JP2024072698A - Ophthalmologic composition for allergy - Google Patents

Abstract

To provide an ophthalmologic composition having superior antiallergic action.SOLUTION: An ophthalmologic composition for allergy contains at least one selected from the group consisting of (A) chondroitin sulfate and salts thereof, and (B) at least one selected from the group consisting of tranilast, cromoglycate and salts thereof, olopatadine and salts thereof, epinastine and salts thereof, and menthol. Relative to 1 pt.mass of the total content of component (A), the total content of tranilast is 0.4-0.7 pts.mass, the total content of cromoglycate and salts thereof is 0.5-1.5 pts.mass, the total content of olopatadine and salts thereof is 0.05-0.15 pts.mass, the total content of epinastine and salts thereof is 0.03-0.07 pts.mass, and the total content of menthol is 0.001-0.1 pts.mass.SELECTED DRAWING: None

Description

The present invention relates to an ophthalmic composition for allergies.

Antiallergic ingredients that are incorporated into ophthalmic preparations include tranilast, sodium cromoglycate, olopatadine hydrochloride, and epinastine hydrochloride (e.g., Non-Patent Document 1).

On the other hand, chondroitin sulfate or its salts have the effect of promoting energy metabolism, metabolism, and cellular respiration, as well as water retention, and are sometimes incorporated into ophthalmic preparations (for example, Patent Document 1).

JP 2011-148791 A

2017 edition of the approval criteria for manufacturing and selling prescription drugs (supervised by the Japan Society of Regulatory Science)

The object of the present invention is to provide a novel ophthalmic composition with excellent anti-allergic properties.

The present inventors have unexpectedly found that by blending chondroitin sulfate or a salt thereof with an ophthalmic composition containing at least one selected from the group consisting of tranilast, cromoglycic acid and its salts, olopatadine and its salts, epinastine and its salts, and menthol in a specific ratio relative to each drug, the antiallergic effect of the ophthalmic composition is significantly enhanced.

The present invention provides, for example, the following inventions.
[1]
An anti-allergic ophthalmic composition comprising (A) at least one component selected from the group consisting of chondroitin sulfate and its salts, and (B) at least one component selected from the group consisting of tranilast, cromoglycic acid and its salts, olopatadine and its salts, epinastine and its salts, and menthol, wherein, per 1 part by mass of component (A), the content of tranilast is 0.4 to 0.7 parts by mass, the content of cromoglycic acid and its salts is 0.5 to 1.5 parts by mass, the content of olopatadine and its salts is 0.05 to 0.15 parts by mass, the content of epinastine and its salts is 0.03 to 0.07 parts by mass, and the content of menthol is 0.001 to 0.1 part by mass.
[2]
The ophthalmic composition according to [1], wherein the total content of the component (A) is 1 w/v % based on the total amount of the ophthalmic composition.
[3]
The ophthalmic composition according to [1] or [2], which is an eye drop.

The present invention provides an ophthalmic composition with excellent anti-allergic properties.

The following describes in detail the embodiments of the present invention. However, the present invention is not limited to the following embodiments. In this specification, unless otherwise specified, the unit of content "%" means "w/v%" and is synonymous with "g/100 mL."

[Component (A)]
The ophthalmic composition according to this embodiment contains (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof (also simply referred to as "component (A)").

There are no particular limitations on chondroitin sulfate and its salts, so long as they are medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable.

Examples of salts of chondroitin sulfate include alkali metal salts and alkaline earth metal salts. Examples of alkali metal salts include sodium salt and potassium salt. Examples of alkaline earth metal salts include magnesium salt and calcium salt.

As chondroitin sulfate and its salts, chondroitin sulfate and alkali metal salts of chondroitin sulfate are preferred, chondroitin sulfate and sodium chondroitin sulfate are more preferred, and sodium chondroitin sulfate is even more preferred.

