TWI673066B - Liquid composition and method of producing the same - Google Patents

Abstract

A liquid composition comprising an oil in which (A) vitamin A, (B) a nonionic surfactant, (C) an antioxidant fat-soluble component other than vitamin A, and (D) a polyol are dissolved therein The phase is added to the aqueous phase and is stirred at an emulsification temperature of 0 to 50 ° C to perform emulsification, and includes components A to D, a content-to-weight ratio D / (A + C) of 0.7 to 4, and 0.05 to Component B content of 0.15 w / v%. When formulated with fat-soluble ingredients such as vitamin A, the liquid composition has high transparency and increases absorption of vitamin A by mucous membranes such as the cornea, conjunctiva, nasal mucosa, and oropharyngeal mucosa, making the effect of vitamin A more significant. In the method of manufacturing this composition, the emulsification temperature can be kept low.

Description

Liquid composition and manufacturing method thereof

The present invention relates to a liquid composition including vitamin A, and a method for manufacturing the same.

Surfactants are required for the emulsification of vitamin A. Japanese Patent No. 5084967 and International Publication WO 2013/183778 describe a technique for increasing the absorption of vitamin A at a hydrophobic interface by reducing the amount of a surfactant. However, only reducing the amount of the surfactant therein or on its own would make the appearance of the emulsion less transparent, so there is a need to further improve the appearance stability. Furthermore, in order to ensure the stability of active ingredients (such as vitamin A), there is also a need to lower the emulsification temperature.

Reference list

Patent Document 1: JP-B 5084967

Patent Document 2: WO 2013/183778

It is therefore an object of the present invention to provide a liquid composition which is soluble in fat When sexual ingredients (such as vitamin A) are blended, they have high transparency and increase the absorption of vitamin A in the mucous membranes such as the cornea, conjunctiva, nasal mucosa, and oropharyngeal mucosa, making the effect of vitamin A more significant. Another object of the present invention is to provide a method for manufacturing the liquid composition which can maintain a low emulsification temperature.

As a result of extensive research to achieve the above purpose, the inventors of the present invention have found that by using a polyhydric alcohol and a nonionic surfactant together during emulsification, a liquid composition with high transparency can be obtained and nonionic can be reduced. And the absorption of vitamin A into the mucosa. The inventors of the present case have also found that, unlike the prior art in which the composition must be heated to 75 to 90 ° C. during emulsification and then cooled and subsequently manufactured, these steps are not required, which can simplify the manufacturing process and reduce advantageous.

Therefore, in a first aspect, the present invention provides a liquid composition in which (A) vitamin A, (B) a nonionic surfactant, and (C) an antioxidant other than vitamin A are dissolved therein. The soluble component and the oil phase of the (D) polyol are added to the water phase and stirred at an emulsification temperature of 0 to 50 ° C. to obtain emulsification. The composition system includes components A to D, a content-to-weight ratio D / (A + C) of 0.7 to 4, and a component B content of 0.05 to 0.15 w / v%.

In a preferred embodiment of the liquid composition of the present invention, the content of component D is 0.05 to 0.4 w / v%.

In another preferred embodiment, component B is polyoxyethylene hydrogenated castor oil.

In another preferred embodiment, component C is vitamin E and / or dibutylhydroxytoluene.

In another preferred embodiment, component D is propylene glycol and / or glycerin.

The liquid composition is generally an ophthalmic composition.

In a second aspect, the present invention provides a method for manufacturing a liquid composition including (A) vitamin A, (B) a non-ionic surfactant, and (C) an antioxidant fat-soluble component other than vitamin A And (D) a polyol having a content-to-weight ratio D / (A + C) of 0.7 to 4 and a component B content of 0.05 to 0.15 w / v%, the method comprising dissolving components A to D therein The oil phase is added to the water phase and stirred at an emulsification temperature of 0 to 50 ° C. to perform an emulsification step.

