JP2015101582A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ophthalmic composition that exhibits the dry eye treatment effect of vitamin A and reduces blurs after instillation.SOLUTION: A ophthalmic composition comprises (A) vitamin A, (B) nonionic surfactant of 0.05-1.5 W/V%, (C) hydroxypropyl methylcellulose of 0.1-0.8 W/V%, and (D) polyvinyl pyrrolidone.

Description

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

  Vitamin A is a component that is highly effective for dry eyes. So far, a method for improving the effectiveness by blending a water-soluble polymer compound and increasing the retention of vitamin A has been proposed, but the effect has not been sufficient. In addition, a technique for improving the effect of treating dry eye by blending polyoxyethylene polyoxypropylene glycol with a composition containing vitamin A 50,000 units / 100 mL or more has been proposed (Patent Document 1: Japanese Patent Laid-Open No. 2005-26883). 2011-06348). Furthermore, when vitamin A is in a low concentration, the use of other surfactants and the like have been required to exhibit the effect of treating dry eye of vitamin A and improve the feeling of use.

JP 2011-06348 A

  By blending polyoxyethylene polyoxypropylene glycol, the dry eye treatment effect is improved, but there is a symptom of blurring after instillation when the blending amount is large. In addition, when a water-soluble polymer compound is added, the effect of treating dry eye is improved, but there is also a symptom of blurring after instillation. It is important to reduce blurring after instillation, especially since dry eye patients have less tear fluid and are more likely to feel blurring in the eyes. The present invention has been made in view of the above circumstances, and an object thereof is to provide an ophthalmic composition in which the effect of vitamin A on dry eye treatment is exhibited and blurring after instillation is reduced.

  As a result of intensive studies to achieve the above object, the present inventor has formulated (B) nonionic surfactant 0.05 to 1.5 g / 100 mL in (A) ophthalmic composition containing vitamin A. , (C) Hydroxypropylmethylcellulose and (D) Polyvinylpyrrolidone together with a specific water-soluble polymer compound and (C) Hydroxypropylmethylcellulose is blended in an amount of 0.1 to 0.8 g / 100 mL, It has been found that vitamin A exhibits the effect of dry eye treatment, blurring after instillation is reduced, and has a remarkable effect as a dry eye treatment agent, and has led to the present invention.

Accordingly, the present invention provides the following ophthalmic compositions.
[1]. (A) Vitamin A,
(B) Nonionic surfactant 0.05-1.5 W / V%,
An ophthalmic composition containing (C) hydroxypropylmethylcellulose 0.1 to 0.8 W / V% and (D) polyvinylpyrrolidone.
[2]. The ophthalmic composition according to [1], wherein the mass ratio represented by (C) :( D) is 1.5: 1 to 30: 1.
[3]. (D) The ophthalmic composition according to [1] or [2], wherein the content of the component is 0.01 to 0.5 g / 100 mL.
[4]. (A) The ophthalmic composition according to any one of [1] to [3], wherein the component is one or more selected from retinol palmitate, retinol acetate, and retinoic acid.
[5]. (B) The ophthalmic use according to any one of [1] to [4], wherein the component is at least one selected from polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid ester Composition.
[6]. (C) The ophthalmic composition according to any one of [1] to [5], wherein the hydroxypropylmethylcellulose has a weight average molecular weight of 5 to 600,000 (g / mol).
[7]. (D) The ophthalmic composition according to any one of [1] to [6], wherein the polyvinylpyrrolidone has a weight average molecular weight of 3 to 1.5 million (g / mol).
[8]. The ophthalmic composition according to any one of [1] to [7], which is a dry eye therapeutic agent.

  ADVANTAGE OF THE INVENTION According to this invention, while providing the dry eye therapeutic effect of vitamin A, the blurring after instillation can be reduced and the ophthalmic composition which has a remarkable effect as a dry eye therapeutic agent can be provided.

