JP2018024662A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ophthalmic composition that can improve various symptoms of eyes.SOLUTION: An ophthalmic composition contains (A) at least one selected from the vitamin A group of 40,000-200,000 IU/100 mL, (B) at least one selected from the group consisting of butylhydroxyanisol and a salt thereof, and (C) at least one component selected from the group consisting of a decongestant, a muscle eye regulator, an anti-inflammatory agent, a vitamin agent, an amino acid and a thickener.SELECTED DRAWING: None

Description

  The present invention relates to ophthalmic compositions.

  Many ophthalmic compositions are marketed to relieve or prevent eye symptoms such as eye fatigue, conjunctival redness, blurred vision, blepharitis, itchy eyes, light-induced ophthalmitis, and eye disease. ,It is used. These ophthalmic compositions are normally approved as active ingredients for ophthalmic preparations for over-the-counter medicines. Decongestants, eye muscle modifiers, anti-inflammatory agents, antihistamines, vitamins, amino acids, sulfa antibacterial agents It is prepared by combining components such as inorganic salts, polymer thickeners, preservatives, and other additives in combination (for example, Patent Document 1).

JP 2004-59479 A

  In recent years, there has been a demand for an ophthalmic composition that can improve eye symptoms more effectively due to the overuse of the eye due to the spread of personal computers, the spread of contact lenses, and the increased scattering of antigenic substances.

  An object of the present invention is to provide an ophthalmic composition that can improve various symptoms of the eye.

  The present inventors include (B) at least one selected from the group consisting of (B) butylhydroxyanisole and a salt thereof, and (C) decongestion in at least one selected from a predetermined amount of (A) vitamin A. An ophthalmic composition containing a combination of at least one component selected from the group consisting of an agent, an eye muscle modulator, an anti-inflammatory agent, a vitamin agent, an amino acid, and a thickener effectively reduces various symptoms of the eye I found that it can be improved. The present invention is based on this novel finding.

The present invention provides the following inventions, for example.
[1]
(A) 40-200,000 IU / 100 mL of at least one selected from vitamins A, (B) at least one selected from the group consisting of butylhydroxyanisole and salts thereof, and (C) a decongestant An ophthalmic composition comprising at least one component selected from the group consisting of an eye muscle modifier, an anti-inflammatory agent, a vitamin agent, amino acids, and a thickener.
[2]
The ophthalmic composition according to [1], further comprising (D) at least one selected from the group consisting of dibutylhydroxytoluene and salts thereof.
[3]
The ophthalmic composition according to [1] or [2], further comprising (E) a terpenoid.
[4]
The ophthalmic composition according to any one of [1] to [3], which is used for improving complex eye symptoms.

  According to the present invention, an ophthalmic composition that can improve various symptoms of the eye can be provided.

  Hereinafter, embodiments for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

  The ophthalmic composition according to this embodiment comprises (A) at least one selected from vitamin A (also referred to as “(A) component”) 40,000 to 200,000 IU / 100 mL, and (B) butylhydroxyanisole. And at least one selected from the group consisting of salts thereof (also referred to as “component (B)”), and (C) a decongestant, an eye muscle regulator, an anti-inflammatory agent, a vitamin agent, amino acids, and thickening Contains at least one component selected from the group consisting of agents (also referred to as “component (C)”).

[Component (A)]
The vitamin A as component (A) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of vitamin A include, for example, retinol (vitamin A1), 3-dehydroretinol (vitamin A2) and derivatives thereof, and salts thereof.

  Examples of the vitamin A derivatives include, for example, retinol palmitate, retinol acetate, retinol butyrate, retinol propionate, retinol octylate, retinol laurate, retinol oleate, and retinol linolenate and other monovalent carboxylic acids. Examples include esters.

  The form of the salt of vitamin A is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Carboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.), oxy Carboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salt (eg, hydrochloride, sulfate) , Nitrates, hydrobromides, phosphates, etc.) and salts with organic bases (eg methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.) Salt, etc.), salt with an inorganic base [for example, ammonium salts; alkali metal (sodium, potassium etc.), alkaline earth metal (calcium, magnesium etc.), salts with metals such as aluminum, etc.] and the like. One of these salts may be selected and used alone, or two or more may be used in any combination.

  As vitamin A, a derivative of retinol is preferable, an ester of retinol and a monovalent carboxylic acid is more preferable, and retinol palmitate and retinol acetate are more preferable.

  As vitamin A, a synthetic product may be used, or an extract obtained from a natural product (for example, vitamin A oil or the like) may be used. Vitamin A oil is a fatty oil obtained from animal tissue containing retinol, or a concentrate thereof, or a vegetable oil added to them. Commercially available vitamin A can be used. Vitamin A may be used individually by 1 type, or may be used in combination of 2 or more type.

  The content of the component (A) in the ophthalmic composition according to this embodiment is preferably such that the total content of the component (A) is 40,000 to 200,000 IU / 100 mL based on the total amount of the ophthalmic composition. More preferably, it is 40,000 to 100,000 IU / 100 mL, more preferably 45,000 to 60,000 IU / 100 mL, and more preferably 48,000 to 550,000 IU / 100 mL. Is more preferable.

  “IU” means an international unit determined by the method described in the 16th revised Japanese Pharmacopoeia Vitamin A quantification method and the like. For example, in the 16th revision of the Japanese Pharmacopoeia, it is stated that retinol acetate contains 2.5 million units of vitamin A per gram, and retinol palmitate contains 1.5 million units of vitamin A per gram. ing.

[(B) component]
The component (B) butylhydroxyanisole (BHA) and a salt thereof are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Examples of the “salt” in the component (B) include basic salts such as salts with inorganic bases such as alkali metal salts and alkaline earth metal salts, and salts with organic bases, such as sodium, potassium, calcium and magnesium. , Ammonium, or a salt with diethanolamine, ethylenediamine or the like. Also, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N -Salts of amines such as methylglucamine and L-glucamine; salts with basic amino acids such as lysine, δ-hydroxylysine and arginine may also be used. In addition, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, apple Salts with organic acids such as acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid, gluconic acid, palmitic acid; It may be a salt with an acidic amino acid such as aspartic acid or glutamic acid. The “salt” in the component (B) includes solvates and hydrates of salts.

  As butylhydroxyanisole and its salt, butylhydroxyanisole is preferable.

  As the component (B), commercially available products may be used. As the component (B), one type may be used alone, or two or more types may be used in combination.

  Content of (B) component in the ophthalmic composition which concerns on this embodiment is not specifically limited, According to the kind of (B) component, the kind and content of another compounding component, the use, formulation form, etc. of ophthalmic composition Is set as appropriate. As content of (B) component, from a viewpoint which shows the effect by this invention more notably, for example, the total content of (B) component is 0.00001-0.01w on the basis of the total amount of ophthalmic composition. / V% is preferable, 0.00005 to 0.004 w / v% is more preferable, 0.0001 to 0.001 w / v% is still more preferable, and 0.0002 to 0.0005 w Even more preferred is / v%.

  In the ophthalmic composition according to the present embodiment, the content ratio of the component (B) to the component (A) is not particularly limited, the types of the components (A) and (B), the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (B) relative to the component (A) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (A) contained in the ophthalmic composition according to this embodiment is 10,000 IU. In contrast, the total content of component (B) is preferably 0.000005 to 0.001 g / 10,000 IU, more preferably 0.00001 to 0.0005 g / 10,000 IU, More preferably, it is 0.00025-0.0001 g / 10,000 IU.

