Ophthalmic composition having inhibited irritating sensation

Abstract

To provide an ophthalmic composition with an inhibited sense of irritation, an irritation-inhibiting agent for an ophthalmic composition, a method for inhibiting irritation from an ophthalmic composition, and a method for assessing ophthalmic irritation.SOLUTION: The problem is solved by an ophthalmic composition with an inhibited sense of irritation, containing: one selected from the group consisting of following components (A-1), (A-2), (A-3), and (A-4); and optionally, (B) a TRPA1 agonist. (A-1) a hyperemia removal component, (A-2) an antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineol, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) a local anesthetic component.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition with reduced irritation, an irritation suppressant for an ophthalmic composition, a method for suppressing irritation of an ophthalmic composition, and a method for evaluating eye irritation. [Background technology]

[0002] TRP (Transient Receptor Potential) channels are cation channels with a transmembrane domain, and are thought to function as tetramers. TRP channels are a family of cation channels that function in various aspects of sensory reception, and there are many TRP channel molecules that respond to various stimuli (Non-Patent Document 1). TRPM8 is a cell sensor involved in the feeling of coolness, TRPA1 in pain, and TRPV1 in burning sensation. It has also been reported that TRPA1 and TRPV1 are involved in discomfort and pain in the eye (Non-Patent Document 2).

[0003] l-Menthol is a TRPM8 agonist and is used as a cooling agent in eye drops and other products. However, it is also a TRPA1 agonist and is known to give the eyes a tingling sensation as well as a cooling sensation. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Biochemistry, Vol. 81, No. 11, pp. 962-983, 2009 [Non-Patent Document 2] Curr. Ophthalmol. Rep. (2015), 3: 111-121 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide an ophthalmic composition with reduced irritation, an irritation suppressant for an ophthalmic composition, a method for suppressing irritation of an ophthalmic composition, and a method for evaluating eye irritation. [Means for solving the problem]

[0006] As a result of extensive research, the present inventors have discovered that an ophthalmic composition containing a specific component can suppress the irritation to the eyes caused by TRPA1 agonists such as l-menthol, in particular, can suppress the irritation while maintaining the refreshing sensation of l-menthol and the like, and further, can solve the above-mentioned problems.

[0007] That is, the present invention includes the following inventions. [1] An ophthalmic composition with reduced irritation, comprising at least one component selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4): (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient. [2] An ophthalmic composition with reduced irritation, comprising at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4), and (B) a TRPA1 agonist: (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient. [3] (B) The ophthalmic composition described in [2] above, wherein the TRPA1 agonist is l-menthol. [4] The ophthalmic composition according to any one of [1] to [3] above, wherein the congestion relief component (A-1) is at least one selected from the group consisting of tetrahydrozoline, naphazoline, and pharma- ceutically acceptable salts thereof. [5] The ophthalmic composition according to any one of [1] to [3] above, wherein the (A-2) antihistamine component is at least one selected from the group consisting of chlorpheniramine, diphenhydramine, and pharma- ceutically acceptable salts thereof. [6] The ophthalmic composition according to any one of the above [1] to [3], wherein the local anesthetic component (A-4) is chlorobutanol. [7] The ophthalmic composition according to any one of [1] to [6], wherein the irritation is pain caused by dry eye, allergies, or the like. [8] An irritation suppressant for an ophthalmic composition, comprising at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4): (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient. [9] (B) An agent for suppressing irritation in an ophthalmic composition containing l-menthol, The composition contains at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4): (B) Irritation suppressant for an ophthalmic composition containing l-menthol: (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient.

[10] An agent for suppressing pain caused by dry eye, allergies, etc., comprising at least one component selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4): (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient.

[11] An ophthalmic composition for suppressing pain caused by dry eye, allergies, etc., comprising at least one component selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4): (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient.

[12] A method for suppressing irritation caused by an ophthalmic composition containing a (B) TRPA1 agonist, comprising further comprising at least one component selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4): (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient.

[13] A method for evaluating eye irritation caused by a test sample, comprising contacting the test sample with a TRPA1-expressing cell and measuring the change in intracellular calcium ion concentration caused by the test sample via TRPA1.

[14] Use of at least one component selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4) for the manufacture of an ophthalmic composition in which the irritation caused by a TRPA1 agonist (B) is suppressed: (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient.

[15] An agent for suppressing irritation while maintaining the refreshing sensation of a (B) TRPA1 agonist, for use in an ophthalmic composition containing a (B) TRPA1 agonist, comprising: Contains at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4); and As a result, the refreshing sensation of the (B) TRPA1 agonist is maintained at the same level as that of the ophthalmic composition not containing the component (A), while the irritating sensation is suppressed more than that of the ophthalmic composition not containing the component (A). (B) Irritation suppressant for an ophthalmic composition containing a TRPA1 agonist: (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient.

[16] A method for suppressing a sense of irritation while maintaining a sense of coolness caused by a (B) TRPA1 agonist, for use in an ophthalmic composition containing a (B) TRPA1 agonist, comprising: By including at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4), The ophthalmic composition is characterized in that the cooling sensation of the (B) TRPA1 agonist in the ophthalmic composition is maintained at the same level as that of the ophthalmic composition not containing the (A) component, while the irritation is suppressed more than that of the ophthalmic composition not containing the (A) component. (B) Method for suppressing irritation of an ophthalmic composition containing a TRPA1 agonist: (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient.

