JPWO2018117014A1 - Ophthalmic composition and method for producing the same - Google Patents

Abstract

(A) (A-1) One or more kinds selected from vitamin A and (A-2) vitamin E, and (B) a nonionic surfactant are contained, and their compounding mass ratio is (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 having a transmittance of 70% or more.

Description

  The present invention relates to an ophthalmic composition containing one or more selected from vitamin A and vitamin E.

  The tear fluid layer is essential for maintaining the function of the eye in order to prevent evaporation of water from tears and to remove foreign substances, and it must be stable on the surface of the eye to fulfill its role. is necessary. This tear oil layer is composed of lipids (meibum) secreted from the meibomian glands, and the main components are wax esters, cholesterol esters, phospholipids and the like. On the other hand, these components increase the percentage of saturated lipids due to aging and hormonal changes, affect the stabilization of the tear fluid layer, increase the evaporation of the tear fluid layer, and cause dry eye symptoms. Furthermore, it is said to have a deep relationship with eye fatigue. In particular, in meibomian gland dysfunction, it is known that lipid saturation proceeds excessively and the above symptoms worsen. On the other hand, it has been reported that the generation of lipid peroxide from the tear fluid layer also induces eye discomfort. The cause of the generation of lipid peroxide from the tear oil layer includes oxidation by light having a short wavelength such as ultraviolet light or blue light. In recent years, it has been considered that the risk of oxidation is increasing because the working time in the VDT equipment, which is the source of blue light, has been prolonged.

  In order to suppress the generation of lipid peroxide in the tear fluid layer, it is conceivable to supply an antioxidant component to the tear fluid layer with an ophthalmic composition such as eye drops. However, in the conventional ophthalmic composition, the antioxidant component is not sufficiently transferred to the tear fluid layer and is discharged from the conjunctival sac, and the effect of suppressing lipid peroxide generation is insufficient.

JP 2013-253063 A

  The present invention has been made in view of the above circumstances, and vitamin A and vitamin E, which are fat-soluble antioxidant components, are released from the composition by dilution of tears (hereinafter referred to as the release property of the component (A) from the composition). It is an object of the present invention to provide a composition that can be supplied to the tear oil layer, can suppress the generation of lipid peroxide, and can prevent discomfort caused by lipid peroxide.

  As a result of intensive studies to achieve the above-mentioned object, the present inventors have made vitamin A and / or dilute into tears after instillation by using a composition in which the type and ratio of the nonionic surfactant are limited. Alternatively, it was found that vitamin E can be released (separated / floated) from the composition and supplied to the tear oil layer. Furthermore, the composition of the present invention can suppress the generation of lipid peroxide, and further, eye fatigue, blurring of the eye, blurred vision, dryness of the eyes, foreign body sensation, eye pain, and dazzling eyes. The present inventors have found that eye discomfort can be prevented such as heavy eyes, itchy eyes, eye discomfort, eye grease, lacrimation, and hyperemia.

Accordingly, the present invention provides the following ophthalmic composition and method for producing the same.
[1]. (A) one or more selected from (A-1) vitamin A and (A-2) vitamin E;
One or more nonionic surfactants selected from (B) (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, and (B-3) other nonionic surfactants These blending mass ratios are
(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 an ophthalmic composition having a transmittance of 70% or more.
[2]. The ophthalmic composition according to [1], wherein the component (A) is (A-2) vitamin E.
[3]. The ophthalmology according to [1] or [2], wherein the (B) nonionic surfactant comprises one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. Composition.
[4]. Furthermore, (C) The ophthalmic composition in any one of [1]-[3] containing a terpenoid.
[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 lipid peroxide generation in a tear fluid layer or preventing ocular discomfort caused by lipid peroxide.
[7]. The method to manufacture the ophthalmic composition in any one of [1]-[6] including the refinement | miniaturization process by high pressure emulsification.

  Vitamin A, vitamin E, etc. are released by dilution of tears, they can be sufficiently supplied to the tear oil layer, the generation of lipid peroxide can be suppressed, and further, eye discomfort caused by lipid peroxide can be prevented An object is to provide an ophthalmic composition and a method for producing the same.

Hereinafter, the present invention will be described in detail.
One or more types selected from (A) (A-1) vitamin A and (A-2) vitamin E. These are ingredients known as fat-soluble vitamins.
(A-1) Vitamin A
Examples of vitamin A include, 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, etc., alone or in combination of two or more Can be used. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate is preferred.

(A-2) Vitamin E
As vitamin E, for example, tocopherol, tocotrienol, their salts, and derivatives (esters) are used as a generic term. Specifically, for example, there are d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and the like, and examples of these derivatives include vitamin E acetate (tocopherol acetate). , Vitamin E nicotinic acid ester, vitamin E succinic acid ester, vitamin E linolenic acid ester and the like can be mentioned, and these can be used singly or in appropriate combination of two or more. Of these, tocopherol acetate (such as d-α-tocopherol acetate and dl-α-tocopherol acetate) is preferable. As the component (A), (A-2) vitamin E is preferable.

  The total amount of the component (A-1) and the component (A-2) is preferably 0.0001 to 1 W / V% (mass / volume%, g / 100 mL, the same applies hereinafter) in the ophthalmic composition. 001 to 0.5 W / V% is more preferable, and 0.01 to 0.1 W / V% is particularly preferable. By setting it to 0.0001 W / V% or more, the antioxidant effect is more exhibited, and when it is 1 W / V% or more, it becomes easy to feel eye irritation.

  In the present invention, (A-1) / [(A-1) + (A-2)] ≦ 0.1. If this ratio exceeds 0.1, the releasability of the component (A) from the composition becomes insufficient.

  In addition, although the compounding quantity of (A-1) component will not be specifically limited if the said ratio is satisfy | filled from a viewpoint of the discharge | release from a composition, 0-0.1W / V% is preferable in a composition, 0W / V% may be sufficient. On the other hand, it is preferable to contain 0.005 W / V% or more from a viewpoint of lipid peroxide suppression. The amount of component (A-2) is not particularly limited as long as it satisfies the above ratio, but is preferably 0.00009 to 1 W / V%, more preferably 0.001 to 0.5 W / V%, and 01 to 0.1 W / V% is more preferable.

(B) Nonionic surfactant The (B) nonionic surfactant of the present invention includes (B-1) polyoxyethylene castor oil (may be described as POE castor oil), (B-2) polyoxy It is classified into ethylene hardened castor oil (may be described as POE hardened castor oil), (B-3) other nonionic surfactants, and is one or more nonionic surfactants selected from these. As the component (B), since the release from the composition can be maintained even when blended at a relatively high concentration, (B-1) polyoxyethylene castor oil and (B -2) It is preferable to use 1 or more types chosen from polyoxyethylene hydrogenated castor oil. Furthermore, it is more preferable that two or more kinds of nonionic surfactants are blended from the viewpoint of composition stability.

(B-1) Polyoxyethylene castor oil Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide to castor oil, and the number of average addition moles of ethylene oxide is different. The type of is known. Although there is no limitation in particular about the average addition mole number of the ethylene oxide in polyoxyethylene castor oil, 3-60 mol is illustrated. Specifically, polyoxyethylene castor oil 3 (the number is the average number of moles of ethylene oxide added, hereinafter the same), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor Examples include oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, and the like. These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. Among these, it is preferable to use polyoxyethylene castor oil 35.

  (B-1) Although the compounding quantity in the case of mix | blending a component will not be specifically limited if the following ratio is satisfy | filled, 0.000001 W / V% or more is preferable in a composition, and 0.00001 W / V% or more is more preferable. . By setting it as the above or more, a composition becomes more uniform. From the viewpoint of safety, 1.0 W / V% or less is preferable.

