JP7081909B2 - Ophthalmic composition - Google Patents

Description

The present invention relates to ophthalmic compositions.

Many ophthalmic compositions are commercially available to relieve or prevent eye symptoms such as eye fatigue, conjunctival congestion, blurred vision, blepharitis, itching of the eyes, light-induced eye inflammation, and eye diseases. ,in use. These ophthalmic compositions are usually approved as active ingredients for over-the-counter ophthalmic agents, such as decongestants, eye muscle regulators, anti-inflammatory agents, antihistamines, vitamins, amino acids, and sulfa antibacterial agents. , Inorganic salts, high molecular weight viscous agents, antiseptic components and other components, and other additives are combined and blended (for example, Patent Document 1).

Japanese Unexamined Patent Publication No. 2004-59479

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

An object of the present invention is to provide an ophthalmic composition capable of improving various eye symptoms.

The present inventors have included at least one selected from a predetermined amount of (A) vitamin A, (B) at least one selected from the group consisting of butyl hydroxyanisole and a salt thereof, and (C) hyperemic removal. An ophthalmic composition containing a combination of at least one component selected from the group consisting of agents, eye muscle regulators, anti-inflammatory agents, vitamins, amino acids and thickeners effectively treats various eye symptoms. I found that it could be improved. The present invention is based on this novel finding.

The present invention provides, for example, the following inventions.
[1]
(A) At least one selected from vitamin A is 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 antihyperemic agent. An ophthalmic composition comprising at least one ingredient selected from the group consisting of eye muscle regulators, anti-inflammatory agents, vitamins, amino acids and thickeners.
[2]
The ophthalmic composition according to [1], further comprising (D) at least one selected from the group consisting of (D) dibutylhydroxytoluene and a salt thereof.
[3]
The ophthalmic composition according to [1] or [2], which further contains (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, it is possible to provide an ophthalmic composition capable of improving various eye symptoms.

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

In the ophthalmic composition according to the present embodiment, at least one selected from (A) vitamin A (also referred to as “(A) component”) is 40,000 to 200,000 IU / 100 mL, and (B) butyl hydroxyanisole. At least one selected from the group consisting of and salts thereof (also referred to as "component (B)"), and (C) decongestant, ophthalmic muscle regulator, anti-inflammatory agent, vitamin agent, amino acids and thickening agent. It contains at least one component (also referred to as "component (C)") selected from the group consisting of agents.

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

The form of the derivative of vitamin A is, for example, a monovalent carboxylic acid such as retinol palmitate, retinyl acetate, retinol butyrate, retinol propionate, retinol octylate, retinol lauryl, retinol oleate and retinolelinolenic acid. Esther can be mentioned.

The form of the salt of Vitamin A is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, but specifically, an organic acid salt [for example, mono]. Carbonate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.), oxy Carboxylate (milk salt, tartrate, citrate, etc.), organic sulfonate (methane sulfonate, toluene sulfonate, tosilate, etc.), etc.], inorganic acid salt (eg, hydrochloride, sulfate, etc.) , Nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picolin, etc.) , Salts with inorganic bases [eg, ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc.] and the like. These salts may be selected from one kind and used alone, or two or more kinds may be used in any combination.

As the 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 further preferable.

As the vitamin A, a synthetic product may be used, or an extract obtained from a natural product (for example, vitamin A oil, etc.) may be used. The vitamin A oil is a fatty oil obtained from animal tissues or the like containing retinol, a concentrate thereof, or a vegetable oil added thereto as appropriate. Commercially available vitamin A can also be used. One type of vitamin A may be used alone, or two or more types may be used in combination.

Regarding the content of the component (A) in the ophthalmic composition according to the present embodiment, the total content of the component (A) is preferably 40,000 to 200,000 IU / 100 mL based on the total amount of the ophthalmic composition. It is more preferably 40,000 to 100,000 IU / 100 mL, further preferably 45,000 to 60,000 IU / 100 mL, and further preferably 48,000 to 55,000 IU / 100 mL. More preferred.

"IU" means an international unit obtained by the method described in the 16th revised Japanese Pharmacopoeia Vitamin A Quantification Method, etc. For example, in each article of the 16th revised Japanese Pharmacopoeia, it is stated that retinyl acetate contains 2.5 million units or more of vitamin A per gram, and retinyl palmitate contains 1.5 million units or more of vitamin A per gram. ing.

[(B) component]
The component (B), butylated hydroxyanisole (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 salts with inorganic bases such as alkali metal salts and alkaline earth metal salts, and basic salts such as salts with organic bases, such as sodium, potassium, calcium and magnesium. , Ammonium, or salts with diethanolamine, ethylenediamine and the like. In addition, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N. -Amine salt such as methylglucamine and L-glucamine; a salt with a basic amino acid such as lysine, δ-hydroxylysine and arginine may be used. Further, 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, silicic 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 a solvate of the salt and a hydrate.

As the butylhydroxyanisole and a salt thereof, butylhydroxyanisole is preferable.

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

The content of the component (B) in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of the component (B), the type and content of other compounding components, the use of the ophthalmic composition, the formulation form, and the like. Is set as appropriate. Regarding the content of the component (B), from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the component (B) is 0.00001 to 0.01w based on the total amount of the ophthalmic composition. It is preferably / v%, more preferably 0.00005 to 0.004 w / v%, further preferably 0.0001 to 0.001 w / v%, and further preferably 0.0002 to 0.0005 w. It is even more preferable that it is / v%.

The content ratio of the component (B) to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (A) and the component (B), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (B) to the component (A), 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 the present embodiment is 10,000 IU. On the other hand, the total content of the component (B) is preferably 0.000005 to 0.001 g / 10,000 IU, more preferably 0.00001 to 0.0005 g / 10,000 IU, and 0. It is more preferably 0.0025 to 0.0001 g / 10,000 IU.

