JP6615548B2 - Ophthalmic composition - Google Patents

Description

  The present invention relates to ophthalmic compositions useful for ocular allergic symptoms.

  Various compositions containing pranoprofen, chlorpheniramine maleate, and cromoglycate are known as ophthalmic compositions that can be used for ocular allergy symptoms such as pollen. Planoprofen is an anti-inflammatory agent that suppresses prostaglandin production, chlorpheniramine maleate is an antihistamine that antagonizes histamine receptors, and cromoglycate inhibits the release of chemical mediators such as histamine. It is an agent.

Ophthalmic compositions have been attempted to improve various properties for comfortable use as well as improved efficacy.
However, further improvement in characteristics from a wider variety of angles is desired.

  This invention makes it a subject to provide the ophthalmic composition provided with the characteristic superior to the conventional ophthalmic composition.

As an ophthalmic composition and method capable of solving the above-mentioned problems, the present invention provides the following composition and method.
Item 1. (a) at least one selected from the group consisting of 0.07 w / v% or more pranoprofen and a salt thereof, and (b) at least one selected from the group consisting of chlorpheniramine and a salt thereof (preferably, Ophthalmic composition containing 0.02 w / v% or more) and / or at least one selected from the group consisting of cromoglycic acid and a salt thereof with respect to the total amount of the composition.
Item 2. (a) at least one selected from the group consisting of 0.07 w / v% or more pranoprofen and a salt thereof, and (b) at least one selected from the group consisting of chlorpheniramine and a salt thereof (preferably, The ophthalmic composition according to Item 1, comprising 0.02 w / v% or more) and at least one selected from the group consisting of cromoglycic acid and a salt thereof with respect to the total amount of the composition.
Item 3. Item 3. The ophthalmic composition according to Item 1 or 2, which is contained in a container made of polyolefin or terephthalic acid ester.
Item 4. Item 4. The item according to any one of Items 1 to 3, wherein the content of at least one selected from the group consisting of pranoprofen and a salt thereof is 0.07 to 0.15 w / v% based on the total amount of the composition. Ophthalmic composition.
Item 5. Item 5. The item according to any one of Items 1 to 4, wherein the content of at least one selected from the group consisting of chlorpheniramine and a salt thereof is 0.02 to 0.03 w / v% with respect to the total amount of the composition. Composition.
Item 6. Item 6. The composition according to any one of Items 1 to 5, wherein the content of at least one selected from the group consisting of cromoglycic acid and a salt thereof is 0.5 to 2 w / v% with respect to the total amount of the composition.
Item 7. Furthermore, the composition in any one of claim | item 1 -6 containing a nonionic surfactant.
Item 8. Furthermore, the composition in any one of claim | item 1 -7 containing a terpenoid.
Item 9. Item 9. The composition according to any one of Items 1 to 8, further comprising dibutylhydroxytoluene and / or butylhydroxyanisole.

Item 10. The ophthalmic composition comprises (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof, and (b) at least one selected from the group consisting of chlorpheniramine and a salt thereof. By blending at least one selected from the group consisting of species (preferably 0.02 w / v% or more with respect to the total amount of the composition) and / or cromoglycic acid and a salt thereof, A method to improve the drainage from the container.
Item 11. (a) at least one selected from the group consisting of 0.07 w / v% or more pranoprofen and a salt thereof, and (b) at least one selected from the group consisting of chlorpheniramine and a salt thereof (preferably, 0.02 w / v% or more) and / or at least one selected from the group consisting of cromoglycic acid and a salt thereof with respect to the total amount of the composition to improve the preservative effect or the storage effect .
Item 12. (a) at least one selected from the group consisting of 0.07 w / v% or more pranoprofen and a salt thereof, and (b) at least one selected from the group consisting of chlorpheniramine and a salt thereof (preferably, Inhibition of protein adsorption to contact lenses (0.02 w / v% or more) and / or at least one selected from the group consisting of cromoglycic acid and salts thereof with respect to the total amount of the composition ( In particular, a method for imparting the ability to suppress protein adsorption to contact lenses).
Item 13. (a) at least one selected from the group consisting of 0.07 w / v% or more pranoprofen and a salt thereof, and (b) at least one selected from the group consisting of chlorpheniramine and a salt thereof (preferably, In combination with at least one selected from the group consisting of 0.02 w / v% and / or cromoglycic acid and a salt thereof with respect to the total amount of the composition, the anti-inflammatory ability or the production of inflammatory cytokines A method of imparting suppression ability.
Item 14. (a) at least one selected from the group consisting of 0.07 w / v% or more pranoprofen and a salt thereof, and (b) at least one selected from the group consisting of chlorpheniramine and a salt thereof (preferably, Combining at least one selected from the group consisting of 0.02 w / v% and / or cromoglycic acid and its salt with respect to the total amount of the composition, it causes eye discomfort (itching, foreign body sensation) And the like.

  The ophthalmic composition of the present invention comprises (a) one or more of 0.07 w / v% or more of pranoprofen and a salt thereof, and (b) one or more of chlorpheniramine and a salt thereof (particularly, 0.02 w / v). / V% or higher) and / or one or more of cromoglycic acid and its salts.

  The ophthalmic composition of the present invention has significantly low wettability with respect to containers for ophthalmic compositions when the liquid flows. That is, when the ophthalmic composition is used or transported, such as when the liquid moves, the ophthalmic composition container has low wettability. The rest can be suppressed. For this reason, inconveniences such as drying and precipitation of the liquid remaining on the wall surface can be suppressed, and the ophthalmic composition can be used up with a small residual liquid amount.

It is a graph which shows the protein adsorption increase rate (%) with respect to the ophthalmic composition of the comparative example 3-1 of each ophthalmic composition in the protein adsorption test to a contact lens.

Hereinafter, the present invention will be described in detail.
One aspect of the ophthalmic composition of the present application is (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof, and (b) a group consisting of chlorpheniramine and a salt thereof. And / or at least one selected from the group consisting of cromoglycic acid and a salt thereof.
In another aspect of the ophthalmic composition of the present application, (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof, and (b) 0.02 w / v% or more of It is a composition comprising at least one selected from the group consisting of chlorpheniramine and a salt thereof and / or at least one selected from the group consisting of cromoglycic acid and a salt thereof.

A preferred embodiment of the present invention is:
(a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof; and (b) selected from the group consisting of 0.02 w / v% or more of chlorpheniramine and a salt thereof. An ophthalmic composition comprising at least one selected from the group consisting of: The ophthalmic composition of this embodiment can further contain at least one selected from the group consisting of cromoglycic acid and salts thereof.
In another preferred embodiment of the present invention, (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof, and (b) a group consisting of cromoglycic acid and a salt thereof. It is an ophthalmic composition containing at least one selected from the above. The ophthalmic composition of this embodiment can further contain at least one selected from the group consisting of chlorpheniramine and a salt thereof.

Planoprofen and / or its salt (component (a))
The planoprofen salt may be a pharmaceutically or physiologically acceptable salt, such as an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.), Salts with inorganic bases such as ammonium salts, metal salts (aluminum salts, etc.), organic amine salts (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, And salts with organic bases such as picoline salts).
Planoprofen and its salts include those in the form of hydrates.
Planoprofen and its salt can be used singly or in combination of two or more.
Of the pranoprofen and / or its salt, the most preferred is pranoprofen.

The content of pranoprofen and / or a salt thereof in the ophthalmic composition is 0.07 w / v% or more, preferably 0.08 w / v% or more, and 0.09 w / v based on the total amount of the composition. v% or more is more preferable, and 0.1 w / v% or more is even more preferable.
In addition, the content of pranoprofen and / or a salt thereof in the ophthalmic composition can be, for example, 1 w / v% or less, and 0.5 w / v% or less with respect to the total amount of the composition. And can be 0.2 w / v% or less, 0.15 w / v% or less, or 0.11 w / v% or less.
The content of pranoprofen is particularly preferably 0.1 w / v%.
If it is the said range, the effect of this invention will fully be acquired.

