JP5800072B2 - Ophthalmic composition and method for suppressing cloudiness / precipitation - Google Patents

Description

  The present invention relates to an ophthalmic composition containing vitamin A, and more specifically, an ophthalmic composition having a stable appearance, which does not cause white turbidity / precipitation due to storage stability and freezing and thawing of vitamin A, and this composition The present invention relates to a method for suppressing cloudiness / precipitation caused by freezing and thawing of an object. Furthermore, the present invention relates to a dry eye therapeutic agent having an effect of treating corneal / conjunctival damage and containing vitamin A.

  Vitamin A has attracted attention as an effective component for the prevention and treatment of cornea, conjunctiva and keratoses of skin mucous membranes. In recent years, the effect of vitamin A on dry eye symptoms such as corneal / conjunctival dryness has been reported. However, vitamin A, which is a fat-soluble vitamin, is very sensitive to air, light, heat, acid, metal ions, and the like, and particularly unstable in an aqueous solution, so it is suitable for ophthalmic compositions such as eye drops. It was difficult to mix stably.

  As a technique for stabilizing such unstable vitamin A, conventionally, a method of stabilizing with a nonionic surfactant such as polyoxyethylene hydrogenated castor oil (Patent Documents 1 and 2: JP-A-5-331056, Japanese Patent Laid-Open No. 6-40907), a method of stabilizing with vitamin E which is a hydrophobic antioxidant (see Patent Document 3: Japanese Patent Laid-Open No. 6-247853), and stabilization from the container / packaging surface Techniques (see Patent Document 4: Japanese Patent Application Laid-Open No. 2003-113078), stabilization techniques manufactured by high-energy emulsification (Patent Document 5: refer to Japanese Patent Application Laid-Open No. 2002-332225), and the like have been proposed.

  Dry eye refers to a state in which the keratoconjunctiva on the eyeball surface is damaged due to qualitative or quantitative abnormality of tears. Tear fluid consists of three layers: an oil layer, an aqueous layer, and a mucin layer. When the qualitative and quantitative balance of this three-layer structure is destroyed, the tear fluid becomes unstable, the cornea is damaged, and dry eye Is triggered. In dry eye treatment, it is important to restore the three-layer structure of the tear oil layer, water layer, and mucin layer, and to treat corneal disorders.

  Vitamin A is known as an essential substance for proliferation and differentiation of epithelial cells, and promotes mucin production (for example, Non-Patent Document 1: Kubo, Y., J Jpn Ophthalmol Sci. 103, 580-583. 1999.), and the effect of healing corneal wounds (see, for example, Non-Patent Document 2: Ubels, JL, Curr Eye Res. 4, 1049-1057.1985.). Thus, vitamin A is expected to be a useful drug for dry eye treatment that is effective in “recovery of mucous layer of tear fluid” and “treatment of keratoconjunctival disorder”. From the above, a dry eye therapeutic agent containing vitamin A having a high dry eye therapeutic effect has been desired.

Japanese Patent Laid-Open No. 5-33156 JP-A-6-40907 Japanese Patent Laid-Open No. 6-247853 Japanese Patent Laid-Open No. 2003-113078 JP 2002-332225 A JP 2001-322936 A

Kubo, Y. et al. , J Jpn Ophthalmol Sci. 103, 580-583.1999. Ubels, J .; L. Curr Eye Res. 4,1049-1057.1985.

The present inventors have conducted studies to obtain a higher level of stabilization of vitamin A, in particular, a stable ophthalmic preparation even in a vitamin A high concentration range where it is difficult to ensure stability. Oxyethylene polyoxypropylene glycol was selected. However, preparations formulated with polyoxyethylene polyoxypropylene glycol, when stored at low temperatures, especially when frozen, cause white turbidity and white precipitation when thawed, and the appearance deteriorates further due to repeated freezing and thawing. It became clear that there was. Usually, eye drops can be stored at room temperature or in a refrigerator. In more extreme cases, the eye drops may be frozen, such as being left in a refrigerator at a low temperature or being left in a cold area in winter. Accordingly, there has been a demand for improved storage stability in cold storage and freezing and thawing.
The present invention has been made in view of the above circumstances, and is an ophthalmic composition containing vitamin A and polyoxyethylene polyoxypropylene glycol, which is excellent in storage stability of vitamin A and at the time of freezing and thawing. The purpose of the present invention is to provide an ophthalmic composition that does not cause white turbidity / precipitation and has a stable appearance, and a method for suppressing white turbidity / precipitation by freezing and thawing the composition.
Another object of the present invention is to provide a dry eye therapeutic agent in which the effect of vitamin A on the treatment of corneal / conjunctival damage is improved.