[(C) component]
The component (C) is at least one component selected from the group consisting of decongestants, eye muscle regulators, anti-inflammatory agents, vitamins, amino acids and thickeners.

The decongestant as a 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 decongestants include imidazoline-based decongestants such as tetrahydrozoline, naphazoline, oxymetazoline, xylometazoline and salts thereof, and epinephrine, ephedrine, phenylephrine and salts thereof. As the decongestant, an imidazoline-based decongestant is preferable, tetrahydrozoline, naphazoline, and salts thereof are more preferable, and tetrahydrozoline hydrochloride is further preferable.

As the decongestant, a commercially available one may be used. The decongestant may be used alone or in combination of two or more.

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

Specific examples of the eye muscle regulator include neostigmine, tropicamide, helenien, atropine and salts thereof. As the eye muscle regulator, neostigmine and a salt thereof are preferable, and neostigmine methylsulfate is more preferable.

As the eye muscle regulator, a commercially available one may be used. The eye muscle regulator may be used alone or in combination of two or more.

The anti-inflammatory agent as a component (C) is a compound having an anti-inflammatory or anti-inflammatory effect, 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 anti-inflammatory agents include velverine, azulene (azulene, azulene sulfonic acid, kamaazulene, guaiazulene, etc.), allantin, zinc sulfate, zinc lactate, lysozyme, glycyrrhizinic acid, epsilon-aminocaproic acid, selecoxib, rofecoxib, indomethacin, Included are diclofenac, bromfenac, pyroxicum, meroxycam, methyl salicylate, ibuprofen, ibuprofen piconol, bufexamac, butyl flufenate, bendazac, ketoprofen, fervinac, planoprofen and salts thereof. As the anti-inflammatory agent, velverine, azulene sulfonic acid, allantin, zinc sulfate, zinc lactate, glycyrrhizinic acid, epsilon-aminocaproic acid, planoprofen and salts thereof are preferable, and velverin chloride, berberine sulfate, sodium azulene sulfonate, allantin , Dipotassium glycyrrhizinate, epsilon-aminocaproic acid is more preferred, dipotassium glycyrrhizinate, epsilon-aminocaproic acid is even more preferred, and dipotassium glycyrrhizinate is even more preferred.

As the anti-inflammatory agent, a commercially available one may be used. The anti-inflammatory agent may be used alone or in combination of two or more.

The vitamin preparation (excluding the component corresponding to the component (A)) which is the component (C) is particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. However, it can be appropriately selected from known vitamins and used.

Specific examples of vitamin preparations include vitamin Es (d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, etc.), derivatives thereof, 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, pantenol, vitamin B6 (pyridoxin, pyridoxal and pyridoxamine), biotin, folic acid and vitamin B12 (cyanocobalamine). , Hydroxocobalamine, methylcobalamine and adenosylcobalamine) and water-soluble vitamins such as salts thereof. Specific examples of the vitamin salt include flavin adenine dinucleotide sodium, pyridoxine hydrochloride, calcium pantothenate, sodium pantothenate and the like. Specific examples of vitamin derivatives include tocopherol acetate.

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

As the vitamin preparation, a commercially available vitamin preparation may be used. The vitamin preparation may be used alone or in combination of two or more.

The amino acids as the component (C) are a compound having an amino group and a carboxyl group in the molecule, a derivative thereof, and a salt thereof. The amino acids are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and can be appropriately selected and used 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 monoaminomonocarboxylic acids such as glycine, alanine, aminobutyric acid, and aminovaleric acid, monoaminodicarboxylic acids such as aspartic acid, and glutamate, and diamino acids such as arginine and lysine. Examples include monocarboxylic acids and salts thereof. Specific examples of the amino acid derivative and its salt include an amino acid derivative such as aminoethyl sulfonic acid (taurine) and a salt thereof. The amino acids may be D-form, L-form, or DL-form. As the amino acids, monoaminodicarboxylic acid, amino acid derivative and salts thereof are preferable, aspartic acid, taurine and salts thereof are more preferable, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium (equal amount mixture). , Taurine is even more preferred, and taurine is even more preferred.

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

The thickener as a 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), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, etc.], cellulose thickeners [ For example, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (2208, 2906, 2910, etc.), carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose or salts thereof], polyethylene glycol (Macrogol 300, Macrogol 400, etc.) , Macrogol 1500, Macrogol 4000, etc.) and mucopolysaccharides [eg, chondroitin sulfate, alginic acid, hyaluronic acid or salts thereof] and salts thereof. Examples of the salt of the thickener include a salt with an inorganic base. As the thickener salt, 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 further preferable.

As the thickener, vinyl-based thickeners, cellulosic-based thickeners, polyethylene glycols and mucopolysaccharides are preferable. Examples of vinyl thickeners include polyvinyl alcohol, polyvinylpyrrolidone and carboxyvinyl polymers. Examples of the cellulosic thickener include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose and salts thereof. Examples of polyethylene glycol include macrogol 300 and macrogol 400. Examples of the mucopolysaccharide include chondroitin sulfate and its salt, alginic acid and its salt, and hyaluronic acid and its salt.

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

As the thickener, a commercially available thickener may be used. The thickener may be used alone or in combination of two or more.

The "salt" in the component (C) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, there are salts with inorganic bases such as alkali metal salts and alkaline earth metal salts, and basic salts such as salts with organic bases, such as sodium, potassium, calcium, magnesium, ammonium, diethanolamine, ethylenediamine and the like. And salt can be mentioned. In addition, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N. -Amine salt such as methylglucamine and L-glucamine; a salt with a basic amino acid such as lysine, δ-hydroxylysine and arginine may be used. Further, 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, silicic 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 (C) includes a solvate of the salt and a hydrate.

