TWI787221B - Ophthalmic composition and its production method - Google Patents

Abstract

An ophthalmic composition, which contains: (A) at least one selected from (A-1) vitamin A and (A-2) vitamin E; and (B) a nonionic surfactant, the mass ratio of which is formulated Satisfy (A-1)/[(A-1)+(A-2)]≦0.1, 0.05<[(B-1)+(B-2)+(B-3)]/(A), [ (B-1)/0.25+(B-2)/0.01+(B-3)/0.1]/[(A-1)+(A-2)]×(A-1)/[(A-1 )+(A-2)]+[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/[(A-1)+(A-2)]×( A-2)/[(A-1)+(A-2)]≦10, and the transmittance of the ophthalmic composition is 70% or more.

Description

Composition for ophthalmology and its production method

The present invention relates to an ophthalmic composition containing one or more vitamins selected from vitamin A and vitamin E and a production method thereof.

The tear oil layer prevents the evaporation of tear moisture and removes foreign matter, so it is essential to maintain the function of the eye, and it needs to be stabilized on the surface of the eye in order to fully exert its function. This tear oil layer contains lipids (meibum) secreted from the meridian glands, and its main components are wax esters, cholesteryl esters, phospholipids, and the like. On the other hand, these components increase the proportion of saturated lipids due to aging or hormonal changes, which affect the stability of the tear oil layer, accelerate the evaporation of the tear water layer, and become the cause of dry eye symptoms. It is said that it has a lot to do with eye fatigue. In particular, it is known that, with regard to meridian insufficiency, excessive saturation of lipid proceeds to aggravate the symptoms. On the other hand, it has been reported that eye discomfort is also induced by the generation of lipid peroxide from the tear oil layer. The cause of lipid peroxide generation from the tear fluid oil layer includes oxidation caused by short-wavelength light such as ultraviolet light or blue light. In recent years, the work time using VDT equipment, which is a source of generation of blue light, has become longer, so it is considered that the risk of oxidation increases.

In order to suppress the generation of lipid peroxide in the tear oil layer, it is considered that an antioxidant component is supplied to the tear oil layer by an ophthalmic composition such as eye drops. However, in previous ophthalmic compositions, the antioxidant components could not sufficiently migrate to the tear oil layer and thus Expelled from the conjunctival sac, the effect of inhibiting the production of lipid peroxide is not sufficient.

[Prior art literature]

[Patent Document]

[Patent Document 1] Japanese Patent Laid-Open No. 2013-253063

The present invention is made in view of the above circumstances, and an object of the present invention is to provide a composition in which vitamin A or vitamin E, which is a fat-soluble antioxidant component, is easily released from the composition by tear dilution (hereinafter referred to as It is described as (A) component release from the composition), and these can be supplied to the tear oil layer, thereby suppressing the generation of lipid peroxide, and further preventing eye discomfort caused by lipid peroxide.

The inventors of the present invention have conducted diligent research to achieve the above object, and as a result, found that by making a composition with limited types and ratios of nonionic surfactants, diluting them in tears after instillation, by The vitamin A and/or vitamin E are released (separated, floated) from the composition and can be supplied to the tear oil layer. It was further found that the composition of the present invention can inhibit the production of lipid peroxide, thereby preventing eye fatigue and blurred eyes caused by lipid peroxide. Hazy, dry eyes, foreign body sensation, eye pain, glare, heavy eyelids, eye itching, eye discomfort, eye fat, tearing, congestion and other uncomfortable symptoms of the eyes, thus completing the present invention.

Therefore, the present invention provides the following ophthalmic composition and its production method.

[1]. An ophthalmic composition comprising:

(A) one or more selected from (A-1) vitamin A and (A-2) vitamin E; and (B) selected from (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene Hydrogenated castor oil and (B-3) more than one nonionic surfactant in other nonionic surfactants, the deployment mass ratio of these satisfies (A-1)/[(A-1)+(A-2 )]≦0.1, 0.05<[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)], [(B-1)/0.25+ (B-2)/0.01+(B-3)/0.1]/[(A-1)+(A-2)]×(A-1)/[(A-1)+(A-2)] +[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/[(A-1)+(A-2)]×(A-2)/[(A -1)+(A-2)]≦10, and the transmittance of the ophthalmic composition is 70% or more.

[2]. The ophthalmic composition according to [1], wherein the component (A) is (A-2) vitamin E.

[3]. The ophthalmic composition as described in [1] or [2], wherein (B) the nonionic surfactant comprises (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene castor oil One or more kinds of ethylene hydrogenated castor oil.

[4]. The ophthalmic composition according to any one of [1] to [3], further comprising (C) a terpene.

[5]. The ophthalmic composition according to any one of [1] to [4], which is an eye drop.

[6]. The ophthalmic composition according to any one of [1] to [5], which is used for suppressing tears The lipid peroxide of the liquid oil layer is produced or used to prevent eye discomfort symptoms caused by lipid peroxide.

