JP2020147557A - Ophthalmic composition having inhibited irritating sensation - Google Patents

Abstract

To provide an ophthalmic composition wherein the sense of irritation is suppressed, an irritation-inhibiting agent for an ophthalmic composition, a method for inhibiting irritation caused by an ophthalmic composition, and a method for assessing ophthalmic irritation.SOLUTION: An ophthalmic composition having inhibited irritating sensation contains a hyperemia removal component, and optionally contains (B) a TRPA1 agonist.SELECTED DRAWING: None

Description

The present invention relates to an ophthalmic composition in which the sensation of irritation is suppressed, an ophthalmic composition inhibitor, a method for suppressing irritation of the ophthalmic composition, and a method for evaluating eye irritation.

The TRP (Transient Receptor Potential) channel is a cation channel having a transmembrane region and is considered to function as a tetramer. TRP channels are a family of cation channels that function in various aspects of sensory receptor, and there are many TRP channel molecules that respond to various stimuli (Non-Patent Document 1). TRPM8 is a cell sensor involved in a refreshing sensation, TRPA1 is a pain, and TRPV1 is a cell sensor involved in a burning sensation. It has been reported that TRPA1 and TRPV1 are also involved in discomfort and pain in the eye (Non-Patent Document 2).

Although l-menthol is used as a refreshing agent in eye drops and the like, it is also known to give a refreshing sensation and a stimulating sensation to the eyes because it is also a TRPA1 agonist.

Biochemistry, Vol. 81, No. 11, pp.962-983, 2009 Curr. Ophthalmol. Rep. (2015), 3: 111-121

An object of the present invention is to provide an ophthalmic composition in which the sensation of irritation is suppressed, an irritation inhibitor for the ophthalmic composition, a method for suppressing irritation of the ophthalmic composition, and a method for evaluating eye irritation.

As a result of intensive research, the present inventor has found that an ophthalmic composition containing a specific component can suppress the irritation to the eye caused by a TRPA1 agonist such as l-menthol, and can solve the above-mentioned problems. I found it.

That is, the present invention includes the following inventions.
[1] It is characterized by containing at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4). Ophthalmic composition with suppressed irritation:
(A-1) Hyperemic removal component,
(A-2) Antihistamine,
(A-3) At least one selected from the group consisting of camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methyl acetate, and (A-4) a local anesthetic component.
[2] At least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4), and (B) TRPA1 agonist. An ophthalmic composition with suppressed irritation, characterized by containing
(A-1) Hyperemic removal component,
(A-2) Antihistamine,
(A-3) At least one selected from the group consisting of camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methyl acetate, and (A-4) a local anesthetic component.
[3] (B) The ophthalmic composition according to the above [2], wherein the TRPA1 agonist is l-menthol.
[4] (A-1) Any one of the above [1] to [3], wherein the decongestant component is at least one selected from the group consisting of tetrahydrozoline, naphazoline, and pharmaceutically acceptable salts thereof. The ophthalmic composition according to.
[5] (A-2) Any one of the above [1] to [3], wherein the antihistamine is at least one selected from the group consisting of chlorpheniramine, diphenhydramine, and pharmaceutically acceptable salts thereof. The ophthalmic composition according to.
[6] (A-4) The ophthalmic composition according to any one of [1] to [3] above, wherein the local anesthetic component is chlorobutanol.
[7] The ophthalmic composition according to [1] to [6], wherein the irritation is pain caused by dry eye, allergy, or the like.
[8] It is characterized by containing at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4). Stimulation inhibitor for ophthalmic compositions:
(A-1) Hyperemic removal component,
(A-2) Antihistamine,
(A-3) At least one selected from the group consisting of camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methyl acetate, and (A-4) a local anesthetic component.
[9] The irritation inhibitor for the ophthalmic composition according to the above [8], for suppressing pain caused by dry eye, allergies, or the like.
[10] (B) An ophthalmic composition containing a TRPA1 agonist is further composed of the following components (A-1), (A-2), (A-3), and (A-4). (B) A method for suppressing irritation of an ophthalmic composition derived from a TRPA1 agonist, which comprises containing at least one selected from the group:
(A-1) Hyperemic removal component,
(A-2) Antihistamine,
(A-3) At least one selected from the group consisting of camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methyl acetate, and (A-4) a local anesthetic component.
[11] A method for evaluating eye irritation by a test sample, which comprises contacting a test sample with TRPA1-expressing cells and measuring the amount of change in intracellular calcium ion concentration caused by the test sample via TRPA1.

The ophthalmic composition of the present invention contains at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4). In addition, (B) TRPA1 agonist may or may not be contained, and has the effect of suppressing irritation: (A-1) decongestant component, (A-2) antihistamine, ( A-3) At least one selected from the group consisting of camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methyl acetate, and (A-4) a local anesthetic component.
Preferably, the irritation is derived from the (B) TRPA1 agonist contained in the ophthalmic composition, but if the ophthalmic composition does not contain the (B) TRPA1 agonist, the ophthalmic composition is administered. It is preferable that animals such as humans exhibit pain symptoms due to dry eye, allergies, etc., or the stimulation receptor TRPA1 of the animal is activated.
The present invention also provides a method for suppressing irritation of an ophthalmic composition and a method for evaluating eye irritation using a test sample.

FIG. 1 shows the results of a stimulus suppression confirmation test for a TRPA1 agonist (l-menthol) by the components constituting the ophthalmic composition of the present invention. FIG. 2 visualizes the TRPA1 inhibitory effect and shows the results with borneol (reference example), tetrahydrozoline hydrochloride and peppermint oil (example). FIG. 3 shows the results of a test for confirming a refreshing sensation and a stimulating sensation in humans by using l-menthol (comparative example) in combination with l-menthol and tetrahydrozoline hydrochloride (example).

The ophthalmic composition of the present invention contains at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4). : Selected from the group consisting of (A-1) decongestant, (A-2) antihistamine, (A-3) camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methylacetate. At least one and (A-4) local anesthetic component. Preferably, the ophthalmic composition of the present invention further comprises (B) a TRPA1 agonist.