The content of the component (C) in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of the component (C), the type and content of other compounding components, the use of the ophthalmic composition, the formulation form, and the like. Is set as appropriate. Regarding the content of the component (C), from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the component (C) is 0.0001 to 10 w / v based on the total amount of the ophthalmic composition. %, More preferably 0.0005 to 5 w / v%, further preferably 0.001 to 2 w / v%, and further preferably 0.01 to 1 w / v%. More preferred.

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 exerting the effect of the present invention more remarkably. It is preferably 0.0005 to 0.5 w / v%, more preferably 0.001 to 0.1 w / v%, and further preferably 0.01 to 0.05 w / v%. Is particularly preferable.

The total content of the (C) ophthalmic muscle regulator in the ophthalmic composition according to the present embodiment is 0.0001 to 0.1 w based on the total amount of the ophthalmic composition from the viewpoint of exerting the effect according to the present invention more remarkably. It is preferably / v%, more preferably 0.001 to 0.01 w / v%, and even more preferably 0.004 to 0.005 w / v%.

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 exerting the effect of the present invention more remarkably. It is preferably 0.005 to 2 w / v%, more preferably 0.05 to 1.5 w / v%, and even more preferably 0.1 to 1 w / v%. Even more preferably, it is particularly preferably 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 exerting the effect of the present invention more remarkably. It is preferably 0.01 to 0.75 w / v%, more preferably 0.05 to 0.5 w / v%, and more preferably 0.09 to 0.2 w / v%. It is particularly preferable to have.

The total content of the amino acids (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 exerting the effect of the present invention more remarkably. 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 (C) thickener 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 remarkable effect of the present invention. It is preferably 0.05 to 3 w / v%, more preferably 0.1 to 1 w / v%, and more preferably 0.25 to 0.5 w / v%. Especially preferable.

The ophthalmic composition according to the present embodiment is selected from two or more different classifications selected from decongestants, eye muscle regulators, anti-inflammatory agents, vitamins, amino acids and thickeners as the component (C). It is preferable to contain a combination of components selected from three or more different classifications, and more preferably to contain a combination of components selected from each of four or more different classifications. It is even more preferable to contain a combination of components selected from each of five or more different categories, and it is particularly preferable to contain a combination of components selected from all six categories.

The content ratio of the component (C) to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (A) and the component (C), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (C) to the component (A), 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 the present embodiment is 10,000 IU. On the other hand, the total content of the 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. It is more preferably .5 g / 10,000 IU.

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

When the ophthalmic composition according to the present embodiment contains (C) an eye muscle regulator, the content ratio of the (C) eye muscle regulator 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 the present embodiment is 10,000 IU, whereas the total content of the (C) eye muscle regulator is 0.00005 to 0.01 g / 10,000. It is preferably IU, more preferably 0.0001 to 0.005 g / 10,000 IU, and even more preferably 0.0005 to 0.002 g / 10,000 IU.

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 the component (A) contained in the ophthalmic composition according to the embodiment is 10,000 IU, whereas the total content of the (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 even more preferably 0.01 to 0.05 g / 10,000 IU.

When the ophthalmic composition according to the present embodiment contains (C) a vitamin preparation, the content ratio of the (C) vitamin preparation to the (A) component is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, the present embodiment. It is preferable that the total content of the (C) vitamin preparation is 0.0005 to 0.1 g / 10,000 IU with respect to the total content of the component (A) contained in the ophthalmic composition according to the above. , 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 contains (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, for example, the present embodiment. The total content of the amino acids (C) is preferably 0.005 to 1 g / 10,000 IU with respect to the total content of the component (A) contained in the ophthalmic composition according to It is more preferably 0.01 to 0.5 g / 10,000 IU, and even more preferably 0.05 to 0.2 g / 10,000 IU.

When the ophthalmic composition according to the present embodiment contains (C) a thickener, the content ratio of the (C) thickener 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 the embodiment is 10,000 IU, whereas the total content of the thickener (C) is 0.001 to 5 g / 10,000 IU. It is more preferably 0.005 to 0.1 g / 10,000 IU, and even more preferably 0.01 to 0.05 g / 10,000 IU.

The content ratio of the component (C) to the component (B) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (B) and the component (C), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (C) to the component (B), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (B) contained in the ophthalmic composition according to the present embodiment is 1 part by mass. On the other hand, the total content of the component (C) is preferably 1 to 50,000 parts by mass, more preferably 10 to 30,000 parts by mass, and further preferably 100 to 10,000 parts by mass.

When the ophthalmic composition according to the present embodiment contains (C) a hyperemic remover, the content ratio of the (C) hyperemic remover to the component (B) is, for example, from the viewpoint of further enhancing the effect of the present invention. The total content of the (C) hyperemic remover is preferably 10 to 1000 parts by mass, preferably 50 to 1 part by mass, based on 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the embodiment. It is more preferably 500 parts by mass, and even more preferably 100 to 200 parts by mass.

When the ophthalmic composition according to the present embodiment contains (C) an eye muscle regulator, the content ratio of the (C) eye muscle regulator 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 part by mass, and the total content of the (C) eye muscle regulator is preferably 1 to 100 parts by mass. It is more preferably 5 to 50 parts by mass, and even more preferably 10 to 20 parts by mass.

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. The total content of the (C) anti-inflammatory agent is preferably 50 to 10000 parts by mass, preferably 100 to 1 part by mass, based on 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the embodiment. It 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 to the (B) component is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, the present embodiment. The total content of the vitamin preparation (C) is preferably 10 to 5000 parts by mass, preferably 50 to 1000 parts by mass, based on 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the above. Is more preferable, and 100 to 400 parts by mass is further preferable.

When the ophthalmic composition according to the present embodiment contains (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 effect of the present invention, for example, the present embodiment. The total content of (C) amino acids is preferably 100 to 50,000 parts by mass, preferably 500 to 10,000 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 above. Is more preferable, and 1000 to 4000 parts by mass is further preferable.

