WO2020184479A1 - Ophthalmic composition having inhibited irritating sensation - Google Patents

Ophthalmic composition having inhibited irritating sensation Download PDF

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Publication number
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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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/en
Priority to JP2021505049A priority patent/JPWO2020184479A1/ja
Publication of WO2020184479A1 publication Critical patent/WO2020184479A1/en

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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.

Abstract

The present invention addresses the problem of providing an ophthalmic composition wherein the sense of irritation imparted is suppressed, an irritation-inhibiting agent for an ophthalmic composition, a method for inhibiting irritation caused by an ophthalmic composition, and a method for assessing ophthalmic irritation. The problem is solved by an ophthalmic composition having inhibited irritating sensation and characterized by containing: one selected from the group consisting of (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; and optionally, (B) a TRPA1 agonist.

Description

刺激感が抑制された眼科組成物Ophthalmic composition with suppressed irritation
　本発明は、刺激感が抑制された眼科組成物、眼科組成物用の刺激抑制剤、眼科組成物の刺激を抑制する方法及び眼刺激の評価方法に関する。 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.
　ＴＲＰ（Ｔｒａｎｓｉｅｎｔ　Ｒｅｃｅｐｔｏｒ　Ｐｏｔｅｎｔｉａｌ）チャネルは膜貫通領域を有する陽イオンチャネルであり、４量体として機能すると考えられている。ＴＲＰチャネルは感覚受容のさまざまな局面で機能する陽イオンチャネルファミリーであり、多様な刺激に応答する多くのＴＲＰチャネル分子が存在する（非特許文献１）。ＴＲＰＭ８は清涼感、ＴＲＰＡ１は痛み、ＴＲＰＶ１は灼熱感に関与する細胞センサである。眼においてもＴＲＰＡ１及びＴＲＰＶ１が不快感や痛みに関与していることが報告されている（非特許文献２）。 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, and TRPV1 is a cell sensor involved in a burning sensation. It has been reported that TRPA1 and TRPV1 are also involved in discomfort and pain in the eye (Non-Patent Document 2).
　ｌ－メントールは、ＴＲＰＭ８アゴニストであり、点眼剤等において清涼化剤として用いられるが、ＴＲＰＡ１アゴニストでもあるため、眼に清涼感とともに刺激感を与えることも知られている。 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.
　本発明の課題は、刺激感が抑制された眼科組成物、眼科組成物用の刺激抑制剤、眼科組成物の刺激を抑制する方法及び眼刺激の評価方法を提供することである。 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.
　本発明者は、鋭意研究を重ねた結果、特定の成分を含有する眼科組成物が、ｌ－メントール等のＴＲＰＡ１アゴニストによる、眼への刺激感を抑制出来ること、特に、ｌ－メントール等の清涼感を維持しつつ刺激感を抑制出来ること、さらに、上記課題を解決できることを見出した。 As a result of diligent research, 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.
　すなわち、本発明は、以下の各発明を包含する。
［１］　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有することを特徴とする、刺激感が抑制された眼科組成物：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［２］　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種と、（Ｂ）ＴＲＰＡ１アゴニストとを含有することを特徴とする、刺激感が抑制された眼科組成物：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［３］　（Ｂ）ＴＲＰＡ１アゴニストがｌ－メントールである前記［２］に記載の眼科組成物。
［４］　（Ａ－１）充血除去成分が、テトラヒドロゾリン、ナファゾリン、及びそれらの薬学上許容される塩からなる群より選択される少なくとも１種である、前記［１］～［３］のいずれかに記載の眼科組成物。
［５］　（Ａ－２）抗ヒスタミン成分が、クロルフェニラミン、ジフェンヒドラミン、及びそれらの薬学上許容される塩からなる群より選択される少なくとも１種である、前記［１］～［３］のいずれかに記載の眼科組成物。
［６］　（Ａ－４）局所麻酔成分が、クロロブタノールである、前記［１］～［３］のいずれかに記載の眼科組成物。
［７］　［１］～［６］に記載の眼科組成物であって、刺激がドライアイやアレルギー等に由来する疼痛である眼科組成物。
［８］　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有することを特徴とする、眼科組成物用の刺激抑制剤：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［９］　（Ｂ）ｌ－メントールを含有する眼科組成物用の、刺激感を抑制するための剤であって、
　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有することを特徴とする、
　（Ｂ）ｌ－メントールを含有する眼科組成物用の、刺激抑制剤：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［１０］　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有することを特徴とする、ドライアイやアレルギー等に由来する疼痛を抑制するための剤：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［１１］　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有することを特徴とする、ドライアイやアレルギー等に由来する疼痛抑制用の眼科組成物：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［１２］　（Ｂ）ＴＲＰＡ１アゴニストを含有する眼科組成物に、さらに、以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有させることを特徴とする、（Ｂ）ＴＲＰＡ１アゴニストに由来する眼科組成物の刺激を抑制する方法：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［１３］　被験試料を、ＴＲＰＡ１発現細胞と接触させ、前記被験試料によりＴＲＰＡ１を介して引き起こされる細胞内カルシウムイオン濃度の変化量を測定することを特徴とする、被験試料による眼刺激の評価方法。
［１４］　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種の、（Ｂ）ＴＲＰＡ１アゴニストの刺激感が抑制された眼科組成物製造のための使用：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［１５］　（Ｂ）ＴＲＰＡ１アゴニストを含有する眼科組成物用の、（Ｂ）ＴＲＰＡ１アゴニストの清涼感を維持しつつ刺激感を抑制するための剤であって、
　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有すること、及び
　そのことにより、（Ｂ）ＴＲＰＡ１アゴニストの清涼感が（Ａ）成分不含の前記眼科組成物と同等に維持されつつ、刺激感が（Ａ）成分不含の前記眼科組成物よりも抑制されることを特徴とする、
　（Ｂ）ＴＲＰＡ１アゴニストを含有する眼科組成物用の、刺激抑制剤：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［１６］　（Ｂ）ＴＲＰＡ１アゴニストを含有する眼科組成物用の、（Ｂ）ＴＲＰＡ１アゴニストによる清涼感を維持しつつ刺激感を抑制する方法であって、
　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有させることにより、
　前記眼科組成物における（Ｂ）ＴＲＰＡ１アゴニストの清涼感を（Ａ）成分不含の前記眼科組成物と同等に維持しつつ、刺激感が（Ａ）成分不含の前記眼科組成物よりも抑制されることを特徴とする、
　（Ｂ）ＴＲＰＡ１アゴニストを含有する眼科組成物の刺激抑制方法：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。
［１７］　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種の、
　（Ｂ）ＴＲＰＡ１アゴニストを含有する眼科組成物の製造のための使用であって、
　前記眼科組成物が、（Ｂ）ＴＲＰＡ１アゴニストの清涼感を（Ａ）成分不含の眼科組成物と同等に維持しつつ、（Ｂ）ＴＲＰＡ１アゴニストの刺激感が（Ａ）成分不含の眼科組成物よりも抑制されることを特徴とする、使用：
（Ａ－１）充血除去成分、
（Ａ－２）抗ヒスタミン成分、
（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
（Ａ－４）局所麻酔成分。 That is, the present invention includes the following inventions.
[1] It is characterized by containing at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4). Ophthalmic composition with suppressed irritation:
(A-1) 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.
[2] At least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4), and (B) TRPA1 agonist. An ophthalmic composition with suppressed irritation, characterized by containing
(A-1) 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.
[3] (B) The ophthalmic composition according to the above [2], wherein the TRPA1 agonist is l-menthol.
[4] (A-1) Any one of the above [1] to [3], wherein the decongestant component is at least one selected from the group consisting of tetrahydrozoline, naphazoline, and pharmaceutically acceptable salts thereof. The ophthalmic composition according to.
[5] (A-2) The antihistamine component is at least one selected from the group consisting of chlorpheniramine, diphenhydramine, and pharmaceutically acceptable salts thereof, according to the above [1] to [3]. The ophthalmic composition according to any.
[6] (A-4) The ophthalmic composition according to any one of [1] to [3] above, wherein the local anesthetic component is chlorobutanol.
[7] The ophthalmic composition according to [1] to [6], wherein the irritation is pain caused by dry eye, allergy, or the like.
[8] It is characterized by containing at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4). Stimulation inhibitor for ophthalmic compositions:
(A-1) 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.
[9] (B) An agent for suppressing irritation for an ophthalmic composition containing l-menthol.
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).
(B) Stimulation inhibitor for ophthalmic compositions containing l-menthol:
(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.
[10] 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). Agents for controlling 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.
[11] 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 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). (B) A method for suppressing irritation of an ophthalmic composition derived from a TRPA1 agonist, which comprises containing at least one selected from the group:
(A-1) 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.
[13] 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.
[14] At least one (B) TRPA1 agonist selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4). Use for the production of ophthalmic compositions 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.