Advantageous effects of the invention

The liquid composition containing vitamin A of the present invention has high transparency and increases absorption of vitamin A in mucosa such as cornea, conjunctiva, nasal mucosa and oropharyngeal mucosa, making the effect of vitamin A more significant. The liquid composition manufacturing method of the present invention can maintain a low emulsification temperature.

The objects, features and advantages of the present invention will be made clearer from the following detailed description.

The liquid composition of the present invention has antioxidants other than (A) vitamin A, (B) nonionic surfactant, and (C) vitamin A dissolved therein. The fat-soluble component and the oil phase of the polyol (D) are added to the water phase, and are obtained by stirring and emulsification at an emulsification temperature of 0 to 50 ° C. The composition system includes components A to D, a content-to-weight ratio D / (A + C) of 0.7 to 4, and a component B content of 0.05 to 0.15 w / v%.

(A) Vitamin A

Herein, examples of vitamin A (in addition to vitamin A itself) include vitamin A-containing mixtures such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid ester. Specific examples include retinyl palmitate, retinyl acetate, retinol, retinoic acid, and retinoid. Among these, retinyl palmitate, retinyl acetate and retinoic acid are preferred. Retinyl palmitate is generally sold in quantities of 1,000,000 to 1,800,000 International Units (hereinafter abbreviated as "I.U."). A specific example is retinyl palmitate (1,740,000 I.U.) available from DSM Nutrition Japan K.K.

(C) Antioxidant fat-soluble ingredients other than component A

Examples of component C include, but are not particularly limited to, the following. The antioxidant fat-soluble ingredients other than the component A as the component C may be one type used alone or two or more types used in a suitable combination.

Examples include fat-soluble vitamins such as vitamin E, vitamin D and vitamin K, and derivatives thereof, and fat-soluble antioxidants such as dibutylhydroxytoluene (dibutylhydroxytoluene), butylhydroxyanisole, and ellagic acid.

Illustrative examples of vitamin E include tocopherol acetate (dl-α-tocopheryl acetate, d-α-tocopheryl acetate (vitamin E)), tocopherol succinate ), And its derivatives. Illustrative examples of vitamin D include cholecalciferol, 1α, 25-dihydroxycholecalciferol, and derivatives thereof. Illustrative examples of vitamin K include phytomenadione and derivatives thereof. Component C is preferably vitamin E and / or dibutylhydroxytoluene.

The combined content of components A and C, expressed as the total amount of components A and C relative to the total amount of the liquid composition, is preferably 0.05 to 0.1 w / v% (herein and hereinafter, "w / v% "" Represents the number of grams per 100 mL of the components in the composition, g / 100 mL), more preferably 0.08 to 0.1 w / v%. By setting the combined content of components A and C to at least 0.05 w / v%, the absorption of vitamin A in the mucosa can be increased, and the effect of vitamin A is more significant. On the other hand, by setting the combined content to 0.1 w / v% or less, better transparency can be obtained.

(B) Non-ionic surfactant

Examples of component B include, but are not particularly limited to, the following nonionic surfactants, which can be used alone or in a suitable combination of two or more of them: sorbitan fatty acid ester and Polyoxyethylene sorbitan fatty acid ester) such as polyoxyethylene sorbitan monooleate; sugar alcohol fatty acid esters such as sucrose fatty acid ester; polyol fatty acids Polyhydric alcohol fatty acid esters such as glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyethylene glycerol fatty acid esters, and polyethylene glycerol Fatty acid ester (polyethylene glycol fatty acid ester); ether or ester surfactants such as polyoxyethylene alkyl ether, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene Polyoxyethylene alkyl phenyl ether and polyoxyethylene hydrogenated castor oil; and fatty acid alkanolamides such as lauric acid diethanolamide. Among these, polyoxyethylene hydrogenated castor oil is preferable, and polyoxyethylene (60) hydrogenated castor oil (added polyoxyethylene (EO) mole number is 60) is particularly preferable. Polyoxyethylene sorbitan fatty acid esters or polyoxyethylene-polyoxypropylene copolymers can be used with polyoxyethylene hydrogenated castor oil.

