Ophthalmic composition, method for photostabilization, and method for inhibiting discoloration

Abstract

To solve the novel problem that component (A) in light exposure becomes unstable and the discoloration of a composition is promoted, when (A) phenylephrine or a salt thereof and (B) vitamin E are used in combination in the composition.SOLUTION: Provided is an ophthalmic composition containing: (A) phenylephrine or its salt; (B) vitamin E:0.020w / v% or more; and (C) one or more selected from boric acid, trometamol, edetic acid, phosphoric acid, citric acid, their salts, borax, sodium chloride, potassium chloride, multivalent alcohols, terpenoids, antihistamine component and mucopolysaccharides.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition containing phenylephrine or a salt thereof, as well as a method for inhibiting discoloration and a method for photostabilization. [Background technology]

[0002] Phenylephrine is an ingredient known as an adrenergic α1 receptor agonist. It has also been shown to have tear film stabilizing effects and meibum secretion promoting effects, making it a promising treatment for dry eye.

[0003] On the other hand, phenylephrine is known to deteriorate and turn brown in its aqueous solution, and methods proposed for stabilizing this include maintaining the pH at around 1, blocking oxygen, and adding chelating agents, antioxidants, and sorbic acid (Patent Document 1: JP 63-33327 A). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 63-33327 Summary of the Invention [Problem to be solved by the invention]

[0005] Vitamin E is a useful component as an antioxidant component, etc. However, when (A) phenylephrine or a salt thereof and (B) vitamin E are combined and blended in a composition, new problems arise in that component (A) becomes unstable and discoloration of the composition is accelerated upon exposure to light. The present invention aims to solve the above problems. [Means for solving the problem]

[0006] As a result of intensive research into achieving the above-mentioned object, the inventors have discovered that the above-mentioned problems can be solved by incorporating into an ophthalmic composition containing (A) phenylephrine or a salt thereof and (B) vitamin E one or more components selected from (C) boric acid, trometamol, edetic acid, phosphoric acid, citric acid, salts thereof, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides, and have thus completed the present invention.

[0007] Therefore, the present invention provides the following inventions. 1. (A) phenylephrine or a salt thereof, (B) Vitamin E: 0.020 w / v% or more, and (C) An ophthalmic composition containing one or more selected from boric acid, trometamol, edetic acid, phosphoric acid, citric acid, salts thereof, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides. 2. The ophthalmic composition according to 1, wherein the content mass ratio represented by (B) / (A) is 0.4 or more. 3. A method for photostabilizing an ophthalmic composition containing (A) phenylephrine or a salt thereof, and (B) vitamin E: 0.020 w / v% or more, comprising blending (C) one or more selected from boric acid, trometamol, edetic acid, phosphoric acid, citric acid, salts thereof, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides. 4. A method for photostabilizing component (A) in an ophthalmic composition containing (A) phenylephrine or a salt thereof, and (B) vitamin E: 0.020 w / v% or more, by incorporating (C) one or more selected from boric acid, trometamol, edetic acid, phosphoric acid, citric acid, salts thereof, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides. 5. A method for inhibiting discoloration of an ophthalmic composition containing (A) phenylephrine or a salt thereof, and (B) vitamin E: 0.020 w / v% or more, comprising blending (C) one or more selected from boric acid, trometamol, edetic acid, phosphoric acid, citric acid, salts thereof, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides. Effect of the Invention

[0008] According to the present invention, it is possible to provide an ophthalmic composition in which, when (A) phenylephrine or a salt thereof and (B) vitamin E are combined and incorporated into an ophthalmic composition, destabilization of component (A) and discoloration of the ophthalmic composition upon exposure to light are suppressed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] [Component (A)] The component (A) is one or more selected from phenylephrine and its salts, and may be used alone or in combination of two or more. For example, phenylephrine salts include phenylephrine hydrochloride, phenylephrine acetate, and other pharma- ceutical acceptable salts.

[0010] The amount of component (A) in the ophthalmic composition is preferably 0.01 to 5 w / v% (mass / volume%, g / 100 mL, the same applies below), more preferably 0.02 to 1 w / v%, even more preferably 0.05 to 0.2 w / v%, and particularly preferably 0.05 to 0.1 w / v%. By making the amount 0.01 w / v% or more, the vasoconstriction effect, mydriatic effect, and meibum secretion promotion effect are more effectively exhibited, and the above-mentioned problems are more likely to occur, and by making the amount within the more preferable range, the effect of component (C) in suppressing the destabilization of component (A) and discoloration of the ophthalmic composition due to exposure to light when (A) phenylephrine or a salt thereof and (B) vitamin E are combined and incorporated into the ophthalmic composition (hereinafter, may be simply referred to as photostabilization effect) is more effectively exhibited.