[(A-1) Hyperemic removal component]
The decongestant components include, for example, tetrahydrozoline, naphazoline, oxymetazoline, or their hydrochlorides, nitrates, and other imidazoline-based decongestant components, epinephrine, ephedrine, methylephedrine, phenylephrine, and pharmaceutically acceptable salts thereof. It is preferable, but not limited to, at least one selected from the group consisting of.
Of these decongestant components, preferably, for example, imidazoline-based decongestant components, more preferably tetrahydrozoline, naphazoline and pharmaceutically acceptable salts thereof, still more preferably tetrahydrozoline and pharmaceutically acceptable salts thereof, particularly preferably. Is tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride).

When the ophthalmic composition of the present invention contains the component (A-1), the ratio of the component (A-1) is, for example, 0.0001 w / v% or more at the lower limit with respect to the total amount of the ophthalmic composition. It may be 0003w / v% or more and 0.0005w / v% or more. Further, it may be 0.01 w / v% or more. When the ophthalmic composition of the present invention contains the component (A-1), the ratio of the component (A-1) is, for example, an upper limit of 0.5 w / v% or less with respect to the total amount of the ophthalmic composition. It may be 0.3 w / v% or less, 0.1 w / v% or less, 0.05 w / v% or less.
Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.

When the ophthalmic composition of the present invention contains the component (A-1), the proportion of the component (A-1) is, for example, usually 0.001 or more at the lower limit as compared with the case where the component (B) is 1. Yes, it is 0.01 or more, preferably 0.1 or more, more preferably 0.2 or more, and particularly preferably 0.5 or more. Further, the ratio of the component (A-1) to the component (B) 1 is preferably, for example, an upper limit of 1000 or less, more preferably 800 or less, and further preferably 50 or less. It is preferably 10 or less, and particularly preferably 10 or less.
Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.

[(A-2) Antihistamine]
As the antihistamine, for example, at least one selected from the group consisting of chlorpheniramine, diphenhydramine, ketotifen, iproheptine, levocabastine, olopatadine and pharmaceutically acceptable salts thereof is preferably used, but is not limited thereto.
Among these antihistamines, preferably, ketotiphen fumarate, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate (chlorfenlamin maleate), levocabastine hydrochloride, olopatadine hydrochloride and the like can be mentioned, and more preferably ketotiphen. Fumarate, diphenhydramine hydrochloride, chlorpheniramine maleate, levocabastine hydrochloride, olopatadine hydrochloride and the like can be mentioned, more preferably diphenhydramine hydrochloride, chlorpheniramine maleate and the like, and even more preferably chlor. Examples include phenylamine maleate.

When the ophthalmic composition of the present invention contains the component (A-2), the ratio of the component (A-2) is, for example, 0.001 w / v% or more at the lower limit with respect to the total amount of the ophthalmic composition. It may be 003 w / v% or more, 0.005 w / v% or more, 0.01 w / v% or more. Further, the upper limit may be 0.5 w / v% or less, 0.3 w / v% or less, 0.05 w / v% or less, 0.03 w / v% or less.
Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.

When the ophthalmic composition of the present invention contains the component (A-2), the ratio of the component (A-2) is, for example, when the lower limit is 0.01 or more, as compared with the case where the component (B) is 1. It is preferably 0.05 or more, more preferably 0.1 or more, and particularly preferably 0.1 or more. Further, the ratio of the component (A-2) to the component (B) 1 is preferably, for example, an upper limit of 1000 or less, more preferably 800 or less, and further preferably 500 or less. It is more preferably 100 or less, and particularly preferably 10 or less.
Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.

[(A-3) component]
The ophthalmic composition of the present invention contains, as the component (A-3), at least one selected from the group consisting of camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methyl acetate. These may be d-form, l-form, or dl-form.

In addition, the component (A-3) of the present invention can be used in a state of being contained in an essential oil. As the essential oil containing the component (A-3), for example, one or more of peppermint oil, cool mint oil, spare mint oil, peppermint oil, uikyo oil, kehi oil, bergamot oil, eucalyptus oil, cinnamon oil, rose oil and the like. Among them, peppermint oil or cool mint oil is particularly preferable.

When the ophthalmic composition of the present invention contains the component (A-3), the ratio of the component (A-3) is, for example, 0.00001 w / v% or more at the lower limit with respect to the total amount of the ophthalmic composition. 0.0005w / v% or more, 0.0001w / v% or more, 0.0003w / v% or more, 0.0005w / v% or more, 0.0007w / v% or more, 0.0008w / v% or more, 0.0009w / It may be v% or more and 0.001 w / v% or more.
When the ophthalmic composition of the present invention contains the component (A-3), the ratio of the component (A-3) to the total amount of the ophthalmic composition is, for example, an upper limit of 5 w / v% or less, 3 w / V% or less, 2w / v% or less, 1.5w / v% or less, 1.2w / v% or less, 1w / v% or less, 0.9w / v% or less, 0.8w / v% or less, 0. It may be 7 w / v% or less, 0.6 w / v% or less, 0.5 w / v% or less, 0.3 w / v% or less, 0.1 w / v% or less.
Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.
In particular, further, the proportion of the component (A-3) is, for example, 0.00001 w / v% to 2 w / v% in total (for example, 0.00005 to 1 w / v in total) with respect to the total amount of the ophthalmic composition. %), Preferably a total of 0.0001 to 0.1 w / v% (eg, 0.0003 to 0.05 w / v%), and even more preferably a total of 0.0005 to 0.02 w / v% (%). For example, it may be about 0.001 to 0.01 w / v% in total). Further, the ratio of the component (A-3) may be, for example, the lower limit of 0.00000005% or more, 0.00000005% or more, 0.000001% or more with respect to the total amount of the ophthalmic composition.