[15] An agent for an ophthalmic composition containing (B) a TRPA1 agonist, for suppressing a feeling of irritation while maintaining a refreshing feeling of the (B) TRPA1 agonist.
Containing at least one selected from the group consisting of the following (A-1) component, (A-2) component, (A-3) component, and (A-4) component, and thereby. (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). To do,
(B) Stimulation inhibitor for ophthalmic compositions containing TRPA1 agonists:
(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.
[16] 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.
By containing at least one selected from the group consisting of the following (A-1) component, (A-2) component, (A-3) component, and (A-4) component,
While maintaining the refreshing sensation of the (B) TRPA1 agonist in the ophthalmic composition at the same level as the ophthalmic composition without the component (A), the irritation sensation is suppressed as compared with the ophthalmic composition without the component (A). Characterized by
(B) Method for suppressing irritation of ophthalmic composition containing TRPA1 agonist:
(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.
[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 production of ophthalmic compositions containing TRPA1 agonists.
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.
　本発明の眼科組成物は、以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有することを特徴とし、さらに、（Ｂ）ＴＲＰＡ１アゴニストを含んでも含まなくてもよく、刺激感が抑制されるという効果を奏する：（Ａ－１）充血除去成分、（Ａ－２）抗ヒスタミン成分、（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び（Ａ－４）局所麻酔成分。
　好ましくは、当該刺激感は、眼科組成物中に含まれる（Ｂ）ＴＲＰＡ１アゴニストに由来するものであるが、眼科組成物中に（Ｂ）ＴＲＰＡ１アゴニストが含まれない場合を含めて、当該刺激感が、眼科組成物を投与されるヒト等の動物がドライアイやアレルギー等による疼痛症状であるか、又は当該動物の刺激受容体ＴＲＰＡ１が活性化されたことに由来するものであることが好ましい。
　特に、眼科組成物中に含まれる（B）ＴＲＰＡ１アゴニストがメントールである場合には、清涼感を保持しつつ、刺激感を抑制することが可能となる。
　また、本発明では、眼科組成物の刺激を抑制する方法及び被験試料による眼刺激の評価方法も提供する。 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.
Preferably, 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. However, it is preferable that 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.
In particular, when 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.
図１は、本発明の眼科組成物を構成する成分による、ＴＲＰＡ１アゴニスト（ｌ－メントール）に対する刺激抑制確認試験の結果を示す。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. 図２は、ＴＲＰＡ１阻害効果を可視化したものであり、ボルネオール（参考例）、テトラヒドロゾリン塩酸塩及びペパーミントオイル（実施例）による結果を示す。FIG. 2 visualizes the TRPA1 inhibitory effect and shows the results with borneol (reference example), tetrahydrozoline hydrochloride and peppermint oil (example). 図３は、ｌ－メントール（比較例）とｌ－メントール及びテトラヒドロゾリン塩酸塩の併用（実施例）による、ヒトでの清涼感及び刺激感確認試験の結果を示す。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).
　本発明の眼科組成物は、以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含む：（Ａ－１）充血除去成分、（Ａ－２）抗ヒスタミン成分、（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び（Ａ－４）局所麻酔成分。好ましくは、（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を有効成分として含む。
　なお、本明細書において、特に記載のない限り、含有量の単位「％」は「ｗ／ｖ％」を意味し、「ｇ／１００ｍＬ」と同義である。 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.
In the present specification, unless otherwise specified, the unit of content "%" means "w / v%" and is synonymous with "g / 100 mL".
〔（Ａ－１）充血除去成分〕
　充血除去成分としては、例えば、テトラヒドロゾリン、ナファゾリン、オキシメタゾリン、又はそれらの塩酸塩、硝酸塩などの、イミダゾリン系の充血除去成分、エピネフリン、エフェドリン、メチルエフェドリン、フェニレフリン及びこれらの薬学上許容される塩からなる群より選択される少なくとも１種を用いることが好ましいが、これらに限定されない。
　これら充血除去成分のうち、好ましくは、例えば、イミダゾリン系充血除去成分、より好ましくは、テトラヒドロゾリン、ナファゾリン及びその薬学上許容される塩、さらに好ましくは、テトラヒドロゾリン及びその薬学上許容される塩、特に好ましくは、テトラヒドロゾリン塩酸塩（塩酸テトラヒドロゾリン）である。 [(A-1) Decongestant component]
The decongestant components include, for example, tetrahydrozoline, naphazoline, oxymetazoline, or their hydrochlorides, nitrates, and other imidazoline-based decongestant components, epinephrine, ephedrine, methylephedrine, phenylephrine, and pharmaceutically acceptable salts thereof. It is preferable, but not limited to, at least one selected from the group consisting of.
Of these decongestant components, preferably, for example, imidazoline-based decongestant components, more preferably tetrahydrozoline, naphazoline and pharmaceutically acceptable salts thereof, still more preferably tetrahydrozoline and pharmaceutically acceptable salts thereof, particularly preferably. Is tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride).
　本発明の眼科組成物が（Ａ－１）成分を含む場合、（Ａ－１）成分の含有量は、特に限定されず、(Ａ－１)成分の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(Ａ－１)の含有量としては、本発明の効果をより顕著に奏する観点から、眼科組成物の全量に対して、例えば、(Ａ－１)成分の総含有量の下限が０．０００１ｗ／ｖ％以上、０．０００３ｗ／ｖ％以上、０．０００５ｗ／ｖ％以上が好ましい。また、０．０１ｗ／ｖ％以上がさらに好ましい。また、本発明の眼科組成物が（Ａ－１）成分を含む場合、（Ａ－１）成分の含有量は、本発明の効果をより顕著に奏する観点から、眼科組成物の全量に対して、例えば、上限が０．５ｗ／ｖ％以下、０．３ｗ／ｖ％以下、０．１ｗ／ｖ％以下、０．０５ｗ／ｖ％以下が好ましい。
　また、上記した下限と上限が任意に組み合わせられてもよい。 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 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. Regarding 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. Further, 0.01 w / v% or more is more preferable. When 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. For example, 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.
　本発明の眼科組成物が（Ａ－１）成分を含む場合、（Ｂ）成分に対する（Ａ－１）成分の含有比率は特に限定されず、(Ａ－１)成分の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。（Ｂ）成分に対する（Ａ－１）成分の含有比率としては、本発明による効果をより顕著に奏する観点から、例えば、本願発明にかかる眼科組成物に含まれる（Ａ－１）成分の総含有量は、（Ｂ）成分の総含有量１重量部に対して、例えば、下限が通常０．００１重量部以上であり、０．０１重量部以上であることが好ましく、０．１重量部以上がより好ましく、０．２重量部以上であることがさらに好ましく、０．５重量部以上であることが特に好ましい。また、（Ａ－１）成分の総含有量は、（Ｂ）成分の総含有量１重量部に対して、例えば、上限が、通常１０００重量部以下であり、８００重量部以下であることが好ましく、５０重量部以下であることがより好ましく、１０重量部以下であることがさらに好ましい。
　また、上記した下限と上限が任意に組み合わせられてもよい。 When the ophthalmic composition of the present invention contains the component (A-1), 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. Regarding 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. Regarding the amount, for example, 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. Further, 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.
〔（Ａ－２）抗ヒスタミン成分〕
　抗ヒスタミン成分としては、例えば、クロルフェニラミン、ジフェンヒドラミン、ケトチフェン、イプロヘプチン、レボカバスチン、オロパタジン及びこれらの薬学上許容される塩からなる群より選択される少なくとも１種を用いることが好ましいが、これらに限定されない。
　これら抗ヒスタミン成分のうち、好ましくは、ケトチフェンフマル酸塩、イプロヘプチン、ジフェンヒドラミン塩酸塩、クロルフェニラミンマレイン酸塩（マレイン酸クロルフェンラミン）、レボカバスチン塩酸塩、オロパタジン塩酸塩等が挙げられ、より好ましくは、ケトチフェンフマル酸塩、ジフェンヒドラミン塩酸塩、クロルフェニラミンマレイン酸塩、レボカバスチン塩酸塩、オロパタジン塩酸塩等が挙げられ、更に好ましくは、ジフェンヒドラミン塩酸塩、クロルフェニラミンマレイン酸塩が挙げられ、更により好ましくはクロルフェニラミンマレイン酸塩が挙げられる。 [(A-2) Antihistamine component]
As 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.
Among 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. , Ketotiphen fumarate, diphenhydramine hydrochloride, chlorpheniramine maleate, levocabastine hydrochloride, olopatazine hydrochloride and the like, more preferably diphenhydramine hydrochloride, chlorpheniramine maleate and the like, and even more preferably. Includes chlorpheniramine maleate.
