JP7014078B2 - Ophthalmic composition and precipitation suppression method - Google Patents

Description

The present invention relates to an ophthalmic composition containing berberine or a salt thereof and a method for suppressing precipitation.

Berberine or a salt thereof is known to have an anti-inflammatory effect and a high antibacterial property against bacteria (Patent Document 1: Japanese Patent Application Laid-Open No. 2008-24700, Patent Document 2: Japanese Patent Application Laid-Open No. 2001-64108). On the other hand, vitamin A is known as an essential substance for the proliferation and differentiation of epithelial cells, and has been reported to have an action of promoting mucin production and an action of healing corneal wounds (Patent Document 3: Patent No. 5673531). .. From the above, an ophthalmic composition in which berberine or a salt thereof and vitamin A are used in combination has been desired.

Japanese Unexamined Patent Publication No. 2008-24700 Japanese Unexamined Patent Publication No. 2001-64108 Japanese Patent No. 5673531

When (A) berberine or a salt thereof is used in combination with (B) a fat-soluble component consisting of retinol palmitate (B-1) and d-α-tocophenol acetate (B-2), it is thawed after cryopreservation. (Hereinafter, it may be referred to as "freeze-thaw".) There was a problem that berberine was precipitated. In order to suppress this precipitation, the formulation of (C) glycyrrhizic acid or a salt thereof was effective, but the formulation of the component (C) deteriorates the stability of the retinol palmitate ester (B-1). Has occurred.

The present invention has been made in view of the above circumstances, and suppresses the precipitation of berberine by thawing of an ophthalmic composition containing the above components (A), (B) and (D) after cryopreservation, and at the same time. It is an object of the present invention to provide an ophthalmic composition containing berberine or a salt thereof, which has excellent stability of vitamin A.
Hereinafter, the precipitation of berberine by thawing after cryopreservation of an ophthalmic composition may be described as "precipitation in freeze-thaw", and the (preservation) stability of vitamin A may be described as "VA stability".

As a result of diligent studies to achieve the above object, the present inventors have obtained results.
(A) Velverin or its salt (B) Fat-soluble component consisting of vitamin A (B-1) and vitamin E (B-2): 0.09 w / v% or less (C) Glycyrrhizinic acid or its salt, and (D) ) Contains a nonionic surfactant, the compounding mass ratio represented by (C) / (D) is 1.5 or more, and the compounding mass represented by (D) / ((A) + (B)). It has been found that the above-mentioned problems can be solved by using an ophthalmic composition having a ratio of 1.0 to 5.0, and the present invention has been made.

Therefore, the present invention provides the following.
[1]. (A) Velverin or its salt (B) Fat-soluble component consisting of vitamin A (B-1) and vitamin E (B-2): 0.09 w / v% or less (C) Glycyrrhizinic acid or its salt, and (D) ) Contains a nonionic surfactant, the compounding mass ratio represented by (C) / (D) is 1.5 or more, and the compounding mass represented by (D) / ((A) + (B)). An ophthalmic composition having a ratio of 1.0 to 5.0.
[2]. The ophthalmic composition according to [1], wherein the ophthalmic composition is an eye drop.
[3]. (A) Berberine or a salt thereof (B) A fat-soluble component consisting of vitamin A (B-1) and vitamin E (B-2), and (D) an ophthalmic composition containing a nonionic surfactant.
(C) Glycyrrhizic acid or a salt thereof is blended, and the blending amount of the component (B) is 0.09 w / v% or less in the ophthalmic composition, and the blending mass ratio represented by (C) / (D) is used. In the freeze-thaw of the above-mentioned ophthalmic composition, the compounding mass ratio represented by 1.5 or more and (D) / ((A) + (B)) is 1.0 to 5.0. A method for suppressing velverin precipitation.
[4]. (A) Berberine or a salt thereof (B) A fat-soluble component consisting of vitamin A (B-1) and vitamin E (B-2), and (D) an ophthalmic composition containing a nonionic surfactant.
(C) Glycyrrhizic acid or a salt thereof is blended, and the blending amount of the component (B) is 0.09 w / v% or less in the ophthalmic composition, and the blending mass ratio represented by (C) / (D) is used. Vitamin A (B-1) is stable, characterized by having a compounding mass ratio of 1.5 or more and represented by (D) / ((A) + (B)) of 1.0 to 5.0. A method for suppressing the precipitation of velverine in freezing and thawing of the above-mentioned ophthalmic composition.