[17] At least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4): (B) Use for the manufacture of an ophthalmic composition containing a TRPA1 agonist, The ophthalmic composition maintains the cooling sensation of the TRPA1 agonist (B) equivalent to that of an ophthalmic composition not containing the component (A), while suppressing the irritating sensation of the TRPA1 agonist (B) more than that of an ophthalmic composition not containing the component (A). Use: (A-1) Decongestant component, (A-2) antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient. Effect of the Invention

[0008] The ophthalmic composition of the present invention 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), and may or may not further contain (B) a TRPA1 agonist, and has the effect of suppressing the sensation of irritation: (A-1) a congestion relief component, (A-2) an antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) a local anesthetic component. Preferably, the irritating sensation is derived from the (B) TRPA1 agonist contained in the ophthalmic composition. However, including cases in which the ophthalmic composition does not contain the (B) TRPA1 agonist, it is preferable that the irritating sensation is derived from a pain symptom caused by dry eye, allergy, etc. in an animal such as a human to which the ophthalmic composition is administered, or from activation of the irritant receptor TRPA1 in the animal. In particular, when the (B) TRPA1 agonist contained in the ophthalmic composition is menthol, it is possible to suppress the sense of irritation while maintaining a refreshing sensation. The present invention also provides a method for suppressing irritation caused by an ophthalmic composition and a method for evaluating eye irritation caused by a test sample. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows the results of a test to confirm the inhibition of irritation caused by a TRPA1 agonist (l-menthol) by the components constituting the ophthalmic composition of the present invention. [Diagram 2] FIG. 2 visualizes the TRPA1 inhibitory effect, and shows the results for borneol (Reference Example), tetrahydrozoline hydrochloride, and peppermint oil (Example). [Diagram 3] FIG. 3 shows the results of a test to confirm the cooling sensation and irritation sensation in humans by using l-menthol (Comparative Example) and a combination of l-menthol and tetrahydrozoline hydrochloride (Example). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The ophthalmic composition of the present invention contains at least one selected from the group consisting of the following (A-1) component, (A-2) component, (A-3) component, and (A-4) component: (A-1) a congestion relief component, (A-2) an antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) a local anesthetic component. Preferably, the ophthalmic composition contains at least one selected from the group consisting of (A-1), (A-2), (A-3), and (A-4) component as an active ingredient. In this specification, unless otherwise specified, the unit of content "%" means "w / v%" and is synonymous with "g / 100 mL".

[0011] [(A-1) Decongestant component] As the congestion relief component, it is preferable to use at least one selected from the group consisting of imidazoline congestion relief components such as tetrahydrozoline, naphazoline, oxymetazoline, or their hydrochlorides or nitrates, epinephrine, ephedrine, methylephedrine, phenylephrine, and pharma- ceutically acceptable salts thereof, but this is not limited thereto. Of these congestion relief components, preferred are, for example, imidazoline congestion relief components, more preferred are tetrahydrozoline, naphazoline and pharma- ceutical acceptable salts thereof, even more preferred are tetrahydrozoline and pharma- ceutical acceptable salts thereof, and particularly preferred is tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride).

[0012] When the ophthalmic composition of the present invention contains the component (A-1), the content of the component (A-1) is not particularly limited, and is appropriately set according to the type of the component (A-1), the type and content of other blended components, the use and formulation form of the ophthalmic composition, etc. With respect to the content of (A-1), from the viewpoint of more significantly achieving the effects of the present invention, the lower limit of the total content of the component (A-1) is, for example, 0.0001 w / v% or more, 0.0003 w / v% or more, or 0.0005 w / v% or more, relative to the total amount of the ophthalmic composition. Also, 0.01 w / v% or more is more preferable. Furthermore, when the ophthalmic composition of the present invention contains the component (A-1), the content of the component (A-1) is, for example, preferably 0.5 w / v% or less, 0.3 w / v% or less, 0.1 w / v% or less, or 0.05 w / v% or less, relative to the total amount of the ophthalmic composition, from the viewpoint of more significantly achieving the effects of the present invention. Moreover, the above lower and upper limits may be combined in any manner.

[0013] When the ophthalmic composition of the present invention contains the (A-1) component, the content ratio of the (A-1) component to the (B) component is not particularly limited, and is appropriately set according to the type of the (A-1) component, the type and content of other blended components, the use and formulation form of the ophthalmic composition, etc. As for the content ratio of the (A-1) component to the (B) component, from the viewpoint of more significantly exhibiting the effects of the present invention, for example, the total content of the (A-1) component contained in the ophthalmic composition of the present invention is, for example, usually 0.001 parts by weight or more, preferably 0.01 parts by weight or more, more preferably 0.1 parts by weight or more, even more preferably 0.2 parts by weight or more, and particularly preferably 0.5 parts by weight or more, per 1 part by weight of the total content of the (B) component. In addition, the total content of the (A-1) component is, for example, usually 1000 parts by weight or less, preferably 800 parts by weight or less, more preferably 50 parts by weight or less, and even more preferably 10 parts by weight or less, per 1 part by weight of the total content of the (B) component. Moreover, the above lower and upper limits may be combined in any manner.

[0014] [(A-2) Antihistamine component] As the antihistamine component, it is preferable to use at least one selected from the group consisting of, for example, chlorpheniramine, diphenhydramine, ketotifen, iproheptine, levocabastine, olopatadine, and pharma- ceutical acceptable salts thereof, but the present invention is not limited to these. Of these antihistamine components, preferred are ketotifen fumarate, iproheptine, diphenhydramine hydrochloride, chlorpheniramine maleate (chlorpheniramine maleate), levocabastine hydrochloride, olopatadine hydrochloride, etc., more preferred are ketotifen fumarate, diphenhydramine hydrochloride, chlorpheniramine maleate, levocabastine hydrochloride, olopatadine hydrochloride, etc., even more preferred are diphenhydramine hydrochloride and chlorpheniramine maleate, and even more preferred is chlorpheniramine maleate.

[0015] When the ophthalmic composition of the present invention contains the (A-2) component, the content of the (A-2) component is not particularly limited, and is appropriately set according to the type of the (A-2) component, the type and content of other blended components, the use and formulation form of the ophthalmic composition, etc. Regarding the content of (A-2), from the viewpoint of more significantly achieving the effects of the present invention, the lower limit of the total content of the (A-2) component is, for example, 0.001 w / v% or more, 0.003 w / v% or more, 0.005 w / v% or more, or 0.01 w / v% or more, relative to the total amount of the ophthalmic composition, is preferably. Furthermore, when the ophthalmic composition of the present invention contains the (A-2) component, the content of the (A-2) component is, for example, 0.5 w / v% or less, 0.3 w / v% or less, 0.05 w / v% or less, or 0.03 w / v% or less, relative to the total amount of the ophthalmic composition, is preferably, from the viewpoint of more significantly achieving the effects of the present invention. Moreover, the above lower and upper limits may be combined in any manner.

