JP7676769B2 - Ophthalmic composition - Google Patents

Description

The present invention relates to an ophthalmic composition containing berberine or a salt thereof.

Berberine or its salts are known to have anti-inflammatory effects and high antibacterial properties against bacteria. On the other hand, vitamin A is known to be an essential substance for the proliferation and differentiation of epithelial cells, and has been reported to promote mucin production and heal corneal wounds (Patent Document 1: Japanese Patent No. 5673531). Vitamin E is also a useful component as an antioxidant component. For these reasons, there has been a demand for an ophthalmic composition that uses berberine or its salts in combination with vitamin A or vitamin E.

JP 2020-15683 A

When (A) berberine or a salt thereof, (B) one or more selected from (B1) vitamin A and (B2) vitamin E, and (D) a nonionic surfactant are used in combination, a problem occurs in that the transmittance of the ophthalmic composition deteriorates when the composition is subjected to repeated freezing and thawing. Hereinafter, the deterioration of the transmittance of the ophthalmic composition when the composition is subjected to repeated freezing and thawing may be referred to as "deterioration of transmittance due to repeated freezing and thawing."

The present invention has been made in consideration of the above circumstances, and aims to provide an ophthalmic composition containing berberine or a salt thereof, which contains the above components (A), (B) and (D) and in which deterioration of the transmittance of the ophthalmic composition caused by repeated freezing and thawing is suppressed.

As a result of intensive research into achieving the above object, the inventors discovered that the above problem could be solved by adding (C) phenylephrine or a salt thereof to an ophthalmic composition containing the above components (A), (B), and (D), and thus came up with the present invention.

Accordingly, the present invention provides the following ophthalmic compositions.
1. (A) berberine or a salt thereof,
(B) one or more selected from (B1) vitamin A and (B2) vitamin E;
An ophthalmic composition comprising (C) phenylephrine or a salt thereof, and (D) a nonionic surfactant.
2. The ophthalmic composition according to 1, wherein the content mass ratio represented by the following formula satisfies 2.4≦((C)+(D))/((A)+(B))≦23.
3. The content of the component (A) is 0.01 to 0.025 w/v%,
The content of the component (B1) is 0.02 to 0.04 w/v%,
The content of the component (B2) is 0.02 to 0.05 w/v%,
The content of the component (C) is 0.1 to 0.6 w/v%, and the content of the component (D) is 0.14 to 0.56 w/v%.
3. The ophthalmic composition according to 1 or 2,
4. The ophthalmic composition according to any one of 1 to 3, further comprising (E) one or more members selected from chondroitin sulfate and its salts, glycyrrhizinic acid and its salts, and propylene glycol.
5. The ophthalmic composition according to 4, wherein the content mass ratio represented by the following formula satisfies 2.0≦((D)+(E))/((A)+(B))≦20.
6. The ophthalmic composition according to 4 or 5, wherein the content of component (E) is 0.05 w/v % or more.

According to the present invention, it is possible to provide an ophthalmic composition containing berberine or a salt thereof, in which deterioration of the transmittance of the ophthalmic composition caused by repeated freezing and thawing is suppressed.

The present invention will be described in detail below.
[Component (A)]
The component (A) of the present invention is berberine or a salt thereof, which may 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. It may also be a hydrate. For example, Japanese Pharmacopoeia: berberine chloride hydrate, manufactured by Alps Industries Co., Ltd., may be used.

The content of component (A) in the ophthalmic composition is preferably 0.005 w/v% (mass/volume%, g/100 mL) or more, and from the viewpoint of suppressing precipitation during freezing and thawing and deterioration of transmittance due to repeated freezing and thawing, it is preferably 0.1 w/v% or less, and more preferably 0.01 to 0.025 w/v%.

[(B) Component]
The component (B) of the present invention is at least one selected from (B1) vitamin A and (B2) vitamin E, and two or more of them can be used in appropriate combination.

(B-1) Vitamin A
Vitamin A is an effective ingredient for preventing and treating keratosis of the cornea, conjunctiva, skin and mucous membrane, corneal epithelial disorder, etc., and also has the effect of stabilizing the tear lipid layer. In particular, vitamin A is useful for contact lens users, who are prone to corneal epithelial disorder. Examples of vitamin A include vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid esters, and can be used alone or in appropriate combination of two or more. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, retinoid, etc. Among them, retinol palmitate, retinol acetate, and retinoic acid are preferred. Retinol palmitate is commercially available in amounts of usually 1 to 1.8 million international units/g (hereinafter, may be abbreviated as I.U./g). Specific examples include retinol palmitate (1.74 million I.U./g) manufactured by DSM and retinol palmitate manufactured by Sigma-Aldrich.

