TWI429424B - Ophthalmic compositions and the stabilization of vitamin A - Google Patents

Description

Ophthalmic composition and vitamin A stabilization method

The present invention relates to an ophthalmic composition containing a high concentration of vitamin A.

Vitamin A is attracting attention as an effective ingredient for preventing and treating cornea, conjunctiva, and keratosis of the skin and mucous membranes. Further, the vitamin A of the fat-soluble vitamin is extremely sensitive to air, light, heat, acid, metal ions, etc., and is extremely unstable in an aqueous solution, and therefore it is extremely difficult to stably mix with an ophthalmic composition such as an eye drop.

As a technique for stabilizing the unstable vitamin A, a non-ionic surfactant such as a hardened castor oil such as polyethylene is disclosed in the prior art (for example, Japanese Patent Publication No. Hei 5-331056: Patent Document 1 A method for stabilizing a vitamin E type of a hydrophobic antioxidant (for example, JP-A-6-247853: Patent Document 2), and a stabilization technique by a container or a packaging surface (e.g., JP-A-6-40907) Japanese Patent Laid-Open Publication No. JP-A No. 2002-332225 (Patent Document 5). However, in the advanced technology, when the concentration is high (50,000 units or more), the stability required for the pharmaceutical level cannot be sufficiently satisfied. Therefore, it is expected that an ophthalmic composition containing a high concentration of vitamin A can further enhance the technology of vitamin A stabilization.

[Patent Document 1] Japanese Patent Publication No. 5-331056

[Protocol 2] Unexamined-Japanese-Patent No. 6-247853

[Property Document 3] Unexamined Patent Publication No. 6-40907

[Patent Document 4] JP-A-2003-113078

[Patent Document 5] JP-A-2002-332225

In view of the above problems, the present invention provides an ophthalmic composition containing a high concentration of vitamin A for stabilizing vitamin A, and a method for stabilizing vitamin A.

In order to achieve the object, the inventors of the present invention found that 0.40/V% or more of polyoxyethylene polyoxypropylene diol is blended in an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A. After trometamol, the stability of vitamin A can be significantly improved, and the present invention is completed.

Accordingly, the present invention provides an ophthalmic composition described below and a method for stabilizing vitamin A.

[1] An ophthalmic composition containing (A) 50,000 units/100 mL or more of vitamin A and (B) 0.4 W/V% or more of polyoxyethylene polyoxypropylene diol, and (C) trometamol.

[2] The ophthalmic composition contained in [1] of the component (A) having a content of 100,000 units/100 mL or more.

[3] The ophthalmic composition contained in [1] of the component (A) having a content of 200,000 units/100 mL or more.

[4] The ophthalmic composition contained in [1] of the component (A) having a content of 300,000 units/100 mL or more.

[5] Further comprising the ophthalmic composition contained in (D) an antioxidant [1].

[6] (D) The ophthalmic composition contained in vitamin E and/or dibutylhydroxytoluene [5].

[7] (A) The ophthalmic composition contained in the vitamin A palmitate, vitamin A acetate or vitamin A acid [1].

[8] (B): The ophthalmic composition contained in [1] [1] represented by (C) and (C) has a mass ratio of 1:30 to 30:1.

[9] In the ophthalmic composition containing 50,000 units/100 mL or more of vitamin A, 0.4 W/V% or more of polyoxyethylene polyoxypropylene diol and (C) trometamol are used as vitamin A. Stability method.

According to the present invention, even if a high concentration of vitamin A is blended, an ophthalmic composition containing vitamin A which stabilizes vitamin A and a method for stabilizing vitamin A can be provided.

[Best form of implementation of the invention]

Hereinafter, the present invention will be described in detail. The ophthalmic composition of the present invention contains (A) 50,000 units/100 mL or more of vitamin A and (B) 0.4 W/V% or more of polyoxyethylene polyoxypropylene diol and (C) trometamol. Further, as another subject of the present invention, an ophthalmic composition having an effect of improving dry eye is provided, and the present invention has an effect of improving dry eye.

