KR20150018509A - Composition for mucous membranes - Google Patents

Abstract

(A '): a fat-soluble active ingredient of 0.001 to 1.0 W / V%, and (B) a polyoxyethylene polyoxypropylene copolymer in a weight ratio of 1: (A ') and (B) is added to an aqueous phase containing 75 to 90 ° C and stirred, and the components (A') and (B) By weight of a fat-soluble active ingredient-containing nano-emulsion particle.

Description

COMPOSITION FOR MUCOUS MEMBRANES [0002]

TECHNICAL FIELD The present invention relates to a mucosal composition comprising a nanoemulsion containing a lipophilic active ingredient.

Active ingredients such as fat-soluble vitamin A are attracting attention as effective ingredients for treatment of cornea, conjunctiva, nasal mucosa and pharynx. However, these active ingredients are very sensitive to air, light, heat, acids, metal ions and the like. Especially, they are extremely unstable in an aqueous solution and therefore they can be used as eye drops, rhinitis medicines, It is a problem to be stably incorporated into a composition for a mucosa such as a liquid agent and a gagging agent.

Various measures (setting of the highest optimum pH, filling of nitrogen in the pill, combination with an antioxidant, coloring of the container, etc.) have been taken in order to stabilize these active ingredients, for example, vitamin A in a solution . Surfactants are required for emulsification of lipid-soluble components such as vitamin A. When too much is added, the stability of vitamin A and the like is poor, and when it is small, appearance uniformity can not be maintained (separation of vitamin A and the like) .

In the case of eye drops containing these active ingredients, for example, vitamin A, an increase in vitamin A, the addition of an absorption promoting agent to the cornea, and the addition of a thickening agent have been carried out as measures for increasing the effectiveness of vitamin A, A stability, irritation to eyes, and a feeling of stickiness remain.

Japanese Patent Application Laid-Open No. 11-302195 Japanese Patent Application Laid-Open No. 2003-113078

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above circumstances, and it is an object of the present invention to provide a composition for a mucosal membrane which, when compounding a fat-soluble active ingredient such as vitamin A in a mucosal composition, Solubilizing the liposoluble active ingredient in mucous membranes such as nasal mucosa, nasal mucosa, oropharynx, and exhibiting the effect more effectively.

DISCLOSURE OF THE INVENTION The present inventors have intensively studied in order to achieve the above object, and as a result, they have found that the amount of a nonionic surfactant to a fat-soluble active ingredient is within a specific range, Phase is added to the aqueous phase and stirred, the above problems can be solved and the present invention has been accomplished.

Accordingly, the present invention provides a composition for the following mucous membrane.

[One]. (A ') a fat-soluble active ingredient of 0.001 to 1.0 W / V%, and (B) a nonionic surfactant in a mass ratio of 1: 0.4 to 25 and 1: 0.4 to 24.0 Soluble active ingredient and the component (B) is added to an aqueous phase at 75 to 90 ° C and stirred, and the nano-emulsion particle containing the fat-soluble active ingredient and the component (B) .

[2]. (A) a fat-soluble active ingredient of 0.005 to 0.2 W / V%, and (B) a nonionic surfactant comprising a polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as essential components, in a total amount of the nonionic surfactant (A ') and (B') in a weight ratio of 1: 0.4 to 7.0, (D) a refreshing agent, (A ') and (B) as a constituent component, which is obtained by adding an oil phase containing water to a water phase of 75 to 90 ° C and stirring the resulting oil phase.

[3]. (BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) , And (E) 0.5 to 2.0 W / V% boric acid and / or borax, in a weight ratio of 1: 0.4 to 25,

The nano emulsion particles obtained by adding and stirring the oil phase containing components (A ') and (BI) to an aqueous phase at 75 to 90 ° C and containing the components (A') and (BI) ≪ / RTI >

[4]. (BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) And (G) a water-soluble polymeric compound in a mass ratio of 1: 0.4 to 10,

The nano emulsion particles obtained by adding and stirring the oil phase containing components (A ') and (BI) to an aqueous phase at 75 to 90 ° C and containing the components (A') and (BI) ≪ / RTI >

According to the present invention, it is possible to maintain the stability of the fat-soluble active ingredient, to make the appearance of the composition for mucosal membrane uniform, to enhance the adsorption of the liposoluble active ingredient to the mucosa of the cornea or the like, Composition can be provided.

1 is a chart showing measurement results of EGPC in Examples 1-4;
2 is a chart showing the measurement results of EGPC of Example 17;

Hereinafter, the present invention will be described in detail.

(A ') 0.001 to 1.0 W / V% of a fat-soluble active ingredient and (B) a nonionic surfactant in a mass ratio represented by (A') :( B) of 1: 0.4 to 24.0 (A ') and (B), which is obtained by adding an oil phase containing the components (A') and (B) to an aqueous phase of 75 to 90 ° C and stirring the mixture, Containing nano-emulsion particles containing an active ingredient.

The significance of the term of the present invention is defined as follows.

"Nano emulsion particle" means a nano emulsion particle containing a fat-soluble active ingredient, for example, (A) vitamin A in the emulsion particle, and a fat-soluble active ingredient and (B) a nonionic surfactant. The particle diameter of the nano emulsion particles is preferably 1 nm or more and less than 500 nm, more preferably 10 nm to 500 nm, and even more preferably 10 nm to 300 nm. For example, a particularly preferable range is more than 40 nm and not more than 140 nm (especially when the fat-soluble active ingredient is vitamin A). When the particle diameter exceeds 40 nm, the releasing property of the active ingredient from the active ingredient-containing nano-emulsion particles, for example, the adsorption of the effective ingredient to the cornea in eye drops or the like is further improved. In this respect, the lower limit is particularly preferably 45 nm or more, 50 nm or more, and 55 nm or more. On the other hand, when the particle diameter of the nano-emulsion particles is 140 nm or less, the appearance of the composition is transparent. In this respect, the thickness is preferably 115 nm or less, more preferably 110 nm or less. In the present invention, the particle diameter refers to the average diameter (median diameter nm) of the particle distribution calculated from the scattered light intensity. The particle size is measured by a variety of measuring apparatuses which use a principle such as light scattering, using a constant temperature bath under a constant temperature condition of 25 ° C.

&Quot; Fat-soluble active ingredient pre-ionic surfactant " refers to a nonionic surfactant that does not contain a fat-soluble active ingredient, and includes " pre-micelle " and " free (free) surfactant molecule ".

· "Pre-micelle" means a surfactant aggregate containing no fat-soluble active ingredient.

&Quot; Glassy surfactant molecule " refers to a surfactant that does not form micelles (aggregates).

&Quot; Oil-blended component " includes a surfactant such as a " fat-soluble component " such as a fat-soluble active ingredient and a component (B)

&Quot; Water-containing composition component " includes water and a water-soluble component dissolved in water, and is compounded in " Water ".

Examples of fat-soluble active ingredients include fat-soluble active ingredients other than the following (A) vitamin A and (C) (A) components.

(A) Vitamin A

Examples of vitamin A include not only vitamin A itself but also vitamin A-containing mixtures such as vitamin A oil and vitamin A derivatives such as vitamin A fatty acid ester. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Among them, retinol palmitate, retinol acetate and retinoic acid are preferred. Retinol palmitate is generally commercially available in the range of 1,000,000 to 1,800,000 international units (hereinafter abbreviated as IU), specifically, retinol palmitate ester (1.74 million IU) manufactured by DSM Nutrition Co., Ltd. .

(C) a fat-soluble active ingredient other than the component (A)

No particular limitation is imposed on the fat-soluble active ingredient other than the component (A), but the following may be included, and they may be used alone or in combination of two or more.

Antioxidants such as tocopherol acetate (dl-α-tocopherol acetate, d-α-tocopherol acetate (vitamin E)), dibutylhydroxytoluene, butylhydroxyanisole and nordihydroguaiaretic acid, Tocopherol, and dibutylhydroxytoluene.

Vitamins such as vitamin D and vitamin K, steroidal anti-inflammatory drugs such as dexamethasone, betamethasone and prednisolone, immunosuppressants such as cyclosporin, tacrolimus and paclitaxel, antibacterial agents such as clarithromycin and oproxacin, An anti-inflammatory agent such as diphenhydramine, ketoprofen, salicylic acid glycol, indymethacin, ameloxazone, beclometasone propionic acid ester, mometasone furan carboxylic acid ester and fluticasone furan carboxylic acid ester, Vasoconstrictors such as epinephrine, and local anesthetics such as lidocaine.

The total amount of the fat-soluble active ingredients, specifically, the total amount of the components (A) and (C) is preferably 0.001 to 1.0 W / V% (as the total amount of the components (A) g / 100 ml), preferably 0.005 to 0.5 W / V%, more preferably 0.01 to 0.4 W / V%, still more preferably 0.05 to 0.175 W / V%. In addition, it can be appropriately selected in accordance with the effectiveness and application of the compounding ingredients.

For example, in the case of (A) a composition using vitamin A or an ophthalmic composition, it is preferably 0.003 to 0.3 W / V% (g / 100 ml) based on the total amount of the composition. When the ophthalmic composition is a cleansing agent , More preferably 0.005 to 0.05 W / V% (g / 100 ml), and still more preferably 0.006 to 0.04 W / V%. When the ophthalmic composition is an eye drop, 0.006 to 0.3 W / V% (g / 100 ml) is more preferable, and 0.01 to 0.2 W / V% is more preferable. Vitamin A has the effect of treating corneal and conjunctival injuries, improvement of dry eye, improvement of tired eyes and irritated eyes. In this range, a desired effect can be obtained. If too much, vitamin A can not be emulsion, have.

Particularly, in the case of an antioxidant selected from (C) tocopherol acetate and dibutylhydroxytoluene, one kind may be used, but two or more kinds may be used in combination. As a result, the storage stability (residual ratio) of (A) vitamin A is further improved. The blending amount of the component (C) is preferably 0.001 to 0.5 W / V%, more preferably 0.003 to 0.1 W / V% with respect to the total amount of the composition. When the component (C) is tocopherol acetate, the blending amount is preferably 0.01 to 0.5 W / V%, more preferably 0.02 to 0.2 W / V%, still more preferably 0.03 to 0.05 W / V% Do. (C) is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, and even more preferably 0.003 to 0.005 W / V% based on the total amount of the composition, Is more preferable. By setting this range, (A) the storage stability of vitamin A and the appearance transparency are further improved.

(B) a nonionic surfactant

Examples of the nonionic surfactant to be used in the present invention include nonionic surfactants selected from the following (BI) polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester, (B-II) polyoxyethylene polyoxypropylene copolymer . When the components (B-I) and (B-II) are represented collectively, the component (B) is used.

(B-I) nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid esters

Polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid ester. Examples of the polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil, And a combination with a free and polyoxyethylene sorbitan fatty acid ester is more preferable.

Examples of the polyoxyethylene hardened castor oil include polyoxyethylene hardened castor oil 60 (polyoxyethylene (60) hardened castor oil) and polyoxyethylene hardened castor oil 40 (polyoxyethylene (40) hardened castor oil) Among them, polyoxyethylene hardened castor oil 60 (polyoxyethylene (60) hardened castor oil) is preferable. Examples of polyoxyethylene sorbitan fatty acid esters include sorbitan monolaurate (20) sorbitan (polyisobutyl 20), monopalmitic acid POE (20) sorbitan (polyisobutyl 40), monostearic acid POE (20) sorbitan (20) sorbitan (PORISOLBETO 65) and monooleic acid POE (20) sorbitan (POORISOLBETO 80), among which POE (20) sorbitan monooleate Bitterness (polysorbate 80) is preferred. These may be used singly or in combination of two or more.

(B-II)

Examples of the polyoxyethylene polyoxypropylene copolymer include polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) Glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (20) polyoxypropylene (20) May be used alone or in combination of two or more. Among them, polyoxyethylene (200) polyoxypropylene (70) glycol is preferable.

The amount of the component (B) is preferably from 1: 0.4 to 24.0, more preferably from 1: 0.4 to 20.0, in terms of the mass ratio represented by (A) + (C) More preferably 1: 0.4 to 12.0, further preferably 1: 0.4 to 10.0, particularly preferably 1: 0.4 to 7.0, and 1: 0.9 to 2.0. When the amount of the (B) nonionic surfactant per total amount of the component (A) and the component (C) is 0.4 or more, a uniform emulsion can be obtained. Further, at 24.0 or less, the adsorbability of the fat-soluble active ingredient to the mucous membrane of the cornea or the like is improved, and the effect of the component (A) is exhibited in a small amount.

(B-I) nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester

(A) + (C): (B-I) = 1: 0.4 to 10.0, more preferably 1: 0.4 to 9.0, further preferably 1: 0.4 to 5.0.

(B-II)

In the case of a polyoxyethylene polyoxypropylene copolymer

(A) + (C): (B-II) = 1: 0.8 to 24.0, more preferably 1: 2.0 to 20.0, further preferably 1: 2.0 to 8.0.

If the amount of the nonionic surfactant (B) per total amount of the component (A) and the component (C) is too small, the oil component can not be sufficiently emulsified and the appearance transparency deteriorates or the emulsion does not become a stable emulsion. On the other hand, when the amount of the nonionic surfactant (B) per the total amount of the component (A) and the component (C) is too large, a composition for a mucus membrane having a small emulsion particle size, a more uniform appearance and transparency, The effect of improving the adsorption of the components (A) and (C) to the cornea or the like becomes insufficient. As a result, the effect of improving the action of the components (A) and (C) The effect becomes insufficient and the chemical stability (residual ratio) of the fat soluble component becomes poor.

The blending amount of the component (B) is determined by the amount relative to the component (A), and is 0.0004 to 2 W / V%, preferably 0.0004 to 1.5 W / V% based on the total amount of the composition. When two or more of them are used in combination, the amount of the component (B) is the total amount.

Hereinafter, the present invention will be described in more detail with respect to the components (A), (B) and (B).

I- (1): HCO-VA low concentration

(A) Vitamin A 0.003 W / V% or more and less than 0.015 W / V%

(B-I) a non-ionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester, in a mass ratio represented by (A): (B-I) of from 1: 3.0 to 10.0,

(C) a fat-soluble active ingredient other than the component (A)

(BI) and (C) is obtained by adding an oil phase containing the components (A), (BI) and (C) Wherein the nano-emulsion particle comprises a nano-particle.

As described above, it is possible to maintain the stability of vitamin A, make the appearance of the composition for mucosal membrane uniform, and increase the absorption of vitamin A into the cornea (vitamin A absorption rate of 50% or more).

The blending amount of the component (A) is preferably 0.003 W / V% or more, less than 0.015 W / V%, preferably 0.006 to 0.015 W / V% or less and preferably 0.01 to 0.015 W / V% or less based on the whole composition. Vitamin A has an effect of treating corneal and conjunctival injuries, improving dry eye, improving tired eyes and diminished eyes. The present invention is based on the finding that the amount of vitamin A in the mucosa of the cornea or the like The adsorption can be increased, so that an intended effect can be obtained.