(B-2) Vitamin E
Examples of vitamin E include tocopherol acetate (d-α-tocopherol acetate, dl-α-tocopherol acetate), which may be used alone or in appropriate combination of two or more. Among these, d-α-tocopherol acetate is preferred. Specific examples include d-α-tocopherol acetate and Riken E Acetate α, both manufactured by Riken Vitamin Co., Ltd.

The total content of the (B) components in the ophthalmic composition is preferably 0.01 w/v% or more, and from the viewpoint of suppressing deterioration of transmittance due to repeated freezing and thawing, it is preferably 0.09 w/v% or less. The content of the (B1) component is preferably 0.005 to 0.08 w/v%, more preferably 0.02 to 0.04 w/v%. The content of the (B2) component is preferably 0.005 to 0.08 w/v%, more preferably 0.02 to 0.05 w/v%. When 1.74 million I.U./g is used, it is preferably 8,700 to 139,200 international units/100 mL, more preferably 348,000 to 87,000 international units/100 mL.

[(C) Component]
The component (C) is one or more selected from phenylephrine and its salts, and can be used alone or in combination of two or more. For example, the phenylephrine salt can be phenylephrine hydrochloride, phenylephrine acetate, or other pharmacopoeia salts. For example, the phenylephrine hydrochloride can be phenylephrine hydrochloride, as listed in the Japanese Pharmacopoeia, manufactured by Iwaki Pharmaceutical Co., Ltd.

The content of component (C) in the ophthalmic composition is preferably 0.08 to 0.8 w/v%, and more preferably 0.1 to 0.6 w/v%, in order to suppress precipitation during freezing and thawing and deterioration of transmittance due to repeated freezing and thawing.

[(D) Component]
The component (D) of the present invention is a nonionic surfactant, and may 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 in combination. Specific examples 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, etc.

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 added moles of ethylene oxide are known. The average added moles of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but examples include 3 to 60 moles. Specific examples include polyoxyethylene castor oil 3 (average added moles of EO: 3), polyoxyethylene castor oil 10 (average added moles of EO: 10), polyoxyethylene castor oil 20 (average added moles of EO: 20), polyoxyethylene castor oil 35 (average added moles of EO: 35), polyoxyethylene castor oil 40 (average added moles of EO: 40), polyoxyethylene castor oil 50 (average added moles of EO: 50), and polyoxyethylene castor oil 60 (average added moles of EO: 60). Among these, polyoxyethylene castor oil 35 is preferred.

Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types with different average added moles of ethylene oxide are known. There are no particular limitations on the average added moles of ethylene oxide in polyoxyethylene hydrogenated castor oil, but examples include 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (average number of moles of EO added: 5), polyoxyethylene hydrogenated castor oil 10 (average number of moles of EO added: 10), polyoxyethylene hydrogenated castor oil 20 (average number of moles of EO added: 20), polyoxyethylene hydrogenated castor oil 30 (average number of moles of EO added: 30), polyoxyethylene hydrogenated castor oil 40 (average number of moles of EO added: 40), polyoxyethylene hydrogenated castor oil 50 (average number of moles of EO added: 50), polyoxyethylene hydrogenated castor oil 60 (average number of moles of EO added: 60), polyoxyethylene hydrogenated castor oil 80 (average number of moles of EO added: 80), polyoxyethylene hydrogenated castor oil 100 (average number of moles of EO added: 100), etc. are mentioned. Among them, polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 are preferable.

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

Polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is not particularly limited, and those listed in the Pharmaceutical Additives Standards (Pharmaceutical Additives 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 either a block copolymer or a random polymer. Specifically, polyoxyethylene (200) polyoxypropylene (70) glycol: Lutrol F127 (manufactured by BASF), Unilube 70DP-950B (manufactured by NOF Corporation), polyoxyethylene (120) polyoxypropylene (40) glycol: Pluronic F-87 (manufactured by BASF), polyoxyethylene (160) polyoxypropylene (30) glycol: Pluronic F-68 (manufactured by BASF), Pronon #188P (manufactured by NOF Corporation), polyoxyethylene (42) polyoxypropylene (67) glycol: Pluronic P123 (manufactured by BASF), polyoxyethylene (54) polyoxypropylene (39) glycol: Pluronic P85 (manufactured by BASF), Pronon #235P (manufactured by NOF Corporation), polyoxyethylene (20) polyoxypropylene (20) glycol: Pluronic L-44, Tetronic (manufactured by BASF), and the like. Of these, polyoxyethylene (200) polyoxypropylene (70) glycol is preferred.