When the ophthalmic composition according to the present embodiment contains (C) a thickener, the content ratio of the (C) thickener to the component (B) is, for example, from the viewpoint of further enhancing the effect of the present invention. The total content of the (C) thickener is preferably 10 to 5000 parts by mass, preferably 50 to 50 parts by mass, based on 1 part by mass of the total content of the component (B) contained in the ophthalmic composition according to the embodiment. It is more preferably 1000 parts by mass, and even more preferably 100 to 400 parts by mass.

[(D) component]
The ophthalmic composition according to the present embodiment further preferably contains at least one selected from the group consisting of (D) dibutylhydroxytoluene and a salt thereof (also referred to as "component (D)"). When the ophthalmic composition further contains the component (D), the effect according to the present invention is more remarkably exhibited. The 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 referred to as 2,6-di-tert-butyl-4-methylphenol.

Examples of the salt of dibutyl hydroxytoluene include organic acid salts [for example, monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylates (fumaric acid). Salts, maleates, succinates, malonates, etc.), oxycarboxylates (milk salts, tartrates, citrates, etc.), organic sulfonates (methanesulfonates, toluenesulfonates, tosylates, etc.) Salts, etc.)], inorganic acid salts (eg, hydrochlorides, sulfates, nitrates, hydrobromates, phosphates), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine). , Salts with organic amines such as pyrrolidine, tripyridine, picolin), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), metals such as aluminum, etc. Various salts such as [salt with salt] can be mentioned.

As the dibutylhydroxytoluene and its salt, dibutylhydroxytoluene is preferable.

As the dibutylhydroxytoluene and its salt, commercially available ones may be used. The dibutylhydroxytoluene and its salt may be used alone or in combination of two or more.

The content of the component (D) in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of the component (D), the type and content of other compounding components, the use of the ophthalmic composition, the formulation form, and the like. Is set as appropriate. Regarding the content of the component (D), from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the component (D) is 0.00001 to 0.1w based on the total amount of the ophthalmic composition. It is preferably / v%, more preferably 0.0001 to 0.05 w / v%, further preferably 0.001 to 0.01 w / v%, and further preferably 0.004 to 0.006 w. It is even more preferable that it is / v%.

The content ratio of the component (D) to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (A) and the component (D), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (D) to the component (A), 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 the present embodiment is 10,000 IU. On the other hand, the total content of the component (D) is preferably 0.00005 to 0.01 g / 10,000 IU, more preferably 0.0001 to 0.005 g / 10,000 IU, and 0. It is even more preferably 0.007 to 0.002 g / 10,000 IU, and even more preferably 0.0007 to 0.0013 g / 10,000 IU.

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

The content ratio of the component (D) to the component (C) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (C) and the component (D), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (D) to the component (C), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (C) contained in the ophthalmic composition according to the present embodiment is 1 part by mass. On the other hand, the total content of the 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. Is more preferable.

[(E) component]
The ophthalmic composition according to the present embodiment preferably further contains (E) a terpenoid (also referred to as "component (E)"). When the ophthalmic composition further contains a terpenoid, the effect of the present invention is more pronounced. 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 that have at least one ring structure in the molecule. Examples of the cyclic terpene include menthol, camphor, borneol (also referred to as “ryuno”), menthone, cineole, carvone, anethole, eugenol, limonene, pinene, and derivatives thereof.

Acyclic terpenes are terpenoids that do not have an intramolecular ring structure. 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, uikyo oil, keihi oil, rose oil and the like.

The terpenoid may be d-form, l-form or dl-form, and may be dl-menthol, d-menthol, l-menthol, dl-camphr, d-camfur, l-camphr, dl-borneol, d-borneol, l-borneol. , Dl-Menthol, d-Menthol, l-Menthol are exemplified. However, some terpenoids such as geraniol and cineole may not have optical isomers.

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

Commercially available terpenoids may be used. The terpenoid may be used alone or in combination of two or more.

The content of the component (E) in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of the component (E), the type and content of other compounding components, the use of the ophthalmic composition, the formulation form, and the like. Is set as appropriate. Regarding the content of the component (E), from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the terpenoid is 0.00001 to 1 w / v% based on the total amount of the ophthalmic composition. It is preferably 0.0001 to 0.5 w / v%, more preferably 0.0005 to 0.1 w / v%, and even more preferably 0.001 to 0.05 w / v%. Is particularly preferred.

The content ratio of the component (E) to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (A) and the component (E), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (E) to the component (A), 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 the present embodiment is 10,000 IU. On the other hand, 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, and 0. It is more preferably .0001 to 0.001 g / 10,000 IU.

The content ratio of the component (E) to the component (B) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (B) and the component (E), the types and contents of the other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (E) to the component (B), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (B) contained in the ophthalmic composition according to the present embodiment is 1 part by mass. 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 more preferably 1 to 10 parts by mass. More preferred.

The content ratio of the component (E) to the component (C) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (C) and the component (E), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (E) to the component (C), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (C) contained in the ophthalmic composition according to the present embodiment is 1 part by mass. 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. Is even more preferable.