[0016] When the ophthalmic composition of the present invention contains the (A-2) component, the content ratio of the (A-2) component to the (B) component is not particularly limited and is appropriately set depending on the type of the (A-2) component, the type and content of other blended components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, for example, the content ratio of the (A-2) component to the (B) component is, for example, preferably a lower limit of 0.002 parts by weight or more, more preferably 0.004 parts by weight or more, even more preferably 0.01 parts by weight or more, even more preferably 0.05 parts by weight or more, and particularly preferably 0.1 parts by weight or more, per part by weight of the total content of the (B) component. Furthermore, the proportion of the (A-2) component, relative to 1 part by weight of the (B) component, is, for example, preferably at most 50,000 parts by weight, more preferably at most 5,000 parts by weight, even more preferably at most 1,000 parts by weight, even more preferably at most 800 parts by weight, even more preferably at most 500 parts by weight, even more preferably at most 100 parts by weight, and particularly preferably at most 10 parts by weight. Moreover, the above lower and upper limits may be combined in any manner.

[0017] [Component (A-3)] The ophthalmic composition of the present invention contains, as component (A-3), at least one selected from the group consisting of camphor, menthone, isomenthol, cineol, menthofuran, pinene, limonene, neomenthol, and methyl acetate, which may be in the d-, l-, or dl-form.

[0018] Furthermore, the component (A-3) of the present invention can be used as an essential oil containing the component (A-3). Examples of the essential oil containing the component (A-3) include one or more of peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, cinnamon oil, and rose oil, among which peppermint oil or cool mint oil is particularly preferred.

[0019] When the ophthalmic composition of the present invention contains component (A-3), the proportion of component (A-3) as the total amount of component (A-3) relative to the total amount of the ophthalmic composition may be, for example, a lower limit of 0.00001 w / v% or more, 0.00005 w / v% or more, 0.0001 w / v% or more, 0.0003 w / v% or more, 0.0005 w / v% or more, 0.0007 w / v% or more, 0.0008 w / v% or more, 0.0009 w / v% or more, or 0.001 w / v% or more. Furthermore, when the ophthalmic composition of the present invention contains component (A-3), the proportion of component (A-3) relative to the total amount of the ophthalmic composition may be, for example, an upper limit of 5 w / v% or less, 3 w / v% or less, 2 w / v% or less, 1.5 w / v% or less, 1.2 w / v% or less, 1 w / v% or less, 0.9 w / v% or less, 0.8 w / v% or less, 0.7 w / v% or less, 0.6 w / v% or less, 0.5 w / v% or less, 0.3 w / v% or less, or 0.1 w / v% or less. Moreover, the above lower and upper limits may be combined in any manner. In particular, the proportion of the (A-3) component may be, for example, a total of 0.00001 w / v% to 2 w / v% (for example, a total of 0.00005 to 1 w / v%), preferably a total of 0.0001 to 0.1 w / v% (for example, a total of 0.0003 to 0.05 w / v%), and more preferably a total of 0.0005 to 0.02 w / v% (for example, a total of 0.001 to 0.01 w / v%), relative to the total amount of the ophthalmic composition. Furthermore, the proportion of the (A-3) component may be, for example, a lower limit of 0.00000005% or more, 0.0000005% or more, or 0.000001% or more, relative to the total amount of the ophthalmic composition. The origin of the component (A-3) is not particularly limited, and includes origin from essential oils.

[0020] When the ophthalmic composition of the present invention contains the (A-3) component, the content ratio of the (A-3) component to the (B) component is not particularly limited and is appropriately set depending on the type of the (A-3) component, the types and contents of other blended components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content ratio of the (A-3) component to the (B) component may be, for example, a lower limit of 0.000001 parts by weight or more, 0.00001 parts by weight or more, 0.0001 parts by weight or more, 0.001 parts by weight or more, 0.005 parts by weight or more, 0.01 parts by weight or more, 0.1, 1 parts by weight or more per part by weight of the total content of the (B) component. Furthermore, the upper limit of the proportion of the (A-3) component relative to 1 part by weight of the (B) component may be, for example, below 500,000 parts by weight, not more than 300,000 parts by weight, not more than 15,000 parts by weight, not more than 800 parts by weight, not more than 500 parts by weight, not more than 100 parts by weight, or not more than 10 parts by weight. Moreover, the above lower and upper limits may be combined in any manner.

[0021] [Component (A-4)] As the local anesthetic component, chlorobutanol is preferred. In addition, in the present invention, other local anesthetic components known in the art, such as procaine hydrochloride or lidocaine hydrochloride, may be used in place of chlorobutanol, or chlorobutanol may be used in combination with other known local anesthetic components.

[0022] In particular, when the ophthalmic composition of the present invention contains the component (A-4), the proportion of the component (A-4) is, for example, preferably 0.001 to 2.5 w / v%, more preferably 0.01 to 1 w / v%, even more preferably 0.05 to 0.5 w / v%, and particularly preferably 0.1 to 0.25%, relative to the total amount of the ophthalmic composition.

[0023] When the ophthalmic composition of the present invention contains the (A-4) component, the content ratio of the (A-4) component to the (B) component is not particularly limited, and is appropriately set according to the type of the (A-4) component, the type and content of other blended components, the use and formulation form of the ophthalmic composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content ratio of the (A-4) component to the (B) component may be, for example, a lower limit of 0.01 parts by weight or more, 0.1 parts by weight or more, or 1 part by weight or more per 1 part by weight of the total content of the (B) component. In addition, the ratio of the (A-3) component may be, for example, an upper limit of 5000 parts by weight or less, 3500 parts by weight or less, 1000 parts by weight or less, 500 parts by weight or less, 100 parts by weight or less, 50 parts by weight or less, or 10 parts by weight or less per 1 part by weight of the (B) component. Moreover, the above lower and upper limits may be combined in any manner.

[0024] [Component (A)] In this specification, the components (A-1), (A-2), (A-3), and (A-4) are sometimes collectively referred to as the component (A). The component (A) is preferably used in combination with a plurality of components, more preferably in combination with two or more groups selected from the group consisting of (A-1) to (A-4), and even more preferably in combination with three or more groups.