(A) Vitamin A

Examples of the vitamin A include, in addition to the vitamin A itself, a vitamin A-containing mixture such as a vitamin A oil or a vitamin A derivative such as a vitamin A fatty acid ester. Specifically, for example, vitamin A palmitate, vitamin A acetate, vitamin A, vitamin A acid, retinoid and the like. Among them, vitamin A palmitate, vitamin A acetate, and vitamin A acid are preferred. Vitamin A palmitate is usually marketed at 1 million to 1.8 million international units (hereinafter referred to as the unit or IU), for example: Roche, vitamins, "Potassium palmitate" manufactured by Nippon Stock Co., Ltd. (1.7 million IU/g) ) et al.

The component (A) may be used singly or in combination of two or more kinds, and the content thereof is 50,000 units/100 mL or more for the total amount of the ophthalmic composition. Vitamin A has the effect of treating corneal and conjunctival damage, improving dry eye syndrome, improving eye fatigue and blurred vision. After making 50,000 units/100mL or more, these effects can be more apparent. From the viewpoint of such effects, the amount of the component (A) is preferably 100,000 units/100 mL or more, preferably 200,000 units/100 mL or more, and more preferably 300,000 units/100 mL or more. From the perspective of stability, the upper limit is 500,000 units / 100mL or less. The above amount is represented by W (mass) / V (volume)% (g / 100mL), and it is preferably in the range of 0.03 to 0.3 W/V% depending on the unit of the vitamin A to be blended.

(B) Polyoxyethylene polyoxypropylene diol

In the present invention, after the (B) polyoxyethylene polyoxypropylene diol is used, the ophthalmic composition containing 500,000 units/100 mL or more of vitamin A can maintain its stability and is less irritating to the eyes. Improve the treatment of corneal damage and the effect of treating dry eye. Such effects are not sufficient for surfactants such as sorbitan fatty acid esters which are commonly used for eye drops, and polyoxyethylene hardened castor oil. The polyoxyethylene polyoxypropylene diol is not particularly limited, and those contained in the pharmaceutical additive specifications (pharmaceutical additive specifications) 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 from 5 to 100, more preferably from 20 to 70, which may be a block copolymer. It can also be a random polymer.

Specifically, for example, polyoxyethylene (200) polyoxypropylene (70) diol: Lutrol F127 (manufactured by BASF), Unilub 70 DP-950B (manufactured by Nippon Oil Co., Ltd.), polyoxyethylene (120) polyoxidation Propylene (40) diol (Prulonic F-87), polyethylene oxide (160) poly propylene oxide (30) diol (Prulonic F-68, alias Polocthamer 188): Pronon #188P (Nippon Oil (share)), etc. Polyethylene oxide (42) polyoxypropylene (67) diol (Prulonic P123, alias Polychethamer 403), polyethylene oxide (54) polyoxypropylene (39) diol (Prulonic P85): Pronon #235P (Nippon Oil (shares) )), etc., examples of polyoxyethylene (20) polyoxypropylene (20) diol (Prulonic L-44), tetronic, and the like. Among them, polyoxyethylene (200) polyoxypropylene (70) diol, polyethylene oxide (160) polyoxypropylene (30) diol, polyethylene oxide (54) polyoxypropylene (39) diol is preferred. By.

(B) The component may be used singly or in combination of two or more kinds, and the content thereof is preferably 0.4 W/V% or more for the total amount of the ophthalmic composition, preferably 0.4 to 5 W/V. %, preferably 0.5~3W/V%, especially ideally 0.6~2W/V%, ideally 1~2W/V%. When it is less than 0.4 W/V%, the solubilization of vitamin A becomes difficult, and it is preferable that it is 5 W/V% or less from the viewpoint of the storage stability of vitamin A.

From the viewpoint of preservation and stability of vitamin A, (A) and (B) represented by [(A) vitamin A unit / 100 mL] / [(B) polyoxyethylene polyoxypropylene diol g / 100 mL] The ratio of ingredients is 10,000 to 150,000, preferably 15,000 to 100,000, and more preferably 25,000 to 50,000.