(A) Vitamin A
As vitamin A, in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters, etc. can be used alone or in appropriate combination of two or more. Can be used. Specific examples include retinol palmitate, retinol acetate, retinoic acid, retinol, retinoic acid, and retinoid. Of these, retinol palmitate, retinol acetate, and retinoic acid are preferred. Retinol palmitic acid esters are usually commercially available from 1 million to 1.8 million international units (hereinafter abbreviated as units or I.U.), specifically, Retinol palmitic acid manufactured by Roche Vitamin Japan Co., Ltd. Esters (1.7 million IU / g) and the like. The amount of vitamin A is preferably 10,000 to 500,000 units / 100 mL, more preferably 30,000 to 500,000 units / 100 mL, and particularly preferably 50,000 to 300,000 units / 100 mL. 10,000 units / 100 mL or more is preferable from the viewpoint of the effect of dry eye treatment, and 500,000 units / 100 mL or less is preferable from the viewpoint of vitamin A stability.

(B) Nonionic surfactant Examples of the nonionic surfactant include polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid ester, one type alone or two or more types. It can be appropriately selected and used. Of these, polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil are preferable from the viewpoint of dry eye treatment effect.

  The polyoxyethylene polyoxypropylene glycol is not particularly limited, and those described in the pharmaceutical additive standards (medicine regulations) can be used. The average degree of polymerization of ethylene oxide is preferably 4 to 200, more preferably 20 to 200, and the average degree of polymerization of propylene oxide is preferably 5 to 100, more preferably 20 to 70, and may be a block copolymer or a random polymer. Specifically, polyoxyethylene (200) polyoxypropylene (70) glycol: Lutrol F127 (manufactured by BASF), Unilube 70DP-950B (manufactured by NOF Corporation), polyoxyethylene (120) polyoxypropylene (40) Glycol (Pluronic F-87), Polyoxyethylene (160) Polyoxypropylene (30) Glycol (Pluronic F-68, also known as Poloxamer 188): Pronon # 188P (Nippon Yushi Co., Ltd.) and other polyoxyethylene (42) Polyoxypropylene (67) glycol (Pluronic P123, also known as Poloxamer 403), Polyoxyethylene (54) Polyoxypropylene (39) Glycol (Pluronic P85): Pronon # 235P (Nippon Yushi Co., Ltd.), etc. Kishiechiren (20) polyoxypropylene (20) glycol (Pluronic L-44), Tetronic and the like. Of these, polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, and polyoxyethylene (54) polyoxypropylene (39) glycol are preferred.

  As polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, poly Examples thereof include oxyethylene hydrogenated castor oil 60 and polyoxyethylene hydrogenated castor oil 100. Among these, polyoxyethylene hydrogenated castor oil 60 is preferable.

  Examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene monooxylate (20) sorbitan (polysorbate 80), polyoxyethylene sorbitan monostearate (polysorbate 60) And polyoxyethylene sorbitan tristearate (polysorbate 65). These may be used alone or in appropriate combination of two or more. Among these, polysorbate 80 is preferable.

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

(C) Hydroxypropyl methylcellulose The weight average molecular weight of hydroxypropylmethylcellulose is preferably 50,000 (g / mol) or more from the viewpoint of more effective dry eye treatment, and 600,000 from the viewpoint of further preventing blurring after instillation. (G / mol) or less is preferable. More preferably, it is 100-500,000 (g / mol), More preferably, it is 200-400,000 (g / mol). The weight average molecular weight is measured with a GPC-MALLS system.

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

(D) Polyvinylpyrrolidone The weight average molecular weight of polyvinylpyrrolidone is preferably 30,000 (g / mol) or more from the viewpoint of more effective in treating dry eye, and 1.5 million (g) from the point of preventing blurring after instillation. / Mol) or less. More preferably, it is 10-1.3 million (g / mol), More preferably, it is 80-1.2 million (g / mol). The weight average molecular weight is measured with a GPC-MALLS system.