When an essential oil containing the component (A-3) in the ophthalmic composition is used, for example, the lower limit of the component (A-3) in the essential oil is 0.0001 w / v with respect to the total amount of the ophthalmic composition. % Or more, 0.0005 w / v% or more, 0.001 w / v% or more, 0.0015 w / v% or more. Further, for example, the upper limit of the component (A-3) in the essential oil is 0.2 w / v% or less, 0.1 w / v% or less, 0.05 w / v% or less, based on the total amount of the ophthalmic composition. It may be 0.02 w / v% or less. Further, the upper limit may be 90 w / v% or less, 80 w / v% or less, 60 w / v% or less, 30 w / v% or less, 10 w / v% or less, and 1 w / v% or less.
Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.
In particular, the proportion of the essential oil containing the component (A-3) is, for example, 0.00001 w / v% to 2 w / v% in total (for example, 0.00005 to 0.00005 in total) with respect to the total amount of the ophthalmic composition. 1 w / v%), preferably a total of 0.0001 to 0.1 w / v% (eg, 0.0003 to 0.05 w / v%), more preferably a total of 0.0005 to 0.02 w / It may be about v% (for example, 0.001 to 0.01 w / v% in total).
When an essential oil containing the component (A-3) is used in the ophthalmic composition, the essential oil is appropriately adjusted so that the content of the component (A-3) in the essential oil satisfies the above ratio. To.

When the ophthalmic composition of the present invention contains the component (A-3), the ratio of the component (A-3) is, for example, the lower limit is 0.000001 or more, as compared with the case where the component (B) is 1. It may be 0.00001 or more, 0.0001 or more, 0.001 or more, 0.005 or more, 0.01 or more, 0.1, 1 or more. Further, the ratio of the component (A-3) may be, for example, an upper limit of 800 or less, 500 or less, 100 or less, or 10 or less with respect to the component (B) 1.
Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.

[(A-4) component]
Chlorobutanol is preferable as the local anesthetic component. Further, in the present invention, in addition to chlorobutanol, a local anesthetic component known in the art such as procaine hydrochloride or lidocaine hydrochloride may be used in place of chlorobutanol or in combination with chlorobutanol.

In particular, when the ophthalmic composition of the present invention contains the component (A-4), this ratio is preferably 0.001 to 2.5 w / v%, for example, 0.01 to the total amount of the ophthalmic composition. ~ 1 w / v% is more preferable, 0.05 to 0.5 w / v% is further preferable, and 0.1 to 0.25% is particularly preferable.

When the ophthalmic composition of the present invention contains the component (A-4), the ratio of the component (A-4) is, for example, the lower limit is 0.01 or more, as compared with the case where the component (B) is 1. It may be 0.1 or more and 1 or more. Further, the ratio of the component (A-3) to the component (B) 1 may be, for example, an upper limit of 5000 or less, 3500 or less, 1000 or less, 500 or less, 100 or less, 50 or less, 10 or less. Good.
Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.

[(A) component]
In the present specification, the component (A-1), the component (A-2), the component (A-3), and the component (A-4) may be collectively referred to as the component (A). Further, the component (A) is preferably used in combination of a plurality of components, and more preferably in combination of two or more groups selected from the groups consisting of (A-1) to (A-4). It is more preferable to use a combination of groups or more.

[(B) TRPA1 agonist]
The ophthalmic composition of the present invention preferably contains a TRPA1 agonist. TRPA1 agonists irritate the eye. As the TRPA1 agonist, menthol is preferable.
The menthol is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable, and may be d-form, l-form, or dl-form, but l-menthol is preferable.

Further, as the menthol, an essential oil containing menthol may be used. Examples of such essential oils include essential oils such as peppermint oil, peppermint oil, cool mint oil, and spare mint. Commercially available menthol can also be used. As for menthol and essential oil, one kind may be used alone, or two or more kinds may be used in combination.

The content of menthol in the ophthalmic composition of the present invention is preferably 0.00001 to 0.5 w / v%, preferably 0.0001 to 0.25 w / v%, based on the total amount of the ophthalmic composition. More preferably, it is more preferably 0.0005 to 0.1 w / v%, and further preferably 0.001 to 0.08 w / v%. When essential oil containing menthol as the component (A-3) and menthol as the component (B) are used, the sum of the amount of menthol contained in the essential oil and the amount of menthol of the component (B) satisfies the above ratio. Is set to.
When the (B) TRPA1 agonist and the essential oil containing the (B) TRPA1 agonist are used in combination, the total content of the desired (B) TRPA1 agonist to be blended and the desired (B) TRPA1 agonist in the essential oil is used. Is set to satisfy the above ratio.

The ophthalmic composition of the present invention contains at least one selected from the group consisting of the component (A-1), the component (A-2), the component (A-3), and the component (A-4). , The feeling of irritation can be suppressed. Furthermore, when the ophthalmic composition of the present invention contains the (B) TRPA1 agonist, it is particularly preferable because the irritation sensation caused by the TRPA1 agonist contained in the ophthalmic composition can be suppressed. It is also preferable that an animal such as a human being to which the ophthalmic composition is administered exhibits pain symptoms due to dry eye, allergies, or the like, or the stimulus receptor TRPA1 of the animal is activated.

The ophthalmic composition of the present invention may further contain a nonionic surfactant in addition to the above-mentioned components. The nonionic surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable. Specific examples of the nonionic surfactant include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene cured castor oil, polyoxyethylene castor oil, polyoxyethylene-polyoxypropylene block copolymer, and polyoxyethylene-polyoxypropylene. Block copolymer adducts, polyoxyethylene-polyoxypropylene alkyl ethers, polyoxyethylene alkyl phenyl ethers and the like.

As a more specific example of the nonionic surfactant, for example, polyoxyethylene (hereinafter, also referred to as POE) -polyoxypropylene (hereinafter, also referred to as POP) glycol (for example, Poroxummer 407, Poroxummer 235, Poroxumer 188 Pore-POP block copolymer adduct of ethylenediamine such as poroxamine; POE monolaurate (20) sorbitan (polysorbate 20), POE monooleate (20) sorbitan (polysorbate 80), POE sorbitan monostearate. POE sorbitan fatty acid esters such as (polysorbate 60) and POE sorbitan tristearate (polysorbate 65); POE (5) hardened castor oil, POE (10) hardened castor oil, POE (20) hardened castor oil, POE (40) POE cured castor oil such as cured castor oil, POE (50) cured castor oil, POE (60) cured castor oil, POE (100) cured castor oil; POE (3) castor oil, POE (10) castor oil, POE ( 35) POE castor oil such as castor oil; POE (9) POE alkyl ethers such as lauryl ether; POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether; POE (10) nonionic phenyl ether and the like POE alkylphenyl ethers; polyethylene glycols monostearate such as polyoxyl 40 stearate and the like. The numbers in parentheses indicate the average number of moles of POP or POE added.