[7]. A method for producing an ophthalmic composition, the ophthalmic composition being the ophthalmic composition described in any one of [1] to [6], the method comprising micronizing the ophthalmic composition by high-pressure emulsification transformation step.

The object of the present invention is to provide an ophthalmic composition and its production method, in which vitamin A, vitamin E, etc. are released by dilution of tears, and these can be sufficiently supplied to the tear oil layer, thereby inhibiting The production of lipid peroxide can prevent eye discomfort caused by lipid peroxide.

Hereinafter, the present invention will be described in detail.

(A) At least one selected from (A-1) vitamin A and (A-2) vitamin E

These are well-known components as fat-soluble vitamins.

(A-1) Vitamin A

As vitamin A, for example, in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters, and the like can be used alone or in appropriate combination of two or more. . specific and Examples thereof include retinyl palmitate, retinyl acetate, retinol, retinoic acid, and retinoids. Among them, retinyl palmitate is preferred.

(A-2) Vitamin E

As vitamin E, for example, tocopherol, tocotrienol (tocotrienol), and these salts and derivatives (esters) are used collectively. Specifically, there are d-α-tocopherol, d1-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, etc., and examples of derivatives thereof include vitamin E, B Ester (tocopheryl acetate), vitamin E nicotinate, vitamin E succinate, vitamin E hypolinoleate, etc., can be used alone or in combination of two or more as appropriate. Among them, tocopheryl acetate (d-α-tocopherol acetate, d1-α-tocopherol acetate, etc.) is preferable. The (A) component is preferably (A-2) vitamin E.

The total amount of (A-1) component and (A-2) component in the ophthalmic composition is preferably 0.0001W/V%~1W/V% (mass/volume%, g/100mL, the same below), more The best is 0.001W/V%~0.5W/V%, and the most preferable is 0.01W/V%~0.1W/V%. By setting it as 0.0001 W/V% or more, an antioxidant effect can be exhibited further, and when it is 1 W/V% or more, it will become easy to feel eye irritation.

In the present invention, (A-1)/[(A-1)+(A-2)]≦0.1. When this ratio exceeds 0.1, the releasability of (A) component from a composition will become inadequate.

Furthermore, from the viewpoint of releasability from the composition, the compounding amount of the component (A-1) is not particularly limited as long as it satisfies the above-mentioned ratio, but it is preferably 0W/V% to 0.1W in the composition /V%, can also be 0W/V%. On the other hand, from the viewpoint of inhibiting lipid peroxidation, it is preferable to contain 0.005 W/V% or more. (A-2) Preparation of ingredients The amount is not particularly limited as long as it satisfies the ratio, but is preferably 0.00009W/V%~1W/V%, more preferably 0.001W/V%~0.5W/V%, and still more preferably 0.01W/V% ~0.1W/V%.

(B) Non-ionic surfactant

The (B) nonionic surfactant of the present invention is classified into (B-1) polyoxyethylene castor oil (sometimes described as POE castor oil), (B-2) polyoxyethylene hydrogenated castor oil (sometimes described as POE hydrogenated castor oil), (B-3) other nonionic surfactants, and are one or more nonionic surfactants selected from these. As component (B), since release from the composition can be maintained even when formulated at a relatively high concentration, it is preferable to use components selected from (B-1) in terms of the clarity of the composition. One or more types of polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. Furthermore, from the viewpoint of composition stability, it is more preferable to mix two or more types of nonionic surfactants.

(B-1) Polyoxyethylene castor oil

Polyoxyethylene castor oil (POE castor oil) is a compound obtained by adding and polymerizing ethylene oxide to castor oil, and several types are known in which the average molar number of added ethylene oxide is different. The average number of moles of ethylene oxide added to polyoxyethylene castor oil is not particularly limited, and can be, for example, 3 moles to 60 moles. Specifically, polyoxyethylene castor oil 3 (the value is the average added mole number of ethylene oxide, the same applies hereinafter), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35 , Polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, etc. These polyoxyethylene castor oils can be used alone or in combination of two or more. use. Among them, polyoxyethylene castor oil 35 is preferably used.

The compounding amount of the component (B-1) is not particularly limited as long as it satisfies the following ratio, but it is preferably 0.000001 W/V% or more in the composition, more preferably 0.00001 W/V% or more. By setting it as above, a composition becomes more uniform. From the viewpoint of safety, it is preferably 1.0 W/V% or less.

(B-2) Polyoxyethylene hydrogenated castor oil

Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by adding and polymerizing ethylene oxide to hydrogenated castor oil, and several types are known in which the average molar number of added ethylene oxide is different. The average added mole number of ethylene oxide in polyoxyethylene hydrogenated castor oil is not particularly limited, and may be 5 to 100 moles as an example. Specifically, polyoxyethylene hydrogenated castor oil 5 (the value is the average added mole number of ethylene oxide, the same applies below), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene Hydrogenated castor oil 30, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, polyoxyethylene hydrogenated castor oil 100, etc. These polyoxyethylene hydrogenated castor oils can be used individually by 1 type or in appropriate combination of 2 or more types. Among them, polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 are preferably used.

