KR102453524B1 - Ophthalmic composition and manufacturing method thereof - Google Patents

Abstract

(A) at least one selected from (A-1) vitamin A and (A-2) vitamin E, and (B) a nonionic surfactant, wherein the blending mass ratio thereof 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)]× An ophthalmic composition satisfying (A-2)/[(A-1)+(A-2)]≤10 and having a transmittance of 70% or more.

Description

Ophthalmic composition and manufacturing method thereof

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

The tear oil layer is essential for maintaining the function of the eye in order to prevent evaporation of water from tears or to remove foreign substances, and it is necessary to be stable on the surface of the eye in order to perform its role sufficiently. This lacrimal oil layer is composed of lipids (meibom) secreted from meibomian glands, and important components are wax esters, cholesterol esters, phospholipids, and the like. On the other hand, these components increase the ratio of saturated lipids due to aging or hormonal changes, which affects the stabilization of the tear oil layer, and the evaporation of the tear water layer is enhanced, causing dry eye symptoms. It can also be said that it has a deep relationship with eye fatigue. In particular, in meibomian gland dysfunction, it is known that the above symptoms are exacerbated by excessive lipid saturation. On the other hand, it has been reported that the generation of lipid peroxide from the lacrimal oil layer also causes eye discomfort. The cause of the generation of lipid peroxide from the tear oil layer is oxidation by short-wavelength light such as ultraviolet light or blue light. It is thought that the risk of oxidation is increasing because the working time in VDT equipment, which is the source of blue light, is increasing in recent years.

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 an eye drop. However, in the conventional ophthalmic composition, the antioxidant component is not sufficiently transferred to the lacrimal oil layer and is discharged from the conjunctival sac, and the effect of suppressing the generation of lipid peroxide is insufficient.

Japanese Patent Laid-Open No. 2013-253063

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 easily released from the composition by dilution of tear fluid (hereinafter, referred to as "releasing release from the composition of component (A)"). , an object of the present invention is to provide a composition capable of supplying them to the lacrimal oil layer, suppressing the generation of lipid peroxide, and preventing unpleasant symptoms caused by lipid peroxide.

As a result of intensive studies to achieve the above object, the present inventors have made a composition in which the type and ratio of the nonionic surfactant are limited, so that vitamin A and/or vitamin E is released from the composition (separation/floating) by dilution in tears after instillation. ) and found that they could be supplied to the tear oil layer. In addition, the composition of the present invention can suppress the generation of lipid peroxide, and furthermore, eye fatigue caused by lipid peroxide, eye cloudiness and dullness, dry eyes, foreign body sensation, eye pain, dazzling eyes, and heavy eyes , the present invention has been achieved by discovering that it is possible to prevent eye discomfort symptoms such as itchiness, discomfort in the eyes, mucus, oily eyes, and redness.

Accordingly, the present invention provides the following ophthalmic composition and a method for preparing the same.

[One]. (A) (A-1) at least one selected from vitamin A and (A-2) vitamin E;

(B) at least one nonionic surfactant selected from (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil and (B-3) other nonionic surfactants; Their compounding mass ratio,

(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)]× An ophthalmic composition satisfying (A-2)/[(A-1)+(A-2)]≤10 and 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 ophthalmic solution according to [1] or [2], wherein (B) the nonionic surfactant contains at least one selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. for composition.

[4]. The ophthalmic composition according to any one of [1] to [3], further comprising (C) 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 for suppressing the generation of lipid peroxide in the lacrimal oil layer or for preventing eye discomfort caused by the lipid peroxide.

[7]. A method for producing the ophthalmic composition according to any one of [1] to [6], comprising a micronization step by high pressure emulsification.

(Effects of the Invention)

An ophthalmic composition capable of releasing vitamin A, vitamin E, etc. by dilution of tear fluid to sufficiently supply them to the tear oil layer, suppressing the generation of lipid peroxide, and preventing eye discomfort caused by lipid peroxide, and its composition It aims to provide a manufacturing method.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

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

These are ingredients known as fat-soluble vitamins.