[Component (C)]
Component (C) is at least one component selected from the group consisting of a decongestant, an eye muscle regulator, an anti-inflammatory agent, a vitamin agent, amino acids, and a thickener.

  The decongestant which is component (C) is a compound having an action of suppressing hyperemia and a salt thereof. The decongestant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As the decongestant, for example, a known decongestant such as an imidazoline-based decongestant can be appropriately selected and used.

  Specific examples of the decongestant include imidazoline decongestants such as tetrahydrozoline, naphazoline, oxymetazoline, xylometazoline, and salts thereof, and epinephrine, ephedrine, phenylephrine, and salts thereof. As the decongestant, an imidazoline decongestant is preferable, tetrahydrozoline, naphazoline, and salts thereof are more preferable, and tetrahydrozoline hydrochloride is still more preferable.

  A commercially available decongestant may be used. One type of decongestant may be used alone, or two or more types may be used in combination.

  The ocular muscle modifier that is component (C) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of the eye muscle modulator include a cholinesterase inhibitor having an active center similar to acetylcholine.

  Specific examples of the eye muscle modulating agent include neostigmine, tropicamide, helenien, atropine and salts thereof. As an eye muscle regulating agent, neostigmine and its salt are preferable, and neostigmine methylsulfate is more preferable.

  A commercially available eye muscle modifier may be used. One type of ocular muscle modifier may be used alone, or two or more types may be used in combination.

  The anti-inflammatory agent as component (C) is a compound having an anti-inflammatory action or an anti-inflammatory action, and a salt thereof. The anti-inflammatory agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Specific examples of the anti-inflammatory agent include berberine, azulene (azulene, azulenesulfonic acid, kamaazulene, guaiazulene, etc.), allantoin, zinc sulfate, zinc lactate, lysozyme, glycyrrhizic acid, epsilon-aminocaproic acid, celecoxib, rofecoxib, indomethacin, Diclofenac, bromfenac, piroxicam, meloxicam, methyl salicylate, ibuprofen, ibuprofen piconol, bufexamac, butyl fenfenac, bendazac, ketoprofen, felbinac, pranoprofen and their salts. As the anti-inflammatory agent, berberine, azulene sulfonic acid, allantoin, zinc sulfate, zinc lactate, zinc glycyrrhizic acid, epsilon-aminocaproic acid, pranoprofen and salts thereof are preferable, berberine chloride, berberine sulfate, sodium azulene sulfonate, allantoin More preferred are dipotassium glycyrrhizinate and epsilon-aminocaproic acid, more preferred are dipotassium glycyrrhizinate and epsilon-aminocaproic acid, and even more preferred is dipotassium glycyrrhizinate.

  A commercially available anti-inflammatory agent may be used. An anti-inflammatory agent may be used individually by 1 type, or may be used in combination of 2 or more type.

  The vitamin (C) component (excluding the component corresponding to component (A)) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. It can be used by appropriately selecting from known vitamins.

  Specific examples of vitamin preparations include vitamin Es (d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, etc.), their derivatives, and fats such as salts thereof Soluble vitamins, as well as vitamin B1, vitamin B2 (flavin adenine dinucleotide), niacin (nicotinic acid and nicotinic acid amide), pantothenic acid, panthenol, vitamin B6 (pyridoxine, pyridoxal and pyridoxamine), biotin, folic acid and vitamin B12 (cyanocobalamin) Water-soluble vitamins such as hydroxocobalamin, methylcobalamin and adenosylcobalamin) and salts thereof. Specific examples of vitamin salts include flavin adenine dinucleotide sodium, pyridoxine hydrochloride, calcium pantothenate, sodium pantothenate and the like. Specific examples of vitamin derivatives include, for example, tocopherol acetate.

  As the vitamin, cyanocobalamin, flavin adenine dinucleotide, panthenol, pyridoxine, tocopherol, and derivatives thereof, and salts thereof are preferable, and cyanocobalamin, flavin adenine dinucleotide sodium, panthenol, tocopherol acetate, and pyridoxine hydrochloride are more preferable. Pantenol and pyridoxine hydrochloride are more preferred, and pyridoxine hydrochloride is even more preferred.

  A commercially available vitamin preparation may be used. A vitamin agent may be used individually by 1 type, or may be used in combination of 2 or more type.

  The (C) component amino acids are compounds having an amino group and a carboxyl group in the molecule, derivatives thereof, and salts thereof. The amino acids are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, and can be appropriately selected from known amino acids.

  Specific examples of amino acids include amino acids and salts thereof, and amino acid derivatives and salts thereof. Specific examples of amino acids and salts thereof include, for example, monoamino monocarboxylic acids such as glycine, alanine, aminobutyric acid and aminovaleric acid, monoaminodicarboxylic acids such as aspartic acid and glutamic acid, diamino such as arginine and lysine. Examples thereof include monocarboxylic acids and salts thereof. Specific examples of amino acid derivatives and salts thereof include amino acid derivatives such as aminoethylsulfonic acid (taurine) and salts thereof. Amino acids may be any of D-form, L-form, and DL-form. As amino acids, monoaminodicarboxylic acids, amino acid derivatives, and salts thereof are preferable, aspartic acid, taurine and salts thereof are more preferable, potassium aspartate, magnesium aspartate, magnesium potassium aspartate (equivalent mixture) Taurine is still more preferred, and taurine is even more preferred.

  As amino acids, commercially available ones may be used. Amino acids may be used alone or in combination of two or more.

  The thickener as component (C) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Specific examples of the thickener include vinyl thickeners [for example, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, etc.], cellulose thickeners [ For example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910, etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose, or a salt thereof], polyethylene glycol (Macrogol 300, Macrogol 400, etc.) , Macrogol 1500, Macrogol 4000, etc.) and mucopolysaccharides [eg chondroitin sulfate, alginic acid, hyaluronic acid or their salts] Their salts to. Examples of the salt of the thickener include a salt with an inorganic base. As a salt of a thickener, an alkali metal salt and an alkaline earth metal salt are preferable, a sodium salt, a potassium salt, a calcium salt, and a magnesium salt are more preferable, and a sodium salt is still more preferable.

  As the thickener, vinyl thickener, cellulose thickener, polyethylene glycol and mucopolysaccharide are preferable. Examples of the vinyl thickener include polyvinyl alcohol, polyvinyl pyrrolidone, and carboxyvinyl polymer. Examples of the cellulose-based thickener include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof. Examples of polyethylene glycol include Macrogol 300 and Macrogol 400. Examples of mucopolysaccharides include chondroitin sulfate and salts thereof, alginic acid and salts thereof, and hyaluronic acid and salts thereof.

  As the thickener, carboxyvinyl polymer, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium chondroitin sulfate and sodium hyaluronate are more preferable, polyvinylpyrrolidone (K25, K90), carboxyvinyl polymer, hydroxyethylcellulose. Hydroxypropylmethylcellulose (2208, 2906, 2910), sodium chondroitin sulfate and sodium hyaluronate are more preferred, sodium chondroitin sulfate and sodium hyaluronate are even more preferred, and sodium chondroitin sulfate is particularly preferred.

  A commercially available thickener may be used. A thickener may be used individually by 1 type, or may be used in combination of 2 or more type.