According to the present invention, it is possible to provide an ophthalmic composition containing berberine or a salt thereof, which suppresses the precipitation of berberine after freezing and thawing of the ophthalmic composition and has excellent stability of vitamin A. ..

Hereinafter, the present invention will be described in detail.
[(A) component]
The component (A) of the present invention is berberine or a salt thereof, and can be used alone or in combination of two or more. Examples of berberine or a salt thereof include sulfates such as berberine sulfide and berberine chloride, and hydrochlorides. Further, it may be a hydrate or the like.

The blending amount of the component (A) is preferably 0.0005 to 0.1 w / v% (mass / volume%, g / 100 mL) in the ophthalmic composition (hereinafter, may be simply referred to as a composition). , 0.001 to 0.025 w / v%, more preferably 0.001 to 0.02 w / v%. From the viewpoint of antibacterial effect, the above lower limit or more is preferable, and from the viewpoint of precipitation suppressing effect in freeze-thaw and VA stability, the above upper limit or less is preferable.

[(B) component]
The component (B) of the present invention is a fat-soluble component composed of (B) vitamin A (B-1) and vitamin E (B-2), and may be used alone or in combination of two or more. can.

(B-1) Vitamin A
Examples of vitamin A include vitamin A-containing mixtures such as vitamin A oil and vitamin A derivatives such as vitamin A fatty acid ester, in addition to vitamin A itself, and one type alone or two or more types may be used as appropriate. Can be done. Specific examples thereof include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Of these, retinol palmitate ester, retinyl acetate ester, and retinoic acid are preferable. The retinol palmitate ester is usually commercially available in the range of 1 to 1.8 million international units / g (hereinafter abbreviated as I.U./g), and specifically, the retinol palmitate ester manufactured by DSM [174]. 10,000 I. U. / G)], retinol palmitate manufactured by Sigma-Aldrich, and the like.

(B-2) Vitamin E
Examples of vitamin E include tocopherol acetate (d-α-tocopherol acetate, dl-α-tocopherol acetate), which can be used alone or in combination of two or more. Of these, d-α-tocopherol acetate is preferred.

The blending amount of the whole component (B) is 0.09 w / v% or less in the composition, preferably 0.01 to 0.09 w / v%, more preferably 0.02 to 0.07 w / v%. More preferably, 0.03 to 0.06 w / v%. When it is 0.01 w / v% or more, the action effect and VA stability of VA are further improved, and when it exceeds the upper limit of 0.09 w / v%, the precipitation suppressing effect in freeze-thaw is lowered.

The blending amount of (B-1) is preferably 0.0025 to 0.08 w / v%, more preferably 0.005 to 0.05 w / v%, and 0.006 to 0.03 w / v% in the composition. Is even more preferable. If it is less than the above lower limit, the keratoconjunctival injury healing effect of vitamin A may be insufficient, and if it exceeds the above upper limit, the precipitation suppressing effect in freezing and thawing may be lowered.

The blending amount of (B-2) is preferably 0.0075 to 0.08 w / v%, more preferably 0.02 to 0.07 w / v%, and 0.03 to 0.06 w / v% in the composition. Is even more preferable. If it is less than the above lower limit, the VA stability may be lowered, and if it exceeds the above upper limit, the precipitation suppressing effect in freezing and thawing may be lowered.

[(C) component]
The component (C) of the present invention is glycyrrhizic acid or a salt thereof, and can be used alone or in combination of two or more. Examples of glycyrrhizic acid or salts thereof include glycyrrhizic acid itself, disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, monoammonium glycyrrhizinate and the like.