[(F) component]
The ophthalmic composition according to this embodiment preferably further contains (F) a nonionic surfactant (also referred to as "(F) component"). When the ophthalmic composition further contains a nonionic surfactant, the effect according to the present invention is more remarkable. The nonionic surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

Examples of the nonionic surfactant include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitate POE (20) sorbitan (polysorbate 40), monostearate POE (20) sorbitan (polysorbate 60), and tristearate. POE sorbitan fatty acid esters such as acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE / POP glycols; POE-hardened sardine oil 40, POE-hardened sardine oil 50, POE-hardened sardine oil 60, POE-hardened sardine oil 80, etc. , POE Himashima Oil 7, POE Himashima Oil 10, POE Himashima Oil 13.5, POE Himashima Oil 17, POE Himashima Oil 20, POE Himashima Oil 25, POE Himashima Oil 30, POE Himashima Oil 35, POE Himashima Oil 50, etc. Himasi oil; polyethylene glycol monostearate (2EO), polyethylene glycol monostearate (4EO), polyethylene glycol monostearate (9EO), polyethylene glycol monostearate (10EO) , Monostearate Polyethylene Glycol (23EO), Monostearate Polyethylene Glycol (25EO), Monostearate Polyethylene Glycol (32EO), Monostearate Polyethylene Glycol (40EO, Stearic Acid) Polyoxyl 40), polyethylene glycol monostearate (45EO), polyethylene glycol monostearate (55EO), polyethylene glycol monostearate (75EO), polyethylene glycol monostearate (140EO. ) And the like; POE alkyl ethers such as POE (9) lauryl ether; POE (20) POP (4) POE-POP alkyl ethers such as cetyl ether; POE (10) nonylphenyl ether and the like Examples thereof include POE alkylphenyl ethers. In the above-exemplified compounds, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of added moles.

As the nonionic surfactant, POE sorbitan fatty acid esters, POE / POP glycols, POE cured castor oil, POE castor oil, polyethylene glycol monostearate are preferable, and polysorbate 80, poroxsummer 407, POE cured 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 cured castor oil 60 are even more preferable.

As the nonionic surfactant, a commercially available one may be used. The nonionic surfactant may be used alone or in combination of two or more.

The content of the component (F) in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of the component (F), the type and content of other compounding components, the use of the ophthalmic composition, the formulation form, and the like. Is set as appropriate. Regarding the content of the component (F), from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the component (F) is 0.001 to 5 w / v based on the total amount of the ophthalmic composition. %, More preferably 0.01 to 3 w / v%, even more preferably 0.1 to 1 w / v%, and 0.1 to 0.5 w / v%. Is even more preferable.

The content ratio of the component (F) to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (A) and the component (F), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (F) to the component (A), 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 the present embodiment is 10,000 IU. On the other hand, the total content of the component (F) is preferably 0.001 to 1 g / 10,000 IU, more preferably 0.005 to 0.5 g / 10,000 IU, and more preferably 0.01. It is more preferably ~ 0.1 g / 10,000 IU.

The content ratio of the component (F) to the component (B) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (B) and the component (F), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (F) to the component (B), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (B) contained in the ophthalmic composition according to the present embodiment is 1 part by mass. On the other hand, the total content of the component (F) is preferably 10 to 30,000 parts by mass, more preferably 100 to 10,000 parts by mass, and further preferably 200 to 5,000 parts by mass.

The content ratio of the component (F) to the component (C) in the ophthalmic composition according to the present embodiment is not particularly limited, and the types of the component (C) and the component (F), the types and contents of other compounding components, and the like. It is appropriately set according to the use of the ophthalmic composition, the form of the formulation, and the like. Regarding the content ratio of the component (F) to the component (C), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (C) contained in the ophthalmic composition according to the present embodiment is 1 part by mass. On the other hand, the total content of the 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. Is even more preferable.

[Buffering agent]
The ophthalmic composition according to this embodiment preferably further contains a buffer. When the ophthalmic composition further contains a buffer, the effect of the present invention is more pronounced. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

Examples of the buffer include a borate buffer, a phosphate buffer, a carbon dioxide buffer, a citrate buffer, and an acetate buffer.

Examples of the borate buffer include borate, borate alkali metal salt, borate alkaline earth metal salt and the like. Examples of the phosphoric acid buffer include phosphoric acid, or a phosphate such as an alkali metal phosphate metal salt and an alkaline earth metal phosphate salt. Examples of the carbonic acid buffer include carbonic acid, or carbonates such as alkali carbonate metal salts and alkaline earth metal carbonates. Examples of the citrate buffer include citrate, an alkali metal citrate salt, and an alkaline earth metal citrate salt. Moreover, you may use the hydrate of each salt as a buffering agent. As a more specific example, but not limited to, as a borate buffer, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borosand, etc.); as a phosphate buffer. , Phosphate or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Carbonate or a salt thereof (sodium hydrogencarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogencarbonate, magnesium carbonate, etc.) as a buffer; citric acid or a salt thereof (sodium citrate, sodium citrate, etc.) as a citrate buffer. Potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); Examples of the acetate buffer include acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.).

As the buffer, a borate buffer, a phosphate buffer, a carbon dioxide buffer, and a citrate buffer are more preferable, a borate buffer and a phosphate buffer are further preferable, and a borate buffer is even more preferable. 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 a combination of boric acid, boric acid and borax, and more preferably. Boric acid can be mentioned.

As the buffering agent, a commercially available one may be used. The buffer may be used alone or in combination of two or more.

The content of the buffering agent in the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of the buffering agent, the type and content of other compounding ingredients, the use of the ophthalmic composition, the formulation form, and the like. To. Regarding the content of the buffer, from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the buffer is 0.01 to 10 w / v% based on the total amount of the ophthalmic composition. , More preferably 0.05 to 5 w / v%, and even more preferably 0.1 to 2 w / v%.

The content ratio of the buffering agent to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and the type of the component (A) and the buffering agent, the type and content of other compounding components, and the ophthalmic composition. It is appropriately set according to the intended use, the form of the formulation, and the like. Regarding the content ratio of the buffer to the component (A), from the viewpoint of further enhancing the effect of the present invention, for example, with respect to the total content of the component (A) contained in the ophthalmic composition according to the present embodiment of 10,000 IU. 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. It is more preferably / 10,000 IU.

The content ratio of the buffering agent to the component (B) in the ophthalmic composition according to the present embodiment is not particularly limited, and the type of the component (B) and the buffering agent, the type and content of other compounding components, and the ophthalmic composition. It is appropriately set according to the intended use, the form of the formulation, and the like. Regarding the 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. The total content of the buffer is preferably 10 to 30,000 parts by mass, more preferably 100 to 10,000 parts by mass, and even more preferably 200 to 5,000 parts by mass.

