JP2024150782A - Ophthalmic composition for improving complex eye symptoms - Google Patents

Abstract

To provide an ophthalmic composition that can improve eye symptoms.SOLUTION: An ophthalmic composition for improving composite eye symptoms contains (A) at least one selected from the group of vitamin A of 40,000-200,000 IU/100 mL, and (B) a lipid-soluble antioxidant.SELECTED DRAWING: None

Description

The present invention relates to an ophthalmic composition for improving complex eye symptoms.

Many ophthalmic compositions are commercially available and used to relieve or prevent eye symptoms such as eye fatigue, conjunctival congestion, blurred vision, blepharitis, itchy eyes, photoophthalmia, and eye diseases. These ophthalmic compositions are usually prepared by combining and blending ingredients approved as active ingredients in over-the-counter ophthalmic drugs, such as decongestants, ocular muscle regulators, anti-inflammatory agents, antihistamines, vitamins, amino acids, sulfa-based antibacterial agents, inorganic salts, polymeric thickeners, and preservatives, as well as other additives (e.g., Patent Document 1).

JP 2004-59479 A

In recent years, the spread of personal computers has led to increased strain on the eyes, the widespread use of contact lenses, and increased dispersion of antigenic substances, creating a demand for ophthalmic compositions that can more effectively improve eye conditions.

The present invention aims to provide an ophthalmic composition that can improve various eye conditions.

The present invention relates to an ophthalmic composition for improving complex eye symptoms, which can significantly improve complex eye symptoms by combining and formulating a predetermined amount of (A) vitamin A and (B) a fat-soluble antioxidant.

The present invention provides, for example, the following inventions.
[1]
An ophthalmic composition for improving a complex eye symptom, comprising (A) 40,000 to 200,000 IU/100 mL of vitamin A and (B) a fat-soluble antioxidant.
[2]
The ophthalmic composition according to [1], comprising, as component (A), at least one selected from the group consisting of retinol, its derivatives, and salts thereof.
[3]
The ophthalmic composition according to [1] or [2], further comprising (C) at least one component selected from the group consisting of a decongestant, an ocular muscle regulating agent, an anti-inflammatory agent, an antihistamine, a vitamin, and an amino acid.
[4]
The ophthalmic composition according to any one of [1] to [3], wherein the complex ocular symptom is a complex symptom of two or more ocular symptoms selected from the group consisting of eye fatigue, conjunctival congestion, blurred vision, blepharitis, itchy eyes, photoophthalmia, eye disease, decreased visual function, and eye discomfort.
[5]
The ophthalmic composition according to any one of [1] to [4], further comprising a buffer.
[6]
The ophthalmic composition according to any one of [1] to [5], further comprising a nonionic surfactant.
[7]
The ophthalmic composition according to any one of [1] to [6], further comprising a terpenoid.

The present invention provides an ophthalmic composition that can improve various eye conditions.

The following describes in detail the embodiments of the present invention. However, the present invention is not limited to the following embodiments.

The ophthalmic composition for improving complex eye symptoms according to this embodiment (sometimes simply referred to as the "ophthalmic composition") contains (A) 40,000 to 200,000 IU/100 mL of vitamin A (also referred to as the "(A) component") and (B) a fat-soluble antioxidant (also referred to as the "(B) component").

In this specification, "complex eye symptoms" refers to a combination of two or more eye symptoms such as eye fatigue, conjunctival congestion, blurred vision, blepharitis, itchy eyes, photoophthalmia, eye disease, decreased visual function, and eye discomfort. The composite eye symptoms are preferably a combination of two or more eye symptoms such as eye fatigue, conjunctival congestion, blurred vision, itchy eyes, decreased visual function, and eye discomfort (e.g., discomfort when wearing hard contact lenses or soft contact lenses), and more preferably a combination of eye symptoms such as eye fatigue, conjunctival congestion, blurred vision, itchy eyes, decreased visual function, and eye discomfort. Examples of the complex eye symptoms include eye fatigue, conjunctival congestion, blurred vision, blepharitis, itchy eyes, photophthamus, eye disease, and discomfort when wearing hard contact lenses, and may also include eye fatigue, conjunctival congestion, blurred vision, blepharitis, itchy eyes, photophthamus, eye disease, discomfort when wearing hard contact lenses, and decreased visual function. Improvement of the complex eye symptoms includes alleviation, treatment, and prevention of the complex eye symptoms.

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

Examples of derivatives of vitamin A include esters with monocarboxylic acids such as retinol palmitate, retinol acetate, retinol butyrate, retinol propionate, retinol octylate, retinol laurate, retinol oleate, and retinol linoleate.