The blending amount of the component (C) is preferably 0.01 to 0.5 w / v%, more preferably 0.03 to 0.4 w / v%, and more preferably 0.05 to 0.3 w / v% in the composition. More preferred. Above the above lower limit, the effect of suppressing precipitation in freezing and thawing is further improved, and below the above upper limit, VA stability is further improved.

[(D) component]
The component (D) of the present invention is a nonionic surfactant, and can be used alone or in combination of two or more. From the viewpoint of vitamin A storage stability, it is preferable to use two or more kinds in an appropriate combination. Specific examples thereof include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester), polyoxyethylene polyoxypropylene glycol (POEPOP glycol), polyethylene glycol fatty acid ester and the like. Be done.

Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and several types with different average number of moles of ethylene oxide are known. .. The average number of moles of ethylene oxide added to the polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles is exemplified. Specifically, polyoxyethylene castor oil 3 (EO average number of added moles 3), polyoxyethylene castor oil 10 (EO average number of added moles 10), polyoxyethylene castor oil 20 (EO average number of added moles 20), poly Oxyethylene castor oil 35 (EO average number of added moles 35), polyoxyethylene castor oil 40 (EO average number of added moles 40), polyoxyethylene castor oil 50 (EO average number of added moles 50), polyoxyethylene castor oil 60 (The average number of added moles of EO is 60) and the like. Of these, polyoxyethylene castor oil 35 is preferable.

Polyoxyethylene hydrogenated castor oil (POE cured castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types with different average number of moles of ethylene oxide are known. ing. The average number of moles of ethylene oxide added to the polyoxyethylene hydrogenated castor oil is not particularly limited, but 5 to 100 mol is exemplified. Specifically, polyoxyethylene cured castor oil 5 (EO average number of added moles 5), polyoxyethylene cured castor oil 10 (EO average number of added moles 10), polyoxyethylene cured castor oil 20 (EO average number of added moles 20). ), Polyoxyethylene cured castor oil 30 (EO average number of added moles 30), Polyoxyethylene cured castor oil 40 (EO average number of added moles 40), Polyoxyethylene cured castor oil 50 (EO average number of added moles 50), Polyoxyethylene cured castor oil 60 (EO average number of added moles 60), polyoxyethylene cured castor oil 80 (EO average number of added moles 80), polyoxyethylene cured castor oil 100 (EO average number of added moles 100), etc. Will be. Of these, polyoxyethylene hydrogenated castor oil 60 is preferable.

Examples of the polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester) include monolaurate polyoxyethylene (20) sorbitan (polysorbate 20), monopalmitate polyoxyethylene (20) sorbitan (polysorbate 40), and monostearate polyoxyethylene. Examples thereof include sorbitan (polysorbate 60), polyoxyethylene tristearate (20) sorbitan (polysorbate 65), and polyoxyethylene monooleate (20) sorbitan (polysorbate 80). Of these, polyoxyethylene monooleate (20) sorbitan (polysorbate 80) is preferable.

The polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is not particularly limited, and those described in the pharmaceutical additive standard (pharmaceutical supplementary regulations) can be used. The average degree of polymerization of ethylene oxide is preferably 4 to 200, more preferably 20 to 200, the average degree of polymerization of propylene oxide is preferably 5 to 100, more preferably 20 to 70, and it 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 Nippon Yushi Co., Ltd.), etc., Polyoxyethylene (120) polyoxypropylene. (40) Glycol: Pluronic F-87 (manufactured by BASF), Polyoxyethylene (160) Polyoxypropylene (30) Glycol: Pluronic F-68 (manufactured by BASF), Pronon # 188P (manufactured by Nippon Oil & Fats Co., Ltd.) Etc., Polyoxyethylene (42) Polyoxypropylene (67) Glycol: Pluronic P123 (manufactured by BASF), Polyoxyethylene (54) Polyoxypropylene (39) Glycol: Pluronic P85 (manufactured by BASF), Pronon # 235P ( Examples thereof include polyoxyethylene (20) polyoxypropylene (20) glycol: Pluronic L-44, Tetronic (manufactured by BASF) and the like (manufactured by Nippon Oil & Fats Co., Ltd.). Of these, polyoxyethylene (200) polyoxypropylene (70) glycol is preferable.