The blending amount of the component (B-I) is 1: 3.0 to 10.0 in terms of the mass ratio represented by (A): (B-I). From the viewpoint of appearance transparency of the composition, the lower limit is preferably 5 or more, more preferably 6 or more. In terms of adsorption to the vitamin A in the cornea, the upper limit is preferably 9 or less, more preferably 8 or less.

The blending amount of the component (B-I) is determined by the amount relative to the component (A), and it is preferably 0.009 to less than 0.15 W / V% with respect to the total amount of the composition.

The blending amount of the component (C) is preferably 0.001 to 0.5 W / V%, more preferably 0.003 to 0.1 W / V% based on the total amount of the composition, and the blending amount of the component (C) to be.

I- (2): HCO-VA medium concentration

(B-I) a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester in a mass ratio of 1: 1.6 to 7.0, represented by (A): (B-I)

(C) a fat-soluble active ingredient other than the component (A)

(BI) and (C) is obtained by adding an oil phase containing the components (A), (BI) and (C) Wherein the nano-emulsion particle comprises a nano-particle. Further, it can be divided into a range of 1: 3.0 to 7.0 (high ratio) and a range of 1: 1.6 or more except for the above (low ratio).

I- (2) -H: HCO-VA medium concentration, high ratio

Particularly, when the mass ratio represented by (A): (BI) is 1: 3.0 to 7.0, the stability of vitamin A is maintained and the appearance of the composition is made transparent and the vitamin The release of A is high and, for example, the adsorption of the cornea to vitamin A at the time of instillation (diluted state with leakage) increases, and the amount of vitamin A is in the range of 0.015 to 0.05 W / V% The effect of vitamin A is exerted.

In the case of the above ratio, the blending amount of the component (A) is preferably from 0.015 to 0.05 W / V% (g / 100 ml), more preferably from 0.02 V / W% to 0.05 V / W% V / W% and not more than 0.04 W / V% are particularly preferable.

The blending amount of the component (B) is preferably 1: 3.0 to 7.0, more preferably 1: 3.0 to 1: 6.0, and more preferably 1: 3.0 to 1: 5.5 in terms of the mass ratio represented by (A): (B-I). When the amount of the nonionic surfactant (B) of the vitamin A sugar (A) is too small, the oil component can not be sufficiently emulsified and the appearance transparency is deteriorated or the emulsion is not stable. (B-1) is determined by the amount relative to the component (A), preferably 0.045 to 0.35 W / V% based on the total amount of the composition. On the other hand, if the amount of (BI) nonionic surfactant (A) in the vitamin A sugar is too large, a composition having a small emulsion particle size, a clear appearance, and excellent external appearance stability of the preparation can be obtained. As a result, the effect of the desired vitamin A (the effect of healing corneal and conjunctival injuries, dry eye improvement, tired eye, poor eyesight improvement) is insufficient. Further, if the concentration of the (B-I) nonionic surfactant is too high, the chemical stability (residual ratio) of the vitamin A may be deteriorated.

The blending amount of the component (C) is preferably 0.001 to 0.5 W / V%, more preferably 0.003 to 0.1 W / V% with respect to the total amount of the composition. When the component (C) is tocopherol acetate, the blending amount is preferably 0.01 to 0.5 W / V%, more preferably 0.02 to 0.12 W / V%, and even more preferably 0.03 to 0.05 W / V% based on the total amount of the ophthalmic composition More preferable. By setting this range, (A) the storage stability of vitamin A and the appearance transparency are further improved.

When the component (C) is dibutylhydroxytoluene, the blending amount is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, more preferably 0.003 to 0.005 W / V% is more preferable. By setting this range, (A) the storage stability of vitamin A and the appearance transparency are further improved. Further, as the component (C), it is more preferable to use the above-mentioned tocopherol acetate and dibutylhydroxytoluene in combination.

I- (2) -L: HCO-VA medium concentration / low ratio

Particularly, when the mass ratio represented by (A): (BI) is less than 1: 1.6 to 3 and less than 1: 1.6 to 3.0, the stability of vitamin A is maintained, the appearance of the composition for mucosal membranes is made uniform, It is possible to remarkably enhance the absorption of vitamin A into the cornea (the absorption rate of vitamin A is not less than 60%, suitably not less than 69% by mass).

The blending amount of the component (A) is 0.015 to 0.05 W / V% (g / 100 ml) with respect to the total amount of the composition. Vitamin A has an effect of treating corneal and conjunctival injuries, improvement of dry eyes, improvement of tired eyes and diminished eyes. In this range, a desired effect can be obtained. If too much, vitamin A can not be emulsified and may be separated .

The blending amount of the component (B-I) is preferably 1: 1.6 to less than 3, and more preferably 1: 2 to less than 3.0 in mass ratio represented by (A): (B-I). Within this range, it is possible to obtain a remarkable effect of enhancing the adsorption of vitamin A on the cornea.

The amount of component (B-I)

The blending amount of the component (B-I) is determined by the amount relative to the component (A), and is preferably 0.024 to less than 0.15 W / V% with respect to the total amount of the composition.

The blending amount of the component (C) is preferably 0.001 to 0.5 W / V%, more preferably 0.003 to 0.1 W / V% based on the total amount of the composition, and the blending amount of the component (C) to be.

I- (3): High concentration of HCO-VA

(A) Vitamin A: more than 0.05 W / V%, not more than 0.3 W / V%

(B-I) a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester in a mass ratio of 1: 1.6 to 5.0,

(C) a fat-soluble active ingredient other than the component (A)

(BI) and (C) is obtained by adding an oil phase containing the components (A), (BI) and (C) Wherein the nano-emulsion particle comprises a nano-particle.

With this, it is possible to maintain the stability of vitamin A, make the appearance of the composition for mucosal membrane uniform, and increase the absorption of vitamin A into the cornea (vitamin A absorption rate of 40% or more).

The blending amount of the component (A) is more than 0.05 W / V% and not more than 0.3 W / V% with respect to the total amount of the composition, more preferably not less than 0.05% and not more than 0.2 W / V%. Vitamin A has an effect of treating corneal and conjunctival injuries, improving dry eye, improving tired eyes and diminished eyes. However, the present invention is not limited to vitamin A in the amount of vitamin A, The adsorption can be increased, so that an intended effect can be obtained.

The blending amount of the component (B-I) is 1: 1.6 to 5.0 in a mass ratio represented by (A): (B-I). In terms of appearance transparency of the composition, the lower limit is preferably 2.0 or more, more preferably 2.5 or more. In terms of adsorption to the vitamin A in the cornea, the upper limit is preferably 4.0 or less, more preferably 3.0 or less.

The amount of component (B-I)

The blending amount of the component (B-I) is determined by the amount relative to the component (A), and is preferably more than 0.08 W / V% and not more than 1.5 W / V% with respect to the total amount of the composition.

The blending amount of the component (C) is preferably 0.001 to 0.5 W / V%, more preferably 0.003 to 0.1 W / V% based on the total amount of the composition, and the blending amount of the component (C) to be.

Ⅱ- (1): Low concentration of EOPO-VA

(A) 0.003 to 0.025 W / V% of vitamin A,

(B-II) polyoxyethylene polyoxypropylene copolymer in a weight ratio of (A): (B-II) of from 1: 11 to 24,

(C) a fat-soluble active ingredient other than the component (A)

(A), (B-II), and (B-2), which is obtained by adding an oil phase containing the components (A) and And a nano-emulsion particle comprising the component (C) as a constituent component.

As described above, it is possible to maintain the stability of vitamin A, make the appearance of the composition for mucosal membrane uniform, and increase the absorption of vitamin A into the cornea (vitamin A absorption rate of 50% or more).

The blending amount of the component (A) is preferably 0.003 to 0.025 W / V%, more preferably 0.01 to 0.025 W / V% based on the whole amount of the composition. Vitamin A has an effect of treating corneal and conjunctival injuries, improving dry eye, improving tired eyes and diminished eyes. The present invention is based on the finding that the amount of vitamin A in the mucosa of the cornea or the like The adsorption can be increased, so that an intended effect can be obtained.

The blending amount of the component (B-II) is preferably from 1: 11 to 24, and more preferably from 15 to 24 in terms of the mass ratio represented by (A): (B-II). In view of appearance transparency of the composition, it is preferably at least 15, more preferably at least 17. In terms of adsorption to the vitamin A in the cornea, the upper limit is preferably 24 or less, more preferably 20 or less.

(B-II) component

The blending amount of the component (B-II) is determined by the amount relative to the component (A), and it is preferably 0.033 to 0.6 W / V% with respect to the total amount of the composition.

The blending amount of the component (C) is preferably 0.001 to 0.5 W / V%, more preferably 0.003 to 0.1 W / V% based on the total amount of the composition, and the blending amount of the component (C) to be.

Ⅱ- (2): High concentration of EOPO-VA

(A) Vitamin A is more than 0.025 and 0.085 W / V% or less,

(B-II) polyoxyethylene polyoxypropylene copolymer in a weight ratio of (A): (B-II) of from 1: 8 to 13,

(C) a fat-soluble active ingredient other than the component (A)

(A), (B-II), and (B-2), which is obtained by adding an oil phase containing the components (A) and And a nano-emulsion particle comprising the component (C) as a constituent component.

With this, it is possible to maintain the stability of vitamin A, make the appearance of the composition for mucosal membrane uniform, and increase the absorption of vitamin A into the cornea (vitamin A absorption rate of 45% or more).

The blending amount of the component (A) is preferably 0.025 W / V% or more and 0.085 W / V% or less, more preferably 0.025 W / V% or more and 0.075 W / V% or less based on the total amount of the composition. Vitamin A has an effect of treating corneal and conjunctival injuries, improving dry eye, improving tired eyes and diminished eyes. However, the present invention is not limited to vitamin A in the amount of vitamin A, The adsorption can be increased, so that an intended effect can be obtained.

The blending amount of the component (B-II) is 1: 8 to 13 in terms of the mass ratio represented by (A): (B-II). In terms of appearance transparency of the composition, the lower limit is preferably 10 or more, more preferably 11 or more. In terms of adsorption to the vitamin A in the cornea, the upper limit is preferably 12.5 or less, more preferably 12 or less.

(B-II) component

The blending amount of the component (B-II) is determined by the amount relative to the component (A), preferably 0.2 to 1.105 W / V% based on the total amount of the composition.

(C) and the amount of component

The blending amount of the component (C) is preferably 0.001 to 0.5 W / V%, more preferably 0.003 to 0.1 W / V% based on the total amount of the composition, and the blending amount of the component (C) to be.

[Manufacturing method]

The composition of the present invention is obtained by adding an oil phase containing the oil soluble active ingredients ((A) and (C)) and (B) to an aqueous phase at 75 to 90 캜 and stirring. That is, the method for producing the composition for mucus membranes of the present invention is characterized in that the oil phase containing the oil soluble active components ((A) and (C)) and the component (B) And stirring the mixture. The "oil phase" is blended with an "oil phase composition component" such as a surfactant such as the "fat-soluble active ingredient" and the (B) component of (A) or (C) And water-soluble components (water-soluble drug, inorganic salt, water-soluble polymer, preservative, etc.).

The blending amount of the oil-blending component in the mucosal composition is preferably 10 W / V% or less, more preferably 7 W / V% or less, and further preferably 5 W / V% or less. By setting this range, appearance uniformity is further improved.

The oil phase temperature is preferably 50 to 90 占 폚, more preferably 65 to 90 占 폚, and further preferably 70 to 85 占 폚. By setting the temperature within this range, a uniform state of oil phase can be obtained, and a composition for a mucous membrane having a more uniform appearance can be obtained.

The important point in the present invention is an aqueous phase temperature of 75 to 90 占 폚, preferably 80 to 90 占 폚, more preferably 82 to 90 占 폚, still more preferably 83 to 90 占 폚. If the temperature is too low, a nanoemulsion can not be obtained with the amount of the nonionic surfactant (B) of the present invention, and a composition for a uniform appearance can not be obtained. On the other hand, if the temperature is too high, the fat-soluble active ingredient may decompose.

The amount of the water phase (water phase amount) at the time of adding and stirring the oil phase is not particularly limited, but is preferably 50 W / V% or more of the total composition as in the case of a composition containing an emulsion, V% or more is more preferable.

The oil phase is quickly added to the water phase. The average temperature of the aqueous phase from the start of stirring to the end of stirring after the addition of oil phase is preferably 75 to 90 占 폚, more preferably 80 to 90 占 폚, still more preferably 82 to 90 占 폚, particularly preferably 83 to 90 占 폚, 90 ° C. In addition, the permissible amplitude with respect to the average temperature of the water phase is ± 4 ° C. The cooling is performed after the completion of the stirring, and the cooling temperature after the completion of the stirring is not included in the above temperature.

The stirring time is preferably 5 to 60 minutes from the end of the dropwise addition of the oil phase, and more preferably 5 to 30 minutes. By making the time longer than the above, the charged oil phase can be dispersed more uniformly in the water phase.

The stirring method for adding the oil phase to the water phase may be any ordinary stirring method used when preparing a composition such as eye drops and is suitably carried out using pulsators, propeller blades, paddle blades, turbine blades, etc., It is preferable to set the degree of bubbling so as not to be extremely bubbled.

As described above, the present inventors have found that when the amount of the nonionic surfactant (B) to the fat-soluble active ingredients (A) and (C) is within a specific range, (A), (B) and (C) as constituent components, that is, " vitamin A-containing nano emulsion particles " (hereinafter referred to as " nano- , &Quot; liposoluble active ingredient-containing nanoemulsion particles "), it is possible to obtain a cosmetic composition for uniform appearance and to improve the stability of the fat-soluble active ingredient, . ≪ / RTI > As a result of further studies by the present inventors, the following findings were obtained. One of the reasons why the composition of the present invention has increased adsorption to the vitamin A in the cornea is that the "vitamin A free (B) nonionic surfactant" adheres to the surface of the eye and the "vitamin A- The adhesion to the surface of the eye is inhibited. Therefore, it is presumed that the adsorption of vitamin A on the cornea is improved.

The ratio of the component (B) constituting the "lipophilic active component-free preionic surfactant", that is, the "micelle" and the "glass surfactant molecule" to the total amount of the component (B) is less than 44 mass% And more preferably 43 mass% or less. In addition, the lower limit is preferably 0 mass%, that is, not including, but may be 1 mass% or 0.01 mass%. The proportion of the component (B) constituting the " fat-soluble active ingredient-containing nano emulsion particle " with respect to the total amount of the component (B) is preferably more than 56 mass% and more preferably 100 mass% , And the upper limit is not limited, but may be 99% by mass.

The composition such as "liposoluble active ingredient-containing nano emulsion particle", "pre-micelle" and "glass surfactant molecule" in the composition for mucosal membranes can be measured using Eluent gel permeation chromatography (hereinafter referred to as EGPC).