The content of component B is 0.05 to 0.15 w / v%, preferably 0.06 to 0.08 w / v%, with respect to the total amount of the liquid composition. When the content of component B is less than 0.05 w / v%, the transparency of the liquid composition is insufficient, and when the content of component B is more than 0.15 w / v%, the absorption of vitamin A into the mucosa is insufficient.

The content-to-weight ratio B / (A + C) is preferably 0.70 to 2.0, and more preferably 0.75 to 1.0. Setting this ratio within the above range is to further improve the transparency of the liquid composition and absorption of vitamin A into the mucosa.

(D) Polyol

Examples of component D include, but are not particularly limited to, polyhydric alcohols such as, which may be used alone or in a suitable combination of two or more of them: propylene glycol, glycerol, erythritol, sorbitol, lactitol (lactitol), maltitol, mannitol, xylitol, polyglycerol and polyethylene glycol. Among these, propylene glycol and glycerin are preferable. In the case of glycerol, it is preferred to use glycerin in preparing the oil phase in which components A to D are dissolved, which is diluted with water to a concentration of 60 to 90 wt%, preferably 70 to 80 wt%, and then diluted Of glycerin.

The content of the component D is preferably 0.05 to 0.4 w / v%, and more preferably 0.15 to 0.27 w / v% based on the total amount of the liquid composition. The content of component D is set to at least 0.05 w / v% to further improve the transparency of the liquid composition, and the content is set to 0.4 w / v% or less to further increase the absorption of vitamin A in the mucosa.

The content-to-weight ratio D / (A + C) must be 0.7 to 4, preferably 0.8 to 3, and more preferably 2 to 3. When the content-to-weight ratio D / (A + C) is lower than 0.7, the transparency of the liquid composition is insufficient, and when the content-to-weight ratio D / (A + C) is higher than 4, the absorption of vitamin A into the mucosa is insufficient. Furthermore, when this ratio is higher than 4, a mixture of oil-soluble components (components A and C), non-ionic The surfactant (B) and the polyhydric alcohol (D) easily undergo phase separation, which is not conducive to obtaining a uniform emulsion.

As needed

In addition to the above-mentioned components, the liquid composition of the present invention may include various ingredients formulated in a composition for mucosa (as long as the advantageous effects of the present invention are not impaired). Examples of these ingredients include various drugs and additives described below, any of which can be used alone or in a suitable combination of two or more of them. Examples of such ingredients are buffers, humectants, sugars, preservatives, pH adjusters, tonicity agents, stabilizers, algefacients, moisturizers, and drugs. Each of these may be used alone or in a suitable combination of two or more of them, and may be included in an appropriate amount.

Illustrative examples of buffering agents include boric acid and its salts (e.g., borax), citric acid and its salts (e.g., sodium citrate), phosphoric acid and its salts (e.g., disodium hydrogen phosphate) , Tartaric acid and its salts (e.g. sodium tartrate), gluconic acid and its salts (e.g. sodium gluconate), acetic acid and its salts (e.g. sodium acetate), carbonic acid and its salts (e.g. sodium bicarbonate), tromethamine Trometamol, and various amino acids (e.g., ε-aminocaproic acid, potassium aspartate, aminoethylsulfonic acid, glutamic acid, and Sodium glutamate). Among these, tromethamine is preferred from the viewpoints of low irritation and composition storage efficiency. With the use of boric acid or borax, an extremely high composition Composition preserving efficacy. The content of the buffering agent is preferably 0.001 to 10 w / v%, and more preferably 0.01 to 5 w / v% based on the total amount of the liquid composition.