The form of the salt of vitamin A is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable, but specific examples include organic acid salts (e.g., monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylates (fumarate, maleate, succinate, malonate, etc.), oxycarboxylates (lactate, tartrate, citrate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.), inorganic acid salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases (e.g., ammonium salts; salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.), etc. These salts may be used alone or in any combination of two or more.

As vitamin A, retinol derivatives are preferred, esters of retinol and monocarboxylic acids are more preferred, and retinol palmitate and retinol acetate are even more preferred.

As vitamin A, synthetic substances may be used, or extracts obtained from natural substances (such as vitamin A oil) may be used. Vitamin A oil is fatty oil obtained from animal tissues containing retinol, or a concentrate thereof, or a product obtained by appropriately adding vegetable oil to either of these. As vitamin A, commercially available products may also be used. One type of vitamin A may be used alone, or two or more types may be used in combination.

The content of component (A) in the ophthalmic composition according to this embodiment is, based on the total amount of the ophthalmic composition, preferably 40,000 to 200,000 IU/100 mL, more preferably 40,000 to 100,000 IU/100 mL, even more preferably 45,000 to 60,000 IU/100 mL, and even more preferably 48,000 to 55,000 IU/100 mL.

"IU" refers to the international unit calculated by the method described in the Vitamin A Quantitative Method in the 16th Revised Japanese Pharmacopoeia. For example, the monographs of the 16th Revised Japanese Pharmacopoeia state that retinol acetate contains at least 2.5 million units of vitamin A per gram, and retinol palmitate contains at least 1.5 million units of vitamin A per gram.

[Component (B)]
The fat-soluble antioxidant, which is the component (B), is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of fat-soluble antioxidants include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tocopherol, tocopherol derivatives (tocopherol acetate, tocopherol nicotinate, tocopherol succinate, tocopherol calcium succinate, etc.), nordihydroguaiaretic acid, propyl gallate, fat-soluble vitamin C derivatives, and salts thereof. Tocopherol and tocopherol derivatives may be α, β, γ, δ-tocopherol and derivatives thereof, and may be either d-form (natural vitamin E, etc.) or dl-form.

As fat-soluble antioxidants, dibutylhydroxytoluene, butylhydroxyanisole, tocopherol, tocopherol derivatives and salts thereof are preferred, dibutylhydroxytoluene and tocopherol derivatives are more preferred, and dibutylhydroxytoluene and d-α-tocopherol acetate are even more preferred.

(B) The fat-soluble antioxidant may be a commercially available product. The fat-soluble antioxidant may be used alone or in combination of two or more. It is preferable to use two or more types of fat-soluble antioxidants in combination.

The content of component (B) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of component (B), the type and content of other blended components, the intended use of the ophthalmic composition, the formulation form, and the like. From the viewpoint of more significantly achieving the effects of the present invention, the content of component (B) is, for example, preferably 0.00001 to 1 w/v%, more preferably 0.0001 to 0.5 w/v%, even more preferably 0.001 to 0.1 w/v%, and even more preferably 0.004 to 0.075 w/v%, based on the total amount of the ophthalmic composition.

When dibutylhydroxytoluene is used as component (B), the content of dibutylhydroxytoluene is, for example, preferably 0.00001 to 0.1 w/v%, more preferably 0.0001 to 0.05 w/v%, even more preferably 0.001 to 0.01 w/v%, and even more preferably 0.004 to 0.006 w/v%, based on the total amount of the ophthalmic composition.

When tocopherol acetate is used as component (B), the content of tocopherol acetate is, for example, preferably 0.001 to 1 w/v%, more preferably 0.005 to 0.5 w/v%, even more preferably 0.01 to 0.1 w/v%, even more preferably 0.03 to 0.075 w/v%, particularly preferably 0.04 to 0.06 w/v%, and most preferably 0.045 to 0.055 w/v%, based on the total amount of the ophthalmic composition.

The content ratio of component (B) to component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the types of components (A) and (B), the types and contents of other blended components, the use and formulation form of the ophthalmic composition, etc. As for the content ratio of component (B) to component (A), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of component (B) in the ophthalmic composition according to this embodiment is preferably 0.0001 to 0.1 g/10,000 IU, more preferably 0.0005 to 0.025 g/10,000 IU, and even more preferably 0.001 to 0.015 g/10,000 IU, relative to the total content of component (A) in the ophthalmic composition according to this embodiment being 10,000 IU.

The ophthalmic composition according to this embodiment preferably further contains (C) at least one component selected from the group consisting of a decongestant, an ocular muscle regulator, an anti-inflammatory agent, an antihistamine, a vitamin preparation, and an amino acid (also referred to as "component (C)").