  The “salt” in the component (C) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples include basic salts such as salts with inorganic bases such as alkali metal salts and alkaline earth metal salts, and salts with organic bases, such as sodium, potassium, calcium, magnesium, ammonium, or diethanolamine, ethylenediamine, etc. And the salt. Also, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N -Salts of amines such as methylglucamine and L-glucamine; salts with basic amino acids such as lysine, δ-hydroxylysine and arginine may also be used. In addition, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, apple Salts with organic acids such as acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid, gluconic acid, palmitic acid; It may be a salt with an acidic amino acid such as aspartic acid or glutamic acid. The “salt” in component (C) includes solvates and hydrates of salts.

  Content of (C) component in the ophthalmic composition which concerns on this embodiment is not specifically limited, According to the kind of (C) component, the kind and content of another compounding component, the use, formulation form, etc. of ophthalmic composition Is set as appropriate. The content of the component (C) is, for example, from the viewpoint of more prominently achieving the effects of the present invention, for example, based on the total amount of the ophthalmic composition, the total content of the component (C) is 0.0001 to 10 w / v. %, More preferably 0.0005 to 5 w / v%, still more preferably 0.001 to 2 w / v%, and further preferably 0.01 to 1 w / v%. Is more preferable.

  The total content of the (C) decongestant in the ophthalmic composition according to the present embodiment is 0.0001 to 1 w / v% based on the total amount of the ophthalmic composition from the viewpoint of more prominently achieving the effects of the present invention. It is preferably 0.0005 to 0.5 w / v%, more preferably 0.001 to 0.1 w / v%, and 0.01 to 0.05 w / v%. It is particularly preferred that

  The total content of the (C) eye muscle modulator in the ophthalmic composition according to the present embodiment is 0.0001 to 0.1 w on the basis of the total amount of the ophthalmic composition from the viewpoint of more prominently achieving the effects of the present invention. / V% is preferable, 0.001 to 0.01 w / v% is more preferable, and 0.004 to 0.005 w / v% is still more preferable.

  The total content of the (C) anti-inflammatory agent in the ophthalmic composition according to the present embodiment is 0.0005 to 5 w / v% based on the total amount of the ophthalmic composition from the viewpoint of more prominently achieving the effects of the present invention. It is preferably 0.005 to 2 w / v%, more preferably 0.05 to 1.5 w / v%, and more preferably 0.1 to 1 w / v%. Even more preferred is 0.2 to 0.25 w / v%.

  The total content of the (C) vitamin preparation in the ophthalmic composition according to the present embodiment is 0.005 to 1 w / v% based on the total amount of the ophthalmic composition from the viewpoint of more prominently achieving the effects of the present invention. It is preferably 0.01 to 0.75 w / v%, more preferably 0.05 to 0.5 w / v%, and 0.09 to 0.2 w / v%. It is particularly preferred.

  The total content of (C) amino acids in the ophthalmic composition according to the present embodiment is 0.01 to 5 w / v% based on the total amount of the ophthalmic composition from the viewpoint of more prominently achieving the effects of the present invention. It is preferably 0.05 to 3 w / v%, more preferably 0.1 to 2 w / v%, and particularly preferably 0.5 to 1.5 w / v%. preferable.

  The total content of the thickener (C) in the ophthalmic composition according to the present embodiment is 0.01 to 5 w / v% based on the total amount of the ophthalmic composition from the viewpoint of more prominently achieving the effects of the present invention. It is preferably 0.05 to 3 w / v%, more preferably 0.1 to 1 w / v%, and further preferably 0.25 to 0.5 w / v%. Particularly preferred.

  The ophthalmic composition according to the present embodiment is selected from two or more different classifications selected from a decongestant, an eye muscle regulator, an anti-inflammatory agent, a vitamin agent, amino acids and a thickener as the component (C). It is preferable to include a combination of components selected from three or more different classifications, and it is preferable to include a combination of components selected from four or more different classifications. Is more preferable, and it is even more preferable to include a combination of components selected from five or more different classifications, and it is particularly preferable to include a combination of components selected from all six classifications.

  In the ophthalmic composition according to the present embodiment, the content ratio of the component (C) to the component (A) is not particularly limited, the types of the components (A) and (C), the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (C) relative to the component (A) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (A) contained in the ophthalmic composition according to this embodiment is 10,000 IU. In contrast, the total content of component (C) is preferably 0.0005 to 2 g / 10,000 IU, more preferably 0.001 to 1 g / 10,000 IU, and 0.01 to 0. More preferably, it is 5 g / 10,000 IU.

  When the ophthalmic composition which concerns on this embodiment contains (C) decongestant, as a content ratio of (C) decongestant with respect to (A) component, from a viewpoint of improving the effect by this invention further, for example, this The total content of component (A) contained in the ophthalmic composition according to the embodiment is 10,000 IU, and the total content of (C) decongestant is 0.0005 to 0.1 g / 10,000 IU. It is preferably 0.001 to 0.05 g / 10,000 IU, more preferably 0.005 to 0.02 g / 10,000 IU.

  When the ophthalmic composition according to the present embodiment includes (C) an eye muscle modifier, the content ratio of the (C) eye muscle modifier relative to the component (A) is, for example, from the viewpoint of further enhancing the effect of the present invention. The total content of the component (A) contained in the ophthalmic composition according to this embodiment is 10,000 IU, and the total content of the (C) eye muscle regulator is 0.00005 to 0.01 g / 10,000. IU is preferable, 0.0001 to 0.005 g / 10,000 IU is more preferable, and 0.0005 to 0.002 g / 10,000 IU is still more preferable.

  When the ophthalmic composition according to the present embodiment contains (C) an anti-inflammatory agent, the content ratio of the (C) anti-inflammatory agent to the component (A) is, for example, from the viewpoint of further enhancing the effect of the present invention. The total content of component (A) contained in the ophthalmic composition according to the embodiment is 10,000 IU, and the total content of (C) anti-inflammatory agent is 0.001 to 0.5 g / 10,000 IU. It is preferably 0.005 to 0.1 g / 10,000 IU, and more preferably 0.01 to 0.05 g / 10,000 IU.

  When the ophthalmic composition according to the present embodiment includes (C) a vitamin preparation, the content ratio of the (C) vitamin preparation with respect to the component (A) is, for example, from the viewpoint of further enhancing the effect of the present invention. It is preferable that the total content of (C) vitamin preparation is 0.0005 to 0.1 g / 10,000 IU with respect to the total content of 10,000 IU of the component (A) contained in the ophthalmic composition according to 0.001 to 0.05 g / 10,000 IU, more preferably 0.005 to 0.02 g / 10,000 IU.

  When the ophthalmic composition according to the present embodiment includes (C) amino acids, the content ratio of the (C) amino acids to the component (A) is, for example, from the viewpoint of further enhancing the effect of the present invention. The total content of (C) amino acids is preferably 0.005 to 1 g / 10,000 IU with respect to 10,000 IU of the total component (A) contained in the ophthalmic composition according to the present invention. It is more preferably 0.01 to 0.5 g / 10,000 IU, and further preferably 0.05 to 0.2 g / 10,000 IU.