[0011] [(B) Component] The component (B) is vitamin E, and is used as a general term for, for example, tocopherol, tocotrienol, their salts, and derivatives (esters). Specific examples include d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and the like, and examples of derivatives thereof include vitamin E acetate (tocopherol acetate), vitamin E nicotinate, vitamin E succinate, vitamin E linoleate, and the like, and one type can be used alone or two or more types can be used in appropriate combination. Among them, tocopherol acetate (d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.) is preferred.

[0012] The blending amount of the (B) component in the ophthalmic composition is 0.020 w / v% or more, preferably 0.020 to 0.1 w / v%, more preferably 0.025 to 0.1 w / v%, and even more preferably 0.03 to 0.05 w / v%. By making it 0.020 w / v% or more, the effect of blending the (B) component is easily exhibited, and the above-mentioned problems are easily caused. By making it in the more preferable range, the light stabilization effect of the (C) component is more effectively exhibited.

[0013] The content mass ratio represented by (B) / (A) is preferably 0.4 or more, and more preferably 0.4 to 1. If the content mass ratio is 0.4 or more, the effects of components (A) and (B) are easily exhibited, but the above-mentioned problems are likely to occur. On the other hand, if the content mass ratio is 1 or less, the light stabilizing effect of component (C) is more effectively exhibited. Note that the ratio is a w / v% ratio, but is the same value as the mass ratio.

[0014] [(C) component] The component (C) is one or more selected from boric acid, trometamol, edetic acid, phosphoric acid, citric acid, salts thereof, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides, and can be used alone or in combination of two or more. The incorporation of the component (C) can provide a light stabilizing effect.

[0015] Examples of edetic acid and its salts include sodium edetate and sodium edetate hydrate. Examples of phosphoric acid and its salts include sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. Citric acid and its salts include sodium citrate, citric acid monohydrate, and the like.

[0016] Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol, with propylene glycol being preferred. Examples of terpenoids include menthol, camphor, borneol, geraniol, cineol, linalool, etc., and may be in the d-, l- or dl-form, with l-menthol being preferred. Antihistamine components include chlorpheniramine and its salts, diphenhydramine and its salts, etc., with chlorpheniramine maleate being preferred. Examples of mucopolysaccharides include chondroitin sulfate and its salts, hyaluronic acid and its salts, and the like, with sodium chondroitin sulfate being preferred.

[0017] The amount of component (C) to be added is appropriately selected from the range of 0.001 to 5 w / v % in the ophthalmic composition. The preferred ranges for each component are as follows: The blending amount of boric acid and its salts in the ophthalmic composition is preferably 0.1 to 5 w / v %, more preferably 0.2 to 3 w / v %, and even more preferably 0.5 to 2 w / v %. The amount of trometamol or a salt thereof in the ophthalmic composition is preferably 0.01 to 2 w / v %, more preferably 0.03 to 1.5 w / v %, and even more preferably 0.05 to 1 w / v %. The blending amount of edetic acid and its salts in the ophthalmic composition is preferably 0.001 to 0.2 w / v %, more preferably 0.005 to 0.15 w / v %, and even more preferably 0.01 to 0.1 w / v %. The amount of phosphoric acid and its salts in the ophthalmic composition is preferably 0.05 to 2.0 w / v%, more preferably 0.1 to 1.5 w / v%, further preferably 0.1 to 0.8 w / v%, and particularly preferably 0.2 to 0.5 w / v%. The blending amount of citric acid and salts thereof in the ophthalmic composition is preferably 0.01 to 1 w / v %, more preferably 0.05 to 0.5 w / v %, and even more preferably 0.1 to 0.2 w / v %. The blending amount of borax in the ophthalmic composition is preferably 0.01 to 2 w / v %, more preferably 0.02 to 1.0 w / v %, and even more preferably 0.05 to 0.6 w / v %. The amount of sodium chloride or potassium chloride blended in the ophthalmic composition is preferably 0.01 to 2 w / v%, more preferably 0.05 to 1.5 w / v%, even more preferably 0.1 to 1 w / v%, and particularly preferably 0.1 to 0.5 w / v%. The amount of the polyhydric alcohol in the ophthalmic composition is preferably 0.1 to 5 w / v %, more preferably 0.2 to 3 w / v %, and even more preferably 0.5 to 2 w / v %. The amount of the terpenoid in the ophthalmic composition is preferably 0.001 to 0.1 w / v %, more preferably 0.002 to 0.05 w / v %, and even more preferably 0.003 to 0.03 w / v %. The amount of the antihistamine component in the ophthalmic composition is preferably 0.001 to 0.1 w / v %, more preferably 0.003 to 0.08 w / v %, and even more preferably 0.005 to 0.05 w / v %. The amount of mucopolysaccharide in the ophthalmic composition is preferably 0.01 to 1 w / v %, more preferably 0.02 to 0.9 w / v %, and even more preferably 0.03 to 0.8 w / v %.