　本発明の眼科組成物が（Ａ－２）成分を含む場合、（Ａ－２）成分の含有量は、特に限定されず、(Ａ－２)成分の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(Ａ－２)の含有量としては、本発明の効果をより顕著に奏する観点から、眼科組成物の全量に対して、例えば、(Ａ－２)成分の総含有量の下限が０．００１ｗ／ｖ％以上、０．００３ｗ／ｖ％以上、０．００５ｗ／ｖ％以上、０．０１ｗ／ｖ％以上が好ましい。また、本発明の眼科組成物が（Ａ－２）成分を含む場合、（Ａ－２）成分の含有量は、本発明の効果をより顕著に奏する観点から、眼科組成物の全量に対して、例えば、（Ａ－２）成分の総含有量の上限が０．５ｗ／ｖ％以下、０．３ｗ／ｖ％以下、０．０５ｗ／ｖ％以下、０．０３ｗ／ｖ％以下が好ましい。
　また、上記した下限と上限が任意に組み合わせられてもよい。 When the ophthalmic composition of the present invention contains the component (A-2), 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. Regarding 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. When the ophthalmic composition of the present invention contains the component (A-2), 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. For example, 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.
　本発明の眼科組成物が（Ａ－２）成分を含む場合、（Ｂ）成分に対する（Ａ－２）成分の含有比率は特に限定されず、(Ａ－２)成分の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。（Ｂ）成分に対する（Ａ－２）成分の含有比率としては、本発明による効果をより顕著に奏する観点から、例えば、本願発明にかかる眼科組成物に含まれる（Ａ－２）成分の総含有量は、（Ｂ）成分の総含有量１重量部に対して、例えば、下限が、０．００２重量部以上であることが好ましく、０．００４重量部以上であることがより好ましく、０．０１重量部以上であることが更に好ましく、０．０５重量部以上であることが更により好ましく、０．１重量部以上であることが特に好ましい。また、（Ａ－２）成分の割合は、（Ｂ）成分１重量部に対して、例えば、上限が、５００００重量部以下であることが好ましく、５０００重量部以下がより好ましく、１０００重量部以下であることが更に好ましく、８００重量部以下であることが更により好ましく、５００重量部以下であることが更に好ましく、１００重量部以下が更により好ましく、１０重量部以下であることが特に好ましい。
　また、上記した下限と上限が任意に組み合わせられてもよい。 When the ophthalmic composition of the present invention contains the component (A-2), 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. Regarding 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. Regarding the amount, for example, 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.
〔（Ａ－３）成分〕
　本発明の眼科組成物は、（Ａ－３）成分として、カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、メチルアセテートからなる群より選択される少なくとも１種を含む。これらは、ｄ体、ｌ体又はｄｌ体のいずれであってもよい。 [(A-3) component]
The ophthalmic composition of the present invention contains, as the component (A-3), at least one selected from the group consisting of camphor, menthol, isomenthol, cineole, mentholan, pinene, limonene, neomenthol, and methyl acetate. These may be d-form, l-form, or dl-form.
　また、本発明の（Ａ－３）成分は、（Ａ－３）成分を含有する精油として使用することが出来る。（Ａ－３）成分を含有する精油としては、例えば、ハッカ油、クールミント油、スペアミント油、ペパーミント油、ウイキョウ油、ケイヒ油、ベルガモット油、ユーカリ油、シナモン油、ローズ油等の１種以上が挙げられ、中でもハッカ油またはクールミント油が特に好ましい。 Further, the component (A-3) of the present invention can be used as an essential oil containing the component (A-3). As 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. Among them, peppermint oil or cool mint oil is particularly preferable.
　本発明の眼科組成物が（Ａ－３）成分を含む場合、（Ａ－３）成分の割合は、（Ａ－３）成分の総量として、眼科組成物の全量に対して、例えば、下限が０．００００１ｗ／ｖ％以上、０．００００５ｗ／ｖ％以上、０．０００１ｗ／ｖ％以上、０．０００３ｗ／ｖ％以上、０．０００５ｗ／ｖ％以上、０．０００７ｗ／ｖ％以上、０．０００８ｗ／ｖ％以上、０．０００９ｗ／ｖ％以上、０．００１ｗ／ｖ％以上であってもよい。
　また、本発明の眼科組成物が（Ａ－３）成分を含む場合、（Ａ－３）成分の割合は、眼科組成物の全量に対して、例えば、上限が５ｗ／ｖ％以下、３ｗ／ｖ％以下、２ｗ／ｖ％以下、１．５ｗ／ｖ％以下、１．２ｗ／ｖ％以下、１ｗ／ｖ％以下、０．９ｗ／ｖ％以下、０．８ｗ／ｖ％以下、０．７ｗ／ｖ％以下、０．６ｗ／ｖ％以下、０．５ｗ／ｖ％以下、０．３ｗ／ｖ％以下、０．１ｗ／ｖ％以下であってもよい。
　また、上記した下限と上限が任意に組み合わせられてもよい。
　特に、さらに、（Ａ－３）成分の割合は、眼科組成物の全量に対して、例えば、合計で０．００００１ｗ／ｖ％～２ｗ／ｖ％（例えば、合計で０．００００５～１ｗ／ｖ％）、好ましくは、合計で０．０００１～０．１ｗ／ｖ％（例えば、０．０００３～０．０５ｗ／ｖ％）、さらに好ましくは、合計で０．０００５～０．０２ｗ／ｖ％（例えば、合計で０．００１～０．０１ｗ／ｖ％）程度であってもよい。さらに、（Ａ－３）成分の割合は、眼科組成物の全量に対して、例えば、下限が０．０００００００５％以上、０．００００００５％以上、０．０００００１％以上であっても良い。
（Ａ－３）成分の由来は特に限定されず、精油由来も含まれる。 When the ophthalmic composition of the present invention contains the component (A-3), the ratio of the component (A-3) is, for example, the lower limit of the total amount of the component (A-3) with respect to the total amount of the ophthalmic composition. 0.00001w / v% or more, 0.00005w / v% or more, 0.0001w / v% or more, 0.0003w / v% or more, 0.0005w / v% or more, 0.0007w / v% or more, 0. It may be 0008w / v% or more, 0.0009w / v% or more, 0.001w / v% or more.
When the ophthalmic composition of the present invention contains the component (A-3), the ratio of the component (A-3) to the total amount of the ophthalmic composition is, for example, an upper limit of 5 w / v% or less, 3 w / V% or less, 2w / v% or less, 1.5w / v% or less, 1.2w / v% or less, 1w / v% or less, 0.9w / v% or less, 0.8w / v% or less, 0. It may be 7 w / v% or less, 0.6 w / v% or less, 0.5 w / v% or less, 0.3 w / v% or less, 0.1 w / v% or less.
Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.
In particular, further, the proportion of the component (A-3) is, for example, 0.00001 w / v% to 2 w / v% in total (for example, 0.00005 to 1 w / v in total) with respect to the total amount of the ophthalmic composition. %), Preferably a total of 0.0001 to 0.1 w / v% (eg, 0.0003 to 0.05 w / v%), and even more preferably a total of 0.0005 to 0.02 w / v% (%). For example, it may be about 0.001 to 0.01 w / v% in total). Further, the ratio of the component (A-3) may be, for example, 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.
　本発明の眼科組成物が（Ａ－３）成分を含む場合、（Ｂ）成分に対する（Ａ－３）成分の含有比率は特に限定されず、(Ａ－３)成分の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。（Ｂ）成分に対する（Ａ－３）成分の含有比率としては、本発明による効果をより顕著に奏する観点から、（Ｂ）成分の総含有量１重量部に対して、例えば、下限が、０．０００００１重量部以上、０．００００１重量部以上、０．０００１重量部以上、０．００１重量部以上、０．００５重量部以上、０．０１重量部以上、０．１、１重量部以上であってもよい。また、（Ａ－３）成分の割合は、（Ｂ）成分１重量部に対して、例えば、上限が、５０００００重量部下、３０００００重量部以下、１５０００重量部以下、８００重量部以下、５００重量部以下、１００重量部以下、１０重量部以下であってもよい。
　また、上記した下限と上限が任意に組み合わせられてもよい。 When the ophthalmic composition of the present invention contains the component (A-3), 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. Regarding 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. 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 part by weight or more There may be. 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.
〔（Ａ－４）成分〕
　局所麻酔成分としては、クロロブタノールが好ましい。また、本発明においては、クロロブタノールの他、塩酸プロカイン又は塩酸リドカイン等の当分野で公知の局所麻酔成分をクロロブタノールの代わりに用いるか、又はクロロブタノールと他の公知の局所麻酔成分を併用してもよい。 [(A-4) component]
Chlorobutanol is preferable as the local anesthetic component. Further, in the present invention, in addition to chlorobutanol, a local anesthetic component known in the art such as procaine hydrochloride or lidocaine hydrochloride is used instead of chlorobutanol, or chlorobutanol and other known local anesthetic components are used in combination. You may.