[0025] [Component (B): TRPA1 agonist] The ophthalmic composition of the present invention preferably contains a TRPA1 agonist. The TRPA1 agonist causes irritation to the eye. The TRPA1 agonist is preferably menthol. Menthol is not particularly limited as long as it is medicamentarily, pharmacologically or physiologically acceptable, and may be in any of the d-, l- or dl-forms, with l-menthol being preferred.

[0026] Furthermore, as the menthol, an essential oil containing menthol may be used.

[0027] The content of menthol in the ophthalmic composition of the present invention is preferably 0.00001 to 0.5 w / v%, more preferably 0.0001 to 0.25 w / v%, further preferably 0.0005 to 0.1 w / v%, and further preferably 0.001 to 0.08 w / v% based on the total amount of the ophthalmic composition. When an essential oil containing menthol is used, the total amount of menthol, including the amount of menthol contained in the essential oil, is set to satisfy the above ratio.

[0028] The ophthalmic composition of the present invention can suppress irritation by containing at least one selected from the group consisting of (A-1), (A-2), (A-3), and (A-4) components. Furthermore, when the ophthalmic composition of the present invention contains (B) a TRPA1 agonist, it is particularly preferable because it can suppress irritation caused by the TRPA1 agonist contained in the ophthalmic composition. It is also preferable that an animal such as a human to which the ophthalmic composition is administered shows a pain symptom due to dry eye or allergy, or that the irritant receptor TRPA1 of the animal is activated.

[0029] 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 medicamentarily, pharmacologically or physiologically acceptable. Specific examples of the nonionic surfactant include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene-polyoxypropylene block copolymer adduct, polyoxyethylene-polyoxypropylene alkyl ether, and polyoxyethylene alkyl phenyl ether.

[0030] More specific examples of nonionic surfactants include polyoxyethylene (hereinafter also referred to as POE)-polyoxypropylene (hereinafter also referred to as POP) glycols (e.g., poloxamers such as poloxamer 407, poloxamer 235, and poloxamer 188); POE-POP block copolymer adducts of ethylenediamine such as poloxamine; POE sorbitan fatty acid esters such as POE(20) sorbitan monolaurate (polysorbate 20), POE(20) sorbitan monooleate (polysorbate 80), POE sorbitan monostearate (polysorbate 60), and POE sorbitan tristearate (polysorbate 65); POE(5) hardeners such as POE(20) sorbitan monolaurate (polysorbate 20), POE(20) sorbitan monooleate (polysorbate 80), POE sorbitan monostearate (polysorbate 60), and POE sorbitan tristearate (polysorbate 65); POE hydrogenated castor oil, POE(10) hydrogenated castor oil, POE(20) hydrogenated castor oil, POE(40) hydrogenated castor oil, POE(50) hydrogenated castor oil, POE(60) hydrogenated castor oil, POE(100) hydrogenated castor oil, etc.; POE castor oil, such as POE(3) castor oil, POE(10) castor oil, POE(35) castor oil, 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) nonylphenyl ether; monostearate polyethylene glycols, such as polyoxyl 40 stearate. The numbers in parentheses indicate the average number of moles of POP or POE added.

[0031] Among these nonionic surfactants, from the viewpoint of significantly exhibiting the effects of the present invention, POE-POP glycol, POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE castor oil, and polyethylene glycol monostearate are preferred, and poloxamer 407, POE (20) sorbitan monooleate (polysorbate 80), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), POE (40) hydrogenated 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), and polyoxyl 40 stearate are more preferred, and POE (20) sorbitan monooleate and POE (60) hydrogenated castor oil are particularly preferred.

[0032] These nonionic surfactants may be synthesized by a known method or may be commercially available. The nonionic surfactants may be used alone or in any combination of two or more. The content of the nonionic surfactant can be appropriately set depending on the type of nonionic surfactant, the types and amounts of other components, the application of the ophthalmic composition, and the like.

[0033] The ophthalmic composition of the present invention may also contain a surfactant other than the nonionic surfactant. Such a surfactant is not particularly limited as long as it is medicamentarily, pharmacologically or physiologically acceptable, and specific examples thereof include anionic surfactants such as polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, alkyl sulfates, and N-acyltaurine salts, and amphoteric surfactants such as lauryl dimethylaminoacetate betaine.

[0034] As an example, the total content of the surfactant relative 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% or more, even 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. Also, the upper limit is not limited, but is preferably 10 w / v% or less, more preferably 5 w / v% or less, even more preferably 1 w / v% or less, and particularly preferably 0.5 w / v% or less. Also, the above-mentioned lower limit and upper limit may be arbitrarily combined.

[0035] 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 cellulose-based 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, glycosaminoglycans such as chondroitin sulfate and its salts, and hyaluronic acid and its salts, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K17, K25, K30, K90, etc.), vinyl polymers such as carboxyvinyl polymers and its salts, dextran, macrogol (polyethylene glycol) such as macrogol 6000, macrogol 4000, and macrogol 400, gellan gum, and alginic acid and its salts.Here, the salt is not particularly limited, but sodium salt is preferable. From the viewpoint of exhibiting the effect of the present invention significantly, glycosaminoglycan, cellulose polymer, or vinyl polymer is preferred, glycosaminoglycan is more preferred, chondroitin sulfate, hyaluronic acid and their salts are more preferred, and sodium chondroitin sulfate (sodium chondroitin sulfate ester) and sodium hyaluronate are even more preferred. These thickeners may be synthesized by known methods and used, or may be obtained and used as commercially available products. These thickeners may be used alone or in combination of two or more.

[0036] The total content of the thickener can be appropriately set according to the type of thickener used, the type and amount of other blended components, the purpose of the ophthalmic composition, etc. The total content of the thickener relative 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, even more preferably 0.001 w / v% or more, even 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. In addition, the total content of the thickener relative to the total amount of the ophthalmic composition is not limited, but is preferably 5 w / v% or less, more preferably 3 w / v% or less, even more preferably 1 w / v% 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 relative to the total amount of the ophthalmic composition is not limited, but is preferably 0.0001 to 5 w / v%, more preferably 0.0005 to 3 w / v%, even more preferably 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%, and most preferably 0.05 to 0.3 w / v%.