Among these nonionic surfactants, POE-POP glycol, POE sorbitan fatty acid esters, POE-hardened castor oil, POE castor oil, and polyethylene glycol monostearate are preferable from the viewpoint of remarkably exerting the effect of the present invention. , Poroxummer 407, monooleic acid POE (20) sorbitan (polysorbate 80), POE (60) hardened castor oil (polyoxyethylene hydrogenated castor oil 60), POE (40) cured castor oil (polyoxyethylene hydrogenated castor oil 40) , POE (3) castor oil (polyoxyethylene castor oil 3), POE (10) castor oil (polyoxyethylene castor oil 10), POE (35) castor oil (polyoxyethylene castor oil 35), polyoxyl stearate 40 Is more preferable, and POE (20) sorbitan monooleate and POE (60) hardened castor oil are particularly preferable.

These nonionic surfactants may be synthesized and used by a known method, or commercially available products may be obtained and used. The nonionic surfactant may be used alone or in any combination of two or more.
The content of the nonionic surfactant can be appropriately set according to the type of the nonionic surfactant, the type and amount of other components, the use of the ophthalmic composition, and the like.

In addition, the ophthalmic composition of the present invention may contain a surfactant other than the nonionic surfactant. Such a surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable, and specific examples thereof include, for example, polyoxyethylene alkyl ether phosphate and polyoxy. Anionic surfactants such as ethylene alkyl ether sulfate, alkylbenzene sulfonate, alkyl sulfate, N-acyl taurine salt and the like, or, for example, amphoteric surfactant such as lauryldimethylaminoacetate betaine and the like can be mentioned.

As an example, the total content of the surfactant with respect to the total amount of the ophthalmic composition is not limited, but for example, the lower limit is preferably 0.0001 w / v% or more, more preferably 0.0005 w / v%. As described above, it is more preferably 0.001 w / v% or more, particularly preferably 0.005 w / v% or more, and most preferably 0.01 w / v% or more. The upper limit is not limited, but is preferably 10 w / v% or less, more preferably 5 w / v% or less, still more preferably 1 w / v% or less, and particularly preferably 0.5 w / v% or less. .. Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.

In the present invention, the ophthalmic composition may further contain a thickener in addition to the above-mentioned components. Specific examples of the thickener include cellulosic polymer compounds such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), carboxymethyl cellulose and its salts, and carboxyethyl cellulose and its salts. Vinyl such as chondroitin sulfate and salts thereof, glycosaminoglycans such as hypromellose and salts thereof, polyvinyl alcohol (completely or partially saponified products), polyvinylpyrrolidone (K17, K25, K30, K90, etc.), carboxyvinyl polymers and salts thereof. Examples thereof include macromolecules, dextran, macrogol 6000, macrogol 4000, macrogol (polyethylene glycol) such as macrogol 400, gellan gum, alginic acid and salts thereof. Here, the salt is not particularly limited, but a sodium salt is preferable.
From the viewpoint of significantly exerting the effect of the present invention, glycosaminoglycan, cellulose-based polymer, or vinyl-based polymer is preferable, glucosaminoglycan is more preferable, chondroitin sulfate, hyaluronic acid, and salts thereof are more preferable. Sodium chondroitin sulfate (sodium chondroitin sulfate) and sodium hyaluronate are more preferable. These thickeners may be synthesized and used by a known method, or commercially available products may be obtained and used. These thickeners may be used alone or in combination of two or more.

The total content of the thickener can be appropriately set according to the type of thickener to be used, the type and amount of other compounding components, the use of the ophthalmic composition, and the like. The total content of the thickener, with respect to the total amount of the ophthalmic composition, is not limited, but is preferably 0.0001 w / v% or more, more preferably 0.0005 w / v% or more, still more preferably 0. It is 001 w / v% or more, more preferably 0.005 w / v% or more, even more preferably 0.01 w / v% or more, and most preferably 0.05 w / v% or more. The total content of the thickener is not limited, but is preferably 5 w / v% or less, more preferably 3 w / v% or less, still more preferably 1 w / v, based on the total amount of the ophthalmic composition. % Or less, even more preferably 0.5 w / v% or less, and most preferably 0.3 w / v% or less. The total content of the thickener is not limited, but is preferably 0.0001 to 5 w / v%, more preferably 0.0005 to 3 w / v%, still more preferably 0.0005 to 3 w / v%, based on the total amount of the ophthalmic composition. 0.001 to 1 w / v%, even more preferably 0.005 to 0.5 w / v%, particularly preferably 0.01 to 0.5 w / v%, most preferably 0.05 to 0.3 w. / V%.

In the present invention, the ophthalmic composition may further contain a buffer in addition to the above-mentioned components. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable. Examples of such a buffer include borate buffer, phosphate buffer, carbon dioxide buffer, citric acid buffer, acetate buffer, tris buffer, aspartic acid, aspartate, epsilon-aminocaproic acid and the like. Be done. As the buffering agent, a boric acid buffering agent, a phosphoric acid buffering agent, a carbonic acid buffering agent, and a citric acid buffering agent are preferable.

As a more specific example, as a borate buffer, but not limited to, boric acid or a salt thereof (sodium citrate, potassium tetraborate, potassium metaborate, ammonium borate, boar sand, etc.); as a phosphate buffer. , Phosphate or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); As a buffer, carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citrate buffer, citrate or a salt thereof (sodium citrate, Potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) as an acetate buffer; aspartic acid or a salt thereof (Sodium citrate, magnesium aspartate, potassium aspartate, magnesium aspartate / potassium mixture, etc.) can be exemplified. Further, a hydrate of each salt may be used as a raw material for producing the buffer.

These buffers may be synthesized and used by a known method, or commercially available products may be obtained and used. These buffers may be used alone or in any combination of two or more.