In this specification, the "weight average molecular weight" can be determined by using gel permeation chromatography in which a multi-angle light scattering detector (MALS detector) and a differential refractive index detector (RI detector) are connected online. Specifically, the following conditions are presented.
<Standard sample preparation>
10 mL of 0.1 M aqueous sodium nitrate solution was added to 5 mg of chondroitin sulfate or a salt thereof, and the mixture was gently stirred at room temperature until completely dissolved.
<Conditions for measuring weight average molecular weight>
Apparatus: Gel permeation chromatography - multi-angle light scattering meter Detector: Differential refractive index detector (Optilab rEX, manufactured by Wyatt Technology)
Multi-angle light scattering detector (DAWN HELEOS, manufactured by Wyatt Technology)
Column: Shodex OHpak SB-806M HQ x 2 (φ7.8 mm x 30 cm, Showa Denko)
Solvent: 0.1 M sodium nitrate aqueous solution Flow rate: 0.7 mL/min
Column temperature: 23°C
Detector temperature: 23°C
Injection volume: 0.2 mL
Data processing: Wyatt Technology data processing system (ASTRA)

The molecular weight of chondroitin sulfate and its salts is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable, but examples of lower limits of the weight average molecular weight calculated by the above method include 8,000 or more, 10,000 or more, 15,000 or more, and 20,000 or more. Examples of upper limits of the weight average molecular weight calculated by the above method include 60,000 or less, 50,000 or less, 45,000 or less, 40,000 or less, 35,000 or less, and 30,000 or less. Examples of preferred weight average molecular weight ranges are 8,000 to 60,000, 20,000 to 45,000, and 20,000 to 30,000.

Chondroitin sulfate and its salts can be commercially available. Chondroitin sulfate and its salts can be used alone or in combination of two or more. Chondroitin sulfate and its salts can be used in combination with chondroitin sulfates and their salts having various weight-average molecular weights. For example, sodium chondroitin sulfate having a weight-average molecular weight of 56,000 can be used in combination with sodium chondroitin sulfate having a weight-average molecular weight of 25,000. When using such combinations, it is preferable to use chondroitin sulfate and its salts having a weight-average molecular weight of 8,000 to 50,000, preferably 9,000 to 45,000, more preferably 10,000 to 40,000, and even more preferably 20,000 to 30,000 as raw materials.

The total content of the component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and is appropriately set according to the type and content of other blended components, the formulation form of the ophthalmic composition, etc. The lower limit of the total content of the component (A) may be, for example, 0.5 w/v% or more, preferably 0.7 w/v% or more, and more preferably 0.9 w/v% or more, from the viewpoint of more significantly achieving the effects of the present invention. The upper limit of the total content of the component (A) may be, for example, 3.0 w/v% or less, 2.0 w/v% or less, or 1.2 w/v% or less, and preferably 1.1 w/v% or less, from the viewpoint of more significantly achieving the effects of the present invention. In addition, the total content of the component (A) in the ophthalmic composition according to this embodiment may be 1.0 w/v% based on the total amount of the ophthalmic composition.

[Component (B)]
The ophthalmic composition of this embodiment contains, in addition to component (A), (B) at least one selected from the group consisting of tranilast, cromoglycic acid and its salts, olopatadine and its salts, epinastine and its salts, and menthol (also simply referred to as "component (B)").

[Tranilast]
There are no particular limitations on the tranilast, so long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable. Commercially available tranilast can also be used.

When tranilast is used as component (B), the content of tranilast in the ophthalmic composition according to this embodiment may be, for example, 0.001 w/v% or more, preferably 0.01 to 10 w/v%, more preferably 0.05 to 5 w/v%, even more preferably 0.07 to 2 w/v%, even more preferably 0.1 to 1 w/v%, particularly preferably 0.3 to 1 w/v%, particularly preferably 0.4 to 0.7 w/v%, and most preferably 0.5 w/v% based on the total amount of the ophthalmic composition.

When tranilast is used as component (B), the content ratio of tranilast per 1 part by mass of component (A) in the ophthalmic composition according to this embodiment is preferably 0.4 to 0.7 parts by mass, and more preferably 0.5 parts by mass. This allows for excellent anti-allergic action.

[Cromoglycic acid and its salts]
Cromolyn acid and its salts are not particularly limited as long as they are medicamentally, pharmacologically (pharmaceutical) or physiologically acceptable. An example of a salt of cromoglycic acid is sodium cromoglycate. As cromoglycic acid and its salts, sodium cromoglycate is preferred.

Cromolyn acid and its salts may be commercially available. Cromolyn acid and its salts may be used alone or in combination of two or more.

When cromoglycic acid and its salts are used as component (B), the total content of cromoglycic acid and its salts in the ophthalmic composition according to this embodiment may be, for example, 0.1 to 10 w/v% relative to the total amount of the ophthalmic composition, preferably 0.2 to 8 w/v%, more preferably 0.3 to 5 w/v%, even more preferably 0.5 to 3 w/v%, particularly preferably 0.7 to 2 w/v%, more particularly preferably 0.8 to 1.5 w/v%, even more particularly preferably 0.9 to 1.2 w/v%, and most preferably 1.0 w/v%.