Examples of the polyethylene glycol fatty acid ester include polyethylene glycol stearate-25 and polyethylene glycol stearate-40, with polyethylene glycol stearate-40 being preferred.

Of these, polyoxyethylene hydrogenated castor oil is preferable, and a combination of polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester is preferable.

The blending amount of the component (D) is preferably 0.01 to 1.0 w / v%, more preferably 0.05 to 0.8%, still more preferably 0.1 to 0.5 w / v% in the composition. ..

In the present invention, the compounding mass ratio of the component (C) to the component (D) represented by (C) / (D) is 1.5 or more, preferably 1.5 to 5.0, and 1.8. ~ 4.0 is more preferable, and 2.0 to 3.0 is even more preferable. If the above ratio is less than 1.5, the precipitation suppressing effect and VA stability in freezing and thawing become insufficient. On the other hand, 5.0 or less is preferable from the viewpoint of VA stability.

Further, the compounding mass ratio of the component (D) to the total amount of the component (A) and the component (B) represented by (D) / ((A) + (B)) is 1.0 to 5.0. Yes, 1.0 to 2.0 is preferable, and 1.2 to 1.7 is more preferable. If the ratio is less than 1.0, the precipitation suppressing effect in freezing and thawing becomes insufficient, and if it exceeds 5.0, the precipitation suppressing effect and VA stability in freezing and thawing become insufficient.

The compatibility of the precipitation suppressing effect in freeze-thaw and the VA stability, which is the effect of the present invention, does not mean that the blending amount of the (D) nonionic surfactant is simply increased, but the above-mentioned (C) glycyrrhizinic acid or It can be obtained by adjusting the blending of the salt and the blending ratio.

[Other ingredients]
The composition of the present invention may contain an appropriate amount of other components to be blended in the ophthalmic composition as long as the effects of the present invention are not impaired. Examples of other components include the following, and one type can be used alone or two or more types can be used in combination as appropriate.

Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. In addition, these may be either d-body, l-body or dl-body. When the saccharide is blended, the blending amount is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and further preferably 0.001 to 0.1 w / v% in the composition. preferable.

Examples of the buffering agent include boric acid or a salt thereof (hosand, etc.), tromethamole, citric acid or a salt thereof (sodium citrate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, etc.). , Tartrate acid or its salt (sodium tartrate, etc.), gluconic acid or its salt (sodium gluconate, etc.), acetic acid or its salt (sodium acetate, etc.), carbonic acid or its salt (sodium hydrogencarbonate, etc.), various amino acids (epsilon- Aminocaproic acid, potassium aspartate, aminoethylsulfonic acid, glutamate, sodium glutamate) and the like can be mentioned. Of these, boric acid, borax, and tromethamole are preferable. When the buffer is blended, the blending amount is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 2 w / v%, still more preferably 0.001 to 1 w / v% in the composition. ..

Examples of the pH adjusting agent include an inorganic acid or an inorganic alkaline agent. Specifically, examples of the inorganic acid include (dilute) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like. The pH of the composition is preferably 3.5 to 8.0, more preferably 5.5 to 8.0. From the viewpoint of the effect of suppressing precipitation in freezing and thawing, 6.0 to 8.0 is more preferable. The pH is measured at 25 ° C. using a pH meter (HM-25R, DKK-TOA CORPORATION).

Examples of the tonicity agent include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like. Can be mentioned. From the viewpoint of further improving various symptoms caused by the destabilization of the tear oil layer, it is preferable to add sodium chloride or potassium chloride to make it isotonic. The osmotic pressure ratio of the composition to physiological saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and most preferably 0.83 to 1.20. The osmotic pressure is measured at 25 ° C. using an automatic osmometer (A2O, Advanced Instruments).