The content of the buffering agent in the ophthalmic composition of the present invention can be appropriately set according to the type of the buffering agent used, the type and amount of other compounding components, the use of the ophthalmic composition, and the like. As an example, the total content of the buffer to the total amount of the ophthalmic composition is not limited, but is preferably 0.01 w / v% or higher, more preferably 0.05 w / v% or higher, still more preferably 0.1 w / v /. It is v% or more, particularly preferably 0.3 w / v% or more. The total content of the buffering agent relative to the total amount of the ophthalmic composition is not limited, but is preferably 10 w / v% or less, more preferably 5 w / v% or less, still more preferably 3 w / v% or less, and particularly preferably 2 w / v /. It is v% or less. The total content of the buffering agent relative to the total amount of the ophthalmic composition is not limited, but is preferably 0.01 to 10 w / v%, more preferably 0.05 to 5 w / v%, still more preferably 0.1 to 3 w. / V%, particularly preferably 0.3 to 2 w / v%.

In the present invention, the ophthalmic composition may further contain an isotonic agent in addition to the above-mentioned components. The tonicity agent is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable.
Specific examples of the tonicity agent include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol and the like. Among these tonicity agents, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, and propylene glycol are preferably mentioned from the viewpoint of significantly exerting the effect of the present invention. These isotonic agents may be used alone or in combination of two or more.

The content of the tonicity agent in the ophthalmic composition of the present invention can be appropriately set according to the type of tonicity agent to be used, the type and amount of other compounding components, the use of the ophthalmic composition, and the like. As an example, the total content of the buffer to the total amount of the ophthalmic composition is not limited, but is preferably 0.01-10 w / v%, preferably 0.05-5 w / v%, more preferably 0.1. It is ~ 3w / v%.

In the ophthalmic composition of the present invention, various additives are appropriately selected according to a conventional method according to the use and formulation form as long as the effects of the present invention are not impaired, and one or more of them are used in combination. It may be contained in an appropriate amount. As such additives, for example, the active ingredient (pharmacological activity) described in the Encyclopedia of Pharmaceutical Additives 2016 (edited by the Japan Pharmaceutical Additives Association) or the 2012 edition of the Standards for Manufacturing and Marketing of General-Purpose Drugs (Regulatory Science Society). Examples thereof include various additives described in (ingredients, physiologically active ingredients, etc.) and the like. The following additives can be mentioned as typical components.
Carrier: An aqueous solvent such as water or hydrous ethanol.
Chelating agent: For example, ethylenediamine diacetic acid (EDDA), ethylenediamine triacetic acid, ethylenediaminetetraacetic acid (EDTA), N- (2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTPA) and the like.
Base: For example, octyldodecanol, titanium oxide, potassium bromide, plastibase, etc.

pH regulator: For example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine and the like.
Stabilizers: For example, sodium formaldehyde sulfoxylate (longalit), sodium hydrogen sulfite, sodium pyrosulfite, aluminum monostearate, glycerin monostearate, cyclodextrin, monoethanolamine and the like.
Preservatives, bactericides or antibacterial agents: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride, etc.), Gloquil (trade name manufactured by Rhodia) etc.

Sugars: For example, glucose, cyclodextrin, alpha-cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin and the like. These may be d-form, l-form or dl-form.

In addition, the ophthalmic composition according to the present embodiment containing an appropriate amount of various pharmacologically active ingredients and physiologically active ingredients in addition to the above ingredients, as long as the effects of the present invention are not impaired. You may. The ingredients are not particularly limited, and examples thereof include active ingredients in various pharmaceutical products described in the 2012 edition of the OTC drug manufacturing and marketing approval standard (supervised by the Japan Regulatory Science Society). For example, specific examples of the components used in ophthalmic drugs include the following components.
Eye muscle regulators: for example, cholinesterase inhibitors such as neostigmine methyl sulfate, tropicamide, atropine helenien sulfate and the like.
Vitamins: For example, flavin adenine dinucleotide (FAD), flavin adenine dinucleotide sodium, pyridoxin hydrochloride, cyanocobalamine, retinol acetate, retinol palmitate, pantenol, ascorbic acid, tocopherol acetate, d-α-tocopherol acetate, succinic acid Tocopherol, tocopherol nicotinate, tocopherol linolenate, etc.
Amino acids: For example, L-glutamic acid, potassium L-aspartate, magnesium / potassium L-aspartate, aminoethylsulfonic acid (taurine) and the like.
Anti-inflammatory agents: For example, glycyrrhizic acid, dipotassium glycyrrhizinate, glycyrrhetin, methyl salicylate, glycol salicylate, azulene sulfonic acid, sodium azulene sulfonate, allantin, tranexamic acid, velverin, lysoteam, lysoteam chloride, velverin sulfate, velverin Sulfate hydrate, epsilon-aminocaproic acid, indomethacin, planoprofen, ibuprofen, ibuprofen piconol, ketoprofen, diclofenac sodium, bromfenac sodium, fervinac, bendazac, piroxicam, bufexamac, butyl flufenamic acid, zinc sulfate hydrate etc.
Astringent: For example, zinc oxide, zinc lactate, zinc sulfate, etc. These may be hydrates.
Switch components: For example, sodium cromoglycate, pranoprofen, etc.

Others: For example, sulfamethoxazole, sodium sulfamethoxazole, sulfisoxazole, sodium sulfisomidin, purple root, horse chestnut, and their salts, creatinine, tyroxapole, sesame oil, castor oil, dibutylhydroxy. Toluene, phenylethyl alcohol, etc.

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

The water used in the ophthalmic composition of the present invention may be any pharmaceutically, pharmacologically or physiologically acceptable water. Examples of such water include distilled water, normal water, purified water, sterile purified water, water for injection, distilled water for injection, and the like. Their definitions are based on the 17th revised Japanese Pharmacopoeia.

The ophthalmic composition of the present invention is one or more selected from the group consisting of a desired amount of (A-1) component, (A-2) component, (A-3) component and (A-4) component, and It can optionally be prepared by adding and mixing (B) a TRPA agonist and, if necessary, other components to the desired concentration. For example, it can be prepared by dissolving or dispersing those components in purified water, adjusting the pH and osmotic pressure to a predetermined value, and sterilizing by filtration sterilization or the like.

The pH of the ophthalmic composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically or physiologically acceptable range. For example, the pH of the ophthalmic composition can be appropriately set according to the use, formulation form, usage method, etc. of the ophthalmic composition, and may be, for example, 4.0 to 9.5, and 4.0 to 9. It is preferably 0, more preferably 4.5 to 9.0, even more preferably 4.5 to 8.5, and even more preferably 5.0 to 8.5.