(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 is an average addition of ethylene oxide. Several types with different numbers of moles are known. Although there is no limitation in particular about the average addition mole number of the ethylene oxide in polyoxyethylene hydrogenated castor oil, 5-100 mol is illustrated. Specifically, polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 30, Examples include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, and polyoxyethylene hydrogenated castor oil 100. These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. Among these, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.

  (B-2) Although the compounding quantity in the case of mix | blending a component will not be specifically limited if the following ratio is satisfy | filled, 0.000001 W / V% or more is preferable in a composition, and 0.00001 W / V% or more is more preferable. . By setting it as the above or more, a composition becomes more uniform. From the viewpoint of safety, 1.0 W / V% or less is preferable.

(B-3) Other nonionic surfactants As nonionic surfactants other than (B-1) and (B-2), polysorbate 80 (polyoxyethylene (20) sorbitan monolaurate) (inside) The numerical values are the average added mole number of ethylene oxide, the same applies hereinafter, and polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester), poloxamer represented by polyoxyethylene-polyoxypropylene block copolymer (POEPOP glycol), mono Examples include polyethylene glycol monostearate typified by polyethylene glycol stearate (10), and these can be used alone or in combination of two or more. However, lecithin, hydrogenated lecithin, phospholipids such as phosphatidylcholine and phosphatidylglycerol, which are difficult to desorb from the interface, are not separated from vitamin A or / and vitamin E by dilution of tears, and are not easily transferred to the tear fluid layer. It is preferable not to be included.

  (B-3) Although the compounding quantity in the case of mix | blending a component will not be specifically limited if the following ratio is satisfy | filled, 0.000001 W / V% or more is preferable in a composition, More preferably, it is 0.00001 W / V% or more. And by setting it as the above or more, a composition becomes more uniform. From the viewpoint of safety, 0.5 W / V% or less is preferable.

(B) The nonionic surfactant of a component is mix | blended in the following ratios. In addition, although the following ratio is W / V% ratio, it becomes the same value as 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 the component (B), B) Defines the amount of nonionic surfactant. If 0.05 <[(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)] is not satisfied, a uniform composition is not obtained. The desired transmittance cannot be obtained. The ratio is more preferably 0.1 ≦, and further preferably 0.5 ≦. In addition, although the upper limit of [(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)] is not particularly limited, the composition of component (A) 2.0 or less is preferable from the viewpoint of releasability from water.

On the other hand,
[(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
If this is not satisfied, the desired component (A) release property cannot be obtained. The ratio is preferably ≦ 8. In addition,
[(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)])
The lower limit is not particularly limited, but is preferably more than 0.25 from the viewpoint of transmittance.

  The above formula for determining the blending conditions defines the amounts of (B-1), (B-2), and (B-3) relative to (A-1) and (A-2). (B) Since the blending conditions of (A) differ depending on the type of nonionic surfactant, each is divided by a specific coefficient for the type of component (B). For example, when comparing (B-1) /0.25 and (B-3) /0.1, the upper limit of blending of (B-1) is 2.5 times higher than (B-3). It means that. Moreover, since the upper limit of each active agent blending of the component (B) differs depending on the type of the component (A), [(B-1) /0.25+ (B-2) /0.01+ (B-3) / 0 .1] represents a formula relating to the upper limit of the amount of each component (B) relative to (A-1), and [[B-1) /0.1+ (B-2) /0.2+ (B-3) / 0. .05] represents a formula relating to the upper limit of blending of each component (B) relative to (A-2). They are divided by the sum (A-1) + (A-2) of the component (A). In addition, when both (A-1) and (A-2) are included, the influence is increased or decreased depending on the blending ratio, so that (A-1) / [(A-1) + (A-2) ] And (A-2) / [(A-1) + (A-2)].

  For example, in the case of (A-2) component 1.0 W / V%, if (B-1) alone, more than 0.05 W / V%, 1.0 W / V% or less, (B-2) alone If it exists, it is necessary to be more than 0.05 W / V% and not more than 2.0 W / V%, and if it is (B-3) alone, it needs to be more than 0.05 W / V% and 0.5 W / 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 0.1 W / V%, (A-2) component 0.9 W / V%, (B- 1) If alone,> 0.05 W / V%, 1.1 W / V% or less, (B-2) If alone,> 0.05 W / V%, 0.7 W / V% or less, (B -3) If it is single, it is necessary to make it more than 0.05 W / V% and 0.5 W / V% or less.

  Cationic surfactants typified by benzalkonium chloride and benzethonium chloride, anionic surfactants typified by sodium lauryl sulfate and sorbic acid or salts thereof, and amphoteric surfactants typified by lauramine oxide. The agent inhibits separation of the component (A) and the surfactant by dilution of the tears, and the component (A) is less likely to be transferred to the tear fluid layer, so that the content is preferably 0.1 W / V% or less in the composition. , 0.01 W / V% or less is more preferable, and it is particularly preferable that the content is not substantially contained.

  The ophthalmic composition of the present invention may further contain (C) a terpenoid. By blending the terpenoid, release properties such as enhancing the release properties of the component (A) from the composition can be adjusted, and further, the effect of suppressing the generation of lipid peroxide can be enhanced. The terpenoid in the present invention has a structure having an isoprene unit as a structural unit, and examples thereof include terpene hydrocarbon, terpene alcohol, terpene aldehyde, and terpene ketone. Also, depending on the number of carbons, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes. Specific examples include monoterpenes such as menthol, menthone, camphor, borneol, rünou, geraniol, cineole, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids. Among these, it is preferable to use a monoterpene. These terpenoids can be used in any of d-form, l-form or dl-form. Among these, menthol, menthone, camphor, borneol, geraniol, cineol and linalool are preferable, and menthol, camphor, borneol, geraniol, cineol and linalool are more preferable. 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, mint oil, peppermint oil, spearmint oil, and essential oils of dipterocarpaceae, rosmarin oil, lavender oil, and the like. (A) Bergamot oil and eucalyptus oil are preferable from the viewpoint of enhancing the release from the composition of the component.

  The blending amount of the component (C) is 0.0001 to 0.2 W / V% in the composition, and is appropriately selected from the other blending components such as the type of the component (C), the component (B) and the blending amount thereof. 0.001-0.1 W / V% is preferable. In this blending concentration range, there is little risk of precipitation of (C) terpenoids regardless of the types and blending amounts of other blending components. Moreover, 0.005 W / V% or more is more preferable from a viewpoint of lipid peroxide generation | occurrence | production suppression, and 0.075 W / V% or less is further more preferable from a viewpoint of reducing irritation.

[Other ingredients]
An appropriate amount of other components can be blended in the composition of the present invention as long as the effects of the present invention are not impaired. Examples of other components include oil components, preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, drugs, and the like. These components can be blended singly or in appropriate combination of two or more. The compounding amount of the components shown below is a preferable range when blending.

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

  Among the preservatives, examples of the preservative having a hydrophobic portion such as an alkyl chain or a benzene ring include thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconic acid, methyl paraoxybenzoate, ethyl paraoxybenzoate, and the like ( Since the component A) is less likely to be transferred to the tear oil layer, the composition preferably has a content of 0.1 W / V% or less, more preferably 0.01 W / V% or less, and even more preferably does not contain substantially.

  Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. In addition, these may be any of d-form, l-form, or dl-form. 0.001 to 5.0 W / V% is preferable in the composition, 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 buffer include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, sodium hydrogen carbonate and the like. The blending amount of the buffer is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 2 W / V%, and still more preferably 0.001 to 1 W / V%.