  When the ophthalmic composition which concerns on this embodiment contains (C) thickener, as a content ratio of (C) thickener with respect to (A) component, from a viewpoint of improving the effect by this invention further, for example, this The total content of component (A) contained in the ophthalmic composition according to the embodiment is 10,000 IU, and the total content of (C) thickener is 0.001 to 5 g / 10,000 IU. Preferably, it is 0.005-0.1 g / 10,000 IU, more preferably 0.01-0.05 g / 10,000 IU.

  In the ophthalmic composition according to the present embodiment, the content ratio of the (C) component to the (B) component is not particularly limited, the types of the (B) component and (C) component, the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (C) relative to the component (B) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of the component (C) is preferably 1 to 50000 parts by mass, more preferably 10 to 30000 parts by mass, and still more preferably 100 to 10000 parts by mass.

  When the ophthalmic composition which concerns on this embodiment contains (C) decongestant, as a content ratio of (C) decongestant with respect to (B) component, from a viewpoint of improving the effect by this invention further, for example, this It is preferable that the total content of the (C) decongestant is 10 to 1000 parts by mass with respect to 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the embodiment. More preferably, it is 500 mass parts, and it is still more preferable that it is 100-200 mass parts.

  When the ophthalmic composition according to the present embodiment includes (C) an eye muscle modifier, the content ratio of the (C) eye muscle modifier relative to the component (B) is, for example, from the viewpoint of further enhancing the effect of the present invention. The total content of the component (B) contained in the ophthalmic composition according to the present embodiment is preferably 1 to 100 parts by mass with respect to the total content of the component (B). It is more preferable that it is 5-50 mass parts, and it is still more preferable that it is 10-20 mass parts.

  When the ophthalmic composition according to the present embodiment contains (C) an anti-inflammatory agent, the content ratio of the (C) anti-inflammatory agent to the component (B) is, for example, from the viewpoint of further enhancing the effect of the present invention. It is preferable that the total content of (C) the anti-inflammatory agent is 50 to 10000 parts by mass with respect to 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the embodiment. The amount is more preferably 5000 parts by mass, and further preferably 500 to 1000 parts by mass.

  When the ophthalmic composition according to the present embodiment contains (C) a vitamin preparation, the content ratio of the (C) vitamin preparation relative to the component (B) is, for example, from the viewpoint of further enhancing the effect of the present invention. It is preferable that the total content of the (C) vitamin preparation is 10 to 5000 parts by mass, and 50 to 1000 parts by mass with respect to 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to It is more preferable that it is 100 to 400 parts by mass.

  When the ophthalmic composition according to the present embodiment includes (C) amino acids, the content ratio of the (C) amino acids to the component (B) is, for example, from the viewpoint of further enhancing the effects of the present invention. The total content of (C) amino acids is preferably 100 to 50000 parts by mass, and 500 to 10000 parts by mass with respect to 1 part by mass of the total content of component (B) contained in the ophthalmic composition according to It is more preferable that it is 1000-4000 mass parts.

  When the ophthalmic composition which concerns on this embodiment contains (C) thickener, as a content ratio of (C) thickener with respect to (B) component, from a viewpoint of improving the effect by this invention further, for example, this It is preferable that the total content of (C) thickener is 10 to 5000 parts by mass with respect to 1 part by mass of the total content of component (B) contained in the ophthalmic composition according to the embodiment. The amount is more preferably 1000 parts by mass, and still more preferably 100 to 400 parts by mass.

[Component (D)]
The ophthalmic composition according to this embodiment preferably further contains (D) at least one selected from the group consisting of dibutylhydroxytoluene and a salt thereof (also referred to as “component (D)”). The effect by this invention is show | played more notably because an ophthalmic composition contains (D) component further. Dibutylhydroxytoluene and its salt are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Dibutylhydroxytoluene (BHT) is a known compound also called 2,6-di-tert-butyl-4-methylphenol.

  Examples of salts of dibutylhydroxytoluene include, for example, organic acid salts [for example, monocarboxylic acid salts (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumaric acid). Salt, maleate, succinate, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylic acid) Salts)], inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine) , Salts with organic amines such as pyrrolidine, tripyridine, picoline), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.) Alkaline earth metals (calcium, magnesium, etc.), it includes various salts of salt], etc. with a metal such as aluminum.

  As dibutylhydroxytoluene and its salt, dibutylhydroxytoluene is preferable.

  Commercially available dibutylhydroxytoluene and salts thereof may be used. Dibutylhydroxytoluene and its salt may be used individually by 1 type, or may be used in combination of 2 or more type.

  Content of (D) component in the ophthalmic composition which concerns on this embodiment is not specifically limited, According to the kind of (D) component, the kind and content of another compounding component, the use, formulation form, etc. of ophthalmic composition Is set as appropriate. As content of (D) component, from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, based on the total amount of the ophthalmic composition, the total content of (D) component is 0.00001 to 0.1 w. / V% is preferable, 0.0001 to 0.05 w / v% is more preferable, 0.001 to 0.01 w / v% is further preferable, and 0.004 to 0.006 w is preferable. Even more preferred is / v%.

  In the ophthalmic composition according to the present embodiment, the content ratio of the component (D) to the component (A) is not particularly limited, the types of the components (A) and (D), the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (D) relative to the component (A) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (A) contained in the ophthalmic composition according to this embodiment is 10,000 IU. In contrast, the total content of component (D) is preferably 0.00005 to 0.01 g / 10,000 IU, more preferably 0.0001 to 0.005 g / 10,000 IU, It is more preferable that it is .0005 to 0.002 g / 10,000 IU, and it is even more preferable that it is 0.0007 to 0.0013 g / 10,000 IU.

  In the ophthalmic composition according to the present embodiment, the content ratio of the (D) component to the (B) component is not particularly limited, the types of the (B) component and (D) component, the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (D) relative to the component (B) is, for example, from the viewpoint of further enhancing the effects of the present invention, for example, 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of the component (D) is preferably 1 to 100 parts by mass, more preferably 3 to 50 parts by mass, and still more preferably 10 to 30 parts by mass.

  In the ophthalmic composition according to the present embodiment, the content ratio of the (D) component to the (C) component is not particularly limited, the types of the (C) component and the (D) component, the types and contents of the other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (D) relative to the component (C) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, 1 part by mass of the total content of the component (C) contained in the ophthalmic composition according to the present embodiment. The total content of component (D) is preferably 0.0001 to 10 parts by mass, more preferably 0.0005 to 5 parts by mass, and 0.001 to 0.5 parts by mass. More preferably.

[(E) component]
The ophthalmic composition according to this embodiment preferably further contains (E) terpenoid (also referred to as “(E) component”). When the ophthalmic composition further contains a terpenoid, the effect of the present invention is more remarkably exhibited. The terpenoid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Examples of terpenoids include cyclic terpenes and acyclic terpenes.

  Cyclic terpenes are terpenoids having at least one ring structure in the molecule. Examples of the cyclic terpene include menthol, camphor, borneol (also referred to as “ryuunou”), menthone, cineol, carvone, anethole, eugenol, limonene, pinene, and derivatives thereof.

  Acyclic terpenes are terpenoids that do not have a ring structure in the molecule. Examples of the acyclic terpene include geraniol, citronellol, linalool, linalyl acetate, and derivatives thereof.

  In the present invention, an essential oil containing the above compound may be used as the terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, and rose oil.