That is, the sample was detected by RI (detecting nonionic surfactant and lipophilic component) and UV (detecting only oily component), respectively, and by the elution time and peak area, UV detection), "pre-micelle (RI detection)" and "glass surfactant molecule (RI detection)", and the ratio can be calculated. If all of them are contained in the sample, RI shows peaks in the order of (1) "liposoluble active ingredient-containing nano emulsion particles", (2) "pre-micelle" and (3) "glass surfactant molecule" , A peak of (1) appears. Details The conditions are described in the examples.

The adsorption rate of the fat soluble active ingredient to the mucosa is preferably at least 10%, more preferably at least 20%, and even more preferably at least 30%. For example, in the case of the ophthalmic composition of the present invention in which vitamin A is blended, the absorption rate of vitamin A at the time of triple dilution is closer to 100%, but it is also related to the blending amount of vitamin A, A higher adsorption rate is preferable. For example, when the amount of vitamin A is low, the adsorption rate is preferably 50% or more, and when it is a high amount, it is preferably 40% or more. The method for measuring the effective component adsorption rate is the method described in the following embodiment.

Accordingly, the present invention relates to a composition of the components (A) and (B) as the composition of the components and the proportions of the components I- (1) to (3) and II- And a vitamin A-containing nano emulsion particle comprising the component (C) as a constituent component, wherein the ratio of the fat-soluble active ingredient or the vitamin A-free nonionic surfactant is less than 44 mass% of the total amount of the component (B) do.

(A) a nonionic surfactant selected from (A) 0.015 to 0.05 W / V% of vitamin A, (BI) polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester, (A), (B) and (C) as a constituent component, and (C) an antioxidant selected from tocopherol acetate and dibutylhydroxytoluene in a weight ratio of 1: Nano emulsion particles, wherein the ratio of the vitamin A-free nonionic surfactant to the total amount of the component (B) is less than 44% by mass.

(A) 0.001 to 1.0 W / V% of a fat-soluble active ingredient comprising an antioxidant selected from vitamin A, (C) tocopherol acetate and dibutylhydroxytoluene, and (BI) polyoxyethylene hydrogenated castor oil and polyoxy (A) + (C): (B) a nonionic surfactant selected from a nonionic surfactant selected from the group consisting of a polyoxyethylene polyoxypropylene copolymer and a polyoxyethylene polyoxypropylene copolymer, Wherein the ratio of the fat-soluble active ingredient to the vitamin A-free nonionic surfactant is from 1: 0.4 to 24.0 in terms of mass ratio of (B) to (B) ) Component is less than 44 mass% of the total amount of the composition.

The blending amount of the fat-soluble active ingredient is 0.001 to 1.0 W / V% (g / 100 ml), more preferably 0.005 to 0.5 W / V%, further preferably 0.01 to 0.4 W / V% 0.05 to 0.175 W / V% is particularly preferable.

(B) is preferably from 1: 0.4 to 20.0, more preferably from 1: 0.4 to 15.0, even more preferably from 1: 0.4 to 20.0, in a mass ratio represented by (A): More preferably from 1: 0.4 to 10.0, particularly preferably from 1: 0.4 to 7.0, and from 1: 0.9 to 2.0. In the case of a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester, (BI) is more preferably from 1: 0.4 to 10.0, further preferably from 1: 0.4 to 9.0, from 1: 0.4 to 5.0 Is particularly preferably 1: 0.8 to 20.0, more preferably 1: 2.0 to 20.0, and 1: 2.0 to 8.0 in the case of a nonionic surfactant selected from polyoxyethylene polyoxypropylene copolymer (B-II) Is particularly preferable. The amounts of the components (A) to (C) are as described above.

(A) a nonionic surfactant selected from (A) 0.015 to 0.05 W / V% of vitamin A, (BI) polyoxyethylene hardened castor oil and polyoxyethylene sorbitan fatty acid ester, (A), (B) and (C) as the constituent components, and (C) an antioxidant selected from tocopherol acetate and dibutylhydroxytoluene in a weight ratio of 1: Particles, wherein the ratio of the pre-ionic surfactant to the total amount of the component (B) is less than 44 mass%.

(A) is 0.015 to 0.05 W / V% (g / 100 ml), more preferably 0.02 V / W% and more preferably 0.05 V / W% % And 0.04 W / V% or less is particularly preferable.

The amount of the component (B) is preferably from 1: 3.0 to 7.0, more preferably from 1: 3.0 to 6.0, and still more preferably from 1: 3.0 to 5.5 in terms of the mass ratio represented by (A): (B) When the amount of the nonionic surfactant (B) of the vitamin A sugar (A) is too small, the oil component can not be sufficiently emulsified and the appearance transparency is deteriorated or the emulsion is not stable.

(C) Antioxidant

Examples of the antioxidant used in the present invention include tocopherol acetate such as d-α-tocopherol acetate (vitamin E) and dibutylhydroxytoluene, which may be used alone or in combination of two or more. By blending these antioxidants, the storage stability (residual ratio) of (A) vitamin A is improved.

When the component (C) is tocopherol acetate, the blending amount is preferably 0.01 to 0.5 W / V%, more preferably 0.02 to 0.2 W / V%, still more preferably 0.03 to 0.05 W / V% Do. (C) is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, and even more preferably 0.003 to 0.005 W / V% based on the total amount of the composition, Is more preferable. By setting this range, (A) the storage stability of vitamin A and the appearance transparency are further improved.

The composition for a mucus membrane of the present invention may be prepared in the form of a liquid, a gel or the like. Specific examples of the use form include ophthalmic compositions, more specifically, ophthalmic compositions such as eyedrops (for example, general eye drops, contact lens eyedroppers, etc.), eyelashes (general eye washers, contact lenses, Mouthwashes, mouthwashes, mouthwashes, toothpastes, etc.), contact lens mounting solutions, and contact lens separating liquids; mouth sprays such as point nose drops, .

[Optional ingredients]

In addition to the above components, the composition of the present invention can be compounded with various components incorporated in the composition for mucosal membranes within a range not to impair the effects of the present invention. Examples of the components include various drugs and various additives shown below, and they may be used singly or in combination of two or more. These components include polyhydric alcohols, buffers, viscosifiers, saccharides, preservatives, pH adjusters, isotonic agents, stabilizers, refreshing agents, moisturizers, and drugs. These can be used alone or in combination of two or more kinds, and a suitable amount can be added.

Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. The content of the polyhydric alcohol is preferably 0.01 to 5 W / V%, more preferably 0.05 to 3 W / V%, in the composition for a mucosa.

Examples of the buffering agent include boric acid or a salt thereof such as borax, citric acid or its salt such as sodium citrate, phosphoric acid or its salt such as sodium monohydrogenphosphate, tartaric acid or its salt such as sodium tartrate, Or a salt thereof (such as sodium gluconate), acetic acid or its salt (such as sodium acetate), carbonic acid or its salt (such as sodium hydrogencarbonate), trometamol, various amino acids (such as epsilon-aminocaproic acid, potassium aspartate, Sulfonic acid, glutamic acid, sodium glutamate, etc.). Among them, trometamol is preferable from the viewpoints of low stimulus and preservative effect of the composition. In addition, when boric acid and borax are used in combination, a particularly high preservative effect can be obtained. The content of the buffering agent is preferably 0.001 to 10 W / V%, more preferably 0.01 to 5 W / V%, based on the whole amount of the mucosal composition.

Examples of the viscosifier include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, alginic acid, Carrageenan, gelatin, and the like. The content of the viscous agent with respect to the total amount of the mucosal composition is, for example, 0.001 to 10 W / V%, preferably 0.001 to 5 W / V%, more preferably 0.01 to 3 W / V%.

Examples of the saccharides include glucose, cyclodextrin, xylitol, sorbitol and mannitol. They may be either D-shaped, L-shaped or DL-shaped. The content of the saccharide with respect to the total amount of the mucosal composition is, for example, 0.001 to 10 W / V%, preferably 0.005 to 5 W / V%, more preferably 0.01 to 3 W / V%.

As the pH adjuster, it is preferable to use an inorganic acid or an inorganic alkaline agent. Examples of the inorganic acid include (heme) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like. Among them, hydrochloric acid and sodium hydroxide are preferable. The pH (20 ° C) of the composition for mucus membranes of the present invention is preferably 4.0 to 9.0, more preferably 5.0 to 8.0, and still more preferably 6.0 to 8.0. In the present invention, the pH is measured at 20.degree. C. using a pH-permeation meter (HOSM-1, DOWIDIKEKE CO., LTD.). The content of the pH adjuster with respect to the total amount of the mucoadhesive composition is, for example, 0.00001 to 10 W / V%, preferably 0.0001 to 5 W / V%, more preferably 0.001 to 3 W / V%.

The preservative may be compounded within a range not to impair the effect of the present invention. The composition for a mucosa according to the present invention may be preservative-free which does not contain a preservative in terms of stimulation. Examples of the preservative include benzalkonium chloride, benzethonium chloride, sorbic acid or salts thereof, paraoxybenzoic acid esters (such as methylparaben, ethylparaben, propylparaben), chlorhexidine gluconate, thimerosal, phenylethyl alcohol, Polyoxyethylene glycine, polyoxyethylene glycine, aminoethylglycine, polydronium chloride, and polyhexanedic acid hydrochloride. The content of the preservative with respect to the total amount of the mucoadhesive composition is, for example, 0.00001 to 5 W / V%, preferably 0.0001 to 3 W / V%, more preferably 0.001 to 2 W / V%. When the antiseptic-free formulation is used, the buoyant force may be combined with one or more kinds of sodium edetate, boric acid and trometamol, suitably two or more of them in combination. In addition, even when the unit dose container or the filter attachment container is used, the preservative-free formulation can be used.

Examples of isotonic agents include sodium chloride, potassium chloride, glycerin, and the like. The content of the isotonic agent relative to the total amount of the mucosal composition is, for example, 0.001 to 5 W / V%, preferably 0.01 to 3 W / V%, more preferably 0.1 to 2 W / V%.

Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, and ascorbic acid. The content of the stabilizer with respect to the total amount of the mucoadhesive composition is, for example, 0.001 to 5 W / V%, preferably 0.01 to 3 W / V%, more preferably 0.1 to 2 W / V%.

Examples of the refreshing agent include menthol, camphor, borneol, geraniol, linalool, cineol and the like. The content of the refreshing agent relative to the total amount of the mucosal film composition is preferably from 0.0001 to 2 W / V%, more preferably from 0.001 to 1 W / V%, still more preferably from 0.005 to 0.5 W / V% Particularly preferably 0.007 to 0.3 W / V%.

Examples of the drug (pharmaceutically active ingredient) include decongestants such as napazolin hydrochloride, tetrahydrozolin hydrochloride, phenylephrine hydrochloride, ephedrine hydrochloride, dl-methyl ephedrine hydrochloride, tetrahydrozoline nitrate, Aminocaproic acid, allantoin, berberine chloride, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, (Such as hydrochloric acid, diphenhydramine hydrochloride, isopentyl hydrochloride, chlorpheniramine hydrochloride, etc.), water-soluble vitamins (such as acetic acid, Vitamin B ₂ , vitamin B ₆ and vitamin B ₁₂ ), amino acids (for example, potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate and the like) (Such as alginate, cotton, sulfur, isopropylmethyl phenol and hinokitiol), antiallergic agents (cromoglycic acid, kettifen fumarate, tranilast etc.), topical anesthetics (e.g. lidocaine hydrochloride, procaine hydrochloride, Etc.), mydriatic agents (cyclopentolate hydrochloride, tropicamide, etc.), cataract treatment agents (pyrrenoxine, glutathione, etc.).

The content of these components is appropriately selected depending on the kind of the preparation, the kind of the drug, and the content of the various components are already known in the art. For example, in the case of an ophthalmic composition, it can be appropriately selected from the range of 0.0001 to 30 W / V%, preferably 0.001 to 10 W / V% with respect to the total amount of the ophthalmic composition. More specifically, the content of each component with respect to the total amount of the ophthalmic composition is as follows.

For example, it is 0.0001 to 0.5 W / V%, preferably 0.0005 to 0.3 W / V%, more preferably 0.001 to 0.1 W / V%.

For example, 0.0001 to 10 W / V%, preferably 0.0001 to 5 W / V%.

For example, from 0.0001 to 10 W / V%, preferably from 0.001 to 5 W / V%.

Water-soluble vitamin is 0.0001 to 1 W / V%, preferably 0.0001 to 0.5 W / V%.

Amino acid, it is 0.0001 to 10 W / V%, preferably 0.001 to 3 W / V%.

For example, from 0.00001 to 10 W / V%, and preferably from 0.0001 to 10 W / V% in the case of a sulfacer or a bactericide.

The antiallergic agent is, for example, 0.0001 to 10 W / V%, preferably 0.001 to 5 W / V%.

For example, 0.001 to 1 W / V%, preferably 0.005 to 1 W / V% in the case of a topical anesthetic, a shodong agent and a cataract treatment agent.

Water is used as the solvent of the water phase. As the water, purified water, sterilized water and the like can be used and appropriately selected in accordance with the water phase. The content of the whole amount of the composition is preferably 100 (the balance), preferably 90 to 99.999 W / V% To 99.995 W / V% is more preferable.

Among them, the following optional components are preferable.

Ⅲ. At least one selected from the group consisting of lower alcohols, sugar alcohols, sugars, chlorpheniramine maleate, diphenhydramine hydrochloride and flavin adenine dinucleotide sodium

By adding the above-mentioned component III, the stability of the fat-soluble active ingredient, particularly vitamin A, can be further improved. Examples of the component III include lower alcohols, sugar alcohols, sugars, chlorpheniramine maleate, diphenhydramine hydrochloride, flavin adenine dinucleotide sodium, etc. These can be used singly or in combination of two or more . Examples of the lower alcohol include ethanol, propylene glycol, and glycerin. As the sugar alcohol, mannitol can be mentioned. Examples of sugar include glucose and the like. Among them, chlorpheniramine maleate, ethanol, diphenhydramine hydrochloride, and glycerin are preferable.

The blending amount of the component III is preferably 0.01 to 10 W / V%, more preferably 0.02 to 8 W / V%, in the total amount of the composition. By setting this range, an effect of further enhancing the stability of vitamin A can be obtained.

IV. At least one compound selected from inorganic salts, organic acids, organic acid salts, amino acids, amino acid salts, alkaline drugs and salts thereof

By adding the component (IV), the adsorption of the vitamin A on the fat soluble active ingredient, particularly the mucous membrane of the eye, on the mucous membrane is remarkably improved. Specific examples of the component IV include inorganic salts such as potassium chloride, disodium hydrogenphosphate, sodium hydrogenphosphate, calcium chloride, sodium hydrogencarbonate and sodium carbonate, organic acids and organic acid salts such as citric acid and sodium citrate, glutamic acid, sodium glutamate, potassium aspartate, Magnesium aspartate, taurine and

Epimeric aminocaproic acid and the like, basic salts such as amino acid salts, pyridoxine hydrochloride, tetrahydrozolinic acid hydrochloride, berberine chloride and lysozyme hydrochloride, and salts thereof, and they can be used singly or in combination of two or more have.