Examples of the stabilizer include sodium edetate, sodium edetate hydrate, cyclodextrin, sulfites, dibutylhydroxytoluene and the like. From the viewpoint of VA stability, it is preferable to add sodium edetate, sodium edetate hydrate, sulfite, and dibutylhydroxytoluene. When the stabilizer is blended, the blending amount is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v% in the composition. Is even more preferable.

Examples of the refreshing agent include menthol, camphor, borneol, geraniol, cineole, linalool and the like. It may be d-body, l-body or dl-body. When the refreshing agent is blended, the blending amount is preferably 0.0001 to 0.2 w / v% in the composition.

Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like. When the polyhydric alcohol is blended, the blending amount is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v% in the ophthalmic composition. v% is more preferred.

Examples of the viscous agent include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer and the like. When a viscous agent is blended, the blending amount thereof is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v% in the composition. Is even more preferable.

Examples of the preservative include benzalkonium chloride, benzethonium chloride, sorbic acid, thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconic acid, methyl paraoshiki benzoate, ethyl paraoxybenzoate and the like. These are preferably 0.1 w / v% or less, more preferably 0.01 w / v% or less, further preferably 0.001 w / v% or less, and most preferably 0.0001 w / v% or less in the composition. You don't have to.

Examples of the oil component include liquid paraffin, castor oil, soybean oil, olive oil, sesame oil, corn oil, palm oil, almond oil, medium-chain fatty acid triglyceride, white vaseline, mixed tocopherol, liquid paraffin, wax ester, sterol ester and the like. .. When the oil component is blended, the blending amount thereof is preferably 0.001 to 1.0 w / v% in the composition.

Examples of the drug (pharmaceutically active ingredient) include decongestant components (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, nafazoline hydrochloride, nafazoline nitrate, phenilefurin hydrochloride, dl-methylephedrine hydrochloride, etc.), anti-inflammatory / convergence. Agents (eg, epsilon-aminocaproic acid, allantin, sodium azulene sulfonate, zinc sulfate, zinc lactate, lysoteam hydrochloride, etc.), antihistamines, etc., water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamine, pyridoxin hydrochloride, pantenol, etc.) , Calcium pantothenate, sodium pantothenate, etc.), amino acids (eg, potassium L-aspartate, magnesium L-aspartate, potassium-magnesium L-aspartate (equal mixture), aminoethylsulfonic acid, sodium chondroitin sulfate, etc. ), Sulfa agents and the like. When a drug is blended, an effective appropriate amount of each drug can be selected as the blending amount of the drug, but 0.001 to 5 w / v% is preferable in the composition, and 0.001 to 1 w / v% is preferable. More preferably, 0.001 to 0.1 w / v% is even more preferable.

As the water, purified water, sterile water, or the like can be used, and the blending amount of water can be the balance of the composition. Specifically, 90 to 99.9 w / v% is preferable, and 93 to 98 w / v% is more preferable in the composition.

[Production method]
The method for producing the composition of the present invention is not particularly limited, and for example, a mixed solution of an oily component such as component (B) and a surfactant component such as component (D) can be used as a component (A) and a component (C). It can be obtained by mixing with an aqueous solution containing an aqueous component such as, emulsifying, adjusting the pH, and then adjusting the total volume with water. The mixing method of each liquid may be a general method, and is appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, etc., but the rotation speed is not particularly limited and should be set to such that it does not foam violently. Is preferable. The mixing temperature of each liquid is not particularly limited, but it is preferable that both the oily component and the surfactant component are equal to or higher than the melting temperature, and specifically, it is appropriately selected from the range of 40 to 95 ° C.

Further, the obtained composition may be filled in a resin container and then sealed with a package to enclose the inert gas concentration in the space formed between the container and the package for ophthalmology. The composition may be filled in a resin container and sealed by a package together with an oxygen scavenger.

[Ophthalmic composition]
The transmittance of the composition of the present invention is preferably 70 to 100%, more preferably 90 to 100%. The transmittance of the present invention refers to the transmittance at a wavelength of 600 nm measured using a spectrophotometer (for example, UV-1800, Shimadzu Corporation).