The compounding amount of the component (B-2) is not particularly limited as long as it satisfies the following ratio, but it is preferably 0.000001 W/V% or more in the composition, more preferably 0.00001 W/V% or more. By setting it as above, a composition becomes more uniform. From the viewpoint of safety, it is preferably 1.0 W/V% or less.

(B-3) Other nonionic surfactants

Examples of nonionic surfactants other than (B-1) and (B-2) include polysorbate 80 (polyoxyethylene (20) sorbitan oleate) (values in ( ) are ethylene oxide The average number of added moles, the same below), represented by polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester), polyoxyethylene-polyoxypropylene block copolymer (POEPOP diol) poloxamer, polyethylene glycol monostearate represented by polyethylene glycol monostearate (10), etc., can be used alone or in combination of two or more. Among them, phospholipids such as lecithin or hydrogenated lecithin, phosphatidylcholine, or phosphatidylglycerol, which are difficult to desorb from the interface, are not separated from vitamin A and/or vitamin E by tear dilution, and are difficult to release into the tear oil layer. Therefore, it is preferable not to include substantially.

The blending amount when blending the component (B-3) is not particularly limited as long as it satisfies the following ratio, but it is preferably 0.000001W/V% or more in the composition, more preferably 0.00001W/V% or more, by setting As described above, the composition becomes more uniform. From the viewpoint of safety, it is preferably 0.5 W/V% or less.

(B) The nonionic surfactant of a component can be prepared in the following ratio. In addition, the following ratio is a W/V% ratio, and it becomes the same value as a mass ratio.

0.05<[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)], [(B-1)/0.25+(B-2) /0.01+(B-3)/0.1]/[(A-1)+(A-2)]×(A-1)/[(A-1)+(A-2)]+[(B- 1)/0.1+(B-2)/0.2+(B-3)/0.05]/[(A-1)+(A-2)]×(A-2)/[(A-1)+( A-2)]≦10,

(B-1) Polyoxyethylene castor oil

(B-2) Polyoxyethylene hydrogenated castor oil

(B-3) Other nonionic surfactants

[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)] is the blending lower limit of (B) component, which specifies (B) non-ionic interface The quantity of an active agent with respect to (A) component. If 0.05<[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)] is not satisfied, a uniform composition cannot be obtained and Set as the target transmittance. Furthermore, the ratio is more preferably 0.1≦, further preferably 0.5≦. Furthermore, the upper limit of [(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)] is not particularly limited. From the viewpoint of the releasability of substances, it is preferably 2.0 or less.

On the other hand, the deployment upper limit is [(B-1)/0.25+(B-2)/0.01+(B-3)/0.1]/[(A-1)+(A-2)]×(A- 1)/[(A-1)+(A-2)]+[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/[(A-1)+ (A-2)]×(A-2)/[(A-1)+(A-2)]≦10, and if the above-mentioned conditions are not satisfied, the target releasability of the component (A) cannot be obtained. The ratio is preferably≦8. Furthermore, [(B-1)/0.25+(B-2)/0.01+(B-3)/0.1]/[(A-1)+(A-2)]×(A-1)/[ (A-1)+(A-2)]+[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/[(A-1)+(A-2 )]×(A-2)/[(A-1)+(A-2)] is not particularly limited, but it is preferably more than 0.25 from the viewpoint of transmittance.

The above-mentioned formulas for determining the preparation conditions define the amounts of (B-1), (B-2), (B-3) relative to (A-1), (A-2). According to the kind of (B) nonionic surfactant Since the compounding conditions of (A) are different according to the type, the types of (B) components are respectively divided by inherent coefficients. The inherent coefficient means, for example, that (B-1) has a compounding upper limit 2.5 times higher than (B-3) when comparing (B-1)/0.25 and (B-3)/0.1. In addition, since the upper limit of each active agent formulation of (B) component differs depending on the type of (A) component, [(B-1)/0.25+(B-2)/0.01+(B-3)/0.1] represents The formula of the formulation upper limit of each (B) component with respect to (A-1), [(B-1)/0.1+(B-2)/0.2+(B-3)/0.05] shows that each (B) The formula of the upper limit of the compounding of a component with respect to (A-2). Divide these by the sum (A-1)+(A-2) of the (A) component. Furthermore, in the case where both (A-1) and (A-2) are included, the influence is greater or lesser depending on the deployment ratio, so as its weight, multiply (A-1)/[(A- 1)+(A-2)] and (A-2)/[(A-1)+(A-2)].

