TWI629057B - Ophthalmic composition - Google Patents

Abstract

The present invention provides an ophthalmic composition which not only exerts the therapeutic effect of vitamin A on dry eye, but also reduces blurring after eye drops. The ophthalmic composition of the present invention contains: (A) vitamin A, (B) nonionic surfactant 0.05 W/V% to 1.5 W/V%, (C) hydroxypropyl methylcellulose 0.1 W/V% ~0.8 W/V%, and (D) polyvinylpyrrolidone.

Description

Ophthalmic composition

The present invention relates to an ophthalmic composition containing vitamin A.

Vitamin A is a highly effective ingredient for dry eye. Conventionally, there has been proposed a method of improving the effectiveness of vitamin A by increasing the retention of vitamin A by blending a water-soluble polymer compound, but this effect is not sufficient. In addition, there is a technique for improving the therapeutic effect of dry eye by formulating a polyoxyethylene polyoxypropylene diol in a composition containing 50,000 units/100 mL or more of vitamin A (Patent Document 1: Japanese Patent Laid-Open No. 2011- Bulletin 06348). Further, when the vitamin A is in a low concentration, it is required to exhibit not only the therapeutic effect of dry eye syndrome of vitamin A but also the feeling of use, etc., even when other surfactants are used.

[Prior Art Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2011-06348

By blending polyoxyethylene-polyoxypropylene glycol, the therapeutic effect of dry eye syndrome is improved. High, but if the amount is too much, you will see blurred symptoms after eye drops. Further, when a water-soluble polymer compound is formulated, the therapeutic effect of dry eye is improved, but a blurred symptom is also observed after eye drops. In particular, patients with dry eye syndrome are less likely to feel blurred due to less tears, so it is important to reduce blurring after eye drops. The present invention has been made in view of the above circumstances, and it is therefore an object of the invention to provide an ophthalmic composition which not only exhibits the therapeutic effect of dry eye of vitamin A but also reduces blurring after eye drops.

The present inventors conducted active research to achieve the above object, and as a result, found that (B) a nonionic surfactant 0.05g/100 mL to 1.5 g/100 mL was formulated in an ophthalmic composition containing (A) vitamin A. And a specific water-soluble polymer compound such as (C) hydroxypropylmethylcellulose and (D) polyvinylpyrrolidone is used in combination, and the amount of (C) hydroxypropylmethylcellulose is set to 0.1. g/100 mL to 0.8 g/100 mL, thereby exhibiting the therapeutic effect of dry eye syndrome of vitamin A, and reducing the blurring after eye drops, and has a remarkable effect as a therapeutic agent for dry eye, thereby forming the present invention.

Accordingly, the present invention provides the following ophthalmic composition.

[1]. An ophthalmic composition comprising: (A) vitamin A, (B) nonionic surfactant 0.05 W/V% to 1.5 W/V%, (C) hydroxypropyl methylcellulose 0.1 W/V%~0.8W/V%, and (D) polyvinylpyrrolidone.

[2] The ophthalmic composition according to [1], wherein (C): (D) The mass ratio is 1.5:1~30:1.

[3] The ophthalmic composition according to [1] or [2] wherein the content of the component (D) is from 0.01 W/V% to 0.5 W/V%.

[4] The ophthalmic composition according to any one of [1] to [3] wherein the component (A) is selected from the group consisting of retinol palmitic acid ester and retinol acetic acid. One or more of ester and retinoic acid.

The ophthalmic composition according to any one of [1] to [4] wherein the component (B) is selected from the group consisting of polyoxyethylene polyoxypropylene diol, polyoxyethylene hardened castor oil, and polyoxygen One or more of the ethylene sorbitan fatty acid esters.

[6] The ophthalmic composition according to any one of [1] to [5] wherein (C) hydroxypropylmethylcellulose has a weight average molecular weight of 50,000 (g/mol) to 600,000 (g/mol).

[7] The ophthalmic composition according to any one of [1] to [6] wherein (D) polyvinylpyrrolidone has a weight average molecular weight of 30,000 (g/mol) to 1.5 million ( g/mol).