The composition of the present invention is preferably a liquid from the viewpoint of facilitating adaptation to the eyes, and the viscosity at 25 ° C. is preferably 20 mPa · s or less, more preferably 10 mPa · s or less, still more preferably 5 mPa · s or less. The viscosity is measured using a cone plate type viscometer (DV2T, Eiko Seiki Co., Ltd.).

The composition of the present invention may be used as a liquid as it is, or may be prepared as a gel or the like. Specific examples of use include eye drops (for example, general eye drops, contact lens eye drops, etc.), eye wash agents (general eye drops, eye drops used after removing contact lenses, etc.), and contact lenses. Examples include mounting liquid, contact removal liquid, and the like. Above all, it is suitable as an ophthalmic composition for contact lenses such as an eye drop for contact lenses, an eye wash used after removing the contact lens, a contact lens mounting solution, and a contact taking-out solution. The soft contact lens is not particularly limited, such as a hard contact lens, an O ₂ hard contact lens, a soft contact lens, and a silicone hydrogel contact lens.

When the composition of the present invention is used as an eye drop or an eye drop for contact lenses, it is preferable to instill 1 to 3 drops of 10 to 100 μL at a time, preferably 1 to 6 times a day, and 10 to 10 to a time. More preferably, 1 to 3 drops of 50 μL, 1 to 6 times per day. It is more preferable to take 1 to 3 drops of 10 to 30 μL at a time, 1 to 6 times a day. When used as an eye wash, it is preferable to wash the eyes 3 to 6 mL at a time, 3 to 6 times a day.

[Method of suppressing berberine precipitation in freeze-thaw]
The present invention provides a method for suppressing berberine precipitation in the following freeze-thaw.
(A) Berberine or a salt thereof (B) A fat-soluble component consisting of vitamin A (B-1) and vitamin E (B-2), and (D) an ophthalmic composition containing a nonionic surfactant.
(C) Glycyrrhizic acid or a salt thereof is blended, and the blending amount of the component (B) is 0.09 w / v% or less in the ophthalmic composition, and the blending mass ratio represented by (C) / (D) is used. In the freeze-thaw of the above-mentioned ophthalmic composition, the compounding mass ratio represented by 1.5 or more and (D) / ((A) + (B)) is 1.0 to 5.0. A method for suppressing velverin precipitation.
(A) Berberine or a salt thereof (B) A fat-soluble component consisting of vitamin A (B-1) and vitamin E (B-2), and (D) an ophthalmic composition containing a nonionic surfactant.
(C) Glycyrrhizic acid or a salt thereof is blended, and the blending amount of the component (B) is 0.09 w / v% or less in the ophthalmic composition, and the blending mass ratio represented by (C) / (D) is used. Vitamin A (B-1) is stable, characterized by having a compounding mass ratio of 1.5 or more and represented by (D) / ((A) + (B)) of 1.0 to 5.0. A method for suppressing the precipitation of velverine in freezing and thawing of the above-mentioned ophthalmic composition.
In the above method, suitable components, blending amounts and the like are the same as described above.

Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. The “%” of the composition indicates w / v% (g / 100 mL), the “%” of the composition indicates w / v%, and the ratio indicates the mass ratio (the same value as the w / v% ratio).

[Examples, comparative examples]
Each aqueous component containing the components (A) and (C) shown in the table below was dissolved in 90 mL of water and heated and mixed at 90 ° C. for 15 minutes to obtain an aqueous component aqueous solution. At the same time, a premix of the components (B) and (D) was prepared and heated and mixed at 90 ° C. for 15 minutes. Next, a predetermined amount of the premix was added to the aqueous aqueous solution solution, and the mixture was further heated and mixed at 90 ° C. for 15 minutes. Then, it was cooled to room temperature, and water was added so that it became 100 mL. The obtained composition was evaluated as follows. The results are also shown in the table.

