WO2020184479A1 - 刺激感が抑制された眼科組成物 - Google Patents

刺激感が抑制された眼科組成物 Download PDF

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WO2020184479A1
WO2020184479A1 PCT/JP2020/009847 JP2020009847W WO2020184479A1 WO 2020184479 A1 WO2020184479 A1 WO 2020184479A1 JP 2020009847 W JP2020009847 W JP 2020009847W WO 2020184479 A1 WO2020184479 A1 WO 2020184479A1
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component
ophthalmic composition
menthol
irritation
trpa1
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PCT/JP2020/009847
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English (en)
French (fr)
Japanese (ja)
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雅俊 羽賀
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ロート製薬株式会社
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Priority to CN202080013192.3A priority Critical patent/CN113423428A/zh
Priority to JP2021505049A priority patent/JPWO2020184479A1/ja
Publication of WO2020184479A1 publication Critical patent/WO2020184479A1/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/84—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving inorganic compounds or pH

Definitions

  • the present invention relates to 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.
  • 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 refreshing sensation
  • TRPA1 is a pain
  • 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).
  • L-Menthol is a TRPM8 agonist and is used as a refreshing agent in eye drops and the like, but since it is also a TRPA1 agonist, it is also known to give a refreshing sensation and an irritating sensation to the eyes.
  • An object of the present invention is to provide an ophthalmic composition in which a feeling 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.
  • the present inventor has been able to suppress the irritation to the eyes caused by TRPA1 agonists such as l-menthol in ophthalmic compositions containing specific components, in particular, refreshing of l-menthol and the like. It was found that the stimulus can be suppressed while maintaining the sensation, and that the above problems can be solved.
  • the present invention includes the following inventions.
  • 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) Decongestant component, (A-2) Antihistamine component, (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.
  • An ophthalmic composition with suppressed irritation characterized by containing (A-1) Decongestant component, (A-2) Antihistamine component, (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.
  • 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) Decongestant component, (A-2) Antihistamine component, (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.
  • A-1 Decongestant component
  • A-2 Antihistamine component
  • A-3 At least one selected from the group consisting of camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methyl acetate
  • A-4 a local anesthetic component
  • Ophthalmic composition for suppressing pain caused by dry eye, allergies, etc .: (A-1) Decongestant component, (A-2) Antihistamine component, (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. [12] (B) An ophthalmic composition containing a TRPA1 agonist is further composed of the following components (A-1), (A-2), (A-3), and (A-4).
  • 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) Decongestant component, (A-2) Antihistamine component, (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.
  • 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.
  • At least one (B) TRPA1 agonist selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4).
  • B) The refreshing sensation of the TRPA1 agonist is maintained at the same level as that of the ophthalmic composition containing no component (A), while the stimulating sensation is suppressed as compared with the ophthalmic composition containing no component (A).
  • a method for an ophthalmic composition containing (B) a TRPA1 agonist which suppresses irritation while maintaining a refreshing sensation due to the (B) TRPA1 agonist.
  • the ophthalmic composition maintains the refreshing sensation of the (B) TRPA1 agonist in the same manner as the ophthalmic composition without the component (A), while the irritation sensation of the (B) TRPA1 agonist is the ophthalmic composition without the component (A).
  • Use characterized by being more suppressed than objects: (A-1) Decongestant component, (A-2) Antihistamine component, (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.
  • 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). Further, it may or may not contain a TRPA1 agonist, and has an effect of suppressing irritation: (A-1) decongestation component, (A-2) anti-histamine component. , (A-3) at least one selected from the group consisting of camphor, menthol, isomenthol, cineole, mentoflan, pinene, limonene, neomenthol, and methyl acetate, and (A-4) a local anesthetic component.
  • the stimulus is derived from the (B) TRPA1 agonist contained in the ophthalmic composition, including the case where the ophthalmic composition does not contain the (B) TRPA1 agonist.
  • the animal such as a human being to which the ophthalmic composition is administered has a pain symptom due to dry eye, allergy or the like, or the stimulus receptor TRPA1 of the animal is activated.
  • the (B) TRPA1 agonist contained in the ophthalmic composition is menthol, it is possible to suppress the irritation sensation while maintaining the refreshing sensation.