[0037] In the present invention, the ophthalmic composition may further contain a buffering agent in addition to the above-mentioned components. The buffering agent is not particularly limited as long as it is medicamentarily, pharmacologically, or physiologically acceptable. Examples of such buffering agents include borate buffering agents, phosphate buffering agents, carbonate buffering agents, citrate buffering agents, acetate buffering agents, Tris buffering agents, aspartic acid, aspartic acid salts, and epsilon-aminocaproic acid. As the buffering agent, borate buffering agents, phosphate buffering agents, carbonate buffering agents, and citrate buffering agents are preferred.

[0038] More specific examples include, but are not limited to, borate buffers such as boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffers such as phosphoric acid or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); carbonate buffers such as carbonic acid or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citrate buffers such as citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); acetate buffers such as acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); and aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, a mixture of magnesium and potassium aspartate, etc.). Hydrates of each salt may also be used as raw materials for producing the buffer.

[0039] These buffering agents may be synthesized by a known method or may be commercially available. These buffering agents may be used alone or in any combination of two or more.

[0040] The content of the buffering agent in the ophthalmic composition of the present invention can be appropriately set depending on the type of buffering agent used, the type and amount of other blended components, the use of the ophthalmic composition, etc. As an example, the total content of the buffering agent relative to the total amount of the ophthalmic composition is not limited, but is preferably 0.01 w / v% or more, more preferably 0.05 w / v% or more, even more preferably 0.1 w / v% or more, and 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, even more preferably 3 w / v% or less, and particularly preferably 2 w / 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%, even more preferably 0.1 to 3 w / v%, and particularly preferably 0.3 to 2 w / v%.

[0041] In the present invention, the ophthalmic composition may further contain an isotonicity agent in addition to the above-mentioned components. The isotonicity agent is not particularly limited as long as it is medicamentarily, pharmacologically, or physiologically acceptable. Specific examples of the isotonicity agent include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium thiosulfate, magnesium sulfate, glycerin, and propylene glycol. Among these isotonicity agents, from the viewpoint of significantly achieving the effects of the present invention, preferred are sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, and propylene glycol. These isotonicity agents may be used alone or in any combination of two or more.

[0042] The content of the isotonicity agent in the ophthalmic composition of the present invention can be appropriately set depending on the type of isotonicity agent used, the types and amounts of other blended components, the use of the ophthalmic composition, etc. As an example, 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%, preferably 0.05 to 5 w / v%, and more preferably 0.1 to 3 w / v%.

[0043] The ophthalmic composition of the present invention may contain various additives in appropriate amounts, selected according to the intended use and formulation, in the usual manner, and one or more additives may be used in combination, as long as the effects of the present invention are not impaired. Examples of such additives include the various additives listed in the 2016 Dictionary of Pharmaceutical Additives (edited by the Japan Pharmaceutical Additives Association) or the 2012 edition of the Approval Standards for Manufacturing and Marketing General Medicines (General Incorporated Association, Society of Regulatory Science). Representative additives include the following. Carrier: For example, an aqueous solvent such as water or aqueous ethanol. Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc. Bases: For example, octyldodecanol, titanium oxide, potassium bromide, plastibase, etc.

[0044] pH adjusters: for example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine, etc. Stabilizers: for example, sodium formaldehyde sulfoxylate (Rongalit), sodium hydrogen sulfite, sodium pyrosulfite, aluminum monostearate, glycerin monostearate, cyclodextrin, monoethanolamine, etc. Preservatives, disinfectants, or antibacterial agents: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride, etc.), Gloquil (trade name, manufactured by Rhodia), etc.

[0045] Sugars: for example, glucose, cyclodextrin, alpha-cyclodextrin, etc. Sugar alcohols: for example, xylitol, sorbitol, mannitol, glycerin, etc. These may be in the d-, l- or dl-form.

[0046] In addition, the ophthalmic composition with reduced irritation according to the present embodiment may contain various pharmacologically active ingredients and physiologically active ingredients in combination in appropriate amounts in addition to the above ingredients, as long as the effects of the present invention are not hindered. The ingredients are not particularly limited, and examples thereof include active ingredients in various medicines listed in the 2012 edition of the General Drug Manufacturing and Sales Approval Standards (supervised by the Japan Society of Regulatory Science). For example, specific examples of ingredients used in ophthalmic drugs include the following ingredients. Ocular muscle regulating drugs: For example, cholinesterase inhibitors such as neostigmine methylsulfate, tropicamide, atropine helenien sulfate, etc. Vitamins: For example, flavin adenine dinucleotide (FAD), flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, retinol acetate, retinol palmitate, panthenol, ascorbic acid, tocopherol acetate, d-α-tocopherol acetate, tocopherol succinate, tocopherol nicotinate, tocopherol linoleate, etc. Amino acids: For example, L-glutamic acid, potassium L-aspartate, magnesium and potassium L-aspartate, aminoethylsulfonic acid (taurine), etc. Anti-inflammatory agents: for example, glycyrrhizic acid, dipotassium glycyrrhizinate, glycyrrhetin, methyl salicylate, glycol salicylate, azulene sulfonic acid, sodium azulene sulfonate, allantoin, tranexamic acid, berberine, lysozyme, lysozyme chloride, berberine chloride, berberine sulfate, berberine sulfate hydrate, epsilon-aminocaproic acid, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, diclofenac sodium, bromfenac sodium, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, zinc sulfate hydrate, etc. Astringents: For example, zinc oxide, zinc lactate, zinc sulfate, etc. These may be in the form of hydrates. Switch ingredients: for example, sodium cromoglycate, pranoprofen, etc.

[0047] Others: For example, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, lithosphaeria root, horse chestnut, and their salts, creatinine, tyloxapol, sesame oil, castor oil, dibutylhydroxytoluene, phenylethyl alcohol, etc.

[0048] When the ophthalmic composition of the present invention contains water, from the viewpoint of more significantly exhibiting the effects of the present invention, the water content is, for example, preferably 80 w / v% or more and less than 100 w / v%, more preferably 85 w / v% or more and 99.5 w / v% or less, and even more preferably 90 w / v% or more and 99.2 w / v% or less, based on the total amount of the ophthalmic composition.

[0049] The water used in the ophthalmic composition of the present invention may be any water that is medicamentally, pharmacologically, or physiologically acceptable. Examples of such water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection. The definitions of these are based on the 17th edition of the Japanese Pharmacopoeia.