  As a result of intensive studies to achieve the above object, the present inventors have added (C) to (G) components to an ophthalmic composition containing (A) vitamin A and (B) polyoxyethylene polyoxypropylene glycol. : (C) trometamol, (D) polyhydric alcohol, (E) saccharide, (F) phosphoric acid and its salt, and (G) one or more components selected from monovalent neutral salts, preferably It has been found that by combining two or more types in combination, the storage stability of vitamin A is excellent, and clouding and precipitation in freezing and thawing can be suppressed, and the present invention has been made.

  Although the detailed mechanism for suppressing white turbidity and precipitation in freezing and thawing is not clear, polyoxyethylene polyoxypropylene glycol has a narrow L1 micelle region of the aqueous solution with respect to its concentration, and it becomes a viscous gel state with slight concentration Prone. On the other hand, nonionic surfactants such as polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester have the L1 micelle region spreading to a high concentration side and are not easily affected by the concentration effect. That is, white turbidity / precipitation during freezing and thawing is a problem specific to polyoxyethylene polyoxypropylene glycol.

When the hydration water of the ethylene oxide chain of polyoxyethylene polyoxypropylene glycol is frozen, the free volume of the ethylene oxide chain decreases, and the packed form of the polyoxyethylene polyoxypropylene glycol molecule is an associated state with a smaller curvature than the spherical micelle. It changes to a form that is easy to take. It can also be considered that micelle cores aggregate together due to the orientation and uneven distribution of already frozen vitamin A, and precipitate as white turbidity.
In contrast, by adding the above-described cloudiness / precipitation inhibiting component, freezing of bulk water can be prevented, or by penetrating into the ethylene oxide chain of micelles, the orientation of the ethylene oxide chain can be disturbed to prevent freezing of the ethylene oxide chain. Thus, it can be considered that white turbidity and precipitation during freezing and thawing can be prevented by stabilizing the association state of micelles.

Accordingly, the present invention provides the following ophthalmic composition and a method for suppressing cloudiness and precipitation by freezing and thawing the composition.
[1]. (A) Vitamin A selected from retinol palmitate, retinol acetate and retinoic acid ;
(B) polyoxyethylene polyoxypropylene glycol;
(C) and trometamol,
The following (D) to (G):
(D) glycerin or propylene glycol (E) xylitol, sorbitol, mannitol or trehalose (F) sodium dihydrogen phosphate (G) and one kind selected from sodium chloride ,
(C) The ophthalmic composition characterized in that the compounding amount of trometamol is 0.001 to 5 W / V% .
[ 2 ]. (C) ~ (G) the total amount of component is an 0.001~5W / V% [1] Symbol ophthalmic compositions of the mounting.
[ 3 ]. (B) The ophthalmic composition of [1] or [2] whose compounding quantity of a component is 0.4-5 W / V%.
[ 4 ]. (A) The ophthalmic composition in any one of [1]-[ 3 ] whose compounding quantity of a component is 50,000-500,000 units / 100mL.
[ 5 ]. The ophthalmic composition according to any one of [1] to [ 4 ], wherein the amount of the cationic surfactant and the hydrophobic preservative is 0.004 W / V% or less.
[ 6 ]. The ophthalmic composition according to any one of [1] to [ 4 ], which contains no preservative.
[ 7 ]. The ophthalmic composition according to any one of [1] to [ 6 ], which is for contact lenses.
[ 8 ]. The ophthalmic composition according to any one of [ 4 ] to [ 7 ], which is a dry eye therapeutic agent.
[ 9 ]. (A) Vitamin A selected from retinol palmitate, retinol acetate and retinoic acid , (B) ophthalmic composition containing polyoxyethylene polyoxypropylene glycol, (C) trometamol and the following (D) to (G):
(D) glycerin or propylene glycol (E) xylitol, sorbitol, blended one and selected from mannitol or trehalose (F) Sodium dihydrogen phosphate (G) Sodium chloride <br/>, blending of (C) trometamol amount, white turbidity and precipitation suppressing method according to freeze-thaw, wherein 0.001~5W / V% der Rukoto.