  Examples of the pH adjuster include an inorganic acid or an inorganic alkali agent. 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 hydrogen carbonate and the like. The pH of the composition is preferably 3.5 to 8.0, more preferably 5.5 to 8.0. The pH is measured at 25 ° C. using a pH meter (HM-25R, Toa DKK Co.).

  Examples of tonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. 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 most preferably 0.83 to 1.20. The osmotic pressure is measured using an automatic osmometer (A2O, Advanced Instruments) at 25 ° C.

  Examples of the stabilizer include sodium edetate, sodium edetate hydrate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like. The blending amount of the stabilizer is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 1 W / V%, and still more preferably 0.001 to 0.1 W / V%. Dibutylhydroxytoluene inhibits the separation of the component (A) and the surfactant due to dilution of tears, and the component (A) is less likely to be supplied to the tear fluid layer.

  Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. When the polyhydric alcohol is blended, the blending amount of the polyhydric alcohol is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 1 W / V%, and 0.001 to 0.00. 1 W / V% is more preferable.

  Examples of the thickener include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, and the like. When blending a thickener, 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 preferable.

  Examples of drugs (pharmaceutical active ingredients) include decongestants (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.) Anti-inflammatory / astringent (eg, neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride Salt), antihistamines (eg diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, bread Nord, calcium pantothenate, sodium pantothenate, etc.), amino acids (eg, potassium L-aspartate, magnesium L-aspartate, potassium L-aspartate / magnesium (equal mixture)), aminoethylsulfonic acid, sodium chondroitin sulfate Etc.), sulfa drugs and the like. When a drug is blended, the effective content of each drug can be selected as the drug content, but 0.001 to 5.0 W / V% is preferable in the composition, and 0.001 to 1 W / V% Is more preferable, and 0.001-0.1 W / V% is still more preferable.

[Production method]
The production method of the composition of the present invention is not particularly limited. For example, a mixed solution of an oil component such as component (A) and a surfactant component such as component (B) is mixed with an aqueous solution containing an aqueous component. After emulsification and pH adjustment, the total volume can be obtained with water. The mixing method of each liquid may be a general method, and is appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, etc., but the rotation speed is not particularly limited and should be set to a level that does not cause intense foaming. Is preferred. The mixing temperature of each liquid is not particularly limited, but it is preferable that both the oil component and the surfactant component are equal to or higher than the melting temperature, and specifically, appropriately selected from the range of 40 to 95 ° C. More preferably, a miniaturization step by high-pressure emulsification is performed. From the viewpoint of improving the clarity of the composition, it is preferable to increase the number of passes at a high pressure, and from the viewpoint of improving production efficiency, it is preferable to reduce the number of passes at a low pressure, and the injection pressure is 100. -245 MPa is preferable, 150-245 MPa is more preferable, and 200-245 MPa is more preferable. Further, it is preferable to apply a back pressure, preferably 1 to 10 MPa, and more preferably 2 to 5 MPa. Further, the number of passes is preferably 1 to 10 times, and more preferably 1 to 5 times. The temperature during high-pressure emulsification is appropriately selected from the range of 20 to 90 ° C.

  In addition, after filling the obtained composition into a resin container, it is further sealed with a package, and an inert gas concentration may be sealed in a space formed between the container and the package. The composition 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 preferably an “aqueous ophthalmic composition”. In the present invention, the “aqueous ophthalmic composition” refers to an ophthalmic composition in which the medium is water. In addition, the blending amount of water is preferably 90.0 to 99.5 W / V% in the composition from the viewpoint of facilitating mixing with tears and facilitating transfer of the component (A) to tears, 95 0.0-98.0 W / V% is more preferable.

  The composition of the present invention is preferably a liquid in terms of facilitating adaptation to the eyes, and the viscosity at 25 ° C. facilitates mixing with tear fluid and facilitates transfer of component (A) to tear fluid. It is preferably 20 mPa · s or less, more preferably 10 mPa · s or less, further preferably 5 mPa · s or less, and particularly preferably 2 mPa · s or less. The viscosity is measured using a cone plate viscometer (DV2T, Eihiro Seiki Co., Ltd.).

  The composition of the present invention is preferably clear from the viewpoint of facilitating discovery when foreign matter is mixed. 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%, 90 to 100% is more preferable.

  The median diameter of the aggregate of the surfactant and the component (A) contained in the composition of the present invention is measured with a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.), and the composition is stable. From the viewpoint of properties, 1 to 200 nm is preferable, 1 to 100 nm is more preferable, 1 to 60 nm is further preferable, and 1 to 40 nm is particularly preferable.

  The composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye wash, etc., but the tear dilution ratio is high, and the release of the surfactant from the component (A) is further promoted. Since the release of the component A) from the composition is improved, and the supply of the component (A) to the tear fluid layer is performed efficiently, eye drops for eye drops and eye drops for contact lenses (eye drops for contact lens wearers) It can be suitably used as an eye drop such as an agent. The contact lens is not particularly limited, such as a hard contact lens or a soft contact lens.

  When used as eye drops or eye drops for contact lenses, it is preferable to apply 10 to 100 μL per time 1 to 3 drops 1 to 6 times per day, and the effect of inhibiting lipid peroxide generation by overflowing from the eyes Since there is a risk of decreasing, 10 to 50 μL per time is more preferably 1 to 6 times per 1 to 3 drops per day, and 10 to 30 μL per time is more preferably 1 to 6 times per 1 to 3 drops per day. When used as an eye wash, it is preferable to wash 3-6 mL per day and 3-6 times per day.

  The composition of the present invention prevents tear lipid oxidation due to VDT work or ultraviolet rays, etc., and causes eye discomfort due to lipid peroxide (eye fatigue, blurred vision, blurred vision, dry eyes, foreign body sensation, eye pain, (Dazzling eyes, heavy eyes, itchy eyes, eye discomfort, eye oil, lacrimation, hyperemia, etc.) It is effective for preventing unpleasant symptoms, and particularly effective for improving symptoms of eye fatigue, foreign body sensation, eye pain, and eye discomfort.

  The effective amount, administration method, formulation and the like are as described above. For example, as the amount of component (A), 0.0001 to 1 mg per adult is divided into 1 to 6 times a day and administered to the eye. To do.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” of the composition is W / V%. The ratio is a W / V% ratio, which is the same value as the mass ratio.

[Examples and Comparative Examples]
Each aqueous component described in the following table was dissolved in 90 mL of water and heated and mixed at 90 ° C. for 15 minutes. At the same time, a premix of the component (A) and the component (B) was prepared and heated and mixed at 90 ° C. for 15 minutes. Next, a predetermined amount of the premix was added to the aqueous solution, and further heated and mixed at 90 ° C. for 15 minutes. Then, it cooled to room temperature, adjusted pH, and added water so that it might be set to 100 mL. Further, using a high-pressure emulsifier (Starburst Mini, Sugino Machine Co., Ltd.), treatment was performed 5 times at an injection pressure of 200 MPa and a back pressure of 3 MPa to prepare eye drops (ophthalmic composition). The following evaluation was performed about the obtained eye drop. The results are also shown in the table. In addition, the viscosity at 25 degreeC of the eyedrops obtained in each Example was the range of 0.5-2.0 mPa * s.