For example, in the case of (A-2) component 1.0W/V%, if (B-1) alone, it needs to be more than 0.05W/V% and 1.0W/V% or less, if (B-2) It needs to be more than 0.05W/V% and 2.0W/V% or less alone, and (B-3) alone needs to be more than 0.05W/V% and 0.5W/V% or less. In the case of the composite composition of (A-1) and (A-2), for example, in the case of (A-1) component 0.1W/V% and (A-2) component 0.9W/V%, if ( B-1) alone, it needs to be more than 0.05W/V% and 1.1W/V% or less, and if (B-2) is alone, it needs to be more than 0.05W/V% and 0.7W/V% or less, If (B-3) is independent, it needs to be more than 0.05 W/V% and 0.5 W/V% or less.

Furthermore, cationic surfactants represented by benzalkonium chloride or benzethonium chloride, The anionic surfactant represented by sodium lauryl sulfate or sorbic acid or a salt thereof, and the amphoteric surfactant represented by laurylamine oxide inhibit the separation of the (A) component and the surfactant by tear dilution, The component (A) is less likely to migrate to the tear oil layer, so it is more preferably 0.1 W/V% or less in the composition, more preferably 0.01 W/V% or less, and is most preferably not substantially contained.

The ophthalmic composition of this invention may further contain (C) terpene. By compounding terpenoids, the release property of the component (A) from the composition can be improved to adjust the release property, and furthermore, the effect of suppressing the generation of lipid peroxide can be enhanced. The terpenes of the present invention have a structure having an isoprene unit as a constituent unit, and examples thereof include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. In addition, monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes exist depending on the number of carbon atoms. Specifically, monoterpenes such as menthol, menthone, camphor, borneol, borneol, geraniol, eucalyptol, linalool, citronellol, and limonene; Tetraterpenes such as terpenes, carotenoids, etc. Among them, monoterpenes are preferably used. Any of d-body, l-body, or dl-body may be used for these terpenes. Among them, menthol, menthone, camphor, borneol, geraniol, eucalyptol, and linalool are preferred, and menthol, camphor, borneol, geraniol, eucalyptol, and linalool are more preferred. In addition, in this invention, the essential oil containing the said compound can also be used as a terpene. Examples of such essential oils include eucalyptus oil, bergamot oil, anise oil, rose oil, mentha oil, peppermint oil, spearmint oil, and dipterocarp essential oils, rosemary oil, lavender oil, etc. Bergamot oil and eucalyptus oil are preferable at the point of improving the releasability of the component (A) from the composition.

The blending amount of (C) component is 0.0001W/V%~0.2W/V% in the composition, which can be selected according to the type of (C) component, other blending ingredients such as (B) component and their blending amount, etc. The best is 0.001W/V%~0.1W/V%. In this compounded concentration range, there is little concern about the precipitation of (C) terpenoids regardless of the type or compounded amount of other compounded components. In addition, from the viewpoint of suppressing the generation of lipid peroxide, it is more preferably 0.005 W/V% or more, and from the viewpoint of reducing irritation, it is further preferably 0.075 W/V% or less.

[other ingredients]

Appropriate amounts of other components can be formulated in the composition of the present invention within the range not impairing the effect of the present invention. Examples of other components include oil components, preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, viscous agents, drugs, and the like. These components can be formulated individually by 1 type or in combination of 2 or more types suitably. The compounding quantity of the component shown below is a preferable range at the time of compounding.

Examples of oil components include castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglycerides, white petrolatum, purified lanolin, cholesterol, mixed tocopherols, and liquid paraffin Wait. The blending amount of the oil component in the composition is preferably 0.001W/V%~1.0W/V%, more preferably 0.001W/V%~0.5W/V%, and most preferably 0.001W/V%~0.25W /V%.

Examples of preservatives having a hydrophobic portion such as an alkyl chain or a benzene ring include: thimerosal, phenylethyl alcohol, alkylaminoethylglycine, gluconate chloride Hexidine (chlorhexidine gluconate), methyl p-oxybenzoate, ethyl p-oxybenzoate, etc., (A) component is difficult to migrate to the tear oil layer, so in In the composition, it is preferably at most 0.1 W/V%, more preferably at most 0.01 W/V%, and still more preferably not substantially contained.

As sugars, glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc. are mentioned. Furthermore, these may be any of d-body, l-body or dl-body. The blending amount of sugar in the composition is preferably 0.001W/V%~5.0W/V%, more preferably 0.001W/V%~1W/V%, and even more preferably 0.001W/V%~0.1W/V %.

Examples of the buffering agent include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogenphosphate, sodium dihydrogenphosphate, glacial acetic acid, tromethamine, and sodium hydrogencarbonate. The amount of the buffering agent in the composition is preferably 0.001W/V%~5.0W/V%, more preferably 0.001W/V%~2W/V%, and more preferably 0.001W/V%~1W/V %.