  The content of polyvinylpyrrolidone in the ophthalmic composition is preferably 0.01 W / V% or more from the viewpoint of more effective in treating dry eye, and 0.5 W / V from the viewpoint of further preventing blurring after instillation. % Or less is preferable. More preferably, it is 0.02-0.3 W / V%, More preferably, it is 0.03-0.2 W / V%.

  In the present invention, by combining a specific water-soluble polymer compound (C) hydroxypropylmethylcellulose and (D) polyvinylpyrrolidone, the effect of treating dry eye is improved and blurring after instillation can be prevented. . Even when combined with methyl cellulose, polyvinyl alcohol, or the like, the intended effect cannot be obtained. In addition, with the above combination, it is possible to exhibit the stability of vitamin A and the effect of treating dry eye even when the content of (B) nonionic surfactant is as low as 0.05 to 1.5 W / V%. It becomes.

  The content mass ratio represented by (C) :( D) is preferably 1.5: 1 to 30: 1, more preferably 4: 1 to 20: 1, and even more preferably 5: 1 to 10: 1. . (D) With respect to polyvinylpyrrolidone 1, (C) Hydroxypropyl methylcellulose is 1.5 or more, so that the effect of preventing blurring after instillation is more exhibited. Demonstrated.

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

  In the ophthalmic composition of the present invention, various components to be blended in the ophthalmic composition can be blended within a range that does not impair the effects of the present invention. These components include polyhydric alcohols, buffers, thickeners, antioxidants, sugars, pH adjusters, preservatives, isotonic agents, stabilizers, cooling agents, drugs, water, and the like. . These can be used individually by 1 type or in combination of 2 or more types, respectively, and can mix | blend suitable amount.

  Examples of the polyhydric alcohol 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 ophthalmic composition.

  Examples of the buffer include boric acid or a salt thereof (such as borax), 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 (tartaric acid) Sodium), gluconic acid or a salt thereof (sodium gluconate, etc.), acetic acid or a salt thereof (sodium acetate, etc.). Among them, trometamol is preferred from the viewpoint of mildness and the antiseptic effect of the composition. Furthermore, when boric acid and borax are used in combination, a particularly high antiseptic effect is obtained. The content of the buffer is preferably 0.001 to 10 W / V%, more preferably 0.01 to 5 W / V% in the ophthalmic composition. In addition, it is preferable to mix | blend trometamol from the point of the preservation stability of vitamin A.

  Examples of the thickener include hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, and the like. The content of the thickening agent is preferably 0.5 W / V% or less, and may not be blended.

  By blending an antioxidant, the storage stability of vitamin A is improved. Antioxidants include d-α-tocopherol, d-β-tocopherol, d-γ-tocopherol, d-δ-tocopherol, dl-α-tocopherol, d-α-tocopherol acetate, dl-α-tocopherol acetate, Vitamin Es such as dl-β-tocopherol acetate, dl-γ-tocopherol acetate, dl-δ-tocopherol acetate, dl-α-tocopherol acetate, fat-soluble antioxidants such as dibutylhydroxytoluene and butylhydroxyanisole, vitamins And water-soluble antioxidants such as C, hydroquinone, cysteine, and glutathione. The content of the antioxidant is preferably 0.005 to 5 W / V% in the ophthalmic composition, more preferably 0.005 to 1 W / V%, and still more preferably 0.005 to 0.2 W / V. %.

  Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. These may be any of D-form, L-form and DL-form. The content of the saccharide is preferably 0.001 to 10 W / V% in the ophthalmic composition, more preferably 0.005 to 5 W / V%, and still more preferably 0.01 to 3 W / V%.

  As the pH adjuster, it is preferable to use an inorganic acid or an inorganic alkali agent. For example, (diluted) hydrochloric acid is mentioned as an inorganic acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. Of these, hydrochloric acid, sodium hydroxide, and potassium hydroxide are preferable. The pH (20 ° C.) of the ophthalmic composition is preferably 3.8 to 8.0, more preferably 5.0 to 7.5. In the present invention, pH is measured at 20 ° C. using a pH osmometer (for example, HOSM-1, Toa DKK Co., Ltd.). The content of the pH adjuster is appropriately selected depending on the target pH range, but is preferably 0.00001 to 10 W / V%, more preferably 0.0001 to 5 W / V%, and even more preferably in the ophthalmic composition. Is 0.001 to 3 W / V%.

