comparative Examples]

Each of the aqueous components in the following table was dissolved in 90 mL of purified water, and heated and mixed at 90°C for 15 minutes. Separately, a preliminary mixture of (A) liquid paraffin, (B) nonionic surfactant and (C) 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, followed by heating and mixing at 90°C for 15 minutes. Then, it cooled to room temperature, adjusted the pH, and purified water was added so that it might become 100 mL. Incidentally, the viscosity of each example was in the range of 0.5 to 2.0 mPa·s. About the obtained composition, the following evaluation was performed. Record the results in the table.

[Atomization of emulsion particles]

The particle diameter of the emulsion particles in the composition immediately after production was measured using ELSZ-200ZS, manufactured by Otsuka Corporation. From the obtained particle diameter, the atomization of the emulsion particles in the composition is shown in the following evaluation criteria. The particle diameter was the average diameter (median diameter nm) of the volume-based particle size distribution calculated from the scattered light intensity, and was performed under constant temperature conditions at 25°C.

[Evaluation standard]

○: Compared with the comparative example which does not contain (C) component (and (D) component), micronization is confirmed

×: Compared with the comparative example not containing the (C) component (and (D) component), no atomization was observed.

[Measurement of transmittance]

The composition immediately after production was measured for transmittance (%) at a wavelength of 600 nm using an ultraviolet-visible near-infrared spectrophotometer UV-1800 (Shimazu Seisakusho Co., Ltd.).

[Improvement of transmittance]

○: Compared with the comparative example which does not contain the component (C) (and the component (D)), the transmittance was improved.

×: Compared with the comparative example not containing the (C) component (and (D) component), the transmittance was 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%

"○" or higher is called pass.

Comparing Samples 1-1 to 1-2 and Comparative Samples 1-1 to 1-2, the liquid paraffin as component (A) and POE castor oil as component (B) were 3≤(B)/(A)≤ By blending (C) l-menthol in the aqueous composition contained in a ratio of 25, the light transmittance of 600 nm was increased and the particle diameter was decreased. From the above point of view, by blending (C) l-menthol in the composition, the emulsion particles are micronized, and the transmittance of the composition is improved. On the other hand, when comparing Comparative Samples 1-3 with Comparative Samples 1-3', when (B)/(A) is 1, the particle diameter and transmittance were almost the same, and the above effect was not obtained.

In the following external appearance storage stability evaluation, all of the compositions of Examples were "o".

[Appearance storage stability]

20 g of the composition was put into a glass bottle (20 mL in volume), and left still for 48 hours at room temperature. Then, the external appearance storage stability of the stored product was visually observed, and it judged with the following criteria.

[Evaluation standard]

○: The appearance does not change from immediately after production

×: Creaming or the like occurs, and there is a change in the appearance of the emulsion compared to immediately after production.

The compositions of the examples were all "◎" or "○" in the following tear oil layer stability test.

The results of Examples 3-1 and 3-7 and Comparative Examples A and B are shown below.

[Leakage oil layer stability test]

The evaluation of the leakage fluid layer stability was performed by measuring the BUT (break up time) of the leakage fluid layer using a dry eye observation device DR-1 (manufactured by Kowa Corporation). The DR-1 is a device capable of measuring the interference image of light reflected from the interface between the surface of the leaky fluid layer and the water layer. In healthy eyes, a uniform gray or white interference image is observed, and when the tear fluid layer collapses, the interference image disappears. Subjects were instilled with 30 µL of each composition, and after 10 minutes had elapsed, the eyes were blinked several times, and the time from blinking to the collapse of the tear fluid layer (oil layer BUT) was measured. As subjects, 13 eyes of 7 people with oil layer BUT of 10 seconds or less before instillation were selected. The result is shown in the following evaluation criteria from the average value of 13 eyes of 7 people. It was judged that the oil layer BUT, which was less than 10 seconds, did not exceed 10 seconds for a composition that did not contain fluctuations within days or days, and liquid paraffin, and that improvement for more than 10 seconds had sufficient usefulness.

[Evaluation standard]

◎: Oil layer BUT is more than 60 seconds

○: Oil layer BUT is 30 seconds or more and less than 60 seconds

●: Oil layer BUT is more than 10 seconds and less than 30 seconds

× (Not possible): Oil layer BUT is less than 10 seconds

More than “●” is called pass.