  According to the present invention, there is provided an ophthalmic composition having a stable appearance, in which vitamin A is stably blended and does not cause white turbidity / precipitation even when frozen and thawed, and a method for suppressing white turbidity / precipitation by freezing and thawing this composition Can be provided.

The ophthalmic composition of the present invention comprises (A) vitamin A selected from retinol palmitate, retinol acetate and retinoic acid , (B) polyoxyethylene polyoxypropylene glycol, (C) trometamol , D) to (G):
(D) glycerin or propylene glycol (E) xylitol, sorbitol, contain one and selected from mannitol or trehalose (F) Sodium dihydrogen phosphate (G) Sodium chloride <br/>, blending of (C) trometamol the amount is the 0.001~5W / V% der shall.

[(A) Vitamin A]
Examples of vitamin A include, 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, and the like. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate, retinol acetate, and retinoic acid are preferred. Retinol palmitate is usually commercially available from 1 million to 1.8 million international units (hereinafter abbreviated as IU). Specifically, retinol palmitate (manufactured by DSM Nutrition Japan Co., Ltd.) 1.7 million I.U./g).

  (A) A component can be used individually by 1 type or in combination of 2 or more types, The compounding quantity is preferably 50,000-500,000 units / 100mL with respect to the ophthalmic composition whole quantity, 000 to 300,000 units / 100 mL is more preferable, and 100,000 to 200,000 units / 100 mL is more preferable. When expressed in terms of W (mass) / V (volume)% (g / 100 mL), 0.03 to 0.3 W / V% is preferable, depending on the unit of vitamin A to be blended, and 0.03 to 0.18 W. / V% is more preferable, and 0.06 to 0.12 W / V% is more preferable. Vitamin A has the effect of treating corneal / conjunctival damage, dry eye, and fatigue / hazy eyes, but if it is less than 50,000 units / 100 mL, the effect of treating corneal / conjunctival damage is insufficient. If the amount exceeds 500,000 units / 100 mL, there may be a problem of side effects.

[(B) Polyoxyethylene polyoxypropylene glycol]
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, Lutrol F127 (manufactured by BASF), Unilube 70DP-950B (manufactured by NOF Corporation), etc., polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (196) polyoxypropylene (67) Polyoxyethylene such as glycol (Pluronic F127, also known as Poloxamer 407), polyoxyethylene (120) polyoxypropylene (40) glycol (Pluronic F-87), Pronon # 188P (manufactured by NOF Corporation) (160) Polyoxypropylene (30) glycol (Pluronic F-68, also known as Poloxamer 188), Polyoxyethylene (42) Polyoxypropylene (67) glycol (Pluronic P123, also known as Poloxamer 403), Pronon # 235P ( Polyoxyethylene (54) Polyoxypropylene (39) Glycol (Pluronic P85), Polyoxyethylene (20) Polyoxypropylene (20) Glycol (Pluronic L-44), Tetronic etc. Can be mentioned. Of these, polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, and polyoxyethylene (54) polyoxypropylene (39) glycol are preferred.

(B) A component can be used individually by 1 type or in combination of 2 or more types. The blending amount in the ophthalmic composition is preferably 5 W / V% or less, more preferably 0.4 to 5 W / V%, from the viewpoint of storage stability of vitamin A, corneal / conjunctival damage treatment, and dry eye treatment effect. . If it is less than 0.4 W / V%, solubilization of vitamin A may be difficult. Further, the cloudiness / precipitation at the time of freezing and thawing is less likely to occur as the blending amount of the component (B) is smaller. Therefore, the content of the component (B) is preferably 5 W / V% or less.