[0050] The ophthalmic composition of the present invention can be prepared by adding and mixing a desired amount of one or more selected from the group consisting of the (A-1) component, the (A-2) component, the (A-3) component, and the (A-4) component, and optionally the (B) TRPA agonist, and further, if necessary, other components to a desired concentration. For example, it can be prepared by dissolving or dispersing those components in purified water, adjusting the pH and osmotic pressure to a predetermined value, and sterilizing the composition by filtration sterilization or the like. It is preferable that the ophthalmic composition of the present invention does not contain benzalkonium chloride or a salt thereof, caffeine or a salt thereof, or retinol palmitate having 50,000 units or more, but these may be contained.

[0051] The pH of the ophthalmic composition of the present invention is not particularly limited as long as it is within a medicamentarily, pharmacologically, or physiologically acceptable range. For example, the pH of the ophthalmic composition may be appropriately set depending on the purpose, formulation form, method of use, etc. of the ophthalmic composition, and may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, even more preferably 4.5 to 8.5, and even more preferably 5.0 to 8.5.

[0052] 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 purpose, formulation, and method of use of the ophthalmic composition, and can be, for example, 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and even more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacopoeia, and the osmotic pressure is measured with reference to the osmometric method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, allowing it to cool in a desiccator (silica gel), accurately measuring 0.900 g of it, and dissolving it in purified water to make exactly 100 mL; alternatively, a commercially available standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be used.

[0053] The viscosity of the ophthalmic composition of the present invention is not particularly limited as long as it is within a medicamentarily, 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'×R24) is preferably 0.1 to 10,000 mPa·s, more preferably 0.1 to 8,000 mPa·s, even more preferably 0.1 to 1,000 mPa·s, even more preferably 0.1 to 100 mPa·s, and particularly preferably 1 to 20 mPa·s.

[0054] The ophthalmic composition of the present invention can be in various formulation forms depending on the purpose, such as liquids, gels, semi-solids (ointments, etc.), etc.

[0055] The ophthalmic composition of the present invention can be used, for example, as eye drops (also called eye drops or eye drops; eye drops include eye drops that can be applied while wearing contact lenses), artificial tears, eyewash (also called eyewash or eyewash medicine; eyewash includes eyewashes that can be used to wash the eyes while wearing contact lenses), compositions for contact lenses [contact lens wearing solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning and preservative), packaging solution for contact lenses, etc.], etc. It should be noted that the term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0056] The ophthalmic composition of the present invention is preferably an eye drop (including an eye drop that can be applied while wearing contact lenses) because it can more significantly exhibit the effects of the present invention. When the ophthalmic composition according to the present embodiment is an eye drop, the dosage and administration method are not particularly limited as long as it is effective and has few side effects. For example, for adults (15 years or older) and children aged 7 years or older, 1 to 7 drops per time is preferable, and 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops per time is more preferable. When 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops per time are used, 5 to 6 times a day can be exemplified. In addition, 4 to 6 drops per time may be applied 3 to 6 times a day.

[0057] The ophthalmic composition of the present invention is provided in any container. The container for containing the ophthalmic composition according to the present embodiment is not particularly limited, and may be made of glass or plastic, for example. It is preferably made of plastic. Examples of plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, copolymers of monomers constituting these, and mixtures of two or more of these. It is preferably polyethylene terephthalate. In addition, the container for containing the ophthalmic composition according to the present embodiment may be a transparent container that allows the inside of the container to be visually observed, or may be an opaque container that makes it difficult to visually observe the inside of the container. It is preferably a transparent container. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container.

[0058] The container for storing the ophthalmic composition of the present invention may be equipped with a nozzle. The material of the nozzle is not particularly limited, and may be made of, for example, glass or plastic. The nozzle is preferably made of plastic. Examples of plastic include Examples of the polymer include polybutylene terephthalate, polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, copolymers of monomers constituting these polymers, and mixtures of two or more of these polymers.

[0059] The container for housing the ophthalmic composition of the present invention may be of a multi-dose type that contains an amount for multiple uses, or may be of a unit-dose type that contains an amount for single use.

[0060] [Ophthalmic composition or pain suppressant for suppressing pain caused by dry eye, allergies, etc.] In addition, the ophthalmic composition of the present invention contains at least one selected from the group consisting of the above-mentioned components (A-1), (A-2), (A-3), and (A-4), and can therefore reduce pain caused by dry eye, allergies, and the like, which are caused by activation of the irritant receptor TRPA1. Thus, as one embodiment of the present invention, there is provided an ophthalmic composition for suppressing pain caused by dry eye, allergies, etc., and an agent for suppressing pain caused by dry eye, allergies, etc., which contain component (A). This is based on reports that TRPA1 is also involved in pain caused by dry eye (see, for example, Neuroscience. 2015 Apr 2;290:204-13). The pain may be due to allergies as well as dry eye. Note that dry eye includes not only dry eye according to the dry eye diagnostic criteria, but also dry eyes.

[0061] [Irritation suppressant for ophthalmic compositions] The present invention also provides an irritation suppressant for an ophthalmic composition. The composition and form of the components (A) and (B) in the irritation suppressant are as described above for the ophthalmic composition. As one embodiment of the present invention, there is provided an agent for suppressing irritation of an ophthalmic composition containing component (B) and component (A) as an active ingredient. When the TRPA1 agonist is menthol, it can suppress irritation of the ophthalmic composition while maintaining a refreshing feeling.

[0062] [Method for suppressing irritation caused by ophthalmic compositions] The present invention also provides a method for suppressing irritation of an ophthalmic composition, comprising adding component (A) and component (B) to the ophthalmic composition. Specifically, the method for suppressing irritation of an ophthalmic composition derived from a TRPA1 agonist (B) is characterized in that the ophthalmic composition containing a TRPA1 agonist (B) further contains a decongestant component (A-1), an antihistamine component (A-2), at least one selected from the group consisting of camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and at least one selected from the group consisting of a local anesthetic component (A-4).