The content ratio of the buffer to the component (C) in the ophthalmic composition according to the present embodiment is not particularly limited, and the type of the component (C) and the buffer, the type and content of other compounded components, and the ophthalmic composition. It is appropriately set according to the intended use, the form of the formulation, and the like. The content ratio of the buffer to the component (C) is, for example, 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 buffer 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 (pharmaceutically) or physiologically acceptable range. The pH of the ophthalmic composition according to the present embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, and 4.5 to 9.0. Is more preferable, 4.5 to 8.5 is further preferable, and 5.0 to 8.5 is even more preferable.

The ophthalmic composition according to the present embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary. The appropriate osmotic pressure ratio can be appropriately set depending on the use, formulation form, usage method, etc. of the ophthalmic composition, and can be, for example, 0.4 to 5.0, and 0.6 to 3.0. It is preferably 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 (osmotic pressure of 0.9w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacy, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacy. 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) is prepared by drying sodium chloride (standard reagent of the Japanese Pharmacopoeia) at 500 to 650 ° C. for 40 to 50 minutes and then in a desiccator (silica gel). After allowing to cool, 0.900 g thereof can be accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for measuring osmotic pressure ratio (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 (pharmaceutically) 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 rotary viscometer (RE550 type viscometer, manufactured by Tohoku Sangyo Co., Ltd., rotor; 1 ° 34'× R24) is 1 to 10000 mPa. It is preferably s, more preferably 1 to 8000 mPa · s, further preferably 1 to 1000 mPa · s, even more preferably 1 to 100 mPa · s, and 1 to 20 mPa · s. It is particularly preferable to have.

The ophthalmic composition according to the present embodiment contains an appropriate amount of a combination of various pharmacologically active ingredients and components selected from physiologically active ingredients in addition to the above-mentioned components as long as the effects of the present invention are not impaired. May be good. The component is not particularly limited, and examples thereof include the active ingredient in an ophthalmic drug described in the 2012 version of the OTC drug manufacturing and marketing approval standard (supervised by the Regulatory Science Society). Specific examples of the components used in ophthalmic drugs include the following components.
Anti-allergic agents: for example, sodium cromoglycate, tranilast, pemirolast potassium, acitazanolast and the like.
Antihistamines: for example, chlorpheniramine maleate, diphenhydramine hydrochloride, etc.
Sulfa agent: For example, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidin sodium and the like.
Steroids: For example, fluticasone propionate, fluticasone furancarboxylate, mometasone furancarboxylate, beclomethasone propionate, flunisolide and the like.
Local anesthetic: for example, lidocaine, procaine, etc.
Others: For example, rebamipide.

For the ophthalmic composition according to the present embodiment, as long as the effect of the present invention is not impaired, various additives are appropriately selected according to a conventional method according to the use and the formulation form, and one or more. May be contained in an appropriate amount in combination with. Examples of such additives include various additives described in the Pharmaceutical Additives Dictionary 2007 (edited by the Japan Pharmaceutical Additives Association). The following additives are typical ingredients.
Carrier: An aqueous solvent such as water or hydrous ethanol.
Chelating agent: For example, ethylenediamine diacetic acid (EDDA), ethylenediamine triacetic acid, ethylenediaminetetraacetic acid (EDTA), N- (2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTPA) and the like.
Base: For example, octyldodecanol, titanium oxide, potassium bromide, plastic base, etc.
pH adjuster: For example, hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine and the like.
Stabilizers: For example, sodium formaldehyde sulfoxylate (longalit), sodium hydrogen sulfite, sodium pyrosulfite, aluminum monostearate, glycerin 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 tenside: for example, betaine lauryldimethylaminoacetate.
Preservatives, bactericides or antibacterial agents: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalconium 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.), Glowkill (manufactured by Rhodia) Product name) etc.
Isotonic agents: for example, sodium bisulfite, sodium bisulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol and the like.
Sugars: For example, glucose, cyclodextrin, etc.
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 water content is, for example, based on the total amount of the ophthalmic composition, from the viewpoint of exerting the effect of the present invention more remarkably. , 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. Is even more preferable.

The water used in the ophthalmic composition according to the present embodiment may be pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such water include distilled water, normal water, purified water, sterile purified water, injection water, distilled water for injection and the like. 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, it can be prepared by dissolving or dispersing those components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like.

The ophthalmic composition according to the present embodiment can take various pharmaceutical forms depending on the purpose. Examples of the pharmaceutical form include liquids, gels, semi-solids (ointments, etc.) and the like.

The ophthalmic composition according to the present embodiment is, for example, an eye drop (also referred to as an eye drop or an eye drop; the eye drop includes an eye drop that can be instilled while wearing a contact lens), an artificial tear solution, and an eye wash. (Also referred to as eye drops or eye drops. The eye drops include eye drops that can be washed while wearing contact lenses.), Composition for contact lenses [Contact lens wearing solution, composition for contact lens care (contact lenses) It can be used as a disinfectant, a preservative for contact lenses, a cleaning agent for contact lenses, a cleaning preservative for contact lenses), etc.]. The "contact lens" includes a hard contact lens and a soft contact lens (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 instilled while wearing a contact lens) because the effect of the present invention can be exerted more remarkably. When the ophthalmic composition according to the present embodiment is an eye drop, the dosage and administration thereof is not particularly limited as long as it is effective and has few side effects, but for example, adults (15 years old or older) and 7 years old. For the above children, a method of instilling 1 to 2 drops 4 times a day, 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops 5 to 6 times a day. The method to be used can be exemplified.