[(C) to (G) White turbidity / precipitation inhibiting component in freezing and thawing]
(C) Trometamol The amount of trometamol is, for example, preferably 0.001 to 5 W / V%, more preferably 0.01 to 3 W / V%, and further preferably 0.1 to 2 W / V% in the ophthalmic composition. preferable. By adding 0.001 W / V% or more, white turbidity / precipitation suppression can be further obtained. The greater the amount of trometamol, the higher the white turbidity / precipitation suppressing effect. However, if it exceeds 5 W / V%, the osmotic pressure may increase too much, and a feeling of irritation may be felt.
(D) Polyhydric alcohol Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. Among these, glycerin and propylene glycol are preferable, and glycerin is more preferable.

  The blending amount of the polyhydric alcohol is, for example, preferably 0.001 to 5 W / V% in the ophthalmic composition, more preferably 0.005 to 3 W / V%, and still more preferably 0.01 to 2 W / V%. If it is less than 0.001 W / V%, the antifreezing effect is weak and the cloudiness / precipitation may not be suppressed. If it exceeds 5 W / V%, the osmotic pressure may increase excessively.

(E) Saccharides Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, mannitol, trehalose and the like. These may be any of d-form, l-form or dl-form. Among these, xylitol, sorbitol, mannitol and trehalose are preferable, sorbitol, mannitol and trehalose are more preferable, and mannitol and trehalose are further preferable.

  The blending amount of the saccharide is, for example, preferably 0.001 to 5 W / V%, more preferably 0.005 to 3 W / V%, still more preferably 0.01 to 2 W / V% in the ophthalmic composition. 05-1 W / V% is particularly preferable. If it is less than 0.001 W / V%, the antifreezing effect is weak and the cloudiness / precipitation may not be suppressed. If it exceeds 5 W / V%, the osmotic pressure may increase excessively.

(F) Phosphoric acid and salts thereof Phosphoric acid, monosodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, disodium hydrogen phosphate, dihydrogen phosphate Examples include potassium and dipotassium hydrogen phosphate. Among these, monosodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, and disodium hydrogen phosphate are preferable, and sodium dihydrogen phosphate, sodium hydrogen phosphate, and disodium hydrogen phosphate are more preferable. More preferred is disodium hydrogen phosphate. The blending amount of phosphoric acid and its salt is, for example, preferably 0.001 to 5 W / V%, more preferably 0.005 to 3 W / V% in the ophthalmic composition, and further 0.01 to 2 W / V%. 0.05 to 1 W / V% is particularly preferable. If it is less than 0.001 W / V%, the antifreezing effect is weak and the cloudiness / precipitation may not be suppressed. If it exceeds 5 W / V%, the osmotic pressure may increase excessively.

(G) Monovalent neutral salt Examples of the monovalent neutral salt include sodium chloride and potassium chloride. Of these, sodium chloride is preferred. The blending amount of the monovalent neutral salt is preferably 0.001 to 5 W / V% in the ophthalmic composition, more preferably 0.01 to 3 W / V%, still more preferably 0.1 to 2 W / V%, 0.1-1 W / V% is particularly preferable. If it is less than 0.001 W / V%, the antifreezing effect is weak, and white turbidity / precipitation may not be suppressed. If it exceeds 5 W / V%, the osmotic pressure may increase excessively.