[8] The ophthalmic composition according to any one of [1] to [7] which is a therapeutic agent for dry eye.

According to the present invention, it is possible to provide an ophthalmic composition which not only exhibits the therapeutic effect of vitamin A for dry eye, but also reduces blurring after eye drops, and has a remarkable effect as a therapeutic agent for dry eye.

(A) Vitamin A

In addition to the vitamin A itself, vitamin A may be used alone or in combination with a vitamin A derivative such as a vitamin A fatty acid ester, and the like. Specific examples thereof include retinyl palmitate, retinyl acetate, retinoic acid, retinol, and retinoid. Among them, preferred are retinyl palmitate, retinyl acetate, and retinoic acid. Retinyl palmitate is usually marketed with 1 million international units to 1.8 million international units (hereinafter referred to as units or IUs), specifically Japanese Roche Vitamin Japan Co., Ltd. Yellow alcohol palmitate (1.7 million IU / g) and the like. The amount of vitamin A is preferably from 10,000 units/100 mL to 500,000 units/100 mL, more preferably from 30,000 units/100 mL to 500,000 units/100 mL, particularly preferably from 50,000 units/100 mL to 300,000 units/100 mL. In terms of the therapeutic effect of dry eye, it is preferably 10,000 units/100 mL or more, and in terms of stability of vitamin A, it is preferably 500,000 units/100 mL or less.

(B) Nonionic surfactant

Examples of the nonionic surfactants include polyoxyethylene polyoxypropylene diol, polyoxyethylene hardened castor oil, and polyoxyethylene sorbitan fatty acid ester. These may be used alone or in combination of two or more. Among them, in terms of the therapeutic effect of dry eye, polyoxyethylene polyoxypropylene diol and polyoxyethylene hardened castor oil are preferred.

The polyoxyethylene polyoxypropylene diol is not particularly limited, and those described in the pharmaceutical additive specifications (medicine addition regulations) can be used. The average degree of polymerization of ethylene oxide is preferably from 4 to 200, more preferably from 20 to 200, and the average degree of polymerization of propylene oxide is preferably from 5 to 100, more preferably from 20 to 70, which may be a block copolymer. It can also be a random polymer. Specifically, polyoxyethylene (200) polyoxypropylene (70) diol: Lutrol F127 (manufactured by BASF), Unilub 70DP-950B (Japan) Production of fats and oils, etc., polyoxyethylene (120) polyoxypropylene (40) diol (Pluronic F-87), polyoxyethylene (160) polyoxypropylene (30) diol ( Pluronic F-68, alias Poloxamer 188): Pronon #188P (Japanese fats and oils), etc., polyoxyethylene (42) polyoxypropylene (67) Glycol (Pluronic P123, alias Poloxamer 403), polyoxyethylene (54) polyoxypropylene (39) diol (Pluronic P85): Pronon (Pronon) #235P (Japanese fats and oils), etc., polyoxyethylene (20) polyoxypropylene (20) diol (Pluronic L-44), Tetronic, etc. Among them, polyoxyethylene (200) polyoxypropylene (70) diol, polyoxyethylene (160) polyoxypropylene (30) diol, and polyoxyethylene (54) polyoxypropylene (39) diol are preferable.

Polyoxyethylene hardened castor oil can be enumerated: polyoxyethylene hardened castor oil 5, polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 50, poly Oxyethylene hardened castor oil 60, polyoxyethylene hardened castor oil 100, and the like. Among them, polyoxyethylene hardened castor oil 60 is preferred.

Polyoxyethylene sorbitan fatty acid ester can be enumerated: polylaurate Ethylene (20) sorbitan (polysorbate 20), monooleic acid polyoxyethylene (20) sorbitan (polysorbate 80), polyoxyethylene sorbitan monostearate ( The polysorbate 60), the polyoxyethylene sorbitan tristearate (polysorbate 65), and the like may be used alone or in combination of two or more. Among them, polysorbate 80 is preferred.