(A-1) Vitamin A

Examples of the vitamin A include vitamin A-containing mixtures such as vitamin A oil and vitamin A derivatives such as vitamin A fatty acid ester, in addition to vitamin A itself, alone or in combination of two or more. Can be used. Specific examples thereof include retinol palmitic acid ester, retinol acetate ester, retinol, retinoic acid, and retinoid. Especially, retinol palmitic acid ester is preferable.

(A-2) Vitamin E

As vitamin E, for example, tocopherol, tocotrienol, salts and derivatives (esters) thereof are used generically. Specifically, for example, there are d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and the like, and derivatives thereof include, for example, vitamin E acetic acid ester (tocopherol acetate). , vitamin E nicotinic acid ester, vitamin E succinic acid ester, vitamin E linolenic acid ester, and the like, and may be used alone or in combination of two or more. Among them, tocopherol acetate (such as d-α-tocopherol acetate and dl-α-tocopherol acetate) is preferred. (A) As a component, (A-2) vitamin E is preferable.

The total amount of component (A-1) and component (A-2) is preferably 0.0001 to 1 W/V% (mass/volume %, g/100 ml, the same as below) in the ophthalmic composition, and 0.001 to 0.5 W/V % is more preferable, and 0.01 to 0.1 W/V% is particularly preferable. By setting it as 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. When this ratio exceeds 0.1, the releasability from the composition of (A) component will become inadequate.

In addition, the compounding quantity of (A-1) component is although it will not specifically limit if the said ratio is satisfy|filled from a viewpoint of releasability from a composition, 0-0.1 W/V% of a composition is preferable, and 0 W/V% may be sufficient. On the other hand, from the viewpoint of suppressing lipid peroxide, it is preferable to include 0.005 W/V% or more. (A-2) Although it will not specifically limit if the compounding quantity of a component is satisfy|filling the said ratio, 0.00009-1W/V% is preferable, 0.001-0.5W/V% is more preferable, 0.01-0.1W/V% is more preferably.

(B) nonionic surfactant

(B) Nonionic surfactant of the present invention is (B-1) polyoxyethylene castor oil (sometimes referred to as POE castor oil), (B-2) polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) may be described) and (B-3) other nonionic surfactants, and at least one nonionic surfactant selected from these. As the component (B), since release properties from the composition can be maintained even when blended at a relatively high concentration, it is advantageous for the clarity of the composition, (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene cured It is preferable to use at least one selected from castor oil. Moreover, it is more preferable that 2 or more types of nonionic surfactant are mix|blended from the point 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 several types from which the average added mole number of ethylene oxide differ are known. Although there is no limitation in particular about the average added mole number of ethylene oxide in polyoxyethylene castor oil, 3-60 mol is illustrated. Specifically, polyoxyethylene castor oil 3 (a numerical value is the average added mole number of ethylene oxide, as follows), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, and the like. These polyoxyethylene castor oil can be used individually by 1 type or in combination of 2 or more types. Especially, 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 in a composition is preferable, and 0.00001 W/V% or more is more preferable. By setting it as the above, a composition becomes more uniform. From a safety point of view, 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 several types from which the average added mole number of ethylene oxide differ are known. Although there is no limitation in particular about the average added mole number of ethylene oxide in polyoxyethylene hydrogenated castor oil, 5-100 mol is illustrated. Specifically, polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average added moles of ethylene oxide, the same is hereinafter), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 30, poly oxyethylene 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. are mentioned. These polyoxyethylene castor oil can be used individually by 1 type or in combination of 2 or more types. Especially, 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 as long as the following ratio is satisfied, 0.000001 W/V% or more in a composition is preferable, and 0.00001 W/V% or more is more preferable. By setting it as the above, a composition becomes more uniform. From a safety point of view, 1.0 W/V% or less is preferable.