The ophthalmic composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary. The appropriate osmotic pressure ratio can be appropriately set depending on the use, formulation form, usage method, etc. of the ophthalmic composition, and can be, for example, 0.4 to 5.0, and 0.6 to 3.0. It is preferably 0.8 to 2.2, more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacy, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacy. Measure with reference to (freezing point depression method). The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared in a desiccator (silica gel) after drying sodium chloride (standard reagent of the Japanese Pharmacopoeia) at 500 to 650 ° C. for 40 to 50 minutes. Allow to cool, weigh accurately 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution).

The viscosity of the ophthalmic composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically or physiologically acceptable range. For example, the viscosity at 20 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34'x R24) is preferably 0.1 to 10000 mPa · s, 0.1. It is more preferably ~ 8000 mPa · s, further preferably 0.1 to 1000 mPa · s, even more preferably 0.1 to 100 mPa · s, and particularly 1 to 20 mPa · s. preferable.

The ophthalmic composition of the present invention can take various formulation forms depending on the intended purpose. Examples of such formulation forms include liquid preparations, gel preparations, semi-solid preparations (ointments, etc.) and the like.

The ophthalmic composition of the present invention is, for example, an eye drop (also referred to as an eye drop or an eye drop; the eye drop includes an eye drop that can be instilled while wearing contact lenses), an artificial tear solution, an eye wash (eye wash). Also referred to as liquid or eye drops. The eye drops include eye drops that can be washed while wearing contact lenses), composition for contact lenses [contact lens wearing solution, composition for contact lens care (contact lens disinfectant). , Contact lens preservatives, contact lens cleaning agents, contact lens cleaning preservatives), etc.].
The "contact lens" includes a hard contact lens and a soft contact lens (including both ionic and non-ionic, and both a silicone hydrogel contact lens and a non-silicone hydrogel contact lens).

The ophthalmic composition of the present invention is preferably an eye drop (including an eye drop that can be instilled while wearing contact lenses) because the effect of the present invention can be exerted more remarkably. When the ophthalmic composition according to the present embodiment is an eye drop, the dosage and administration thereof is not particularly limited as long as it is effective and has few side effects, but for example, adults (15 years old or older) and 7 years old. In the case of the above-mentioned children, 1 to 7 drops at a time are preferable, and 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops at a time are more preferable. In the case of 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops at a time, a method of instilling 5 to 6 times a day can be exemplified. In addition, 4 to 6 drops may be instilled 3 to 6 times a day.

The ophthalmic composition of the present invention is provided in an arbitrary container. The container for accommodating the ophthalmic composition according to the present embodiment is not particularly limited, and may be made of glass or plastic, for example. It is preferably made of plastic. Examples of the plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, a copolymer of polyimide and the monomers constituting these, and a mixture of two or more of these. Preferably, it is polyethylene terephthalate. Further, the container for accommodating the ophthalmic composition according to the present embodiment may be a transparent container in which the inside of the container can be visually recognized, or an opaque container in which the inside of the container is difficult to visually recognize. A transparent container is preferable. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container.

A nozzle may be attached to the container containing the ophthalmic composition of the present invention. The material of the nozzle is not particularly limited, and for example, it may be made of glass or plastic. It is preferably made of plastic. As for plastic, for example
Examples thereof include polybutylene terephthalates, polyethylene, polypropylene, polyethylene terephthalates, polyethylene naphthalates, copolymers of monomers constituting these, and mixtures of two or more of these.

The container containing the ophthalmic composition of the present invention may be a multi-dose type containing a plurality of uses, or a unit-dose type containing a single use.

[Stimulation inhibitor for ophthalmic compositions]
The present invention also provides an irritation inhibitor for ophthalmic compositions. As the formulation and form of the irritation inhibitor, the same composition as the above-mentioned ophthalmic composition can be used.
When the TRPA1 agonist is menthol, the irritation inhibitor of the present invention can suppress irritation of an ophthalmic composition while maintaining a refreshing sensation. Further, since the irritation inhibitor of the present invention can suppress the irritation of the ophthalmic composition derived from the TRPA1 agonist, the pain caused by dry eye can be suppressed. This is based on the fact that TRPA1 has also been reported to be involved in dry eye pain (see, eg, Neuroscience. 2015 Apr 2; 290: 204-13). Further, the pain may be derived from allergies as well as from dry eye. The term "dry eye" includes not only dry eye according to the dry eye diagnostic criteria but also dry eyes.

[Method of suppressing irritation of ophthalmic composition]
The present invention also provides a method of suppressing irritation of an ophthalmic composition. Specifically, in addition to (B) an ophthalmic composition containing a TRPA1 agonist, (A-1) a decongestant component, (A-2) an antihistamine, (A-3) camphor, menthone, isomenthol, cineole, It is characterized by containing at least one selected from the group consisting of mentoflan, pinen, limonene, neomenthol, and methyl acetate, and at least one selected from the group consisting of (A-4) chlorobutanol. , (B) A method of suppressing irritation of an ophthalmic composition derived from a TRPA1 agonist.

[Evaluation method of eye stimulation]
The present invention also provides a method for evaluating eye irritation. For example, a method for evaluating eye irritation by a test sample, which comprises contacting a test sample with TRPA1-expressing cells and measuring the amount of change in intracellular calcium ion concentration caused by the test sample via TRPA1. is there.
As a test sample used in the evaluation method of the present invention, for example, a combination of (B) TRPA1 agonist and a component usually used in the field of ophthalmic composition can be used. For example, such a component may be the above-mentioned (A-1) component, (A-2) component, (A-3) component, or (A-4) component, and is a surfactant. Sticky agents, buffers, tonicity agents, carriers, chelating agents, bases, pH regulators, stabilizers, preservatives, fungicides or antibacterial agents, sugars, sugar alcohols, eye muscle regulators, vitamins, It may be an amino acid, an antibacterial agent, an astringent agent or the like.
Moreover, (B) TRPA1 agonist may be used as a control (control sample) with a test sample.
The TRPA1-expressing cells are not particularly limited as long as they can stably carry the hTRPA1 gene, but for example, T-REx-293 cells, HEK293T cells and the like are preferable.
The change in intracellular calcium ion concentration in the above method is measured with a commercially available microplate reader, a fluorescence microscope, or the like using, for example, a known Ca ²⁺ concentration indicator, Fluo-4, Fluo-8, or Fluo-2. , Can be observed.
In the present invention, by measuring the amount of change in the intracellular calcium ion concentration, it is possible to obtain information such as the presence or absence of eye irritation and the intensity of eye irritation. In addition, the intracellular calcium ion concentration is observed over time by adjusting the time for contacting the test sample or the control sample with the TRPA1-expressing cells, and information on the affinity of the test sample for the TRPA1-expressing cells (for example, the test sample). Correlation with the LogP value (partition coefficient) and the like) can also be obtained.
As a method for bringing the test sample into contact with TRPA1-expressing cells, for example, the test sample or a diluted solution thereof, or artificial tears containing the test sample is added to cultured TRPA1-expressing cells or animals such as humans. , The method of instilling, etc.