[Component (C)]
The decongestant, which is the component (C), is a compound having an effect of suppressing congestion, or a salt thereof. The decongestant is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) 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 tetrahydrozoline, naphazoline, oxymetazoline, xylometazoline, epinephrine, ephedrine, phenylephrine, and salts thereof. As the decongestant, tetrahydrozoline, naphazoline, and salts thereof are preferred, and tetrahydrozoline hydrochloride is more preferred.

A commercially available decongestant may be used. A single decongestant may be used alone, or two or more decongestant may be used in combination.

The ocular muscle regulating agent, which is component (C), is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable. Examples of ocular muscle regulating agents include cholinesterase inhibitors that have an active center similar to that of acetylcholine.

Specific examples of eye muscle adjusters include neostigmine, tropicamide, helenien, atropine, and salts thereof. As eye muscle adjusters, neostigmine and its salts are preferred, and neostigmine methylsulfate is more preferred.

The eye muscle regulating agent may be a commercially available product. The eye muscle regulating agent may be used alone or in combination of two or more types.

The anti-inflammatory agent, which is component (C), is a compound having an anti-inflammatory or anti-inflammatory effect, or a salt thereof. There are no particular limitations on the anti-inflammatory agent, so long as it is medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable.

Specific examples of anti-inflammatory agents include berberine, azulenes (azulene, azulene sulfonic 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 flufenamate, bendazac, ketoprofen, felbinac, pranoprofen, and salts thereof. As anti-inflammatory agents, berberine, azulene sulfonic acid, allantoin, zinc sulfate, zinc lactate, glycyrrhizic acid, epsilon-aminocaproic acid, pranoprofen and salts thereof are preferred, berberine chloride, berberine sulfate, sodium azulene sulfonate, allantoin, dipotassium glycyrrhizinate, epsilon-aminocaproic acid are more preferred, and dipotassium glycyrrhizinate is even more preferred.

Commercially available anti-inflammatory agents may be used. Anti-inflammatory agents may be used alone or in combination of two or more.

The antihistamine, which is component (C), is a compound having an antihistamine effect, or a salt thereof. There are no particular limitations on the antihistamine, so long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

Specific examples of antihistamines include chlorpheniramine, iproheptine, diphenhydramine, ketotifen, olopatadine, levocabastine, and salts thereof. As antihistamines, chlorpheniramine, diphenhydramine, and salts thereof are preferred, chlorpheniramine maleate and diphenhydramine hydrochloride are more preferred, and chlorpheniramine maleate is even more preferred.

Commercially available antihistamines may be used. Antihistamines may be used alone or in combination of two or more.

The vitamin preparation which is component (C) (excluding components which fall under components (A) or (B)) is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable, and may be appropriately selected from known vitamins for use.

Specific examples of vitamin preparations include water-soluble vitamins such as vitamin B1, vitamin B2 (flavin adenine dinucleotide), niacin (nicotinic acid and nicotinamide), pantothenic acid, panthenol, vitamin B6 (pyridoxine, pyridoxal and pyridoxamine), biotin, folic acid and vitamin B12 (cyanocobalamin, hydroxocobalamin, methylcobalamin and adenosylcobalamin) and their salts. Specific examples of vitamin salts include, for example, sodium flavin adenine dinucleotide, pyridoxine hydrochloride, calcium pantothenate and sodium pantothenate. As vitamin preparations, cyanocobalamin, flavin adenine dinucleotide, panthenol, pyridoxine and their salts are preferred, cyanocobalamin, sodium flavin adenine dinucleotide, panthenol and pyridoxine hydrochloride are more preferred, and pyridoxine hydrochloride is even more preferred.

Commercially available vitamin preparations may be used. Vitamin preparations may be used alone or in combination of two or more types.

The amino acids that are component (C) are compounds that have an amino group and a carboxyl group in the molecule, and their derivatives and salts. There are no particular limitations on the amino acids, so long as they are medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable, and any amino acid can be appropriately selected from known amino acids for use.

Specific examples of amino acids include amino acids and their salts, amino acid derivatives and their salts, and mucopolysaccharides and their derivatives and their salts. Specific examples of amino acids and their salts include monoaminomonocarboxylic acids such as glycine, alanine, aminobutyric acid, and aminovaleric acid, monoaminodicarboxylic acids such as aspartic acid and glutamic acid, and diaminomonocarboxylic acids such as arginine and lysine, and their salts. Specific examples of amino acid derivatives and their salts include amino acid derivatives such as aminoethylsulfonic acid (taurine) and their salts. Examples of mucopolysaccharides and their derivatives and their salts include chondroitin sulfate and its salts. The amino acids may be D-, L-, or DL-isomers. As amino acids, monoaminodicarboxylic acids, amino acid derivatives, mucopolysaccharides and their salts are preferred, aspartic acid, taurine, chondroitin sulfate and their salts are more preferred, potassium aspartate, magnesium aspartate, magnesium potassium aspartate (mixture of equal parts), taurine, sodium chondroitin sulfate are even more preferred, and taurine is even more preferred.