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

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

The content of component (D) in the ophthalmic composition is preferably 0.02 to 2 w/v%, more preferably 0.07 to 0.9 w/v%, and even more preferably 0.14 to 0.56 w/v%, in order to prevent deterioration of transmittance due to repeated freezing and thawing.

When polyoxyethylene hydrogenated castor oil is used, it is preferably contained in the ophthalmic composition at 0.01 to 1.0 w/v%, more preferably 0.05 to 0.8 w/v%, and even more preferably 0.1 to 0.5 w/v%. When polyoxyethylene sorbitan fatty acid ester is used, it is preferably contained in the ophthalmic composition at 0.01 to 1.0 w/v%, more preferably 0.02 to 0.1 w/v%, and even more preferably 0.04 to 0.06 w/v%.

[(E) component]
In order to suppress precipitation during freezing and thawing, the ophthalmic composition of the present invention preferably contains (E) one or more selected from chondroitin sulfate and its salts, glycyrrhizic acid and its salts, and propylene glycol. The (E) component can be used alone or in combination of two or more. Examples of chondroitin sulfate and its salts include sodium chondroitin sulfate ester (external standard sodium chondroitin sulfate) manufactured by Maruha Nichiro Co., Ltd., sodium chondroitin sulfate manufactured by Seikagaku Corporation, and sodium chondroitin sulfate manufactured by Nippon Biocon Co., Ltd. Examples of glycyrrhizinate salts include dipotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, tripotassium glycyrrhizinate, and monoammonium glycyrrhizinate.

When component (E) is included, the content in the ophthalmic composition is preferably 0.05 w/v% or more in order to suppress precipitation during freezing and thawing, and is preferably 1.25 w/v% or less in order to suppress deterioration of transmittance due to repeated freezing and thawing, and more preferably 0.1 to 1.25 w/v%.

The mass content ratio represented by the formula below is preferably 2.4≦((C)+(D))/((A)+(B))≦23, more preferably 2.5 to 10, and even more preferably 2.6 to 8.0, in order to prevent deterioration of transmittance due to repeated freezing and thawing.

The content mass ratio represented by the formula below is preferably 2.0≦((D)+(E))/((A)+(B))≦20, and more preferably 2.5 to 18. From the viewpoint of suppressing precipitation during freezing and thawing, a content mass ratio of 2.0 or more is preferable, and from the viewpoint of suppressing deterioration of transmittance due to repeated freezing and thawing, a content mass ratio of 20 or less is preferable.

[Other ingredients]
The composition of the present invention may contain other components that are to be incorporated into ophthalmic compositions in appropriate amounts, provided that the effects of the present invention are not impaired. Examples of other components include the following, which may be used alone or in appropriate combination of two or more.

Examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc. These may be in the d-, l-, or dl-form. When sugars are added, their content in the composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.

Examples of buffering agents include boric acid or its salts (e.g., borax), trometamol, citric acid or its salts (e.g., sodium citrate), phosphoric acid or its salts (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate), tartaric acid or its salts (e.g., sodium tartrate), gluconic acid or its salts (e.g., sodium gluconate), acetic acid or its salts (e.g., sodium acetate), carbonic acid or its salts (e.g., sodium hydrogen carbonate), and various amino acids (epsilon-aminocaproic acid, potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate). Among these, boric acid, borax, and trometamol are preferred. When a buffering agent is added, the content in the composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 2 w/v%, and even more preferably 0.001 to 1 w/v%.

Examples of pH adjusters include inorganic acids and inorganic alkali agents. Specifically, an example of an inorganic acid is (dilute) hydrochloric acid. Examples of inorganic alkali agents include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. The pH of the composition is preferably 3.5 to 8.0, and more preferably 5.5 to 8.0, from the viewpoint of further improving the various symptoms caused by destabilization of the tear lipid layer. The pH is measured at 25°C using a pH meter (HM-25R, DKK Toa Corporation).

Examples of isotonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. In order to further improve the symptoms caused by destabilization of the tear lipid layer, it is preferable to incorporate sodium chloride or potassium chloride to make the composition 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 stabilizers include sodium edetate, sodium edetate hydrate, cyclodextrin, sulfite, dibutylhydroxytoluene, etc. From the viewpoint of VA stability, it is preferable to incorporate sodium edetate, sodium edetate hydrate, sulfite, and dibutylhydroxytoluene. When a stabilizer is incorporated, the content in the composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.