[0018] The content mass ratio represented by (C) / (A) is appropriately selected from the range of 0.01 to 50 from the viewpoint of the light stabilizing effect, and the preferred ranges of each component are as follows: In the case of boric acid and its salts, 1-50 is preferable, 2-30 is more preferable, and 5-20 is even more preferable. In the case of trometamol, the concentration is preferably 0.1 to 30, more preferably 0.3 to 20, and even more preferably 0.5 to 10. In the case of edetic acid and its salts, the concentration is preferably 0.01 to 5, more preferably 0.05 to 1.5, and even more preferably 0.1 to 1. In the case of phosphoric acid and its salts, 0.5 to 20 is preferable, 1 to 15 is more preferable, 1 to 8 is further preferable, and 2 to 5 is particularly preferable. In the case of citric acid and its salts, the ratio is preferably 0.1 to 10, more preferably 0.5 to 5, and even more preferably 1 to 2. In the case of borax, the concentration is preferably 0.1-20, more preferably 0.2-10, and even more preferably 0.5-6. In the case of sodium chloride or potassium chloride, the amount is preferably 0.1 to 20, more preferably 0.5 to 15, further preferably 1 to 10, and particularly preferably 1 to 5. In the case of polyhydric alcohols, 1-50 is preferable, 2-30 is more preferable, and 5-20 is even more preferable. In the case of terpenoids, the content is preferably 0.01 to 1, more preferably 0.02 to 0.5, and even more preferably 0.03 to 0.3. In the case of an antihistamine component, the concentration is preferably 0.01 to 1, more preferably 0.03 to 0.8, and even more preferably 0.05 to 0.5. In the case of mucopolysaccharides, 0.1-10 is preferable, 0.2-9 is more preferable, and 0.3-8 is even more preferable.

[0019] [Other ingredients] The ophthalmic composition of the present invention may contain other components to be added to the ophthalmic composition in an appropriate amount, so long as the effects of the present invention are not impaired. Examples of other components include surfactants, preservatives, sugars, buffers, pH adjusters, isotonicity agents, stabilizers, thickeners, oily components, and drugs other than antihistamine components. These components may be added alone or in combination of two or more. The amounts of the components shown below are the preferred ranges when added, and are the amounts in the ophthalmic composition.

[0020] The surfactant is preferably a nonionic surfactant. The nonionic surfactant is not particularly limited, and the nonionic surfactant used in the ophthalmic composition can be used alone or in combination of two or more. Specifically, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and other nonionic surfactants than those mentioned above can be mentioned.

[0021] 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 is exemplified as 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). These polyoxyethylene castor oils can be used alone or in appropriate combination of two or more. From the viewpoint of reducing the irritation felt when instilled into the eyes, it is preferable to use polyoxyethylene castor oil 35, and it is preferable to use one that complies with the Pharmaceutical Additives Standards 2003.

[0022] 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. The average added moles of ethylene oxide in polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified as 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (EO average number of added moles: 5), polyoxyethylene hydrogenated castor oil 10 (EO average number of added moles: 10), polyoxyethylene hydrogenated castor oil 20 (EO average number of added moles: 20), polyoxyethylene hydrogenated castor oil 30 (EO average number of added moles: 30), polyoxyethylene hydrogenated castor oil 40 (EO average number of added moles: 40), polyoxyethylene hydrogenated castor oil 50 (EO average number of added moles: 50), polyoxyethylene hydrogenated castor oil 60 (EO average number of added moles: 60), polyoxyethylene hydrogenated castor oil 80 (EO average number of added moles: 80), polyoxyethylene hydrogenated castor oil 100 (EO average number of added moles: 100), etc. can be mentioned. These polyoxyethylene hydrogenated castor oils can be used alone or in appropriate combination of two or more. From the viewpoint of reducing the irritation when applied to the eye, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60. It is preferable to use one that complies with the Pharmaceutical Additives Standards 2003, and a commercially available product such as polyoxyethylene (60) hydrogenated castor oil: HCO-60, manufactured by Nippon Surfactant Kogyo Co., Ltd., is mentioned.

[0023] Specific examples of polyoxyethylene 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). These polyoxyethylene sorbitan fatty acid esters can be used alone or in appropriate combination of two or more. Among them, it is preferable to use polyoxyethylene (20) sorbitan monooleate (polysorbate 80). Examples of commercially available products include polysorbate 80 (Rheodol TW-O120V, manufactured by Kao Corporation).