Commercially available amino acids may be used. One type of amino acid may be used alone, or two or more types may be used in combination.

The "salt" in component (C) is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) 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, including salts with sodium, potassium, calcium, magnesium, ammonium, diethanolamine, ethylenediamine, and the like. In addition, salts may be salts of amines, such as ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, and L-glucamine; salts with basic amino acids, such as lysine, δ-hydroxylysine, and arginine. Furthermore, it may be a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid; a salt with an organic acid such as methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic 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, or palmitic acid; or a salt with an acidic amino acid such as aspartic acid or glutamic acid. The "salt" in component (C) includes solvates and hydrates of the salt.

The content of component (C) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of component (C), the type and content of other blended components, the intended use of the ophthalmic composition, the formulation form, and the like. From the viewpoint of more significantly achieving the effects of the present invention, the content of component (C) is, for example, preferably 0.0001 to 10 w/v%, more preferably 0.0005 to 5 w/v%, even more preferably 0.001 to 2 w/v%, and even more preferably 0.01 to 1 w/v%, based on the total amount of the ophthalmic composition.

From the viewpoint of achieving the effects of the present invention more significantly, the total content of the congestion reducer (C) in the ophthalmic composition according to this embodiment is preferably 0.0001 to 1 w/v%, more preferably 0.0005 to 0.5 w/v%, even more preferably 0.001 to 0.1 w/v%, and particularly preferably 0.01 to 0.05 w/v%, based on the total amount of the ophthalmic composition.

From the viewpoint of achieving the effects of the present invention more significantly, the total content of the ocular muscle regulating agent (C) in the ophthalmic composition according to this embodiment is preferably 0.0001 to 0.1 w/v%, more preferably 0.001 to 0.01 w/v%, and even more preferably 0.004 to 0.005 w/v%, based on the total amount of the ophthalmic composition.

From the viewpoint of achieving the effects of the present invention more significantly, the total content of the anti-inflammatory agent (C) in the ophthalmic composition according to this embodiment is preferably 0.0005 to 5 w/v%, more preferably 0.005 to 1 w/v%, even more preferably 0.05 to 0.5 w/v%, and particularly preferably 0.2 to 0.25 w/v%, based on the total amount of the ophthalmic composition.

From the viewpoint of achieving the effects of the present invention more significantly, the total content of the antihistamine (C) in the ophthalmic composition according to this embodiment is preferably 0.001 to 1 w/v%, more preferably 0.005 to 0.1 w/v%, even more preferably 0.015 to 0.05 w/v%, and particularly preferably 0.025 to 0.04 w/v%, based on the total amount of the ophthalmic composition.

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

From the viewpoint of achieving the effects of the present invention more significantly, the total content of the amino acids (C) in the ophthalmic composition according to this embodiment is preferably 0.01 to 10 w/v%, more preferably 0.05 to 7.5 w/v%, even more preferably 0.1 to 5 w/v%, and particularly preferably 0.5 to 2 w/v%, based on the total amount of the ophthalmic composition.

The ophthalmic composition according to this embodiment preferably contains, as component (C), a combination of components selected from two or more different classes selected from congestion decongestants, ocular muscle regulating agents, anti-inflammatory agents, antihistamines, vitamins, and amino acids, more preferably a combination of components selected from three or more different classes, even more preferably a combination of components selected from four or more different classes, even more preferably a combination of components selected from five or more different classes, and particularly preferably a combination of components selected from all six classes.

The content ratio of component (C) to component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and is appropriately set depending on the types of components (A) and (C), the types and contents of other blended components, the use and formulation form of the ophthalmic composition, etc. As for the content ratio of component (C) to component (A), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of component (C) in the ophthalmic composition according to this embodiment is preferably 0.0005 to 2 g/10,000 IU, more preferably 0.001 to 1 g/10,000 IU, and even more preferably 0.01 to 0.5 g/10,000 IU, relative to the total content of component (A) of 10,000 IU.

The content ratio of the (C) component to the (B) component in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the types of the (B) and (C) components, the types and contents of other blended components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of further enhancing the effect of the present invention, for example, the content ratio of the (C) component to the (B) component is preferably 0.001 to 50,000 parts by mass, more preferably 0.01 to 5,000 parts by mass, and even more preferably 0.1 to 500 parts by mass, of the total content of the (C) component per 1 part by mass of the total content of the (B) component contained in the ophthalmic composition according to this embodiment.