(C)trometamol

In the ophthalmic composition of the present invention, it is preferred to add trometamol by enhancing the preservation stability of vitamin A. The effect of enhancing the preservation stability of vitamin A in trometamol is a novel discovery of the present invention. This sequence is not clear and can be inferred from the following. The polyoxyethylene polyoxypropylene diol is a nonionic surfactant having a polyoxyethylene (EO) chain and a polyoxypropylene (PO) chain. The EO chain is the outer side and the PO chain is the inner side, and the vitamin A is encapsulated to form a colloidal particle. After coexistence with trometamol, the -NH ₂ group present in trometamol is directly bonded to the ether bond of the EO chain, so that the structure of the colloidal particles is extremely strong. Trometamol further reduces the degree of freedom by bonding the EO chain to the outer side of the colloidal particles, thereby reducing the molecular mobility of the PO chain inside the colloidal particles. From the above, it can be confirmed that trometamol can impart stability to the colloidal particles formed by vitamin A and polyoxyethylene polyoxypropylene diol, and as a result, the preservation stability of vitamin A is also imparted.

(C) The content of trometamol is preferably 0.01 to 5 W/V% for the total amount of the ophthalmic composition, preferably 0.05 to 5 W/V%, and more preferably 0.1 to 3 W/V%, which is particularly desirable. The value is 0.5~2W/V%. When it is less than 0.01 W/V%, it is feared that the preservation effect of vitamin A is insufficient, and if it exceeds 5 W/V%, it may cause irritation to the eyes. Moreover, from the viewpoint of preservation and stability of vitamin A, (B): (C) represents a mass ratio of (B) component to (C) component of 1:30 to 30; one is preferred, preferably 1:20~20:1, the better is 1:10~10:1, and the best is 1:10~3:1.

(D) Antioxidants

In the ophthalmic composition of the present invention, it is preferred to add an antioxidant to enhance the preservation stability of vitamin A. As antioxidants, such as: d-α-tocopherol, d-β-tocopherol, d-γ-tocopherol, d-δ-tocopherol, dl-α-tocopherol, d-α-tocopherol acetate, Vitamin E, dibutyl acetate, dl-β-tocopherol acetate, dl-β-tocopherol acetate, dl-γ-tocopherol acetate, dl-δ-tocopherol acetate, nicotinic acid dl-α-tocopherol Examples of water-soluble antioxidants such as hydroxytoluene and butyl hydroxyanisole, vitamin C, hydrogen roller, cysteine, glutathione, etc., among which are fat-soluble antioxidants such as vitamin E. More preferably, it is preferably d-α-tocopherol acetate or dibutylhydroxytoluene, and the most preferred one is acetic acid d-α-tocopherol. Also, vitamin E and dibutylhydroxytoluene may be used in combination.

The antioxidant may be used singly or in combination of two or more kinds, and the content thereof is preferably 0.005 to 5 W/V% for the total amount of the ophthalmic composition. In this range, the vitamin A can be further improved. The storage stability is preferably 0.005~1W/V%, and more preferably 0.005~0.2W/V%.

In the ophthalmic composition of the present invention, various components added to the ophthalmic composition can be blended in addition to the above components without departing from the effects of the present invention. As such components, such as: polyol, surfactants other than (B) components, buffers, thickeners, sugars, pH adjusters, preservatives, isotonic agents, stabilizers, cooling agents, drugs , water and other examples. These may be used singly or in combination of two or more kinds as appropriate, and may be blended in an appropriate amount.

Examples of the polyvalent alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. The content of the polyvalent alcohol is preferably 0.01 to 5 W/V% for the total amount of the ophthalmic composition, and more preferably 0.05 to 3 W/V%.

Surfactants other than the component (B) may be used in combination, such as polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester (polysorbate 80), and the like. After being used together, it will further enhance the stability of stability. These contents are preferably 0.0001 to 5 W/V% for the total amount of the ophthalmic composition, and more preferably 0.005 to 3 W/V%. In addition, the effect of treating cornea and conjunctival damage, and the treatment of dry eye syndrome, the less the amount of these surfactants, the better, 0.5W / V% or less.