Examples of cooling agents include menthol, camphor, borneol, geraniol, cineol, linalool, etc. Any of the d-, l- or dl-isomers may be used. When a cooling agent is added, the content is preferably 0.0001 to 0.2 w/v% in the composition.

Examples of polyhydric alcohols include glycerin, butylene glycol, and polyethylene glycol. Among these, glycerin, butylene glycol, and polyethylene glycol are preferred. When polyhydric alcohols are included, their content in the ophthalmic composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.

Examples of thickening agents include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, polyacrylic acid, carboxyvinyl polymer, etc. When a thickening agent is added, its content in the composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.

Preservatives include benzalkonium chloride, benzethonium chloride, sorbic acid, thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine, gluconic acid, methyl parahydroxybenzoate, and ethyl parahydroxybenzoate. These are preferably present in an amount of 0.005 w/v% or less in the composition, more preferably 0.001 w/v% or less, and even more preferably 0.0001 w/v% or less, and may not be included at all. If you have dry eyes or dry eye symptoms, or if you want to prevent dry eyes, it is preferable not to include a preservative.

Examples of oily components include liquid paraffin, castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglycerides, white petrolatum, mixed tocopherols, liquid paraffin, wax esters, sterol esters, etc. When an oil component is added, its content in the composition is preferably 0.001 to 1.0 w/v%, more preferably 0.001 to 0.5 w/v%, and even more preferably 0.001 to 0.25 w/v%.

Examples of drugs (pharmacologically active ingredients) include congestion relief ingredients (e.g., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, naphazoline hydrochloride, naphazoline nitrate, dl-methylephedrine hydrochloride, etc.), anti-inflammatory/astringent agents (e.g., epsilon-aminocaproic acid, allantoin, sodium azulene sulfonate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), antihistamines, water-soluble vitamins (sodium flavin adenine dinucleotide, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.), amino acids (e.g., potassium L-aspartate, magnesium L-aspartate, potassium and magnesium L-aspartate (mixture of equal parts), aminoethylsulfonic acid, etc.), and sulfa drugs. When drugs are included, the content of each drug can be selected based on the effective amount of the drug, but it is preferably 0.001 to 5 w/v% in the composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.

Purified water, sterilized water, etc. can be used as the water, and the content of water can be the remainder of the composition. Specifically, the content of water in the composition is preferably 90 to 99.9 w/v %, and more preferably 93 to 98 w/v %.

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

The ophthalmic composition of the present invention is preferably a liquid in order to facilitate application to the eye, and the viscosity at 25°C is preferably 20 mPa·s or less, more preferably 10 mPa·s or less, and even more preferably 5 mPa·s or less. The viscosity is measured using a cone-plate viscometer (DV2T, Eiko Seiki Co., Ltd.).

The ophthalmic composition of the present invention may be prepared as a liquid formulation or as a gel formulation. Specific examples of the form of use include eye drops (e.g., general eye drops, eye drops for contact lenses, etc.), eyewash (general eyewash, eyewash used after removing contact lenses, etc.), contact lens wetting solution, contact lens removal solution, etc. Among these, the ophthalmic composition is suitable as a contact lens ophthalmic composition such as contact lens eye drops, eyewash used after removing contact lenses, contact lens wetting solution, contact lens removal solution, etc. Soft contact lenses are not particularly limited to hard contact lenses, _O2 hard contact lenses, soft contact lenses, silicone hydrogel contact lenses, etc.

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

The present invention also provides the following method for suppressing deterioration in the transmittance of an ophthalmic composition caused by repeated freezing and thawing.
(A) berberine or a salt thereof,
(B) one or more selected from (B1) vitamin A and (B2) vitamin E;
A method for suppressing deterioration of the transmittance of an ophthalmic composition caused by repeated freezing and thawing, comprising blending (C) phenylephrine or a salt thereof with an ophthalmic composition containing (D) a nonionic surfactant. In this method, the preferred components and contents thereof are the same as those described above.

The present invention will be specifically described below 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 1 to 7 are reference examples.