As the cloudiness / precipitation inhibiting component, (C) trometamol is preferable. These cloudiness / precipitation-inhibiting components can be used alone or in combination of two or more, for example, two or more of the same components can be combined, such as using two or more of component (D). Good. When two or more kinds are combined, it is more preferable because a synergistic effect is obtained in the freezing suppression effect of bulk water and ethylene oxide chain hydrated water. Among these components, it is particularly preferable to combine (C) trometamol with other components, and it is preferable to use two or more of glycerin, trometamol, and trehalose, particularly glycerin and trometamol. The ethylene oxide chain hydrated water is preferable from the viewpoint of antifreezing effect. For example, trometamol not only prevents freezing of bulk water, but also binds to the ethylene oxide chain of micelles, so that glycerin penetrates into the ethylene oxide chain, thereby disturbing the orientation of the ethylene oxide chain and preventing the freezing of the ethylene oxide chain. I think that. The ophthalmic composition of the present invention preferably contains trometamol from the viewpoint of improving the storage stability of vitamin A. Although this mechanism is not clear, for example, it can be considered as follows. Polyoxyethylene polyoxypropylene glycol is a nonionic surfactant having a polyoxyethylene (EO) chain and a polyoxypropylene (PO) chain. Encapsulates vitamin A with the EO chain on the outside and the PO chain on the inside to form micelles. When trometamol coexists, the —NH ₂ group present in trometamol is directly bonded to the ether bond of the EO chain, thereby strengthening the micelle structure. Furthermore, trometamol binds to the EO chain outside the micelle, thereby strengthening the micelle structure and reducing the degree of freedom. As a result, the molecular mobility of the PO chain inside the micelle is reduced. From the above, it is considered that trometamol contributes to the stabilization of micelles formed from vitamin A and polyoxyethylene polyoxypropylene glycol, and consequently contributes to the storage stability of vitamin A.

  The total amount of these components (C) to (G) is preferably 0.001 to 5 W / V% in the ophthalmic composition, but particularly in the case of using two types in combination, 0.01 to 0.01% in the ophthalmic composition. 5 W / V% is more preferable, still more preferably 0.1 to 4 W / V%, particularly preferably 0.5 to 3 W / V%, and particularly preferably 1 to 3 W / V%. Moreover, when using 3 or more types together, 0.01-5 W / V% is more preferable, More preferably, it is 0.1-4 W / V%.

Moreover, the total of (C)-(G) component is preferable 0.02-200 mass part per 1 mass part of (A) component.
Furthermore, the total of the components (C) to (G) is preferably 0.001 to 20 parts by mass per 1 part by mass of the component (A) + (B).

[Other ingredients]
In the ophthalmic composition of the present invention, in addition to the above components, 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. Examples of these components include surfactants other than the component (B), buffers, thickeners, 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.

(I) Surfactant other than component (B) Surfactants other than component (B) include, for example, nonionic surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and alkyldiaminoethyl. Examples include glycine-type amphoteric surfactants such as glycine. These compounding amounts are preferably 0.0001 to 10 W / V%, more preferably 0.005 to 5 W / V% in the ophthalmic composition. However, from the viewpoint of the effect of treating corneal / conjunctival damage and dry eye, the amount of these surfactants should be small, preferably 0.5 W / V% or less.

(Ii) Preservatives Preservatives can be blended within a range that does not impair the effects of the present invention. However, the ophthalmic composition of the present invention should not contain any preservatives from the viewpoint of eye irritation. Is preferred. 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. The blending amount of the preservative with respect to the total amount of the ophthalmic composition is, for example, 0.00001 to 5 W / V%, preferably 0.0001 to 3 W / V%, more preferably 0.001 to 2 W / V%. .

  However, cationic surfactants such as benzalkonium chloride and benzethonium chloride, and hydrophobic preservatives such as parabens (methylparaben, ethylparaben, propylparaben, etc.) and chlorobutanol inhibit vitamin A corneal / conjunctival damage treatment. The effect is found. Therefore, these compounding amounts are preferably 0.004 W / V% or less in the composition, more preferably 0.003 W / V% or less, and it is more preferable that these are not contained and not included. The mechanism by which they inhibit the therapeutic effect on corneal / conjunctival damage is not clear, but (B) polyoxyethylene polyoxypropylene glycol wraps vitamin A with the EO chain on the outside and the PO chain on the inside to form micelles. These micelles are adsorbed on the cornea surface, and vitamin A is absorbed inside the cornea. Cationic surfactants have surface-active properties, and hydrophobic preservatives have high hydrophobicity, which changes the micelle surface state, thereby inhibiting the adsorption of vitamin A to the cornea. As a result, the cornea・ It is considered to inhibit the conjunctival damage treatment effect and dry eye improvement. On the other hand, a highly hydrophilic substance such as sorbic acid or a salt thereof does not affect the internal state of the micelle and therefore does not inhibit the absorption promoting effect of vitamin A.