As a pH adjuster, an inorganic acid or an inorganic alkaline agent is mentioned. For example, (diluted) hydrochloric acid is mentioned as an inorganic acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the like. The pH of the composition is preferably from 3.5 to 8.0, more preferably from 5.5 to 8.0. In addition, the measurement of pH was performed at 25 degreeC using the pH meter (HM-25R, Toa DKK Co., Ltd.).

As a tonicity agent, for example, sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. can be enumerated. Best for tensioning. The relative saline osmotic pressure of the composition is preferably 0.60-2.00, more preferably 0.60-1.55, most preferably 0.83-1.20. Furthermore, the measurement of osmotic pressure was carried out at 25° C. using an automatic osmometer (A2O, Advanced Instruments, Inc.).

As a stabilizer, edetate sodium, edetate sodium hydrate, cyclodextrin, sulfite, dibutylhydroxytoluene etc. are mentioned, for example. The blending amount of the stabilizer in the composition is preferably 0.001W/V%~5.0W/V%, more preferably 0.001W/V%~1W/V%, more preferably 0.001W/V%~0.1W/ V%. Since dibutylhydroxytoluene inhibits the separation of (A) component and surfactant by tear fluid dilution, since it is difficult to supply (A) component to a tear fluid oil layer, it is more preferable not to contain substantially.

Glycerin, propylene glycol, butylene glycol, polyethylene glycol etc. are mentioned as a polyhydric alcohol. In the case of blending polyols, the blending amount of polyols in the composition is preferably 0.001W/V%~5.0W/V%, more preferably 0.001W/V%~1W/V%, even more preferably 0.001 W/V%~0.1W/V%.

Examples of viscous agents include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, Carboxyvinyl polymer, etc. In the case of blending a viscous agent, the blending amount in the composition is preferably 0.001W/V%~5.0W/V%, more preferably 0.001W/V%~1W/V%, and even more preferably 0.001W/V% V%~0.1W/V%.

As the drug (pharmaceutical active ingredient), for example, a decongestant ingredient (for example, epinephrine (epinephrine), epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline (naphazoline) salt salt, naphazoline nitrate, phenylephrine (phenylephrine) hydrochloride, dl-methylephedrine hydrochloride, etc.), anti-inflammatory. Astringents (eg, neostigmine methyl sulfate, ε-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, azulene Sodium sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), antihistamines (e.g., diphenhydramine hydrochloride, chlorpheniramine salt (chlorpheniramine maleate), water-soluble vitamins (flavin adenine dinucleotide sodium (flavin adenine dinucleotide sodium), cyanocobalamin (cyanocobalamin), pyridoxine hydrochloride (pyridoxine hydrochloride), pantothene Alcohol (panthenol), calcium pantothenate, sodium pantothenate, etc.), amino acids (for example, potassium L-aspartate, magnesium L-aspartate, potassium L-aspartate. Magnesium (equivalent mixture), amino ethyl sulfonic acid, sodium chondroitin sulfate, etc.), sulfonamide (sulfa drug), etc. In the case of compounding drugs, the content of the drug can be selected according to the effective adaptive amount of each drug, but it is preferably 0.001W/V%~5.0W/V% in the composition, and more preferably 0.001W/V%~ 1W/V%, and preferably 0.001W/V%~0.1W/V%.

[Production method]

The method for producing the composition of the present invention is not particularly limited, and can be obtained, for example, by mixing a mixed solution of an oily component such as (A) component and a surfactant component such as (B) component with an aqueous solution containing an aqueous component After emulsification and pH adjustment, the total volume was adjusted with water. The mixing method of each liquid can be a general method, and can be suitably carried out by using a pulsator, a propeller blade, a blade, a turbine blade, etc., and the rotation speed is not particularly limited, but it is preferable to set it to a level that does not cause violent foaming . The mixing temperature of each liquid is not particularly limited, but it is preferable that both the oily component and the surfactant component are above the melting temperature, specifically, it is suitably selected from the range of 40°C to 95°C. It is more preferable to perform a micronization step by high-pressure emulsification. Regarding the high-pressure emulsification conditions, mention From the point of view of clarification of high composition, it is preferable to increase the number of passes under high pressure, and from the point of view of improving production efficiency, it is preferable to reduce the number of passes under low pressure. The injection pressure is preferably 100MPa~245MPa, and more preferably Preferably it is 150MPa~245MPa, more preferably 200MPa~245MPa. It is preferable to further apply back pressure, and it is preferably 1MPa~10MPa, more preferably 2MPa~5MPa. Furthermore, the number of passes is preferably 1 time to 10 times, more preferably 1 time to 5 times. The temperature at the time of high-pressure emulsification is preferably selected from the range of 20°C to 90°C.

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

[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 vehicle is water. Furthermore, in terms of being easy to mix with tears so that component (A) can easily migrate to tears, the amount of water formulated in the composition is preferably 90.0W/V%~99.5W/V%, more preferably 95.0 W/V%~98.0W/V%.