[0024] Other nonionic surfactants include polyoxyethylene polyoxypropylene glycol (POEPOP glycol) such as poloxamer, polyethylene glycol monostearate (10), polyethylene glycol monostearate (40), and the like.

[0025] When a nonionic surfactant is added, the amount of the nonionic surfactant added is not particularly limited as long as the above ratio is satisfied, but the amount is preferably 0.0001 to 10 w / v %, and more preferably 0.0001 to 5 w / v %, in the ophthalmic composition. When polyoxyethylene castor oil is included, the amount of the polyoxyethylene castor oil in the ophthalmic composition is preferably 0.003 to 10 w / v %, more preferably 0.003 to 5 w / v %, and even more preferably 0.03 to 1 w / v %. When polyoxyethylene hydrogenated castor oil is added, its content in the ophthalmic composition is preferably 0.003 to 10 w / v %, more preferably 0.003 to 5 w / v %, and even more preferably 0.03 to 1 w / v %. When the nonionic surfactant is incorporated, the amount thereof in the ophthalmic composition is preferably 0.0003 to 1 w / v %, more preferably 0.0003 to 0.5 w / v %, and even more preferably 0.003 to 0.2 w / v %.

[0026] Examples of preservatives include benzalkonium chloride, benzethonium chloride, thimerosal, phenylethyl alcohol, alkyl polyaminoethyl glycine, alkyl diaminoethyl glycine and / or a salt thereof (e.g., alkyl diaminoethyl glycine hydrochloride), chlorhexidine gluconate, methyl paraoxybenzoate, ethyl paraoxybenzoate, ethyl propyl paraoxybenzoate, sodium benzoate, sorbic acid, boric acid, borax, sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogensulfite, potassium hydrogensulfite and other sulfites, chlorobutanol, oxyquinoline sulfate, benzyl alcohol, polyhexamethylene biguanide, and polydonium chloride. When a preservative is added, its content in the composition can be 0.0001 to 0.5 w / v%, but is preferably 0.1 w / v% or less, more preferably 0.01 w / v% or less, even more preferably 0.005 w / v% or less, particularly preferably 0.001 w / v% or less, and most preferably 0.0001 w / v% or less. In addition, when dry eyes or dry eye symptoms are present or for the prevention thereof, it is preferable not to add a preservative.

[0027] Examples of the sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc. These may be in the D-, L- or DL-form. When the sugars are incorporated, the amount of the sugars incorporated 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% in the ophthalmic composition.

[0028] Examples of the buffering agent include glacial acetic acid, sodium hydrogen carbonate, etc. When a buffering agent is added, the amount of the buffering agent added 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 % in the ophthalmic composition.

[0029] Examples of the pH adjuster include inorganic acids and inorganic alkali agents. For example, an example of an inorganic acid is (dilute) hydrochloric acid. Examples of the inorganic alkali agent include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. The pH of the ophthalmic composition can be 3.5 to 13.0, and is preferably 3.5 to 8.0, and more preferably 5.5 to 7.5, from the viewpoint of further improving various symptoms caused by destabilization of the tear lipid layer. The pH is measured at 25°C using a pH meter (HM-25R, Toa DKK Corporation).

[0030] Examples of isotonicity agents include calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. The osmotic pressure ratio of the ophthalmic 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, from the viewpoint of further improving various symptoms caused by destabilization of the tear lipid layer. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 17th revised Japanese Pharmacopoeia. In the present invention, the osmotic pressure is measured at 25°C using an automatic osmometer (A2O, Advanced Instruments).

[0031] Examples of the stabilizer include cyclodextrin, sulfite (water-soluble antioxidant), dibutylhydroxytoluene (fat-soluble antioxidant), etc. When a stabilizer is added, the amount of the stabilizer added 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% in the ophthalmic composition.

[0032] Examples of the thickening agent include water-soluble polymer compounds, such as polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymer, etc. When a thickening agent is added, the amount of the thickening agent added 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% in the ophthalmic composition.

[0033] Examples of oily components include soybean oil, olive oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglyceride, liquid paraffin, white petrolatum, refined lanolin, cholesterol, etc. The amount of the oily component in the ophthalmic 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%.

[0034] Examples of drugs (pharmaceutical active ingredients) other than antihistamine ingredients include congestion relief ingredients (e.g., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, dl-methylephedrine hydrochloride, etc.), anti-inflammatory and astringent agents (e.g., neostigmine methylsulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, etc.), and Examples of vitamins that are essential for the synthesis of vitamin C include vitamin D3, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.), fat-soluble vitamins (vitamin A), amino acids (e.g. potassium L-aspartate, magnesium L-aspartate, potassium and magnesium L-aspartate (equal mixture), aminoethylsulfonic acid, etc.), and sulfa drugs.