　特に、本発明の眼科組成物が（Ａ－４）成分を含む場合、この割合は、眼科組成物の全量に対して、例えば、０．００１～２．５ｗ／ｖ％が好ましく、０．０１～１ｗ／ｖ％がより好ましく、０．０５～０．５ｗ／ｖ％が更に好ましく、０．１～０．２５％が特に好ましい。 In particular, when the ophthalmic composition of the present invention contains the component (A-4), this ratio is preferably 0.001 to 2.5 w / v%, for example, 0.01 to the total amount of the ophthalmic composition. It is more preferably ~ 1 w / v%, further preferably 0.05 to 0.5 w / v%, and particularly preferably 0.1 to 0.25%.
　本発明の眼科組成物が（Ａ－４）成分を含む場合、（Ｂ）成分に対する（Ａ－４）成分の含有比率は特に限定されず、(Ａ－４)成分の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。（Ｂ）成分に対する（Ａ－４）成分の含有比率としては、本発明による効果をより顕著に奏する観点から、（Ｂ）成分の総含有量１重量部に対して、例えば、下限が、０．０１重量部以上、０．１重量部以上、１重量部以上であってもよい。また、（Ａ－３）成分の割合は、（Ｂ）成分１重量部に対して、例えば、上限が、５０００重量部以下、３５００重量部以下、１０００重量部以下、５００重量部以下、１００重量部以下、５０重量部以下、１０重量部以下であってもよい。
　また、上記した下限と上限が任意に組み合わせられてもよい。 When the ophthalmic composition of the present invention contains the component (A-4), 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. Regarding 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.
〔（Ａ）成分〕
　本明細書において、（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分をまとめて、（Ａ）成分と総称することもある。また、（Ａ）成分は複数成分を組み合わせて使用することが好ましく、（Ａ－１）～（Ａ－４）からなる群より選択される２群以上を組み合わせて使用することがより好ましく、３群以上を組み合わせて使用することが更に好ましい。 [(A) component]
In the present specification, the component (A-1), the component (A-2), the component (A-3), and the component (A-4) may be collectively referred to as the component (A). Further, the component (A) is preferably used in combination of a plurality of components, and more preferably in combination of two or more groups selected from the groups consisting of (A-1) to (A-4). It is more preferable to use a combination of groups or more.
〔（Ｂ）成分：ＴＲＰＡ１アゴニスト〕
　本発明の眼科組成物は、ＴＲＰＡ１アゴニストを含むことが好ましい。ＴＲＰＡ１アゴニストは、眼に刺激感を与える。ＴＲＰＡ１アゴニストとしては、メントールが好ましい。
　メントールは、医薬上、薬理学的に又は生理学的に許容されるものであれば、特に制限されず、ｄ体、ｌ体、ｄｌ体のいずれであってもよいが、ｌ－メントールが好ましい。 [Component (B): TRPA1 agonist]
The ophthalmic composition of the present invention preferably contains a TRPA1 agonist. TRPA1 agonists irritate the eye. As the TRPA1 agonist, menthol is preferable.
The menthol is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable, and may be d-form, l-form, or dl-form, but l-menthol is preferable.
　また、メントールとして、メントールを含有する精油を使用してもよい。 Further, as the menthol, an essential oil containing menthol may be used.
　本発明の眼科組成物におけるメントールの含有量は、眼科組成物の全量に対して、０．００００１～０．５ｗ／ｖ％であることが好ましく、０．０００１～０．２５ｗ／ｖ％であることがより好ましく、０．０００５～０．１ｗ／ｖ％であることがさらに好ましく、０．００１～０．０８ｗ／ｖ％であることが更に好ましい。なお、メントールを含む精油を使用する場合は、精油中に含まれるメントール量を含めたメントール量の総和が上記割合を満たすように設定される。 The content of menthol in the ophthalmic composition of the present invention is preferably 0.00001 to 0.5 w / v%, preferably 0.0001 to 0.25 w / v%, based on the total amount of the ophthalmic composition. More preferably, it is more preferably 0.0005 to 0.1 w / v%, and further preferably 0.001 to 0.08 w / v%. When 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.
　本発明の眼科組成物は、（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含むことにより、刺激感が抑制され得る。さらに、本発明の眼科組成物が、（Ｂ）ＴＲＰＡ１アゴニストを含む場合、眼科組成物中に含まれるＴＲＰＡ１アゴニストによる刺激感を抑制することが出来るため、特に好ましい。眼科組成物を投与されるヒト等の動物がドライアイやアレルギー等による疼痛症状を示しているか、又は当該動物の刺激受容体ＴＲＰＡ１が活性化されていることも好ましい。 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. Furthermore, when the ophthalmic composition of the present invention contains the (B) TRPA1 agonist, it is particularly preferable because the irritation sensation caused by the TRPA1 agonist contained in the ophthalmic composition can be suppressed. It is also preferable that an animal such as a human being to which the ophthalmic composition is administered exhibits pain symptoms due to dry eye, allergies, or the like, or the stimulus receptor TRPA1 of the animal is activated.
　本発明の眼科組成物は、上記した成分の他に、更に非イオン界面活性剤を含んでもよい。非イオン界面活性剤は、医薬上、薬理学的に又は生理学的に許容されるものであれば、特に制限されない。非イオン界面活性剤の具体例としては、例えば、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレン－ポリオキシプロピレンブロックコポリマー、ポリオキシエチレン－ポリオキシプロピレンブロックコポリマー付加物、ポリオキシエチレン－ポリオキシプロピレンアルキルエーテル、ポリオキシエチレンアルキルフェニルエーテルが挙げられる。 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. Block copolymer adducts, polyoxyethylene-polyoxypropylene alkyl ethers, polyoxyethylene alkyl phenyl ethers and the like.
　非イオン界面活性剤のより具体的な例として、例えば、ポリオキシエチレン（以下、ＰＯＥともいう。）－ポリオキシプロピレン（以下、ＰＯＰともいう。）グリコール（例えば、ポロクサマー４０７、ポロクサマー２３５、ポロクサマー１８８等のポロクサマー類）；ポロキサミンなどのエチレンジアミンのＰＯＥ－ＰＯＰブロックコポリマー付加物；モノラウリル酸ＰＯＥ（２０）ソルビタン（ポリソルベート２０）、モノオレイン酸ＰＯＥ（２０）ソルビタン（ポリソルベート８０）、ＰＯＥソルビタンモノステアレート（ポリソルベート６０）、ＰＯＥソルビタントリステアレート（ポリソルベート６５）等のＰＯＥソルビタン脂肪酸エステル類；ＰＯＥ（５）硬化ヒマシ油、ＰＯＥ（１０）硬化ヒマシ油、ＰＯＥ（２０）硬化ヒマシ油、ＰＯＥ（４０）硬化ヒマシ油、ＰＯＥ（５０）硬化ヒマシ油、ＰＯＥ（６０）硬化ヒマシ油、ＰＯＥ（１００）硬化ヒマシ油などのＰＯＥ硬化ヒマシ油；ＰＯＥ（３）ヒマシ油、ＰＯＥ（１０）ヒマシ油、ＰＯＥ（３５）ヒマシ油などのＰＯＥヒマシ油；ＰＯＥ（９）ラウリルエーテルなどのＰＯＥアルキルエーテル類；ＰＯＥ（２０）ＰＯＰ（４）セチルエーテルなどのＰＯＥ・ＰＯＰアルキルエーテル類；ＰＯＥ（１０）ノニルフェニルエーテルなどのＰＯＥアルキルフェニルエーテル類；ステアリン酸ポリオキシル４０などのモノステアリン酸ポリエチレングリコール類などが挙げられる。なお、括弧内の数字はＰＯＰ又はＰＯＥの平均付加モル数を示す。 As a more specific example of the nonionic surfactant, for example, polyoxyethylene (hereinafter, also referred to as POE) -polyoxypropylene (hereinafter, also referred to as POP) glycol (for example, Poroxummer 407, Poroxummer 235, Poroxumer 188) Pore-POP block copolymer adducts of ethylenediamine such as poroxamine; POE monolaurate (20) sorbitan (polysorbate 20), POE monooleate (20) sorbitan (polysorbate 80), POE sorbitan monostearate, etc. 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. The numbers in parentheses indicate the average number of moles of POP or POE added.