As a buffer, 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 phosphate), tartaric acid or a salt thereof (sodium tartrate, etc.), Gluconic acid or a salt thereof (sodium gluconate or the like), acetic acid or a salt thereof (sodium acetate or the like), and in combination with boric acid and borax, a highly highly anticorrosive effect is particularly preferable. The content of the buffering agent is preferably 0.001 to 10 W/V% for the total amount of the ophthalmic composition, and more preferably 0.01 to 5 W/V%. Further, by blending boric acid or citric acid, it is intended to make vitamin A more stable.

As a thickener, such as: polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, etc. example. By coordinating with these, the retention is improved, and the effect of treating corneal and conjunctival damage is further enhanced. The content of the viscosifying agent for the total amount of the ophthalmic composition is preferably 0.001 to 10 W/V%, preferably 0.001 to 5 W/V%, and more preferably 0.01 to 3 W/V%.

Examples of the sugar include glucose, cyclodextrin, xylitol, sorbitol, and mannitol. Further, these may be any D body, L body or DL body. The content of the sugar for the total amount of the ophthalmic composition is, for example, 0.001 to 10 W/V%, preferably 0.005 to 5 W/V%, and more preferably 0.01 to 3 W/V%.

As the pH adjuster, it is preferred to use an inorganic acid or an inorganic base. Examples of inorganic acids are, for example, (alkenyl) hydrochloric acid. Examples of the inorganic alkali agent include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogencarbonate. Among them, hydrochloric acid and sodium hydroxide are preferred. The pH of the ophthalmic composition of the present invention (20 ° C) is preferably 4.0 to 9.0, preferably 5.0 to 8.0, more preferably 6.0 to 8.0. Further, in the present invention, the pH is measured by a pH osmometer (HOSM-1, East Asia DKK (share)) at 20 °C. The content of the pH adjusting agent for the total amount of the ophthalmic composition is preferably 0.00001 to 10 W/V%, preferably 0.0001 to 5 W/V%, and more preferably 0.001 to 3 W/V%.

As a preservative, such as: alkyl dimethyl benzyl ammonium chloride, benzyl ethylamine, sorbic acid or its salt, p-hydroxybenzoic acid ester (methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, pair Examples of propyl hydroxybenzoate, chlorhexidine glucenate, metilosal, phenylethyl alcohol, alkyldiamine ethylglycolic acid, polyhexanide hydrochloride, polydronium chloride, and the like. The content of the preservative for the total amount of the ophthalmic composition is 0.00001 to 5 W/V%, preferably 0.0001 to 3 W/V%, and more preferably 0.001 to 2 W/V%.

In addition, in the treatment of the cornea, conjunctival damage and the improvement of dry eye, in the present invention, a cationic surfactant selected from the group consisting of alkyl dimethyl benzyl ammonium chloride and benzyl ammonium chloride (partially a cationic preservative), a content of a hydrophobic preservative selected from the group consisting of a paraben (methylparaben, ethylparaben, propylparaben, etc.) and chlorobutanol. W/V% or less is preferable, and the better one is 0.003 W/V% or less. It is not included, and it is more desirable to make it without adding. The effect of these disturbances on the treatment of corneal and conjunctival damage is not clear, but can be inferred as follows. (B) Polyoxyethylene polyoxypropylene glycol is a rubber particle coated with vitamin A, which has an EO chain as an outer side and a PO chain as an inner side. The colloidal particles are adsorbed on the surface of the cornea, and vitamin A is absorbed inside the cornea. The cationic surfactant can change the state of the surface of the colloid by high interfacial activity through the interfacial activity, and the hydrophobic preservative hinders the adsorption of the vitamin A cornea. The result is considered to hinder the treatment of corneal and conjunctival injury. The effect and improvement of dry eye syndrome. Further, since the hydrophilicity of sorbic acid or a salt thereof does not affect the state of the surface of the colloidal particles, the effect of promoting the absorption of vitamin A is not inhibited. Further, the above-mentioned components are a part of the preservative, and the antiseptic property in the case where no preservative is added may be used in combination of one or more kinds or a combination of two or more kinds selected from the group consisting of disodium ethylenediaminetetraacetate, boric acid and trometamol. Moreover, when the unit doors container is provided and the container of the filter is attached, no preservative may be added.