Chlorpheniramine and / or its salt (component (b))
The salt of chlorpheniramine may be a pharmaceutically or physiologically acceptable salt, for example, an organic acid salt such as maleate or fumarate; an inorganic acid salt such as hydrochloride or sulfate; a metal salt And the like. Among the salts, organic acid salts are preferable, and maleic acid salts are particularly preferable.
Chlorpheniramine and a salt thereof may be in the form of a hydrate, and may be any of d-form, l-form, and dl-form.
Chlorpheniramine and its salt can be used individually by 1 type or in combination of 2 or more types.
Of chlorpheniramine and / or a salt thereof, most preferred is chlorpheniramine maleate.

When the ophthalmic composition of the present application contains chlorpheniramine and / or a salt thereof as component (b), the content of chlorpheniramine and / or a salt thereof in the ophthalmic composition is preferably relative to the total amount of the composition. Is 0.02 w / v% or more, 0.025 w / v% or more, and preferably 0.03 w / v% or more.
Further, the content of chlorpheniramine and / or a salt thereof in the ophthalmic composition can be, for example, 1 w / v% or less, or 0.1 w / v% or less with respect to the total amount of the composition. It can also be 0.05 w / v% or less, and can also be 0.04 w / v% or less.
The content of chlorpheniramine is particularly preferably 0.03 w / v%.
If it is the said range, the effect of this invention will fully be acquired.

When the ophthalmic composition of the present application contains chlorpheniramine and / or a salt thereof as the component (b), the content of chlorpheniramine and / or a salt thereof in the ophthalmic composition is the amount of pranoprofen and / or a salt thereof. 0.001 weight part or more is preferable with respect to 1 weight part, 0.01 weight part or more is more preferable, 0.05 weight part or more is still more preferable, 0.1 weight part or more is still more preferable. Further, it may be 0.3 parts by weight or more.
Further, the content of chlorpheniramine and / or a salt thereof in the ophthalmic composition is preferably 5 parts by weight or less, more preferably 1 part by weight or less with respect to 1 part by weight of pranoprofen and / or a salt thereof. 0.5 parts by weight or less is even more preferable, and 0.3 parts by weight or less is even more preferable.
The content of chlorpheniramine and / or its salt in the ophthalmic composition is particularly preferably 0.3 parts by weight with respect to 1 part by weight of pranoprofen and / or its salt.
If it is the said range, the effect of this invention will fully be acquired.

Cromoglycic acid and / or its salt (component (b))
The salt of cromoglycic acid may be a pharmaceutically or physiologically acceptable salt, such as an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.), ammonium, etc. Salts, salts with inorganic bases such as metal salts (aluminum salts, etc.), organic amine salts (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt And a salt with an organic base such as a salt). Preferred among the salts are salts with inorganic bases, especially alkali metal salts, especially sodium salts.
Cromoglycic acid and its salts include those in the form of hydrates.
Cromoglycic acid and its salt can be used individually by 1 type or in combination of 2 or more types.
Of cromoglycic acid and / or its salt, sodium cromoglycate is most preferred.

When the ophthalmic composition of the present application contains cromoglycic acid and / or a salt thereof as component (b), the content of cromoglycic acid and / or a salt thereof in the ophthalmic composition is 0.01 w relative to the total amount of the composition. / V% or more is preferable, 0.1 w / v% or more is more preferable, 0.5 w / v% or more is still more preferable, 1 w / v% or more is further more preferable, 1 w / v%, or 2 w / v% Is particularly preferred.
Further, the content of cromoglycic acid and / or a salt thereof in the ophthalmic composition is preferably 10 w / v% or less, more preferably 5 w / v% or less, and more preferably 3 w / v% or less with respect to the total amount of the composition. Even more preferred is 2 w / v% or less.
If it is the said range, the effect of this invention will fully be acquired.

When the ophthalmic composition of the present application contains cromoglycic acid and / or its salt as component (b), the content of cromoglycic acid and / or its salt in the ophthalmic composition is 1 weight of pranoprofen and / or its salt. The amount is preferably 0.1 parts by weight or more, more preferably 1 part by weight or more, still more preferably 5 parts by weight or more, and still more preferably 10 parts by weight or more.
Further, the content of cromoglycic acid and / or salt thereof in the ophthalmic composition is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, with respect to 1 part by weight of pranoprofen and / or its salt. 30 parts by weight or less is even more preferable, and 20 parts by weight or less is even more preferable.
The content of cromoglycic acid and / or a salt thereof in the ophthalmic composition is, as one of the most preferred embodiments, 10 parts by weight with respect to 1 part by weight of pranoprofen and / or a salt thereof.
If it is the said range, the effect of this invention will fully be acquired.

The ophthalmic composition of the present invention preferably contains both chlorpheniramine and / or a salt thereof and cromoglycic acid and / or a salt thereof as the component (b).
In this case, the content ratio of both components in the ophthalmic composition is preferably 0.1 parts by weight or more of cromoglycic acid and / or its salt with respect to 1 part by weight of chlorpheniramine and / or its salt. The above is more preferable, 10 parts by weight or more is even more preferable, and 30 parts by weight or more is even more preferable.
Further, the content of cromoglycic acid and / or salt thereof in the ophthalmic composition is preferably 1000 parts by weight or less, more preferably 500 parts by weight or less, with respect to 1 part by weight of chlorpheniramine and / or its salt. 200 parts by weight or less is even more preferred, 150 parts by weight or less is even more preferred, and 100 parts by weight or less is particularly preferred.
The content ratio of cromoglycic acid and / or its salt to 1 part by weight of chlorpheniramine and / or its salt in the ophthalmic composition is 33.3 wt. Per 1 part by weight of cromoglycic acid and / or its salt. Is one of the most preferred embodiments.
If it is the said range, the effect of this invention will fully be acquired.

Nonionic Surfactant The ophthalmic composition of the present invention has an effect of reducing wettability to containers and the like, an effect of improving storage efficacy, an effect of suppressing protein adsorption to contact lenses, an effect of suppressing inflammation, an eye itch or a foreign body sensation. It is preferable to contain a nonionic surfactant from the viewpoint of more prominently reducing the discomfort symptoms such as tired eyes.
Nonionic surfactants include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), and tristearic acid POE. (20) POE sorbitan fatty acid esters such as sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE POP block copolymers; POE hydrogenated castor oil such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil 80; POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil POE castor oil such as 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, POE castor oil 50; polyethylene monostearate Glycol (2E.O.), polyethylene glycol monostearate (4E.O.), polyethylene glycol monostearate (9E.O.), polyethylene glycol monostearate (10E.O.), polyethylene glycol monostearate ( 23E.O.), polyethylene glycol monostearate (25E.O.), polyethylene glycol monostearate (32E.O.), polyethylene glycol monostearate (40E.O., polyoxyl 40 stearate), monostearic acid Poly Polyethylene monostearate such as tylene glycol (45E.O.), polyethylene glycol monostearate (55E.O.), polyethylene glycol monostearate (75E.O.), polyethylene glycol monostearate (140E.O.), etc. POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether, etc. Can be mentioned. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added.

  Among these, nonionic POE sorbitan fatty acid esters; POE / POP block copolymers; POE hydrogenated castor oil; POE castor oil and polyethylene glycol monostearate are preferable, and polysorbate 80, poloxamer is preferable in that the effect of the present invention is further improved. 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 are more preferable, polysorbate 80, POE hydrogenated castor oil 60 are more preferable, and polysorbate 80 is particularly preferred.