The content of the nonionic surfactant in the ophthalmic composition is 0.05 W/V% to 1.5 W/V% (g/100 mL), preferably 0.1 W/V% to 1.2 W/V%. If the content is less than 0.05W/V%, it is emulsified. The solubilization effect and the dry eye treatment effect are insufficient. On the other hand, if it exceeds 1.5 W/V%, blurring after eye drop occurs.

(C) hydroxypropyl methylcellulose

In terms of the effect of the therapeutic effect of dry eye, the weight average molecular weight of hydroxypropylmethylcellulose is preferably 50,000 (g/mol) or more, and the aspect of blurring after eye drop is further prevented. Good is below 600,000 (g/mol). More preferably, it is 100,000 (g/mol) to 500,000 (g/mol), and more preferably 200,000 (g/mol) to 400,000 (g/mol). Further, the weight average molecular weight was measured by a gel permeation chromatography-Gel Permeation Chromatography-Multi-Angle Laser Light Scattering (GPC-MALLS) system.

The ophthalmic composition has a content of hydroxypropylmethylcellulose of 0.1 W/V% to 0.8 W/V%, preferably 0.2 W/V% to 0.7 W/V%, more preferably 0.2 W/V. %~0.5W/V%. When the content of the component (C) is less than 0.1 W/V%, the target dry eye treatment effect cannot be exhibited. On the other hand, if it exceeds 0.8 W/V%, blurring after eye drop occurs.

(D) polyvinylpyrrolidone

In view of the effect of the therapeutic effect of dry eye, the weight average molecular weight of the polyvinylpyrrolidone is preferably 30,000 (g/mol) or more, and it is more preferable in terms of preventing blurring after eye drop. It is less than 1.5 million (g/mol). More preferably, it is 100,000 (g/mol) to 1.3 million (g/mol), and particularly preferably 800,000 (g/mol) to 1.2 million (g/mol). In addition, the weight average molecular weight was measured using a GPC-MALLS system.

In terms of the effect of the therapeutic effect of dry eye, the content of the ophthalmic composition of polyvinylpyrrolidone is preferably 0.01 W/V% or more, and the aspect of blurring after eye drop is further prevented. It is preferably 0.5 W/V% or less. More preferably, it is 0.02 W/V% to 0.3 W/V%, and particularly preferably 0.03 W/V% to 0.2 W/V%.

In the present invention, by combining a specific water-soluble polymer compound such as (C) hydroxypropylmethylcellulose and (D) polyvinylpyrrolidone, the therapeutic effect of dry eye is improved and can be prevented. Blurring after the eye drops. Even if methyl cellulose, polyvinyl alcohol, or the like is combined, the intended effect cannot be obtained. In addition, by the combination, the content of the (B) nonionic surfactant is in the range of 0.05 W/V% to 1.5 W/V%, and the stability of vitamin A and the therapeutic effect of dry eye can also be exerted. .

(C): The quality of the content represented by (D) is preferably 1.5:1 to 30:1, more preferably 4:1 to 20:1, and particularly preferably 5:1 to 10:1. When the (C) hydroxypropylmethylcellulose is 1.5 or more with respect to (D) polyvinylpyrrolidone 1, the blurring prevention effect after eye drop is further exhibited, and when it is 30 or less, More effective treatment of dry eye syndrome.

The total amount of the component (C) and the component (D) is preferably 0.11 W/V% to 1.3 W/V%, more preferably 0.15 W/V% to 1.3 W/V%, and particularly preferably 0.23 W/V%. ~0.7W/V%.

In the ophthalmic composition of the present invention, various components to be formulated in the ophthalmic composition can be blended in a range that does not impair the effects of the present invention. Examples of such components include polyhydric alcohols, buffers, thickeners, antioxidants, sugars, pH adjusters, preservatives, isotonic agents, stabilizers, cooling agents, drugs, and water. These components may be used alone or in combination of two or more kinds, and may be appropriately adjusted.