Illustrative examples of humectants include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, Polyethylene glycol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, alginic acid, carrageenan, and gelatin. The content of the humectant is preferably 0.001 to 10 w / v%, more preferably 0.001 to 5 w / v%, and still more preferably 0.01 to 3 w / v% based on the total amount of the liquid composition.

Illustrative examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, and mannitol. These can be D-form, L-form or DL-form. The saccharide content is preferably 0.001 to 10 w / v%, more preferably 0.005 to 5 w / v%, and still more preferably 0.01 to 3 w / v% based on the total amount of the liquid composition.

It is preferable to use an inorganic acid or an inorganic base as a pH adjusting agent. An example of an inorganic acid is (dilute) hydrochloric acid. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. Among these, hydrochloric acid and sodium hydroxide are preferred. The pH value (at 20 ° C) of the liquid composition of the present invention is preferably 4.0 to 9.0, more preferably 5.0 to 8.0, and even more preferably 6.0 to 8.0. In the practice of the present invention, pH is measured at 20 ° C using a pH osmometer (pH osmometer) (HOSM-1 from DKK-Toa Corporation). The content of the pH adjusting agent is preferably 0.00001 to 10 w / v%, more preferably 0.0001 to 5 w / v%, and still more preferably 0.001 to 3 w / v% based on the total amount of the liquid composition.

The preservative contained may be within a range that does not detract from the advantageous effects of the present invention, although it is possible to make the liquid composition of the present invention preservative-free in order to minimize irritation; that is, the composition does Contains preservatives. Illustrative examples of preservatives include benzalconium chloride, benzethonium chloride, sorbic acid and its salts, p-hydroxybenzoate esters (e.g., p-hydroxybenzoate Methylparaben, ethylparaben, propylparaben, chlorhexidine gluconate, thimerosal, Phenethyl alcohol, alkyldiaminoethylglycine hydrochloride, polidronium chloride, and polyhexanide hydrochloride. The content of the preservative based on the total amount of the liquid composition is preferably 0.00001 to 5 w / v%, more preferably 0.0001 to 3 w / v%, and even more preferably 0.001 to 2 w / v%. Without preservatives, from the standpoint of preservative efficacy, one or more compounds need to be included, preferably two or more compounds selected from disodium edetate, boric acid, and tromethamine The combination. In addition, when the composition is packed in a unit-dose container or a container with a filter, the composition can be made free of a preservative.

Illustrative examples of tonicity agents include sodium chloride and potassium chloride. The content of the tonicity agent is preferably 0.001 to 5 w / v%, more preferably 0.01 to 3 w / v%, and still more preferably 0.1 to 2 w / v% based on the total amount of the liquid composition.

Illustrative examples of stabilizers include disodium edetate, cyclodextrin, sulfite, and ascorbic acid. The content of the stabilizer based on the total amount of the liquid composition is preferably 0.001 to 5 w / v%, more preferably 0.01 to 3 w / v%, and still more preferably 0.1 to 2 w / v%.

Illustrative examples of algefacient include menthol, camphor, borneol, geraniol, linalool, and cineol. The content of the cooling agent is preferably 0.0001 to 2 w / v%, more preferably 0.001 to 1 w / v%, still more preferably 0.005 to 0.5 w / v%, and most preferably 0.007 based on the total amount of the liquid composition. To 0.3w / v%.

Illustrative examples of drugs (pharmacologically active ingredients) that may be suitably included are decongestants (e.g., naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride) (phenylephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate) , Anti-inflammatory agents / astringents (e.g., neostigmine methyl sulfate, ε-aminocaproic acid, allantoin, berberine chloride, zinc sulfate, zinc lactate, lysobacteria Lysozyme chloride, dipotassium glycyrrhizate, ammonium glycyrrhizate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, Azulene sodium sulfonate), antihistamines (e.g. iproheptine hydrochloride, diphenhydramine hy drochloride), isothipendyl hydrochloride, chlorpheniramine maleate), water-soluble vitamins (e.g., vitamin B ₂ , vitamin B ₆ and active form of vitamin B ₁₂ ), Amino acids (such as potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate), sulfonamides, fungicides ( For example, sulfur, isopropylmethylphenol, β-isopropyl Hinokitiol), anti-allergic agents (e.g. cromoglycic acid, ketotifen fumarate, tranilast), local anesthetics (e.g. lidocaine hydrochloride) (lidocaine hydrochloride), procaine hydrochloride, dibucaine hydrochloride), mydriatics (e.g., cyclopentolate hydrochloride, tropicamide) And therapeutic agents for cataracts (eg, pirenoxine, glutamine sulphur).