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

  When a nonionic surfactant is blended in the ophthalmic composition of the present invention, as an example of the blending amount, the total amount of the surfactant is 0.001 w / v% or more, particularly 0 in terms of the total amount of the ophthalmic composition. 0.005% or more, especially 0.01 w / v% or more, especially 0.05% or more. Further, the total amount of the surfactant with respect to the total amount of the ophthalmic composition is 5 w / v% or less, especially 1% or less, especially 0.5 w / v% or less, especially 0.3% or less.

Refreshing agent The ophthalmic composition of the present invention has an effect of reducing wettability to containers and the like, an effect of improving the preservation effect, an effect of suppressing protein adsorption to contact lenses, an effect of suppressing inflammation, an itching of the eyes or a foreign body sensation, and a tired eye. It is preferable to contain a refreshing agent from the viewpoint of exhibiting the effect of reducing the unpleasant symptoms as described above more remarkably.
Examples of the refreshing agent include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and agate. These may be any of d-form, l-form or dl-form. These may be either d-form, l-form or dl-form, and also include essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil. .
Among these, terpenoids are preferable in that the effect of the present invention is further improved, and menthol, camphor, geraniol, cineol, borneol, and ryuno are preferable, menthol, camphor, and borneol are more preferable, and menthol is more preferable.
A commercially available cooling agent can also be used.
A refreshing agent may be used individually by 1 type, or may be used in combination of 2 or more type.

  When a cooling agent is blended in the ophthalmic composition of the present invention, as an example of the blending amount, the total amount of the cooling agent is 0.0001 w / v% or more, particularly 0.0005, based on the total amount of the ophthalmic composition. % Or more, especially 0.001 w / v% or more, and especially 0.005% or more. The total amount of the refreshing agent is 1 w / v% or less, particularly 0.1% or less, especially 0.05 w / v% or less, especially 0.02% or less, based on the total amount of the ophthalmic composition.

Antioxidant The ophthalmic composition of the present invention has an effect of reducing wettability to containers and the like, an effect of improving the preservation effect, an effect of suppressing protein adsorption to contact lenses, an effect of suppressing inflammation, an itching of the eyes or a foreign body sensation, and tired eyes. It is preferable to contain an antioxidant from the viewpoint of more prominently reducing the unpleasant symptoms.
Examples of fat-soluble antioxidants include butyl group-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbyl palmitate, ascorbyl stearate, ascorbine Ascorbic acid esters such as aminopropyl phosphate, tocopherol phosphate ascorbate, triphosphate ascorbate, palmitate ascorbate; tocopherols such as α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol; acetic acid Tocopherol derivatives such as tocopherol, tocopherol nicotinate, tocopherol succinate; such as ethyl gallate, propyl gallate, octyl gallate, dodecyl gallate Gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechin, tannin, curcumin; retinol, retinol ester (retinol acetate) , Retinol propionate, retinol butyrate, retinol octylate, retinol laurate, retinol stearate, retinol myristate, retinol oleate, retinol linolenate, retinol linoleate, retinol palmitate, etc., retinal, retinal ester (retinal acetate, Retinal propionate, retinal palmitate, etc.), retinoic acid, retinoic acid ester (methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid) , Retinoic acid tocopherol, etc.), retinol dehydro form, retinal dehydro form, retinoic acid dehydro form, provitamin A (α-carotene, β-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, β-cryptoxanthin, echinenone Etc.), vitamin A such as vitamin A; CoQ10 and the like.
Water-soluble antioxidants include ascorbic acid and ascorbic acid derivatives (ascorbic acid-2-sodium sulfate, sodium ascorbate, ascorbic acid-2-magnesium phosphate, ascorbic acid-2-sodium phosphate, etc.) Sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, disodium edetate, tetrasodium edetate, and the like.
Among them, a fat-soluble antioxidant is preferable, a butyl group-containing phenol is more preferable, and dibutylhydroxytoluene (BHT) is particularly preferable in that the effect of the present invention is further improved.

A commercially available thing can also be used for an antioxidant.
An antioxidant may be used individually by 1 type, or may be used in combination of 2 or more type.
When an antioxidant is blended in the ophthalmic composition of the present invention, as an example of the blending amount, the total amount of the antioxidant is 0.0001 w / v% or more, especially 0.0005 w with respect to the total amount of the ophthalmic composition. / V% or more, in particular 0.001 w / v% or more, especially 0.004 w / v% or more. Further, the total amount of the antioxidant is 1 w / v% or less, especially 0.1 w / v% or less, especially 0.01 w / v% or less, especially 0.006 w / v% or less, based on the total amount of the ophthalmic composition. Is mentioned.

Preservatives, bactericides, or antibacterial agents The ophthalmic composition of the present invention has a wettability-lowering effect on containers and the like, a storage effect improving effect, a protein adsorption inhibitory effect on contact lenses, an inflammation inhibitory effect, an eye itch or a foreign body sensation, etc. It is preferable to contain a preservative, a disinfectant, or an antibacterial agent from the viewpoint of more remarkably reducing the allergic symptoms and unpleasant symptoms such as tired eyes.
Examples of preservatives, bactericides, or antibacterial agents include polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, chlorobutanol, Sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoate (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (Specific examples include polyhexamethylene biguanide or a hydrochloride thereof) and Glow Kill (manufactured by Rhodia).
Among them, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, quaternary ammonium salt, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoic acid ester, in that the effect of the present invention is further improved Biguanide compounds are preferred, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds are more preferred, and benzalkonium chloride and polyhexamethylene biguanide are more preferred.

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

  When preservatives, bactericides, or antibacterial agents are blended in the ophthalmic composition of the present invention, as an example of the blending amount, the total amount of the preservatives, bactericides, or antibacterial agents, 0.000001 w / v% or more, especially 0.00001 w / v% or more, especially 0.00005 w / v% or more, especially 0.001 w / v% or more, especially 0.005 w / v% or more. Further, the total amount of antiseptics, bactericides, or antibacterial agents is 1 w / v% or less, especially 0.1 w / v% or less, especially 0.05 w / v% or less, especially 0, based on the total amount of the ophthalmic composition. 0.02 w / v% or less, especially 0.01 w / v% or less.

Buffering agent The ophthalmic composition of the present invention has an effect of reducing wettability to containers and the like, an effect of improving storage efficacy, an effect of suppressing protein adsorption to contact lenses, an effect of suppressing inflammation, an eye itch or a foreign body sensation, and tired eyes. It is preferable to contain a buffering agent from the standpoint of more prominently reducing such discomfort symptoms.
Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproate buffer, aspartate buffer, and the like.
Examples of the components of the boric acid buffer include boric acid and borates (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.). The borate may be a hydrate.
Phosphate buffer components include phosphoric acid, phosphate (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, And calcium dihydrogen phosphate). The phosphate may be a hydrate.
Examples of the component of the carbonate buffer include carbonic acid and carbonate (such as potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, magnesium carbonate).
Examples of the citrate buffer component include citric acid and citrate (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate).
Examples of the component of the acetate buffer include acetic acid and acetate (such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate).
Examples of the components of the aspartic acid buffer include aspartic acid and aspartic acid salts (such as sodium aspartate, magnesium aspartate, and potassium aspartate).
Among these, a borate buffer and a phosphate buffer are preferable, and a borate buffer is more preferable in that the effect of the present invention is further improved. The boric acid buffer is preferably a combination of boric acid and its salt, more preferably a combination of boric acid and an alkali metal salt of boric acid and / or an alkaline earth metal salt, and an alkali metal of boric acid and boric acid. A combination with a salt is further preferred, and a combination of boric acid and borax is even more preferred.

A commercially available buffer can also be used.
A buffering agent can be used individually by 1 type or in combination of 2 or more types.