  • 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 irritation 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). : From the group consisting of (A-1) decongestant component, (A-2) anti-histamine component, (A-3) camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methyl acetate. At least one selected and (A-4) local anesthetic component. Preferably, 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) is contained as an active ingredient.
  • the unit of content "%" means "w / v%" and is synonymous with "g / 100 mL”.
  • 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.
  • 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.
  • 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
  • the content of the component (A-1) is not particularly limited, and the type of the component (A-1), the type and content of other compounding components are included. It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like.
  • the content of (A-1) for example, the lower limit of the total content of the component (A-1) is 0.0001 w with respect to the total amount of the ophthalmic composition from the viewpoint of exerting the effect of the present invention more remarkably.
  • / V% or more, 0.0003 w / v% or more, 0.0005 w / v% or more is preferable.
  • the ophthalmic composition of the present invention contains the component (A-1), the content of the component (A-1) is based on the total amount of the ophthalmic composition from the viewpoint of exerting the effect of the present invention more remarkably.
  • the upper limit is preferably 0.5 w / v% or less, 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.
  • the content ratio of the component (A-1) to the component (B) is not particularly limited, and the type of the component (A-1) and other compounding components Is appropriately set according to the type and content of the ophthalmic composition, the use of the ophthalmic composition, the formulation form, and the like.
  • the content ratio of the component (A-1) to the component (B) from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the component (A-1) contained in the ophthalmic composition according to the present invention.
  • the lower limit is usually 0.001 part by weight or more, preferably 0.01 part by weight or more, and 0.1 part by weight or more with respect to 1 part by weight of the total content of the component (B). Is more preferable, 0.2 parts by weight or more is further preferable, and 0.5 parts by weight or more is particularly preferable.
  • the total content of the component (A-1) may be, for example, an upper limit of usually 1000 parts by weight or less and 800 parts by weight or less with respect to 1 part by weight of the total content of the component (B). It is preferably 50 parts by weight or less, more preferably 10 parts by weight or less. Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.
  • the antihistamine component 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 limited thereto. Not done.
  • these antihistamine components preferably, ketotiphen fumarate, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate (chlorphenramine maleate), levocabastine hydrochloride, olopatazine hydrochloride and the like can be mentioned, and more preferably.
  • the content of the component (A-2) is not particularly limited, and the type of the component (A-2), the type and content of other compounding components are included. It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like.
  • the content of (A-2) for example, the lower limit of the total content of the component (A-2) is 0.001 w with respect to the total amount of the ophthalmic composition from the viewpoint of exerting the effect of the present invention more remarkably.
  • / V% or more, 0.003 w / v% or more, 0.005 w / v% or more, 0.01 w / v% or more is preferable.
  • the content of the component (A-2) is based on the total amount of the ophthalmic composition from the viewpoint of exerting the effect of the present invention more remarkably.
  • the upper limit of the total content of the component (A-2) is preferably 0.5 w / v% or less, 0.3 w / v% or less, 0.05 w / v% or less, and 0.03 w / v% or less. Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.
  • the content ratio of the component (A-2) to the component (B) is not particularly limited, and the type of the component (A-2) and other compounding components Is appropriately set according to the type and content of the ophthalmic composition, the use of the ophthalmic composition, the formulation form, and the like.
  • the content ratio of the component (A-2) to the component (B) from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the component (A-2) contained in the ophthalmic composition according to the present invention.
  • the lower limit is preferably 0.002 parts by weight or more, more preferably 0.004 parts by weight or more, based on 1 part by weight of the total content of the component (B). It is more preferably 01 parts by weight or more, further preferably 0.05 parts by weight or more, and particularly preferably 0.1 parts by weight or more.
  • the ratio of the component (A-2) is preferably, for example, an upper limit of 50,000 parts by weight or less, more preferably 5,000 parts by weight or less, and 1,000 parts by weight or less with respect to 1 part by weight of the component (B). It is even more preferably 800 parts by weight or less, further preferably 500 parts by weight or less, even more preferably 100 parts by weight or less, and particularly preferably 10 parts by weight or less. Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.
  • 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.
  • the component (A-3) of the present invention can be used as an essential oil containing the component (A-3).
  • the essential oil containing the component (A-3) for example, one or more of peppermint oil, cool mint oil, sparemint oil, peppermint oil, uikyo oil, kehi oil, bergamot oil, eucalyptus oil, cinnamon oil, rose oil and the like.