  Examples of preservatives include benzalkonium chloride, benzethonium chloride, sorbic acid or salts thereof, paraoxybenzoic acid esters (methylparaben, ethylparaben, propylparaben, etc.), chlorhexidine gluconate, thimerosal, phenylethyl alcohol, alkyldiaminoethyl hydrochloride Examples include glycine, polyhexanide hydrochloride, and polydronium chloride. From the viewpoint of dry eye treatment effect, sorbic acid or a salt thereof is preferable. In the ophthalmic composition, the content of the preservative is, for example, 0.00001 to 5 W / V%, preferably 0.0001 to 3 W / V%, and more preferably 0.001 to 2 W / V%. In addition, since the preservative may worsen dry eye symptoms, it can be used without any formulation. When the preservative is not added, the preservative power may be one or more, preferably two or more, in combination of sodium edetate, boric acid and trometamol. Moreover, when it is set as a unit dose container and a container with a filter, it can be set as preservative-free.

  Examples of the isotonic agent include sodium chloride and potassium chloride. The content of the isotonizing agent with respect to the total amount of the ophthalmic 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, dibutylhydroxytoluene and the like. The content of the stabilizer in the ophthalmic 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 is preferably 0.0001 to 5 W / V%, more preferably 0.001 to 2 W / V%, and more preferably 0.005 to 1 W / V%, as the total amount of the compound in the ophthalmic composition. Is more preferable, and 0.007 to 0.8 W / V% is particularly preferable.

Examples of drugs (pharmaceutical active ingredients) include decongestants (for example, naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate), anti-inflammatory / astringent agents (For example, neostigmine methyl sulfate, ε-aminocaproic acid, allantoin, berberine chloride, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, sodium azulene sulfonate, etc.) , Antihistamines (eg, iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipentyl hydrochloride, chlorpheniramine maleate), water-soluble vitamins Activated vitamin B _2, vitamin B _6, vitamin B _12, etc.), amino acids (e.g., L- potassium aspartate, L- magnesium aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), sulfa drugs, fungicides (e.g., Sulfur, isopropylmethylphenol, hinokitiol, etc.), antiallergic agents (cromoglycic acid, ketotifen fumarate, tranilast, etc.), local anesthetics (eg lidocaine, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, etc.), mydriatics (cyclohexane hydrochloride) Pentolate, tropicamide, etc.) and a cataract treatment agent (pyrenoxine, glutathione, etc.) can be appropriately blended.

  The content of these components is appropriately selected according to the type of preparation, the type of drug, and the like, and the content of various components is known in the art. For example, 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 in the ophthalmic composition is as follows.

If it is a decongestant, 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%.
If it is a flame retardant / astringent, it is 0.0001-10 W / V%, for example, Preferably it is 0.0001-5 W / V%.
If it is an antihistamine, it is 0.0001-10W / V%, for example, Preferably it is 0.001-5W / V%.
If it is a water-soluble vitamin, it is 0.0001-1 W / V%, Preferably it is 0.0001-0.5 W / V%.
If it is an amino acid, it is 0.0001-10W / V%, Preferably it is 0.001-3W / V%.
If it is a sulfa agent and a disinfectant, it is 0.00001-10W / V%, for example, Preferably it is 0.0001-10W / V%.
If it is an antiallergic agent, it is 0.0001-10 W / V%, for example, Preferably it is 0.001-5 W / V%.
In the case of a local anesthetic, mydriatic, or cataract therapeutic agent, for example, it is 0.001 to 1 W / V%, preferably 0.005 to 1 W / V%.