  When blending a buffering agent in the ophthalmic composition of the present invention, the blending amount of the buffering agent varies depending on the type of buffering agent, the type and amount of other blending components, and cannot be defined uniformly, for example, The total amount of the buffering agent is 0.001 w / v% or more, especially 0.01 w / v% or more, especially 0.05 w / v% or more, especially 0.1 w / v% or more with respect to the total amount of the ophthalmic composition. Is mentioned. Further, the total amount of the buffering agent is 10 w / v% or less, particularly 5 w / v% or less, especially 3 w / v% or less, especially 2 w / v% or less with respect to the total amount of the ophthalmic composition.

The ophthalmic composition of the amino acid invention is effective for reducing wettability on containers, etc., improving storage efficacy, inhibiting protein adsorption to contact lenses, inhibiting inflammation, allergic symptoms such as itching of eyes or feeling of foreign bodies, and tired eyes It is preferable to contain an amino acid from the viewpoint of exhibiting the effect of reducing unpleasant symptoms more remarkably.
For example, aminoethyl sulfonic acid (taurine), glutamic acid, creatinine, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, sodium glutamate, magnesium glutamate, epsilon-aminocaproic acid, glycine, alanine, arginine, Examples include lysine, γ-aminobutyric acid, γ-aminovaleric acid, and chondroitin sodium sulfate. These may be d-form, l-form or dl-form.
Among them, aminoethylsulfonic acid, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, epsilon-aminocaproic acid, sodium chondroitin sulfate are preferable, aminoethylsulfonic acid, Potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, and sodium chondroitin sulfate are more preferable, and sodium chondroitin sulfate is even more preferable.

A commercially available amino acid can also be used.
An amino acid can be used individually by 1 type or in combination of 2 or more types.

  When an amino acid is blended with the ophthalmic composition of the present invention, as an example of the blending amount, for example, with respect to the total amount of the ophthalmic composition, the total amount of amino acids is 0.01 w / v% or more, especially 0.05 w / v%. Above all, 0.1 w / v% or more, especially 0.3 w / v% or more can be mentioned. Further, the total amount of amino acids is 10 w / v% or less, particularly 5 w / v% or less, especially 1 w / v% or less, especially 0.5 w / v% or less with respect to the total amount of the ophthalmic composition.

The property of the pharmaceutical ophthalmic composition is not particularly limited, and may be any property such as liquid, fluid, gel, or semi-solid. Moreover, the liquid form, the fluid form, the gel form, or the semi-solid form by preparation at the time of use is also included. The semi-solid state refers to a property having plasticity that can be deformed by applying force, such as an ointment.

In addition, the ophthalmic composition has an effect of reducing wettability to containers and the like, an effect of improving storage efficiency, an effect of suppressing protein adsorption to contact lenses, an effect of suppressing inflammation, an itching of the eyes or a foreign body sensation, and an uncomfortable feeling such as tired eyes. From the standpoint of more significantly reducing the symptoms, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier) or an oily composition (oil or hydrophobic base or carrier). May be mainly included).
The content of water in the case of the aqueous composition is preferably 50% by weight or more, more preferably 75% by weight or more, and still more preferably 90% by weight or more based on the total amount of the preparation. Moreover, 95 weight% or more or 98 weight% or more may be sufficient. In addition, the base or carrier may be composed only of water.
The water content in the case of an oily composition is preferably less than 50% by weight, more preferably 30% by weight or less, and even more preferably 20% by weight or less, based on the total amount of the preparation.
The ophthalmic composition of the present invention is preferably an aqueous composition.

The dosage form of the ophthalmic composition of the present invention is not particularly limited. For example, eye drops (also referred to as eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), eye wash , Eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens mounting solution, intraocular injection (eg, intravitreal injection), contact lens solution (cleaning solution, preservation solution, disinfectant solution, multi-purpose solution, Package solutions), preservatives for isolated ocular tissues such as the cornea for transplantation, and perfusate during surgery. Eye drops, eye washes and eye ointments include those used when wearing contact lenses.
The dosage form of the ophthalmic composition of the present invention is preferably eye drops, eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens mounting solution, contact lens solution (cleaning solution, preservative solution, disinfectant) Liquid, multipurpose solution, package solution), and more preferably eye drops, eye wash, contact lens mounting liquid, contact lens liquid (cleaning liquid, preservative liquid, disinfectant liquid, multipurpose solution, package solution), etc. Even more preferred are eye drops and eye wash, and particularly preferred are eye drops.

In particular, the ophthalmic composition of the present invention has an effect of reducing wettability with respect to containers and the like, and thus is particularly useful in eye drops in which the amount used at one time is small.
The ophthalmic composition of the present invention is also useful as an eye drop for contact lenses, an eye wash for contact lenses, a contact lens mounting solution, and a contact lens solution because the increase in protein adsorption to contact lenses is suppressed. It is.
The “contact lens” includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).
The ophthalmic composition of the present invention may be a single-use unit dose or a multi-dose that can be repeatedly used. However, since it is excellent in storage effect, it is preferably contained and used in a multi-dose form.

  The ophthalmic composition of the present invention comprises the above components (a) and (b), a pharmaceutically acceptable base or carrier, and optionally, a pharmaceutically acceptable additive of the ophthalmic composition, and others. For example, it can be prepared by a conventional method described in the 16th revised Japanese Pharmacopoeia Manual.

Examples of the base or carrier base or carrier include water; polar solvents such as ethanol; oily bases and the like. A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

Additives Additives, eg, pH adjusting agents, isotonic agents, thickening or thickening agents, chelating agents, stabilizing agents, oils, sugars, high molecular compounds, such as polyhydric alcohols.
An additive can be used individually by 1 type or in combination of 2 or more types. Moreover, about each additive, 1 type can be used individually or in combination of 2 or more types.

Specific examples of the additive are exemplified below.
<PH regulator>
Examples of pH regulators include hydrochloric acid, sulfuric acid, polyphosphoric acid, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, potassium hydroxide, hydroxide Examples include calcium, magnesium hydroxide, triethanolamine, monoethanolamine, and diisopropanolamine.

<Isotonic agent>
Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol.

<Thickener or thickener>
Examples of thickeners or thickeners include guar gum, hydroxypropyl guar gum, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, gum arabic, karaya gum, xanthan gum, agar, alginic acid , Α-cyclodextrin, dextrin, dextran, mucopolysaccharide (heparin analog, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid, hyaluronate (sodium salt)), starch, chitin and its derivatives, chitosan and Its derivatives, carrageenan, sorbitol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl polymers such as polyvinyl methacrylate Compound, alkali metal salt of polyacrylic acid (sodium salt, potassium salt, etc.), amine salt of polyacrylic acid (monoethanolamine salt, diethanolamine salt, triethanolamine salt, etc.), ammonium salt of polyacrylic acid Carboxyvinyl polymer, casein, gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (such as sodium salt), alginate (such as propylene glycol ester), tragacanth powder, And triisopropanolamine.

<Stabilizer>
Examples of the stabilizer include trometamol, sodium formaldehyde sulfoxylate (Longalite), monoethanolamine, aluminum monostearate, and glyceryl monostearate.

<Oil content>
Examples of the oil include animal oil such as squalane, liquid paraffin, mineral oil such as petrolatum, vegetable oil such as castor oil and sesame oil.

<Sugar>
Examples of the saccharide include monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like.

<Polymer compound>
High molecular compounds include heparin analogs, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid, mucopolysaccharides such as hyaluronate, alginic acid, sodium alginate, dextrin, dextran, pectin, polyvinyl alcohol (complete or Partially saponified products), polyvinylpyrrolidone, carboxyvinyl polymer, macrogol and pharmaceutically acceptable salts thereof. Examples of the salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and metal salts such as aluminum salt.