When cromoglycic acid and its salts are used as component (B), the content ratio of cromoglycic acid and its salts in the ophthalmic composition according to this embodiment to 1 part by mass of component (A) is preferably 0.5 to 1.5 parts by mass, more preferably 1 part by mass. This allows for excellent anti-allergic action.

[Olopatadine and its salts]
Olopatadine and its salts are not particularly limited as long as they are medicamentally, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of olopatadine salts include olopatadine hydrochloride. Olopatadine and its salts are preferably olopatadine hydrochloride.

Olopatadine and its salts may be commercially available. Olopatadine and its salts may be used alone or in combination of two or more.

When olopatadine and its salts are used as component (B), the total content of olopatadine and its salts in the ophthalmic composition according to this embodiment may be, for example, 0.001 to 0.5 w/v%, preferably 0.002 to 0.2 w/v%, more preferably 0.003 to 0.15 w/v%, even more preferably 0.005 to 0.12 w/v%, even more preferably 0.01 to 0.1 w/v%, and particularly preferably 0.08 to 0.12 w/v%, based on the total amount of the ophthalmic composition.

When olopatadine and its salts are used as component (B), the content ratio of olopatadine and its salts per 1 part by mass of component (A) in the ophthalmic composition according to this embodiment is preferably 0.05 to 0.15 parts by mass, and more preferably 0.1 part by mass. This allows the composition to have an excellent anti-allergic effect.

[Epinastine and its salts]
Epinastine and its salts are not particularly limited as long as they are medicamentally, pharmacologically (pharmaceutical) or physiologically acceptable. An example of an epinastine salt is epinastine hydrochloride. As epinastine and its salts, epinastine hydrochloride is preferred.

Epinastine and its salts may be commercially available. Epinastine and its salts may be used alone or in combination of two or more.

When epinastine and its salts are used as component (B), the total content of epinastine and its salts in the ophthalmic composition according to this embodiment is, for example, preferably 0.0003 to 5 w/v%, more preferably 0.001 to 1 w/v%, even more preferably 0.005 to 0.5 w/v%, particularly preferably 0.01 to 0.1 w/v%, and most preferably 0.05 w/v%, relative to the total amount of the ophthalmic composition.

When epinastine and its salts are used as component (B), the content ratio of epinastine and its salts in the ophthalmic composition according to this embodiment per 1 part by mass of component (A) is preferably 0.03 to 0.07 parts by mass, more preferably 0.05 parts by mass. This allows for excellent anti-allergic action.

〔menthol〕
There are no particular limitations on the menthol, so long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.

Menthol may be in the d-, l- or dl-form, and examples include l-menthol, d-menthol and dl-menthol. In addition, essential oils containing menthol may be used as component (B). Examples of such essential oils include peppermint oil, cool mint oil, spearmint oil and peppermint oil.

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

When menthol is used as component (B), the content of menthol in the ophthalmic composition according to this embodiment may be, for example, 0.0001 w/v% or more, 0.0005 w/v% or more, 0.001 w/v% or more, 0.002 w/v% or more, 0.003 w/v% or more, 0.004 w/v% or more, 0.005 w/v% or more, 0.006 w/v% or more, 0.007 w/v% or more, 0.008 w/v% or more, 0.009 w/v% or more, or 0.01 w/v% or more, relative to the total amount of the ophthalmic composition.

When menthol is used as component (B), the content of menthol in the ophthalmic composition according to this embodiment may be, for example, 1 w/v% or less, 0.1 w/v% or less, 0.09 w/v% or less, 0.08 w/v% or less, 0.07 w/v% or less, 0.06 w/v% or less, 0.05 w/v% or less, 0.04 w/v% or less, 0.03 w/v% or less, or 0.02 w/v% or less, based on the total amount of the ophthalmic composition. When an essential oil containing menthol is used as component (B), the content of the essential oil is set so that the menthol content in the blended essential oil satisfies the above content.

When menthol is used as component (B), the content ratio of menthol relative to 1 part by mass of component (A) in the ophthalmic composition according to this embodiment is not limited, but since the anti-allergic effect can be further improved, the content ratio of menthol relative to 1 part by mass of component (A) in the ophthalmic composition according to this embodiment may be, for example, 0.0001 to 1 part by mass, preferably 0.001 to 0.1 part by mass, more preferably 0.005 to 0.05 parts by mass, even more preferably 0.005 to 0.03 parts by mass, and particularly preferably 0.005 to 0.02 parts by mass. Note that when an essential oil containing menthol is used as component (B), the blending ratio of the essential oil is set so that the menthol content in the blended essential oil satisfies the above blending ratio.