(B-3) Other nonionic surfactants

As the nonionic surfactant other than (B-1) and (B-2), polysorbate 80 (polyoxyethylene (20) sorbitan monostearate) (the numerical values in () are the average added moles of ethylene oxide, the same as below) Polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester), poloxamer represented by polyoxyethylene-polyoxypropylene block copolymer (POEPOP glycol), monostearic acid represented by polyethylene glycol (10) Polyethylene glycol etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. However, phospholipids such as lecithin, hydrogenated lecithin, phosphatidylcholine, and phosphatidylglycerol, which are difficult to detach from the interface, are not separated into vitamin A and/or vitamin E by lacrimal dilution and are difficult to transfer to the lacrimal oil layer. It is preferable not to

(B-3) Although the compounding quantity in the case of mix|blending a component is not specifically limited as long as the following ratio is satisfied, 0.000001 W/V% or more in a composition is preferable, More preferably, it is 0.00001 W/V% or more, and the above-mentioned By setting it as, a composition becomes more uniform. From a safety point of view, 0.5 W/V% or less is preferable.

(B) The nonionic surfactant of component is mix|blended in the following ratios. In addition, although the following ratio is a 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 lower limit of mixing of component (B), (A) B) The amount of nonionic surfactant is defined. If 0.05<[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)] is not satisfied, a uniform composition is not obtained and the target transmittance can't get Moreover, as for the said ratio, 0.1 ≤ is more preferable, and 0.5 ≤ is still more preferable. In addition, although the upper limit of [(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)] is not specifically limited, From the composition of (A) component 2.0 or less is preferable from the viewpoint of the release property.

On the other hand, the upper limit of the combination 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 this is not satisfied, the target release property of component (A) 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)])

Although the lower limit of is not specifically limited, More than 0.25 is preferable from a viewpoint of transmittance|permeability.

The above formula for determining the compounding conditions stipulates the amounts of (B-1), (B-2) and (B-3) with respect to (A-1) and (A-2). (B) Since the compounding conditions of (A) differ according to the kind of nonionic surfactant, it divides by each unique coefficient with respect to the kind of (B) component. Intrinsic coefficient, for example, compared with (B-1)/0.25 and (B-3)/0.1, it means that the upper limit of the compounding of (B-1) is 2.5 times higher than that of (B-3) . In addition, since each active agent formulation upper limit of (B) component differs depending on the type of component (A), [(B-1)/0.25+(B-2)/0.01+(B-3)/0.1] is The formula related to the upper limit of mixing of each component (B) with respect to (A-1) is shown, and [(B-1)/0.1+(B-2)/0.2+(B-3)/0.05] is (A- The formula regarding the compounding upper limit of each (B) component with respect to 2) is shown. They are divided by the sum of components (A) (A-1) + (A-2). In addition, when both (A-1) and (A-2) are included, the influence is large or small depending on the blending ratio, so the weight is (A-1)/[(A-1)+(A-2). )] and (A-2)/[(A-1)+(A-2)] are added.

For example, in the case of (A-2) component 1.0 W/V%, (B-1) alone exceeds 0.05 W/V%, 1.0 W/V% or less, and (B-2) alone, 0.05 W/V %, 2.0 W/V% or less, and (B-3) alone, it is necessary to set it to 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, (A-1) component 0.1W/V%, (A-2) component 0.9W/V%, (B-1) ) alone, more than 0.05W/V%, 1.1W/V% or less, (B-2) alone, more than 0.05W/V%, 0.7W/V% or less, (B-3) alone, 0.05W/V% Exceeding, it is necessary to set it as 0.5 W/V% or less.

In addition, cationic surfactants typified by benzalkonium chloride or benzethonium chloride, anionic surfactants typified by sodium lauryl sulfate or sorbic acid or its salts, and amphoteric surfactants typified by lauramine oxide are ) inhibits the separation of the component and the surfactant, so that the component (A) is less likely to migrate to the tear oil layer, more preferably 0.1 W/V% or less in the composition, and still more preferably 0.01 W/V% or less, , it is particularly preferred to substantially not contain .