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

The buffering agent is, for example, boric acid or a salt thereof (borax or the like), citric acid or a salt thereof (such as sodium citrate), phosphoric acid or a salt thereof (such as sodium monohydrogen phosphate), tartaric acid or a salt thereof (such as sodium tartrate), or gluconic acid. Or a salt thereof (sodium gluconate or the like), acetic acid or a salt thereof (sodium acetate or the like), and among them, in terms of low irritation and a preservative effect of the composition, trometamol is preferred. Further, when boric acid or borax is used in combination, a particularly high anticorrosive effect is obtained. The content of the buffer in the ophthalmic composition is preferably 0.001 W/V% to 10 W/V%, more preferably 0.01 W/V% to 5 W/V%. Further, in terms of improving the storage stability of vitamin A, it is preferred to formulate tromethamine.

Examples of the thickener include hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, and a carboxyvinyl polymer. The content of the thickening agent is preferably 0.5 W/V%. In the following, it may not be deployed.

By formulating antioxidants, the storage stability of vitamin A is improved. Antioxidants include: d-α-tocopherol (d-α-tocopherol), d-β-tocopherol, d-γ-tocopherol, d-δ-tocopherol, dl-α-tocopherol, acetic acid d- --tocopherol, acetic acid dl-α-tocopherol, acetic acid dl-β-tocopherol, acetic acid dl-γ-tocopherol, acetic acid dl-δ-tocopherol, nicotinic acid dl-α-tocopherol, etc. , fat-soluble antioxidants such as dibutylhydroxytoluene and butylhydroxyanisole, water-soluble antioxidants such as vitamin C, hydroquinone, cysteine, and glutathione. The content of the antioxidant in the ophthalmic composition is preferably from 0.005 W/V% to 5 W/V%, more preferably from 0.005 W/V% to 1 W/V%, and particularly preferably from 0.005 W/V% to 0.2 W/ V%.

Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, and mannitol. Further, the saccharides may be any of a D body, an L body, or a DL body. In the ophthalmic composition, the content of the saccharide is preferably 0.001 W/V% to 10 W/V%, more preferably 0.005 W/V% to 5 W/V%, and particularly preferably 0.01 W/V% to 3 W/V%. .

The pH adjuster is preferably an inorganic acid or an inorganic alkali agent. For example, the inorganic acid may be exemplified by (diluted) hydrochloric acid. Examples of the inorganic alkali agent include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogencarbonate. Among them, hydrochloric acid, sodium hydroxide, and potassium hydroxide are preferred. The pH of the ophthalmic composition (20 ° C) is preferably 3.8 to 8.0, more preferably 5.0 to 7.5. Further, in the present invention, the pH can be measured at 20 ° C using a pH osmometer (for example, HOSM-1, East Asian DKK (strand), etc.). The content of the pH adjuster can be appropriately selected depending on the target pH range, and is preferably in the ophthalmic composition. 0.00001W/V%~10W/V%, more preferably 0.0001W/V%~5W/V%, especially preferably 0.001W/V%~3W/V%.

Examples of the preservative include benzalkonium chloride, benzethonium chloride, sorbic acid or a salt thereof, p-hydroxybenzoate (methylparaben), Ethyl paraben, propylparaben, etc., chlorhexidine gluconate, thimerosal, phenylethyl alcohol, alkyldiamine hydrochloride Ethylglycine, polyhexanide hydrochloride, polidronium chloride, and the like. In terms of the therapeutic effect of dry eye, sorbic acid or a salt thereof is preferred. The content of the preservative in the ophthalmic composition is, for example, 0.00001 W/V% to 5 W/V%, preferably 0.0001 W/V% to 3 W/V%, more preferably 0.001 W/V% to 2 W/V%. . Further, since the preservative has a possibility of worsening the symptoms of dry eye, it may not be formulated. In order to prevent the corrosion resistance in the case where the preservative is not prepared, one or more, preferably two or more kinds of sodium edetate, boric acid and tromethamine are preferably combined. Further, in the case of a unit dose container or a container with a filter, the preservative may not be prepared.

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

Examples of the stabilizer include sodium ethylenediaminetetraacetate, cyclodextrin, sulfite, dibutylhydroxytoluene, and the like. In the ophthalmic composition, the content of the stabilizer is, for example, It is 0.001 W/V% to 5 W/V%, preferably 0.01 W/V% to 3 W/V%, more preferably 0.1 W/V% to 2 W/V%.