[0063] [Method for evaluating eye irritation] The present invention also provides a method for evaluating eye irritation caused by a test sample, which comprises contacting the test sample with a TRPA1-expressing cell and measuring the amount of change in intracellular calcium ion concentration caused by the test sample via TRPA1. As a test sample used in the evaluation method of the present invention, for example, a combination of (B) TRPA1 agonist and a component commonly used in the field of ophthalmic compositions can be used. For example, such a component may be the above-mentioned (A-1), (A-2), (A-3), or (A-4), or may be a surfactant, a thickener, a buffer, an isotonicity agent, a carrier, a chelating agent, a base, a pH regulator, a stabilizer, a preservative, a bactericide or antibacterial agent, a sugar, a sugar alcohol, an eye muscle regulating agent, a vitamin, an amino acid, an anti-inflammatory agent, an astringent, etc. In addition, (B) a TRPA1 agonist may be used as a control (control sample) for the test sample. There are no particular limitations on the TRPA1-expressing cells as long as they are capable of stably retaining the hTRPA1 gene. For example, T-REx-293 cells, HEK293T cells, and the like are preferred. In the above method, the change in intracellular calcium ion concentration can be measured using, for example, a known Ca 2+ Using a concentration indicator, Fluo-4, Fluo-8, Fluo-2, or the like, measurement and observation can be performed using a commercially available microplate reader, a fluorescence microscope, or the like. In the present invention, by measuring the change in intracellular calcium ion concentration, it is possible to obtain information such as the presence or absence of eye irritation and the strength of eye irritation. In addition, by adjusting the time for contacting the test sample and the control sample with the TRPA1-expressing cells, it is possible to observe the intracellular calcium ion concentration over time and obtain information regarding the affinity of the test sample for the TRPA1-expressing cells (for example, correlation with the LogP value (partition coefficient) of the test sample, etc.). Furthermore, examples of methods for contacting a test sample with TRPA1-expressing cells include adding the test sample or a diluted solution thereof, or artificial tears containing the test sample, to cultured TRPA1-expressing cells or animals such as humans, and administering the resultant eye drops.

[0064] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples in any way. EXAMPLES

[0065] <Cells used> Preparation of T-REx-293 cell line harboring the hTRPA1 gene hTRPA1 mRNA was extracted from human WI38 cells. HEK cells stably expressing hTRPA1 were created using Invitrogen's tetracycline-controlled T-REx expression system. hTRPA1 cDNA, amplified by RT-PCR using hTRPA1 mRNA as a template, was incorporated into pcDNA4 / TO (Invitrogen), a mammalian cell gene expression vector, and then introduced into T-REx-293 cells using Lipofectamin 2000 reagent, an Invitrogen gene introduction reagent. Zeocin was incorporated into pcDNA4 / TO, which holds a plasmid (blasticidin resistance gene) for maintaining the T-Rex system in T-REx-293 cells. A T-REx-293 cell line stably carrying the hTRPA1 gene was established using the antibiotics Zeocin 500 μg / mL and blasticidin 10 μg / mL.

[0066] <Cell culture> T-REx-293 cells carrying hTRPA1 were cultured in the presence of 5% carbon dioxide using DMEM medium containing 10% FBS, 100 unit / mL penicillin, 100 mg / mL streptomysin, and 250 ng / mL amphotericin B. During subculture, 200 μg / mL Zeocin and 5 μg / mL blasticidin were added, and the maximum number of passages was 50 or less. Specifically, T-REx-293 cells were cultured in a 60 mm dish as a preculture until they became semi-confluent, and then washed with PBS(-). The cells were detached from the dish by 1x Trypsin / EDTA treatment, and DMEM medium was added. The cells were then transferred to a 15 mL tube and centrifuged at 800 rpm at room temperature for 4 minutes. The DMEM medium was removed by suction, and the cells were loosened by tapping, after which fresh DMEM medium was added and approximately 40 x 10 4 ~50×10 4 A cell suspension was prepared by adjusting the cell number to 100 cells / mL. At this time, 1μg / mL tetracycline was added for receptor expression. The prepared cell suspension was dispensed into 96-well plates in 100μL portions and incubated overnight at 37℃ in a 5% CO2 incubator before use in the test.

[0067] [Test Example 1] Confirmation test of suppression of irritation by l-menthol Menthol is known to stimulate the stimulatory receptor TRPA1 by activating it. Therefore, l-menthol and a test sample (Example) were administered to the above-mentioned cells to confirm whether the test sample inhibited the TRPA1 activity caused by l-menthol. Ca 2+ The change in TRP activity was observed using a concentration indicator (Fluo-4 or Fluo-8 (AAT Bioquest, Inc.)). 2+ The concentration indicator was first incorporated into T-REx-293 cells carrying hTRPA1, and the amount of fluorescence was measured using a microplate reader. Specifically, the experiment was carried out according to the following protocol. The 96-well plate that had been prepared the day before (cell culture as described above) was removed from the incubator, and the DMEM medium was removed by decantation. The plate was gently washed with 100 μL / well of a buffer solution (pH 7.4, 5.37 mM KCl, 0.44 mM KH2PO4, 137 mM NaCl, 0.34 mM Na2HPO4, 5.56 mM D-glucose, 20 mM HEPES, 1 mM CaCl2, 0.1% bovine serum albumin, 2.5 mM probenecid, remaining purified water), and 50 μL of the above buffer solution dissolved with 1.5 μM Fluo-8 was added to each well, and the plate was then treated in a 37°C, 5% CO2 incubator for 1 hour. After incubation, the above buffer solution containing Fluo-8 was removed by decantation, and the plate was gently washed with 100 μL / well of the above buffer solution. Further, 180 μL / well of the same buffer solution was added, and measurement was started with a Flexstation II (registered trademark) or Flexstation III (registered trademark) microplate reader (Molecular Devices, Sunnyvale, CA, USA). 30 seconds after the start of the microplate reader measurement, 20 μL / well of the test sample was added, and the maximum fluorescence intensity was measured from 5 to 120 seconds after the addition, and this value was taken as the fluorescence intensity.