The ophthalmic composition of the present invention may further contain (C) a terpenoid. By blending the terpenoid, the release property, such as improving the release property from the composition of component (A), can be adjusted, and the effect of suppressing the generation of lipid peroxide can be enhanced. The terpenoid in the present invention has a structure in which an isoprene unit is a structural unit, and examples thereof include terpene hydrocarbons, terpene alcohols, terpene aldehydes and terpene ketones. Further, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes depending on the number of carbon atoms. Specifically, monoterpenes such as menthol, menthone, camphor, borneol, ginseng, geraniol, cineol, linalol, citronellol and limonene, diterpenes such as retinol and retinal, tetraterpenes such as carotenoid, etc. can be heard Especially, it is preferable to use a monoterpene. Any of d-form, l-form, or dl-form can be used for these terpenoids. Among these, menthol, menthone, camphor, borneol, geraniol, cineol, and linalol are preferable, and menthol, camphor, borneol, geraniol, cineol, and linalol are more preferable. Moreover, in this invention, you may use the essential oil containing the said compound as a terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, and essential oils of plants of the family Ipsidae, rosemarine oil, lavender oil, and the like. (A) Bergamot oil and eucalyptus oil are preferable at the point which improves the releasability from the composition of a component.

(C) The compounding amount of the component is 0.0001 to 0.2 W/V% in the composition, and is appropriately selected from the type of component (C), other compounding components such as (B) component, and its compounding amount, etc., and 0.001 to 0.1 W/V% is preferable In this blending concentration range, there is little risk of precipitation of (C) terpenoids without affecting the type or blending amount of other blending components. Further, from the viewpoint of suppressing the generation of lipid peroxide, 0.005 W/V% or more is more preferable, and from the viewpoint of reducing irritation, 0.075 W/V% or less is still more preferable.

[Other Ingredients]

In the composition of the present invention, other components may be blended in an appropriate amount within a range that does not impair the effects of the present invention. Examples of the other components include oil components, preservatives, sugars, buffers, pH adjusters, isotonic agents, stabilizers, polyhydric alcohols, thickeners, drugs, and the like. These components can be mix|blended individually by 1 type or in combination of 2 or more types. The compounding quantity of the component shown below is a preferable range in the case of mix|blending.

Examples of the oil component include castor oil, soybean oil, olive oil, sesame oil, corn oil, palm oil, almond oil, medium-chain fatty acid triglycerides, white petrolatum, refined lanolin, cholesterol, mixed tocopherols, 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, thimerosal, phenylethyl alcohol, alkylaminoethyl glycine, chlorhexidine gluconic acid, methyl paroxybenzoate, ethyl paraoxybenzoate, etc. are mentioned as preservatives having a hydrophobic part such as an alkyl chain or a benzene ring, but (A) component Since it becomes difficult to transfer to the tear oil layer, 0.1 W/V% or less is preferable in the composition, 0.01 W/V% or less is more preferable, and it is more preferable that it does not contain substantially.

Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, and mannitol. In addition, any of d-form, l-form, or dl-form may be sufficient as these. 0.001-5.0 W/V% is preferable in a composition, as for the compounding quantity of saccharides, 0.001-1 W/V% is more preferable, 0.001-0.1 W/V% is still more preferable.

Examples of the buffer include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogenphosphate, sodium dihydrogenphosphate, glacial acetic acid, trometamol, and sodium hydrogen chloride. 0.001-5.0 W/V% is preferable in a composition, as for the compounding quantity of a buffer, 0.001-2 W/V% is more preferable, 0.001-1 W/V% is still more preferable.

An inorganic acid or an inorganic alkali agent is mentioned as a pH adjuster. For example, (dilute) hydrochloric acid is mentioned as an inorganic acid. Examples of the inorganic alkali agent include sodium hydroxide, potassium hydroxide, sodium carbonate and sodium hydrogen chloride. 3.5-8.0 are preferable and, as for pH of a composition, 5.5-8.0 are more preferable. In addition, the measurement of pH is performed using the pH meter (HM-25R, DKK-TOA CORPORATION) at 25 degreeC.

Examples of the tonicity agent include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen chloride, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc., preferably 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. In addition, the measurement of osmotic pressure is performed using an automatic osmotic pressure meter (A2O, ADVANCED INSTRUMENTS, INC.) at 25 degreeC.

Examples of the stabilizer include sodium edetate, sodium edetate hydrate, cyclodextrin, sulfite, and dibutylhydroxytoluene. 0.001-5.0 W/V% is preferable in a composition, as for the compounding quantity of a stabilizer, 0.001-1 W/V% is more preferable, 0.001-0.1 W/V% is still more preferable. Since dibutylhydroxytoluene inhibits the separation of the component (A) and the surfactant by dilution of the tear fluid and makes it difficult for the component (A) to be supplied to the tear oil layer, it is more preferable not to contain dibutylhydroxytoluene substantially.

Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol and polyethylene glycol. In the case of blending the polyhydric alcohol, the blending amount of the polyhydric alcohol in the composition is preferably 0.001 to 5.0 W/V%, more preferably 0.001 to 1 W/V%, and still more preferably 0.001 to 0.1 W/V%.

Examples of the viscous agent include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, and carboxyvinyl polymer. When mix|blending a viscous agent, 0.001-5.0 W/V% is preferable in a composition, as for the compounding quantity, 0.001-1 W/V% is more preferable, 0.001-0.1 W/V% is still more preferable.

As the drug (pharmaceutically active ingredient), for example, a decongestant component (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine) hydrochloride, etc.), anti-inflammatory and astringent agents (e.g., neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride), antihistamines (e.g. diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adidine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate) etc.), amino acids (for example, potassium L-aspartate, magnesium L-aspartate, potassium/magnesium L-aspartate (equivalent mixture), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), sulfase, etc. are mentioned. In the case of compounding a drug, the content of the drug can be selected from an effective appropriate amount of each drug, but in the composition, 0.001 to 5.0 W/V% is preferable, 0.001 to 1 W/V% is more preferable, and 0.001 to 0.1 W/V% V% is more preferable.

[Manufacturing method]

Although the method for producing the composition of the present invention is not particularly limited, for example, a mixed solution of an oily component such as component (A) and a surfactant component such as component (B) is mixed with an aqueous solution containing an aqueous component to emulsify, After pH adjustment, it can be obtained by preparing the total volume with water. The mixing method of each liquid is good as a general method, and it is suitably performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, etc., The number of rotations is not specifically limited, It is preferable to set to such a degree that it does not bubble heavily. Although the mixing temperature of each liquid is not specifically limited, It is preferable that both an oil-based component and a surfactant component are the melting|fusing temperature or more, Specifically, it selects suitably in the range of 40-95 degreeC. More preferably, the refinement|miniaturization process by high pressure emulsification is performed. The high-pressure emulsification condition is preferably to increase the number of passes at high pressure from the viewpoint of improving the clarity of the composition, and it is preferable to decrease the number of passes at a low pressure from the viewpoint of improving production efficiency, and the injection pressure is 100 to 245 MPa It is preferable, 150-245 Mpa is more preferable, and 200-245 Mpa is still more preferable. Moreover, it is preferable to apply a back pressure, 1-10 Mpa is preferable, and 2-5 Mpa is more preferable. Moreover, 1-10 times are preferable and, as for the number of passes, 1-5 times are more preferable. The temperature at the time of high pressure emulsification is suitably selected in the range of 20-90 degreeC.

In addition, after the composition obtained is filled in a resin container, it may be further sealed with a package to seal the inert gas concentration in the space formed between the container and the package, or the ophthalmic composition may be filled in a resin container to obtain an oxygen scavenger It may be sealed together with a packaging body.

[Ophthalmic composition]

It is preferable that the composition of this invention is "aqueous ophthalmic composition". In the present invention, "aqueous ophthalmic composition" refers to an ophthalmic composition in which the medium is water. In addition, the mixing amount of water is preferably 90.0 to 99.5 W/V% in the composition, and 95.0 to 98.0 W/V% in the composition from the viewpoint of facilitating mixing with the tear fluid and facilitating the transfer of the component (A) to the tear fluid. more preferably.

The composition of the present invention is preferably a liquid from the viewpoint of facilitating eye adaptation, and the viscosity at 25°C facilitates mixing with the tear fluid and facilitates the transfer of the component (A) to the tear fluid. 20 mPa·s or less is preferable, 10 mPa·s or less is more preferable, 5 mPa·s or less is still more preferable, and 2 mPa·s or less is particularly preferable. In addition, the measuring method of a viscosity is performed using a cone plate type viscometer (for example, DV2T, EKO INSTRUMENTS INC.).