[0035] Examples of the 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. One type can be used alone or two or more types can be used in appropriate combination. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Among these, retinol palmitate, retinol acetate, and retinoic acid are preferred. Retinol palmitate is usually commercially available with 1 to 1.8 million international units / g (hereinafter abbreviated as IU / g), and specific examples include retinol palmitate [1.74 million IU / g] manufactured by DSM and retinol palmitate manufactured by Sigma-Aldrich.

[0036] When a drug other than an antihistamine component is added, the amount of the drug can be selected based on the effective amount of each drug, but the amount 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% in the ophthalmic composition.

[0037] [Ophthalmic composition] The ophthalmic composition of the present invention is preferably an "aqueous ophthalmic composition". In the present invention, the "aqueous ophthalmic composition" refers to an ophthalmic composition whose medium is water. The content of water in the ophthalmic composition is preferably 90.0 to 99.5 w / v%, more preferably 95.0 to 98.0 w / v%.

[0038] The viscosity of the ophthalmic composition at 25°C is preferably 1.1 to 50 mPa·s, more preferably 40 mPa·s or less, 30 mPa·s or less, 20 mPa·s or less, 15 mPa·s or less, 12 mPa·s or less, 10 mPa·s or less, 8 mPa·s or less, 5 mPa·s or less, and 4 mPa·s or less, and particularly preferably 3 mPa·s or less. The viscosity of the ophthalmic composition of the present invention is measured at 25°C using a B-type rotational viscometer according to the method described in the "Single cylindrical rotational viscometer (Brookfield type viscometer)" of the "Second rotational viscometer method" of the "Viscosity measurement method" of the general test method described in the 17th revised Japanese Pharmacopoeia. The conditions such as the rotor to be used and the rotation speed are selected depending on the viscosity range. The measuring device may be a cone-plate type viscometer (for example, DV2T (Eiko Seiki Co., Ltd.)).

[0039] Color of the ophthalmic composition (b * ) is preferably less than 0.7, more preferably 0.65 or less, and even more preferably 0.6 or less, from the viewpoint of preventing discoloration.

[0040] The formulation of the ophthalmic composition of the present invention is not particularly limited, and can be suitably used, for example, as eye drops (including eye drops that can be applied while wearing contact lenses), eyewash, contact lens wetting solution, contact lens removal solution, etc. In particular, it can be suitably used as eye drops and contact lens wetting solution, and eye drops are particularly preferred. Among these, it is suitable as an ophthalmic composition for contact lenses used by contact lens wearers, such as eye drops that can be applied while wearing contact lenses, contact lens wetting solution, contact lens removal solution, etc.

[0041] Contact lenses include, but are not limited to, hard contact lenses (including O2 hard contact lenses), soft contact lenses (including both ionic and non-ionic), silicone hydrogel contact lenses, colored contact lenses, etc. When no preservative is added, the composition is particularly suitable for soft contact lenses and silicone hydrogel contact lenses.

[0042] [How to use] In the case of eye drops (including eye drops for contact lenses), it is preferable to instill 1 to 3 drops of 5 to 100 μL at one time, 1 to 6 times per day, more preferably 1 to 3 drops of 10 to 50 μL at one time, 1 to 6 times per day, and even more preferably 1 to 3 drops of 10 to 30 μL at one time, 1 to 6 times per day. In the case of an eyewash, it is preferable to use 1 to 20 mL per time, more preferably 1 to 10 mL, and even more preferably 3 to 6 mL. It is preferable to wash the eyes 1 to 6 times a day, and more preferably 3 to 6 times a day. In the case of a contact lens wetting solution, it is preferable to apply 1 to 3 drops, and more preferably 1 to 2 drops, to a contact lens each time.

[0043] [Manufacturing method] The method for producing the ophthalmic composition of the present invention is not particularly limited, but for example, a mixed solution containing an oily component such as component (B) is mixed with an aqueous solution containing aqueous components such as components (A) and (C) to emulsify, and after adjusting the pH, the total volume is adjusted with water to obtain the composition. The method for mixing each liquid may be a general method, and is appropriately performed using a pulsator, propeller blade, paddle blade, turbine blade, etc., but the rotation speed is not particularly limited, and it is preferable to set it to a level that does not cause vigorous foaming. The mixing temperature of each liquid is not particularly limited, but it is preferable that both the oily component and the surfactant component are at or above the melting temperature, and specifically, it is appropriately selected from the range of 40 to 95 ° C.