The content of these ingredients is appropriately selected according to the consideration of the type of preparation and the type of drug, and the contents of various ingredients are known in the related technical field. For example, when the composition of the present invention is prepared as an ophthalmic composition, the content of these ingredients may be suitably selected from 0.0001 based on the total amount of the ophthalmic composition. The range is from 30 to 30 w / v%, preferably from 0.001 to 10 w / v%. The content of each component relative to the total amount of the ophthalmic composition is described in detail below.

If the drug is a decongestant, its content is, for example, 0.0001 to 0.5 w / v%, preferably 0.0005 to 0.3 w / v%, and more preferably 0.001 to 0.1 w / v%.

If the drug is an anti-inflammatory agent / astringent, its content is, for example, 0.0001 to 10 w / v%, preferably 0.0001 to 5 w / v%.

If the drug is an antihistamine, its content is, for example, 0.0001 to 10 w / v%, preferably 0.001 to 5 w / v%.

If the drug is a water-soluble vitamin, its content is, for example, 0.0001 to 1 w / v%, preferably 0.0001 to 0.5 w / v%.

If the drug is an amino acid, its content is, for example, 0.0001 to 10 w / v%, preferably 0.001 to 3 w / v%.

If the drug is a sulfa or a bactericide, its content is, for example, 0.00001 to 10 w / v%, preferably 0.0001 to 10 w / v%.

If the drug is an anti-allergic agent, its content is, for example, 0.0001 to 10 w / v%, preferably 0.001 to 5 w / v%.

If the drug is a local anesthetic, mydriatic or cataract, its content is, for example, 0.001 to 1 w / v%, preferably 0.005 to 1 w / v%.

The water system is used as a solvent in the water phase. Purified water, sterilized water, or the like can be used as water, which is appropriately selected depending on the water phase. The water content relative to the total amount of the composition should be such that the total amount of the composition is 100 (this amount of water is hereinafter referred to as "balance"), and is preferably 90 To 99.999 w / v%, more preferably 95 to 99.995 w / v%.

The liquid composition of the present invention is suitable as a composition for mucosa applied to mucosa such as cornea, conjunctiva, nasal mucosa and oropharyngeal mucosa. Examples of such compositions are ophthalmic compositions, more specifically eye drops (e.g., general eye drops and eye drops for contact lenses), eye wash (e.g., general eye wash or Eyewash solution used after contact lenses), solution used when wearing contact lenses, and solution used when taking off contact lenses; nasal drops, nasal spray, and oral spray Oral spray and throat spray include articles for oral and throat diseases. More preferably, it is used as an ophthalmic composition.

Production method

The manufacturing method of the liquid composition of the present invention requires adding an oil phase in which the components A to D are dissolved to the water phase and stirring at an emulsification temperature of 0 to 50 ° C. for emulsification. In the practice of the present invention, the transparency of the liquid composition is further improved by adding a polyol as a component D to the mixture before, rather than after, emulsification. Therefore, the polyol is used together with the non-ionic type during emulsification. Surfactant.