In terms of being easy to adapt to the eyes, the composition of the present invention is preferably a liquid, and in terms of being easy to mix with tears so that component (A) can easily migrate to tears, the viscosity at 25°C is preferably 20mPa. s or less, more preferably 10mPa. s or less, and preferably 5mPa. s or less, preferably 2mPa. below s. In addition, the measuring method of the viscosity was performed using the cone-plate viscometer (DV2T, Yinghong Seiki Co., Ltd.).

The composition of the present invention is preferably clear from the point of view of facilitating detection of foreign substances. Specifically, the transmittance at a wavelength of 600 nm measured using a spectrophotometer (UV-1800, Shimadzu Corporation) is 70% or more, preferably 70% to 100%, more preferably 75% to 100%, More preferably, it is 90%~100%.

The median diameter of the association of the surfactant and component (A) contained in the composition of the present invention is measured using a particle diameter measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.). In terms of properties, it is preferably from 1nm to 200nm, more preferably from 1nm to 100nm, further preferably from 1nm to 60nm, and especially preferably from 1nm to 40nm.

The composition of the present invention can be preferably used as eye drops, eye drops for contact lenses, eye washes, etc., because the tear dilution ratio is high, and the detachment of the surfactant from (A) component is further promoted, and the separation of (A) component In terms of improving the release properties of the composition and effectively supplying the (A) component to the tear oil layer, it can be used particularly preferably as eye drops, eye drops for contact lenses (drops for contact lens wearers) eye drops) and other eye drops. Contact lenses are not particularly limited to hard contact lenses, soft contact lenses, and the like.

When used as eye drops or eye drops for contact lenses, preferably 1 drop to 3 drops of 10 μL to 100 μL each time and 1 to 6 times a day, there is lipid peroxide caused by overflow from the eyes There is concern about the reduction of the inhibitory effect, so it is better to instill 1 to 3 drops of 10 μL to 50 μL each time and 1 to 6 times a day, and it is more preferable to instill 1 drop to 3 drops of 10 μL to 30 μL each time and to instill it once a day ~6 times. When used as an eyewash, it is preferably 3mL~6mL each time and wash eyes 3~6 times a day.

The composition of the present invention prevents the oxidation of tear fluid lipids caused by VDT operations or ultraviolet rays, and has uncomfortable symptoms of the eyes (eye fatigue, blurred eyes, hazy eyes, dry eyes, foreign body sensation, eye pain, glare) caused by lipid peroxides. , heavy eyelids, eye itching, eye discomfort, eye fat, tearing, congestion, etc.), it is effective for inhibiting the production of lipid peroxide in the tear oil layer, and for preventing eye discomfort caused by lipid peroxide Comfort symptoms, especially effective for improving eye fatigue, foreign body sensation, eye pain, and eye discomfort.

The effective dose, administration method, formulation, etc. are as described above, for example, as the amount of (A) component, 0.0001 mg to 1 mg is administered to the eyes once to 6 times per adult per day.

[Example]

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 addition, in the following examples, unless otherwise indicated, "%" of a composition is W/V%. The ratio is a W/V% ratio, and has the same value as the mass ratio.

[Example, comparative example]

Each aqueous component described in the following table|surface was dissolved in 90 mL of water, and it heated and mixed at 90 degreeC for 15 minutes. Simultaneously, a premix of (A) component and (B) component was produced, and it heat-mixed at 90 degreeC for 15 minutes. Next, a predetermined amount of the premix was added to the aqueous solution, followed by heating and mixing at 90° C. for 15 minutes. Then, it cooled to room temperature, adjusted pH, and added water so that it may become 100 mL. Furthermore, using a high-pressure emulsification machine (Star Burst Mini, Japan Sugino Machine (sugino machine) (stock)), The treatment was performed five times at a spray pressure of 200 MPa and a back pressure of 3 MPa to prepare eye drops (ophthalmic composition). The obtained eye drops were evaluated as follows. Record the results together in the table. Furthermore, the viscosity of the eye drops obtained in each example at 25°C was 0.5mPa. s~2.0mPa． range of s.

[Releasability of (A) component by dilution]

It is said that the average human tears are 7 μL, and in the case of instilling eye drops of 30 μL to 60 μL, the dilution is about 1.12 to 1.23 times. In this test, in order to evaluate the composition (A) which is soluble by tear dilution, it floats (release) at the air-liquid interface, and observes when the composition is diluted with a dilution factor of about 1.2 times using physiological saline as a model tear fluid. The (A) component on the water surface is free. Use a measuring bottle with a narrow opening for easy observation. Specifically, 10 mL of physiological saline was added to a 50 mL measuring bottle, and eye drops were injected into the opening. In addition, a measuring bottle having a dilution rate of 1.2 times when pouring into the opening was used, and the area of the opening was 152 mm ² . Regarding the observation of component (A) on the water surface, a fluorescent lamp is used as a light source and the liquid surface is irradiated with light, the interference light of the oil floating on the liquid surface is observed, and the ratio of the area of the oil interference light occupied by the water surface is calculated, And it evaluated according to the following reference|standard. Furthermore, in any of the Examples and Comparative Examples, no interference light of the oil was observed in the case of no dilution. ○ and ◎ were set as pass.