[Release of component (A) by dilution]
The average amount of human tears is said to be 7 μL, and when an eye drop of 30 to 60 μL is instilled, it will be diluted about 1.12 to 1.23 times. In this test, in order to evaluate that the component (A), which was solubilized by dilution of the tears of the composition, floats at the gas-liquid interface (release), physiological saline was used as a model tear. Release of component (A) on the water surface was observed when the composition was diluted at a dilution ratio of about 1.2. A volumetric flask with a narrow opening was used to facilitate observation. Specifically, 10 mL of physiological saline was added to a 50 mL volumetric flask, and eye drops were poured into the opening. A volumetric flask having a dilution ratio of 1.2 times when poured into the opening was used, and the area of the opening was 152 mm ² . The component (A) on the surface of the water is observed by using a fluorescent lamp as the light source and applying light to the surface of the liquid. And evaluated according to the following criteria. In any of the examples and comparative examples, no oil interference light was observed in the undiluted case. ○ and ◎ are acceptable.
[Evaluation criteria]
◎: Oil interference light is observed at 10% or more of the water surface ○: Oil interference light is observed at less than 10% of the water surface ×: Oil interference light is not observed

[Inhibition rate of lipid peroxide from tear oil layer by UV irradiation (%)]
As a model tear oil layer, an oil film prepared by spreading a rabbit meibom chloroform solution on a water tank imitated with physiological saline was used. Although there was a difference in lipid composition depending on the species of meibum, it was confirmed that there was no difference in membrane stability between human meibum and rabbit meibum, so we decided to use an easily available rabbit meibum. The vicinity of the meibomian gland opening of the eyelid (Funakoshi Co., Ltd.) cut out from the rabbit was pressed with a finger, and the extruded meibum was collected with Kimwipe (manufactured by Nippon Paper Crecia Co., Ltd.). Thereafter, the Kimwipe was put in a glass vial, immersed in a 1: 1 mixture (volume ratio) of chloroform and methanol, treated with ultrasonic waves for 10 minutes, and the liquid was transferred to another glass vial. This operation was repeated three times. Thereafter, the mixture was filtered using a Terumo syringe washed with the chloroform / methanol mixed solution (Termo Co., Ltd., 50 mL) and a membrane filter (Merck Millipore Co., Ltd., Millex GP, 0.22 μm), and the dry weight was precisely balanced. (Measured by Shimadzu Corporation, XS-104). Thereafter, chloroform was added to a concentration of 0.5 mg / mL with a microsyringe (manufactured by Hamilton), the rabbit meibum was dissolved, and stored in a −20 ° C. freezer. Upon use, the temperature was returned to room temperature, and it was confirmed that there was no precipitate. An aqueous layer is formed with 1 mL of physiological saline on a 35 mm dish, a rabbit meibum chloroform solution (0.5 mg / mL) is spread on the surface of 100 μL, 165 μL of each eye drop is added, and irradiated with UV (254 nm) for 1 hour. The whole amount of this solution was collected in a vial. To this, 0.5 mL of 35% TCA (trichloroacetic acid) solution, 1.0 mL of 0.5% TBA (Thiobarbituric acid) solution, 0.2% BHT (butyrated hydroxytoluene) After adding 0.05 mL of a solution and 0.05 mL of a 0.5% SDS (sodium dodecyl sulfate) solution, the mixture was heated at 100 ° C. for 30 minutes. After cooling, 0.5 mL of acetic acid and 1.0 mL of chloroform were added and stirred, followed by centrifugation (3,000 rpm × 10 minutes), and the absorbance of the upper layer was measured at 532 nm. The blank was the absorbance when the same operation was performed except that the rabbit meibom chloroform solution was not developed in the above method. From the obtained absorbance, the lipid peroxide generation inhibition rate (%) from the tear fluid layer was calculated based on the following formula. A result is shown by the following evaluation criteria. ●, ○ and ◎ are acceptable.
Inhibition rate of lipid peroxide from tear oil layer (%) =
(1- (Absorbance when eye drops are added-blank) / (Absorbance when no eye drops are added-blank)) x 100
[Evaluation criteria]
◎: 50% or more ○: 30% or more and less than 50% ●: 10% or more and less than 30% ×: less than 10%

[Symptom prevention effect by VDT work]
Three healthy individuals were instilled with 30 μL of each eye drop in both eyes and imposed VDT work (computer work). Eye fatigue, foreign body sensation, eye pain before instillation, 10 minutes after instillation, and 60 minutes after instillation. The subjective symptoms of eye discomfort were scored from 0 (not felt at all) to 10 (very felt). A result is shown with the following evaluation criteria from the average of three persons. ●, ○ and ◎ are acceptable.
[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 after 10 minutes and less than 7 points ×: 7 points or more after 10 minutes

[Transmissivity]
The transmittance at a wavelength of 600 nm was measured for the eye drop immediately after production using a Hitachi spectrophotometer U-3310. 70% or more is acceptable.

The raw materials used in the above examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.
Retinol palmitate (DSM Nutrition Japan Co., Ltd.)
D-α-Tocopherol acetate (RIKEN E Acetate α, manufactured by Riken Vitamin Co., Ltd.)
Liquid paraffin (KAYDOL, manufactured by Shima Trading Co., Ltd.)
Castor oil (Maltok A, manufactured by Ito Oil Co., Ltd.)
Sesame oil (manufactured by Kaneda Corporation)
Polyoxyethylene castor oil 35: average added mole number of ethylene oxide 35 (Uniox C35, manufactured by NOF Corporation)
Polyoxyethylene hydrogenated castor oil 40 (HCO40, manufactured by Nippon Surfactant Co., Ltd.)
Polyoxyethylene hydrogenated castor oil 60 (HCO 60, manufactured by Nippon Surfactant Co., Ltd.)
Polyethylene glycol monostearate * 1: Average addition mole number of ethylene oxide (MYS10V, manufactured by Nippon Surfactant Co., Ltd.)
Polyethylene glycol monostearate * 2: Average added mole number of ethylene oxide 40 (MYS40MV, manufactured by Nippon Surfactant Co., Ltd.)
Polyethylene glycol monostearate * 3: average added moles of ethylene oxide 100 (EMALEX 8100, manufactured by Nippon Emulsion Co., Ltd.)
POE sorbitan fatty acid ester (Polysorbate 80, manufactured by Kao Corporation)
POEPOP glycol (polyoxyethylene (196) -polyoxypropylene (67) block copolymer (Lutrol F127, manufactured by BASF Japan Ltd.))
Boric acid (manufactured by Kosuge Pharmaceutical Co., Ltd.)
Trometa Mall (Kanto Chemical Co., Ltd.)
Edetate sodium hydrate (Quaret N, manufactured by Nagase ChemteX Corporation)
Sodium chloride (Tonda Pharmaceutical Co., Ltd.)
Sodium hydroxide (Wako Pure Chemical Industries, Ltd.)
Menthol (1-menthol, manufactured by Suzuki Hikaru Co., Ltd.)
dl-Camphor (Nippon Seika Co., Ltd.)
Borneol (d-borneol, manufactured by Yanagisawa Masami Shoten Co., Ltd.)
Geraniol (manufactured by Takasago International Corporation)
Cineol (manufactured by Takasago International Corporation)
Linalool (manufactured by Takasago International Corporation)
Bergamot oil (manufactured by Yamamoto Fragrance Co., Ltd.)
Eucalyptus oil (Ogawa Fragrance Co., Ltd.)

The present invention relates to ophthalmic compositions, and a manufacturing method thereof containing one or more selected from vitamin A and vitamin E.