[0068] The TRP activity (%) was calculated based on the following formula.

number

[0069] Comparative Example 2 (when l-menthol alone was administered) was 100%. The calculation results of the TRP activity of the test samples shown in Table 1 below are shown in FIG. 1. Comparative Example 1 is a control (buffer solution without l-menthol (pH 7.4, 5.37 mM KCl, 0.44 mM KH2PO4, 137 mM NaCl, 0.34 mM Na2HPO4, 5.56 mM D-glucose, 20 mM HEPES, 1 mM CaCl2, 0.1% bovine serum albumin, 2.5 mM probenecid, remaining purified water)), and Comparative Example 2 is a buffer solution similar to Comparative Example 1 in which l-menthol (TRPA1 agonist) is dissolved at a concentration of 66.7 μM. And, in the examples, l-menthol (66.7 μM) and the components shown in Table 1 are dissolved at the concentrations shown in Table 2 in a buffer solution similar to Comparative Example 1.

[0070] [Table 1]

[0071] [Table 2]

[0072] From the results of Figure 1, the ophthalmic composition containing tetrahydrozoline hydrochloride and naphazoline hydrochloride, which are the congestion relief components (A-1) of the present invention, chlorpheniramine maleate and diphenhydramine hydrochloride, which are the antihistamine components (A-2), d-camphor, dl-camphor, (-)-menthone, (+)-isomenthol, 1,8-cineole, menthofuran, α-pinene, β-pinene, (R)-(+)-limonene, (S)-(-)-limonene, neomenthol, methyl acetate, and chlorobutanol, which is the component (A-4), was 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.

[0073] [Test Example 2] Visualization of TRPA1 activation by l-menthol, time-course observation, and binding ability evaluation Based on the same principle as in Test Example 1, Ca 2+ Fluorescence intensity increases depending on Ca concentration 2+ The degree of TRP activation was measured using the concentration indicator Fluo-8. 2+ The concentration indicator was introduced into T-REx-293 cells carrying the hTRPA1 gene, and the amount of fluorescence was visualized using a fluorescence microscope system (Leica, LAS AF6000).

[0074] Approximately 60 x 10 on the cover glass 4 A 20μL suspension of T-REx-293 cells carrying the hTRPA1 gene at 1000 cells / mL in DMEM was dropped onto each slide and incubated overnight at 37℃ in a 5% CO2 incubator. The incubated cover glass was removed from the incubator and the medium was removed by decantation. The cover glass was gently washed with a buffer solution (pH 7.4, 5.37 mM KCl, 0.44 mM KH2PO4, 137 mM NaCl, 0.34 mM Na2HPO4, 5.56 mM D-glucose, 20 mM HEPES, 1 mM CaCl2, remaining purified water), and then the fluorescent indicator Fluo-8 / buffer solution was added and incubated at 37℃ in a 5% CO2 incubator for 1 hour. After incubation, the cover glass was placed on a chamber and the amount of fluorescence was visualized and observed over time using a fluorescence microscope system (Leica, LAS AF6000).

[0075] The flow of this test is as follows: (1) After confirming that the luminescence intensity of 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 confirming the activation of TRPA1, the buffer solution containing l-menthol (66.7 μM) was replaced with a combination of the same concentration of l-menthol and each test sample (tetrahydrozoline hydrochloride 0.003125 w / v%, peppermint oil 0.015 w / v%) to confirm whether TRPA1 activity was inhibited. (3) After the inhibitory effect on TRPA1 activity has been confirmed, the buffer solution containing l-menthol and each test sample is returned to the buffer solution containing l-menthol used in (1), and it is confirmed whether TRPA1 is activated again.

[0076] The results of TRPA1 activation by l-menthol visualized by a fluorescent microscope are shown in Figure 2. After the sample using borneol showed an inhibitory effect on TRPA1 activity, when the test solution was changed back to l-menthol, TRPA1 activity was again observed (see the reference example in Figure 2). On the other hand, when the sample using peppermint oil, an essential oil containing tetrahydrozoline hydrochloride, a congestion relief component (A-1), and (A-3), as the test sample, showed an inhibitory effect on TRPA1 activity, no inhibitory effect was observed or reactivation was weak when the test solution was changed back to menthol only (see the example in Figure 2). That is, it is believed that the components (A-1) and (A-3) of the present invention were each able to maintain their inhibitory effects on the TRPA1 receptor for a certain period of time.

[0077] [Test Example 3] Confirmation test of irritation suppression by tetrahydrozoline hydrochloride in humans Artificial tears (Rohto Soft One Eye Drops, manufactured by Rohto Pharmaceutical Co., Ltd., containing 0.1 w / v% potassium chloride, 0.4 w / v% sodium chloride, boric acid, and a pH regulator) with l-menthol (0.01 w / v%) and polyoxyethylene hydrogenated castor oil (0.1 w / v%) dissolved therein (Comparative Example), and the same artificial tears with l-menthol (0.01 w / v%), polyoxyethylene hydrogenated castor oil (0.1 w / v%), and tetrahydrozoline hydrochloride (0.05 w / v%) dissolved therein (Example) were instilled into the left and right eyes of the same subject, and the results of the evaluation of the cooling sensation and irritation sensation are shown in FIG. 3. The subjects were eight adult males wearing either glasses or without glasses, and the evaluation was performed by quantifying the sensation using a VAS scale (maximum scale: 20).

[0078] As a result, it was shown that by combining l-menthol with tetrahydrozoline hydrochloride, the congestion relief component (A-1), it is possible to maintain the cooling sensation of l-menthol while suppressing the irritation caused by l-menthol. In other words, it was confirmed that the congestion relief component (A-1) of the present invention can suppress the irritation caused by TRPA1 agonists in humans.

[0079] [Formulation example] The formulation examples shown in Tables 4 and 5 below were prepared. Purified water was added to each liquid formulation so that the total volume became 100 mL.

[0080] [Table 4]

[0081] [Table 5] [Industrial Applicability]

[0082] The present invention relates to an ophthalmic composition with reduced irritation, an irritation suppressing agent for an ophthalmic composition, a method for suppressing irritation of an ophthalmic composition, and a method for evaluating eye irritation. The agent of the present invention is useful in the field of medicine.

Claims

[Claim 1] An irritation suppressant for an ophthalmic composition, comprising at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4): (A-1) Decongestant component, (A-2) an antihistamine component, (A-3) at least one selected from the group consisting of camphor, menthone, isomenthol, cineol, menthofuran, pinene, limonene, neomenthol, and methyl acetate, and (A-4) Local anesthetic ingredient.

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