As the isotonic agent, such as sodium chloride, potassium chloride and the like. The isotonic agent is preferably used in an amount of 0.001 to 5 W/V% for the total ophthalmic composition, preferably 0.01 to 3 W/V%, more preferably 0.1 to 2 W/V%.

As the stabilizer, for example, disodium ethylenediaminetetraacetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like. In addition, in the present invention, after the stabilizer is added, the stability of vitamin A is further enhanced. The content of the cryptic agent for the total amount of the ophthalmic composition is preferably 0.001 to 5 W/V%, preferably 0.01 to 3 W/V%, and more preferably 0.1 to 2 W/V%.

Examples of the cooling agent include menthol, camphor, borneol, geraniol, linalool, and eucalyptus. The amount of the cooling agent for the total amount of the ophthalmic composition is preferably 0.0001 to 5 W/V% of the total amount of the compound, preferably 0.001 to 2 W/V%, more preferably 0.005 to 1 W/V%, and particularly The best is 0.007~0.8W/V%.

As a drug (pharmaceutical active ingredient), it can be appropriately blended with, for example, a hyperemia removing agent (eg, naphtholine hydrochloride, tetrahydronaphthyl hydrochloride, dehydrogenated adrenaline, adrenaline, ephedrine hydrochloride, dl-hydrochloric acid). Methyl ephedrine, tetrahydronaphthyl nitrate, naphthyl nitrate, etc., anti-inflammatory, astringent (eg: neostigmine methyl sulfate, ε-aminocaproic acid, allantoin, chlorinated bismuth Alkali, zinc sulfate, zinc lactate, chlorinated lysozyme, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhizic acid, methyl salicylate, tranexamic acid, sodium sulphate, etc.), antihistamines (eg, Iproheptin hydrochloride, 2-Diphenylmethoxy-N,N-dimethylethylamine, 2-diphenylmethyl-N,N-dimethylethylamine, iso-dibenzyl hydroxychloride, chloramphelam maleate, etc.) Water-soluble vitamins (activated vitamin B ₂ , vitamin B ₆ , vitamin B _12, etc.), amino acids (eg, L-aspartate, L-aspartate, aminoethyl sulfonate, cartilage) Sodium sulphate, etc.), vulcanizing agents, bactericides (eg sulfur, isopropyl cresol, hinokitiol, etc.), anti-allergic agents (cromoglicate, ketotifen fumarate, tranilas Te et al), local anesthetics (eg lidocaine, lidocaine hydrochloride, procaine hydrochloride, leucocaine hydrochloride, etc.), sputum (cyclopentolate hydrochloride, tropicamide, etc.), cataract treatment (pirenoxine, valley) Cysteine, 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 well known in the art. For example, the total amount of the ophthalmic composition can be appropriately selected from the range of 0.0001 to 30 W/V%, preferably 0.001 to 10 W/V%. More specifically, the content of each component for the total amount of the ophthalmic composition is as follows.

The blood-removing remover, such as: 0.0001~0.5W/V%, preferably 0.0005~0.3W/V%, and more preferably 0.001~0.1W/V%.

Anti-inflammatory ‧ astringent, such as: 0.0001 ~ 10W / V% should be preferred, preferably 0.0001 ~ 5W / V%.

Antihistamines, such as: 0.0001 ~ 10W / V%, preferably 0.001 ~ 5W / V%.

Water-soluble vitamins, such as: 0.0001 ~ 1W / V% should be preferred, preferably 0.0001 ~ 0.5W / V%.

Amino acids, such as: 0.0001 ~ 10W / V%, preferably 0.001 ~ 3W / V%.

Vulcanizing agent, fungicide, such as: 0.00001 ~ 10W / V% should be preferred, preferably 0.0001 ~ 10W / V%.

Anti-allergic agents, such as: 0.0001 ~ 10W / V% should be preferred, preferably 0.001 ~ 5W / V%.

Local anesthetics, mydriatic agents, cataract therapeutic agents, such as: 0.001 ~ 1W / V% should be preferred, preferably 0.005 ~ 1W / V%.

The ophthalmic composition of the present invention can be directly used as a liquid preparation, or can be prepared into a suspension, a gel, and the like. Specific examples of the form of use include eye-dropping agents (such as general eye drops, eye drops for contact lenses, etc.), eye washes (generally used eye wash, eye wash used after taking out the hidden glasses, etc.), and loading The contact liquid of the contact lens, the removal liquid of the contact lens, and the like.