  Terpenoids may be any of d-form, l-form, and dl-form, and include dl-menthol, d-menthol, l-menthol, dl-camphor, d-camphor, l-camphor, dl-borneol, d-borneol, and l-borneol. , Dl-menton, d-menton, and l-menton. However, optical isomers may not exist depending on terpenoids such as geraniol and cineol.

  As the terpenoid, menthol, camphor, borneol, menthone and eucalyptus oil are preferable, menthol and camphor are more preferable, and l-menthol, d-camphor and dl-camphor are more preferable.

  A commercially available terpenoid may be used. A terpenoid may be used individually by 1 type, or may be used in combination of 2 or more type.

  Content of (E) component in the ophthalmic composition which concerns on this embodiment is not specifically limited, According to the kind of (E) component, the kind and content of another compounding component, the use, formulation form, etc. of an ophthalmic composition Is set as appropriate. As the content of the component (E), for example, the total content of terpenoids is 0.00001 to 1 w / v% on the basis of the total amount of the ophthalmic composition from the viewpoint of more prominently achieving the effects of the present invention. Is preferable, 0.0001 to 0.5 w / v% is more preferable, 0.0005 to 0.1 w / v% is still more preferable, and 0.001 to 0.05 w / v% is preferable. It is particularly preferred.

  In the ophthalmic composition according to the present embodiment, the content ratio of the (E) component to the (A) component is not particularly limited, and the types of (A) and (E) components, the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (E) relative to the component (A) is, for example, from the viewpoint of further enhancing the effects of the present invention, for example, the total content of the component (A) contained in the ophthalmic composition according to this embodiment is 10,000 IU. In contrast, the total content of the component (E) is preferably 0.00001 to 0.1 g / 10,000 IU, more preferably 0.00005 to 0.01 g / 10,000 IU, More preferably, it is 0.0001 to 0.001 g / 10,000 IU.

  In the ophthalmic composition according to the present embodiment, the content ratio of the (E) component to the (B) component is not particularly limited, and the types of the (B) component and (E) component, the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (E) relative to the component (B) is, for example, from the viewpoint of further enhancing the effects of the present invention, for example, 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of the component (E) is preferably 0.01 to 1000 parts by mass, more preferably 0.1 to 500 parts by mass, and 1 to 10 parts by mass. Further preferred.

  In the ophthalmic composition according to the present embodiment, the content ratio of the (E) component to the (C) component is not particularly limited, and the types of the (C) component and (E) component, the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (E) to the component (C) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, 1 part by mass of the total content of the component (C) included in the ophthalmic composition according to the present embodiment. On the other hand, the total content of the component (E) is preferably 0.00001 to 100 parts by mass, more preferably 0.00005 to 10 parts by mass, and 0.0001 to 1 part by mass. More preferably.

[(F) component]
The ophthalmic composition according to this embodiment preferably further contains (F) a nonionic surfactant (also referred to as “component (F)”). The effect by this invention is show | played more notably because an ophthalmic composition contains a nonionic surfactant further. The nonionic surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Nonionic surfactants include, for example, monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), and tristearin. POE sorbitan fatty acid esters such as acid POE (20) sorbitan (polysorbate 65) and monooleic acid POE (20) sorbitan (polysorbate 80); Poloxamer 407, Poloxamer 235, Poloxamer 188, Poloxamer 403, Poloxamer 237, Poloxamer 124, etc. POE / POP glycols; POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil 80, etc .; Oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil such as POE castor oil 35 and POE castor oil 50; polyethylene glycol monostearate (2E.O.), polyethylene glycol monostearate (4E.O.), polyethylene glycol monostearate (9E.O.) , Polyethylene glycol monostearate (10E.O.), polyethylene glycol monostearate (23E.O.), polyethylene glycol monostearate (25E.O.), polyethylene glycol monostearate (32E.O.), mono Polyethylene glycol stearate (40 EO, polyoxyl 40 stearate), polyethylene glycol monostearate (45 EO), polyethylene glycol monostearate (55 EO), polyethylene glycol monostearate (75 EO), monostearin Polyethylene glycol monostearate such as polyethylene glycol acid (140E.O.); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE (10) POE alkylphenyl ethers such as nonylphenyl ether. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added.

  Preferable examples of the nonionic surfactant include POE sorbitan fatty acid esters, POE / POP glycols, POE hydrogenated castor oil, POE castor oil, and polyethylene glycol monostearate. Polysorbate 80, Poloxamer 407, POE hydrogenated castor oil 40, POE Hardened castor oil 60, POE castor oil 3, POE castor oil 10, POE castor oil 35, and polyoxyl 40 stearate are more preferable, and polysorbate 80 and POE hydrogenated castor oil 60 are still more preferable.

  A commercially available nonionic surfactant may be used. A nonionic surfactant may be used individually by 1 type, or may be used in combination of 2 or more type.

  Content of (F) component in the ophthalmic composition which concerns on this embodiment is not specifically limited, According to the kind of (F) component, the kind and content of another compounding component, the use, formulation form, etc. of ophthalmic composition Is set as appropriate. As content of (F) component, from a viewpoint which shows the effect by this invention more notably, for example, the total content of (F) component is 0.001-5 w / v on the basis of the total amount of ophthalmic composition. %, More preferably 0.01 to 3 w / v%, still more preferably 0.1 to 1 w / v%, and 0.1 to 0.5 w / v%. Is even more preferred.

  In the ophthalmic composition according to the present embodiment, the content ratio of the component (F) to the component (A) is not particularly limited, the types of the components (A) and (F), the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (F) relative to the component (A) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (A) contained in the ophthalmic composition according to this embodiment is 10,000 IU. On the other hand, the total content of the component (F) is preferably 0.001-1 g / 10,000 IU, more preferably 0.005-0.5 g / 10,000 IU, More preferably, it is ˜0.1 g / 10,000 IU.

  In the ophthalmic composition according to the present embodiment, the content ratio of the (F) component to the (B) component is not particularly limited, and the types of the (B) component and (F) component, the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (F) relative to the component (B) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of the component (F) is preferably 10 to 30000 parts by mass, more preferably 100 to 10000 parts by mass, and still more preferably 200 to 5000 parts by mass.

  In the ophthalmic composition according to the present embodiment, the content ratio of the (F) component to the (C) component is not particularly limited, and the types of (C) component and (F) component, the types and contents of other compounding components, It is appropriately set according to the use and formulation form of the ophthalmic composition. The content ratio of the component (F) relative to the component (C) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, 1 part by mass of the total content of the component (C) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of component (F) is preferably 0.005 to 1000 parts by mass, more preferably 0.01 to 500 parts by mass, and 0.05 to 100 parts by mass. More preferably.

[Buffer]
The ophthalmic composition according to this embodiment preferably further contains a buffer. The effect by this invention is more notably show | played because an ophthalmic composition contains a buffering agent further. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer.

  Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, alkali metal citrate, alkaline earth metal citrate, and the like. Moreover, you may use the hydrate of each salt as a buffering agent. More specific examples include, but are not limited to, boric acid buffers such as boric acid or salts thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); , Phosphoric acid or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); carbonic acid As a buffer, carbonic acid or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); As a citrate buffer, citric acid or a salt thereof (sodium citrate, Potassium citrate, calcium citrate, sodium dihydrogen citrate, dinatrate citrate Um, etc.); as acetate buffer, acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) can be exemplified.