Examples of the cooling agent include menthol, camphor, borneol, geraniol, linalool, cineole, and the like. In the ophthalmic composition, the content of the cooling agent is preferably 0.0001 W/V% to 5 W/V%, more preferably 0.001 W/V% to 2 W/V%, and particularly preferably 0.005, based on the total amount of the compound. W/V%~1W/V%, especially preferably 0.007W/V%~0.8W/V%.

As a drug (pharmaceutically active ingredient), for example, it can be appropriately formulated: a decongestant (for example, naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride) Hydrochloride, epinephrine, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate, etc., anti-inflammatory. Astringent (for example: neostigmine methylsulfate, ε-aminocaproic acid, allantoin, berberine chloride, zinc sulfate, Zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, sulfonic acid Sodium, etc., antihistaminic agent (eg, iproheptine hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipendyl hydrochloride, Chlorpheniramine maleate, etc., water-soluble vitamins (active vitamin B ₂ , vitamin B ₆ , vitamin B _12, etc.), amino acids (eg, L-aspartate, L- Magnesium aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, etc., sulfa drug, bactericide (for example: sulfur, isopropylmethylphenol, hinokitiol, etc.), Anti-allergic agent (cromoglycic acid), ketotifen fumarate, tranilast, etc., local anesthetics (eg lidocaine, lidocaine hydrochloride, procaine hydrochloride, hydrochloric acid) Bucaine, etc., mydriatic (cyclopentolate hydrochloride, tropicamide, etc.), cataract therapeutics (pirenoxine, glutathione, etc.) ).

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

If it is a decongestant, it is, for example, 0.0001 W/V% to 0.5 W/V%, preferably 0.0005 W/V% to 0.3 W/V%, more preferably 0.001 W/V% to 0.1 W/V%. .

If it is anti-inflammatory. The astringent is, for example, 0.0001 W/V% to 10 W/V%, preferably 0.0001 W/V% to 5 W/V%.

In the case of an antihistamine, for example, it is 0.0001 W/V% to 10 W/V%, preferably 0.001 W/V% to 5 W/V%.

In the case of a water-soluble vitamin, it is 0.0001 W/V% to 1 W/V%, preferably 0.0001 W/V% to 0.5 W/V%.

In the case of an amino acid, it is 0.0001 W/V% to 10 W/V%, preferably 0.001 W/V% to 3 W/V%.

The sulfonamide or bactericide is, for example, 0.00001 W/V% to 10 W/V%, preferably 0.0001 W/V% to 10 W/V%.

In the case of an antiallergic agent, for example, it is 0.0001 W/V% to 10 W/V%, preferably 0.001 W/V% to 5 W/V%.

The local anesthetic, mydriatic, and cataract therapeutic agent are, for example, 0.001 W/V% to 1 W/V%, preferably 0.005 W/V% to 1 W/V%.

The ophthalmic composition of the present invention can be directly prepared into a liquid preparation, or can be prepared into a suspension, a gel, and the like. Specifically, examples of the use form include eye drops (for example, eye drops for general use, eye drops for contact lenses, and the like), eye washes (collectively used for eye washes, and eye washes used after removing contact lenses). Agent, etc.), contact lens fitting liquid, contact lens removal liquid, and the like. Among them, the contact lens user is prone to dry eye syndrome, and therefore the ophthalmic composition of the present invention is suitable as: an eye drop for a contact lens, an eye wash used after removing a contact lens, a contact lens solution, and a contact lens removal. Liquid, etc. In particular, since the amount of the preservative is limited, it is particularly preferable for use in a soft contact lens.

The viscosity of the ophthalmic composition of the present invention is preferably 2.5 mPa. s~120mPa. s, more preferably 6mPa. s~60mPa. s. In addition, an E-type viscometer (for example, VISCONIC ELD-R, Tokyo Keiki Co., Ltd., etc.) is used for viscosity at 20 °C. Determination.