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

Examples of buffers include inorganic buffers, which are buffers derived from inorganic acids, and organic buffers, which are buffers derived from organic acids or organic bases.

Examples of inorganic buffers include boric acid buffers, phosphate buffers, and carbonate buffers. Examples of boric acid buffers include boric acid or its salts (alkali metal borates, alkaline earth metal borates, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphates, alkaline earth metal phosphates, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonates, alkaline earth metal carbonates, etc.). In addition, borate or phosphate hydrates may be used as borate or phosphate buffers. More specific examples of borate buffers include boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffers include phosphoric acid or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffers include carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.).

Examples of organic buffers include citrate buffers, acetate buffers, Tris buffers, and AMPD buffers. Examples of citrate buffers include citric acid or its salts (alkali metal citrate, alkaline earth metal citrate, etc.). Examples of acetate buffers include acetic acid or its salts (alkali metal acetate, alkaline earth metal acetate, etc.). In addition, citrate or acetate hydrates may be used as citrate buffers or acetate buffers. More specific examples of citrate buffers include citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); and acetate buffers include acetic acid or its salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). Examples of Tris buffers include trometamol or its salts (trometamol hydrochloride, etc.). Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol or a salt thereof.

Preferred buffers include boric acid buffers (e.g., a combination of boric acid and borax), phosphate buffers (e.g., a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), and Tris buffers (e.g., trometamol), with boric acid buffers being more preferred and a combination of boric acid and borax being even more preferred.

Commercially available buffers may be used. One type of buffer may be used alone, or two or more types may be used in combination.

The content of the buffering agent in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of buffering agent, the type and content of other blended components, the intended use of the ophthalmic composition, the formulation form, etc. From the viewpoint of more significantly achieving the effects of the present invention, the content of the buffering agent is, for example, preferably 0.01 to 10 w/v%, more preferably 0.05 to 5 w/v%, and even more preferably 0.1 to 3 w/v%, based on the total amount of the ophthalmic composition.

The content ratio of the buffering agent relative to the component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of the component (A) and the buffering agent, the type and content of other blended components, the use and formulation form of the ophthalmic composition, etc. As for the content ratio of the buffering agent relative to the component (A), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the buffering agent relative to the total content of the component (A) contained in the ophthalmic composition according to this embodiment is preferably 0.001 to 3 g/10,000 IU, more preferably 0.005 to 1 g/10,000 IU, and even more preferably 0.01 to 0.5 g/10,000 IU, relative to a total content of 10,000 IU of the component (A).

The content ratio of the buffering agent relative to the component (B) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of the component (B) and the buffering agent, the type and content of other blended components, the intended use of the ophthalmic composition, the formulation form, etc. From the viewpoint of further enhancing the effect of the present invention, for example, the content ratio of the buffering agent relative to the component (B) is preferably 0.01 to 50,000 parts by mass, more preferably 0.5 to 5,000 parts by mass, and even more preferably 1 to 1,000 parts by mass, of the total content of the component (B) contained in the ophthalmic composition according to this embodiment.

[Nonionic Surfactant]
The ophthalmic composition according to the present embodiment preferably further contains a nonionic surfactant. When the ophthalmic composition further contains a nonionic surfactant, the effect of the present invention is more pronounced. The nonionic surfactant is not particularly limited as long as it is medicamentally, pharmacologically (pharmaceutical) or physiologically acceptable.

Examples of nonionic surfactants include POE sorbitan fatty acid esters such as POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60), POE (20) sorbitan tristearate (polysorbate 65), and POE (20) sorbitan monooleate (polysorbate 80); poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 403, and poloxamer 235; POE/POP glycols such as Loxamer 237 and Poloxamer 124; POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, and POE hydrogenated castor oil 80; POE castor oils such as POE castor 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 35, and POE castor oil 50; polyethylene monostearate glycol (2 E.O.), polyethylene glycol monostearate (4 E.O.), polyethylene glycol monostearate (9 E.O.), polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (23 E.O.), polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (32 E.O.), polyethylene glycol monostearate (40 E.O., polyoxyl 40 stearate ... Examples of the polyethylene glycol monostearate include polyethylene glycol monostearate (45 E.O.), polyethylene glycol monostearate (55 E.O.), polyethylene glycol monostearate (75 E.O.), and polyethylene glycol monostearate (140 E.O.); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; and POE alkyl phenyl ethers such as POE (10) nonylphenyl ether. In the above-listed compounds, POE stands for polyoxyethylene, POP stands for polyoxypropylene, and the numbers in parentheses stand for the number of moles added.