The content of the component IV with respect to the total amount of the composition is preferably 0.001 to 5 W / V%, more preferably 0.01 to 2 W / V%. By setting the amount to be in the above range, the effect of blending component IV can be obtained more, and if it is too much, the osmotic pressure becomes too high.

[(D) Curing agent]

In particular, when a refreshing agent is blended, the following invention is provided.

[One]. (A) a fat-soluble active ingredient of 0.005 to 0.2 W / V%, and (B) a nonionic surfactant comprising a polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as essential components in a total amount of a nonionic surfactant (A '): (B), and (D) a refreshing agent in an amount of 0.01 to 0.5 W / V% and a mass ratio of (A' A composition for mucosal membranes comprising nano emulsion particles obtained by adding an oil phase to an aqueous phase at 75 to 90 캜 and stirring and containing the components (A ') and (B) as constituent components.

[2]. (A) a fat-soluble active ingredient of 0.005 to 0.2 W / V%, (B) a nonionic surfactant comprising polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as essential components in an amount of 0.01 (A '): (B) in a weight ratio of 1: 0.4 to 7.0, and (D) a refreshing agent, , Wherein the ratio of the component (A ') pre-ionic surfactant is less than 44 mass% of the total amount of the component (B).

[3]. 1] or [2], wherein the component (A ') is an antioxidant selected from (A-1) vitamin A and (A-2) tocopherol acetate, dibutylhydroxytoluene and butylhydroxyanisole / RTI >

[4]. (D) is at least one selected from the group consisting of l-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus, bergamot oil, geraniol, linalool, cineol, fenugreek, spearmint oil, , Mucilage oil, and peppermint oil. The composition for a mucosa according to any one of [1] to [3]

[5]. The composition for a mucous membrane according to any one of [1] to [4], wherein the oil phase has a temperature of 65 to 90 ° C.

[6]. The composition for a mucous membrane according to any one of [1] to [5], which is an ophthalmic composition.

[7]. (A) a fat-soluble active ingredient of 0.005 to 0.2 W / V%, and (B) a nonionic surfactant comprising a polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as essential components in a total amount of a nonionic surfactant (A '): (B) in a weight ratio of 1: 0.4 to 7.0 to a water phase of 75 to 90 占 폚, 1] or [2].

As described above, by reducing the amount of the surfactant by adding the oil phase to the water phase and stirring the amount of the nonionic surfactant to the oil-soluble active ingredient within a specific range, Stability can be achieved and the surfactant can be reduced. Therefore, it is possible to simultaneously achieve the reduction of the irritation caused by the coexistence of menthol and the surfactant, and at the same time, the durability of the refreshing feeling can be obtained. The present invention can enhance the adsorption of the fat soluble component to the mucous membrane and maintain the stability of the fat soluble component.

(A ') fat-soluble active ingredient

The fat-soluble active ingredient is not particularly limited, but includes the following substances, and they may be used alone or in combination of two or more. Hereinafter, when the components (A-1) to (A-4) are represented collectively, the component (A ') is used.

(A-1)

Vitamin A

Examples of vitamin A include vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid esters. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Among them, retinol palmitate, retinol acetate and retinoic acid are preferred. Retinol palmitic acid ester (hereinafter abbreviated as IU) is generally commercially available in the range of 1,000,000 to 1,800,000 international units, specifically retinol palmitate ester (1.74 million IU) manufactured by DSM Nutrition Co., Ltd. .

(A-2)

Antioxidants such as dicyclohexylcarbodiimide, dicyclohexylcarbodiimide, dicyclohexylcarbodiimide, dicyclohexylcarbodiimide, dicyclohexylcarbodiimide, dicyclohexylcarbodiimide, dicyclohexylcarbodiimide,

(A-3)

Vitamins such as vitamin D and vitamin K, steroidal anti-inflammatory drugs such as dexamethasone, betamethasone and prednisolone, immunosuppressants such as cyclosporin, tacrolimus and paclitaxel, antibacterial agents such as clarithromycin and oproxacin, An anti-inflammatory agent such as diphenhydramine, ketoprofen, salicylic acid glycol, indymethacin, ameloxazone, beclometasone propionic acid ester, mometasone furan carboxylic acid ester and fluticasone furan carboxylic acid ester, Vasoconstrictors such as epinephrine, and local anesthetics such as lidocaine.

(A-4)

Castor oil such as castor oil and homoe oil, liquid paraffin, gelling hydrocarbon, lanolin and the like.

The blending amount of the component (A ') is preferably 0.005 to 0.2 W / V% (g / 100 ml) as the total amount of the component (A') and 0.05 to 0.15 W / V% with respect to the total amount of the composition. In addition, it can be appropriately selected in accordance with the effectiveness and application of the compounding ingredients.

For example, when the composition for a mucous membrane or the composition for ophthalmology using (A-1) vitamin A, 0.0005 to 0.15 W / V% (g / 100 ml) is more preferable for the whole composition, When the composition is a cleanser, it is more preferably 0.0005 to 0.02 W / V% (g / 100 ml), and still more preferably 0.001 to 0.01 W / V%. When the ophthalmic composition is an eye drop, 0.005 to 0.2 W / V% (g / 100 ml) is more preferable, and 0.01 to 0.15 W / V% is more preferable. Vitamin A has the effect of treating corneal and conjunctival injuries, improvement of dry eye, improvement of tired eyes and irritated eyes. In this range, a desired effect can be obtained. If too much, vitamin A can not be emulsion, have.

For example, when the composition for a mucous membrane or the composition for ophthalmology using the component (A-2) is used, the amount of tocetic acid acetate is preferably 0.01 to 0.5 W / V%, more preferably 0.02 to 0.2 W / %, And more preferably 0.03 to 0.05 W / V%. The blending amount of dibutylhydroxytoluene is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, and even more preferably 0.003 to 0.005 W / V% based on the whole amount of the composition.

As the component (A '), (A-1) vitamin A is preferable. Particularly, when vitamin A (A-1) is used, the stability of vitamin A can be maintained, and the adsorption of vitamin A on the cornea at the time of eye drop (diluted state with leakage) can be increased. The antioxidant selected from (A-1) vitamin A and (A-2) tocopherol acetate, dibutylhydroxytoluene and butylhydroxyanisole is preferably used in combination, Two or more agents may be used in combination. Thereby, the storage stability (remaining ratio) of (A-1) vitamin A is further improved. When the component (A-2) is used in combination, the amount of the component (A-2) tocopherol acetate is preferably 0.01 to 0.5 W / V%, more preferably 0.02 to 0.1 W / W / V% is more preferable. When the component (A-2) is dibutylhydroxytoluene, the blending amount is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, more preferably 0.003 to 0.005 W / V% is more preferable. By setting this range, the storage stability and appearance transparency of (A-1) vitamin A are further improved.

(B) a nonionic surfactant

As the nonionic surfactant used in the present invention, polyoxyethylene hardened castor oil or polyoxyethylene sorbitan fatty acid ester may be contained as an essential component and other nonionic surfactants may be contained. These may be used singly or in combination of two or more.

The present invention uses polyoxyethylene hardened castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, but it is also possible to use polyoxyethylene hardened castor oil or polyoxyethylene hardened castor oil and polyoxyethylene sorbitan fatty acid ester in combination . Examples of the polyoxyethylene hardened castor oil include polyoxyethylene hardened castor oil 60 (polyoxyethylene (60) hardened castor oil) and polyoxyethylene hardened castor oil 40 (polyoxyethylene (40) hardened castor oil) Polyoxyethylene hardened castor oil 60 (polyoxyethylene (60) hardened castor oil) is preferred. Examples of polyoxyethylene sorbitan fatty acid esters include sorbitan monolaurate (20) sorbitan (polyisobutyl 20), monopalmitic acid POE (20) sorbitan (polyisobutyl 40), monostearic acid POE (20) sorbitan (20) sorbitan (PORISOLBETO 65), monooleic acid POE (20) sorbitan (POORISOLBETO 80), and monooleic acid POE (20) sorbitan Solvato 80) is preferred.

Examples of the nonionic surfactant other than the above include polyoxyethylene polyoxypropylene copolymer, polyoxyethylene alkyl ether and the like. More specifically, examples of the polyoxyethylene polyoxypropylene copolymer include polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (20) polyoxypropylene . Examples of the polyoxyethylene alkyl ether include polyoxyethylene (9) lauryl ether and the like, and they may be used alone or in combination of two or more. Among them, polyoxyethylene (200) polyoxypropylene (70) glycol is preferable. Two or more kinds may be appropriately combined.

The blending amount of the component (B) is 0.01 to 0.5 W / V% and preferably 0.02 to 0.3 W / V% in the total amount of the nonionic surfactant. When the composition is in this range, it is excellent in the stability of vitamin A and can improve the absorption of vitamin A into the cornea when the component (A ') is transparent in appearance and the component (A-1) contains vitamin A. In view of eye irritation, 0.3 W / V% or less is preferable, and 0.2 W / V% or less is more preferable.

The mass ratio represented by (A ') :( B) is preferably 1: 0.4 to 7.0, more preferably 1: 0.7 to 5.0, and even more preferably 1: 0.9 to 4.0. If the amount of the nonionic surfactant (B) per the oil-soluble active ingredient (A ') is too small, the oil-based component can not be sufficiently emulsified and the appearance transparency deteriorates or the emulsion does not become a stable emulsion. On the other hand, if the amount of (B) nonionic surfactant per (A ') fat-soluble active ingredient is too large, a composition for a mucus membrane having a small emulsion particle size, a more uniform appearance and transparency, , For example, the effect of improving the adsorption of the fat-soluble active ingredient to the cornea or the like is insufficient, and as a result, the effect of improving the action of the desired fat-soluble active ingredient becomes insufficient. In the present invention, at 7.0 or less, the adsorbability of the fat soluble active ingredient to the mucous membrane of the cornea or the like is improved, the effect of the component (A ') is exhibited in a small amount, the stimulation is reduced, Can be obtained.

When the component (A ') contains (A-1) vitamin A, the following amounts and ratios are preferable from the viewpoints of the stability of the vitamin A, the adsorbability thereof, and the appearance of the composition.

I- (1): HCO-VA low concentration

(A-1) Vitamin A 0.003 W / V% or more and less than 0.015 W / V%

(B-I) a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester, in a mass ratio of from 1: 3.0 to 10.0 (B-1)

I- (2): HCO-VA medium concentration

(A-1) 0.015 to 0.05 W / V% of vitamin A,

(BI) polyoxyethylene hydrogenated castor oil and a polyoxyethylene sorbitan fatty acid ester in a mass ratio of 1: 1.6 to 10.0, expressed as (A-1) :( BI), and 1: 1.6 To less than 8.0.

I- (3): High concentration of HCO-VA

(A-1) Vitamin A: more than 0.05 W / V% and not more than 0.2 W / V%

(B-I) polyoxyethylene hydrogenated castor oil 60 and / or monooleic acid POE (20) sorbitan in a mass ratio of from 1: 1.6 to 5.0 (A-1)

(D) A refreshing substance

Examples of the refreshing agent include l-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus, bergamot oil, geraniol, linalool, cineol, fennel, spearmint oil, peppermint oil, Mint oil and peppermint oil, and they may be used singly or in combination of two or more. Among them, 1-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus, bergamot oil and geraniol are preferable.

The blending amount of the component (D) is 0.001 to 0.05 W / V%, preferably 0.003 to 0.03 W / V%, in the composition as the total amount of the refreshing agent. By setting this range, it is possible to obtain a feeling that there is no irritation and a proper cooling sensation continues.

(A ') and (B) obtained by adding an oil phase containing the components (A') and (B) to an aqueous phase at 75 to 90 ° C and stirring the mixture, Mucous membrane composition. The method for producing the composition for mucosal membranes includes the following.

(A) a fat-soluble active ingredient of 0.005 to 0.2 W / V%, (B) a nonionic surfactant comprising polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as essential components in an amount of 0.01 To 0.5W / V%, and (A): (B) in a mass ratio of 1: 0.4 to 7.0 to an aqueous phase at 75 to 90 占 폚 and stirring.

The "oil phase" is blended with an "oil phase compounding component" such as (A ') a "fat-soluble active ingredient" and a nonionic surfactant such as a component (B), and "water" includes water and a water- (Water-soluble drug, inorganic salt, water-soluble polymer, preservative, etc.). (D) The refreshing agent may be added to the oil phase. (D) Among the refreshing agents, if they can be dissolved in water, some of them may be blended into the water phase, and the softening agent may be preliminarily dissolved in a polyhydric alcohol such as propylene glycol A preliminary melt (an accessory) may be separately added, for example, after the stirring.

The concentration of the oil phase mixture component in the composition for mucosa is preferably 3.0 W / V% or less, and more preferably 1.0 W / V% or less. By setting this range, appearance uniformity is further improved.

[(E) boric acid and / or borax]

In particular, when boric acid and / or borax is compounded, the following invention is provided.

[One]. (BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) , And (C) 0.5 to 2.0 W / V% boric acid and / or borax,

The nano emulsion particles obtained by adding and stirring the oil phase containing components (A ') and (BI) to an aqueous phase at 75 to 90 ° C and containing the components (A') and (BI) ≪ / RTI >

[2]. (A '): a composition according to [1], wherein the mass ratio represented by (B-I) is 1: 0.4 to 10.

[3]. The composition according to [1] or [2], wherein the content of the component (C) is 0.8 to 1.7 W / V%.

[4]. (B-II) polyoxyethylene polyoxypropylene copolymer in an amount of 0.6 to 2 W / V%, (A '): (B-II) By weight of boric acid and / or borax, and (C) boric acid and / or borax at 1.2 to 2.0 W / V%

Is obtained by adding an oil phase containing the components (A ') and (B-II) to an aqueous phase at 75 to 90 ° C and stirring the resulting oil phase, Compositions comprising nano emulsion particles.

[5]. And the content of (B-II) is 0.6 to 1.5 W / V%.

[6]. The composition according to any one of [1] to [5], wherein the oil phase has a temperature of 65 to 90 占 폚.

[7]. The composition according to any one of [1] to [6], further comprising (D) sodium edetate and / or trometamol.

[8]. The composition according to any one of [1] to [7], which contains no preservative.

[9]. The composition according to any one of [1] to [8], which is a composition for mucosal membranes.

[10]. (BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) To an aqueous phase at 75 to 90 캜, and stirring the oil phase containing 1: 0.4 to 25 in a mass ratio represented by the following formula.