  As the buffer, a borate buffer, a phosphate buffer, a carbonate buffer, and a citrate buffer are more preferable, a borate buffer and a phosphate buffer are more preferable, and a borate buffer is still more preferable. Specific examples of the boric acid buffer include boric acid, a combination of boric acid and a salt thereof (for example, boric acid and borax), preferably boric acid, a combination of boric acid and borax, and more preferably Boric acid.

  A commercially available buffer may be used. A buffering agent may be used individually by 1 type, or may be used in combination of 2 or more type.

  The content of the buffering agent in the ophthalmic composition according to this embodiment is not particularly limited, and is appropriately set according to the type of buffering agent, the type and content of other compounding components, the use and formulation form of the ophthalmic composition, and the like. The The content of the buffering agent is, for example, from the viewpoint of more prominently achieving the effects of the present invention, for example, the total content of the buffering agent is 0.01 to 10 w / v% based on the total amount of the ophthalmic composition. Is preferable, it is more preferable that it is 0.05-5 w / v%, and it is still more preferable that it is 0.1-2 w / v%.

  In the ophthalmic composition according to this embodiment, the content ratio of the buffer to the component (A) is not particularly limited, and the type of the component (A) and the buffer, the type and content of other compounding components, the ophthalmic composition It is set as appropriate according to the use and formulation form. As a content ratio of the buffering agent with respect to the component (A), from the viewpoint of further enhancing the effect of the present invention, for example, with respect to a total content of 10,000 IU of the component (A) contained in the ophthalmic composition according to the present embodiment. The total content of the buffer is preferably 0.005 to 1 g / 10,000 IU, more preferably 0.01 to 0.5 g / 10,000 IU, and 0.02 to 0.3 g. More preferably, it is 10,000 IU.

  In the ophthalmic composition according to this embodiment, the content ratio of the buffer to the component (B) is not particularly limited, and the type of the component (B) and the buffer, the type and content of other compounding components, the ophthalmic composition It is set as appropriate according to the use and formulation form. As a content ratio of the buffer to the component (B), from the viewpoint of further enhancing the effect of the present invention, for example, with respect to 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the present embodiment. In addition, the total content of the buffer is preferably 10 to 30000 parts by mass, more preferably 100 to 10000 parts by mass, and still more preferably 200 to 5000 parts by mass.

  In the ophthalmic composition according to the present embodiment, the content ratio of the buffering agent to the component (C) is not particularly limited, the type of the component (C) and the buffering agent, the type and content of other compounding components, the ophthalmic composition It is set as appropriate according to the use and formulation form. As a content ratio of the buffer to the component (C), from the viewpoint of further enhancing the effect of the present invention, for example, with respect to 1 part by mass of the total content of the component (C) contained in the ophthalmic composition according to the present embodiment. The total content of the buffering agent is preferably 0.001 to 1000 parts by mass, more preferably 0.005 to 500 parts by mass, and further preferably 0.01 to 200 parts by mass. preferable.

  The pH of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. As pH of the ophthalmic composition which concerns on this embodiment, it may be 4.0-9.5, for example, it is preferable that it is 4.0-9.0, and it is 4.5-9.0. Is more preferable, it is still more preferable that it is 4.5-8.5, and it is still more preferable that it is 5.0-8.5.

  The ophthalmic composition which concerns on this embodiment can be adjusted to the osmotic pressure ratio in the range accept | permitted by a biological body as needed. An appropriate osmotic pressure ratio can be appropriately set according to the use, formulation form, method of use, etc. of the ophthalmic composition. For example, it can be 0.4 to 5.0, Preferably, it is 0.8 to 2.2, more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measure with reference to (freezing point depression method). The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes, and then in a desiccator (silica gel). The solution is allowed to cool and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be used.

  The viscosity of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. As the viscosity of the ophthalmic composition according to the present embodiment, for example, the viscosity at 20 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toyo Sangyo Co., Ltd., rotor: 1 ° 34 ′ × R24) is 1 to 10,000 mPa · s, more preferably 1 to 8000 mPa · s, still more preferably 1 to 1000 mPa · s, still more preferably 1 to 100 mPa · s, and 1 to 20 mPa · s. It is particularly preferred.

The ophthalmic composition according to the present embodiment contains an appropriate amount of a combination of components selected from various pharmacologically active components and physiologically active components in addition to the above components, as long as the effects of the present invention are not impaired. Also good. The said component is not specifically limited, For example, the active ingredient in the ophthalmic medicine described in the over-the-counter medicine manufacture sale approval standard 2012 version (supervised by General Society of Regulatory Science) can be illustrated. Specific examples of components used in ophthalmic drugs include the following components.
Antiallergic agents: for example, sodium cromoglycate, tranilast, pemirolast potassium, acitazanolast and the like.
Antihistamine: for example, chlorpheniramine maleate, diphenhydramine hydrochloride, etc.
Sulfa drugs: For example, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium and the like.
Steroid agents: For example, fluticasone propionate, fluticasone furancarboxylate, mometasone furancarboxylate, beclomethasone propionate, flunisolide and the like.
Local anesthetics: for example, lidocaine, procaine, etc.
Other: For example, rebamipide.

In the ophthalmic composition according to the present embodiment, various additives are appropriately selected according to conventional methods according to the use and the form of the formulation, as long as the effects of the present invention are not impaired. May be used in an appropriate amount. Examples of such additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Carrier: An aqueous solvent such as water or hydrous ethanol.
Chelating agent: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA) and the like.
Base: for example, octyldodecanol, titanium oxide, potassium bromide, plastibase and the like.
pH adjuster: for example, hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine and the like.
Stabilizer: For example, sodium formaldehyde sulfoxylate (Longalite), sodium bisulfite, sodium pyrosulfite, aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine and the like.
Anionic surfactant: For example, polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl ether sulfate, alkylbenzene sulfonate, alkyl sulfate, N-acyl taurine salt and the like.
Amphoteric surfactant: for example, lauryldimethylaminoacetic acid betaine.
Antiseptics, bactericides or antibacterials: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, dehydroacetic acid Sodium, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride, etc.), Glokill (manufactured by Rhodia) Product name) etc.
Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol and the like.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin and the like. These may be d-form, l-form or dl-form.

  When the ophthalmic composition according to the present embodiment contains water, the content of water is, for example, from the viewpoint of more prominently achieving the effect of the present invention, for example, based on the total amount of the ophthalmic composition, 80 w / v% or more and less than 100 w / v%, more preferably 85 w / v% or more and 99.5 w / v% or less, and 90 w / v% or more and 99.2 w / v% or less. More preferably.

  The water used in the ophthalmic composition according to this embodiment may be any pharmaceutical, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such water include distilled water, normal water, purified water, sterilized purified water, water for injection, and distilled water for injection. Their definitions are based on the 16th revised Japanese Pharmacopoeia.

  The ophthalmic composition according to the present embodiment can be prepared by adding and mixing a desired amount of the component (A) and, if necessary, other components to a desired concentration. For example, these components can be dissolved or dispersed in purified water, adjusted to a predetermined pH and osmotic pressure, and sterilized by filtration sterilization or the like.

  The ophthalmic composition according to the present embodiment can take various preparation forms depending on the purpose. Examples of the dosage form include solutions, gels, semi-solid agents (such as ointments) and the like.