As nonionic surfactants, POE sorbitan fatty acid esters; POE-POP glycols; POE hydrogenated castor oil; POE castor oil, and polyethylene glycol monostearate are preferred, with polysorbate 80, poloxamer 407, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, POE castor oil 3, POE castor oil 10, POE castor oil 35, and polyoxyl 40 stearate being more preferred, with polysorbate 80 and POE hydrogenated castor oil 60 being even more preferred, and polysorbate 80 being even more preferred.

As the nonionic surfactant, commercially available ones may be used. As the nonionic surfactant, one type may be used alone, or two or more types may be used in combination.

The content of the nonionic surfactant in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of nonionic surfactant, the type and content of other blended ingredients, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of more significantly achieving the effects of the present invention, the content of the nonionic surfactant is, for example, preferably 0.001 to 5 w/v%, more preferably 0.01 to 3 w/v%, and even more preferably 0.1 to 1 w/v%, based on the total amount of the ophthalmic composition.

The content ratio of the nonionic surfactant to the component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of the component (A) and the nonionic surfactant, the type and content of other blended components, the use and formulation form of the ophthalmic composition, etc. As for the content ratio of the nonionic surfactant to the component (A), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the nonionic surfactant is preferably 0.001 to 1 g/10,000 IU, more preferably 0.005 to 0.5 g/10,000 IU, and even more preferably 0.01 to 0.1 g/10,000 IU, relative to the total content of the component (A) contained in the ophthalmic composition according to this embodiment of 10,000 IU.

The content ratio of the nonionic surfactant relative to the component (B) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the types of the component (B) and the nonionic surfactant, the types and contents of other blended components, the intended use of the ophthalmic composition, the formulation form, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the nonionic surfactant relative to the component (B) is, for example, preferably 0.1 to 1000 parts by mass, more preferably 0.5 to 100 parts by mass, and even more preferably 1 to 50 parts by mass, of the total content of the component (B) contained in the ophthalmic composition according to this embodiment.

[Terpenoids]
The ophthalmic composition according to the present embodiment preferably further contains a terpenoid. 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 medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.

Terpenoids include, for example, cyclic and acyclic terpenes.

Cyclic terpenes are terpenoids that have at least one ring structure in the molecule. Examples of cyclic terpenes include menthol, camphor, borneol (also called "ryunou"), menthone, cineole, carvone, anethole, eugenol, limonene, pinene, and derivatives thereof.

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

In the present invention, essential oils containing the above-mentioned compounds may be used as terpenoids. 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 in the d-, l- or dl-form, and examples include dl-menthol, d-menthol, l-menthol, dl-camphor, d-camphor, l-camphor, dl-borneol, d-borneol, l-borneol, dl-menthone, d-menthone, and l-menthone. However, some terpenoids, such as geraniol and cineol, do not have optical isomers.

As terpenoids, menthol, camphor, borneol, menthone and eucalyptus oil are preferred, menthol and camphor are more preferred, l-menthol and d-camphor are even more preferred, and l-menthol is even more preferred.

The terpenoids may be commercially available. One type of terpenoid may be used alone, or two or more types may be used in combination.

The content of the terpenoid in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of terpenoid, the type and content of other blended ingredients, the purpose and formulation form of the ophthalmic composition, etc. From the viewpoint of more significantly achieving the effects of the present invention, the content of the terpenoid is, for example, preferably 0.00001 to 1 w/v%, more preferably 0.0001 to 0.5 w/v%, and even more preferably 0.0005 to 0.1 w/v%, based on the total amount of the ophthalmic composition.

The content ratio of the terpenoid relative to the component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of the component (A) and the terpenoid, the type and content of other blended components, the purpose and formulation form of the ophthalmic composition, etc. As for the content ratio of the terpenoid relative to the component (A), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the terpenoid relative to the component (A) contained in the ophthalmic composition according to this embodiment is preferably 0.00001 to 0.5 g/10,000 IU, more preferably 0.0001 to 0.1 g/10,000 IU, and even more preferably 0.0005 to 0.005 g/10,000 IU, relative to the total content of the component (A) of 10,000 IU.

The content ratio of the terpenoid relative to the component (B) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of the component (B) and the terpenoid, the type and content of other blended components, the intended use of the ophthalmic composition, the formulation form, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the terpenoid relative to the component (B) is, for example, preferably 0.0001 to 100 parts by mass, more preferably 0.001 to 10 parts by mass, and even more preferably 0.01 to 5 parts by mass, of the total content of the component (B) contained in the ophthalmic composition according to this embodiment.