[11]. (B-II) polyoxyethylene polyoxypropylene copolymer in an amount of 0.6 to 2 W / V%, (A '): (B-II) To an aqueous phase at 75 to 90 캜, and stirring the oil phase containing 1: 5 to 25% by weight of the oil phase.

[12]. (A) a fat-soluble active ingredient of 0.0005 to 1.0 W / V%, (B) a nonionic surfactant, and (C) 0.5 to 2.0 W / V% boric acid and / (BI) of 1: 0.4 to 25, or a ratio of (A ') :( BI) of not more than 0.5 W / V% of polyoxyethylene hydrogenated castor oil and / or polyoxyethylene sorbitan fatty acid ester, (A ') and (B'), wherein the mass ratio of the polyoxyethylene polyoxypropylene copolymer to the polyoxyethylene polyoxypropylene copolymer is from 0.6 to 2 W / V% and the mass ratio of (A ') to (B- ) Component, wherein the proportion of the component (A ') pre-ionic surfactant is less than 44 mass% of the total amount of the component (B).

As described above, by adjusting the amount of the nonionic surfactant to the fat-soluble active ingredient within a specific range, adding the oil phase to the aqueous phase in a specific range of the water phase in the preparation, and stirring the mixture, And a fat-soluble active ingredient-containing nano-emulsion particle. By adding a specific amount of boric acid and / or borax, the appearance of the composition is transparent, the repellency is improved, and the stimulation is suppressed. Further, the adsorption of the fat-soluble active ingredient to the mucous membrane can be enhanced, and the stability of the fat-soluble active ingredient can be maintained.

Hereinafter, when the components (A-1) to (A-4) are represented collectively, the components (A '), (BI) and (B-II) .

(A ') fat-soluble active ingredient

The fat-soluble active ingredient is not particularly limited, but includes the following substances, and they may be used alone or in combination of two or more.

(A-1)

Vitamin A

Examples of vitamin A include vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid esters. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Among them, retinol palmitate, retinol acetate and retinoic acid are preferred. Retinol palmitic acid ester (hereinafter abbreviated as IU) is generally commercially available in the range of 1,000,000 to 1,800,000 international units, specifically retinol palmitate ester (1.74 million IU) manufactured by DSM Nutrition Co., Ltd. .

(A-2)

Tocopherol acetic acid dl-a-tocopherol acetic acid d-alpha -tocopherol (vitamin E)), dibutylhydroxytoluene, butylhydroxyanisole and nordihydroguaiaretic acid.

(A-3)

Vitamins such as vitamin D and vitamin K, steroidal anti-inflammatory drugs such as dexamethasone, betamethasone and prednisolone, immunosuppressants such as cyclosporin, tacrolimus and paclitaxel, antibacterial agents such as clarithromycin and oproxacin, An anti-inflammatory agent such as diphenhydramine, ketoprofen, salicylic acid glycol, indymethacin, ameloxazone, beclometasone propionic acid ester, mometasone furan carboxylic acid ester and fluticasone furan carboxylic acid ester, Vasoconstrictors such as epinephrine, and local anesthetics such as lidocaine.

(A-4)

Castor oil such as castor oil and homoe oil, liquid paraffin, gelling hydrocarbon, lanolin and the like.

The content of the component (A ') is preferably 0.0005 to 1.0 W / V% (g / 100 ml), more preferably 0.001 to 1.0 W / V% More preferably 0.5 W / V%, and particularly preferably 0.005 to 0.2 W / V%. In addition, it can be appropriately selected in accordance with the effectiveness and application of the compounding ingredients.

For example, a composition using (A-1) vitamin A or an ophthalmic composition is preferably 0.005 to 0.3 W / V% (g / 100 ml) based on the total amount of the composition, , More preferably 0.005 to 0.05 W / V% (g / 100 ml), and still more preferably 0.015 to 0.04 W / V%. When the ophthalmic composition is an eye drop, 0.005 to 0.3 W / V% (g / 100 ml) is more preferable, and 0.01 to 0.2 W / V% is more preferable. Vitamin A has the effect of treating corneal and conjunctival injuries, improvement of dry eye, improvement of tired eyes and irritated eyes. In this range, a desired effect can be obtained. If too much, vitamin A can not be emulsion, have.

For example, when the composition is a composition using the component (A-2) or an ophthalmic composition, the amount of tocetic acid acetate is preferably 0.01 to 0.5 W / V%, more preferably 0.02 to 0.2 W / V% , More preferably 0.03 to 0.05 W / V%. The blending amount of dibutylhydroxytoluene is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, and even more preferably 0.003 to 0.005 W / V% based on the whole amount of the composition.

As the component (A '), (A-1) vitamin A is preferable. In particular, when (A-1) vitamin A is used, the stability of vitamin A can be maintained. In addition, the adsorption to vitamin A can be remarkably enhanced. (A-1) vitamin A, the component (A-1) and the antioxidant of component (A-2), suitably selected from tocopherol acetate and dibutylhydroxytoluene One or more, preferably two or more kinds of antioxidants may be used in combination. Thereby, the storage stability (remaining ratio) of (A-1) vitamin A is further improved. When the component (A-2) is used in combination, the amount of the component (A-2) tocopherol acetate is preferably 0.01 to 0.2 W / V%, more preferably 0.02 to 0.1 W / W / V% is more preferable. When the component (A-2) is dibutylhydroxytoluene, the blending amount is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, more preferably 0.003 to 0.005 W / V% is more preferable. By setting this range, the storage stability and appearance transparency of (A-1) vitamin A are further improved.

(B) a nonionic surfactant

Examples of the nonionic surfactant used in the present invention include (B-I) polyoxyethylene hydrogenated castor oil and / or polyoxyethylene sorbitan fatty acid ester and (B-II) polyoxyethylene polyoxypropylene copolymer.

(B-I)

Examples of polyoxyethylene hardened castor oil include polyoxyethylene hardened castor oil 60 (polyoxyethylene (60) hardened castor oil), polyoxyethylene hardened castor oil 40 (polyoxyethylene (40) hardened castor oil), polyoxyethylene sor Examples of non-fat fatty acid esters include sorbitan monolaurate (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polyisobuto 40), monostearic acid POE (20) sorbitan ), Sorbitan tristearate (20) sorbitan (polyisobutyl 65) and sorbitan monooleate (20) sorbitan (polyisobutyl 80). These may be used singly or in combination of two or more. have. Among them, polyoxyethylene hydrogenated castor oil 60 (polyoxyethylene (60) hardened castor oil) and sorbitan monooleate (20) sorbitan (polyisobutyl 80) are preferable.

(B-II)

Examples of the polyoxyethylene polyoxypropylene copolymer include polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) Glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (20) polyoxypropylene (20) May be used alone or in combination of two or more. Among them, polyoxyethylene (200) polyoxypropylene (70) glycol is preferable.

(B-I)

The blending amount of the component (B-I) is 0.5 W / V% or less, preferably 0.01 to 0.2 W / V% based on the total amount of the composition. 0.5 W / V% or less, the vitamin A storage stability and the preservation effect are prevented from deteriorating. The mass ratio represented by (A ') :( B-I) is preferably 1: 0.4 to 25, more preferably 1: 0.4 to 25.0, 1: 0.4 to 10, and 1: 0.5 to 7.0. (B-I) per the fat-soluble active ingredient (A ') is blended at this ratio, the composition becomes clearer in composition and has excellent storage stability and preservation effect of vitamin A.

(B-II)

The blending amount of the component (B-II) is preferably 0.6 to 2 W / V%, more preferably 0.6 to 1.5 W / V%. If the blending amount is small, appearance registration quality deteriorates. If the amount is large, eye irritation, vitamin A preservation stability, and preservation efficacy are deteriorated. The weight ratio of (A '): (B-II) is preferably 1: 5 to 25, more preferably 1: 6 to 20. (B) and (B-II) per the active ingredient of the fat-soluble active ingredient (A) at such a ratio, the composition becomes clearer in appearance and has excellent storage stability and preservation effect of vitamin A.

When the component (A ') contains (A-1) vitamin A, the following amounts and ratios are preferable from the viewpoints of the stability of the vitamin A, the adsorbability thereof, and the appearance of the composition.

I- (1): HCO-VA low concentration

(A-1) Vitamin A 0.003 W / V% or more and less than 0.015 W / V%

(B-I) a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester, in a mass ratio of from 1: 3.0 to 10.0 (B-1)

I- (2): HCO-VA medium concentration

(A-1) 0.015 to 0.05 W / V% of vitamin A,

(BI) a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester is used in a mass ratio of 1: 1.6 to 7.0 represented by (A-1): (BI) In terms of adsorption, it is preferably 1: 1.6 to less than 3, and in view of transparency of the composition, 1: 3 to 7 and 1: 3 to 7.0 are preferable.

I- (3): High concentration of HCO-VA

(A-1) Vitamin A: more than 0.05 W / V%, not more than 0.3 W / V%

(B-I) a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester in a mass ratio of from 1: 1.6 to 5.0 (B-1)

Ⅱ- (1): Low concentration of EOPO-VA

(A-1) 0.003 to 0.025 W / V% of vitamin A,

(B-II) polyoxyethylene polyoxypropylene copolymer in a mass ratio represented by (A-1): (B-II)

Ⅱ- (2): High concentration of EOPO-VA

(A-1) Vitamin A of more than 0.025 and less than 0.085 W / V%

(B-II) polyoxyethylene polyoxypropylene copolymer in a weight ratio of (A-1): (B-II) of from 1: 8 to 13

(E) boric acid and / or borax

By using the component (E) in combination with the composition comprising the nano-emulsion particle containing the fat-soluble active ingredient of the present invention, a composition having improved repellency and suppressed irritation can be obtained.

The blending amount of the component (E) is preferably 0.5 to 2.0 W / V%, more preferably 0.8 to 1.7 W / V% based on the total amount of the composition. If the compounding amount of the component (E) is too small, the intended preservative effect can not be obtained. If the compounding amount is too large, the osmotic pressure becomes high and there is a fear of causing eye irritation

(F) sodium edetate and / or trometamol

In order to enhance the preservative effect, (F) sodium edetate and / or trometamol may be added to the composition of the present invention. The content thereof is preferably 0.01 to 2.0 W / V%, more preferably 0.05 to 1.0 W / V% based on the total amount of the composition. When vitamin A is used as the component (A), the effect of enhancing the adsorption of vitamin A on the mucous membrane can be obtained.

(A ') and (B) obtained by adding an oil phase containing the components (A') and (B) to an aqueous phase at 75 to 90 ° C and stirring the mixture, . The composition of the present invention includes a step of adding an oil phase containing at least the components (A ') and (B) to an aqueous phase at 75 to 90 캜 and stirring the oil phase. The production method is as follows.

(BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) To an aqueous phase of 75 to 90 占 폚 in an amount of 1: 0.4 to 25 in terms of mass ratio, and stirring the mixture.

(B-II) polyoxyethylene polyoxypropylene copolymer in an amount of 0.6 to 2 W / V%, (A '): (B-II) To an aqueous phase at 75 to 90 캜, and stirring the oil phase containing 1: 5 to 25% by weight of the oil phase.

The "oil phase" is blended with an "oil phase composition component" such as a nonionic surfactant such as (A ') "fat soluble component" and (B) component, and "water phase" And water-soluble components (water-soluble drug, inorganic salt, water-soluble polymer, preservative, etc.). The components (E) and (F) are preferably blended in the "water phase" before the "oil phase" is added. The concentration of the oil blending component with respect to the water phase is preferably 1.0 W / V% or less, more preferably 0.5 W / V% or less. By setting this range, appearance uniformity is further improved.

[(G) Water-Soluble Polymer Compound]

In particular, when a water-soluble polymer compound is blended, the following invention is provided.

[One]. (BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) And (G) a water-soluble polymeric compound in a mass ratio of 1: 0.4 to 10,

The nano emulsion particles obtained by adding and stirring the oil phase containing components (A ') and (BI) to an aqueous phase at 75 to 90 ° C and containing the components (A') and (BI) ≪ / RTI >

[2]. (A '): The composition according to [1], wherein the mass ratio represented by (B-I) is 1: 0.4 to 5.

[3]. (B-II) polyoxyethylene polyoxypropylene copolymer in an amount of 0.6 to 2 W / V%, (A '): (B-II) 1: 7 to 11, and (G) a water-soluble polymer compound,

(A) and (B-II) are added to an aqueous phase at 75 to 90 占 폚 and stirred to obtain a nano- A composition comprising an emulsion particle.

[4]. (A '): (B-II) is 1: 8.0 to 10.

[5]. The composition according to any one of [1] to [4], wherein the oil phase has a temperature of 65 to 90 占 폚.

[6]. The composition according to any one of [1] to [5], which is a composition for mucosal membranes.

[7]. The composition according to any one of [1] to [6], which is a composition for attaching a contact lens.

[8]. (BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) To an aqueous phase at 75 to 90 占 폚, and stirring the oil phase containing 1: 0.4 to 10.0 in a mass ratio represented by the following formula.

[9]. (B-II) polyoxyethylene polyoxypropylene copolymer in an amount of 0.6 to 2 W / V%, (A '): (B-II) A process for producing a composition as described in [3], comprising a step of adding an oil phase containing 1: 7 to 11 to a water phase of 75 to 90 占 폚 and stirring.

[10]. (BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) , And (G) a composition containing a water-soluble polymeric compound, or

(B-II) polyoxyethylene polyoxypropylene copolymer in an amount of 0.6 to 2 W / V%, (A '): (B-II) (A ') and a component (B) as constituent components, wherein the composition (A') comprises a water-soluble polymer compound Wherein the ratio of the ionic surfactant to the total amount of the component (B) is less than 44 mass%.

As described above, by adjusting the amount of the nonionic surfactant to the fat-soluble active ingredient within a specific range, adding the oil phase to the aqueous phase in a specific range of the water phase in the preparation, and stirring the mixture, , A nano-emulsion particle containing a fat-soluble active ingredient can be obtained, and a specific amount of the water-soluble polymer compound can be blended to improve dryness (dried eye) and inhibit irritation. Further, the present invention can enhance the adsorption of the fat soluble component to the mucous membrane and maintain the stability of the fat soluble component.

Hereinafter, when the components (A-1) to (A-4) are represented collectively, the components (A '), (BI) and (B-II) .

(A ') fat-soluble active ingredient

The fat-soluble active ingredient is not particularly limited, but includes the following substances, and they may be used alone or in combination of two or more.

(A-1)

Vitamin A

Examples of vitamin A include vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid esters. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Among them, retinol palmitate, retinol acetate and retinoic acid are preferred. Retinol palmitic acid ester (hereinafter abbreviated as IU) is generally commercially available in the range of 1,000,000 to 1,800,000 international units, specifically retinol palmitate ester (1.74 million IU) manufactured by DSM Nutrition Co., Ltd. .

(A-2)

Tocopherol acetic acid dl-a-tocopherol acetic acid d-alpha -tocopherol (vitamin E)), dibutylhydroxytoluene, butylhydroxyanisole and nordihydroguaiaretic acid.