[evaluation criteria]

◎: Oil interference light is observed on more than 10% of the water surface

○: Oil interference light is observed at less than 10% of the water surface

×: Oil interference light was not observed

[Generation of lipid peroxide from tear oil layer induced by ultraviolet irradiation Inhibition rate(%)]

As a model tear oil layer, an oil film produced by spreading on a water tank imitating rabbit meibum chloroform solution with physiological saline was used. Lipid composition differs depending on the type of meibum, but regarding the stability of the membrane, no difference was confirmed between human meibum and rabbit meibum, so rabbit meibum, which is easy to obtain, was used. The vicinity of the meridian gland opening of the eyelid (Funakoshi (Stock)) cut out from a rabbit was pressed with a finger, and the pressed paper (KimWipes) (manufactured by Nippon paper crecia (Stock)) was used to extract the pressed out of the meibum. Afterwards, put the wiping paper into a glass vial, soak it in a 1:1 mixture of chloroform and methanol (volume ratio), perform ultrasonic treatment for 10 minutes, and transfer the solution to another glass vial. in vial. This operation was repeated 3 times. After that, use the chloroform. The methanol mixture was cleaned with a Terumo syringe (manufactured by Terumo, 50 mL) and a membrane filter (manufactured by Merck Millipore, Millex GP, 0.22 μm), and the dry weight was measured with a precision balance (manufactured by Shimadzu Corporation, XS-104). Thereafter, chloroform was added to 0.5 mg/mL using a micro syringe (manufactured by Hamilton), and rabbit meibum was dissolved, and stored in a -20°C refrigerator. Return to room temperature before use, and confirm that there is no precipitate. Form a water layer with 1 mL of physiological saline in a 35 mm dish, spread rabbit meibum chloroform solution (0.5 mg/mL) on 100 μL of water, add 165 μL of each eye drop, and irradiate with UV (254 nm) for 1 hour. The solution was all recovered to the vial, and 0.5 mL of 35% trichloroacetic acid (trichloro acetic acid, TCA) solution, 1.0 mL of 0.5% thiobarbita were added thereto. Thiobarbituric acid (TBA) solution, 0.05 mL of 0.2% butylated hydroxytoluene (BHT) solution, 0.05 mL of 0.5% sodium dodecyl sulfate (SDS) solution, in Heat at 100°C for 30 minutes. After cooling, 0.5 mL of acetic acid and 1.0 mL of chloroform were added and stirred, then centrifuged (3,000 rpm×10 min), and the absorbance of the upper layer was measured at 532 nm. In the blank test, the absorbance was set to the absorbance when the same operation was performed except that the rabbit meibum chloroform solution was not spread in the above method. From the obtained absorbance, the inhibition rate (%) of the generation of lipid peroxide from the tear fluid oil layer was calculated based on the following formula. The results are shown by the following evaluation criteria. ●, ○, and ◎ were set as pass.

Inhibition rate of lipid peroxide generation from tear oil layer (%)=(1-(absorbance when eye drops were added-blank test)/(absorbance when no eye drops were added-blank test))×100%

[evaluation criteria]

◎: More than 50%

○: More than 30% and less than 50%

●: More than 10% and less than 30%

×: less than 10%

[Preventive effect of symptoms caused by VDT work]

Add 30 μL of each eye drop to both eyes of three healthy people, perform VDT operation (computer operation), and apply 0 (not felt at all) to 10 (very strongly felt) before and in the eyes for 10 minutes The subjective symptoms of eye fatigue, foreign body sensation, eye pain, and uncomfortable feeling in the eyes were scored after 60 minutes of instillation. Based on the average of the three The results are shown by the following evaluation criteria. ●, ○, and ◎ were set as pass.

[evaluation criteria]

◎: less than 5 points after 60 minutes (less than 5 points after 10 minutes and less than 5 points after 60 minutes)

○: Less than 5 points after 10 minutes

●: 5 points or more and less than 7 points after 10 minutes

×: 7 points or more after 10 minutes

[Transmittance]

The transmittance at a wavelength of 600 nm was measured for the eye drops immediately after production using a Hitachi spectrophotometer U-3310. Let 70% or more pass.

Raw materials used in the examples are shown below. Furthermore, unless otherwise specified, the amounts of each component in the table are the amounts converted to purity.

Retinyl palmitate (manufactured by DSM Nutrition Japan Co., Ltd.)

Acetate d-α-tocopherol (Riken E Acetate α, manufactured by Riken Vitamin Co., Ltd.)

Liquid paraffin (KAYDOL, made by Shima Trading Co., Ltd.)

Castor oil (Special A grade, manufactured by Ito Oil Co., Ltd.)