  • peppermint oil or cool mint oil is particularly preferable.
  • the ratio of the component (A-3) is, for example, the lower limit of the total amount of the component (A-3) with respect to the total amount of the ophthalmic composition.
  • 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.
  • 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.
  • the ratio of the component (A-3) may be, for example, 0.000000005% or more, 0.00000005% or more, 0.000001% or more at the lower limit with respect to the total amount of the ophthalmic composition.
  • the origin of the component (A-3) is not particularly limited, and the origin of the essential oil is also included.
  • the content ratio of the component (A-3) to the component (B) is not particularly limited, and the type of the component (A-3) and other compounding components Is appropriately set according to the type and content of the ophthalmic composition, the use of the ophthalmic composition, the formulation form, and the like.
  • the content ratio of the component (A-3) to the component (B) for example, the lower limit is 0 with respect to 1 part by weight of the total content of the component (B) from the viewpoint of exerting the effect of the present invention more remarkably.
  • the ratio of the component (A-3) to 1 part by weight of the component (B) is, for example, upper limit of 500,000 parts by weight, 300,000 parts by weight or less, 15,000 parts by weight or less, 800 parts by weight or less, 500 parts by weight. Hereinafter, it may be 100 parts by weight or less and 10 parts by weight or less. Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.
  • Chlorobutanol is preferable as the local anesthetic component. Further, in addition to chlorobutanol, a local anesthetic component known in the art such as procaine hydrochloride or lidocaine hydrochloride is used instead of chlorobutanol, or chlorobutanol and other known local anesthetic components are used in combination. You may.
  • a local anesthetic component known in the art such as procaine hydrochloride or lidocaine hydrochloride is used instead of chlorobutanol, or chlorobutanol and other known local anesthetic components are used in combination. You may.
  • this ratio is preferably 0.001 to 2.5 w / v%, for example, 0.01 to the total amount of the ophthalmic composition. It is more preferably ⁇ 1 w / v%, further preferably 0.05 to 0.5 w / v%, and particularly preferably 0.1 to 0.25%.
  • the content ratio of the component (A-4) to the component (B) is not particularly limited, and the type of the component (A-4) and other compounding components Is appropriately set according to the type and content of the ophthalmic composition, the use of the ophthalmic composition, the formulation form, and the like.
  • the content ratio of the component (A-4) to the component (B) for example, the lower limit is 0 with respect to 1 part by weight of the total content of the component (B) from the viewpoint of exerting the effect of the present invention more remarkably. It may be 0.01 part by weight or more, 0.1 part by weight or more, and 1 part by weight or more.
  • the proportion of the component (A-3) is, for example, 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 weight by weight with respect to 1 part by weight of the component (B). It may be 10 parts by weight or less, 50 parts by weight or less. Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.
  • 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).
  • 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.
  • the ophthalmic composition of the present invention preferably contains a TRPA1 agonist.
  • TRPA1 agonists irritate the eye.
  • 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.
  • an essential oil containing menthol may be used.
  • 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%.
  • the total amount of menthol including the amount of menthol contained in the essential oil is set to satisfy the above ratio.
  • the ophthalmic composition of the present invention comprises at least one selected from the group consisting of component (A-1), component (A-2), component (A-3), and component (A-4). ,
  • the feeling of irritation can be suppressed.
  • 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.
  • 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 hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene-polyoxypropylene block copolymer, and polyoxyethylene-polyoxypropylene.
  • 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 adducts of ethylenediamine such as poroxamine; POE monolaurate (20) sorbitan (polysorbate 20), POE monooleate (20) sorbitan (polysorbate 80), POE sorbitan monostearate, etc.
  • POE polyoxyethylene
  • POP polyoxypropylene glycol
  • POP polyoxypropylene glycol
  • 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) cured 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.
  • POE-POP glycol POE sorbitan fatty acid esters
  • POE-hardened castor oil POE castor oil
  • polyethylene glycol monostearate are preferable from the viewpoint of remarkably exerting the effect of the present invention.
  • Poroxummer 407 POE monooleate (20) sorbitan (polysolvate 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.
  • 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.
  • the ophthalmic composition of the present invention may contain a surfactant other than the nonionic surfactant.