The ophthalmic composition of the present invention is not particularly limited in its preparation method. For example, (B) a nonionic surfactant can be used to dissolve (A) vitamin A in sterilized purified water (residue), followed by addition of each formulation component. (The preparation is carried out in the order of a drug, other components, and a cooling agent), and the pH is adjusted to obtain the ophthalmic composition. Then, it can be aseptically filled in a suitable container, such as a container made of polyethylene terephthalate or the like.

By forming an oxygen-adsorbing pillow package instead of pillow packaging such as polyethylene or polyethylene terephthalate, the stability of vitamin A is further improved. The oxygen adsorption pillow packaging refers to a pillow that can be used to mold an oxygen absorbent that can be actively removed by oxygen remaining in the pillow and oxygen invaded from the outside.

The ophthalmic composition of the present invention is suitable as a therapeutic agent for dry eye, and can be more effective by using 30 μL to 60 μL of one eye drop and 3 to 6 times a day.

[Examples]

Hereinafter, the present invention will be specifically described by way of examples and comparative examples, but the present invention is not limited to the following examples. In addition, unless otherwise indicated, the "%" of the composition is "W/V% by mass", and the ratio indicates the mass ratio.

[Example 1 to Example 27, Comparative Example 1 to Comparative Example 9]

Using (B) polyoxyethylene (200) polyoxypropylene (70) diol, (A) retinyl palmitate is soluble in purified water, and then other compounding ingredients are added, as shown in the following table. The composition of the ophthalmic composition (eye drops). For the resulting eye The composition of the composition was measured by a VISCONIC ELD-R (manufactured by Tokyo Keiki Co., Ltd.) to measure the viscosity at 20 ° C, and the following evaluation was carried out. The results are collectively shown in the table.

Test Example-1 (Dry eye syndrome evaluation test using rabbit corneal epithelial disorder model) [cornea. Conjunctival injury treatment effect]

Use rabbit hemanta treated with heptanol. The cornea of the conjunctival epithelial disorder model. Conjunctival injury healing effect test

Rabbits were treated with heptanol (200 μL of heptanol/ethanol = 8:2 mixture was added to a single eye) to prepare a cornea for rabbits. The conjunctival epithelium gives a model of the disorder. Then, the sample was continuously subjected to eye drops for 11 days (6 times (100 μL/time)/day). During the eye drop, luciferin staining was performed regularly (50 μL of 2% luciferin was added to a single eye), and according to the Lenp criterion, the score was 15 points (the score after the heptanol treatment was set to 15 points, Continuous improvement, reduced scores) to evaluate the cornea. Conjunctival damage healing effect. The evaluation results on the fifth day are shown.

The so-called dry eye syndrome is defined as "the tears caused by a variety of factors and chronic diseases of the corneal and conjunctival epithelium, with eye discomfort or visual dysfunction", the cornea used in this experiment. The conjunctival epithelial disorder model was used as a model for evaluating dry eye syndrome. The results are shown on the basis of the following evaluation criteria.

<Evaluation criteria>

◎: 6 points or more and less than 8 points

○: 8 or more and less than 10

△: 10 points or more and less than 12 points

×: 12 or more points

Test Example-2 (Fuzzy test after eye drop)

5 functional inspectors, 2 drops of the eye drop sample, 1 minute after the eye drop, the Landolt ring alone indicator 5 m from the distance of 5 m (Handaya Co., Ltd., HP) -1226A, International Standard Circular Eye Chart 5M), the fuzzy situation was evaluated by the scores of the following five stages. Based on the average value of five functional inspectors, the results were expressed on the basis of the following evaluation criteria.

<score>

5: Not fuzzy

4: micro blur

3: slightly blurred

2: Pretty fuzzy

1: very fuzzy

<Evaluation criteria>

◎: Average score is 4 or more

○: The average score is 3 or more and less than 4

△: The average score is 2 points or more and less than 3 points.

×: The average score is less than 2 points

When the component (B) is at most the lower limit, the oil component cannot be dissolved and separated. In this case, since the concentration of the oil-soluble component is not always required, unevenness in effect is expected, or blurring after eye drop becomes severe, and evaluation cannot be performed.