  The ophthalmic composition according to the present embodiment includes, for example, eye drops (also referred to as eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), artificial tears, and eye wash. (It is also called eyewash or eyewash. In addition, eyewash includes eyewash that can be washed while wearing contact lenses.) Contact lens composition [Contact lens mounting liquid, contact lens care composition (contact lens) Disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative) and the like. The “contact lens” includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

  The ophthalmic composition according to the present embodiment is preferably an eye drop (including an eye drop that can be applied while wearing a contact lens) because the effects of the present invention can be exhibited more remarkably. When the ophthalmic composition according to the present embodiment is an ophthalmic solution, its usage / dose is not particularly limited as long as it is effective and has few side effects. For example, adults (15 years old and over) and 7 years old In the case of the above children, the method of instilling 1 to 2 drops once 4 times a day, 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops once to 5 to 6 times a day The method used can be illustrated.

  The ophthalmic composition according to the present embodiment may be used for improving complex eye symptoms. As used herein, “composite eye symptoms” refers to eye fatigue, conjunctival redness, blurred vision, blepharitis, eye itchiness, ophthalmitis due to light, eye disease, decreased visual function, and eye failure. It means a symptom in which two or more eye symptoms such as pleasure are combined. Compound eye symptoms include tired eyes, conjunctival redness, blurred vision, itchy eyes, poor visual function, and eye discomfort (eg, discomfort when wearing hard or soft contact lenses). It is preferably a symptom that combines two or more symptoms such as eye fatigue, conjunctival hyperemia, blurred vision, itchy eyes, decreased visual function, and eye discomfort. More preferably. Compound eye symptoms may include, for example, eye fatigue, conjunctival redness, blurred vision, blepharitis, eye itchiness, light-induced eye inflammation, eye disease, and discomfort when wearing hard contact lenses. It may be eye fatigue, conjunctival redness, blurred vision, blepharitis, itchy eyes, eye inflammation caused by light, eye disease, discomfort when wearing a hard contact lens, and deterioration of visual function. Further, the improvement of the complex eye symptom includes alleviation, treatment and prevention of the complex eye symptom.

  The ophthalmic composition according to the present embodiment is provided by being accommodated in an arbitrary container. The container for storing the ophthalmic composition according to the present embodiment is not particularly limited, and may be made of glass or plastic, for example. Preferably it is made of plastic. Examples of the plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, a copolymer of monomers constituting these, and a mixture of these two or more. Polyethylene terephthalate is preferable. Moreover, the container which accommodates the ophthalmic composition which concerns on this embodiment may be a transparent container which can visually recognize the inside of a container, and may be an opaque container where it is difficult to visually recognize the inside of a container. A transparent container is preferable. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container.

  A nozzle may be attached to the container that houses the ophthalmic composition according to the present embodiment. The material of the nozzle is not particularly limited, and may be made of glass or plastic, for example. Preferably it is made of plastic. Examples of the plastic include polybutylene terephthalate, polyethylene, polypropylene, a copolymer of monomers constituting them, and a mixture of these two or more. Polyethylene is preferable.

  As for the nozzle of the container for storing the ophthalmic composition according to the present embodiment, part or all of the wall surface that may come into contact with the content liquid when the cap is attached is polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polystyrene. , Acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, ethylene vinyl alcohol copolymer and the like.

  The container for storing the ophthalmic composition according to the present embodiment may be a multi-dose type in which a plurality of usage amounts are stored or a unit dose type in which a single usage amount is stored.

  The ophthalmic composition according to this embodiment is preferably filled in a container having an internal volume of 4 to 30 mL, more preferably filled in a container having an internal volume of 5 to 20 mL, and the internal volume is It is more preferable that the container is 6 to 16 mL, and it is even more preferable that the container is filled to the inner volume of 10 to 15 mL.

[Mucin production enhancer]
The effect of improving various symptoms of the eye by the ophthalmic composition according to the present invention is based at least in part on the action of enhancing the expression of MUC genes (MUC16, MUC4) by the ophthalmic composition according to the present invention. Therefore, the present invention also provides (A) at least one selected from vitamins A from 40,000 to 200,000 IU / 100 mL, (B) at least one selected from the group consisting of butylhydroxyanisole and a salt thereof, And (C) an MUC gene comprising an ophthalmic composition, comprising at least one component selected from the group consisting of a decongestant, an eye muscle regulator, an anti-inflammatory agent, a vitamin agent, an amino acid, and a thickener. An expression enhancer or a mucin production enhancer can be provided. In the MUC gene expression enhancer or mucin production enhancer according to the present invention, the types and contents of (A) component, (B) component and (C) component, the types and contents of other components, etc. About the formulation form of a composition, a use, etc., it is the same as that of the aspect demonstrated regarding the ophthalmic composition.

[Method of imparting mucin production enhancing action to ophthalmic composition]
The present invention also provides an ophthalmic composition comprising at least one selected from (A) vitamin A and 40,000 to 200,000 IU / 100 mL, (B) butylhydroxyanisole and a salt thereof. Ophthalmic composition comprising blending at least one component selected from the group consisting of one and (C) a decongestant, an eye muscle modulator, an anti-inflammatory agent, a vitamin, an amino acid and a thickener It can also be understood as a method of imparting mucin production enhancing action to a product, or a method of imparting MUC gene (MUC16, MUC4) expression enhancing action to an ophthalmic composition. Regarding the formulation form and use of the ophthalmic composition, such as the types and contents of other components, such as the types and contents of the components (A), (B) and (C) in the method, the ophthalmic composition It is the same as the aspect demonstrated regarding.

  Hereinafter, the present invention will be described more specifically based on examples and the like. However, the present invention is not limited to the following examples.

[Test Example 1: Evaluation of effects after instillation]
In accordance with the formulation described in Table 1, each aqueous composition (eye drops) was prepared and used as a test solution. Each test solution was filled in a 13 mL capacity polyethylene terephthalate eye drop container. After filling, a polyethylene nozzle was attached to the eye drop container.

  As subjects, four office workers who routinely perform VDT (Visual Display Terminals) work for 4 hours or more per day were selected. Two of the subjects are about 50 years old, and as the age progresses, they are subjects who feel strongly symptoms such as eye fatigue and blurred vision. The other two were subjects in their 30s.

  Four test subjects instilled one drop of each test solution into both eyes, and various kinds of eyes after 30 seconds of instillation by “VAS method (Visual Analog Scale)” using a 10 cm straight line with a memory of 0-100. The effect of improving symptoms (eye fatigue, redness of the eyes, blurred vision, itchy eyes, difficulty in focusing, discomfort in the eyes, eye fatigue due to dryness) was evaluated. The higher the score increase value, the more improved the eye symptoms.

Using the score of the test liquid of Comparative Example 1, the score increase rate of the test liquid of each Example was calculated using the following formula.
Rate of increase in score (%) = {(average VAS score value of test liquid of each example−average VAS score value of test liquid of comparative example 1) / average VAS score value of test liquid of comparative example 1} × 100
The average VAS score value is an average value of scores of four subjects.

表１中、パルミチン酸レチノールは、１００ｍＬあたりの配合量を示す。 The results are shown in Table 1.

In Table 1, retinol palmitate indicates the blending amount per 100 mL.