  • 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, and N-acyl taurine salt, or amphoteric surfactants such as betaine lauryldimethylaminoacetate can be mentioned.
  • 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.
  • the ophthalmic composition may further contain a thickener in addition to the above-mentioned components.
  • a 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.
  • Vinyl such as chondroitin sulfate and its salt, glycosaminoglycan such as hypromellose and its salt, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K17, K25, K30, K90, etc.), carboxyvinyl polymer and its salt, etc.
  • examples thereof include macromolecules, dextran, macrogol 6000, macrogol 4000, macrogol (polyethylene glycol) such as macrogol 400, gellan gum, alginic acid and salts thereof.
  • the salt is not particularly limited, but a sodium salt is preferable.
  • glycosaminoglycan, cellulose-based polymer, or vinyl-based polymer is preferable, glucosaminoglycan is more preferable, chondroitin sulfate, hyaluronic acid, and salts thereof are more preferable.
  • chondroitin sulfate sodium chondroitin sulfate
  • 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 ingredients, 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, with respect 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%, and even more preferably 0.0005 to 3 w / v%. 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%.
  • 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, carbonic acid buffer, citric acid buffer, acetate buffer, tris buffer, aspartic acid, aspartate, epsilon-aminocaproic acid and the like. Be done.
  • a boric acid buffering agent, a phosphoric acid buffering agent, a carbonic acid buffering agent, and a citric acid buffering agent are preferable.
  • borate buffer As a more specific example, but not limited to, as a borate buffer, boric acid or a salt thereof (sodium citrate, potassium tetraborate, potassium metaborate, ammonium borate, boar sand, etc.); as a phosphate buffer.
  • boric acid or a salt thereof sodium citrate, potassium tetraborate, potassium metaborate, ammonium borate, boar sand, etc.
  • phosphate buffer As a more specific example, but not limited to, as a borate buffer, 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.);
  • carbonic acid or a salt thereof sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.
  • citrate buffer citrate or a salt thereof
  • 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.
  • These buffers may be synthesized and used by a known method, or a commercially available product may be obtained and used. These buffering agents 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.
  • 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 buffer 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%.
  • 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.
  • 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 any 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.
  • 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%.
  • 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.
  • 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 Over-the-counter Drug Manufacturing and Marketing Approval Standards (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, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriaminetetraacetic acid (DTPA) and the like.
  • Base For example, octyldodecanol, titanium oxide, potassium bromide, plastic base, 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.
  • the ophthalmic composition according to the present embodiment containing an appropriate amount of a combination of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients, as long as the effect of the present invention is not impaired.
  • the ingredients are not particularly limited, and examples thereof include active ingredients in various pharmaceutical products described in the 2012 edition of the OTC drug manufacturing and marketing approval standard (supervised by the Japan Regulatory Science Society).
  • 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, panthenol, ascorbic acid, tocopherol acetate, d- ⁇ -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, berberine, lysoteam, lysoteam chloride, velberin 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
  • sulfamethoxazole for example, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidin sodium, purple root, horse chestnut, and their salts, creatinine, tyroxapole, sesame oil, castor oil, dibutylhydroxy. Toluene, phenylethyl alcohol, etc.
  • 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.
  • a TRPA agonist 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 ophthalmic composition of the present invention preferably does not contain benzalkonium chloride or a salt thereof, caffeine or a salt thereof, or a retinol palmitate ester of 50,000 units or more, but these may be contained.
  • 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.
  • 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, 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 sodium chloride (standard reagent of the Japanese Pharmacopoeia) is dried 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.
  • the viscosity at 20 ° C. measured with a rotary viscometer is preferably 0.1 to 10000 mPa ⁇ s, 0.1. It is more preferably to 8000 mPa ⁇ s, further preferably 0.1 to 1000 mPa ⁇ s, even more preferably 0.1 to 100 mPa ⁇ s, and particularly preferably 1 to 20 mPa ⁇ s. preferable.
  • the ophthalmic composition of the present invention can take various formulation forms depending on the purpose.
  • 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 a contact lens), 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), packaging liquids for contact lenses, etc.] and the like.
  • 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.
  • 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.
  • the number of instillations 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.
  • 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.
  • 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.
  • 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 for accommodating 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.