Examples are shown below, and the present invention will be described in more detail, but the present invention is not limited to the examples.

<Cells used>
Preparation of T-REx-293 cell line carrying the hTRPA1 gene The mRNA of hTRPA1 was extracted from human WI38 cells. HEK cells that stably expressed hTRPA1 were generated using Invitrogen's tetracycline-controlled T-REx expression system. The cDNA of hTRPA1 amplified by RT-PCR using hTRPA1 mRNA as a template was incorporated into pcDNA4 / TO (manufactured by invitrogen), which is a gene expression vector for mammalian cells, and the Lipofectamin 2000 reagent, which is a gene transfer reagent of invitrogen, was used. It was introduced into T-REx-293 cells. Zeocin is integrated into pcDNA4 / TO, and T-REx-293 cells carry a plasmid (blastidin resistance gene) for maintaining the T-Rex system. A T-REx-293 cell line that stably carries the hTRPA1 gene was established using the antibiotics Zeocin 500 μg / mL and Blasticidin 10 μg / mL.

<Cell culture>
T-REx-293 cells carrying hTRPA1 were cultured in DMEM medium containing 10% FBS, 100 unit / mL penicillin, 100 mg / mL streptomysin, 250 ng / mL amphotericin B in the presence of 5% carbon dioxide. At the time of passage, 200 μg / mL Zeocin and 5 μg / mL blastsidedin were added, and the maximum number of passages was 50 or less.
Specifically, as a preculture, T-REx-293 cells were cultured in a 60 mm dish so as to be semi-confluent, and then washed with PBS (-). Cells were stripped from the dish by 1 × Trypsin / EDTA treatment and DMEM medium was added. It was then transferred to a 15 mL tube and centrifuged at 800 rpm for 4 minutes at room temperature. After removing only the DMEM medium by suction and loosening the cells by tapping, add a new DMEM medium and adjust the cell number to about 40 × 10 ⁴ to 50 × 10 ⁴ cell / mL to prepare a cell suspension. Created. At this time, 1 μg / mL tetracycline was added for receptor expression. The prepared cell suspension was dispensed into 96-well plates in 100 μL increments and incubated overnight in a 5% CO ₂ incubator at 37 ° C. for use in the test.

[Test Example 1] Confirmation test for suppression of irritation by l-menthol Menthol is known to activate the stimulus receptor TRPA1 to stimulate it. Therefore, l-menthol and a test sample (Example) were administered to the above-mentioned cells, and it was confirmed whether the test sample inhibited TRPA1 activity by l-menthol.
It was observed whether the TRP activity was changed by using a Ca ²⁺ concentration indicator (Fluo-4 or Fluo-8 (manufactured by AAT Bioquest, Inc.). T-REx-293 in which the Ca ²⁺ concentration indicator previously retained hTRPA1. It was taken up into cells, and the amount of fluorescence was measured with a microplate reader.
Specifically, it was carried out according to the following protocol. The 96-well plate prepared the day before (cell culture described above) was taken out from the incubator, and the DMEM medium was removed by decantation. 100 μL / well buffer (pH 7.4, 5.37 mM KCl, 0.44 mM KH ₂ PO ₄ , 137 mM NaCl, 0.34 mM Na ₂ HPO ₄ , 5.56 mM D-glucose, 20 mM HEPES, 1 mM CaCl ₂ , 0.1% bovine Gently wash with serum albumin, 2.5 mM probenecid., Residual purified water), add 50 μL of the same buffer dissolved in 1.5 μM Fluo-8 to the wells, and then in a 5% CO ₂ incubator at 37 ° C. for 1 hour. Processed. After incubator treatment, the same buffer containing Fluo-8 was decanted and gently washed with 100 μL / well of the same buffer. In addition, 180 μL / well of the same buffer was added and measurements were initiated with a Flexstation II (registered trademark) or Flexstation III (registered trademark) microplate reader (Molecular Devices, Sunnyvale, CA, USA). .. 20 μL / well of the test sample was added 30 seconds after the start of the microplate reader measurement, and the maximum value of the fluorescence amount from 5 seconds to 120 seconds after the addition was measured, and this value was taken as the fluorescence amount.

The TRP activity (%) was calculated based on the following formula.

Comparative Example 2 (when l-menthol alone is administered) is 100%.
The calculation results of the TRP activity of the test samples shown in Table 1 below are shown in FIG. In Comparative Example 1, the control (l-menthol-free buffer solution (pH 7.4, 5.37 mM KCl, 0.44 mM KH ₂ PO ₄ , 137 mM NaCl, 0.34 mM Na ₂ HPO ₄ , 5.56 mM D-glucose, 20 mM HEPES) was used. , 1 mM CaCl ₂ , 0.1% bovine serum albumin, 2.5 mM probenecid., Residual purified water)), and Comparative Example 2 added 66.7 μM of l-menthol (TRPA1 agonist) to the same buffer solution as in Comparative Example 1. It was dissolved at the concentration of. Then, in the example, l-menthol (66.7 μM) and the components shown in Table 1 were dissolved in the same buffer solution as in Comparative Example 1 at the concentrations shown in Table 2.