  The tear fluid layer is essential for maintaining the function of the eye in order to prevent evaporation of water from tears and to remove foreign substances, and it must be stable on the surface of the eye to fulfill its role. is necessary. This tear oil layer is composed of lipids (meibum) secreted from the meibomian glands, and the main components are wax esters, cholesterol esters, phospholipids and the like. On the other hand, these components increase the percentage of saturated lipids due to aging and hormonal changes, affect the stabilization of the tear fluid layer, increase the evaporation of the tear fluid layer, and cause dry eye symptoms. Furthermore, it is said to have a deep relationship with eye fatigue. In particular, in meibomian gland dysfunction, it is known that lipid saturation proceeds excessively and the above symptoms worsen. On the other hand, it has been reported that the generation of lipid peroxide from the tear fluid layer also induces eye discomfort. The cause of the generation of lipid peroxide from the tear oil layer includes oxidation by light having a short wavelength such as ultraviolet light or blue light. In recent years, it has been considered that the risk of oxidation is increasing because the working time in the VDT equipment, which is the source of blue light, has been prolonged.

  In order to suppress the generation of lipid peroxide in the tear fluid layer, it is conceivable to supply an antioxidant component to the tear fluid layer with an ophthalmic composition such as eye drops. However, in the conventional ophthalmic composition, the antioxidant component is not sufficiently transferred to the tear fluid layer and is discharged from the conjunctival sac, and the effect of suppressing lipid peroxide generation is insufficient.

JP 2013-253063 A

The present invention has been made in view of the above circumstances, and vitamin A and vitamin E, which are fat-soluble antioxidant components, are released from the composition by dilution of tears (hereinafter referred to as the release property of the component (A) from the composition). It is an object of the present invention to provide a composition that can be easily supplied to the tear oil layer, can suppress the generation of lipid peroxide, and can prevent eye discomfort caused by lipid peroxide. To do.

  As a result of intensive studies to achieve the above-mentioned object, the present inventors have made vitamin A and / or dilute into tears after instillation by using a composition in which the type and ratio of the nonionic surfactant are limited. Alternatively, it was found that vitamin E can be released (separated / floated) from the composition and supplied to the tear oil layer. Furthermore, the composition of the present invention can suppress the generation of lipid peroxide, and further, eye fatigue, blurring of the eye, blurred vision, dryness of the eyes, foreign body sensation, eye pain, and dazzling eyes. The present inventors have found that eye discomfort can be prevented such as heavy eyes, itchy eyes, eye discomfort, eye grease, lacrimation, and hyperemia.

Accordingly, the present invention provides the following ophthalmic composition and method for producing the same.
[1]. (A) one or more selected from (A-1) vitamin A and (A-2) vitamin E;
One or more nonionic surfactants selected from (B) (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, and (B-3) other nonionic surfactants These blending mass ratios are
(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 an ophthalmic composition having a transmittance of 70% or more.
[2]. The ophthalmic composition according to [1], wherein the component (A) is (A-2) vitamin E.
[3]. The ophthalmology according to [1] or [2], wherein the (B) nonionic surfactant comprises one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. Composition.
[4]. Furthermore, (C) The ophthalmic composition in any one of [1]-[3] containing a terpenoid.
[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 lipid peroxide generation in a tear fluid layer or preventing ocular discomfort caused by lipid peroxide.
[7]. The method to manufacture the ophthalmic composition in any one of [1]-[6] including the refinement | miniaturization process by high pressure emulsification.

  Vitamin A, vitamin E, etc. are released by dilution of tears, they can be sufficiently supplied to the tear oil layer, the generation of lipid peroxide can be suppressed, and further, eye discomfort caused by lipid peroxide can be prevented An object is to provide an ophthalmic composition and a method for producing the same.

Hereinafter, the present invention will be described in detail.
One or more types selected from (A) (A-1) vitamin A and (A-2) vitamin E. These are ingredients known as fat-soluble vitamins.
(A-1) Vitamin A
Examples of vitamin A include, 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, etc., alone or in combination of two or more Can be used. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate is preferred.

(A-2) Vitamin E
As vitamin E, for example, tocopherol, tocotrienol, their salts, and derivatives (esters) are used as a generic term. Specifically, for example, there are d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and the like, and examples of these derivatives include vitamin E acetate (tocopherol acetate). , Vitamin E nicotinic acid ester, vitamin E succinic acid ester, vitamin E linolenic acid ester and the like can be mentioned, and these can be used singly or in appropriate combination of two or more. Of these, tocopherol acetate (such as d-α-tocopherol acetate and dl-α-tocopherol acetate) is preferable. As the component (A), (A-2) vitamin E is preferable.

  The total amount of the component (A-1) and the component (A-2) is preferably 0.0001 to 1 W / V% (mass / volume%, g / 100 mL, the same applies hereinafter) in the ophthalmic composition. 001 to 0.5 W / V% is more preferable, and 0.01 to 0.1 W / V% is particularly preferable. By setting it to 0.0001 W / V% or more, the antioxidant effect is more exhibited, and when it is 1 W / V% or more, it becomes easy to feel eye irritation.

  In the present invention, (A-1) / [(A-1) + (A-2)] ≦ 0.1. If this ratio exceeds 0.1, the releasability of the component (A) from the composition becomes insufficient.

  In addition, although the compounding quantity of (A-1) component will not be specifically limited if the said ratio is satisfy | filled from a viewpoint of the discharge | release from a composition, 0-0.1W / V% is preferable in a composition, 0W / V% may be sufficient. On the other hand, it is preferable to contain 0.005 W / V% or more from a viewpoint of lipid peroxide suppression. The amount of component (A-2) is not particularly limited as long as it satisfies the above ratio, but is preferably 0.00009 to 1 W / V%, more preferably 0.001 to 0.5 W / V%, and 01 to 0.1 W / V% is more preferable.

(B) Nonionic surfactant The (B) nonionic surfactant of the present invention includes (B-1) polyoxyethylene castor oil (may be described as POE castor oil), (B-2) polyoxy It is classified into ethylene hardened castor oil (may be described as POE hardened castor oil), (B-3) other nonionic surfactants, and is one or more nonionic surfactants selected from these. As the component (B), since the release from the composition can be maintained even when blended at a relatively high concentration, (B-1) polyoxyethylene castor oil and (B -2) It is preferable to use 1 or more types chosen from polyoxyethylene hydrogenated castor oil. Furthermore, it is more preferable that two or more kinds of nonionic surfactants are blended from the viewpoint of composition stability.

(B-1) Polyoxyethylene castor oil Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide to castor oil, and the number of average addition moles of ethylene oxide is different. The type of is known. Although there is no limitation in particular about the average addition mole number of the ethylene oxide in polyoxyethylene castor oil, 3-60 mol is illustrated. Specifically, polyoxyethylene castor oil 3 (the number is the average number of moles of ethylene oxide added, hereinafter the same), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor Examples include oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, and the like. These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. Among these, it is preferable to use polyoxyethylene castor oil 35.

  (B-1) Although the compounding quantity in the case of mix | blending a component will not be specifically limited if the following ratio is satisfy | filled, 0.000001 W / V% or more is preferable in a composition, and 0.00001 W / V% or more is more preferable. . By setting it as the above or more, a composition becomes more uniform. From the viewpoint of safety, 1.0 W / V% or less is preferable.

(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 is an average addition of ethylene oxide. Several types with different numbers of moles are known. Although there is no limitation in particular about the average addition mole number of the ethylene oxide in polyoxyethylene hydrogenated castor oil, 5-100 mol is illustrated. Specifically, polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 30, Examples include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, and polyoxyethylene hydrogenated castor oil 100. These polyoxyethylene hydrogenated castor oils can be used singly or in appropriate combination of two or more. Among these, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.

  (B-2) Although the compounding quantity in the case of mix | blending a component will not be specifically limited if the following ratio is satisfy | filled, 0.000001 W / V% or more is preferable in a composition, and 0.00001 W / V% or more is more preferable. . By setting it as the above or more, a composition becomes more uniform. From the viewpoint of safety, 1.0 W / V% or less is preferable.