　これらの非イオン界面活性剤の中でも、本発明の効果を顕著に奏する観点から、ＰＯＥ－ＰＯＰグリコール、ＰＯＥソルビタン脂肪酸エステル類、ＰＯＥ硬化ヒマシ油、ＰＯＥヒマシ油、及びモノステアリン酸ポリエチレングリコール類が好ましく、ポロクサマー４０７、モノオレイン酸ＰＯＥ（２０）ソルビタン（ポリソルベート８０）、ＰＯＥ（６０）硬化ヒマシ油（ポリオキシエチレン硬化ヒマシ油６０）、ＰＯＥ（４０）硬化ヒマシ油（ポリオキシエチレン硬化ヒマシ油４０）、ＰＯＥ（３）ヒマシ油（ポリオキシエチレンヒマシ油３）、ＰＯＥ（１０）ヒマシ油（ポリオキシエチレンヒマシ油１０）、ＰＯＥ（３５）ヒマシ油（ポリオキシエチレンヒマシ油３５）、ステアリン酸ポリオキシル４０がより好ましく、モノオレイン酸ＰＯＥ（２０）ソルビタン、ＰＯＥ（６０）硬化ヒマシ油が特に好ましい。 Among these nonionic surfactants, POE-POP glycol, POE sorbitan fatty acid esters, POE-hardened castor oil, POE castor oil, and polyethylene glycol monostearate are preferable from the viewpoint of remarkably exerting the effect of the present invention. , Poroxummer 407, 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.
　これらの非イオン界面活性剤は、公知の方法により合成して使用しても、市販品を入手して使用してもよい。非イオン界面活性剤は、１種単独で用いてもよく、２種以上を任意に組み合わせて用いてもよい。
　非イオン界面活性剤の含有量は、非イオン界面活性剤の種類、他の成分の種類や量、眼科組成物の用途等に応じて適宜設定できる。 These nonionic surfactants may be synthesized and used by a known method, or commercially available products may be obtained and used. The nonionic surfactant may be used alone or in any combination of two or more.
The content of the nonionic surfactant can be appropriately set according to the type of the nonionic surfactant, the type and amount of other components, the use of the ophthalmic composition, and the like.
　また、本発明の眼科組成物は、非イオン界面活性剤以外の界面活性剤を含んでいてもよい。そのような界面活性剤は、医薬上、薬理学的に又は生理学的に許容されるものであれば、特に制限されないが、具体例としては、例えば、ポリオキシエチレンアルキルエーテルリン酸塩、ポリオキシエチレンアルキルエーテル硫酸塩、アルキルベンゼンスルホン酸塩、アルキル硫酸塩、Ｎ－アシルタウリン塩等の陰イオン界面活性剤等、あるいは、例えば、ラウリルジメチルアミノ酢酸ベタイン等の両性界面活性剤等が挙げられる。 Further, the ophthalmic composition of the present invention may contain a surfactant other than the nonionic surfactant. Such a surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable, and specific examples thereof include, for example, polyoxyethylene alkyl ether phosphate and polyoxy. Anionic surfactants such as ethylene alkyl ether sulfate, alkylbenzene sulfonate, alkyl sulfate, and N-acyl taurine salt, or amphoteric surfactants such as betaine lauryldimethylaminoacetate can be mentioned.
　一例として、眼科組成物の全量に対する界面活性剤の総含有量は、限定はされないが、例えば、下限について、好ましくは、０．０００１ｗ／ｖ％以上であり、より好ましくは０．０００５ｗ／ｖ％以上、さらに好ましくは０．００１ｗ／ｖ％以上、特に好ましくは０．００５ｗ／ｖ％以上であり、最も好ましくは０．０１ｗ／ｖ％以上である。また、上限について、限定はされないが、好ましくは１０ｗ／ｖ％以下であり、より好ましくは５ｗ／ｖ％以下、さらに好ましくは１ｗ／ｖ％以下、特に好ましくは０．５ｗ／ｖ％以下である。また、上記した下限と上限が任意に組み合わせられてもよい。 As an example, the total content of the surfactant with respect to the total amount of the ophthalmic composition is not limited, but for example, the lower limit is preferably 0.0001 w / v% or more, more preferably 0.0005 w / v%. As described above, it is more preferably 0.001 w / v% or more, particularly preferably 0.005 w / v% or more, and most preferably 0.01 w / v% or more. The upper limit is not limited, but is preferably 10 w / v% or less, more preferably 5 w / v% or less, still more preferably 1 w / v% or less, and particularly preferably 0.5 w / v% or less. .. Further, the above-mentioned lower limit and upper limit may be arbitrarily combined.
　本発明において、眼科組成物は、上記した成分の他に、更に増粘剤を含有していてもよい。増粘剤として、具体的には、メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース（ヒプロメロース）、カルボキシメチルセルロース及びその塩、カルボキシエチルセルロース及びその塩等のセルロース系高分子化合物、コンドロイチン硫酸及びその塩並びにヒアルロン酸及びその塩等のグリコサミノグリカン、ポリビニルアルコール（完全又は部分ケン化物）、ポリビニルピロリドン（Ｋ１７、Ｋ２５、Ｋ３０、Ｋ９０など）、カルボキシビニルポリマー及びその塩等のビニル系高分子、デキストラン、マクロゴール６０００、マクロゴール４０００、マクロゴール４００等のマクロゴール（ポリエチレングリコール）、ジェランガム、アルギン酸及びその塩が挙げられる。ここで、その塩とは、特に限定はされないが、ナトリウム塩が好ましい。
　本発明の効果を顕著に奏する観点から、グリコサミノグリカン、セルロース系高分子、又はビニル系高分子が好ましく、グルコサミノグリカンがより好ましく、コンドロイチン硫酸、ヒアルロン酸及びそれらの塩がより好ましく、コンドロイチン硫酸ナトリウム（コンドロイチン硫酸エステルナトリウム）及びヒアルロン酸ナトリウムが更に好ましい。これらの増粘剤は、公知の方法により合成して使用しても、市販品を入手して使用してもよい。これらの増粘剤は、１種を単独で使用してもよく、又は２種以上を組み合わせて使用してもよい。 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. 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. Here, the salt is not particularly limited, but a sodium salt is preferable.
From the viewpoint of significantly exerting the effect of the present invention, glycosaminoglycan, cellulose-based polymer, or vinyl-based polymer is preferable, glucosaminoglycan is more preferable, chondroitin sulfate, hyaluronic acid, and salts thereof are more preferable. Sodium chondroitin sulfate (sodium chondroitin sulfate) and sodium hyaluronate are more preferable. These thickeners may be synthesized and used by a known method, or commercially available products may be obtained and used. These thickeners may be used alone or in combination of two or more.
　増粘剤の総含有量は、使用する増粘剤の種類、他の配合成分の種類や配合量、眼科組成物の用途等に応じて適宜設定できる。眼科組成物の全量に対して、増粘剤の総含有量は、限定はされないが、好ましくは０．０００１ｗ／ｖ％以上であり、より好ましくは０．０００５ｗ／ｖ％以上、さらに好ましくは０．００１ｗ／ｖ％以上、さらに好ましくは０．００５ｗ／ｖ％以上、さらにより好ましくは０．０１ｗ／ｖ％以上、最も好ましくは０．０５ｗ／ｖ％以上である。また、眼科組成物の全量に対して、増粘剤の総含有量は、限定はされないが、好ましくは５ｗ／ｖ％以下であり、より好ましくは３ｗ／ｖ％以下、さらに好ましくは１ｗ／ｖ％以下、更により好ましくは０．５ｗ／ｖ％以下、最も好ましくは０．３ｗ／ｖ％以下である。眼科組成物の全量に対して、増粘剤の総含有量は、限定はされないが、好ましくは０．０００１～５ｗ／ｖ％、より好ましくは、０．０００５～３ｗ／ｖ％、さらに好ましくは０．００１～１ｗ／ｖ％、さらにより好ましくは、０．００５～０．５ｗ／ｖ％、特に好ましくは、０．０１～０．５ｗ／ｖ％、最も好ましくは０．０５～０．３ｗ／ｖ％である。 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%.
　本発明において、眼科組成物は、上記した成分の他に、更に緩衝剤を含有していてもよい。緩衝剤としては、医薬上、薬理学的に又は生理学的に許容されるものであれば、特に制限されない。このような緩衝剤の一例として、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤、トリス緩衝剤、アスパラギン酸、アスパラギン酸塩、イプシロン－アミノカプロン酸等が挙げられる。緩衝剤としては、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤が好ましい。 In the present invention, the ophthalmic composition may further contain a buffer in addition to the above-mentioned components. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable. Examples of such a buffer include borate buffer, phosphate buffer, carbonic acid buffer, citric acid buffer, acetate buffer, tris buffer, aspartic acid, aspartate, epsilon-aminocaproic acid and the like. Be done. As the buffering agent, a boric acid buffering agent, a phosphoric acid buffering agent, a carbonic acid buffering agent, and a citric acid buffering agent are preferable.