<Polyhydric alcohol>
Examples of the polyhydric alcohol include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, and polyvinyl alcohol.

Other Pharmacologically Active Components or Physiologically Active Components In addition to the above components (a) and (b), components having pharmacological activity or physiological activity can be added to the ophthalmic composition of the present invention.
A pharmacologically active ingredient or a physiologically active ingredient can be used individually by 1 type or in combination of 2 or more types.
Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various pharmaceuticals described in the General Occupational Drug Manufacturing and Sales Approval Standards 2012 edition (supervised by the Japanese Society for Regulatory Science). For example, decongestant component, eye muscle modulator component, anti-inflammatory component other than component (a), astringent component, antihistamine component or antiallergic component other than component (b), vitamins, antibacterial agent or bactericidal agent Drugs, local anesthetic ingredients, soothing agents and the like. Specific examples of these drugs are illustrated below.

  Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, and naphazoline nitrate . These may be d-form, l-form or dl-form.

  Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, and atropine sulfate.

  (a) Anti-inflammatory component other than component, astringent component: For example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, sodium azulenesulfonate, dipotassium glycyrrhizinate, diglycyrrhizinate Ammonium, diclofenac sodium, bromfenac sodium, berberine chloride, berberine sulfate and the like.

  (b) component, antihistamine component or antiallergic component other than component (c): for example, salt such as acitazanolast, diphenhydramine or its hydrochloride, ketotifen fumarate, levocabastine or its hydrochloride, anlexanox, ibudilast , Salts such as tazanolast, tranilast, oxatomide, suplatast or tosylate thereof, and pemirolast potassium.

  Vitamins: For example, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, and ubiquinone derivatives.

  Antibacterial component or bactericidal component: for example, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomethol sodium Sulfa drugs such as sodium sulfisomidine, alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, and acyclovir.

Local anesthetic ingredients: for example, procaine hydrochloride, lidocaine hydrochloride, etc.
Soothing agent: Procaine hydrochloride, etc.

  In addition, from the ophthalmic composition of the present invention, lysozyme, sulfa drug, tranilast, ketotifen or a salt thereof, paraoxybenzoic acid ester (particularly methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), glycyrrhizic acid Salts (especially glycyrrhizic acid, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, trisodium glycyrrhizinate, disodium glycyrrhizinate, dipotassium glycyrrhizinate), alginic acid or its salt, berberine or its salt, sorbic acid or its salt, methyl One or more of neostigmine sulfate, an azulene derivative or a salt thereof can be excluded.

pH
The pH of the ophthalmic composition of the present invention is preferably 3 or more, more preferably 4 or more, still more preferably 5 or more, and even more preferably 6 or more. Moreover, 10 or less is preferable, 9 or less is more preferable, 8.5 or less is further more preferable, and 8 or less is still more preferable. If it is the said range, irritation | stimulation to eyes will be suppressed and the said effect of this invention will be acquired.

Osmotic pressure ratio of ophthalmic compositions of the osmotic pressure present invention is preferably 0.4 or more, more preferably 0.6 or more, even more preferably 0.8 or more. Moreover, 5 or less is preferable, 3 or less is more preferable, and 2 or less is still more preferable. If it is the said range, irritation | stimulation to eyes will be suppressed and the said effect of this invention will be acquired.
The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 16th revision Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then released in a desiccator (silica gel). Cool and accurately measure 0.900 g and dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

A container container refers to a package body having a surface that comes into contact with a preparation, such as a container main body part that contains a liquid, a part including an extraction port of the container (nozzle, inner plug), a suction tube, and a cap.
The material which comprises the container which accommodates the ophthalmic composition of this invention can be selected from a wide range.
For example, at least part or all of the contact surface with the ophthalmic composition is made of plastic (for example, polyolefin, acrylic acid resin, terephthalic acid ester, 2,6-naphthalenedicarboxylic acid ester, polycarbonate, polymethylpentene, fluororesin, Vinyl chloride, polyamide, ABS resin, AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, hydrocarbons that may be substituted with halogen atoms), metals (such as aluminum), and glass Examples thereof include a container composed of at least one material selected from the group.

  Examples of polyolefins include polyethylene (including high density polyethylene, low density polyethylene, ultra low density polyethylene, linear low density polyethylene, ultra high molecular weight polyethylene, etc.), polypropylene (isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene). And ethylene-propylene copolymer.

  Examples of the acrylic resin include an acrylic ester such as methyl acrylate, a methacrylic ester such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate.

  Examples of the terephthalic acid ester include polyethylene terephthalate, polytrimethylene terephthalate, and polybutylene terephthalate.

  Examples of 2,6-naphthalenedicarboxylic acid esters include polyethylene naphthalate and polybutylene naphthalate.

  Fluorine resins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene / hexafluoropropylene copolymer, ethylene / tetra Examples thereof include a fluorinated ethylene copolymer and an ethylene / chlorotrifluoroethylene copolymer.

  Examples of the polyamide include nylon.

  Examples of the polyacetal include those composed only of oxymethylene units and those partially containing oxyethylene units.

  Examples of the modified polyphenylene ether include polystyrene-modified polyphenylene ether.

  Examples of polyarylate include amorphous polyarylate.

  Examples of the polyimide include aromatic polyimides such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.
As the container for storing the ophthalmic composition of the present invention, polyolefin and terephthalic acid ester are preferable, terephthalic acid ester is more preferable, polyethylene terephthalate and polybutylene terephthalate are more preferable from the viewpoint of more remarkable wettability reduction effect on the container and the like. Further preferred is polyethylene terephthalate, even more preferred. From another viewpoint, polypropylene, polyethylene, polyethylene terephthalate, and polybutylene terephthalate are preferable, polypropylene, polyethylene terephthalate, polyethylene, and polybutylene terephthalate are more preferable, polyethylene terephthalate and polyethylene are still more preferable, and polyethylene terephthalate is more preferable.
As a container for storing the ophthalmic composition of the present invention, the container material may be a blend polymer with a polymer other than the above-mentioned polymer. When the container material of the container containing the ophthalmic composition of the present invention is a polymer blended with the polymer, the mixing ratio of the polymer and a polymer other than the polymer is not particularly limited as long as the effect of the present invention is achieved, The total weight of the polymer is preferably 30 w / w% or more, more preferably 50 w / w% or more, and even more preferably 65 w / w% or more based on the total amount of the constituent materials. It is especially preferable that it is 80 w / w% or more.

The container should just be comprised with the said material at least one part of the surface which contacts the ophthalmic composition of this application.
For example, a layer or film made of the above material may be formed on the inner surface of the container, or the container itself may be molded from the above material.
In addition, the parts constituting the container (the container body part, the part including the extraction port of the container (nozzle, inner plug), suction tube, cap, etc.) may be made of the above materials, and the whole part of the container may be made of the above materials. It may be comprised. In particular, it is preferable that the container main body portion is made of the above material, and that all of the container main body portion is made of the above material (some layers constituting the container main body are made of the above material. Is not preferred).

Target Diseases The ophthalmic composition of the present invention is caused by pollen, house dust (indoor dust), yellow sand, PM2.5, tick and other eye discomfort (especially allergic symptoms) (eye redness, itching of the eyes, eyes and nibs, etc.) It is useful for prevention, alleviation, improvement, or treatment of blurred vision, eyes with tears, foreign body feeling (feeling of squeaking), fatigue eyes, and the like.
In addition, for example, prevention and alleviation of inflammatory diseases such as blepharitis, conjunctivitis, keratitis, scleritis, superior scleritis, anterior uveitis, postoperative inflammation, lacrimal adenitis, lacrimal cystitis, lacrimal canalitis, etc. Useful for improvement, treatment. Inflammatory diseases may accompany the allergic symptoms described above.
It is also useful for the prevention, alleviation, amelioration, or treatment of symptoms resulting from bacterial infections such as stylus and conjunctivitis.