The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a medicamentously, pharmacologically (pharmaceutical) or physiologically acceptable range. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, even more preferably 4.5 to 8.5, and even more preferably 5.0 to 8.5.

The ophthalmic composition according to this 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 purpose, formulation, method of use, etc. of the ophthalmic composition, and can be, for example, 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and even more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w/v% sodium chloride aqueous solution) based on the 16th Revised Japanese Pharmacopoeia, and the osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring osmolality ratios (0.9 w/v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, allowing it to cool in a desiccator (silica gel), and then accurately weighing out 0.900 g of it and dissolving it in purified water to make exactly 100 mL, or a commercially available standard solution for measuring osmolality ratios (0.9 w/v% sodium chloride aqueous solution) can be used.

The viscosity of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a range that is medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable. The viscosity of the ophthalmic composition according to this embodiment is preferably 0.01 to 10,000 mPa·s, more preferably 0.05 to 8,000 mPa·s, and even more preferably 0.1 to 1,000 mPa·s, at 20°C, measured with a rotational viscometer (RE550 type viscometer, manufactured by Tosangyo Co., Ltd., rotor: 1°34'×R24).

The ophthalmic composition according to the present embodiment may contain a suitable amount of a combination of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients, as long as the effects of the present invention are not impaired. The ingredients are not particularly limited, and examples thereof include active ingredients in ophthalmic drugs listed in the 2012 edition of the General Drug Manufacturing and Sales Approval Standards (supervised by the Japan Society of Regulatory Science). Specific examples of ingredients used in ophthalmic drugs include the following:
Antiallergic agents: for example, sodium cromoglycate, tranilast, pemirolast potassium, ashitazanolast, etc.
Sulfa drugs: for example, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, etc.
Steroids: for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc.
Local anesthetics: for example, lidocaine, procaine, etc.
Others: rebamipide, etc.

In the ophthalmic composition according to the present embodiment, various additives may be appropriately selected according to the intended use and the formulation form, and one or more of them may be used in combination in appropriate amounts in a conventional manner, so long as the effects of the present invention are not impaired. Examples of such additives include those listed in the Pharmaceutical Additives Encyclopedia 2007 (edited by the Japan Pharmaceutical Additives Association).
Representative ingredients include the following additives:
Carrier: For example, an aqueous solvent such as water or aqueous ethanol.
Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and the like.
Bases: For example, octyldodecanol, titanium oxide, potassium bromide, plastibase, etc.
pH adjusters: for example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine, etc.
Stabilizers: for example, sodium formaldehyde sulfoxylate (Rongalit), sodium hydrogen sulfite, sodium pyrosulfite, aluminum monostearate, glycerin monostearate, cyclodextrin, monoethanolamine, etc.
Anionic surfactants: for example, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, alkyl sulfates, N-acyltaurine salts, etc.
Amphoteric surfactants: for example, lauryl dimethylaminoacetate betaine.
Preservatives, disinfectants, or antibacterial agents: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride, etc.), Gloquil (trade name, manufactured by Rhodia), etc.
Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and the like.
Isotonicity agents: for example, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, etc.
Viscosity enhancers: for example, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, sodium chondroitin sulfate, hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, etc.
Sugars: for example, glucose, cyclodextrin, etc.
Sugar alcohols: for example, xylitol, sorbitol, mannitol, glycerin, etc. These may be in the d-, l- or dl-form.

When the ophthalmic composition according to this embodiment contains water, the water content is, for example, preferably 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 even more preferably 90 w/v% or more and 99.2 w/v% or less, based on the total amount of the ophthalmic composition, from the viewpoint of more significantly achieving the effects of the present invention.

The water used in the ophthalmic composition according to this embodiment may be any water that is medicamentally, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of such water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection. These definitions are based on the 16th Edition of the Japanese Pharmacopoeia.

The ophthalmic composition according to this embodiment can be prepared by adding and mixing a desired amount of component (A) and, if necessary, other components to obtain a desired concentration. For example, it can be prepared by dissolving or dispersing those components in purified water, adjusting the pH and osmotic pressure to a predetermined level, and sterilizing the composition by filtration sterilization or the like.

The ophthalmic composition according to this embodiment can be in various formulation forms depending on the purpose. Examples of the formulation form include a liquid, a gel, a semi-solid (ointment, etc.), etc.