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, even more preferably 5.0 to 8.5, particularly preferably 5.0 to 8.0, and even more particularly preferably 5.5 to 8.0.

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 form, 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 17th 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 medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable range. The viscosity of the ophthalmic composition according to this embodiment is preferably 1 to 10,000 mPa·s, more preferably 1 to 8,000 mPa·s, even more preferably 1 to 1,000 mPa·s, even more preferably 1 to 1000 mPa·s, even more preferably 1 to 100 mPa·s, particularly preferably 1 to 20 mPa·s, and most preferably 1.5 to 10 mPa·s, as measured at 20°C using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34'×R24).

The ophthalmic composition according to the present embodiment may contain an appropriate amount of a combination of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients, as long as the effect of the present invention is not impaired. The ingredients are not particularly limited, and examples thereof include active ingredients in ophthalmic drugs listed in the 2017 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 ingredients.
Antiallergic agents other than component (B): For example, pemirolast potassium, ashitazanolast, amlexanox, ibudilast, etc.
Antihistamines other than component (B): For example, chlorpheniramine or a salt thereof, (e.g., chlorpheniramine maleate), diphenhydramine or a salt thereof (e.g., diphenhydramine hydrochloride), iproheptine or a salt thereof (e.g., iproheptine hydrochloride), levocabastine or a salt thereof (e.g., levocabastine hydrochloride), ketotifen or a salt thereof (e.g., ketotifen fumarate), pemirolast potassium, etc.
Steroids: for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc.
Decongestants: for example, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, and the like.
Ocular muscle regulating drugs: for example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically, tropicamide, helenien, atropine sulfate, pilocarpine hydrochloride, etc.
Anti-inflammatory agents: for example, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, sodium azulene sulfonate, glycyrrhizic acid or a salt thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), zinc sulfate, zinc lactate, etc.
Vitamins: for example, retinol acetate, retinol palmitate, tocopherol acetate, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, panthenol, calcium pantothenate, ascorbic acid, sodium ascorbate, etc.
Amino acids: for example, L-arginine, glutamic acid, glycine, alanine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, trimethylglycine, taurine, aspartic acid, and salts thereof.
Astringents: for example, zinc oxide.

In the ophthalmic composition according to the present embodiment, various additives may be appropriately selected according to the purpose and formulation form, and one or more additives may be used in combination in an appropriate amount in accordance with a conventional method, as long as the effects of the present invention are not impaired. Examples of such additives include various additives listed in the Pharmaceutical Additives Encyclopedia 2016 (edited by the Japan Pharmaceutical Additives Association). Representative components include the following additives.
Carrier: For example, an aqueous solvent such as water or aqueous ethanol.
Chelating agents: for example, (EDDA), ethylenediaminetriacetic acid, 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, monoethanolamine, diisopropanolamine, etc.
Surfactants: for example, nonionic surfactants such as tyloxapol, polyoxyethylene sorbitan fatty acid esters, polyoxyl stearates, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and poloxamers; anionic surfactants such as polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, alkyl sulfates, and N-acyltaurine salts; and zwitterionic surfactants such as lauryl dimethylaminoacetate betaine.
Fragrances or freshening agents: for example, menthone, camphor, borneol, geraniol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymene, terpineol, pinene, camphene, isoborneol, fennel, nerol, myrcene, myrcenol, linalool acetate, lavandulol, eucalyptus oil, bergamot oil, fennel oil, cinnamon oil, rose oil, camphor oil, etc. These may be in the d-, l- or dl-form.
Thickeners: for example, cellulose-based polymer compounds such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.; guar gum; hydroxypropyl guar gum; gum arabic; karaya gum; xanthan gum; agar; alginic acid and its salts (sodium salt, etc.); heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and its salts (sodium salt, etc.); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan; monosaccharides such as glucose, etc.
Buffers: for example, borate buffers, phosphate buffers, citrate buffers, carbonate buffers, acetate buffers, lactate buffers, succinate buffers, Tris buffers, AMPD buffers, and the like.
Stabilizers: for example, sodium formaldehyde sulfoxylate (Rongalit), aluminum monostearate, glycerin monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, sodium hydrogensulfite, sodium pyrosulfite, etc.
Preservatives: for example, alkyl polyaminoethyl glycine quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, polydonium chloride, sodium benzoate, ethanol, 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 (polyhexamethylene biguanide), alexidine, etc.), Gloquil (trade name, manufactured by Rhodia), etc.
Isotonicity agents: for example, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, sodium hydrogen sulfite, sodium sulfite, etc.
Sugar alcohols: for example, xylitol, sorbitol, mannitol, glycerin, etc. These may be in the d-, l- or dl-form.
Oils: for example, vegetable oils such as sesame oil, castor oil, soybean oil, olive oil, etc.; animal oils such as squalane, etc.; mineral oils such as liquid paraffin, Vaseline, etc.