  In the present invention, “prevention” includes avoidance of the onset, delay, reduction of the incidence, “relief” includes amelioration of symptoms, suppression of progression of symptoms, “improvement” and “treatment” are symptoms Amelioration of symptoms, suppression of symptom progression, healing or completeness.

Method of Use When the ophthalmic composition of the present invention is a preparation to be applied to the eye, such as eye drops, eye wash, eye ointment, etc., the usage varies depending on the intended symptoms, but for example, once or more twice a day As mentioned above, it can be 3 times or more, 4 times or more, 5 times or more, or 6 times or more. Also, it can be 9 times or less, 8 times or less, 7 times or less, 6 times or less, 5 times or less, or 4 times or less per day. It is particularly preferred to administer 4 times a day.

  Further, the use may be started at the same time or after the symptom appears, but the use may be started 1 day or more before the symptom appears, particularly 3 days or more before, especially 7 days or more before. In addition, use can be started from 10 days or more before symptoms appear. In addition, use may be started within 30 days before the symptoms appear, particularly within 20 days, especially within 14 days. Symptoms can be effectively prevented by using before symptoms appear.

When the ophthalmic composition of the present invention is an eye drop, the eye drop containing each component at the above concentration may be instilled, for example, 1 to 3 drops, preferably 1 to 2 drops. One drop can also be used.
When the ophthalmic composition of the present invention is an eye wash, the eye wash containing each component at the above concentration may be washed using, for example, 1 to 30 mL, preferably 1 to 20 mL, more preferably 4 What is necessary is just to wash eyes using ~ 6mL.
When the ophthalmic composition of the present invention is an eye ointment, an eye ointment containing each component at the above concentration may be applied to, for example, 0.001 to 5 g of eyes per time.

  When the ophthalmic composition of the present invention is a contact lens mounting solution, at the time of wearing or removing the contact lens, for example, 1 to 3 drops, preferably 1 to 2 drops per side, Alternatively, it may be worn after being dropped on both sides and wetted, and is preferably worn after wetting both sides of the contact lens.

Preservation method The ophthalmic composition of the present invention can be stored at room temperature, but is excellent in stability. It can be stably stored even at high or low temperatures of 10 ° C. or higher, 15 ° C. or higher, or 20 ° C. or higher.
Although a preservation | save period is not limited, For example, it can be made into 1 day or more, 2 days or more, 3 days or more, or 4 days or more. Moreover, it can also be made into 1 year or 2 years or more. Also, it can be 3 years or less, 1 year or less, 30 days or less, or 15 days or less.

When the ophthalmic composition of the present invention is a contact lens solution, it is not limited thereto. For example, the ophthalmic composition and the contact lens are contacted for 1 hour or more, 2 hours or more, 4 hours or more, or 1 day or more. I can leave it to you. Moreover, 30 days or less, 14 days or less, 7 days or less, or 2 days or less can be made to contact.
The temperature during the period of contact with the contact lens is the same as that described for the storage method of the ophthalmic composition of the present invention.

In addition, the present invention provides an ophthalmic composition comprising: (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof; and (b) a group consisting of chlorpheniramine and a salt thereof. By blending at least one selected from the group consisting of at least one selected from the group consisting of cromoglycic acid and salts thereof (preferably 0.02 w / v% or more based on the total amount of the composition). And a method for reducing the wettability of the ophthalmic composition with respect to the container or the like during use or transportation, and / or improving the drainage. For this reason, inconveniences such as drying and precipitation of the liquid remaining on the wall surface can be suppressed, and the ophthalmic composition can be used up with a small residual liquid amount. In addition, a certain amount of the ophthalmic composition can be accurately discharged from the container outlet, and the ophthalmic composition can be easily discharged from the container even with a weak force.
The present invention provides an ophthalmic composition comprising: (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof; and (b) a group consisting of chlorpheniramine and a salt thereof. By blending at least one selected (preferably 0.02 w / v% or more with respect to the total amount of the composition) and / or at least one selected from the group consisting of cromoglycic acid and salts thereof, Includes methods for improving preservative or storage efficacy.
The present invention provides an ophthalmic composition comprising: (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof; and (b) a group consisting of chlorpheniramine and a salt thereof. By blending at least one selected (preferably 0.02 w / v% or more with respect to the total amount of the composition) and / or at least one selected from the group consisting of cromoglycic acid and salts thereof, It includes a method for imparting the ability to suppress protein adsorption to a contact lens, in particular, the ability to suppress increase in protein adsorption to a contact lens.
The present invention provides an ophthalmic composition comprising: (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof; and (b) a group consisting of chlorpheniramine and a salt thereof. By blending at least one selected (preferably 0.02 w / v% or more with respect to the total amount of the composition) and / or at least one selected from the group consisting of cromoglycic acid and salts thereof, It includes a method for imparting the ability to suppress inflammation or suppress the production of inflammatory cytokines.
The present invention provides an ophthalmic composition comprising: (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof; and (b) a group consisting of chlorpheniramine and a salt thereof. By blending at least one selected (preferably 0.02 w / v% or more with respect to the total amount of the composition) and / or at least one selected from the group consisting of cromoglycic acid and salts thereof, It includes methods for imparting the ability to suppress allergic symptoms of the eye such as itching and foreign body sensation, and unpleasant symptoms such as fatigued eyes.
In each method of the present invention, the type, concentration, dosage form, pH, osmotic pressure, container and the like of each component are as described for the ophthalmic composition of the present invention.

Test example 1 (liquid drop improvement confirmation test)
Each ophthalmic composition was prepared according to the formulation described in Table 1.

Using a contact angle meter DM-501 (manufactured by Kyowa Interface Science Co., Ltd.), in accordance with the measurement procedure of the expansion / contraction method of the same measuring device, It was measured.
Specifically, a polyethylene terephthalate eye drop container (container body part) is placed on the contact angle meter stage so that the container side peripheral surface is in contact with the stage, that is, the container bottom surface is not in contact with the stage. Without placing the container on the stage, the test solution was set in the dispenser. A droplet of 1 μL of the test solution was dropped on the surface of the container to make a hemisphere. Next, the tip of the liquid discharge part of the dispenser was immediately applied to the upper part of the hemisphere. In this state, the test solution was continuously discharged at a discharge speed of 2 μL / second, and the shape of the droplet was photographed 15 times from the side surface every 0.1 second. Each test solution was measured continuously at the same room temperature using the same type of polyethylene terephthalate eye drop container, and the shape of the droplet was photographed in the same manner.
Next, the left and right contact angles were determined for each image using the analysis software FAMAS of the measuring apparatus. Here, the contact angle means the angle on the side containing the test liquid among the angles formed by the tangent line drawn from the contact surface P of the container surface, test liquid and air to the test liquid and the tangent line drawn on the surface of the container. To do. The time-dependent behavior of the average value of the left and right contact angles every 0.1 second increased as the test liquid was discharged and the droplets expanded, and then became substantially constant. Next, the average values of the left and right contact angles were arranged in the order in which the images were taken. When five consecutive values were selected to determine the standard deviation, the standard deviation decreased with time. The average was calculated for all contact angles with this standard deviation of less than 1.0, and this was taken as the dynamic contact angle (advance angle) in this test. The droplet shape was photographed and the dynamic contact angle was calculated three times for each test solution, and the average of the three dynamic contact angles was taken as the dynamic contact angle between the test solution and the container. The dynamic contact angle was calculated in the same manner when the dynamic contact angle did not change during the process of expanding the droplet.
From the following formula (1), the rate of increase of the dynamic contact angle of each test solution relative to the dynamic contact angle of Comparative Example 1-1 when a polyethylene terephthalate container was used was calculated. The results are shown in Table 1.