A more preferred manufacturing method is described below. Components A to D are mixed together. When glycerin is used as the component D, it is preferable to use a solution of 70 to 80% by weight obtained by diluting glycerin with purified water in advance. The mixture dissolves at a temperature of at least 50 ° C, preferably 60 to 90 ° C. After dissolution, the dissolved mixture is cooled at a temperature of 20 to 40 ° C, preferably 20 to 35 ° C, thereby obtaining a transparent or translucent single-liquid phase (one-liquid phase) (oil phase portion). Emulsification is performed by adding this oil phase portion (while stirring the water phase) to the water phase at 0 to 50 ° C, preferably 10 to 35 ° C. The emulsification temperature in the present invention is the temperature of the water phase before the oil phase portion is added. The emulsification temperature should be a temperature that does not freeze the water phase and does not prevent emulsification. Above 50 ° C, the oil phase cannot be sufficiently emulsified, which can reduce the appearance transparency. The oil phase portion is preferably added to an amount of about four-fifths of the water phase of the total water phase.

The stirring time is preferably 5 to 60 minutes, more preferably 5 to 30 minutes, and even more preferably 5 to 15 minutes. If the stirring time is too short, the added oil phase may not be uniformly dispersed in the water phase. On the other hand, if the stirring time is too long, vitamin A may decompose. Examples of the stirring appliance include a magnetic stirrer and Three-One Motor. The rotation speed depends on the type of rotor, but is preferably set to such a degree that it does not blister.

Examples

The following examples and comparative examples are provided to illustrate the invention, although these examples are not intended to limit the scope of the invention. In the following examples, unless otherwise noted, "%" in the formulation refers to w / v%, and "ratio" refers to weight ratio.

Examples 1 to 14

Fat-soluble ingredients ((A) Vitamin A and (C) Antioxidant fat-soluble ingredients other than Vitamin A), (B) Non-ionic surfactants and (D) Polyols are mixed together before emulsification. Warm to at least 50 ° C and dissolve Decompose, and then cool the mixture to 25 ° C, thus obtaining a clear single liquid phase (oil phase portion). This was then added to the aqueous phase with stirring: at 25 ° C in Examples 1 to 7 and 10 to 14, at 10 ° C in Example 8, and at 50 ° C in Example 9. (Each case, the stirring time is 5 to 10 minutes) for emulsification to obtain the liquid composition of the formulations shown in Tables 1 and 2.

Comparative Examples 1, 2 and 4 to 7

Preparation was carried out according to the examples (aqueous phase temperature was 25 ° C (emulsification temperature)). In Comparative Examples 1, 2, and 4, it was not possible to produce it because the separation occurred at the "oil phase portion" stage described in the production method, and uniformity could not be achieved.

Comparative Example 3

Fat-soluble ingredients ((A) Vitamin A and (C) antioxidant fat-soluble ingredients other than Vitamin A) and (B) non-ionic surfactants are mixed together before emulsification, and the mixture is heated to at least 50 ° C and Dissolve. Next, in order to cool and solidify the mixture to 25 ° C, the mixture was added to the aqueous phase at 25 ° C while stirring at 50 ° C (stirring time was 5 to 10 minutes).

Comparative Example 8

Fat-soluble ingredients ((A) Vitamin A and (C) Antioxidant fat-soluble ingredients other than Vitamin A) and (B) Non-ionic surfactants are used before emulsification Mix together and warm the mixture to at least 50 ° C and dissolve. Next, in order to cool and solidify the mixture to 25 ° C, the mixture was added to the aqueous phase at 25 ° C while stirring at 50 ° C, and then (D) polyol was added while stirring (stirring time is 5 to 10 minutes).

Evaluation of the resulting composition was performed as described below.

Appearance transparency

Immediately after manufacture, the transmittance (%) of the liquid composition was measured using a Hitachi U-3310 spectrophotometer at a wavelength of 600 nm. The transparency of the composition is scored as follows based on the light transmittance.

Transparency scoring benchmark

4: Transmittance is 80% or higher

3: Transmittance is at least 70% but less than 80%

2: Transmittance is at least 60% but less than 70%

1: Transmittance is less than 60% or separation occurs (* floating oil droplets, uneven emulsification)

* Floating oil drops:

Visible particles of 1 mm or larger appear.