[0044] [Container, packaging] The obtained ophthalmic composition may be filled into a resin container and then sealed with a packaging material, and an inert gas such as nitrogen may be sealed in the space formed between the container and the packaging material. Alternatively, the composition may be filled into a resin container and then sealed with a packaging material together with an oxygen scavenger.

[0045] The container is preferably a plastic container, and may be made of a material such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, vinyl chloride, or a composite of these materials. Polyethylene terephthalate is particularly preferred. The amount of the ophthalmic composition in the product can be appropriately selected depending on the product and its method of use. For example, in the case of eye drops, the amount is preferably 2 to 20 mL, more preferably 5 to 20 mL. The container for the ophthalmic composition is not particularly limited, and may be a multi-dose (multi-unit) container or a single-use unit-dose container. A multi-dose (multi-unit) container is preferred.

[0046] The obtained ophthalmic composition may be filled into a resin container and then further sealed with a packaging material, and an inert gas may be sealed in the space formed between the container and the packaging material. Alternatively, the ophthalmic composition may be filled into a resin container and then sealed with a packaging material together with an oxygen scavenger.

[0047] The inner stopper and cap can be made of a material used for containers of known ophthalmic products. The inner stopper is preferably made of polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8. The cap is preferably made of polyethylene or polypropylene.

[0048] [Photostabilization method] The present invention provides the following photostabilization method. The preferred components and amounts are the same as those described above. A method for photostabilizing an ophthalmic composition containing (A) phenylephrine or a salt thereof, and (B) vitamin E: 0.020 w / v% or more, comprising blending (C) one or more selected from boric acid, trometamol, edetic acid, phosphoric acid, citric acid, salts thereof, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides.

[0049] Incidentally, "photostabilization" refers to a method of stabilization against light (light exposure). In the present invention, when (A) phenylephrine or a salt thereof and (B) vitamin E are combined and incorporated into an ophthalmic composition, component (C) plays a role in stabilization. There are no particular limitations on the amount of light exposure, but the "Guidelines for photostability testing of new drug substances and new preparations" require exposure to light with a total illuminance of "1.2 million Lux·hr," and based on this, the amount is appropriately selected while taking into consideration the expiration date of the ophthalmic composition after opening. In the present invention, the method of the examples is adopted.

[0050] The term "photostabilization" includes the above-mentioned (A) stabilization of phenylephrine or a salt thereof, and the present invention provides the following stabilization method. The preferred ingredients and amounts are the same as those described above. A method for photostabilizing component (A) of an ophthalmic composition containing (A) phenylephrine or a salt thereof, and (B) vitamin E: 0.020 w / v% or more, by blending (C) one or more selected from boric acid, trometamol, edetic acid, phosphoric acid, citric acid, salts thereof, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides.

[0051] [How to prevent discoloration] The present invention provides the following discoloration suppression method. The preferred components and amounts are the same as those described above. A method for inhibiting discoloration of an ophthalmic composition comprising (A) phenylephrine or a salt thereof, and (B) vitamin E: 0.020 w / v% or more, and (C) one or more selected from boric acid, trometamol, edetic acid, phosphoric acid, citric acid, salts thereof, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides.

[0052] The above-mentioned discoloration suppression method is a method in which the component (C) suppresses discoloration of an ophthalmic composition exposed to light when the ophthalmic composition contains (A) phenylephrine or a salt thereof and (B) vitamin E in combination. The amount of light exposure is the same as above.

[0053] The discoloration suppression effect is shown in Comparative Example 4 after light irradiation. * It is sufficient that the discoloration is suppressed, and the discoloration suppression rate is preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, 60% or more, or 70% or more. EXAMPLES

[0054] The present invention will be described in detail below with reference to examples, comparative examples and formulation examples, but the present invention is not limited to the following examples. 。 In the following examples, unless otherwise specified, "%" in the composition indicates "w / v% (g / 100 mL)" and ratios indicate w / v% ratios (mass ratios). Example 6 is a reference example.

[0055] [Examples and Comparative Examples] Each aqueous component including the (A) component, (C) component, etc. shown in the table below was dissolved in 1,000 mL of water, and heated and mixed at 90°C for 15 minutes to obtain an aqueous component solution. Separately, a mixed solution of oily components including the (B) component, etc. was heated at 90°C for 15 minutes. Next, a predetermined amount of the heated oily component mixed solution was added to the aqueous component solution, and further heated and mixed at 90°C for 15 minutes. After that, it was cooled to room temperature, and water was added to make the total volume 1,000 mL to obtain an ophthalmic composition. The following photostability test was performed on the obtained ophthalmic composition. The results are shown in the table. The amounts in 100 mL are shown in the table.