From the results of FIG. 1, the (A-1) decongestant component of the present invention, tetrahydrozoline hydrochloride, nafazoline hydrochloride, (A-2) antihistamine, chlorpheniramine maleate, diphenhydramine hydrochloride, (A). -3) Ingredients d-camphor, dl-camphor, (-)-menthol, (+)-isomenthol, 1,8-cineole, mentoflan, α-pinene, β-pinene, (R)-(+) ) -Limonene, (S)-(-)-Limonene, neomenthol, methyl acetate, and an ophthalmic composition containing chlorobutanol, which is a component of (A-4), were able to suppress the irritation caused by the TRPA1 agonist. In addition, the ophthalmic composition containing peppermint oil and eucalyptus oil, which are essential oils containing the component (A-3), was also able to suppress the irritation caused by the TRPA1 agonist.

[Test Example 2] l-visualization of TRPA1 activation of menthol, based on the same principle as time-series observation and binding capacity evaluation in Test Example 1, the Ca ²⁺ concentration indicator Fluo-8 fluorescence amount is increased in accordance with the Ca ²⁺ concentration The degree of activation of TRP was measured using. A Ca ²⁺ concentration indicator was previously incorporated into T-REx-293 cells carrying the hTRPA1 gene, and the amount of fluorescence was visualized with a fluorescence microscope system (Leica, LAS AF6000).

20 μL of T-REx-293 cell DMEM suspension carrying about 60 × 10 ⁴ cell / mL hTRPA1 gene on a cover glass was added dropwise per slide glass and placed overnight in a 5% CO ₂ incubator at 37 ° C. Incubated. The incubated cover glass was removed from the incubator and the medium was decanted. Buffer glass buffer (pH 7.4, 5.37 mM KCl, 0.44 mM KH ₂ PO ₄ , 137 mM NaCl, 0.34 mM Na ₂ HPO ₄ , 5.56 mM D-glucose, 20 mM HEPES, 1 mM CaCl ₂ , residual purified water) After gentle washing with, the fluorescent indicator Fluo-8 / buffer was added and treated in a 5% CO ₂ incubator at 37 ° C. for 1 hour. After the incubator treatment, the cover glass was placed on the chamber, and the amount of fluorescence was visualized and observed over time with a fluorescence microscope system (Leica, LAS AF6000).

The flow of this test is as follows.
(1) After confirming that the amount of light emitted from the fluorescent reagent is stable in the buffer solution, the buffer solution is replaced with a buffer solution containing l-menthol (66.7 μM) to activate TRPA1.
(2) After the activation of TRPA1 was confirmed, a buffer solution containing l-menthol (66.7 μM) was added, and the same concentration of l-menthol and each test sample (tetrahydrozoline hydrochloride 0.003125 w / v%) were added. Instead of the combination with peppermint oil 0.015 w / v%), it is confirmed whether TRPA1 activity is inhibited.
(3) After confirming the inhibitory effect on TRPA1 activity, the buffer solution containing l-menthol and each test sample was returned to the buffer solution containing l-menthol used in (1), and TRPA1 was activated again. Check if it is done.

The result of visualizing TRPA1 activation by l-menthol with a fluorescence microscope is shown in FIG. The sample using borneol as a test sample showed TRPA1 activity inhibitory effect, and then returned to l-menthol to show TRPA1 activity again (see the reference example in FIG. 2). On the other hand, those using tetrahydrozoline hydrochloride, which is a decongestant component (A-1), and peppermint oil, which is an essential oil containing the component (A-3), as test samples showed a TRPA1 activity inhibitory effect, and then the test solution was used. Returning to menthol-only ones showed no inhibitory effect or weak reactivation (see Examples in FIG. 2).
That is, it is considered that the components (A-1) and (A-3) of the present invention were able to sustain the inhibitory effect on the TRPA1 receptor for a while.

[Test Example 3] Confirmation test of suppression of irritation by tetrahydrozoline hydrochloride in humans Artificial tears ("Rohto Soft One Eye Drops" manufactured by Rohto Pharmaceutical Co., Ltd. Potassium chloride 0.1 w / v%, sodium chloride 0.4 w / v%, L-menthol (0.01 w / v%) and polyoxyethylene hydrogenated castor oil (0.1 w / v%) dissolved in boric acid (containing pH adjuster) (comparative example), artificial tears as above L-menthol (0.01 w / v%), polyoxyethylene hydrogenated castor oil (0.1 w / v%) and tetrahydrozoline hydrochloride (0.05 w / v%) dissolved in 1 (Example) are the same. FIG. 3 shows the results of evaluating the refreshing sensation and the stimulating sensation by instilling the left and right eyes of the subject. The subjects were eight adult males with naked eyes or wearing spectacles, and the evaluation was quantified using the VAS scale (maximum scale: 20).

As a result, it was shown that by combining menthol with tetrahydrozoline hydrochloride, which is a decongestant component (A-1), the irritation sensation of l-menthol can be suppressed while maintaining the refreshing sensation of l-menthol. That is, it was confirmed in humans that the (A-1) decongestant component of the present invention can suppress the irritation caused by the TRPA1 agonist.

[Formulation example]
The formulation examples shown in Tables 4 and 5 below were prepared. Purified water was added so that the total volume of each solution was 100 mL.

The present invention relates to an ophthalmic composition in which the sensation of irritation is suppressed, an ophthalmic composition inhibitor, a method for suppressing irritation of the ophthalmic composition, and a method for evaluating eye irritation. The agent of the present invention is useful in the field of pharmaceuticals.

Claims (7)

(A) An ophthalmic composition in which a feeling of irritation is suppressed, which comprises a hyperemic removing component. An ophthalmic composition in which a feeling of irritation is suppressed, which comprises (A) a decongestant component and (B) a TRPA1 agonist. (B) The ophthalmic composition according to claim 2, wherein the TRPA1 agonist is l-menthol. (A) The ophthalmic composition according to any one of claims 1 to 3, wherein the decongestant component is at least one selected from the group consisting of tetrahydrozoline, naphazoline, and pharmaceutically acceptable salts thereof. .. The ophthalmic composition according to any one of claims 1 to 4, wherein the irritation is pain derived from dry eye. (A) An irritation inhibitor for an ophthalmic composition, which comprises a hyperemic removing component. The irritation inhibitor for an ophthalmic composition according to claim 6, which is an agent for suppressing pain caused by dry eye.