In the aqueous ophthalmic composition of the present invention, the effect of stabilizing the tear fluid layer was confirmed.

The raw materials used in preparing the Examples and Comparative Examples are shown below. The amount of each component in the table is the amount in terms of pure powder.

Liquid paraffin: The 16th revised Japanese Pharmacy Act 1 (37.8℃) Kinematic viscosity 76.6mm2/s (KAYDOL, manufactured by Shima Boweki Co., Ltd.)

Liquid paraffin: The 16th revised Japanese Pharmacy Act 1 (37.8℃) Kinematic viscosity 34.8mm2/s (Hi-Call M-172, manufactured by Kaneda Corporation)

Polyoxyethylene (POE) castor oil (polyoxyethylene castor oil 35: Uniox C35, manufactured by Nichiyu 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)

PEG monostearate (polyethylene glycol monostearate (100): EMALEX8100, manufactured by Nippon Emulsion Co., Ltd.)

POE sorbitan fatty acid ester (polyoxyethylene (20) sorbitanoleic acid ester: Leodol TW-O120V, manufactured by Gao Corporation)

POEPOP glycol (polyoxyethylene (200) polyoxypropylene (70) glycol) (LutrolF127, manufactured by BASF Japan)

l-menthol (made by Suzuki Hakka Co., Ltd.)

dl-campo (manufactured by Nippon Seika Co., Ltd.)

d-borneol (manufactured by Yanagisawa Masami Shoten Co., Ltd.)

Geraniol (manufactured by Takasa Koryo High School Co., Ltd.)

Cineol (manufactured by Takasa Koryo High School Co., Ltd.)

Linalool (manufactured by Takasa Koryo High School Co., Ltd.)

Boric acid (manufactured by Kanto Chemical Co., Ltd.)

Trometa Mall (manufactured by Kanto Chemical Co., Ltd.)

Sodium edetate hydrate (Klewat N, manufactured by Nagase Chemtex Co., Ltd.)

Sodium chloride (manufactured by Tomita Seiyaku Co., Ltd.)

Sodium hydroxide (manufactured by Wako Junyaku High School)

Retinol palmitic acid ester (DSM Nutrition Japan Co., Ltd. product, retinol palmitic acid ester, 174 units/g)

D-α-tocopherol acetate (Riken E acetate α, manufactured by Riken Vitamin Co., Ltd.)

Glycerin (Japanese pharmacy glycerin, manufactured by ADEKA Co., Ltd.)

Propylene glycol (Propylene glycol in Japanese pharmacy, manufactured by ADEKA Co., Ltd.)

Benzododecinium bromide (benzyldodecyldimethylammonium bromide, manufactured by Wako Junyaku Kogyo Co., Ltd.)

Sesame oil (Japanese pharmacy store sesame oil, manufactured by Kaneda Corporation)

Castor oil (castor oil at a Japanese pharmacy, manufactured by Kaneda Corporation)

Claims (7)

(A) liquid paraffin, (B) nonionic surfactant, (C) terpenoid is contained, and the compounding mass ratio of (A) component and (B) component represented by (B)/(A) is 3 <(B)/(A)<=25, and the blending amount of component (C) is 0.0001 to 0.5w/v%, The aqueous ophthalmic composition. According to claim 1, further, (D) selected from retinol palmitic acid ester, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyloxyethylphosphorylcholine, sesame oil and castor oil An aqueous ophthalmic composition comprising at least one of which is. The aqueous ophthalmology according to claim 1 or 2, wherein the component (B) contains at least one selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. Dragon composition. The aqueous ophthalmic composition according to any one of claims 1 to 3, wherein the component (C) is at least one selected from menthol, menthone, campo, borneol, geraniol, cineol and linalool. . The aqueous ophthalmic composition according to claim 4, wherein the component (C) is menthol. The aqueous ophthalmic composition according to any one of claims 1 to 5, wherein the transmittance is 50% or more. (A) Liquid paraffin and (B) nonionic surfactant are contained, and the compounding mass ratio of the component (A) and the component (B) represented by (B)/(A) is 3 ≤ (B)/(A) A method for atomizing emulsion particles in an aqueous ophthalmic composition of ?25, wherein 0.0001 to 0.5 w/v% of (C) terpenoid is blended in the aqueous ophthalmic composition.