Formula (1)
Increase rate of dynamic contact angle (%)
= {(Dynamic Contact Angle of Each Test Solution / Dynamic Contact Angle of Comparative Example 1-1) -1} × 100

As shown in Table 1, in Comparative Example 1-1 which further contains 0.05 w / v% of pranoprofen in Comparative Example 1-1, the dynamic contact angle does not contain pranoprofen (Comparative Example 1- Low for 1). On the other hand, when pranoprofen was contained at 0.1 w / v%, it was surprisingly higher than that when pranoprofen was not contained (Example 1-1).
An ophthalmic composition containing 0.1 w / v% of pranoprofen in addition to an ophthalmic composition containing chlorpheniramine maleate and cromoglycate sodium is used when the liquid flows with respect to the container material (polyethylene terephthalate). It was confirmed that the wettability was remarkably low and the wettability suppressing effect was high.
That is, when an ophthalmic composition containing chlorpheniramine maleate, cromoglycate sodium, and pranoprofen exceeding 0.07 w / v% is contained in a container made of polyethylene terephthalate, the ophthalmic composition is used. It was shown that when the liquid moves during transport or when it is transported, the liquid runs out well and the advantageous effect that the liquid remaining on the container or the like is suppressed is obtained.

Test Example 2 (Preservation efficacy test)
Each ophthalmic composition (eye drops) was prepared according to the formulation described in Table 2 below.
Subsequently, the preservation | save efficacy test of the prepared ophthalmic composition was implemented according to the 16th revision Japanese Pharmacopoeia reference information preservation | save efficacy test method. Specifically, first, Staphylococcus aureus (ATCC6538) was inoculated on the surface of a soybean / casein / digest slant medium, and cultured at 33 ° C. for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to prepare a bacterial suspension containing about 1 × 10 ⁴ CFU / mL viable bacteria. The number of viable bacteria in the suspension was measured by separately culturing. Next, 10 mL of each ophthalmic composition sterilized by filtration was filled into a 15 mL CORNING conical tube (PET). This ophthalmic composition was inoculated with a Staphylococcus aureus bacterial solution (suspended in physiological saline) so that the viable cell count (final concentration) was about 1 × 10 ³ CFU / mL, and the sample was well stirred. Samples were stored for 24 hours at 22.5 ° C., protected from light. For samples containing bacteria after storage, the number of viable bacteria was determined by the membrane filter method.
Thereafter, the ratio (%) of the number of viable bacteria relative to the corresponding comparative example was calculated. Corresponding comparative examples are Comparative Example 2-1 for Comparative Example 2-2 and Comparative Example 2-3 for Example 2-1.
The results are shown in Table 2.

  As shown in Table 2, when chlorpheniramine maleate and sodium cromoglycate were added to an ophthalmic composition containing 0.05% w / v pranoprofen, the preservation efficacy was not substantially changed, but pranoprofen was not changed. When chlorpheniramine maleate and sodium cromoglycate were added to the ophthalmic composition containing 0.1 w / v%, a tendency for the viable cell count to decrease significantly was confirmed.

Test Example 3 (protein adsorption test)
Each ophthalmic composition (eye drops) was prepared according to the formulation described in Table 3.

First, contact lenses (etafilcon A lens (manufactured by Johnson & Johnson, trade name: 2 week Accuview)) used in the test were used for each of Comparative Examples 3-2 to 3-4 and Example 3-1. Each piece was immersed in 4.5 mL of the ophthalmic composition and stored at 34 ° C. for 2 days.
In accordance with FDA guidelines, protein solution (buffer solution (sodium chloride: 0.9 w / v%, sodium dihydrogen phosphate dihydrate: 0.045 w / v%), egg white lysozyme 0.120 w / v%, bovine serum albumin In the amount of 0.388 w / v% and bovine globulin in an amount of 0.161 w / v%).
The protein solution (2.0 mL) was placed in a 10 mL vial, and the lens treated with the ophthalmic composition was immersed in the protein solution after wiping off excess water and stored at 34 ° C. for 4 hours.
Next, take out the lens, quickly soak it in 100 mL of physiological saline (about 1 second), rinse the excess protein solution, and then lightly drain the water twice using the edge of a beaker. Was immersed in 2 mL of a protein separation solution (aqueous solution containing 1% sodium carbonate and 1% SDS).
The mixture was shaken at 34 ° C. and 120 rpm for 3 hours or longer, and the protein adsorbed on the lens was collected in a protein separation solution.
Using a micro BCA assay kit (Thermo SCIENTIFIC, Pierce # 23235), the amount of protein in the protein separation solution was quantified as an albumin equivalent by quantifying albumin as a standard, and the amount of protein adsorbed to the lens was obtained. Separately, instead of immersing each contact lens in 4.5 mL of each ophthalmic composition of Comparative Examples 3-2 to 3-4 and Example 3-1, and storing at 34 ° C. for 2 days, contact lenses are comparative examples. The treatment was performed in the same manner as above except that each piece was immersed in 4.5 mL of the ophthalmic composition of 3-1 and stored at 34 ° C. for 6 hours.
The amount of increase in protein adsorption was calculated using the following equation (2).

Formula (2)
Increase rate of protein adsorption relative to Comparative Example 3-1 (%) =
[(Protein adsorption amount of each sample−protein adsorption amount of Comparative Example 3-1) / protein adsorption amount of Comparative Example 3-1] × 100

The results are shown in Table 3 and FIG.
As shown in Table 3 and FIG. 1, when pranoprofen 0.1 w / v% was added, the protein adsorption to the contact lens increased. Chlorpheniramine maleate and sodium cromoglycate were added here. By blending, protein adsorption was remarkably suppressed.
On the other hand, when pranoprofen was 0.05%, the problem of increased protein adsorption did not occur, and when chlorpheniramine maleate and sodium cromoglycate were added here, protein adsorption increased.

Test Example 4 (IL-8 production inhibition test)
Corneal epithelial cells (RIKEN BioResource Center) are seeded in a 96-well plate (Corning) at 1.0x10 ⁴ cells / well and become confluent at 37 ° C, 5% CO ₂ , and humidity of 90% Until cultured.
Each sample formulation having the composition shown in Table 4 below was prepared, and each sample formulation was added to the corneal epithelial cells cultured in 100 μL of the medium in the same amount as the medium, at 37 ° C., 5% CO ₂ , humidity 90 It was cultured for 1 hour under the condition of%. Next, human recombinant TNFα (R & D) was used as TNFα, and this TNFα was added to each well so as to be 10 ng / mL, followed by further culturing for 24 hours under conditions of 37 ° C., 5% CO ₂ and 90% humidity.
The amount of IL-8 produced was evaluated by quantifying the concentration of IL-8 released in the culture supernatant using human CXCL8 / IL-8 Quantikine ELISA Kit (R & D).
Further, a control subjected to the same treatment as Comparative Example 4-1 except that TNF-α was not added was used as a control.
The IL-8 production suppression rate with respect to Comparative Example 4-1 of each formulation example was calculated by the following formula (3).

Formula (3)
IL-8 production inhibition rate relative to Comparative Example 4-1 (%)
= {[(IL-8 concentration of Comparative Example 4-1−IL-8 concentration of control) − (IL-8 concentration of each prescription example−IL-8 concentration of control)] / (IL of Comparative Example 4-1) -8 concentration-control IL-8 concentration)} x 100

The results are shown in Table 4.