(A-3)

Vitamins such as vitamin D and vitamin K, steroidal anti-inflammatory drugs such as dexamethasone, betamethasone and prednisolone, immunosuppressants such as cyclosporin, tacrolimus and paclitaxel, antibacterial agents such as clarithromycin and oproxacin, An anti-inflammatory agent such as diphenhydramine, ketoprofen, salicylic acid glycol, indymethacin, ameloxazone, beclometasone propionic acid ester, mometasone furan carboxylic acid ester and fluticasone furan carboxylic acid ester, Vasoconstrictors such as epinephrine, and local anesthetics such as lidocaine.

(A-4)

Castor oil such as castor oil and homoe oil, liquid paraffin, gelling hydrocarbon, lanolin and the like.

The content of the component (A ') is preferably 0.0005 to 1.0 W / V% (g / 100 ml), more preferably 0.001 to 1.0 W / V% More preferably 0.5 W / V%, and particularly preferably 0.005 to 0.2 W / V%. In addition, it can be appropriately selected in accordance with the effectiveness and application of the compounding ingredients.

For example, a composition using (A-1) vitamin A or an ophthalmic composition is preferably 0.005 to 0.3 W / V% (g / 100 ml) based on the total amount of the composition, , More preferably 0.005 to 0.05 W / V% (g / 100 ml), and still more preferably 0.015 to 0.04 W / V%. When the ophthalmic composition is an eye drop, 0.005 to 0.3 W / V% (g / 100 ml) is more preferable, and 0.01 to 0.2 W / V% is more preferable. Vitamin A has the effect of treating corneal and conjunctival injuries, improvement of dry eye, improvement of tired eyes and irritated eyes. In this range, a desired effect can be obtained. If too much, vitamin A can not be emulsion, have.

For example, when the composition is a composition using the component (A-2) or an ophthalmic composition, the amount of tocetic acid acetate is preferably 0.01 to 0.5 W / V%, more preferably 0.02 to 0.2 W / V% , More preferably 0.03 to 0.05 W / V%. The blending amount of dibutylhydroxytoluene is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, and even more preferably 0.003 to 0.005 W / V% based on the whole amount of the composition.

The component (A ') preferably contains (A-1) vitamin A. In particular, when (A-1) vitamin A is used, the stability of vitamin A can be maintained. In addition, the adsorption to vitamin A can be remarkably enhanced. (A-1) vitamin A, the component (A-1) and the antioxidant of component (A-2), suitably selected from tocopherol acetate and dibutylhydroxytoluene One or more, preferably two or more kinds of antioxidants may be used in combination. Thereby, the storage stability (remaining ratio) of (A-1) vitamin A is further improved. When the component (A-2) is used in combination, the amount of the component (A-2) tocopherol acetate is preferably 0.01 to 0.2 W / V%, more preferably 0.02 to 0.1 W / W / V% is more preferable. When the component (A-2) is dibutylhydroxytoluene, the blending amount is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, more preferably 0.003 to 0.005 W / V% is more preferable. By setting this range, the storage stability and appearance transparency of (A-1) vitamin A are further improved.

(B) a nonionic surfactant

Examples of the nonionic surfactant used in the present invention include (B-I) polyoxyethylene hydrogenated castor oil and / or polyoxyethylene sorbitan fatty acid ester and (B-II) polyoxyethylene polyoxypropylene copolymer.

(B-I)

Examples of polyoxyethylene hardened castor oil include polyoxyethylene hardened castor oil 60 (polyoxyethylene (60) hardened castor oil), polyoxyethylene hardened castor oil 40 (polyoxyethylene (40) hardened castor oil), polyoxyethylene sor Examples of non-fat fatty acid esters include sorbitan monolaurate (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polyisobuto 40), monostearic acid POE (20) sorbitan ), Sorbitan tristearate (20) sorbitan (polyisobutyl 65) and sorbitan monooleate (20) sorbitan (polyisobutyl 80). These may be used singly or in combination of two or more. have. Among them, polyoxyethylene hydrogenated castor oil 60 (polyoxyethylene (60) hardened castor oil) and sorbitan monooleate (20) sorbitan (polyisobutyl 80) are preferable.

(B-II)

Examples of the polyoxyethylene polyoxypropylene copolymer include polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) Glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (20) polyoxypropylene (20) May be used alone or in combination of two or more. Among them, polyoxyethylene (200) polyoxypropylene (70) glycol is preferable.

(B-I)

The blending amount of the component (B-I) is 0.5 W / V% or less, preferably 0.01 to 0.2 W / V% based on the total amount of the composition. 0.5 W / V% or less, the deterioration of the vitamin A storage stability is prevented. The mass ratio represented by (A '): (B-1) is preferably 1: 0.4 to 10, more preferably 1: 0.4 to 10.0, 1: 0.4 to 5.0, and more preferably 1: 0.4 to 5.0.

(B-II)

The blending amount of the component (B-II) is preferably 0.6 to 2 W / V%, more preferably 0.6 to 1.5 W / V% W / V%. If the blending amount is small, appearance registration quality deteriorates. If the amount is large, eye irritation and vitamin A storage stability deteriorate. The mass ratio represented by (A '): (B-2) is preferably 1: 7 to 11, more preferably 1: 7.0 to 11.0, and 1: 8.0 to 10.0.

When the amount of the nonionic surfactant (B) per component (A ') is too small, the oil component can not be sufficiently emulsified, the appearance transparency is deteriorated, or the emulsion is not stable. On the other hand, if the amount of the nonionic surfactant (B) per component (A ') is too large, a composition having a small emulsion particle size, excellent appearance and excellent external appearance stability of the preparation can be obtained. , For example, the effect of vitamin A (healing effects of corneal and conjunctival injuries, improvement of dry eye, improvement of tired eyes and dull eyes) is insufficient, and eye irritation is increased.

When the component (A ') contains (A-1) vitamin A, the following amounts and ratios are preferable from the viewpoints of the stability of the vitamin A, the adsorbability thereof, and the appearance of the composition.

I- (1): HCO-VA low concentration

(A-1) Vitamin A 0.003 W / V% or more and less than 0.015 W / V%

(B-I) a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester, in a mass ratio of from 1: 3.0 to 10.0 (B-1)

I- (2): HCO-VA medium concentration

(A-1) 0.015 to 0.05 W / V% of vitamin A,

(BI) a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester is used in a mass ratio of 1: 1.6 to 7.0 represented by (A-1): (BI) In terms of adsorption, it is preferably 1: 1.6 to less than 3, and in view of transparency of the composition, 1: 3 to 7 and 1: 3 to 7.0 are preferable.

I- (3): High concentration of HCO-VA

(A-1) Vitamin A: more than 0.05 W / V%, not more than 0.3 W / V%

(B-I) a nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester in a mass ratio of from 1: 1.6 to 5.0 (B-1)

Ⅱ- (1): Low concentration of EOPO-VA

(A-1) 0.003 to 0.025 W / V% of vitamin A,

(B-II) polyoxyethylene polyoxypropylene copolymer in a mass ratio represented by (A-1): (B-II)

Ⅱ- (2): High concentration of EOPO-VA

(A-1) Vitamin A of more than 0.025 and less than 0.085 W / V%

(B-II) polyoxyethylene polyoxypropylene copolymer in a weight ratio of (A-1): (B-II) of from 1: 8 to 13

(G) Water-soluble polymer compound

By using the component (G) in combination with the composition comprising the nano-emulsion particle containing the fat-soluble active ingredient of the present invention, a composition having improved dry eyes and suppressed irritation can be obtained. Further, when vitamin A is used as the component (A '), the vitamin A stability improving effect and the vitamin A mucosal adsorption improving effect can be obtained.

Examples of the water-soluble polymeric compound (G) include hyaluronic acid and salts thereof, chondroitin sulfate and salts thereof, polyvinylpyrrolidone (povidone), hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylalcohol, polyethylene glycol, Polyacrylic acid, carboxyvinyl polymer, alginic acid, carrageenan, gelatin and the like. The content of the water-soluble polymer compound with respect to the total amount of the composition is, for example, 0.001 to 10 W / V%, preferably 0.001 to 5 W / V%, more preferably 0.01 to 3 W / V%.

More specifically, the amount of hyaluronic acid and its salt is preferably 0.001 to 0.05 W / V%, and more preferably 0.005 to 0.03 W / V%. The concentration of chondroitin sulfate and its salt is preferably 0.05 to 1.0 W / V%, more preferably 0.25 to 0.75 W / V%. The polyvinylpyrrolidone is preferably 0.01 to 0.2 W / V%, more preferably 0.02 to 0.1 W / V%. The content of hydroxyethyl cellulose, hydroxypropylmethyl cellulose and methyl cellulose is preferably 0.01 to 1 W / V%, more preferably 0.1 to 0.5 W / V%. The polyvinyl alcohol is preferably 0.01 to 2.0 W / V%, more preferably 0.1 to 1.5 W / V%. When the amount is more than the above range, the effect of alleviating the dryness of the eyes can be more obtained. On the other hand, if the amount is too large, the viscosity becomes high and there is a fear of causing sticking.

(F) sodium edetate and / or trometamol may be blended in order to enhance the preservative effect even when the (G) water-soluble polymer compound is blended. The content thereof is preferably 0.01 to 2.0 W / V%, more preferably 0.05 to 1.0 W / V% based on the total amount of the composition.

(A ') and (B) obtained by adding an oil phase containing the components (A') and (B) to an aqueous phase at 75 to 90 ° C and stirring the mixture, . The composition of the present invention includes a step of adding an oil phase containing at least the components (A ') and (B) to an aqueous phase at 75 to 90 캜 and stirring the oil phase. The production method is as follows.

(BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) To a water phase of 75 to 90 占 폚 and stirring the oil phase containing 1: 0.4 to 10 in a mass ratio represented by the following formula.

(B-II) polyoxyethylene polyoxypropylene copolymer in an amount of 0.6 to 2 W / V%, (A '): (B-II) Wherein the oil phase comprising 1: 7 to 11 is added to the water phase at 75 to 90 占 폚 and stirred.

The "oil phase" is blended with an "oil phase composition component" such as a nonionic surfactant such as (A ') "fat soluble component" and (B) component, and "water phase" And water-soluble components (water-soluble drug, inorganic salt, water-soluble polymer, preservative, etc.). The component (G) is preferably blended with the " water " prior to the addition of the " oil phase ". The concentration of the oil blending component relative to the water phase is preferably 1.0 W / V% or less, more preferably 0.55 W / V% or less. By setting this range, appearance uniformity is further improved.

Specific examples of the ophthalmic composition include eye drops (for example, general eye drops, contact lens eyedroppers and the like), cleansers (general cleansers, cleansers used after removing contact lenses, etc.), contact lens mounting solutions, And eye drops are preferable. Among them, since contact lens users tend to be dry eyes, they are suitable for contact lens eyedrops, contact lenses such as cleansers, contact lens mounting solutions, and contact lens separation solutions used after removing contact lenses. Examples of the contact lens include, but are not limited to, a hard contact lens (an oxygen-impermeable hard contact lens, an oxygen-permeable hard contact lens), a soft contact lens (a disposable contact lens, a silicone hydrogel lens, etc.)

The viscosity of the composition for a mucus membrane of the present invention is preferably from 1 to 100 mPa · s, more preferably from 1 to 50 mPa · s, even more preferably from 1 to 30 mPa · s. The viscosity is measured at 20 占 폚 using an E-type clay system (VISCONIC ELD-R, Tokyo Meter Co., Ltd.).

Polyethylene terephthalate, polypropylene and polyethylene are preferable as the material of the container for filling the composition for mucous membranes of the present invention, and polyethylene terephthalate is particularly preferable. The polyethylene terephthalate is not particularly limited as long as it can be formed into a container. The container is preferably an ultraviolet shieldable container.

When the composition for a mucosa of the present invention is filled into a container, it is preferable to fill the container aseptically using a sterilizing filter or the like. The container to be filled may be of a type that can be used any number of times by opening and closing the cap until the filled composition disappears, or may be of a type (unit dose type) that is used once. Further, in the case of a type that can be used any number of times, there may be a micro-hole filter at the outlet of the contents, and bacteria or foreign matter not entering the container. When these containers are also filled, they are preferably sterile.

It is preferable that the container for filling the composition for mucosal membranes of the present invention be sealed with a package and an inert gas is filled between the container and the package (inner space). Examples of the inert gas include gases such as nitrogen, helium, neon, and argon. Further, a deoxidizing agent may be put in a package and sealed, or may be put into a package using a film having an oxygen-absorbing function.

The composition for a mucosal membrane of the present invention is not limited to a specific form, and can be used as a liquid preparation or a spray preparation depending on the purpose. These preparations can be prepared by a routine method, and at this time, in addition to the above-mentioned components, additives for generic use corresponding to the preparation can be used.

Example

EXAMPLES Hereinafter, the present invention will be described in detail by way of examples and comparative examples, but the present invention is not limited to the following examples.

[Practical examples and comparative examples]

(Ophthalmic composition) of the composition (W / V% (g / 100 ml)) listed in the table was obtained by the following production process at the water temperature and oil temperature described in the table. The obtained composition was evaluated in the following manner. The results are listed in the table.

The oil phase (retinol palmitate (vitamin A, 1.74 million IU), d-alpha-tocopherol acetate, dibutylhydroxytoluene and polyoxyethylene hardened castor oil 60 were heated to the set temperature and mixed uniformly, The aqueous phase after the addition of the oil phase from the beginning of the stirring to the end of the stirring was as follows. The temperature of the aqueous phase after the addition of the oil phase from the beginning of the stirring to the end of the stirring was, After the completion of the stirring, the mixture was cooled to room temperature, and other water-containing ingredients were added as needed, and purified water was added so that the total amount became 500 ml.

[Particle size]

(LB-500, manufactured by Horiba Co., Ltd.) were used for the measurement. The measurement was carried out under a constant temperature condition of 25 캜 using a thermostat.

[Appearance (Transmittance (%))]

About the ophthalmic composition immediately after preparation, the transmittance (%) at a wavelength of 600 nm was measured at room temperature using a Hitachi spectrophotometer U-3310.

[Appearance uniformity]

A "," oily components were not separated, an apparent transmittance (%) of less than 80% was evaluated as "good", and 80% or more was evaluated as good: "good".

[Vitamin A stability (residual ratio%)]

The vitamin A content was measured immediately after preparation and after storage in a sealed glass ampoule at 70 DEG C for one week (extreme test). The measurement was carried out by high performance liquid chromatography. Based on the obtained vitamin A content, the vitamin A remaining ratio (%) was calculated based on the following formula.

Vitamin A remaining ratio (%) = [content of vitamin A after storage / content of vitamin A immediately after preparation] × 100

[Absorption rate of vitamin A in triple dilution (%) (assumed at the time of instillation)]

Since the hydrophobicity of the C8 was close to that of the corneal surface, the vitamin A adsorption rate on the C8 silica gel was measured as a model of vitamin A adsorption to the cornea.