  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.

(Iii) Buffering agent Examples of the buffering agent include boric acid or a salt thereof (such as borax), citric acid or a salt thereof (such as sodium citrate), tartaric acid or a salt thereof (such as sodium tartrate), gluconic acid or a salt thereof. (Sodium gluconate and the like), acetic acid or a salt thereof (sodium acetate and the like), various amino acids and the like (epsilon-aminocaproic acid, potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate and the like). Moreover, the trometamol of (C) component can be used also as a buffering agent, and it is preferable from the point of mildness and the antiseptic effect of a composition. Furthermore, when boric acid and borax are used in combination, a particularly high antiseptic effect is obtained. In the present invention, the stability of vitamin A is further improved when boric acid, trometamol, citric acid or a salt thereof is added. The blending amount of the buffering agent is preferably 0.001 to 10 W / V%, more preferably 0.01 to 5 W / V% in the ophthalmic composition.

(Iv) Thickener Examples of the thickener include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, and carboxyvinyl polymer. By blending these, the retention is increased, and the corneal / conjunctival damage healing effect is further improved. The compounding quantity with respect to the ophthalmic composition whole quantity of a viscous agent is 0.001-10 W / V%, for example, Preferably it is 0.001-5 W / V%, More preferably, it is 0.01-3 W / V%.

(V) pH adjuster It is preferable to use an inorganic acid or an inorganic alkali agent as the pH adjuster. 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. Among these, hydrochloric acid and sodium hydroxide are preferable. The pH (20 ° C.) of the ophthalmic composition of the present invention is preferably 4.0 to 9.0, more preferably 5.0 to 8.0, and still more preferably 6.0 to 8.0. . In the present invention, pH is measured at 20 ° C. using a pH osmometer (HOSM-1, manufactured by Toa DKK Corporation). The blending amount of the pH adjuster with respect to the total amount of the ophthalmic composition is, for example, 0.00001 to 10 W / V%, preferably 0.0001 to 5 W / V%, more preferably 0.001 to 3 W / V%. is there.

(Vi) Isotonic agent Examples of the isotonic agent include calcium chloride and magnesium chloride. The amount of the isotonizing agent based on 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%. It is.

(Vii) Stabilizer Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like. In addition, in this invention, when a stabilizer is mix | blended, stability of vitamin A will improve further. The blending amount of the stabilizer 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%. is there.

(Viii) Cooling agent Examples of the cooling agent include menthol, camphor, borneol, geraniol, cineol, linalool, and the like. The blending amount 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 a total amount of the compound in the ophthalmic composition. Is more preferable, and 0.007 to 0.8 W / V% is particularly preferable.

(Ix) Drug (active pharmaceutical ingredient)
Examples of drugs (pharmaceutical active ingredients) include decongestants (eg, naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate); (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); antiallergic agents For example, sodium cromoglycate, ketotifen fumarate, etc.); water-soluble vitamins (activated vitamin B _2, vitamin B _6, vitamin B _12, etc.); amino acids (e.g., potassium L- aspartate, magnesium L- aspartic acid, aminoethyl Sulfonic acid, sodium chondroitin sulfate, glutathione, etc.); sulfa drugs, fungicides (eg, sulfur, isopropylmethylphenol, hinokitiol, etc.); local anesthetics (eg, lidocaine, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, etc.); An agent (for example, tropicamide) can be appropriately blended.

  The compounding amounts of these components in the ophthalmic composition are appropriately selected according to the type of preparation, the type of drug, and the like, and the compounding amounts of various components are known in the art. For example, it is 0.00001 or more with respect to the whole preparation, It is 0.0001-30W / V% especially, Preferably it can select from the range of about 0.001-10W / V%. More specifically, the compounding quantity with respect to the ophthalmic composition whole quantity of each component is as follows, for example.