The ophthalmic composition of the present invention is in the form of a liquid, and when the eye drops are used, the viscosity is preferably from 1 to 100 mPa ‧ s, preferably from 1 to 50 mPa ‧ s, and more preferably from 1 to 30 mP s s. Further, the viscosity measurement was carried out at 20 ° C using an E-type viscometer (VISCONIC FLD-R, Tokyo Keiki Co., Ltd.).

The ophthalmic composition of the present invention is not particularly limited in terms of its preparation method. Generally, vitamin A is solubilized from polyoxyethylene polyoxypropylene diol in sterilized purified water, followed by adding trometamol and each component. It can be obtained after adjusting the pH. Thereafter, aseptic filling is carried out in a suitable container such as a container made of polyethylene terephthalate or the like.

According to the present invention, even if 50,000 units/100 mL or more of vitamin A is blended, vitamin A can be stabilized by blending polyoxyethylene polyoxypropylene diol or trometamol.

The method for stabilizing vitamin A of the present invention comprises: blending 0.4 W/V% or more of polyoxyethylene polyoxypropylene diol with (C) trometamol in an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A; The method for stabilizing vitamin A has the same composition and content as the above ophthalmic composition. Further, the present invention provides a stabilizer for the ophthalmic composition comprising 50,000 units/100 mL or more of vitamin A, which is a stabilizer for vitamin A obtained from polyoxyethylene polyoxypropylene diol and trometamol. In this case, the polyoxyethylene polyoxypropylene diol is blended in an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A in an amount of 0.4 W/V% or more.

Further, in the present invention, after the vitamin A is blended at a high concentration, the effect is further applied to an ophthalmic composition for treating corneal damage and a therapeutic agent for dry eye. In addition, dry eye syndrome is a state in which the keratoconjunctiva on the surface of the eyeball is hindered by the abnormality of the quality or amount of the tear fluid. The tear system is composed of three layers of oil layer, water layer and mucin layer. The quality and quantity of the three-layer structure are damaged, resulting in unstable tears and obstacles in the cornea, causing dry eye syndrome. In the treatment of dry eye, the focus is on restoring the three-layer structure of the oil layer, the water layer and the mucin layer of the tear, and treating the corneal disorder. Further, since the contact lens user is likely to cause dry eye, the ophthalmic composition of the present invention is suitable for eye contact for contact lenses, eye wash after taking out contact lenses, contact lens loading solution, contact lens take-out solution, and the like. When applied to a dry eye treatment, it can be further exerted by eye-dropping once 30 to 60 μL and 3 to 6 times a day.

[Examples]

The following examples and comparative examples are given to illustrate the invention, but the invention is not limited to the examples described below. In addition, the amount in the table, the other represents the pure amount of ingredients.

[Examples 1 to 28, Comparative Examples 1 to 5]

The ophthalmic composition (eyedrop) of the composition shown in Tables 1 to 7 was preliminarily dissolved at 85 ° C by using vitamin A, polyoxyethylene polyoxypropylene diol, and, if necessary, an antioxidant. The sterilized purified water heated to 85 ° C was solubilized, and after cooling, a water-soluble complex component such as trometamol was added thereto, and the pH (20 ° C) was adjusted to 7.0 to obtain an ophthalmic composition. 15 mL of the obtained ophthalmic composition was filled in a 15 mL eye-drop container (made of polyethylene terephthalate). The ophthalmic composition of the examples has sufficient antiseptic properties.

<Residual rate of vitamin A palmitate (%)>

After the production, the content of vitamin A palmitate in the ophthalmic composition was measured after storage for 6 months at 40 ° C and 75% RH (rigid test). The measurement was carried out using high speed liquid chromatography. The vitamin A palmitate residual ratio (%) was calculated from the obtained vitamin A palmitate content based on the following formula.