The (B-3) Other nonionic surfactants (B-1) and (B-2) other than the nonionic surfactant, polysorbate 80 (monooleate polyoxyethylene (20) sorbitan) (() Polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester) represented by average number of moles of ethylene oxide added, the same applies hereinafter), poloxamer represented by polyoxyethylene-polyoxypropylene block copolymer (POEPOP glycol), Examples thereof include polyethylene glycol monostearate typified by polyethylene glycol monostearate (10), and these can be used singly or in appropriate combination of two or more. However, lecithin, hydrogenated lecithin, phospholipids such as phosphatidylcholine and phosphatidylglycerol, which are difficult to desorb from the interface, are not separated from vitamin A or / and vitamin E by dilution of tears, and are not easily transferred to the tear fluid layer. It is preferable not to be included.

  (B-3) Although the compounding quantity in the case of mix | blending a component will not be specifically limited if the following ratio is satisfy | filled, 0.000001 W / V% or more is preferable in a composition, More preferably, it is 0.00001 W / V% or more. And by setting it as the above or more, a composition becomes more uniform. From the viewpoint of safety, 0.5 W / V% or less is preferable.

(B) The nonionic surfactant of a component is mix | blended in the following ratios. In addition, although the following ratio is W / V% ratio, it becomes the same value as 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 the component (B), B) Defines the amount of nonionic surfactant. If 0.05 <[(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)] is not satisfied, a uniform composition is not obtained. The desired transmittance cannot be obtained. The ratio is more preferably 0.1 ≦, and further preferably 0.5 ≦. In addition, although the upper limit of [(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)] is not particularly limited, the composition of component (A) 2.0 or less is preferable from the viewpoint of releasability from water.

On the other hand,
[(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,
If this is not satisfied, the desired component (A) release property cannot be obtained. The ratio is preferably ≦ 8. In addition,
[(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) ]
The lower limit is not particularly limited, but is preferably more than 0.25 from the viewpoint of transmittance.

  The above formula for determining the blending conditions defines the amounts of (B-1), (B-2), and (B-3) relative to (A-1) and (A-2). (B) Since the blending conditions of (A) differ depending on the type of nonionic surfactant, each is divided by a specific coefficient for the type of component (B). For example, when comparing (B-1) /0.25 and (B-3) /0.1, the upper limit of blending of (B-1) is 2.5 times higher than (B-3). It means that. Moreover, since the upper limit of each active agent blending of the component (B) differs depending on the type of the component (A), [(B-1) /0.25+ (B-2) /0.01+ (B-3) / 0 .1] represents a formula relating to the upper limit of the amount of each component (B) relative to (A-1), and [[B-1) /0.1+ (B-2) /0.2+ (B-3) / 0. .05] represents a formula relating to the upper limit of blending of each component (B) relative to (A-2). They are divided by the sum (A-1) + (A-2) of the component (A). In addition, when both (A-1) and (A-2) are included, the influence is increased or decreased depending on the blending ratio, so that (A-1) / [(A-1) + (A-2) ] And (A-2) / [(A-1) + (A-2)].

  For example, in the case of (A-2) component 1.0 W / V%, if (B-1) alone, more than 0.05 W / V%, 1.0 W / V% or less, (B-2) alone If it exists, it is necessary to be more than 0.05 W / V% and not more than 2.0 W / V%, and if it is (B-3) alone, it needs to be more than 0.05 W / V% and 0.5 W / 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 0.1 W / V%, (A-2) component 0.9 W / V%, (B- 1) If alone,> 0.05 W / V%, 1.1 W / V% or less, (B-2) If alone,> 0.05 W / V%, 0.7 W / V% or less, (B -3) If it is single, it is necessary to make it more than 0.05 W / V% and 0.5 W / V% or less.

  Cationic surfactants typified by benzalkonium chloride and benzethonium chloride, anionic surfactants typified by sodium lauryl sulfate and sorbic acid or salts thereof, and amphoteric surfactants typified by lauramine oxide. The agent inhibits separation of the component (A) and the surfactant by dilution of the tears, and the component (A) is less likely to be transferred to the tear fluid layer, so that the content is preferably 0.1 W / V% or less in the composition. , 0.01 W / V% or less is more preferable, and it is particularly preferable that the content is not substantially contained.

  The ophthalmic composition of the present invention may further contain (C) a terpenoid. By blending the terpenoid, release properties such as enhancing the release properties of the component (A) from the composition can be adjusted, and further, the effect of suppressing the generation of lipid peroxide can be enhanced. The terpenoid in the present invention has a structure having an isoprene unit as a structural unit, and examples thereof include terpene hydrocarbon, terpene alcohol, terpene aldehyde, and terpene ketone. Also, depending on the number of carbons, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes. Specific examples include monoterpenes such as menthol, menthone, camphor, borneol, rünou, geraniol, cineole, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids. Among these, it is preferable to use a monoterpene. These terpenoids can be used in any of d-form, l-form or dl-form. Among these, menthol, menthone, camphor, borneol, geraniol, cineol and linalool are preferable, and menthol, camphor, borneol, geraniol, cineol and linalool are more preferable. 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, mint oil, peppermint oil, spearmint oil, and essential oils of dipterocarpaceae, rosmarin oil, lavender oil, and the like. (A) Bergamot oil and eucalyptus oil are preferable from the viewpoint of enhancing the release from the composition of the component.

  The blending amount of the component (C) is 0.0001 to 0.2 W / V% in the composition, and is appropriately selected from the other blending components such as the type of the component (C), the component (B) and the blending amount thereof. 0.001-0.1 W / V% is preferable. In this blending concentration range, there is little risk of precipitation of (C) terpenoids regardless of the types and blending amounts of other blending components. Moreover, 0.005 W / V% or more is more preferable from a viewpoint of lipid peroxide generation | occurrence | production suppression, and 0.075 W / V% or less is further more preferable from a viewpoint of reducing irritation.

[Other ingredients]
An appropriate amount of other components can be blended in the composition of the present invention as long as the effects of the present invention are not impaired. Examples of the other components, oil components, preservatives, sugars, buffering agents, pH adjusting agents, isotonic agents, stabilizing agents, polyhydric alcohols, thickeners, drug, and the like. These components can be blended singly or in appropriate combination of two or more. The compounding amount of the components shown below is a preferable range when blending.

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

As a preservative having a hydrophobic portion such as an alkyl chain or a benzene ring among preservatives, Ji Melo Searle, phenylethyl alcohol, alkyl aminoethyl glycine, chlorhexidine gluconate, methyl parahydroxybenzoate, although ethyl parahydroxybenzoate, and the like , (A) component is less likely to be transferred to the tear oil layer, so that it is preferably 0.1 W / V% or less, more preferably 0.01 W / V% or less in the composition, and substantially no inclusion. preferable.

  Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. In addition, these may be any of d-form, l-form, or dl-form. 0.001 to 5.0 W / V% is preferable in the composition, 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 buffer include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, sodium hydrogen carbonate and the like. The blending amount of the buffer is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 2 W / V%, and still more preferably 0.001 to 1 W / V%.

  Examples of the pH adjuster include an inorganic acid or an inorganic alkali agent. 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 hydrogen carbonate and the like. The pH of the composition is preferably 3.5 to 8.0, more preferably 5.5 to 8.0. The pH is measured at 25 ° C. using a pH meter (HM-25R, Toa DKK Co.).

  Examples of tonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. 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 most preferably 0.83 to 1.20. The osmotic pressure is measured using an automatic osmometer (A2O, Advanced Instruments) at 25 ° C.