　より具体的な例として、限定はされないが、ホウ酸緩衝剤として、ホウ酸又はその塩（ホウ酸ナトリウム、テトラホウ酸カリウム、メタホウ酸カリウム、ホウ酸アンモニウム、ホウ砂等）；リン酸緩衝剤として、リン酸又はその塩（リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、リン酸三ナトリウム、リン酸二カリウム、リン酸一水素カルシウム、リン酸二水素カルシウム等）；炭酸緩衝剤として、炭酸又はその塩（炭酸水素ナトリウム、炭酸ナトリウム、炭酸アンモニウム、炭酸カリウム、炭酸カルシウム、炭酸水素カリウム、炭酸マグネシウム等）；クエン酸緩衝剤として、クエン酸又はその塩（クエン酸ナトリウム、クエン酸カリウム、クエン酸カルシウム、クエン酸二水素ナトリウム、クエン酸二ナトリウム等）；酢酸緩衝剤として、酢酸又はその塩（酢酸アンモニウム、酢酸カリウム、酢酸カルシウム、酢酸ナトリウム等）；アスパラギン酸又はその塩（アスパラギン酸ナトリウム、アスパラギン酸マグネシウム、アスパラギン酸カリウム、アスパラギン酸マグネシウム・カリウム混合物等）が例示できる。また、緩衝剤の製造の原料として、各塩の水和物を用いてもよい。 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.); As a buffer, carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citrate buffer, citrate or a salt thereof (sodium citrate, Potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) as an acetate buffer; aspartic acid or a salt thereof (Sodium citrate, magnesium aspartate, potassium aspartate, magnesium aspartate / potassium mixture, etc.) can be exemplified. Further, a hydrate of each salt may be used as a raw material for producing the buffer.
　これらの緩衝剤は、公知の方法により合成して使用しても、市販品を入手して使用してもよい。これらの緩衝剤は、１種単独で用いてもよく、２種以上を任意に組み合わせて用いてもよい。 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.
　本発明の眼科組成物における緩衝剤の含有量は、使用する緩衝剤の種類、他の配合成分の種類や配合量、眼科組成物の用途等に応じて適宜設定できる。一例として、眼科組成物の全量に対する緩衝剤の総含有量は、限定はされないが、好ましくは０．０１ｗ／ｖ％以上、より好ましくは０．０５ｗ／ｖ％以上、さらに好ましくは０．１ｗ／ｖ％以上、特に好ましくは０．３ｗ／ｖ％以上である。眼科組成物の全量に対する緩衝剤の総含有量は、限定はされないが、好ましくは１０ｗ／ｖ％以下、より好ましくは５ｗ／ｖ％以下、さらに好ましくは３ｗ／ｖ％以下、特に好ましくは２ｗ／ｖ％以下である。眼科組成物の全量に対する緩衝剤の総含有量は、限定はされないが、好ましくは０．０１～１０ｗ／ｖ％、より好ましくは０．０５～５ｗ／ｖ％、さらに好ましくは０．１～３ｗ／ｖ％、特に好ましくは０．３～２ｗ／ｖ％である。 The content of the buffering agent in the ophthalmic composition of the present invention can be appropriately set according to the type of the buffering agent used, the type and amount of other compounding components, the use of the ophthalmic composition, and the like. As an example, the total content of the buffer to the total amount of the ophthalmic composition is not limited, but is preferably 0.01 w / v% or higher, more preferably 0.05 w / v% or higher, still more preferably 0.1 w / v /. It is v% or more, particularly preferably 0.3 w / v% or more. The total content of the buffering agent relative to the total amount of the ophthalmic composition is not limited, but is preferably 10 w / v% or less, more preferably 5 w / v% or less, still more preferably 3 w / v% or less, and particularly preferably 2 w / v /. It is v% or less. The total content of the 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%.
　本発明において、眼科組成物は、上記した成分の他に、更に等張化剤を含有していてもよい。等張化剤としては、医薬上、薬理学的に又は生理学的に許容されるものであれば、特に制限されない。
　等張化剤として、具体的には、亜硫酸水素ナトリウム、亜硫酸ナトリウム、塩化カリウム、塩化カルシウム、塩化ナトリウム、塩化マグネシウム、チオ硫酸ナトリウム、硫酸マグネシウム、グリセリン、プロピレングリコール等が挙げられる。これらの等張化剤の中でも、本発明の効果を顕著に奏させるという観点から、好ましくは、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、グリセリン、及びプロピレングリコールが挙げられる。これらの等張化剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 In the present invention, the ophthalmic composition may further contain an isotonic agent in addition to the above-mentioned components. The tonicity agent is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable.
Specific examples of the tonicity agent include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol and the like. Among these tonicity agents, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, and propylene glycol are preferably mentioned from the viewpoint of significantly exerting the effect of the present invention. These isotonic agents may be used alone or in any combination of two or more.
　本発明の眼科組成物における等張化剤の含有量については、使用する等張化剤の種類、他の配合成分の種類や配合量、眼科組成物の用途等に応じて適宜設定できる。一例として、眼科組成物の全量に対する緩衝剤の総含有量は、限定はされないが、好ましくは０．０１～１０ｗ／ｖ％、好ましくは０．０５～５ｗ／ｖ％、更に好ましくは０．１～３ｗ／ｖ％である。 The content of the tonicity agent in the ophthalmic composition of the present invention can be appropriately set according to the type of tonicity agent to be used, the type and amount of other compounding components, the use of the ophthalmic composition, and the like. As an example, the total content of the buffer to the total amount of the ophthalmic composition is not limited, but is preferably 0.01-10 w / v%, preferably 0.05-5 w / v%, more preferably 0.1. It is ~ 3w / v%.
　本発明の眼科組成物は、本発明の効果を損なわない範囲であれば、その用途及び製剤形態に応じて、常法に従い、様々な添加物を適宜選択し、１種又はそれ以上を併用して適当量含有させてもよい。このような添加物として、例えば、医薬品添加物事典２０１６（日本医薬品添加剤協会編集）又は一般用医薬品製造販売承認基準２０１２年版（一般社団法人　レギュラトリーサイエンス学会）に記載された有効成分（薬理活性成分や生理活性成分等）等に記載された各種添加物が例示できる。代表的な成分として次の添加物が挙げられる。
　担体：例えば、水、含水エタノール等の水性溶媒。
　キレート剤：例えば、エチレンジアミン二酢酸（ＥＤＤＡ）、エチレンジアミン三酢酸、エチレンジアミン四酢酸（ＥＤＴＡ）、Ｎ－（２－ヒドロキシエチル）エチレンジアミン三酢酸（ＨＥＤＴＡ）、ジエチレントリアミン五酢酸（ＤＴＰＡ）等。
　基剤：例えば、オクチルドデカノール、酸化チタン、臭化カリウム、プラスチベース等。 In the ophthalmic composition of the present invention, various additives are appropriately selected according to a conventional method according to the use and formulation form as long as the effects of the present invention are not impaired, and one or more of them are used in combination. It may be contained in an appropriate amount. As such additives, for example, the active ingredient (pharmacological activity) described in the Encyclopedia of Pharmaceutical Additives 2016 (edited by the Japan Pharmaceutical Additives Association) or the 2012 edition of the 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調節剤：例えば、塩酸、酢酸、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化マグネシウム、トリエタノールアミン、ジイソプロパノールアミン等。
　安定化剤：例えば、ナトリウムホルムアルデヒドスルホキシレート（ロンガリット）、亜硫酸水素ナトリウム、ピロ亜硫酸ナトリウム、モノステアリン酸アルミニウム、モノステアリン酸グリセリン、シクロデキストリン、モノエタノールアミン等。
　防腐剤、殺菌剤又は抗菌剤：例えば、塩化亜鉛、塩酸アルキルジアミノエチルグリシン、安息香酸ナトリウム、エタノール、塩化ベンザルコニウム、塩化ベンゼトニウム、グルコン酸クロルヘキシジン、ソルビン酸、ソルビン酸カリウム、デヒドロ酢酸ナトリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、硫酸オキシキノリン、フェネチルアルコール、ベンジルアルコール、ビグアニド化合物（具体的には、塩酸ポリヘキサニド等）、グローキル（ローディア社製　商品名）等。 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.
　糖類：例えば、グルコース、シクロデキストリン、アルファ－シクロデキストリン等。
　糖アルコール類：例えば、キシリトール、ソルビトール、マンニトール、グリセリン等。これらはｄ体、ｌ体又はｄｌ体のいずれでもよい。 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.