[Effect of suppressing berberine precipitation in freeze-thaw]
13 mL of the ophthalmic composition immediately after production was filled in an eye drop container (15 mL), frozen at −20 ° C., and stored for 1 week. After that, it was taken out at room temperature. The transmittance of the thawed ophthalmic composition at a wavelength of 600 nm 3 hours after removal was measured using an ultraviolet-visible near-infrared spectrophotometer UV-1800 (Shimadzu Corporation). The berberine precipitation in freeze-thaw is shown by the following evaluation criteria.
<Evaluation criteria>
⊚: No precipitate is observed and the transmittance is 90% or more. ○: No precipitate is observed, the transmittance is less than 90%, and the transmittance becomes 90% or more when shaken. ●: Precipitation No matter is found, the transmittance is less than 90%, and the transmittance does not change even when shaken. ×: Precipitates are found. “◎”, “○” and “●” are acceptable.
When the precipitate was analyzed, it was confirmed that it was berberine as the component (A).

[VA stability]
The content of retinol palmitate in the ophthalmic composition was measured immediately after production and after storage at 50 ° C. for 2 months (harsh test). The measurement used a high performance liquid chromatograph method. From the obtained retinol palmitate ester content, the retinol palmitate ester residual rate (%) was calculated based on the following formula.
Retinol palmitate residual rate (%) = {Retinol palmitate content after storage / Retinol palmitate content immediately after production} x 100
VA stability is shown by the following evaluation criteria.
<Evaluation criteria>
⊚: 75% or more ○: 70% or more to less than 75% ×: less than 70%

The raw materials used in the above example are shown below. Unless otherwise specified, the amount of each component in the table is a net conversion amount.
Berberine Chloride Hydrate (Berberine Chloride Hydrate, manufactured by Alps Pharmaceutical Co., Ltd.)
Retinol palmitate ester (retinyl palmitate ester [1.74 million I.U./g)], manufactured by DSM)
Acetic acid d-α-tocopherol (RIKEN E acetate α, manufactured by RIKEN Vitamin Co., Ltd.)
Dipotassium glycyrrhizinate (external regulation dipotassium glycyrrhizinate, manufactured by Maruzen Pharmaceuticals Co., Ltd.)
Polyoxyethylene hydrogenated castor oil 60 (HCO60, manufactured by Nippon Surfactant Industry Co., Ltd.)
Polyoxyethylene monooleate (20) Sorbitan (Leodor TW-O120V, manufactured by Kao Corporation)

Claims (4)

(A) Velverin or its salt (B) Fat-soluble component consisting of vitamin A (B-1) and vitamin E (B-2): 0.09 w / v% or less (C) Glycyrrhizinic acid or its salt, and (D) ) Contains a nonionic surfactant, the compounding mass ratio represented by (C) / (D) is 1.5 or more, and the compounding mass represented by (D) / ((A) + (B)). An ophthalmic composition having a ratio of 1.0 to 5.0. The ophthalmic composition according to claim 1, wherein the ophthalmic composition is an eye drop. (A) Berberine or a salt thereof (B) A fat-soluble component consisting of vitamin A (B-1) and vitamin E (B-2), and (D) an ophthalmic composition containing a nonionic surfactant.
(C) Glycyrrhizic acid or a salt thereof is blended, and the blending amount of the component (B) is 0.09 w / v% or less in the ophthalmic composition, and the blending mass ratio represented by (C) / (D) is used. In the freeze-thaw of the above-mentioned ophthalmic composition, the compounding mass ratio represented by 1.5 or more and (D) / ((A) + (B)) is 1.0 to 5.0. A method for suppressing velverin precipitation. (A) Berberine or a salt thereof (B) A fat-soluble component consisting of vitamin A (B-1) and vitamin E (B-2), and (D) an ophthalmic composition containing a nonionic surfactant.
(C) Glycyrrhizic acid or a salt thereof is blended, and the blending amount of the component (B) is 0.09 w / v% or less in the ophthalmic composition, and the blending mass ratio represented by (C) / (D) is used. Vitamin A (B-1) is stable, characterized by having a compounding mass ratio of 1.5 or more and represented by (D) / ((A) + (B)) of 1.0 to 5.0. A method for suppressing the precipitation of velverine in freezing and thawing of the above-mentioned ophthalmic composition.