Sesame oil (made in Kaneda Co., Ltd.)

Polyoxyethylene castor oil 35: the average added mole number of ethylene oxide is 35 (Unioxs C35, manufactured by NOF Co., Ltd.)

Polyoxyethylene hydrogenated castor oil 40 (HCO40, manufactured by Japan Surfactant Industry Co., Ltd.)

Polyoxyethylene hydrogenated castor oil 60 (HCO60, manufactured by Japan Surfactant Industry Co., Ltd.)

Polyethylene glycol monostearate *1: The average molar number of ethylene oxide added is 10 (MYS10V, manufactured by Nippon Surfactant Industry Co., Ltd.)

Polyethylene glycol monostearate *2: The average added molar number of ethylene oxide is 40 (MYS40MV, manufactured by Nippon Surfactant Industry Co., Ltd.)

Polyethylene glycol monostearate *3: The average added molar number of ethylene oxide is 100 (EMALEX8100, manufactured by Nihon Emulsion Co., Ltd.)

POE sorbitan fatty acid ester (polysorbate 80, manufactured by Kao Co., Ltd.)

POEPOP diol (polyoxyethylene (196)-polyoxypropylene (67) block copolymer) (Lutrol F127, manufactured by BASF Japan)

Boric acid (manufactured by Kokai Pharmaceutical Co., Ltd.)

Tromethamine (manufactured by Kanto Chemical Co., Ltd.)

Edetate sodium hydrate (Clewat N, manufactured by Nagase Chemical Co., Ltd.)

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

Sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.)

Menthol (1-menthol, product made in Suzuki Mint Co., Ltd.)

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

Ice flakes (d-borneol, product made in Masami Yanagisawa store Co., Ltd.)

Geraniol (manufactured by Takasago Fragrance Industry Co., Ltd.)

Eucalyptol (manufactured by Takasago Fragrance Industry Co., Ltd.)

Linalool (manufactured by Takasago Fragrance Industry Co., Ltd.)

Bergamot oil (manufactured by Yamamoto Fragrance Co., Ltd.)

Eucalyptus oil (manufactured by Ogawa Fragrance Co., Ltd.)

Claims (9)

An ophthalmic composition comprising: (A) at least one selected from (A-1) vitamin A and (A-2) vitamin E; and (B) selected from (B-1) polyoxyethylene castor oil , (B-2) polyoxyethylene hydrogenated castor oil and (B-3) more than one nonionic surfactant in other nonionic surfactants, the deployment mass ratio of these satisfies (A-1)/[( A-1)+(A-2)]≦0.1, 0.05<[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)], [(B-1)/0.25+(B-2)/0.01+(B-3)/0.1]/[(A-1)+(A-2)]×(A-1)/[(A- 1)+(A-2)]+[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/[(A-1)+(A-2)]× (A-2)/[(A-1)+(A-2)]≦10, and the ophthalmic composition has a transmittance of 70% or more, and does not contain benzalkonium chloride. An ophthalmic composition comprising: (A) at least one selected from (A-1) vitamin A and (A-2) vitamin E; and (B) selected from (B-1) polyoxyethylene castor oil , (B-2) polyoxyethylene hydrogenated castor oil and (B-3) more than one nonionic surfactant in other nonionic surfactants, the deployment mass ratio of these satisfies (A-1)/[( A-1)+(A-2)]≦0.1, 0.05<[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)], In addition, the ophthalmic composition has a transmittance of 70% or more and does not contain benzalkonium chloride. For a 1.2-fold dilution made of physiological saline, a fluorescent lamp is used as a light source and light is irradiated on the liquid surface. When the interference light of the oil floating on the liquid surface is observed, the 1.2-fold dilution made of physiological saline is to add 10 mL of physiological saline to a 50 mL measuring bottle with an opening area of 152 mm ² , and then dilute the obtained The ophthalmic composition is injected into the opening. The ophthalmic composition as described in item 1 or item 2 of the patent application, wherein the component (A) is the (A-2) vitamin E. The ophthalmic composition as described in item 1 or item 2 of the scope of the patent application, wherein (B) the nonionic surfactant comprises polyoxyethylene castor oil selected from the (B-1) and the (B-2) ) One or more types of polyoxyethylene hydrogenated castor oil. The ophthalmic composition as described in claim 1 or claim 2, further comprising (C) terpenes. The ophthalmic composition described in item 1 or item 2 of the patent application does not contain cationic surfactant, anionic surfactant and amphoteric surfactant. The ophthalmic composition as described in item 1 or item 2 of the patent application, which is an eye drop. The ophthalmic composition as described in item 1 or item 2 of the patent scope of the application, which is used for inhibiting the production of lipid peroxide in the tear oil layer or for preventing Discomfort in the eyes caused by lipids. A method for producing an ophthalmic composition, the ophthalmic composition is the ophthalmic composition described in any one of the claims 1 to 8, the method includes miniaturization by high-pressure emulsification step.