Planoprofen promoted IL-8 production, but IL-8 production was suppressed very effectively by combining 0.1 w / v% pranoprofen with chlorpheniramine maleate and cromoglycate sodium.
IL-8 is a leukocyte chemotactic factor produced by various cells such as leukocytes, fibroblasts, and endothelial cells by stimulation of various inflammatory cytokines. Species) and is therefore considered an important mediator of inflammation formation in the body. The said result has shown that the ophthalmic composition of this invention suppressed IL-8 production amount, and this means suppressing the inflammation in a biological body effectively.

Test Example 5 (human eye drop test)
Each ophthalmic composition (eye drops) was prepared according to the formulation shown in Table 5, and 13 mL was filled in an eye drop container (container body portion) made of polyethylene terephthalate having an internal volume of 14.2 mL. After filling, a polyethylene nozzle was attached to the eye drop container. Each eye drop was instilled into 4 subjects with naked eyes, and each eye drop was instilled into each of the left and right eyes, and the feeling of execution after the instillation related to the symptoms shown in Table 5 was evaluated by VAS (Visual analog scale).

Evaluation by VAS was performed as follows. On the subjective symptom survey sheet on which a 100 mm line is drawn, the item related to the sensory sense (itchiness, foreign body sensation) shown in Table 5 is 0 mm when it is not felt at all, and 100 mm is the case when it feels strong. Marked about the degree. This length (mm) was taken as the VAS value. That is, the higher the VAS value, the higher the awareness score of each sensory evaluation item.
Using this VAS value, the VAS improvement rate (%) of the example with respect to Comparative Example 5-1 was obtained using the following formula (4).

Formula (4)
VAS improvement rate (%) relative to Comparative Example 5-1
= {(VAS value of Example-VAS value of Comparative Example 5-1) / VAS value of Comparative Example 5-1} × 100

From the results of Table 5, it can be seen that when pranoprofen, chlorpheniramine maleate, and sodium cromoglycate were used in combination, itching and foreign body sensation were significantly improved.
In addition, when the eye drops further contain sodium chondroitin sulfate, dibutylhydroxytoluene, polysorbate 80, l-menthol, dl-camphor, sodium edetate, and concentrated benzalkonium chloride, itching and foreign body sensation are remarkably improved. Thus, when these one or more components were combined, a tendency to further improve these effects was confirmed.

  Similarly, as a result of evaluating the effect on eye fatigue, the VAS improvement rate (%) of Example 5-2 relative to Comparative Example 5-1 was 26.3%.

Test example 6 (liquid drop improvement confirmation test)
Each ophthalmic composition (eye drops) was prepared according to the formulation described in Table 6.

For each eye drop of Table 6, the dynamic contact angle was measured in the same procedure as in Test Example 1.
The increase rate (%) of the dynamic contact angle with respect to the corresponding test example was calculated by the following formula (5).
The corresponding test examples are Example 6-1 for Comparative Example 6-1 and Example 6-2, and Example 6-3 for Examples 6-4 and 6-5.
The results are shown in Table 6.

Formula (5)
Increase rate of dynamic contact angle for the corresponding test example (%)
= {(Dynamic contact angle of each test solution / dynamic contact angle of corresponding test example) −1} × 100

  As shown in Table 6, when Example 6-1 and Example 6-3 are further mixed with sodium chondroitin sulfate, l-menthol and / or dl-camphor, or dibutylhydroxytoluene, the wettability with respect to the container or the like Was further reduced, and it was confirmed that the wetting suppression effect was improved.

Test Example 7 (preservation efficacy test)
Each ophthalmic composition (eye drops) was prepared according to the formulation in Table 7.
For each eye drop described in Table 7, the number of viable bacteria was determined in the same procedure as in Test Example 2, and the ratio (%) of the viable cell count relative to Comparative Example 7-1 was calculated.

As shown in Table 7, it was confirmed that when pranoprofen 0.1 w / v% was blended, the problem of an increase in the number of viable bacteria and a decrease in storage efficacy occurred. In the case where chlorpheniramine maleate and sodium cromoglycate are further coexisted with pranoprofen 0.1 w / v%, the number of viable bacteria is remarkably reduced and the preservation efficacy is improved, as in Test Example 2. It was confirmed.

Test Example 8 (protein adsorption test)
Each ophthalmic composition (eye drops) was prepared according to the description in Table 8.
For each eye drop shown in Table 8, the amount of protein adsorption was determined in the same procedure as in Test Example 3, and the rate of increase in protein adsorption of Example 8-2 relative to Example 8-1 was calculated using the following formula (6). Was calculated.

Formula (6)
Increase rate of protein adsorption relative to Example 8-1 (%) =
[(Protein adsorption amount of Example 8-2−Protein adsorption amount of Example 8-1) / Protein adsorption amount of Example 8-1] × 100

As shown in Table 8, when dibutylhydroxytoluene coexists in Example 8-1, protein adsorption was further suppressed.

[Formulation example]
Formulation examples of eye drops representing the ophthalmic composition of the present invention are shown in Tables 9 to 14. All units in the table are w / v%. The eye drops prescribed in Formulation Examples 1 to 72 were filled in a polyethylene terephthalate container (container body portion).
In addition, preparation examples 1 ′ to 72 ′ were prepared by filling the eye drops of Preparation Examples 1 to 72 into a polyethylene terephthalate container (container body portion) and equipped with a polyethylene nozzle. Formulation Examples 1 ″ to 72 ″ were prepared by filling the eye drops of Formulation Examples 1 to 72 into a polyethylene terephthalate container (container main body portion) and equipped with a polybutylene terephthalate nozzle.

  The ophthalmic composition of the present invention can prevent, alleviate, ameliorate, or treat allergic symptoms effectively, and has excellent properties as a preparation, and therefore has a very high commercial value.

Claims (11)

(a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof; and (b) selected from the group consisting of 0.02 w / v% or more of chlorpheniramine and a salt thereof. at least one, as well, ophthalmic compositions containing at least one selected from the group consisting of 0.5~2w / v% of click Romoguriku acid and its salts. It is accommodated in a container made of a polyolefin or terephthalic acid ester, according to claim 1 ophthalmic composition. The ophthalmologic according to claim 1 or 2 , wherein the content of at least one selected from the group consisting of pranoprofen and a salt thereof is 0.07 to 0.15 w / v% based on the total amount of the composition. Composition. Content of at least one compound selected from chlorpheniramine the group consisting of a salt thereof, based on the total amount of the composition, according to any one of claims 1 to 3, which is a 0.02~0.03w / v% Composition. The composition according to any one of claims 1 to 4 , wherein the content of at least one selected from the group consisting of cromoglycic acid and a salt thereof is 1 w / v% with respect to the total amount of the composition. The content of at least one selected from the group consisting of cromoglycic acid and a salt thereof is 5 to 20 parts by weight with respect to 1 part by weight of at least one selected from the group consisting of pranoprofen and a salt thereof. The composition in any one of Claims 1-5.   Furthermore, the composition in any one of Claims 1-6 containing a nonionic surfactant.   Furthermore, the composition in any one of Claims 1-7 containing a terpenoid.   Furthermore, the composition in any one of Claims 1-8 containing dibutylhydroxytoluene and / or butylhydroxyanisole. The ophthalmic composition comprises (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof, and (b) 0.02 w / v% or more of chlorpheniramine and a salt thereof. Of at least one selected from the group consisting of, and at least one selected from the group consisting of 0.5 to 2 w / v% cromoglycic acid and a salt thereof, A method of imparting production suppression ability. The ophthalmic composition comprises (a) at least one selected from the group consisting of 0.07 w / v% or more of pranoprofen and a salt thereof, and (b) 0.02 w / v% or more of chlorpheniramine and a salt thereof. By blending at least one selected from the group consisting of, and at least one selected from the group consisting of 0.5 to 2 w / v% cromoglycic acid and salts thereof, itching, foreign body sensation or fatigued eyes A method of imparting suppression ability.