  Examples of the stabilizer include sodium edetate, sodium edetate hydrate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like. The blending amount of the stabilizer is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 1 W / V%, and still more preferably 0.001 to 0.1 W / V%. Dibutylhydroxytoluene inhibits the separation of the component (A) and the surfactant due to dilution of tears, and the component (A) is less likely to be supplied to the tear fluid layer.

  Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. When the polyhydric alcohol is blended, the blending amount of the polyhydric alcohol is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 1 W / V%, and 0.001 to 0.00. 1 W / V% is more preferable.

  Examples of the thickener include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, and the like. When blending a thickener, 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 preferable.

  Examples of drugs (pharmaceutical active ingredients) include decongestants (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.) Anti-inflammatory / astringent (eg, neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride Salt), antihistamines (eg diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, bread Nord, calcium pantothenate, sodium pantothenate, etc.), amino acids (eg, potassium L-aspartate, magnesium L-aspartate, potassium L-aspartate / magnesium (equal mixture)), aminoethylsulfonic acid, sodium chondroitin sulfate Etc.), sulfa drugs and the like. When a drug is blended, the effective content of each drug can be selected as the drug content, but 0.001 to 5.0 W / V% is preferable in the composition, and 0.001 to 1 W / V% Is more preferable, and 0.001-0.1 W / V% is still more preferable.

[Production method]
The production method of the composition of the present invention is not particularly limited. For example, a mixed solution of an oil component such as component (A) and a surfactant component such as component (B) is mixed with an aqueous solution containing an aqueous component. emulsified, after pH adjustment, the total volume can be obtained by more adjustments in water. The mixing method of each liquid may be a general method, and is appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, etc., but the rotation speed is not particularly limited and should be set to a level that does not cause intense foaming. Is preferred. The mixing temperature of each liquid is not particularly limited, but it is preferable that both the oil component and the surfactant component are equal to or higher than the melting temperature, and specifically, appropriately selected from the range of 40 to 95 ° C. More preferably, a miniaturization step by high-pressure emulsification is performed. From the viewpoint of improving the clarity of the composition, it is preferable to increase the number of passes at a high pressure, and from the viewpoint of improving production efficiency, it is preferable to reduce the number of passes at a low pressure, and the injection pressure is 100. -245 MPa is preferable, 150-245 MPa is more preferable, and 200-245 MPa is more preferable. Further, it is preferable to apply a back pressure, preferably 1 to 10 MPa, and more preferably 2 to 5 MPa. Further, the number of passes is preferably 1 to 10 times, and more preferably 1 to 5 times. The temperature during high-pressure emulsification is appropriately selected from the range of 20 to 90 ° C.

Also, after filling the resulting composition into the resin vessel, further sealed by package may be filled with an inert gas to the space formed between the container and the packaging, for ophthalmic The composition 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 preferably an “aqueous ophthalmic composition”. In the present invention, the “aqueous ophthalmic composition” refers to an ophthalmic composition in which the medium is water. In addition, the blending amount of water is preferably 90.0 to 99.5 W / V% in the composition from the viewpoint of facilitating mixing with tears and facilitating transfer of the component (A) to tears, 95 0.0-98.0 W / V% is more preferable.

  The composition of the present invention is preferably a liquid in terms of facilitating adaptation to the eyes, and the viscosity at 25 ° C. facilitates mixing with tear fluid and facilitates transfer of component (A) to tear fluid. It is preferably 20 mPa · s or less, more preferably 10 mPa · s or less, further preferably 5 mPa · s or less, and particularly preferably 2 mPa · s or less. The viscosity is measured using a cone plate viscometer (DV2T, Eihiro Seiki Co., Ltd.).

  The composition of the present invention is preferably clear from the viewpoint of facilitating discovery when foreign matter is mixed. 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%, 90 to 100% is more preferable.

  The median diameter of the aggregate of the surfactant and the component (A) contained in the composition of the present invention is measured with a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.), and the composition is stable. From the viewpoint of properties, 1 to 200 nm is preferable, 1 to 100 nm is more preferable, 1 to 60 nm is further preferable, and 1 to 40 nm is particularly preferable.

  The composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye wash, etc., but the tear dilution ratio is high, and the release of the surfactant from the component (A) is further promoted. Since the release of the component A) from the composition is improved, and the supply of the component (A) to the tear fluid layer is performed efficiently, eye drops for eye drops and eye drops for contact lenses (eye drops for contact lens wearers) It can be suitably used as an eye drop such as an agent. The contact lens is not particularly limited, such as a hard contact lens or a soft contact lens.

  When used as eye drops or eye drops for contact lenses, it is preferable to apply 10 to 100 μL per time 1 to 3 drops 1 to 6 times per day, and the effect of inhibiting lipid peroxide generation by overflowing from the eyes Since there is a risk of decreasing, 10 to 50 μL per time is more preferably 1 to 6 times per 1 to 3 drops per day, and 10 to 30 μL per time is more preferably 1 to 6 times per 1 to 3 drops per day. When used as an eye wash, it is preferable to wash 3-6 mL per day and 3-6 times per day.

  The composition of the present invention prevents tear lipid oxidation due to VDT work or ultraviolet rays, etc., and causes eye discomfort due to lipid peroxide (eye fatigue, blurred vision, blurred vision, dry eyes, foreign body sensation, eye pain, (Dazzling eyes, heavy eyes, itchy eyes, eye discomfort, eye oil, lacrimation, hyperemia, etc.) It is effective for preventing unpleasant symptoms, and particularly effective for improving symptoms of eye fatigue, foreign body sensation, eye pain, and eye discomfort.

  The effective amount, administration method, formulation and the like are as described above. For example, as the amount of component (A), 0.0001 to 1 mg per adult is divided into 1 to 6 times a day and administered to the eye. To do.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” of the composition is W / V%. The ratio is a W / V% ratio, which is the same value as the mass ratio.

[Examples and Comparative Examples]
Each aqueous component described in the following table was dissolved in 90 mL of water and heated and mixed at 90 ° C. for 15 minutes. At the same time, a premix of the component (A) and the component (B) was prepared and heated and mixed at 90 ° C. for 15 minutes. Next, a predetermined amount of the premix was added to the aqueous solution, and further heated and mixed at 90 ° C. for 15 minutes. Then, it cooled to room temperature, adjusted pH, and added water so that it might be set to 100 mL. Further, using a high-pressure emulsifier (Starburst Mini, Sugino Machine Co., Ltd.), treatment was performed 5 times at an injection pressure of 200 MPa and a back pressure of 3 MPa to prepare eye drops (ophthalmic composition). The following evaluation was performed about the obtained eye drop. The results are also shown in the table. In addition, the viscosity at 25 degreeC of the eyedrops obtained in each Example was the range of 0.5-2.0 mPa * s.