[0056] <Discoloration prevention test> The chromaticity (L * , a * , b * After that, 10 mL of the solution was poured into a transparent container (capacity 10 mL) made of PET (polyethylene terephthalate) to prepare a test sample. The test samples were exposed to 15,000 Lux of light from a fluorescent light source at room temperature for 72 hours, resulting in a cumulative exposure of 1,080,000 Lux·hr. After the exposure, the chromaticity (L * , a* , b * ) and b * was used as an index of discoloration (yellow to brownish color), and the discoloration inhibition rate was calculated by the following formula. (a) Visual appearance after testing ○: No discoloration observed ×: Discoloration is observed (b) Discoloration inhibition rate Discoloration inhibition rate (%) = ((Δb * -Δb of the test sample * ) / (Δb of control * ))×100 Δb * = b after light irradiation * -b before light exposure * Δb of control * : Δb of Comparative Example 4 *

[0057] <Phenylephrine stability test> The content of phenylephrine hydrochloride in the preserved samples from the above discoloration inhibition test was measured by high performance liquid chromatography. (survival rate) The residual rate (%) of phenylephrine hydrochloride was calculated from the obtained phenylephrine hydrochloride content according to the following formula. Phenylephrine hydrochloride residual rate (%) = (phenylephrine hydrochloride content after discoloration inhibition test / phenylephrine hydrochloride content immediately after manufacture) x 100

[0058] [Table 1]

[0059] [Table 2]

[0060] [Table 3]

[0061] [Table 4]

[0062] [Prescription example] Ophthalmic compositions having the compositions shown in the following table were prepared in the same manner as in the above Examples. The obtained ophthalmic compositions exhibited the same discoloration suppression effect as in the above Examples.

[0063] [Table 5]

[0064] [Table 6]

[0065] [Table 7]

[0066] [Table 8]

[0067] [Table 9]

[0068] [Table 10]

[0069] [Table 11]

[0070] [Table 12]

[0071] [Table 13]

[0072] The raw materials used in preparing the Examples, Comparative Examples, and Formulation Examples are shown below. The amount of each component in the table is the amount converted to the pure content.

[0073] 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. Phenylephrine hydrochloride: Phenylephrine hydrochloride (crystal), manufactured by Iwaki Pharmaceutical Co., Ltd. d-α-Tocopherol acetate: Riken E Acetate α, manufactured by Riken Vitamin Co., Ltd. Boric acid: Boric acid, manufactured by Kanto Chemical Co., Ltd. Borax: Borax (powder), manufactured by Kosakai Pharmaceutical Co., Ltd. Trometamol: 2-amino-2-hydroxymethyl-1,3-propanediol, manufactured by Kanto Chemical Co., Ltd. Sodium edetate hydrate: Crewat N, manufactured by Nagase Chemtex Corporation Sodium chloride: Sodium chloride (for injection) according to the Japanese Pharmacopoeia, manufactured by Tomita Pharmaceutical Co., Ltd. l-Menthol: l-Menthol (mint), manufactured by Suzuki Mint Co., Ltd. Propylene glycol: ADEKA Chlorpheniramine maleate: Chlorpheniramine maleate (chlorpheniramine maleate), manufactured by Kongo Chemical Co., Ltd. Chondroitin sulfate sodium: Non-standard chondroitin sulfate sodium, manufactured by Maruha Nichiro Co., Ltd. Polyoxyethylene hydrogenated castor oil 60: NIKKOL HCO-60 (medical use), manufactured by Nippon Surfactant Kogyo Co., Ltd. Polysorbate 80: Polyoxyethylene (20) sorbitan monooleate: Rheodol TW-O120V, manufactured by Kao Corporation

Claims

1. (A) phenylephrine or a salt thereof: 0.05 to 0.1 w / v%, (B) Vitamin E: 0.020 w / v% or more, and (C) containing one or more selected from boric acid, trometamol, sodium edetate, sodium edetate hydrate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, citric acid monohydrate, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components, and mucopolysaccharides; The polyhydric alcohol is at least one selected from glycerin, propylene glycol, butylene glycol, and polyethylene glycol; The terpenoid is one or more selected from menthol, camphor, borneol, geraniol, cineole, and linalool; the antihistamine component is one or more selected from chlorpheniramine and its salts, and diphenhydramine and its salts; The mucopolysaccharide is at least one selected from the group consisting of chondroitin sulfate and its salts, and hyaluronic acid and its salts; The amount of component (C) In the case of boric acid and its salts, 0.1 to 2 w / v% in the ophthalmic composition In the case of trometamol, 0.01 to 1 w / v% in the ophthalmic composition; In the case of sodium edetate and sodium edetate hydrate, the concentration is 0.01 to 0.1 w / v% in the ophthalmic composition. In the case of sodium hydrogen phosphate and sodium dihydrogen phosphate, the amount is 0.2 to 0.5 w / v % in the ophthalmic composition. In the case of sodium citrate and citric acid monohydrate, the concentration is 0.1 to 0.2 w / v % in the ophthalmic composition. In the case of borax, 0.01 to 0.6 w / v% in the ophthalmic composition; In the case of sodium chloride or potassium chloride, the amount is 0.01 to 0.5 w / v % in the ophthalmic composition. In the case of polyhydric alcohols, the amount is 0.1 to 2 w / v % in the ophthalmic composition. In the case of terpenoids, 0.001 to 0.03 w / v% in the ophthalmic composition; In the case of an antihistamine component, 0.005 to 0.05 w / v % in the ophthalmic composition; In the case of mucopolysaccharides, the content is 0.03 to 0.8 w / v % in the ophthalmic composition. An ophthalmic composition having a content mass ratio represented by (B) / (A) of 0.4 to 1.