It is preferable that the composition of the present invention is clear from the viewpoint of facilitating detection at the time of mixing of foreign substances. Specifically, transmittance at a wavelength of 600 nm measured using a spectrophotometer (UV-1800, SHIMADZU CORPORATION) is 70% or more, preferably 70-100%, more preferably 75-100%, 90-100% is more preferable.

The median diameter of the aggregate of the surfactant and component (A) contained in the composition of the present invention was measured with a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics CO., LTD.), and 1 in view of the stability of the composition. -200 nm is preferable, 1-100 nm is more preferable, 1-60 nm is still more preferable, 1-40 nm is the most preferable.

Although the composition of the present invention can be preferably used as an eye drop, contact lens eye drop, eye wash, etc., the tear dilution ratio is high, so that the release of the surfactant from the component (A) is more accelerated, and the release of the component (A) from the composition Since the performance is improved and the supply of component (A) to the ophthalmic fluid oil layer is performed efficiently, it can be preferably used as an eye drop, particularly eye drops and contact lens eye drops (eye drops for contact lens wearers). The contact lenses are not particularly limited, such as hard contact lenses and soft contact lenses.

When used as eye drops or eye drops for contact lenses, it is preferable to instill 10 to 100 μl 1 to 3 drops 1 to 6 times a day at a time. Therefore, 10-50 μl of 1-3 drops at a time 1-6 times a day is more preferable, and 10-30 μl of 1-3 drops of 1-6 times a day of 1-6 times is more preferable. do. When used as an eye wash, it is preferable to wash the face 3 to 6 times a day, 3 to 6 ml at a time.

The composition of the present invention prevents oxidation of lacrimal lipids due to VDT work or UV rays, and causes eye discomfort caused by lipid peroxide (eye fatigue, blurry/smoky eyes, dry eyes, foreign body sensation, eye pain, eye irritation) As it has a preventive effect on puffiness, heaviness in the eyes, itching of the eyes, discomfort in the eyes, mucus, oily discharge, redness, etc.) In particular, it is effective for improving symptoms of eye fatigue, foreign body sensation, eye pain, and eye discomfort.

The effective amount, administration method, formulation, etc. 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.

Example

Hereinafter, the present invention will be specifically described by showing examples and comparative examples, but the present invention is not limited to the following examples. In addition, in the following example, when there is no special specification, "%" 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 of the aqueous components shown in the table below was dissolved in 90 ml of water, and heated and mixed at 90 DEG C for 15 minutes. Simultaneously, the premix of (A) component and (B) component was produced, and it heated and mixed for 90 degreeC and 15 minutes. Next, a predetermined amount of the premix was added to the aqueous solution, and the mixture was further heated and mixed at 90°C for 15 minutes. Then, it cooled to room temperature, pH was adjusted, and water was added so that it might become 100 ml. Further, using a high-pressure emulsifier (STAR BURST MINI, SUGINO MACHINE LIMITED CO., LTD.), the treatment was performed 5 times at a jet pressure of 200 MPa and a back pressure of 3 MPa to prepare an eye drop (ophthalmic composition). The following evaluation was performed about the obtained eye drop. The results are written together in the table. In addition, the viscosity at 25 degreeC of the eye drop obtained in each Example was the range of 0.5-2.0 mPa*s.

[Release of component (A) by dilution]

The average human tear fluid is known to be 7 μl, and when 30-60 μl of eye drops are instilled, it is diluted about 1.12 to 1.23 times. In this test, in order to evaluate that component (A), which is solubilized by diluting the tear fluid of the composition, floats at the gas-liquid interface (release property), physiological saline was used as the model tear fluid, and the composition was diluted with a dilution factor of about 1.2 times. (A) Component glass on the water surface at the time was observed. To facilitate observation, a mass flask with a narrow opening was used. Specifically, 10 ml of physiological saline was added to a 50 ml mass flask, and the eye drop was further poured to the opening. In addition, the mass flask from which the dilution rate at the time of pouring to an opening part becomes 1.2 times was used, and the area of the opening part was 152 mm<2>. Observation of component (A) on the water surface uses a fluorescent lamp as a light source to light the liquid surface, observes the oil interference light floating on the liquid surface, and calculates the ratio of the area of the oil interference light area to the surface of the water surface, and evaluates it according to the following criteria did. In addition, in the case of undiluted in any Example and the comparative example, the interference light of oil was not observed. ○ and ◎ indicate pass.