The ophthalmic composition according to this embodiment may be used for improving complex eye symptoms. Here, in the present specification, "complex eye symptoms" include eye fatigue, conjunctival congestion, blurred vision, blepharitis, itchy eyes, eye inflammation due to light rays, eye diseases, deterioration of visual function, and eye failure. It means a combination of two or more eye symptoms such as pleasure. Complex eye symptoms include eye fatigue, conjunctival congestion, blurred vision, itchy eyes, diminished visual function, and eye discomfort (eg, discomfort when wearing hard or soft contact lenses). It is preferable that two or more eye symptoms such as eye fatigue are combined, and eye symptoms such as eye fatigue, conjunctival congestion, blurred vision, itchy eyes, decreased visual function, and eye discomfort are combined. It is more preferable to have. Complex eye symptoms may include, for example, tired eyes, conjunctival congestion, blurred vision, eyelid inflammation, itchy eyes, light-induced eye inflammation, eye disease, and discomfort when wearing hard contact lenses. , Eye fatigue, conjunctival congestion, blurred vision, eyelid inflammation, itchy eyes, eye inflammation due to light rays, eye disease, discomfort when wearing hard contact lenses, and diminished visual function. In addition, improvement of compound eye symptoms includes alleviation, treatment and prevention of compound eye symptoms.

The ophthalmic composition according to this embodiment is provided in an arbitrary container. The container for accommodating the ophthalmic composition according to the present embodiment is not particularly limited, and may be made of glass or plastic, for example. It is preferably made of plastic. Examples of the plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, a copolymer of polyimide and the monomers constituting these, and a mixture of two or more of these. Polyethylene terephthalate is preferred. Further, the container for accommodating the ophthalmic composition according to the present embodiment may be a transparent container in which the inside of the container can be visually recognized, or an opaque container in which the inside of the container is difficult to visually recognize. 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 containing 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. It is preferably made of plastic. Examples of the plastic include polybutylene terephthalate, polyethylene, polypropylene, a copolymer of the monomers constituting them, and a mixture of two or more of these. Polyethylene is preferred.

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

The container for accommodating the ophthalmic composition according to the present embodiment may be a multi-dose type containing a plurality of uses, or a unit-dose type containing a single use.

The ophthalmic composition according to the present 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 has an internal volume of 5 to 20 mL. It is more preferably filled in a container having an internal volume of 6 to 16 mL, and even more preferably filled in a container having an internal volume of 10 to 15 mL.

[Mucin production enhancer]
The effect of the ophthalmic composition according to the present invention on improving various eye symptoms is based, at least in part, on the effect of enhancing the expression of the MUC gene (MUC16, MUC4) by the ophthalmic composition according to the present invention. Therefore, the present invention also comprises (A) at least one selected from the vitamin A class, 40,000 to 200,000 IU / 100 mL, and (B) at least one selected from the group consisting of butylhydroxyanisole and a salt thereof. (C) A MUC gene comprising an ophthalmic composition containing 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. An expression enhancer or a mucin production enhancer can be provided. Ophthalmology, such as the types and contents of (A) component, (B) component and (C) component, and other component types and contents in the MUC gene expression enhancer or mucin production enhancer according to the present invention. The pharmaceutical form and use of the composition are the same as those described for the ophthalmic composition.

[Method of imparting mucin production enhancing effect to ophthalmic composition]
The present invention also comprises, in an ophthalmic composition, (A) at least one selected from vitamin As at least 40,000 to 200,000 IU / 100 mL, (B) at least selected from the group consisting of butyl hydroxyanisole and salts thereof. Ophthalmic composition comprising one and at least one ingredient selected from the group consisting of (C) hyperemic remover, eye muscle regulator, anti-inflammatory agent, vitamin agent, amino acids and thickener. It can also be regarded as a method of imparting an effect of enhancing mucin production to an object, or a method of imparting an effect of enhancing the expression of MUC genes (MUC16, MUC4) to an ophthalmic composition. Regarding the formulation form and use of the ophthalmic composition, such as the type and content of the component (A), the component (B) and the component (C), the type and content of other components, etc. in the method, the ophthalmic composition. It is the same as the aspect described with respect to.

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

[Test Example 1: Evaluation of effect after instillation]
Each aqueous composition (eye drops) was prepared according to the formulation shown in Table 1, and this was used as a test solution. Each test solution was filled with 13 mL in a 13 mL volume 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 a day were selected. The two subjects were around 50 years old and became more and more aware of symptoms such as eye fatigue and haze as they got older. The other two are subjects in their 30s.

Four subjects instilled one drop of each test solution into both eyes and used the "VAS method (Visual Analog Scale)" using a 10 cm straight line with a memory of 0 to 100. Eyes 30 seconds after instillation. The effect of improving symptoms (eye fatigue, red eye, blurred vision, itchy eyes, poor focus, discomfort of the eyes, tired eyes due to dryness) was evaluated. The higher the score increase value, the better the eye symptoms.

Using the score of the test solution of Comparative Example 1, the score increase rate of the test solution of each example was calculated using the following formula.
Score increase rate (%) = {(average VAS score value of the test solution of each example-average VAS score value of the test solution of Comparative Example 1) / average VAS score value of the test solution of Comparative Example 1} × 100
The average VAS score value is an average value of the 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 also shown in Table 1.

In Table 1, the blending amount of retinyl palmitate is shown per 100 mL.

When the component (B) (butylhydroxyanisole) and the component (C) were added to the 50,000 IU / 100 mL vitamin A-containing eye drops, the effects on each effect were significantly improved. In addition, subjects around the age of 50 scored significantly more in terms of "eye strain" (especially "eye strain due to dryness") and "difficulty in focusing" compared to subjects in their 30s. A tendency to rise was confirmed. Regarding the item of "difficulty in focusing", it is considered that the ophthalmic composition according to the present invention improves the repairing action of the cornea, thereby improving the visual function, which makes it easier to focus.