2. (A') at least one selected from the group consisting of ashitazanolast and a salt thereof, (B') a decongestant, and (C') The ophthalmic composition according to claim 1, excluding an aqueous composition comprising at least one member selected from the group consisting of (c'-1) thiosulfates, (c'-2) sulfites, (c'-3) ethylenediaminetetraacetic acid or a salt thereof, (c'-4) citric acid or a salt thereof, (c'-5) vitamin E, (c'-6) benzalkonium chloride, (c'-7) sorbic acid or a salt thereof, (c'-8) alkyldiaminoethylglycine or a salt thereof, (c'-9) benzethonium chloride, (c'-10) allantoin, and (c'-11) a polyoxyethylene sorbitan fatty acid ester.

3. An ophthalmic composition comprising (A) phenylephrine or a salt thereof: 0.05 to 0.1 w / v % and (B) vitamin E: 0.020 w / v % or more, and (C) one or more selected from boric acid, trometamol, sodium edetate, sodium edetate hydrate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, citric acid monohydrate, borax, sodium chloride, potassium chloride, polyhydric alcohols, terpenoids, antihistamine components and mucopolysaccharides, The polyhydric alcohol is at least one selected from glycerin, propylene glycol, butylene glycol, and polyethylene glycol; The terpenoid is one or more selected from menthol, camphor, borneol, geraniol, cineole, and linalool; the antihistamine component is one or more selected from chlorpheniramine and its salts, and diphenhydramine and its salts; The mucopolysaccharide is at least one selected from the group consisting of chondroitin sulfate and its salts, and hyaluronic acid and its salts; The amount of component (C) In the case of boric acid and its salts, 0.1 to 2 w / v% in the ophthalmic composition In the case of trometamol, 0.01 to 1 w / v% in the ophthalmic composition; In the case of sodium edetate and sodium edetate hydrate, the concentration is 0.01 to 0.1 w / v% in the ophthalmic composition. In the case of sodium hydrogen phosphate and sodium dihydrogen phosphate, the amount is 0.2 to 0.5 w / v % in the ophthalmic composition. In the case of sodium citrate and citric acid monohydrate, the concentration is 0.1 to 0.2 w / v % in the ophthalmic composition. In the case of borax, 0.01 to 0.6 w / v% in the ophthalmic composition; In the case of sodium chloride or potassium chloride, the amount is 0.01 to 0.5 w / v % in the ophthalmic composition. In the case of polyhydric alcohols, the amount is 0.1 to 2 w / v % in the ophthalmic composition. In the case of terpenoids, 0.001 to 0.03 w / v% in the ophthalmic composition; In the case of an antihistamine component, 0.005 to 0.05 w / v % in the ophthalmic composition; In the case of mucopolysaccharides, the content is 0.03 to 0.8 w / v % in the ophthalmic composition. The method for inhibiting discoloration of an ophthalmic composition as described above, wherein the content mass ratio represented by (B) / (A) is 0.4 to 1.

4. The ophthalmic composition comprises: (A') at least one selected from the group consisting of ashitazanolast and a salt thereof; (B') a decongestant, and (C') The method for inhibiting discoloration of an ophthalmic composition according to claim 3, which is an ophthalmic composition other than an aqueous composition, characterized in containing at least one selected from the group consisting of (c'-1) thiosulfates, (c'-2) sulfites, (c'-3) ethylenediaminetetraacetic acid or a salt thereof, (c'-4) citric acid or a salt thereof, (c'-5) vitamin E, (c'-6) benzalkonium chloride, (c'-7) sorbic acid or a salt thereof, (c'-8) alkyldiaminoethylglycine or a salt thereof, (c'-9) benzethonium chloride, (c'-10) allantoin, and (c'-11) polyoxyethylene sorbitan fatty acid esters.

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