[Evaluation standard]

(double-circle): Interference light of oil is observed in 10% or more of water surface

○: Interference light of oil is observed in less than 10% of the water surface

x: Interference light of oil is not observed

[Inhibition rate of generation of lipid peroxide from tear oil layer by UV irradiation (%)]

As the model tear oil layer, an oil film prepared by developing a rabbit meibomian chloroform solution on a water tank mimicking physiological saline was used. Although there was a difference in the lipid composition depending on the species of meibom, it was confirmed that there was no difference in membrane stability between human meibom and rabbit meibom, so it was decided to use rabbit meibom, which is easily available. The vicinity of the opening of the meibomian gland of the eyelid (Funakoshi Co., Ltd.) cut out from the rabbit was pressed with a finger, and the extruded meibom was collected by Kimwipe (NIPPON PAPER CRECIA Co., LTD.). Thereafter, the Kimwipe was placed in a glass vial, immersed in a 1:1 mixture (volume ratio) of chloroform and methanol, and ultrasonicated for 10 minutes to transfer the liquid to another glass vial. This operation was repeated 3 times. Thereafter, it was filtered using a TERUMO syringe (manufactured by TERUMO CORPORATION, 50 ml) and a membrane filter (manufactured by Merckmillipore, Millex GP, 0.22 µm) washed with the chloroform-methanol mixture, and the dry weight was measured by a precision cloth (manufactured by Shimadzu Corporation, XS-104). Thereafter, chloroform was added with a micro-syringe (manufactured by Hamilton) to a concentration of 0.5 mg/ml, and rabbit meibom was dissolved and stored in a -20°C freezer. At the time of use, it returned to room temperature, and confirmed that there was no precipitate. A water layer was formed in a 35 mm dish with 1 ml of physiological saline, and 100 μl of rabbit meibom chloroform solution (0.5 mg/ml) was developed on the water surface, and 165 μl of each eye drop was added and irradiated with UV (254 nm) for 1 hour. The entire amount of this solution was recovered in a vial, and 0.5ml of 35% trichloro acetic acid (TCA) solution, 1.0ml of 0.5% thiobarbituric acid (TBA) solution, 0.05ml of 0.2% butylated hydroxytoluene (BHT) solution, 0.5% SDS After adding 0.05 mL of a (sodium dodecyl sulfate) solution, it 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 x 10 minutes), and the absorbance of the upper layer was measured at 532 nm. A blank was taken as the absorbance when an equivalent operation was performed in the above method except that the rabbit meibom chloroform solution was not developed. From the obtained absorbance, the generation inhibition rate (%) of lipid peroxide from the tear oil layer was calculated based on the following formula. A result is shown by the following evaluation criteria. ●, ○ and ◎ are accepted.

Inhibition rate of generation of lipid peroxide from tear oil layer (%) =

(1-(absorbance when adding eye drop-blank)/(absorbance when not adding eye drop-blank) x 100

[Evaluation standard]

◎: 50% or more

○: 30% or more and less than 50%

●: 10% or more and less than 30%

×: less than 10%

[Effect of preventing symptoms by working with VDT]

30 μl of each eye drop was instilled into each eye in 3 healthy subjects, VDT work (computer work) was applied, and eye fatigue, foreign body sensation, and eye pain before instillation, 10 minutes after instillation, and 60 minutes after instillation , the subjective symptoms of eye discomfort were scored on a scale of 0 (not felt at all) to 10 (very felt). A result is shown by the following evaluation criteria from the average of three people. ●, ○ and ◎ are accepted.

[Evaluation standard]

◎: Less than 5 points after 60 minutes (of less than 5 points after 10 minutes, less than 5 points after 60 minutes)

○: Less than 5 points after 10 minutes

●: More than 5 points and less than 7 points after 10 minutes

×: 7 points or more after 10 minutes

[Transmittance]

The transmittance of the eye drop immediately after preparation was measured at a wavelength of 600 nm using a Hitachi spectrophotometer U-3310. 70% or more is considered a pass.