  The ophthalmic composition of the present invention may be used as a solution as it is, or may be prepared as a suspension, a gel or the like. Specifically, eye drops (for example, general eye drops, contact lens eye drops, etc.), eye wash (general eye wash, eye wash used after removing contact lens), contact, etc. A lens mounting liquid, a contact lens removing liquid, and the like can be given. Among them, since the contact lens user is prone to dry eye, the ophthalmic composition of the present invention is an eye drop for contact lens, an eye wash used after removing the contact lens, a contact lens mounting liquid, a contact lens removing liquid, etc. It is suitable as. In particular, since the amount of the preservative is limited, it is particularly preferable for soft contact lenses.

  The viscosity of the ophthalmic composition of the present invention is preferably 2.5 to 120 mPa · s, more preferably 6 to 60 mPa · s. The viscosity is measured at 20 ° C. using an E-type viscometer (for example, VISCONIC ELD-R, Tokyo Keiki Co., Ltd.).

  The preparation method of the ophthalmic composition of the present invention is not particularly limited. For example, (A) Vitamin A is solubilized in sterilized purified water (remainder) with (B) a nonionic surfactant. Then, it can be obtained by adjusting the pH by adding each compounding component (mixed in the order of drug, other components, and cooling agent). Thereafter, it can be aseptically filled into a suitable container such as a container made of polyethylene terephthalate.

  Vitamin A stability is further improved by using oxygen-adsorbing pillow packaging instead of pillow packaging such as polyethylene and polyethylene terephthalate. The oxygen adsorption pillow package is a pillow using an oxygen absorbent kneaded film capable of actively removing oxygen remaining in the pillow and oxygen entering from the outside.

  The ophthalmic composition of the present invention is suitable as an agent for treating dry eye, and the effect thereof can be further exhibited by instilling 30 to 60 μL at a time and 3 to 6 times a day.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. Unless otherwise specified, “%” of the composition is “W / V% mass%”, and the ratio indicates mass ratio.

[Examples 1 to 27, Comparative Examples 1 to 9]
(A) Retinol palmitate is solubilized in purified water with (B) polyoxyethylene (200) polyoxypropylene (70) glycol, and then other ingredients are added, and the composition for ophthalmology shown in the following table is used. A composition (eye drops) was prepared. About the obtained ophthalmic composition, the viscosity of 20 degreeC was measured in VISCONIC ELD-R (made by Tokyo Keiki Co., Ltd.), and the following evaluation was performed. The results are also shown in the table.

Test Example-1
(Dry eye evaluation test using rabbit corneal epithelial disorder model)
[Therapeutic effect of corneal / conjunctival damage]
Corneal / conjunctival damage healing effect test using heptanol-treated rabbit cornea / conjunctival epithelial injury model Treated rabbit with heptanol treatment (heptanol / ethanol = 8: 2 mixed solution with 200 μL per eye) to damage rabbit cornea / conjunctival epithelium. Model was made. Thereafter, the sample was instilled continuously for 11 days (6 times (100 μL / time) / day). During the instillation period, fluorescein staining is periodically performed (2% fluorescein single eye drop of 50 μL), and the corneal / conjunctival damage healing effect is improved to 15 points according to the Lemp criteria (the score immediately after heptanol treatment is 15 points) The score decreases as you go. The evaluation results on the fifth day are shown.
Dry eye is defined as “a chronic disease of tears and keratoconjunctival epithelium due to various factors, accompanied by ocular discomfort and abnormal visual function”. Is used as a model for evaluating dry eye. A result is shown by the following evaluation criteria.
<Evaluation criteria>
◎: 6 points or more and less than 8 points ○: 8 points or more and less than 10 points Δ: 10 points or more and less than 12 points ×: 12 points or more

Test example-2
(Blurring test after instillation)
Five panelists observed the Landolt ring single index 5m (Solder Co., Ltd., HP-1226A International Standard Circular Acuity Table 5M) from a place 5m away 1 minute after instillation of 2 drops of the sample. The degree of blur was evaluated. The results are shown in the following evaluation criteria based on the average value of 5 persons.
<Score>
5: Unblurred 4: Slightly blurred 3: Slightly blurred 2: Pretty blurred 1: Extremely blurred
<Evaluation criteria>
◎: Average score is 4 or more ○: Average score is 3 or more and less than 4 △: Average score is 2 or more and less than 3 ×: Average score is less than 2

  When the component (B) is below the lower limit, the oil component cannot be solubilized and is separated. In this case, since the concentration of the oil-soluble component is not constant, it is expected that the effect varies and the blurring after instillation becomes severe, so the evaluation cannot be performed.