Residual rate of vitamin A palmitate (%) = vitamin A palmitate content after storage / vitamin A palmitate content after manufacture × 100

[Comparative Examples 6, 7]

The ophthalmic composition (eyedrop) having the composition shown in Table 8 was prepared on the basis of Example 1, and the therapeutic effects of corneal and conjunctival damage and eye irritation were evaluated by the following methods as an index for treating dry eye. Results The results of incorporation into Example 1 are shown in the table.

<Therapeutic effect of corneal and conjunctival injury>

The therapeutic effect test of corneal cornea, hemorrhage of conjunctival epithelial disorder model, and conjunctival injury using heptanol treatment.

The rabbit was subjected to heptanol treatment (dropping of heptanol/ethanol = 8:2 into 200 μL of a single eye) to prepare a rabbit corneal and conjunctival epithelial damaged model. Thereafter, the sample was continuously subjected to a blind eye for 11 days (6 times (100 μL/time)/day). During the eye-pointing period, fluorescein staining was performed regularly (2% fluorescein monocular instillation of 50 μL), and according to the Lenp criterion, 15 points (with a score of 15 points after heptanol treatment, according to the effective improvement score) assessment. The results of the evaluation on the 5th day are displayed.

<eye irritation>

Fifteen overclocking eye tests were performed on rabbits at 50 μL/time at intervals of 5 minutes.

After 15 eyes were spotted, fluorescein staining (2% fluorescein monocular drop of 50 μL) was performed, and the corneal damage range was evaluated according to the following criteria.

Score 4: Staining occurs 2/3 or more of the entire area of the cornea

Score 3: less than 2/3 of the total area of the cornea

Score 2: less than 1/3 of the staining in the entire area of the cornea

Score 1: Slightly stained

Score 0: no staining

[Examples 29 to 33]

The ophthalmic composition of Table 9 was prepared on the basis of Example 1, and the residual rate of vitamin A palmitate, the therapeutic effect of corneal and conjunctival damage, and eye irritation were evaluated by the above method. The results are incorporated into the table.

The materials used in the examples are shown.

Polyethylene oxide (200) Polyoxypropylene (70) diol: Uniroob 70 DP-950B, pharmaceutical additive specifications, Nippon Oil (share) or Lutrol F127, pharmaceutical additive specifications, BASF (shares)

Polyethylene oxide (160) polyoxypropylene (30) diol: Pronon # 188P, pharmaceutical additive specifications, Nippon Oil (shares)

Polyethylene oxide (54) Polyoxypropylene (39) diol: Pronon # 235P, pharmaceutical additive specifications, Nippon Oil (shares)

Polyoxyethylene hardened castor oil 60: CHO-60 (medical), pharmaceutical additive specifications, daylight Chemicals (shares)

Polysorbate 80: reodol TW-0120V, Japanese Pharmacy, Kao (share)

Hypromelose: metrose 65SH-4000, Japan Pharmacy, Shin-Etsu Chemical Industry (shares)

Polyvinylpyrrolidone: Ulidone 90F, Japanese Pharmacopoeia, BASF

Claims (8)

An ophthalmic composition comprising (A) 50,000 units/100 mL or more of vitamin A, and (B) 0.4 to 5 W/V% of polyoxyethylene polyoxylene glycol, and (C) ) trometamol, and the mass ratio of the component (B) to the component (C) represented by (B): (C) is 1:20 to 20:1. For example, in the ophthalmic composition of claim 1, wherein the content of the component (A) is 100,000 units/100 mL or more. For example, in the ophthalmic composition of claim 1, wherein the content of the component (A) is 200,000 units/100 mL or more. For example, in the ophthalmic composition of claim 1, wherein the content of the component (A) is 300,000 units/100 mL or more. For example, the ophthalmic composition of claim 1 further contains (D) an antioxidant. An ophthalmic composition according to claim 5, wherein the component (D) is vitamin E and/or dibutylhydroxytoluene. The ophthalmic composition according to claim 1, wherein the component (A) is vitamin A palmitate, vitamin A acetate or vitamin A acid. A method for stabilizing vitamin A, characterized by adding (B) 0.4 to 5 W/V% of polyoxyethylene polyoxypropylene diol and (C) to an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A Trometamol, and the mass ratio of the component (B) to the component (C) represented by (B): (C) is 1:20 to 20:1.