A score of 3 or higher is acceptable.

Vitamin A absorption rate (adsorptivity) (%)

(i) C8 silicone is rinsed with water to remove surface residue and dried.

(ii) Disperse C8 silicone (0.2g) in a 10mL sample and stir 10 minutes.

(iii) The silica gel and the sample are separated by filtration, and the amount of vitamin A in the filter and the amount of vitamin A in the sample (before absorption is generated) are measured by a UV spectrometer.

(iv) Compare the amount of vitamin A obtained, and calculate the vitamin A absorption rate (%).

* C8 Silicone:

Sepra ^TM C8 in bulk from Phenomenex Inc. (particle diameter 50 μm; pore diameter 65 Å)

Absorption rate measurement conditions:

Apparatus: MultiSpec-1500 (Shimadzu Corporation)

Measurement wavelength: 330nm

Measurement temperature: room temperature

The absorption rate (%) is scored based on the following criteria.

Scoring benchmark

3: Absorption rate is 70% or higher

2: Absorption rate is at least 60% but less than 70%

1: Absorption rate is less than 60%

A score of 2 or higher is acceptable.

Japanese Patent Application No. 2014-108039 is incorporated herein by reference.

Although some preferred embodiments have been described, many adjustments and changes can be made by referring to the previous teachings. Therefore, it must be understood that the present invention can be implemented in a manner other than the specific description without departing from the scope of the appended patent application.

Claims (7)

A liquid composition is prepared by dissolving: (A) vitamin A, (B) non-ionic surfactant, selected from polyoxyethylene sorbitan fatty acid ester, Polyoxyethylene glycerol fatty acid ester, polyoxyethylene-polyoxypropylene copolymer, and polyoxyethylene hydrogenated castor oil, (C) antioxidant A fat-soluble component selected from vitamin E and dibutyl hydroxytoluene, and (D) an oil phase of a polyhydric alcohol is added to the water phase and stirred at an emulsification temperature of 0 to 50 ° C. to be emulsified. The composition system includes Components (A) to (D) have a content-to-weight ratio D / (A + C) of 0.7 to 4 and a component (B) content of 0.05 to 0.15 w / v%. For example, the composition of claim 1 has a component (D) content of 0.05 to 0.4 w / v%. For example, the composition of claim 1 in which the component (B) nonionic surfactant is selected from polyoxyethylene sorbitan fatty acid ester and polyoxyethylene hydrogenated castor oil. For example, the composition of claim 1 in which the polyol of component (D) is selected from propylene glycol and glycerin. If the composition in the scope of patent application item 1 is an ophthalmic composition Thing. A liquid composition comprising: (A) vitamin A, (B) non-ionic surfactant, selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glyceryl fatty acid ester, polyoxyethylene-poly Oxypropylene copolymer and polyoxyethylene hydrogenated castor oil, (C) antioxidant fat-soluble component selected from vitamin E and dibutylhydroxytoluene, and (D) polyol, wherein the content weight ratio D / (A + C) is 0.7 to 4, the content of component (B) is 0.05 to 0.15 w / v%, and the vitamin A absorption rate of the liquid composition is at least 60%. A method for manufacturing a liquid composition, the liquid composition comprising (A) vitamin A; (B) a non-ionic surfactant selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glyceryl fatty acid ester , Polyoxyethylene-polyoxypropylene copolymer, and polyoxyethylene hydrogenated castor oil; (C) an antioxidant fat-soluble component selected from vitamin E and dibutylhydroxytoluene; and (D) a polyol; having 0.7 to 4 Content D / (A + C), and component (B) content of 0.05 to 0.15 w / v%, the method includes adding an oil phase in which components (A) to (D) are dissolved The emulsification step is carried out until the aqueous phase is stirred at an emulsification temperature of 0 to 50 ° C.