  • the ophthalmic composition of the present invention is at least one selected from the group consisting of the above-mentioned (A-1) component, (A-2) component, (A-3) component, and (A-4) component. It is also possible to reduce pain caused by dry eye, allergies, etc. due to activation of the stimulus receptor TRPA1 by containing the above. Therefore, as one embodiment of the present invention, an ophthalmic composition for suppressing pain derived from dry eye, allergies, etc., and a pain suppressing agent derived from dry eye, allergies, etc., containing the component (A) are provided. ..
  • 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.
  • dry eye includes not only dry eye according to the dry eye diagnostic criteria but also dry eyes.
  • the present invention also provides an irritation inhibitor for ophthalmic compositions.
  • the composition and form of the component (A) and the component (B) in the irritation inhibitor are as described above for the ophthalmic composition.
  • an irritation inhibitor of an ophthalmic composition containing the component (B), which contains the component (A) as an active ingredient is provided.
  • the present invention also provides a method for suppressing irritation of an ophthalmic composition, which comprises incorporating the component (A) and the component (B) into the ophthalmic composition.
  • a method for suppressing irritation of an ophthalmic composition which comprises incorporating the component (A) and the component (B) into the ophthalmic composition.
  • the present invention also provides a method for evaluating eye irritation.
  • 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.
  • 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.
  • a component may be the above-mentioned (A-1) component, (A-2) component, (A-3) component, or (A-4) component, and is a surfactant.
  • 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.
  • a known Ca 2+ concentration indicator Fluo-4, Fluo-8, or Fluo-2.
  • 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.
  • 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.
  • T-REx-293 cell line carrying the hTRPA1 gene hTRPA1 mRNA was extracted from human WI38 cells.
  • HEK cells that stably expressed hTRPA1 were prepared 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 cDNA4 / TO (manufactured by invitrogen), which is a gene expression vector for mammalian cells, and using Lipofectamine 2000 reagent, which is a gene transfer reagent of invitrogen. It was introduced into T-REx-293 cells.
  • Zeocin is integrated into pcDNA4 / TO, and a plasmid (blastidin resistance gene) for maintaining the T-Rex system is carried in T-REx-293 cells.
  • a T-REx-293 cell line that stably carries the hTRPA1 gene was established using the antibiotics Zeocin 500 ⁇ g / mL and Blasticidin 10 ⁇ g / mL.
  • 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 ⁇ g / mL Zeocin and 5 ⁇ g / mL Blasticidin were added, and the maximum number of passages was 50 or less.
  • T-REx-293 cells were cultured in 60 mm dish so as to be semi-confluent, and then washed with PBS (-).
  • 100 ⁇ L / 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 Gently washed with HEPES, 1 mM CaCl 2 , 0.1% chloride serum albumin, 2.5 mM pH probecid, residual purified water), and 50 ⁇ L of the same buffer solution dissolved in 1.5 ⁇ M Fluo-8 was added to the wells.
  • 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.
  • 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) was used. .56 mM D-glucose, 20 mM HEPES, 1 mM CaCl 2 , 0.1% bovine serum albumin, 2.5 mM probecid, residual purified water)
  • Comparative Example 2 is the same buffer as Comparative Example 1.
  • L-menthol (TRPA1 agonist) was dissolved in a solution at a concentration of 66.7 ⁇ M. Then, in the example, l-menthol (66.7 ⁇ M) 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.
  • the (A-1) decongestant component of the present invention tetrahydrozoline hydrochloride, nafazoline hydrochloride, and (A-2) antihistamine component, chlorpheniramine maleate, diphenhydramine hydrochloride, (A-3)
  • An ophthalmic composition containing (+)-limonene, (S)-(-)-limonene, neomenthol, methylacetate, and chlorobutanol, a component (A-4), was able to suppress the irritation caused by the TRPA1 agonist. ..
  • the ophthalmic composition containing peppermint oil and eucalyptus oil, which are essential oils containing the component (A-3) was also able to suppress
  • the fluorescent indicator Fluo-8 / buffer was added, and the mixture was 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 ⁇ M) to activate TRPA1. (2) After the activation of TRPA1 was confirmed, a buffer solution containing l-menthol (66.7 ⁇ M) 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).
  • 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.
  • the present invention relates to 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.
  • the agent of the present invention is useful in the field of pharmaceuticals.

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