  When the component (B) (butylhydroxyanisole) and the component (C) were added to the 50,000 IU / 100 mL vitamin A combination eye drop, the effect on each effect was remarkably improved. Also, in subjects around 50 years old, compared to subjects in the 30s, the score was significantly higher in items related to “eye fatigue” (particularly “eye fatigue due to dryness”) and “difficulty focusing”. An upward trend was confirmed. With regard to the item “difficulty in focusing”, the ophthalmic composition according to the present invention improves the corneal repairing action, so that the visual function is improved, and this makes it easier to focus.

[Test Example 2: Evaluation of mucin production in corneal epithelial cells 1]
According to the formulation described in Table 2, each aqueous composition was prepared and used as a test solution.

Corneal epithelial cell line HCE-T cells were seeded at 12 Well Plate (Corning) at 1 × 10 ⁵ cells / Well, and cultured under conditions of 37 ° C., 5% CO ₂ and 90% humidity. Medium is DMEM / F12 (manufactured by INVITROGEN), FCS (manufactured by DS Pharma) 5%, DMSO (manufactured by Wako Pure Chemical Industries) 0.5%, recombinant human EGF (manufactured by R & D) 10 ng / mL, insulin What added solution human (made by SIGMA) so that it might become 5 micrograms / mL was used. On the next day, after confirming that the cells were confluent and the medium was removed by suction, 1 mL of each test solution was added to each well (n = 2). After reaction for 7 hours under aerobic and anaerobic conditions at 37 ° C., RNA was extracted from the cells using QIAshredder & RNase Mini Kit (manufactured by QIAGEN), and SuperScriptII (manufactured by Life technologies) was used. Was reverse transcribed into cDNA. QPCR was performed using ABI Quant Studio Real time PCR (manufactured by Thermo Fisher), and the gene expression levels of MUC16 and 18S rRNA were measured using the rise cycle (Ct value) in the real-time PCR method as an index.

The expression rate (%) of the MUC16 gene in each test solution relative to the control was calculated according to the following formula 1, using the same treatment in a medium (medium only) not added with the test component.
Expression 1: Expression rate (%) = [2 ^{-{(Ct value of MUC16 gene in test solution) − (Ct value of 18s rRNA in test solution)}} / 2 ^{− {(Ct value of MUC16 gene of control) -(Ct value of control 18s rRNA)}} ] × 100

Next, the expression increase rate (%) of the MCU16 gene relative to the corresponding comparative example in each test solution was calculated using the expression rate calculated in Equation 1 according to the following Equation 2. The corresponding comparative example of Test Example 2 is Comparative Example 2-1. The results are also shown in Table 2.
Expression 2: Expression increase rate (%) = {(expression rate of each test solution−expression rate of corresponding comparative example) / expression rate of corresponding comparative example} × 100

  In the aqueous composition to which the component (A) (retinol palmitate), the component (B) (butylhydroxyanisole) and the component (C) (aminoethylsulfonic acid or neostigmine methylsulfate) are added, either an aerobic condition or an anaerobic condition is used. In this case, it was confirmed that the expression of the MUC16 gene was increased. The MUC16 gene is a gene related to mucin expression on the ocular surface together with the MUC4 gene. Increased mucin expression makes the tear surface uniform, which also contributes to reducing eye fatigue, blurred vision, eye discomfort, difficulty in focusing, etc. it is conceivable that. In addition, the increase in the expression of the MUC16 gene was significant even under anaerobic conditions. Therefore, the ophthalmic composition of the present invention is remarkably effective even when the contact lens is worn and when an anaerobic state such as sleep occurs.

[Test Example 3: Evaluation of mucin production in corneal epithelial cells 2]
Each aqueous composition was prepared according to the formulation described in Table 3, and this was used as a test solution.

  In the same manner as in Test Example 2, corneal epithelial cell line HCE-T cells were cultured with 12 Well Plate (Corning). After confirming that the cells were confluent and removing the medium by suction, 1 mL of each test solution was added to each well (n = 2). After reaction for 7 hours under anaerobic conditions at 37 ° C., RNA was extracted from the cell using QIAshredder & RNase Mini Kit (QIAGEN), and reversed to cDNA using SuperScriptII (Life technologies). I copied it. QPCR was performed using ABI Quant Studio Real time PCR (manufactured by Thermo Fisher), and the amount of gene expression of MUC4 and 18S rRNA was measured using the rise cycle (Ct value) in the real-time PCR method as an index.

The expression rate (%) of the MUC4 gene in each test solution relative to the control was calculated according to the following formula 3 using the same treatment in a medium (medium only) to which the test component was not added.
Expression 3: Expression rate (%) = [2 ^{-{(Ct value of MUC4 gene in test solution) − (Ct value of 18s rRNA in test solution)}} / 2 ^{− {(Ct value of MUC4 gene of control) -(Ct value of control 18s rRNA)}} ] × 100

  Next, the expression increase rate (%) of the MCU4 gene with respect to the corresponding comparative example in each test solution was calculated according to the above formula 2 using the expression rate calculated by the above formula 3. The corresponding comparative example of Test Example 3 is Comparative Example 3-1. The results are also shown in Table 3.

  In the aqueous composition to which (A) component (retinol palmitate), (B) component (butylhydroxyanisole), and (C) component (aminoethylsulfonic acid, methylostisulfate, or pyridoxine hydrochloride) are added, the expression of MUC4 gene Is confirmed to increase.

[Formulation example]
Eye drops (formulation examples 1 to 40) are prepared according to the formulations shown in the following Tables 4 to 7, and are contained in multi-dose containers (formulation examples 1-1 to 1-40 in containers). In addition, the unit of each component amount in the following Tables 4 to 7 is w / v%. Moreover, in Table 4-Table 7, retinol palmitate shows the compounding quantity per 100 mL.

  Furthermore, eye drops (Formulation Examples 1 to 40) filled in a polyethylene terephthalate multi-dose type container and equipped with a low density polyethylene nozzle were prepared into container preparation examples 2-1 to 2-40, eye drops. (Formulation examples 1 to 40) are filled in a polyethylene terephthalate multi-dose container, and all of the wall surfaces that may come into contact with the content liquid when the cap is attached (during storage) are composed of polybutylene terephthalate. A sample equipped with a nozzle is filled with formulation examples 3-1 to 3-40 and eye drops (formulation examples 1 to 40) into a multi-dose container made of polyethylene terephthalate, and may come into contact with the content liquid. A part of the wall surface with a nozzle made of polyethylene terephthalate is used as a formulation example 4-1 to 4-40 in a container, and eye drops (formulation examples 1 to 40). Formulation examples 5-1 to 5- in containers filled with polyethylene terephthalate multi-dose containers and equipped with a nozzle partly made of polyethylene naphthalate with a part of the wall surface that may come into contact with the liquid content 40.

Claims (4)

  (A) 40-200,000 IU / 100 mL of at least one selected from vitamins A, (B) at least one selected from the group consisting of butylhydroxyanisole and salts thereof, and (C) a decongestant An ophthalmic composition comprising at least one component selected from the group consisting of an eye muscle modifier, an anti-inflammatory agent, a vitamin agent, amino acids, and a thickener.   The ophthalmic composition according to claim 1, further comprising (D) at least one selected from the group consisting of dibutylhydroxytoluene and salts thereof.   The ophthalmic composition according to claim 1 or 2, further comprising (E) a terpenoid.   The ophthalmic composition according to any one of claims 1 to 3, which is used for improving complex eye symptoms.