　また、本実施形態に係る刺激感が抑制された眼科用組成物は、本発明の効果を妨げない限り、上記成分の他に種々の薬理活性成分や生理活性成分を組み合わせて適当量含有していてもよい。成分は特に制限されず、例えば、一般用医薬品製造販売承認基準２０１２年版（一般社団法人レギュラトリーサイエンス学会監修）に記載された各種医薬における有効成分が例示できる。例えば、眼科用薬において用いられる成分として、具体的には、次のような成分が挙げられる。
　眼筋調節薬剤：例えば、ネオスチグミンメチル硫酸塩、トロピカミド、ヘレニエン硫酸アトロピン等のコリンエステラーゼ阻害剤等。
　ビタミン類：例えば、フラビンアデニンジヌクレオチド（ＦＡＤ）、フラビンアデニンジヌクレオチドナトリウム、ピリドキシン塩酸塩、シアノコバラミン、酢酸レチノール、パルミチン酸レチノール、パンテノール、アスコルビン酸、酢酸トコフェロール、酢酸ｄ－α－トコフェロール、コハク酸トコフェロール、ニコチン酸トコフェロール、リノレン酸トコフェロール等。
　アミノ酸類：例えば、Ｌ－グルタミン酸、Ｌ－アスパラギン酸カリウム、Ｌ－アスパラギン酸マグネシウム・カリウム、アミノエチルスルホン酸（タウリン）等。
　消炎剤：例えば、グリチルリチン酸、グリチルリチン酸二カリウム、グリチルレチン、サリチル酸メチル、サリチル酸グリコール、アズレンスルホン酸、アズレンスルホン酸ナトリウム、アラントイン、トラネキサム酸、ベルベリン、リゾチーム、塩化リゾチーム、塩化ベルベリン、ベルベリン硫酸塩、ベルベリン硫酸塩水和物、イプシロン－アミノカプロン酸、インドメタシン、プラノプロフェン、イブプロフェン、イブプロフェンピコノール、ケトプロフェン、ジクロフェナクナトリウム、ブロムフェナクナトリウム、フェルビナク、ベンダザック、ピロキシカム、ブフェキサマク、フルフェナム酸ブチル、硫酸亜鉛水和物等。
　収斂剤：例えば、酸化亜鉛、乳酸亜鉛、硫酸亜鉛等。これらは水和物であってもよい。
　スイッチ成分：例えば、クロモグリク酸ナトリウム、プラノプロフェン等。 In addition, 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. You may. The ingredients are not particularly limited, and examples thereof include active ingredients in various pharmaceutical products described in the 2012 edition of the OTC drug manufacturing and marketing approval standard (supervised by the Japan Regulatory Science Society). For example, specific examples of the components used in ophthalmic drugs include the following components.
Eye muscle regulators: for example, cholinesterase inhibitors such as neostigmine methyl sulfate, tropicamide, atropine helenien sulfate and the like.
Vitamins: For example, flavin adenine dinucleotide (FAD), flavin adenine dinucleotide sodium, pyridoxin hydrochloride, cyanocobalamine, retinol acetate, retinol palmitate, panthenol, ascorbic acid, tocopherol acetate, d-α-tocopherol acetate, succinic acid Tocopherol, tocopherol nicotinate, tocopherol linolenate, etc.
Amino acids: For example, L-glutamic acid, potassium L-aspartate, magnesium / potassium L-aspartate, aminoethylsulfonic acid (taurine) and the like.
Anti-inflammatory agents: For example, glycyrrhizic acid, dipotassium glycyrrhizinate, glycyrrhetin, methyl salicylate, glycol salicylate, azulene sulfonic acid, sodium azulene sulfonate, allantin, tranexamic acid, 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 sulfate, etc. These may be hydrates.
Switch components: For example, sodium cromoglycate, pranoprofen, etc.
　その他：例えば、スルファメトキサゾール、スルファメトキサゾールナトリウム、スルフイソキサゾール、スルフイソミジンナトリウム、紫根、セイヨウトチノキ、及びこれらの塩、クレアチニン、チロキサポール、ゴマ油、ヒマシ油、ジブチルヒドロキシトルエン、フェニルエチルアルコール等。 Others: 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.
　本発明の眼科組成物が水を含有する場合、水の含有量としては、本発明による効果をより顕著に奏する観点から、例えば、眼科組成物の全量を基準として、水の含有量が、８０ｗ／ｖ％以上１００ｗ／ｖ％未満であることが好ましく、８５ｗ／ｖ％以上９９．５ｗ／ｖ％以下であることがより好ましく、９０ｗ／ｖ％以上９９．２ｗ／ｖ％以下であることが更に好ましい。 When the ophthalmic composition of the present invention contains water, the water content is 80 w, for example, based on the total amount of the ophthalmic composition, from the viewpoint of exerting the effect of the present invention more remarkably. It is preferably / v% or more and less than 100 w / v%, more preferably 85 w / v% or more and 99.5 w / v% or less, and 90 w / v% or more and 99.2 w / v% or less. More preferred.
　本発明の眼科組成物に使用される水は、医薬上、薬理学的に又は生理学的に許容されるものであればよい。このような水として、例えば、蒸留水、常水、精製水、滅菌精製水、注射用水及び注射用蒸留水等を挙げることができる。それらの定義は第十七改正日本薬局方に基づく。 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.
　本発明の眼科組成物は、所望量の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分及び（Ａ－４）成分からなる群より選択される１種以上、及び任意で（Ｂ）ＴＲＰＡアゴニスト、さらに、必要に応じて他の成分を、所望の濃度となるように添加及び混和することにより調製することができる。例えば、精製水でそれらの成分を溶解又は分散させ、所定のｐＨ及び浸透圧に調整し、濾過滅菌等により滅菌処理することで調製できる。
　なお、本発明の眼科組成物には、塩化ベンザルコニウム又はその塩、カフェイン又はその塩、５００００単位以上のレチノールパルミチン酸エステルが含まれないことが好ましいが、これらを含んでいてもよい。 The ophthalmic composition of the present invention is one or more selected from the group consisting of a desired amount of (A-1) component, (A-2) component, (A-3) component and (A-4) component, and It can optionally be prepared by adding and mixing (B) a TRPA agonist and, if necessary, other components to the desired concentration. For example, it can be prepared by dissolving or dispersing those components in purified water, adjusting the pH and osmotic pressure to a predetermined value, and sterilizing by filtration sterilization or the like.
The 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.
　本発明の眼科組成物のｐＨは、医薬上、薬理学的に又は生理学的に許容される範囲内であれば、特に限定されるものではない。例えば、眼科組成物のｐＨは、眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定され得るが、例えば、４．０～９．５であってよく、４．０～９．０であることが好ましく、４．５～９．０であることがより好ましく、４．５～８．５であることが更に好ましく、５．０～８．５であることが更により好ましい。 The pH of the ophthalmic composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically or physiologically acceptable range. For example, the pH of the ophthalmic composition can be appropriately set according to the use, formulation form, usage method, etc. of the ophthalmic composition, and may be, for example, 4.0 to 9.5, 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.
　本発明の眼科組成物は、必要に応じて、生体に許容される範囲内の浸透圧比に調節することができる。適切な浸透圧比は、眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定され得るが、例えば、０．４～５．０とすることができ、０．６～３．０とすることが好ましく、０．８～２．２とすることがより好ましく、０．８～２．０とすることが更に好ましい。浸透圧比は、第十七改正日本薬局方に基づき、２８６ｍＯｓｍ（０．９ｗ／ｖ％塩化ナトリウム水溶液の浸透圧）に対する試料の浸透圧の比とし、浸透圧は日本薬局方記載の浸透圧測定法（凝固点降下法）を参考にして測定する。なお、浸透圧比測定用標準液（０．９ｗ／ｖ％塩化ナトリウム水溶液）は、塩化ナトリウム（日本薬局方標準試薬）を５００～６５０℃で４０～５０分間乾燥した後、デシケーター（シリカゲル）中で放冷し、その０．９００ｇを正確に量り、精製水に溶かし正確に１００ｍＬとして調製するか、市販の浸透圧比測定用標準液（０．９ｗ／ｖ％塩化ナトリウム水溶液）を用いることができる。 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).
　本発明の眼科組成物の粘度は、医薬上、薬理学的に又は生理学的に許容される範囲内であれば、特に限定されるものではない。例えば、回転粘度計（ＲＥ５５０型粘度計、東機産業社製、ローター；１°３４‘×Ｒ２４）で測定した２０℃における粘度が０．１～１００００ｍＰａ・ｓであることが好ましく、０．１～８０００ｍＰａ・ｓであることがより好ましく、０．１～１０００ｍＰａ・ｓであることが更に好ましく、０．１～１００ｍＰａ・ｓであることが更により好ましく、１～２０ｍＰａ・ｓであることが特に好ましい。 The viscosity of the ophthalmic composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically or physiologically acceptable range. For example, the viscosity at 20 ° C. measured with a rotary viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34'x R24) is preferably 0.1 to 10000 mPa · s, 0.1. It is more preferably 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.
　本発明の眼科組成物は、目的に応じて種々の製剤形態をとることができる。そのような製剤形態として、例えば、液剤、ゲル剤、半固形剤（軟膏等）等が挙げられる。 The ophthalmic composition of the present invention can take various formulation forms depending on the purpose. Examples of such formulation forms include liquid preparations, gel preparations, semi-solid preparations (ointments, etc.) and the like.