If it is a decongestant, it 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 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%, for example, Preferably it is 0.0001-0.5 W / V%.
If it is an amino acid, it is 0.0001-10 W / V%, for example, Preferably it is 0.001-3 W / 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 a local anesthetic, it is 0.001-1 W / V%, for example, Preferably it is 0.01-1 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.

  In many cases, contact lens users tend to damage the cornea / conjunctiva due to the dryness of the eye caused by the use of contact lenses and develop dry eye symptoms. On the other hand, since vitamin A compounded in the ophthalmic composition of the present invention has a dry eye improving effect, the contact lens user uses the ophthalmic composition of the present invention to produce dry eye. An improvement effect can be expected. Therefore, the ophthalmic composition of the present invention is preferably used for contact lenses. Since the amount of the preservative is limited, it is particularly preferable for soft contact lenses.

  Since the ophthalmic composition of the present invention has an excellent corneal / conjunctival damage treatment effect, it can be used as a dry eye therapeutic agent. The therapeutic agent for dry eye of the present invention can exert its effect more by instilling 30-60 μL at a time, 3-6 times a day.

  The ophthalmic composition of the present invention is liquid, and the viscosity of the ophthalmic solution is preferably 1 to 50 mPa · s, more preferably 1 to 30 mPa · s, still more preferably 1 to 20 mPa · s, 5 mPa · s is more preferable. The viscosity is measured at 20 ° C. using an E-type viscometer (VISCONIC ELD-R, Tokyo Keiki Co., Ltd.).

  The preparation method of the ophthalmic composition of the present invention is not particularly limited. For example, vitamin A is solubilized in purified water with polyoxyethylene polyoxypropylene glycol, and then each component is added. It can be obtained by adjusting the pH. Thereafter, it can be aseptically filled into a suitable container such as a container made of polyethylene terephthalate.

The present invention relates to an ophthalmic composition containing (A) vitamin A selected from retinol palmitate, retinol acetate and retinoic acid , (B) polyoxyethylene polyoxypropylene glycol, (C) trometamol, and (D)-(G):
(D) glycerin or propylene glycol (E) xylitol, sorbitol, blended one and selected from mannitol or trehalose (F) Sodium dihydrogen phosphate (G) Sodium chloride <br/>, blending of (C) trometamol amount, Ru 0.001~5W / V% der provides methods cloudiness and precipitation inhibition by freeze-thaw. In this white turbidity / precipitation suppression method, the components and blending amounts are the same as described above.

EXAMPLES Hereinafter, although an Example, a reference example, a comparative example, and a test example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Examples 1-5 , Reference Examples 1-43, Comparative Examples 1-3]
The ophthalmic compositions (eye drops) having the compositions shown in Tables 1 to 11 were prepared and evaluated as follows. The results are also shown in the table.

<Appearance stability (observation of appearance after freezing and thawing)>
An ophthalmic composition (eye drops) was filled in a polyethylene terephthalate eye drop container (N = 3), and the operations of freezing (−20 ° C.) and thawing (25 ° C.) were repeated 5 times, and evaluated according to the following criteria.
Evaluation Criteria 5: The liquid is clear and no white turbidity / precipitation occurs in the fifth time. 4: The liquid is clear and no white turbidity / precipitation occurs in the fourth time.
In the 5th time, cloudiness or precipitation occurs. 3: In the 3rd time, the liquid is clear and no cloudiness or precipitation occurs.
In the 4th time, cloudiness or precipitation occurs. 2: In the 2nd time, the liquid is clear and no cloudiness or precipitation occurs.
White turbidity or precipitation occurs in the 3rd time. White turbidity or precipitation occurs in the 1st time. Here, “clear” means “no turbidity and clearness”.

<VA stability (retinol palmitate remaining rate (%))>
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 (severe test). The measurement was performed using a high performance liquid chromatograph method. From the obtained retinol palmitate content, the retinol palmitate residual rate (%) was calculated based on the following formula.
Retinol palmitic acid residual ratio (%) = {retinol palmitic acid ester content after storage / retinol palmitic acid ester content immediately after production} × 100
<Evaluation>
◎: 70% or more ○: 65% or more and less than 70% △: 60% or more and less than 65% ×: less than 60%

<Cornea and conjunctival damage treatment effect>
The rabbit was treated with heptanol (heptanol / ethanol = 8: 2 (volume ratio) mixed solution with 200 μL of one eye dropped) to prepare a model in which the rabbit cornea / conjunctival epithelium was damaged. 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 treatment 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. Tables 1 to 11 show the evaluation results on the fifth day.