(i) C8 silica gel was washed with water to remove surface contamination and dried.

(Ii) 10 ml of purified water was mixed with 5 ml of the sample, and 10 ml of C8 silica gel was dispersed in 10 ml of the mixture, followed by stirring for 10 minutes. In the case of high concentration of vitamin A, 0.4 g of C8 silica gel was used in I- (3), and 1.5 g in case of (B-II).

(Iii) The amount of vitamin A in the filtrate and the amount of vitamin A in the sample before adsorption with silica gel were measured by UV spectroscopy.

(Iv) The amount of vitamin A obtained was compared, and the adsorption rate of vitamin A was calculated.

* C8 silica gel: SEPRATM Bulk Filler C8 (particle size: 50 탆, pore diameter: 65 Å) manufactured by Phenomenex Co.,

<Absorbance Measurement Conditions>

Device: Shimazu Corporation MultiSpec-1500

Measured wavelength: 330 nm

Measuring temperature: room temperature

[Percentage of fat-soluble active ingredient pre-ionic surfactant (% by mass)]

The ratio of the "fat soluble active ingredient pre-ionic surfactant" was measured using Eluent gel permeation chromatography (EGPC).

(i) a nonionic surfactant aqueous solution of various concentrations (0.0027 mass%, 0.08 mass%, 0.16 mass%, 0.3 mass%, 0.5 mass%, 1.0 mass% and 3.0 mass%) (polyoxyethylene hydrogenated castor oil 60 ) Was measured by EGPC to prepare a calibration curve of the active agent concentration and the RI peak area value.

(Ii) EGPC measurement conditions

Column: Superose 6 10/300 GL (10 x 300 mm)

Injection: 100 μl

Eluent: aqueous HCO solution (500 ppm)

Flow rate: 0.5 ml / min

Temperature: 35 ℃

Detection: RI, UV (280 nm)

(Iii) A sample is analyzed by EGPC and the nonionic surfactant and the oily component (fat-soluble active component) are detected simultaneously with RI (detecting nonionic surfactant and oily component) and UV (detecting only oily component) Respectively. RI shows peaks in the order of (1) "liposoluble active ingredient-containing nanoemulsion particles" (2) "pre-micelle" and (3) "glass surfactant molecule", and in UV, . The active agent concentration was calculated from the peak area value of RI in the calibration curve obtained in (i), with the peak (RI) other than the peak (1) as the "fat-soluble active ingredient pre-ionic surfactant". &Quot; Percentage (%) of fat-soluble active ingredient pre-ionic surfactant &quot; is shown in the table. In the case of (A) vitamin A such as retinol palmitate in the fat-soluble active ingredient, the ratio of the fat-soluble active ingredient free-ion surfactant (%) to the vitamin A free- ) "In some cases.

In the composition for mucosal membranes (ophthalmic composition) of the Example, nanoemulsion particles containing lipophilic active ingredient containing the above components (A) and (B) were identified. A chart showing the measurement results of the EGPC of Examples 1-4 is shown in Fig. In addition, the composition for a mucosa of the Example had a peak (UV) in which an elution time of a peak top appeared in less than 12 minutes, and a peak (a relatively small particle diameter (UV) Was not shown. In detail, from Fig. 1, peaks were recognized only at 9 minutes and 36 minutes in RI and at 9 minutes in UV. That is, in Examples 1-4, the presence of (1) the "vitamin A-containing nanoemulsion particles" at the elution time of 9 minutes is the peak of RI alone at the elution time of 36 minutes (3) The presence of &quot; glass surfactant molecule &quot; was confirmed.

[Table 1]

With respect to Examples 1-1 and 1-4, 10 ml of purified water was mixed in 5 ml of the sample ([(adsorption ratio of vitamin A at the time of 3-fold dilution (%) (estimated at the time of instillation)] , And 0.2 g of C8 silica gel was dispersed in a solution prepared by dissolving 10 ml thereof. &Quot; was evaluated in the same manner as in &quot; dissolving 0.2 g of C8 silica gel in 10 ml of a stock solution & (A) in that the sample 1-1 is 65% and the sample 1-4 is 30%, and when the sample is not diluted, a remarkable effect of improving the adsorption of the component (A) to the mucous membrane or the like is obtained, The amount of (B) to be added is preferably smaller.

[Table 2]

[Table 3]

[Table 4]

[Practical example I- (1)]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Practical example I- (2) -L]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Practical example I- (3)]

[Table 15]

The ratio of the vitamin A-free nonionic surfactant was 28.5% by mass in Example 3, 30.7% by mass in Example 4, and 47.1% by mass in Comparative Example 2.

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[Practical example II- (1)]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Practical example II- (2)]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Example III]

[Table 29]

[Table 30]

[Example IV]

[Absorption rate (%) of vitamin E in triple dilution (assumed at the time of instillation)]

After the test using C8 silica gel as in the case of the vitamin A adsorption rate, the silica gel and the sample were separated, and the amount of vitamin E before the adsorption of the vitamin E in the filtrate was measured by high performance liquid chromatography. The amount of vitamin E obtained was compared and the adsorption rate of vitamin E was calculated.

[Table 31]

[Table 32]

[Table 33]

A formulation of the ophthalmic composition of the present invention is shown below. The obtained mucosal composition (ophthalmic composition) was uniform in appearance and had a high adsorption rate to the vitamin A in the cornea at the time of eye drops (diluted state with leakage).

[Table 34]

[Table 35]

[Curing agent: Examples 1 to 24, Comparative Examples 1 to 4]

(Ophthalmic composition) of the composition (W / V% (g / 100 ml)) described in the table was obtained by the following production process at the water temperature listed in the table. The obtained composition was evaluated in the following manner. The results are listed in the table.

(Vitamin A, 1.74 million IU), d-? -Tocopherol acetate (tocopherol acetate: vitamin E), dibutylhydroxytoluene and polyoxyethylene hydrogenated castor oil (60) ), 400 ml of water (purified water) warmed to a set temperature was added with stirring using a magnetic stirrer, and the mixture was stirred for 10 minutes from the end of the dropwise addition using a magnetic stirrer. After the completion of the stirring, the water phase is cooled to 50 DEG C or lower, and the component (D) preliminarily dissolved in propylene glycol is slowly added thereto and dissolved by stirring (A '): (A'): (A ') of the mass ratio represented by (A') in Table 1 was added to the water- A portion of (B) is shown as (B) / (A '). (Vitamin A (VA) / (A-1).

[Particle size]

(LB-500, manufactured by Horiba Co., Ltd.) were used for the measurement. The measurement was carried out under a constant temperature condition of 25 캜 using a thermostat. In addition, the particle diameter of the example was less than 1 nm and less than 500 nm, and was a composition containing nano-emulsion particles.

[Appearance (Transmittance (%))]

About the ophthalmic composition immediately after preparation, the transmittance (%) at a wavelength of 600 nm was measured at room temperature using a Hitachi spectrophotometer U-3310.

[Appearance (transparency)]

?,?,?,?,?,?,?,?,?, And?, Respectively.

[Eye irritation (no irritation)]

Four subjects (sensible panelists) with symptoms of dryness or itching of the eyes were evaluated for eye irritation by the following evaluation criteria, without observing one to two drops of the ophthalmic composition.

<Evaluation Criteria>

Stimulus is strong 1 point

Stimulation is a little strong 2 points

Stimulation is weak 3 points

I rarely feel irritation 4 points

I do not feel stimulation at all 5 points

From the average value of the obtained evaluation points, eye irritation (no irritation) is shown.

◎ Average of 4 points or more

3 points or more and less than 4 points ○

2 points or more and less than 3 points △

Less than 2 ×

[Sustainable cooling sensation]

Four subjects (sensible panelists) with symptoms of dryness or itching of the eyes measured the time of the refreshing feeling that they felt pleasantly without taking one to two drops of the ophthalmic composition. The results are shown below from the average of four persons.

◎ over 4 minutes

Less than 3 minutes and less than 4 minutes ○

Less than 3 minutes △

[Table 36]

The following examples and comparative examples were evaluated as follows.

[Stability of Vitamin A]

<Vitamin A remaining ratio>

The content of vitamin A (retinol palmitate) was measured immediately after preparation and after storage in a sealed ampoule at 70 DEG C for one week (extreme test). The measurement was carried out by high performance liquid chromatography. Based on the obtained retinol palmitate content, retinol palmitate residual ratio (%) was calculated based on the following formula.

[Equation 1]

[Absorption rate (%) of vitamin A at the time of 3-fold dilution

Since the hydrophobicity of the corneal surface is close to that of C8, the vitamin A adsorption rate on C8 silica gel was measured as a model of vitamin A adsorption to the cornea.

(i) The C8 silica gel was washed with water, the surface was cleaned of dirt and dried.

(Ii) 10 ml of purified water was added to 5 ml of the sample, and 10 ml of the mixture was added to 0.2 ml of C8 silica gel, followed by stirring for 10 minutes.

(Iii) The silica gel and the sample were separated, and the amount of vitamin A in the sample before adsorption with the amount of vitamin A in the filtrate was measured by high performance liquid chromatography.

(Iv) The amount of vitamin A obtained was compared, and the adsorption rate of vitamin A was calculated.

* C8 silica gel: SEPRATM Bulk Filler C8 (particle size: 50 탆, pore diameter: 65 Å) manufactured by Phenomenex Co.,

[Table 37]

Since the stability of vitamin A is good and the absorption rate of vitamin A is high, the effect of vitamin A is further exerted, and a composition for ophthalmology that is effective for dryness of eyes and tired eyes is obtained.

[Table 38]

[Table 39]

[Table 40]

[Table 41]

[Table 42]

With reference to Reference Example 1 below, the ratio of the fat soluble active ingredient pre-ionic surfactant was measured in the following manner.

[Percentage of fat-soluble active ingredient pre-ionic surfactant (% by mass)]

The ratio of the "fat soluble active ingredient pre-ionic surfactant" was measured using Eluent gel permeation chromatography (EGPC).

(i) a nonionic surfactant aqueous solution of various concentrations (0.0027 mass%, 0.08 mass%, 0.16 mass%, 0.3 mass%, 0.5 mass%, 1.0 mass% and 3.0 mass%) (polyoxyethylene hydrogenated castor oil 60 ) Was measured by EGPC to prepare a calibration curve of the activator concentration and RI peak area value.

(Ii) EGPC measurement conditions

Column: Superose 6 10/300 GL (10 x 300 mm)

Injection: 100 μl

Eluent: aqueous HCO solution (500 ppm)

Flow rate: 0.5 ml / min

Temperature: 35 ℃

Detection: RI, UV (280 nm)

(Iii) A sample is analyzed by EGPC and the nonionic surfactant and the oily component (fat-soluble active component) are detected simultaneously with RI (detecting nonionic surfactant and oily component) and UV (detecting only oily component) Respectively. RI shows peaks in the order of (1) "liposoluble active ingredient-containing nanoemulsion particles" (2) "pre-micelle" and (3) "glass surfactant molecule", and in UV, . The activator concentration was calculated from the peak area value of RI in the calibration curve obtained in (i), as the "fat-soluble active ingredient pre-ionic surfactant" except for peak (RI) The ratio (%) of the fat-soluble active ingredient pre-ionic surfactant is shown in the table.

Reference example 1 (oil phase (retinol palmitate: Vitamin A, 1.74 million I.U.)) 0.026 W / V%, d-alpha-tocopherol acetate. (Purified water) of 85 占 폚 was heated to 85 占 폚 and heated to 85 占 폚, and a water (purified water) 400 of 85 占 폚 was heated to 85 占 폚 and heated to 85 占 폚, 0.05 W / V%, dibutylhydroxytoluene 0.005 W / V%, and polyoxyethylene hardened castor oil 60 Ml with stirring using a magnetic stirrer, and the mixture was stirred for 10 minutes from the completion of dropwise addition using a magnetic stirrer. The aqueous phase temperature after the addition of the oil phase from the start of the stirring to the end of the stirring is the same as the water temperature before the oil phase addition. After completion of the stirring, the mixture was cooled to room temperature, and other water-containing ingredients were added as needed, and purified water was added thereto so that the total amount became 500 ml. A chart showing the measurement results of the obtained EGPC of Reference Example 1 is shown in Fig. In addition, the composition for a mucosa according to Reference Example 1 had a peak (UV) in which an elution time of a peak top appeared in less than 12 minutes, and a peak (peak in a relatively small particle diameter (UV) ) Were not shown. In detail, from Fig. 1, peaks were recognized only at 9 minutes and 36 minutes in RI and at 9 minutes in UV. That is, in Reference Example 1, since there is a peak of RI and UV at an elution time of 9 minutes, (1) the presence of "vitamin A-containing nano emulsion particles" Glass surface-active molecule &quot;.

From the above results, nanoemulsion particles containing lipophilic active ingredient containing the above components (A ') and (B) were identified in the composition for mucus membranes (ophthalmic composition) of Reference Example 1 and Examples. As for the examples, when EGPC was performed, peaks of (1) appeared at the same elution times in RI and UV, and "vitamin A-containing nanoemulsion particles" were confirmed. A chart showing measurement results of the EGPC of Example 17 is shown in Fig. The peak observed at 42 minutes in RI indicates that an additive component such as a cooling agent has been detected. Since the particle diameter of Example 17 is smaller than that of Reference Example 1, the elution time of the peak of (1) is 14 minutes. In Reference Example 1 and Example, the ratio of the fat-soluble active ingredient pre-ionic surfactant was 43 mass% or less of the total amount of the component (B). Specifically, Reference Example 1 was 41 mass%, Example 17 was 18.6 mass%, and Comparative Example 5 was 44.0 mass%.

The prescription of the present invention (Table 43: eye drops or cleansers, Table 44: eyedrops, Table 45: eyedrops) is shown below. Further, in the formulation of the present invention, nano emulsion particles were formed, appearance uniformity, no eye irritation, and pleasant feeling of coolness persisted in the same manner as in the examples.

[Table 43]

[Table 44]

[Table 45]

[Boric acid and / or borax: Examples 1 to 17, Comparative Examples 1 to 5]

(Ophthalmic composition) of the composition (W / V% (g / 100 ml)) listed in the table was obtained by the following production process at the water temperature and oil temperature described in the table. The obtained composition was evaluated in the following manner. The results are listed in the table.

The oil phase (A ') and the component (B) were warmed to a set temperature (65 to 90 ° C) and uniformly mixed. To 400 ml of water (purified water) containing the component (E) Was added with stirring using a stirrer, and the mixture was stirred for 10 minutes from the end of the dropping using a magnetic stirrer. The aqueous phase temperature after the addition of the oil phase from the start of the stirring to the end of the stirring is the same as the water temperature before the oil phase addition. After completion of the stirring, the mixture was cooled to room temperature, and other water-containing ingredients were added as needed, and purified water was added thereto so that the total amount became 500 ml. In the table, the portion (B) for (A ') 1 of the mass ratio represented by (A'): (B) is shown as (B) / (A '). (B) / (A-1) for (VA) 1 represented by (vitamin A (VA)) (B)

[Particle size]

(LB-500, manufactured by Horiba Co., Ltd.) were used for the measurement. The measurement was carried out under a constant temperature condition of 25 캜 using a thermostat. Further, the particle diameter of the example was 1 nm or more and 140 nm, and it was a composition containing nano-emulsion particles.