[Examples and Comparative Examples]
Each aqueous component shown in the table below was dissolved in 1,000 mL of water and mixed at 90° C. for 15 minutes to obtain an aqueous component solution. Separately, a mixed solution of components (B) and (D) was prepared and mixed at 90° C. for 15 minutes. Next, a predetermined amount of the mixed solution of components (B) and (D) was added to the aqueous component solution, and further mixed at 90° C. for 15 minutes. At the same time, a mixed solution of components (A) and (C) was prepared and mixed at 40° C. for 10 minutes. A predetermined amount of the mixed solution of components (A) and (C) was added to the aqueous component solution and mixed. Then, the mixture was cooled to room temperature, and water was added to make the total volume 1,000 mL to obtain an ophthalmic composition. The amount in 100 mL is shown in the table. The obtained ophthalmic composition was evaluated as follows. The results are also shown in the table.

[Transmittance (%)]
Immediately after production, 13 mL of the ophthalmic composition was filled into a polyethylene terephthalate eye drop container (15 mL) to prepare a test sample. The freezing (-20°C)/thawing (25°C) operation was repeated five times, and the following evaluations were performed.
[Transmittance (%)]
After freezing and thawing, the samples were allowed to stand in a dark place at room temperature for 3 days, and then the transmittance (wavelength: 600 nm) of each test sample was measured using an ultraviolet-visible-near infrared spectrophotometer (UV-1800, Shimadzu Corporation). Test samples with a transmittance of 90% or more after the fifth freeze-thaw were rated as "◯" (pass), and samples with a transmittance of less than 90% were rated as "×" (fail).

[Precipitation during freezing and thawing (presence or absence of precipitation)]
The samples were repeatedly frozen and thawed 1 to 5 times, and the presence or absence of precipitate was visually confirmed after each freeze-thaw. After any of the freeze-thaw cycles, the samples were judged as "X" if significant precipitate was observed, "O" if slight precipitate was observed, and "◎" if no precipitate was observed. Analysis of the precipitate confirmed that it contained berberine, the component (A).

The raw materials used in the above examples are shown below. Unless otherwise specified, the amounts of each component in the table are calculated as pure amounts.
Berberine chloride hydrate (JP Berberine chloride hydrate, manufactured by Alps Pharmaceutical Co., Ltd.)
Retinol palmitate (retinol palmitate [1.74 million IU/g], manufactured by DSM)
d-α-tocopherol acetate (Riken E Acetate α, manufactured by Riken Vitamin Co., Ltd.)
Phenylephrine hydrochloride: Japanese Pharmacopoeia Phenylephrine Hydrochloride, manufactured by Iwaki Pharmaceutical Co., Ltd. Polyoxyethylene hydrogenated castor oil 60 (HCO60, manufactured by Nippon Surfactant Kogyo Co., Ltd.)
Polyoxyethylene (20) sorbitan monooleate (Rheodol TW-O120V, manufactured by Kao Corporation)
Sodium chondroitin sulfate (non-regulated sodium chondroitin sulfate, manufactured by Maruha Nichiro Co., Ltd.)
Propylene glycol (Japanese Pharmacopoeia Propylene Glycol, manufactured by ADEKA Corporation)
Dipotassium glycyrrhizinate (non-regulated dipotassium glycyrrhizinate, manufactured by Maruzen Pharmaceuticals)

Claims (6)

(A) berberine or a salt thereof,
(B) one or more selected from (B1) vitamin A and (B2) vitamin E;
(C) phenylephrine or a salt thereof,
(D) a nonionic surfactant , and
(E) one or more selected from chondroitin sulfate and its salts, glycyrrhizinic acid and its salts, and propylene glycol
Contains
The content of the component (A) is 0.01 to 0.025 w/v%,
The content of the component (B) is 0.01 to 0.09 w/v%,
The content of the component (C) is 0.1 to 0.6 w/v%,
The content of the component (D) is 0.14 to 0.56 w/v%, and
The content of the component (E) is 0.1 to 1.25 w/v%
13. An ophthalmic composition comprising : The ophthalmic composition according to claim 1, wherein the mass ratio of the components represented by the following formula is 2.4≦((C)+(D))/((A)+(B))≦23. The component (B) is (B1) vitamin A and (B2) vitamin E,
The content of the component (B1) is 0.02 to 0.04 w/v%,
The content of the component (B2) is 0.02 to 0.05 w/v%,
3. The ophthalmic composition according to claim 1 or 2, The ophthalmic composition according to any one of claims 1 to 3, wherein the component (D) is at least one selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol, and polyethylene glycol fatty acid ester. The ophthalmic composition according to any one of claims 1 to 4, wherein the content mass ratio represented by the following formula is 2.0≦((D)+(E))/((A)+(B))≦20. 6. The ophthalmic composition according to any one of claims 1 to 5, wherein the component (E) is at least one member selected from the group consisting of chondroitin sulfate and salts thereof.