[Release of component (A) by dilution]
The average amount of human tears is said to be 7 μL, and when an eye drop of 30 to 60 μL is instilled, it will be diluted about 1.12 to 1.23 times. In this test, in order to evaluate that the component (A), which was solubilized by dilution of the tears of the composition, floats at the gas-liquid interface (release), physiological saline was used as a model tear. Release of component (A) on the water surface was observed when the composition was diluted at a dilution ratio of about 1.2. A volumetric flask with a narrow opening was used to facilitate observation. Specifically, 10 mL of physiological saline was added to a 50 mL volumetric flask, and eye drops were poured into the opening. A volumetric flask having a dilution ratio of 1.2 times when poured into the opening was used, and the area of the opening was 152 mm ² . The component (A) on the surface of the water is observed by using a fluorescent lamp as the light source and applying light to the surface of the liquid. And evaluated according to the following criteria. In any of the examples and comparative examples, no oil interference light was observed in the undiluted case. ○ and ◎ are acceptable.
[Evaluation criteria]
◎: Oil interference light is observed at 10% or more of the water surface ○: Oil interference light is observed at less than 10% of the water surface ×: Oil interference light is not observed

[Inhibition rate of lipid peroxide from tear oil layer by UV irradiation (%)]
As a model tear oil layer, an oil film prepared by spreading a rabbit meibom chloroform solution on a water tank imitated with physiological saline was used. Although there was a difference in lipid composition depending on the species of meibum, it was confirmed that there was no difference in membrane stability between human meibum and rabbit meibum, so we decided to use an easily available rabbit meibum. The vicinity of the meibomian gland opening of the eyelid (Funakoshi Co., Ltd.) cut out from the rabbit was pressed with a finger, and the extruded meibum was collected with Kimwipe (manufactured by Nippon Paper Crecia Co., Ltd.). Thereafter, the Kimwipe was put in a glass vial, immersed in a 1: 1 mixture (volume ratio) of chloroform and methanol, treated with ultrasonic waves for 10 minutes, and the liquid was transferred to another glass vial. This operation was repeated three times. Thereafter, the mixture was filtered using a Terumo syringe washed with the chloroform / methanol mixed solution (Termo Co., Ltd., 50 mL) and a membrane filter (Merck Millipore Co., Ltd., Millex GP, 0.22 μm), and the dry weight was precisely balanced. (Measured by Shimadzu Corporation, XS-104). Thereafter, chloroform was added to a concentration of 0.5 mg / mL with a microsyringe (manufactured by Hamilton), the rabbit meibum was dissolved, and stored in a −20 ° C. freezer. Upon use, the temperature was returned to room temperature, and it was confirmed that there was no precipitate. An aqueous layer is formed with 1 mL of physiological saline on a 35 mm dish, a rabbit meibum chloroform solution (0.5 mg / mL) is spread on the surface of 100 μL, 165 μL of each eye drop is added, and irradiated with UV (254 nm) for 1 hour. The whole amount of this solution was collected in a vial. To this, 0.5 mL of 35% TCA (trichloroacetic acid) solution, 1.0 mL of 0.5% TBA (Thiobarbituric acid) solution, 0.2% BHT (butyrated hydroxytoluene) After adding 0.05 mL of a solution and 0.05 mL of a 0.5% SDS (sodium dodecyl sulfate) solution, the mixture was heated at 100 ° C. for 30 minutes. After cooling, 0.5 mL of acetic acid and 1.0 mL of chloroform were added and stirred, followed by centrifugation (3,000 rpm × 10 minutes), and the absorbance of the upper layer was measured at 532 nm. The blank was the absorbance when the same operation was performed except that the rabbit meibom chloroform solution was not developed in the above method. From the obtained absorbance, the lipid peroxide generation inhibition rate (%) from the tear fluid layer was calculated based on the following formula. A result is shown by the following evaluation criteria. ●, ○ and ◎ are acceptable.
Inhibition rate of lipid peroxide from tear oil layer (%) =
(1- (Absorbance when eye drops are added-blank) / (Absorbance when no eye drops are added-blank)) x 100
[Evaluation criteria]
◎: 50% or more ○: 30% or more and less than 50% ●: 10% or more and less than 30% ×: less than 10%

[Symptom prevention effect by VDT work]
Three healthy individuals were instilled with 30 μL of each eye drop in both eyes and imposed VDT work (computer work). Eye fatigue, foreign body sensation, eye pain before instillation, 10 minutes after instillation, and 60 minutes after instillation. The subjective symptoms of eye discomfort were scored from 0 (not felt at all) to 10 (very felt). A result is shown with the following evaluation criteria from the average of three persons. ●, ○ and ◎ are acceptable.
[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 after 10 minutes and less than 7 points ×: 7 points or more after 10 minutes

[Transmissivity]
The transmittance at a wavelength of 600 nm was measured for the eye drop immediately after production using a Hitachi spectrophotometer U-3310. 70% or more is acceptable.

The raw materials used in the above examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.
Retinol palmitate (DSM Nutrition Japan Co., Ltd.)
D-α-Tocopherol acetate (RIKEN E Acetate α, manufactured by Riken Vitamin Co., Ltd.)
Liquid paraffin (KAYDOL, manufactured by Shima Trading Co., Ltd.)
Castor oil (Maltok A, manufactured by Ito Oil Co., Ltd.)
Sesame oil (manufactured by Kaneda Corporation)
Polyoxyethylene castor oil 35: average added mole number of ethylene oxide 35 (Uniox C35, manufactured by NOF Corporation)
Polyoxyethylene hydrogenated castor oil 40 (HCO40, manufactured by Nippon Surfactant Co., Ltd.)
Polyoxyethylene hydrogenated castor oil 60 (HCO 60, manufactured by Nippon Surfactant Co., Ltd.)
Polyethylene glycol monostearate * 1: Average addition mole number of ethylene oxide (MYS10V, manufactured by Nippon Surfactant Co., Ltd.)
Polyethylene glycol monostearate * 2: Average added mole number of ethylene oxide 40 (MYS40MV, manufactured by Nippon Surfactant Co., Ltd.)
Polyethylene glycol monostearate * 3: average added moles of ethylene oxide 100 (EMALEX 8100, manufactured by Nippon Emulsion Co., Ltd.)
POE sorbitan fatty acid ester (Polysorbate 80, manufactured by Kao Corporation)
POEPOP glycol (polyoxyethylene (196) -polyoxypropylene (67) block copolymer (Lutrol F127, manufactured by BASF Japan Ltd.))
Boric acid (manufactured by Kosuge Pharmaceutical Co., Ltd.)
Trometa Mall (Kanto Chemical Co., Ltd.)
Sodium edetate hydrate (click Rewa Tsu DOO N, manufactured by Nagase ChemteX Corporation)
Sodium chloride (Tonda Pharmaceutical Co., Ltd.)
Sodium hydroxide (Wako Pure Chemical Industries, Ltd.)
Menthol (1-menthol, manufactured by Suzuki Hikaru Co., Ltd.)
dl-Camphor (Nippon Seika Co., Ltd.)
Borneol (d-borneol, manufactured by Yanagisawa Masami Shoten Co., Ltd.)
Geraniol (manufactured by Takasago International Corporation)
Cineol (manufactured by Takasago International Corporation)
Linalool (manufactured by Takasago International Corporation)
Bergamot oil (manufactured by Yamamoto Fragrance Co., Ltd.)
Eucalyptus oil (Ogawa Fragrance Co., Ltd.)

Claims (7)

(A) one or more selected from (A-1) vitamin A and (A-2) vitamin E;
One or more nonionic surfactants selected from (B) (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, and (B-3) other nonionic surfactants These blending mass ratios are
(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 an ophthalmic composition having a transmittance of 70% or more.   The ophthalmic composition according to claim 1, wherein the component (A) is (A-2) vitamin E.   The ophthalmic composition according to claim 1 or 2, wherein the (B) nonionic surfactant contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. Stuff.   Furthermore, the ophthalmic composition of any one of Claims 1-3 containing (C) terpenoid.   The ophthalmic composition according to any one of claims 1 to 4, which is an eye drop.   The ophthalmic composition according to any one of claims 1 to 5, which is used for suppressing the generation of lipid peroxide in a tear fluid layer or for preventing eye discomfort caused by lipid peroxide.   The method of manufacturing the ophthalmic composition of any one of Claims 1-6 including the refinement | miniaturization process by high pressure emulsification.