Furthermore, the following evaluation was performed.
Test Example-3
<Retinol palmitate residual rate (%)>
A 15 mL polyethylene terephthalate container was filled with 15 mL of the ophthalmic composition. This was subjected to pillow packaging (5 × 10 cm, pillow packaging product) and oxygen absorption pillow packaging (oxygen absorption pillow packaging product). The oxygen absorbing pillow was prepared by cutting an oxygen absorbing film: Histar O ₂ (Star Plastic Industry Co., Ltd.) and using a heat sealer to have a size of 5 × 10 cm. This was stored at 40 ° C. and 75% RH for 6 months. The content of retinol palmitate in the ophthalmic composition was measured immediately after production and after storage for 6 months at 40 ° C. and 75% RH. The measurement was performed using a high performance liquid chromatograph method. From the obtained retinol palmitate content, the residual ratio (%) of retinol 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 immediately after production × 100

The raw materials used in preparing the examples and comparative examples are shown below.
Polyoxyethylene (200) polyoxypropylene (70) glycol:
Unilube 70DP-950B, Supplementary Rules, NOF Corporation or Lutrol F127, Supplementary Rules, BASF Corporation
・ Hydroxypropyl methylcellulose (hypromellose):
Metroise 60SH-4000, JP, Shin-Etsu Chemical Co., Ltd., weight average molecular weight 300,000 (g / mol), Table 1-4 used Metroze 60SH-50, JP, Shin-Etsu Chemical Co., Ltd., weight average molecular weight 7 10,000 (g / mol)
・ Polyvinylpyrrolidone:
Kollidon 90F, JP, BASF Corp .: weight average molecular weight 1 million (g / mol), Table 1-4 used Kollidon 30, JP, BASF Corp .: weight average molecular weight 50,000 (g / mol)
-Polyoxyethylene monooleate (20) sorbitan (polysorbate 80):
Rheodor TW-0120V, JP, Kao Corporation
Polyoxyethylene hydrogenated castor oil 60:
HCO-60 (for medical use), supplementary regulations, Nikko Chemicals Co., Ltd.
・ Polyvinyl alcohol:
Gohsenol EG-05, Nippon Synthetic Chemistry / Methylcellulose:
Metrows SM-4000, JP, Shin-Etsu Chemical Co., Ltd.

Claims (8)

(A) Vitamin A,
(B) Nonionic surfactant 0.05-1.5 W / V%,
An ophthalmic composition containing (C) hydroxypropylmethylcellulose 0.1 to 0.8 W / V% and (D) polyvinylpyrrolidone.   The ophthalmic composition according to claim 1, wherein the mass ratio represented by (C) :( D) is 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 to 0.5 g / 100 mL.   The ophthalmic composition according to any one of claims 1 to 3, wherein the component (A) is at least one member selected from retinol palmitate, retinol acetate, and retinoic acid.   The ophthalmic composition according to any one of claims 1 to 4, wherein the component (B) is at least one selected from polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid ester. object.   (C) The weight average molecular weight of hydroxypropyl methylcellulose is 5 to 600,000 (g / mol), The ophthalmic composition of any one of Claims 1-5.   The weight average molecular weight of (D) polyvinylpyrrolidone is 3 to 1.5 million (g / mol), The ophthalmic composition according to any one of claims 1 to 6.   It is a dry eye therapeutic agent, The ophthalmic composition of any one of Claims 1-7.