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)

[Test Examples 1 to 12]
Vitamin A, polyoxyethylene polyoxypropylene glycol, and antioxidant were preliminarily dissolved at 85 ° C and the preliminarily dissolved product was heated to 85 ° C. Solubilized in sterilized purified water, and after cooling, a water-soluble blending component such as trometamol was added to adjust pH (20 ° C.) to obtain an ophthalmic composition. 15 mL of the obtained ophthalmic composition was filled in an eye drop container with a 15 mL filter (manufactured by polyethylene terephthalate). The ophthalmic compositions of Test Examples 1 to 12 had sufficient antiseptic power. About the obtained ophthalmic composition, the said corneal / conjunctival damage treatment effect was evaluated. The results are also shown in the table.

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）
＊２：プロノン＃１８８Ｐ、薬添規、日本油脂（株）
＊３：プロノン＃２３５Ｐ、薬添規、日本油脂（株）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)
* 2: Pronon # 188P, Supplementary Rules, Nippon Oil & Fats Co., Ltd.
* 3: Pronon # 235P, Supplementary Rules, Nippon Oil & Fats Co., Ltd.

＊１：ユニルーブ７０ＤＰ−９５０Ｂ、薬添規（日油（株）製）又はＬｕｔｒｏｌ Ｆ１
２７、薬添規（ＢＡＳＦ社製）
＊２：プロノン＃１８８Ｐ、薬添規、日本油脂（株）
＊３：プロノン＃２３５Ｐ、薬添規、日本油脂（株）

* 1: Unilube 70DP-950B, Supplementary Rules (manufactured by NOF Corporation) or Lutrol F1
27. Supplementary regulations (made by BASF)
* 2: Pronon # 188P, Supplementary Rules, Nippon Oil & Fats Co., Ltd.
* 3: Pronon # 235P, Supplementary Rules, Nippon Oil & Fats Co., Ltd.

Claims (9)

(A) Vitamin A selected from retinol palmitate, retinol acetate and retinoic acid;
(B) polyoxyethylene polyoxypropylene glycol;
(C) Trometamol,
The following (D) to (G):
(D) glycerin or propylene glycol (E) xylitol, sorbitol, mannitol or trehalose (F) sodium dihydrogen phosphate (G) 1 type selected from sodium chloride,
(C) The ophthalmic composition characterized in that the compounding amount of trometamol is 0.001 to 5 W / V%.   The ophthalmic composition according to claim 1, wherein the total amount of the components (C) to (G) is 0.001 to 5 W / V%.   The ophthalmic composition according to claim 1 or 2, wherein the amount of component (B) is 0.4 to 5 W / V%.   (A) The compounding quantity of a component is 50,000-500,000 units / 100mL, The ophthalmic composition of any one of Claims 1-3.   The ophthalmic composition according to any one of claims 1 to 4, wherein the blending amount of the cationic surfactant and the hydrophobic preservative is 0.004 W / V% or less.   The ophthalmic composition according to any one of claims 1 to 4, which contains no preservative.   It is an object for contact lenses, The ophthalmic composition of any one of Claims 1-6.   The ophthalmic composition according to any one of claims 4 to 7, which is a dry eye therapeutic agent. (A) Vitamin A selected from retinol palmitate, retinol acetate and retinoic acid, (B) ophthalmic composition containing polyoxyethylene polyoxypropylene glycol, (C) trometamol and the following (D) to (G):
(D) Glycerin or propylene glycol (E) Xylitol, sorbitol, mannitol, or trehalose (F) Sodium dihydrogen phosphate (G) One selected from sodium chloride and (C) The amount of trometamol is 0 A turbidity / precipitation suppression method by freezing and thawing, which is 0.001 to 5 W / V%.