Further, the following evaluation was performed.

Test Example-3 <Residual rate (%) of retinyl palmitate>

15 mL of the ophthalmic composition was filled in a 15 mL polyethylene terephthalate container. This was set as a pillow package (5 cm × 10 cm, pillow type package), and an oxygen absorption pillow type package (oxygen absorption pillow type package). The oxygen absorbing pillow was an oxygen absorbing film: highstar O ₂ (Star Plastic Industry Co., Ltd.) was cut, and a heat sealer was used to have a size of 5 cm × 10 cm. The oxygen absorption pillow is at 40 ° C. Store at 75% RH for 6 months. After the manufacturing and after 40 ° C. The retinyl palmitate content in the ophthalmic composition was determined after 6 months of storage at 75% RH. For the measurement, measurement was carried out using high performance liquid chromatography. Based on the obtained retinol palmitate content, the residual ratio (%) of retinyl palmitate was calculated based on the following formula. The results are shown in Table 6 below.

Retinol palmitate residual rate (%) = retinol palmitate content after storage / retinol palmitate content after production × 100

Raw materials used in the preparation of the examples and comparative examples are shown below.

. Polyoxyethylene (200) polyoxypropylene (70) diol: Unilub 70DP-950B, drug addition, Nippon oil (share); or Lutrol F127, drug addition, BASF (BASF )(share)

. Hydroxypropyl methylcellulose (Hypromellose): Metolose 60SH-4000, Japan Bureau, Shin-Etsu Chemical Industry Co., Ltd., weight average molecular weight of 300,000 (g/mol), Table 1 to Table 4 are used

Metolose 60SH-50, Japan Bureau, Shin-Etsu Chemical Industry Co., Ltd., weight average molecular weight is 70,000 (g / mol)

. Polyvinylpyrrolidone: Kollidon 90F, Japan, BASF (shares): weight average molecular weight of 1 million (g / mol), Table 1 ~ Table 4

Kollidon 30, day, BASF (shares): weight average molecular weight of 50,000 (g / mol)

. Monooleic acid polyoxyethylene (20) sorbitan (polysorbate 80): Rheodol TW-0120V, Japanese Bureau, Kao (share)

. Polyoxyethylene hardened castor oil 60: HCO-60 (medical use), drug addition regulations, daylight chemistry (shares)

. Polyvinyl alcohol: Gohsenol EG-05, Japanese synthetic chemistry

. Methylcellulose: Metolose SM-4000, Japan Bureau, Shin-Etsu Chemical Industry Co., Ltd.

Claims (8)

An ophthalmic composition comprising: (A) vitamin A, (B) nonionic surfactant 0.05 W/V% to 1.5 W/V%, (C) hydroxypropyl methylcellulose 0.1 W/V% ~0.8 W/V%, and (D) polyvinylpyrrolidone. The ophthalmic composition according to claim 1, wherein (C): (D) represents a mass ratio of 1.5:1 to 30:1. The ophthalmic composition according to claim 1 or 2, wherein the content of the component (D) is 0.01 W/V% to 0.5 W/V%. The ophthalmic composition according to the first or second aspect of the invention, wherein the component (A) is one or more selected from the group consisting of retinyl palmitate, retinyl acetate, and retinoic acid. The ophthalmic composition according to claim 1 or 2, wherein the component (B) is selected from the group consisting of polyoxyethylene polyoxypropylene diol, polyoxyethylene hardened castor oil, and polyoxyethylene sorbitan. One or more of the fatty acid esters. The ophthalmic composition according to claim 1 or 2, wherein (C) hydroxypropylmethylcellulose has a weight average molecular weight of 50,000 (g/mol) to 600,000 (g/mol). . The ophthalmic composition according to claim 1 or 2, wherein the (D) polyvinylpyrrolidone has a weight average molecular weight of 30,000 (g/mol) to 1.5 million (g/mol). The ophthalmic composition according to claim 1 or 2, which is a therapeutic agent for dry eye.