[Appearance (Transmittance (%))]

With respect to the composition immediately after the preparation, the transmittance (%) at a wavelength of 600 nm was measured at room temperature using a Hitachi spectrophotometer U-3310.

[Appearance (transparency)]

?,?,?,?,?,?,?,?,?, And?, Respectively.

[Eye irritation (no irritation)]

Four OA operators (sensitive panelists) suffering from dry eye suffered from 1 to 2 drops of ophthalmic composition, and eye irritation was evaluated by the following evaluation criteria.

<Evaluation Criteria>

2 points: I felt stimulation.

1 point: slightly stimulated

0 point: I did not feel any irritation

It is a total point of four people, and it shows eye irritation (no stimulus) by the following criteria.

?: 0 to 1 point

?: 2 to 3 points

?: 4 to 5 points

×: 6 points or more

The above-mentioned three points or less were judged to be good.

[Conservation Effectiveness Test]

A test solution (Example and Comparative Example) was prepared with 100 ml of the composition, and this was filtrated and sterilized. For these test solutions, the buoyancy was evaluated according to the 16th revised Japanese Pharmacopoeia reference information retention test. Specifically, each strain was prepared using Gram-negative bacteria (Escherichia coli). Each test solution was inoculated with each of the mycocytes at 10 ⁵ to 10 ⁶ CFU / ml and stored at 23 ° C. After 14 days of inoculation, the test solution was sampled, and the number of bacteria in the test solution was determined by the Kanten's flat plate incineration method, and the survival rate was calculated according to the following formula. The preservative efficacy of the test solution was evaluated based on the following criteria based on the number of bacteria in the test solution.

<Expression>

Survival rate (%) = (number of bacteria after 14 days / initial number of bacteria) x 100

<Criteria>

∘: survival rate after 14 days is 0.1% or less

X: Survival rate after 14 days is more than 0.1%

The stability of vitamin A with respect to the composition of the examples was evaluated by the following method, and all of them were stable at least 55%.

[Stability of Vitamin A]

<Vitamin A remaining ratio>

The content of vitamin A (retinol palmitate) was measured immediately after preparation and after storage in a sealed ampoule at 70 DEG C for one week (extreme test). The measurement was carried out by high performance liquid chromatography. Based on the obtained retinol palmitate content, retinol palmitate residual ratio (%) was calculated based on the following formula.

[Equation 2]

The adsorption of the vitamin A on the composition of the examples was evaluated by the following method, and it was all 19% or more.

[Absorption rate of vitamin A in triple dilution (%) (assumed at the time of instillation)]

Since the hydrophobicity of the corneal surface is close to that of C8, the vitamin A adsorption rate on C8 silica gel was measured as a model of vitamin A adsorption to the cornea.

(i) The C8 silica gel was washed with water, the surface was free from contamination and dried.

(Ii) 10 ml of purified water was mixed with 5 ml of the sample, and 10 ml of the mixture was added to 0.2 ml of C8 silica gel, followed by stirring for 10 minutes.

(Iii) The silica gel and the sample were separated, and the amount of vitamin A in the sample before adsorption with the amount of vitamin A in the filtrate was measured by high performance liquid chromatography.

(Iv) The amount of vitamin A obtained was compared, and the adsorption rate of vitamin A was calculated.

* C8 silica gel: SEPRATM Bulk Filler C8 (particle size: 50 탆, pore diameter: 65 Å) manufactured by Phenomenex Co.,

[Table 46]

[Table 47]

[Table 48]

[Table 49]

[Table 50]

[Table 51]

[Table 52]

In the composition for mucosa (ophthalmic composition) of Reference Example 1 and Example, nanoemulsion particles containing lipophilic active ingredient containing the above components (A ') and (B) were identified. EGPC was also performed for the examples. Peaks of (1) were observed at the same elution times in RI and UV, and "vitamin A-containing nanoemulsion particles" were confirmed. In Reference Example 1 and Example, the ratio of the fat-soluble active ingredient pre-ionic surfactant was 43 mass% or less of the total amount of the component (B).

[Water-Soluble Polymer Compound: Examples 1 to 23, Comparative Examples 1 to 10]

(Ophthalmic composition) of the composition (W / V% (g / 100 ml)) described in the table was obtained by the following production method at the water temperature listed in the table. The obtained composition was evaluated in the following manner. The results are listed in the table.

400 ml of an aqueous phase (purified water) containing the component (A ') and the component (B) was heated to a set temperature (65 to 90 ° C) and uniformly mixed, Was added with stirring using a stirrer, and the mixture was stirred for 10 minutes from the end of the dropping using a magnetic stirrer. The aqueous phase temperature after the addition of the oil phase from the start of the stirring to the end of the stirring is the same as the water temperature before the oil phase addition. After completion of the stirring, the mixture was cooled to room temperature, and other water-containing ingredients were added as needed, and purified water was added thereto so that the total amount became 500 ml. In the table, the part (B) for the mass ratio (A ') 1 represented by (A'): (B) is shown as (B) / (A-1). Further, (B) / (VA) represents the portion of (B) for (VA) 1 represented by (vitamin A (VA)) (B)

[Particle size]

(LB-500, manufactured by Horiba Co., Ltd.) were used for the measurement. The measurement was carried out under a constant temperature condition of 25 캜 using a thermostat. Further, the particle diameter of the example was not less than 1 nm and less than 140 nm, and was a composition containing nano-emulsion particles.

[Appearance (Transmittance (%))]

With respect to the composition immediately after the preparation, the transmittance (%) at a wavelength of 600 nm was measured at room temperature using a Hitachi spectrophotometer U-3310.

[Appearance (transparency)]

?,?,?,?,?,?,?,?,?, And?, Respectively.

[Eye irritation (no irritation)]

Four OA operators (sensitive panelists) suffering from dry eye suffered from 1 to 2 drops of ophthalmic composition, and eye irritation was evaluated by the following evaluation criteria.

<Evaluation Criteria>

2 points: I felt stimulation.

1 point: slightly stimulated

0 point: I did not feel any irritation

It is a total point of four people, and it shows eye irritation (no stimulus) by the following criteria.

?: 0 to 1 point

?: 2 to 3 points

?: 4 to 5 points

×: 6 points or more

The above-mentioned three points or less were judged to be good.

[Drying of the eyes (no drying of the eyes)]

Four OA operators (sensitized panelists) suffering from dry eye were evaluated for dryness of eyes by the following evaluation criteria without taking 1-2 drops of ophthalmic composition.

<Evaluation Criteria>

The time that I did not feel the dryness of the eyes after the instillation (duration of moisture)

5 points: more than 10 minutes

4 points: more than 7 minutes to less than 10 minutes

3 points: more than 4 minutes to less than 7 minutes

2 points: more than 1 minute to less than 4 minutes

1 point: less than 1 minute

The total score of 4 persons indicates the absence of drying of the eyes on the following judgment criteria.

<Criteria>

◎: 16 points or more

○: 13 to 15 points

?: 9 to 12 points

×: 8 points or less

The stability of vitamin A with respect to the composition of the examples was evaluated by the following method, and all of them were stable at least 55%.

[Stability of Vitamin A]

<Vitamin A remaining ratio>

The content of vitamin A (retinol palmitate) was measured immediately after preparation and after storage in a sealed ampoule at 70 DEG C for one week (extreme test). The measurement was carried out by high performance liquid chromatography. Based on the obtained retinol palmitate content, retinol palmitate residual ratio (%) was calculated based on the following formula.

[Equation 3]

The adsorption of the vitamin A on the composition of the examples was evaluated by the following method, and it was all 19% or more.

[Absorption rate of vitamin A in triple dilution (%) (assumed at the time of instillation)]

Since the hydrophobicity of the corneal surface is close to that of C8, the vitamin A adsorption rate on C8 silica gel was measured as a model of vitamin A adsorption to the cornea.

(i) The C8 silica gel was washed with water, the surface was free from contamination and dried.

(Ii) 10 ml of purified water was mixed with 5 ml of the sample, and 10 ml of the mixture was added to 0.2 ml of C8 silica gel, followed by stirring for 10 minutes.

(Iii) The silica gel and the sample were separated, and the amount of vitamin A in the filtrate and the amount of vitamin A in the sample before adsorption were measured by liquid chromatography.

(Iv) The amount of vitamin A obtained was compared, and the adsorption rate of vitamin A was calculated.

* C8 silica gel: SEPRATM Bulk Filler C8 (particle size: 50 탆, pore diameter: 65 Å) manufactured by Phenomenex Co.,

[Table 53]

[Table 54]

[Table 55]

[Table 56]

[Table 57]

[Table 58]

[Table 59]

[Table 60]

[Table 61]

In the composition for mucosa (ophthalmic composition) of Reference Example 1 and Example, nanoemulsion particles containing lipophilic active ingredient containing the above components (A ') and (B) were identified. EGPC was also performed for the examples. Peaks of (1) were observed at the same elution times in RI and UV, and "vitamin A-containing nanoemulsion particles" were confirmed. In Reference Example 1 and Example, the ratio of the fat-soluble active ingredient pre-ionic surfactant was 43 mass% or less of the total amount of the component (B).

Claims (16)

(B), wherein the lipophilic surfactant is contained in an amount of 1: 0.4 to 25, and 1: 0.4 to 24.0 in terms of mass ratio represented by (B) Characterized in that it comprises a nano-emulsion particle obtained by adding an oil phase containing an active ingredient and a component (B) to an aqueous phase at 75 to 90 ° C and stirring the oil phase active ingredient and the component (B) . (A) Vitamin A 0.003 W / V% or more and less than 0.015 W / V%
(BI) a polyoxyethylene hydrogenated castor oil and a polyoxyethylene sorbitan fatty acid ester in a weight ratio of 1: 3.0 to 10.0, expressed as (A): (BI)
(C) a fat-soluble active ingredient other than the component (A)
(A), (BI) and (C) are added to an aqueous phase at 75 to 90 ° C and stirred, and the components (A), Wherein the nano-emulsion particle comprises a nano-emulsion particle. (A) 0.015 to 0.05 W / V% of vitamin A,
(BI) a polyoxyethylene hydrogenated castor oil and a polyoxyethylene sorbitan fatty acid ester in a mass ratio of 1: 1.6 to 7.0, represented by (A): (BI), and
(C) a fat-soluble active ingredient other than the component (A)
(A), (BI) and (C) are added to an aqueous phase of 75 to 90 ° C and stirred, and the components (A), Wherein the nano-emulsion particle comprises a nano-emulsion particle. The method of claim 3,
Wherein the mass ratio of (A): (BI) is 1: 3.0 to 7.0. The method of claim 3,
(A): (BI) is in the range of 1: 1.6 to less than 3.0. (A) Vitamin A: more than 0.05 W / V%, not more than 0.3 W / V%
(BI) a polyoxyethylene hydrogenated castor oil and a polyoxyethylene sorbitan fatty acid ester in a mass ratio of 1: 1.6 to 5.0, represented by (A): (BI)
(C) a fat-soluble active ingredient other than the component (A)
(A), (BI) and (C) are added to an aqueous phase at 75 to 90 ° C and stirred, and the components (A), Wherein the nano-emulsion particle comprises a nano-emulsion particle. (A) 0.001 to 1.0 W / V% of a fat-soluble active ingredient comprising an antioxidant selected from vitamin A and (C) tocopherol acetate and dibutylhydroxytoluene, and (BI) polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitol A nonionic surfactant selected from nonionic surfactants selected from the group consisting of nanoemulsion particles (A) and nonionic surfactants (BI) having a weight ratio of (A) :( BI) Wherein the ratio of the fat-soluble active ingredient or the vitamin A-free nonionic surfactant is less than 44 mass% of the total amount of the (BI) ingredient. (A) 0.003 to 0.025 W / V% of vitamin A,
(B-II) polyoxyethylene polyoxypropylene copolymer in a weight ratio of (A): (B-II) of from 1: 11 to 24,
(C) a fat-soluble active ingredient other than the component (A)
(A), (B-II) and (C) is obtained by adding an oil phase containing the components (A), (B- Wherein the nano-emulsion particle comprises a nano-emulsion particle comprising the nano-particles as a constituent component. (A) Vitamin A is more than 0.025 and 0.085 W / V% or less,
(B-II) polyoxyethylene polyoxypropylene copolymer in a weight ratio of (A): (B-II) of from 1: 8 to 13,
(C) a fat-soluble active ingredient other than the component (A)
(A), (B-II) and (C) is obtained by adding an oil phase containing the components (A), (B- Wherein the nano-emulsion particle comprises a nano-emulsion particle comprising the nano-particles as a constituent component. 10. The method according to any one of claims 1 to 9,
Wherein the component (C) is an antioxidant selected from tocopherol acetate and dibutylhydroxytoluene. 11. The method according to any one of claims 1 to 10,
A composition for a mucous membrane, characterized by being an ophthalmic composition. The method according to any one of claims 2 to 7, characterized by comprising the step of adding an oil phase containing the component (A), the component (BI) and the component (C) &Lt; / RTI &gt; (8) or (9), characterized in that it comprises the step of adding an oil phase containing the component (A), the component (B-II) and the component (C) By weight of the composition. (A) a fat-soluble active ingredient of 0.005 to 0.2 W / V%, and (B) a nonionic surfactant comprising a polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as essential components in a total amount of a nonionic surfactant (A '): (B), and (D) a refreshing agent in an amount of 0.01 to 0.5 W / V% and a mass ratio of (A' A composition for a mucous membrane, which comprises nano-emulsion particles obtained by adding an oil phase to an aqueous phase of 75 to 90 占 폚 and stirring and containing the components (A ') and (B) (BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) , And (E) 0.5 to 2.0 W / V% boric acid and / or borax, in a weight ratio of 1: 0.4 to 25,
The nano emulsion particles obtained by adding and stirring the oil phase containing components (A ') and (BI) to an aqueous phase at 75 to 90 ° C and containing the components (A') and (BI) &Lt; / RTI &gt; (BI), polyoxyethylene hydrogenated castor oil, and / or polyoxyethylene sorbitan fatty acid ester in an amount of 0.5 W / V% or less, and (A '): (BI) And (G) a water-soluble polymeric compound in a mass ratio of 1: 0.4 to 10,
The nano emulsion particles obtained by adding and stirring the oil phase containing components (A ') and (BI) to an aqueous phase at 75 to 90 ° C and containing the components (A') and (BI) &Lt; / RTI &gt;

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