The raw material used in the said example is shown below. In addition, unless otherwise specified, the quantity of each component in a table|surface is a pure part conversion amount.

Retinol palmitic acid ester (manufactured by DSM Nutrition Japan)

Acetate d-α-tocopherol (RIKEN E acetate α, manufactured by RIKEN VITAMIN CO., LTD.)

Liquid paraffin (manufactured by KAYDOL, SHIMA TRADING CO., LTD.)

Castor oil (MARUTOKU A, manufactured by ITOH OIL CHEMICALS CO., LTD.)

Sesame oil (manufactured by KANEDA Co., Ltd.)

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 INDUSTRIES CO., LTD.)

Polyoxyethylene hydrogenated castor oil 60 (HCO60, manufactured by NIPPON SURFACTANT INDUSTRIES CO., LTD.)

Polyethylene glycol monostearate*1: average added mole number of ethylene oxide 10 (MYS10V, manufactured by NIPPON SURFACTANT INDUSTRIES CO., LTD.)

Polyethylene glycol monostearate *2: average added mole number of ethylene oxide 40 (MYS40MV, manufactured by NIPPON SURFACTANT INDUSTRIES CO., LTD.)

Polyethylene glycol monostearate *3: average added mole number of ethylene oxide 100 (EMALEX8100, manufactured by NIPPON SURFACTANT INDUSTRIES 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 KOZAKAI PHARMACEUTICAL CO., LTD.)

Trometamol (manufactured by KANTO CHEMICAL CO., INC.)

Sodium edetate hydrate (CLEWAT N, manufactured by Nagase ChemteX Corporation)

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

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

Menthol (l-menthol, manufactured by SUZUKI MENTHOL CO., LTD.)

dl-camphor (manufactured by NIPPON FINE CHEMICAL CO., LTD.)

Borneol (d-Borneol, manufactured by Yanagisawa Masami Shoten)

Geraniol (manufactured by TAKASAGO INTERNATIONAL CORPORATION)

Cineole (manufactured by TAKASAGO INTERNATIONAL CORPORATION)

Linalol (manufactured by TAKASAGO INTERNATIONAL CORPORATION)

Bergamot oil (manufactured by YAMAMOTO PERFUMERY CO., LTD.)

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

Claims (7)

(A) (A-1) at least one selected from vitamin A and (A-2) vitamin E, and an ophthalmic composition comprising a surfactant,
The surfactant is composed of only a nonionic surfactant,
The nonionic surfactant is
(B) at least one nonionic surfactant selected from (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil and (B-3) other nonionic surfactants; Their compounding mass ratio,
(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)]× satisfy (A-2)/[(A-1)+(A-2)]≤10,
The (A-1) vitamin A is retinol palmitic acid ester, the (A-2) vitamin E is tocopherol acetate, and the (B-1) polyoxyethylene castor oil is polyoxyethylene castor oil 35, (B-2) polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 40 or polyoxyethylene hydrogenated castor oil 60 40 or 100 of monostearic acid polyethylene glycol, POE sorbitan fatty acid ester, or POEPOP glycol,
An ophthalmic composition having a transmittance of 70% or more. The method of claim 1,
(A) An ophthalmic composition wherein the component is (A-2) vitamin E. 3. The method according to claim 1 or 2,
(B) An ophthalmic composition comprising at least one nonionic surfactant selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. 3. The method according to claim 1 or 2,
(C) further comprising a terpenoid,
The (C) terpenoid is menthol, linalol, cineol, bergamot oil, eucalyptus oil, geraniol, borneol or dl-camphor, an ophthalmic composition. 3. The method according to claim 1 or 2,
An ophthalmic composition that is an eye drop. 3. The method according to claim 1 or 2,
An ophthalmic composition for inhibiting the generation of lipid peroxide in the tear oil layer or for preventing eye discomfort caused by lipid peroxide. A method for preparing the ophthalmic composition according to claim 1 or 2, comprising:
A method for producing an ophthalmic composition comprising a refinement process by high pressure emulsification.