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

Corneal epithelial cell lines HCE-T cells were seeded at 12 Well Plate (Corning Inc.) at 1 × 10 ⁵ cells / Well, and cultured at 37 ° C., 5% CO ₂ , and 90% humidity. The 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. A solution human (manufactured by SIGMA) added to 5 μg / mL was used. The next day, after confirming that the medium was confluent and removing the medium by suction, 1 mL of each test solution was added to each well (n = 2). After reacting 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. And reverse transcribed into cDNA. Using ABI Quant Studio Real time PCR (manufactured by Thermo Fisher), qPCR was performed, 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 with respect to the control was calculated according to the following formula 1 using the medium (medium only) to which the test component was not added as a control.
Equation 1: Expression rate (%) = [2 ^{-{(Ct value of MUC16 gene in test solution)-(Ct value of 18s rRNA in test solution)}} / 2 ^{-{(Ct value of control MUC16 gene) -(Ct value of 18s rRNA of control)}} ] × 100

Next, using the expression rate calculated by the formula 1, the expression increase rate (%) of the MCU16 gene in each test solution with respect to the corresponding comparative example was calculated according to the following formula 2. The corresponding comparative example of Test Example 2 is Comparative Example 2-1. The results are also shown in Table 2.
Equation 2: Expression 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) (retinyl palmitate), the component (B) (butylhydroxyanisole) and the component (C) (aminoethylsulfonic acid or neostigmine methylsulfate) are added, either aerobic condition or anaerobic condition is used. It was confirmed that the expression of the MUC16 gene was also increased in the case of. The MUC16 gene, along with the MUC4 gene, is a gene associated with mucin expression on the ocular surface. By increasing the expression of mucin, the surface of tears is made uniform, which also contributes to the suppression of eye strain, blurred vision, eye discomfort, difficulty in focusing, and the like. it is conceivable that. In addition, the increased expression of the MUC16 gene was also remarkable under anaerobic conditions. Therefore, the ophthalmic composition of the present invention is remarkably effective even when wearing contact lenses and when falling into an anaerobic state such as during sleep.

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

Similar to Test Example 2, corneal epithelial cell lines HCE-T cells were cultured in 12 Well Plate (Corning Inc.). After confirming that the medium was confluent and removing the medium by suction, 1 mL of each test solution was added to each well (n = 2). After reacting for 7 hours under anaerobic conditions at 37 ° C., RNA was extracted from the cells using QIAshredder & RNase Mini Kit (manufactured by QIAGEN), and reversed to cDNA using SuperScriptII (manufactured by Life technologies). I copied it. Using ABI Quant Studio Real time PCR (manufactured by Thermo Fisher), qPCR was performed, and the gene expression levels of MUC4 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 MUC4 gene in each test solution with respect to the control was calculated according to the following formula 3 using the medium (medium only) to which the test component was not added as a control.
Equation 3: Expression rate (%) = [2 ^{-{(Ct value of MUC4 gene in test solution)-(Ct value of 18s rRNA in test solution)}} / 2 ^{-{(Ct value of control MUC4 gene) -(Ct value of 18s rRNA of control)}} ] × 100

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

Expression of the MUC4 gene in an aqueous composition containing component (A) (retinyl palmitate), component (B) (butylhydroxyanisole) and component (C) (aminoethyl sulfonic acid, neostigmine methylsulfate, or pyridoxine hydrochloride). Was confirmed to increase.

[Formulation example]
Eye drops (formulation examples 1 to 40) are prepared according to the formulations shown in Tables 4 to 7 below and contained in a multidose-type container (formation examples 1-1 to 1-40 in a container). The unit of each component amount in Tables 4 to 7 below is w / v%. Further, in Tables 4 to 7, the blending amount of retinyl palmitate is shown per 100 mL.

Further, an eye drop (formulation examples 1 to 40) is filled in a polyethylene terephthalate multidose type container, and a container with a low-density polyethylene nozzle is attached to the container in preparation examples 2-1 to 2-40. (Formulation Examples 1 to 40) is filled in a polyethylene terephthalate multidose container, and when the cap is attached (during storage), the entire wall surface that may come into contact with the content liquid is composed of polybutylene terephthalate. Possibility of filling a multi-dose type container made of polyethylene terephthalate with preparation examples 3-1 to 3-40 and eye drops (formulation examples 1 to 40) in a container and contacting the contents with the contents. A multi-dose type container made of polyethylene terephthalate containing a container containing a nozzle in which a part of the wall surface is made of polyethylene terephthalate is contained in a container. Examples of preparations 5-1 to 5-40 in a container were provided with a nozzle in which a part of the wall surface that may come into contact with the content liquid was made of polyethylene terephthalate.

Claims (4)

(A) At least one selected from vitamin A is 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 anti-hyperemic agent. , An ophthalmic composition comprising at least one ingredient selected from the group consisting of eye muscle regulators, anti-inflammatory agents, vitamins, amino acids and thickeners.
The decongestant is tetrahydrozoline and a salt thereof.
The extraocular muscle regulator is neostigmine and a salt thereof.
The anti-inflammatory agents are glycyrrhizic acid and epsilon-aminocaproic acid and salts thereof.
The vitamin preparations are panthenol and pyridoxine and salts thereof .
The amino acids are aspartic acid, aminoethyl sulfonic acid and salts thereof.
The thickener is chondroitin sulfate and a salt thereof, an ophthalmic composition (however, an eye drop containing a quaternary ammonium-type cationic surfactant and sodium sulfite, and 0.06 part by weight of vitamin A palmitate, medium chain. Fatty acid triglyceride 1.0 part by weight, poroxamar 1.0 part by weight, polyethylene glycol 1.0 part by weight, BHA 0.05 part by weight, sorbitol 2.0 part by weight, glycerin 1.5 part by weight, ethylparaben 0.03 part by weight , And water, excluding eye drops totaling 100 parts by weight). The ophthalmic composition according to claim 1, further comprising (D) at least one selected from the group consisting of (D) dibutylhydroxytoluene and a salt 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.