The ophthalmic composition according to this embodiment can be used, for example, as eye drops (also called eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), artificial tears, eyewash (also called eyewash or eyewash. Eyewash includes eyewash that can be applied while wearing contact lenses), and a composition for contact lenses [contact lens wearing solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaner, contact lens cleaning preservative), etc.]. The term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

The ophthalmic composition according to this embodiment is preferably an eye drop (including an eye drop that can be applied while wearing contact lenses) because it can more significantly exert the effects of the present invention. When the ophthalmic composition according to this embodiment is an eye drop, the method of use and dosage are not particularly limited as long as it is effective and has few side effects. For example, for adults (15 years or older) and children aged 7 years or older, 1 to 2 drops can be applied 4 times a day, or 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops can be applied 5 to 6 times a day.

The ophthalmic composition according to the present embodiment is provided in any container. The container for containing the ophthalmic composition according to the present embodiment is not particularly limited, and may be made of glass or plastic, for example. Plastic is preferable. Examples of plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, copolymers of monomers constituting these, and mixtures of two or more of these. Polyethylene terephthalate is preferable. The container for containing the ophthalmic composition according to the present embodiment may be a transparent container that allows the inside of the container to be seen, or may be an opaque container that makes it difficult to see the inside of the 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 holds the ophthalmic composition according to this embodiment. The material of the nozzle is not particularly limited, and may be made of, for example, glass or plastic. Plastic is preferable. Examples of plastic include polybutylene terephthalate, polyethylene, polypropylene, copolymers of monomers constituting these, and mixtures of two or more of these. Polyethylene is preferable.

The container that holds the ophthalmic composition according to this embodiment may be a multi-dose type that holds an amount for multiple uses, or a unit-dose type that holds an amount for a single use.

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, even 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.

The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples.

[Test Example 1: Evaluation of Effect after Instillation]
Each aqueous composition (eye drop) was prepared according to the formulations shown in Tables 1 and 2, and used as a test solution. Each test solution was filled in a 13 mL polyethylene terephthalate eye dropper container. After filling, a polyethylene nozzle was attached to the eye dropper container.

Four office workers who routinely work at VDTs (Visual Display Terminals) for more than four hours a day were selected as subjects. Two of the subjects were around 50 years old, and as they age, they have become more susceptible to symptoms such as eye fatigue and blurred vision. The other two subjects are in their 30s. Before the test, it was confirmed that there was no difference in the condition of each subject's left and right eyes.

For tests A to E, four subjects instilled one drop into either the left or right eye listed in Tables 1 and 2, and evaluated the effect of improving various eye symptoms (eye fatigue, bloodshot eyes, blurred vision, itchy eyes, difficulty focusing, eye discomfort, eye fatigue due to dryness) 30 seconds after instillation using the "VAS method (Visual Analog Scale)" using a 10 cm line marked with 0 to 100. The higher the score increase, the more the eye symptoms improved.

Using the scores of the test solutions of the corresponding reference comparative examples, the score increase rate of the test solutions 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 the corresponding Reference Comparative Example)/average VAS score value of the test solution of the corresponding Reference Comparative Example}×100
The average VAS score is the average of the scores of the four subjects. The test solution of the corresponding comparative example has the same formulation as the test solution of the example except that it does not contain dibutylhydroxytoluene.

表１中、パルミチン酸レチノール及び濃塩化ベンザルコニウム液５０は、１００ｍＬあたりの配合量を示す。

In Table 1, retinol palmitate and concentrated benzalkonium chloride solution 50 indicate the amounts per 100 mL.

表２中、パルミチン酸レチノール及び濃塩化ベンザルコニウム液５０は、１００ｍＬあたりの配合量を示す。

In Table 2, retinol palmitate and concentrated benzalkonium chloride solution 50 indicate the amounts per 100 mL.

The results are shown in Table 3.

When a fat-soluble antioxidant (dibutylhydroxytoluene) was added to 50,000 IU/100 mL of vitamin A eye drops, the effects of each efficacy were significantly improved. Also, compared to subjects in their 30s, subjects around 50 years old tended to have significantly higher scores in the categories of "eye fatigue" (especially "eye fatigue due to dryness") and "difficulty focusing." With regard to the category of "difficulty focusing," it is believed that the ophthalmic composition of the present invention improves the repair function of the cornea, improving visual function and making it easier to focus.

[Formulation example]
Eye drops (Preparation Examples 1 to 88) are prepared according to the formulations shown in Tables 4 to 13 below and stored in multi-dose containers.
The unit of the amount of each component in Tables 4 to 13 is w/v %. In Tables 4 to 13, the amount of retinol palmitate is shown per 100 mL. The pH of Formulation Examples 1 to 30 is 6.5, the pH of Formulation Examples 31 to 60 is 7, and the pH of Formulation Examples 61 to 88 is 6.

Claims (1)

The invention described in this specification.