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 17th edition of the Japanese Pharmacopoeia.

The ophthalmic composition according to this embodiment can be prepared by adding and mixing the desired amounts of component (A), component (B), and other components as necessary to obtain the desired concentrations. For example, it can be prepared by dissolving or dispersing those components in purified water, adjusting the pH and osmotic pressure to the desired levels, 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 the present embodiment can be used, for example, as eye drops (also called eye drops or eye drops. Eye drops include eye drops and artificial tears that can be applied while wearing contact lenses), eyewash (also called eyewash or eyewash. Eyewash includes eyewash that can be used while wearing contact lenses), and contact lens compositions [contact lens wearing solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaner, contact lens cleaning and preservative), contact lens packaging solution, 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 allergy eye drop (including eye drops 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 3 drops, 1 to 2 drops, or 2 to 3 drops are applied 2 to 4 times or 5 to 6 times a day, and 1 to 2 drops are preferably applied 4 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 (PET), 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 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 contains the ophthalmic composition according to this embodiment. The material of the nozzle is not particularly limited, and may be made of glass or plastic, for example. Plastic is preferable. Examples of plastic include polybutylene terephthalate, polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, copolymers of monomers constituting these, and mixtures of two or more of these. From the viewpoint of further enhancing the effects of the present invention, polypropylene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate are preferable as the material of the nozzle, and polyethylene is more 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. It may also be filled in a container having an internal volume of 0.1 to 3 mL, or may be filled in a container having an internal volume of 0.2 to 1 mL.

The ophthalmic composition of this embodiment contains tranilast, cromoglycic acid, olopatadine, epinastine, or menthol, as well as a specific ratio of chondroitin sulfate or a salt thereof for each drug, and since the anti-allergic effect is significantly enhanced, it can be suitably used as an ophthalmic composition for allergies that suppresses bloodshot eyes and itchy eyes. Also, as one embodiment of the present invention, there is provided a method for suppressing an allergic symptom by administering to a subject an ophthalmic composition comprising (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof, and (B) at least one selected from the group consisting of tranilast, cromoglycic acid and salts thereof, olopatadine and salts thereof, epinastine and salts thereof, and menthol, wherein, relative to 1 part by mass of the total content of component (A), the content of tranilast is 0.4 to 0.7 parts by mass, the content of cromoglycic acid and salts thereof is 0.5 to 1.5 parts by mass, the content of olopatadine and salts thereof is 0.05 to 0.15 parts by mass, the content of epinastine and salts thereof is 0.03 to 0.07 parts by mass, and the content of menthol is 0.001 to 0.1 parts by mass. Furthermore, as one embodiment of the present invention, there is provided a use of (A) at least one selected from the group consisting of chondroitin sulfate and its salts, and (B) at least one selected from the group consisting of tranilast, cromoglycic acid and its salts, olopatadine and its salts, epinastine and its salts, and menthol, for the manufacture of an ophthalmic composition for allergies, in which the content of tranilast is 0.4 to 0.7 parts by mass, the content of cromoglycic acid and its salts is 0.5 to 1.5 parts by mass, the content of olopatadine and its salts is 0.05 to 0.15 parts by mass, the content of epinastine and its salts is 0.03 to 0.07 parts by mass, and the content of menthol is 0.001 to 0.1 parts by mass, relative to 1 part by mass of the total content of component (A).

The present invention will be specifically explained below based on test examples, but the present invention is not limited to these. In the following test examples, sodium chondroitin sulfate with a weight-average molecular weight of about 25,000 was used.

[Test Example 1] Degranulation Inhibition Confirmation Test Using Mast Cells Hematopoietic stem cells were collected from rat bone marrow and stimulated with IL-3 and stem cell factor (SCF) to differentiate into mast cells. The obtained rat bone marrow-derived mast cells (BMMC) were sensitized with anti-DNP-IgE (0.1 μg/mL), and the next day, the cells were treated with a 0.1% DMSO solution (and only a 0.1% DMSO solution as a control) containing a predetermined concentration of each drug (tranilast, sodium cromoglycate, olopatadine hydrochloride, epinastine hydrochloride, menthol, and sodium chondroitin sulfate, as well as a combination of each drug and sodium chondroitin sulfate) for 10 minutes. Then, an allergic reaction was induced in the BMMC using DNP-BSA (5 ng/mL), and the degranulation rate of the BMMC was calculated by measuring the β-hexosaminidase activity in the culture supernatant 30 minutes after induction. The degranulation rate when each drug was added in combination with sodium chondroitin sulfate (tranilast, sodium cromoglycate, olopatadine hydrochloride, epinastine hydrochloride, menthol) at a given concentration was defined as a "degranulation level of 100," and the degranulation rate when each drug was added in combination with sodium chondroitin sulfate was shown as a degranulation level. The results are shown in Tables 1 to 5.

As can be seen from Table 1, compared to the use of tranilast (0.01 w/v%) alone, the combination of tranilast (0.01 w/v%) with sodium chondroitin sulfate (0.01 w/v%) promoted degranulation, whereas the combination of tranilast (0.01 w/v%) with sodium chondroitin sulfate (0.02 w/v%) showed a degranulation inhibitory effect. These results demonstrated that the addition of a certain ratio of sodium chondroitin sulfate to tranilast showed a degranulation inhibitory effect.

As can be seen from Table 2, the combination of sodium cromoglycate (1 w/v%) and sodium chondroitin sulfate (0.5 w/v%) showed the same degranulation inhibitory effect as the use of sodium cromoglycate (1 w/v%) alone, whereas the combination of sodium cromoglycate (1 w/v%) and sodium chondroitin sulfate (1 w/v%) significantly increased the degranulation inhibitory effect.

As shown in Table 3, the combination of olopatadine hydrochloride (0.1 w/v%) and sodium chondroitin sulfate (0.5 w/v%) showed the same degranulation inhibitory effect as the use of olopatadine hydrochloride (0.1 w/v%) alone, whereas the combination of olopatadine hydrochloride (0.1 w/v%) and sodium chondroitin sulfate (1 w/v%) significantly increased the degranulation inhibitory effect.

As shown in Table 4, the combination of epinastine hydrochloride (0.05 w/v%) and sodium chondroitin sulfate (0.5 w/v%) showed the same degranulation inhibitory effect as the use of epinastine hydrochloride (0.05 w/v%) alone, whereas the combination of epinastine hydrochloride (0.05 w/v%) and sodium chondroitin sulfate (1 w/v%) significantly increased the degranulation inhibitory effect.

Compared to the use of menthol (0.001 w/v%) alone, the combination of menthol (0.001 w/v%) and sodium chondroitin sulfate (0.5 w/v%) promoted degranulation. On the other hand, as shown in Table 5, the combination of menthol (0.001 w/v%) and sodium chondroitin sulfate (1 w/v%) increased the degranulation inhibitory effect. In addition, compared to the use of menthol (0.01 w/v%) alone, the combination of menthol (0.01 w/v%) and sodium chondroitin sulfate (0.5 w/v%) showed the same degranulation inhibitory effect, while the combination of menthol (0.01 w/v%) and sodium chondroitin sulfate (1 w/v%) significantly increased the degranulation inhibitory effect.

[Formulation example]
Ophthalmic compositions were prepared and filled into PET containers according to the formulations shown in Tables 6 to 8. In Tables 6 to 8, the units of each component are (w/v %).

Claims (3)

An antiallergic ophthalmic composition containing (A) at least one selected from the group consisting of chondroitin sulfate and its salts, and (B) at least one selected from the group consisting of tranilast, cromoglycic acid and its salts, olopatadine and its salts, epinastine and its salts, and menthol, in which the content of tranilast is 0.4 to 0.7 parts by mass, the content of cromoglycic acid and its salts is 0.5 to 1.5 parts by mass, the content of olopatadine and its salts is 0.05 to 0.15 parts by mass, the content of epinastine and its salts is 0.03 to 0.07 parts by mass, and the content of menthol is 0.001 to 0.1 parts by mass, per 1 part by mass of the total content of component (A). The ophthalmic composition according to claim 1, wherein the total content of component (A) is 1 w/v% based on the total amount of the ophthalmic composition. The ophthalmic composition according to claim 1 or 2, which is an eye drop.