　本発明の眼科組成物は、例えば、点眼剤（点眼液又は点眼薬ともいう。また、点眼剤にはコンタクトレンズ装用中に点眼可能な点眼剤を含む。）、人工涙液、洗眼剤（洗眼液又は洗眼薬ともいう。また、洗眼剤にはコンタクトレンズ装用中に洗眼可能な洗眼剤を含む。）、コンタクトレンズ用組成物［コンタクトレンズ装着液、コンタクトレンズケア用組成物（コンタクトレンズ消毒剤、コンタクトレンズ用保存剤、コンタクトレンズ用洗浄剤、コンタクトレンズ用洗浄保存剤）、コンタクトレンズ用のパッケージ液等］等として用いることができる。
　なお、「コンタクトレンズ」は、ハードコンタクトレンズ、ソフトコンタクトレンズ（イオン性及び非イオン性の双方を包含し、シリコーンハイドロゲルコンタクトレンズ及び非シリコーンハイドロゲルコンタクトレンズの双方を包含する）を含む。 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).
　本発明の眼科組成物は、本発明の効果をより顕著に発揮できることから、点眼剤（コンタクトレンズ装用中に点眼可能な点眼剤を含む。）であることが好ましい。本実施形態に係る眼科組成物が点眼剤である場合、その用法・用量としては、効果を奏し、副作用の少ない用法・用量であれば特に限定されないが、例えば成人（１５歳以上）及び７歳以上の小児の場合、１回１～７滴が好ましく、１回１～３滴、１～２滴、又は２～３滴がより好ましい。点眼回数は、１回１～３滴、１～２滴、又は２～３滴の場合、１日５～６回点眼して用いる方法を例示できる。また、１回４～６滴を１日３～６回点眼しても良い。 The ophthalmic composition of the present invention is preferably an eye drop (including an eye drop that can be instilled while wearing contact lenses) because the effect of the present invention can be exerted more remarkably. When the ophthalmic composition according to the present embodiment is an eye drop, the dosage and administration thereof is not particularly limited as long as it is effective and has few side effects, but for example, adults (15 years old or older) and 7 years old. In the case of the above-mentioned children, 1 to 7 drops at a time are preferable, and 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops at a time are more preferable. As for 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.
　本発明の眼科組成物は、任意の容器に収容して提供される。本実施形態に係る眼科組成物を収容する容器については特に制限されず、例えば、ガラス製であってもよく、またプラスチック製であってもよい。好ましくはプラスチック製である。プラスチックとしては、例えば、ポリエチレンテレフタレート、ポリアリレート、ポリエチレンナフタレート、ポリカーボネート、ポリエチレン、ポリプロピレン、ポリイミド及びこれらを構成するモノマーの共重合体、並びにこれら２種以上を混合したものが挙げられる。好ましくは、ポリエチレンテレフタレートである。また、本実施形態に係る眼科組成物を収容する容器は、容器内部を視認できる透明容器であってもよく、容器内部の視認が困難な不透明容器であってもよい。好ましくは透明容器である。ここで、「透明容器」には、無色透明容器及び有色透明容器の双方が含まれる。 The ophthalmic composition of the present invention is provided in an arbitrary container. The container for accommodating the ophthalmic composition according to the present embodiment is not particularly limited, and may be made of glass or plastic, for example. It is preferably made of plastic. Examples of the plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, a copolymer of polyimide and the monomers constituting these, and a mixture of two or more of these. Preferably, it is polyethylene terephthalate. Further, the container for accommodating the ophthalmic composition according to the present embodiment may be a transparent container in which the inside of the container can be visually recognized, or an opaque container in which the inside of the container is difficult to visually recognize. A transparent container is preferable. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container.
　本発明の眼科組成物を収容する容器には、ノズルが装着されてもよい。ノズルの材質については特に制限されず、例えば、ガラス製であってもよく、またプラスチック製であってもよい。好ましくはプラスチック製である。プラスチックとしては、例えば、
ポリブチレンテレフタレート、ポリエチレン、ポリプロピレン、ポリエチレンテレフタレート、ポリエチレンナフタレート及びこれらを構成するモノマーの共重合体、並びにこれら２種以上を混合したものが挙げられる。 A nozzle may be attached to the container containing the ophthalmic composition of the present invention. The material of the nozzle is not particularly limited, and for example, it may be made of glass or plastic. It is preferably made of plastic. As for plastic, for example
Examples thereof include polybutylene terephthalates, polyethylene, polypropylene, polyethylene terephthalates, polyethylene naphthalates, copolymers of monomers constituting these, and mixtures of two or more of these.
　本発明の眼科組成物を収容する容器は、複数回の使用量が収容されるマルチドーズ型であってもよく、単回の使用量が収容されるユニットドーズ型であってもよい。 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.
［ドライアイやアレルギー等に由来する疼痛抑制用の眼科組成物又は疼痛抑制剤］
　また、本発明の眼科組成物は、上記の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有することで、刺激受容体ＴＲＰＡ１が活性化されたことによるドライアイやアレルギー等に由来する疼痛を低減することもできる。
　よって、本発明の一実施形態として、（Ａ）成分を含有する、ドライアイやアレルギー等に由来する疼痛抑制用の眼科組成物、及びドライアイやアレルギー等に由来する疼痛抑制剤が提供される。
　これは、ＴＲＰＡ１がドライアイによる疼痛にも関与することが報告されていることに基づく（例えば、Neuroscience. 2015 Apr 2;290:204-13 参照）。
また、疼痛はドライアイ由来の他、アレルギー由来であってもよい。なお、ドライアイとは、ドライアイ診断基準によるドライアイの他、目の乾きなども含む。 [Ophthalmic composition or pain suppressant for pain control derived from dry eye, allergies, etc.]
In addition, 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. ..
This is based on the fact that TRPA1 has also been reported to be involved in dry eye pain (see, eg, Neuroscience. 2015 Apr 2; 290: 204-13).
Further, the pain may be derived from allergies as well as from dry eye. The term "dry eye" includes not only dry eye according to the dry eye diagnostic criteria but also dry eyes.
〔眼科組成物用の刺激抑制剤〕
　また、本発明は、眼科組成物用の刺激抑制剤も提供する。当該刺激抑制剤における、（Ａ）成分、（Ｂ）成分の配合や形態としては、眼科組成物について、上記で説明した通りである。
　本発明の一実施形態として、（Ａ）成分を有効成分として含有する、（Ｂ）成分を含む眼科組成物の刺激抑制剤が提供される。ＴＲＰＡ１アゴニストがメントールの場合、清涼感を保持しつつ、眼科組成物の刺激を抑制することができる。 [Stimulation inhibitor for ophthalmic compositions]
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.
As an embodiment of the present invention, there is provided an irritation inhibitor of an ophthalmic composition containing the component (B), which contains the component (A) as an active ingredient. When the TRPA1 agonist is menthol, the irritation of the ophthalmic composition can be suppressed while maintaining a refreshing sensation.
〔眼科組成物の刺激を抑制する方法〕
　また、本発明は、眼科組成物に、（Ａ）成分及び（Ｂ）成分を含有させることを含む、眼科組成物の刺激を抑制する方法も提供する。具体的には、（Ｂ）ＴＲＰＡ１アゴニストを含有する眼科組成物に、さらに、（Ａ－１）充血除去成分、（Ａ－２）抗ヒスタミン成分、（Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び（Ａ－４）局所麻酔成分からなる群より選択される少なくとも１種を含有させることを特徴とする、（Ｂ）ＴＲＰＡ１アゴニストに由来する眼科組成物の刺激を抑制する方法、である。 [Method of suppressing irritation of ophthalmic composition]
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. Specifically, in addition to (B) an ophthalmic composition containing a TRPA1 agonist, (A-1) a decongestant component, (A-2) an antihistamine component, (A-3) camphor, menthone, isomenthol, Containing at least one selected from the group consisting of cineole, mentoflan, pinen, limonene, neomenthol, and methyl acetate, and at least one selected from the group consisting of (A-4) local anesthetic components. It is a method (B) of suppressing irritation of an ophthalmic composition derived from a TRPA1 agonist.
〔眼刺激の評価方法〕
　また、本発明は、眼刺激の評価方法も提供する。例えば、被験試料を、ＴＲＰＡ１発現細胞と接触させ、前記被験試料によりＴＲＰＡ１を介して引き起こされる細胞内カルシウムイオン濃度の変化量を測定することを特徴とする、被験試料による眼刺激の評価方法、である。
　本発明の評価方法に用いられる被験試料として、例えば、（Ｂ）ＴＲＰＡ１アゴニストと、眼科組成物の分野で通常用いられる成分との組み合わせを用いることが出来る。例えば、そのような成分としては、上記した（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、又は（Ａ－４）成分であってもよく、界面活性剤、増粘剤、緩衝剤、等張化剤、担体、キレート剤、基剤、ｐＨ調節剤、安定化剤、防腐剤、殺菌剤又は抗菌剤、糖類、糖アルコール類、眼筋調節薬剤、ビタミン類、アミノ酸類、消炎剤、収斂剤等であってもよい。
　また、（Ｂ）ＴＲＰＡ１アゴニストは、被験試料との対照（対照試料）として用いられてもよい。
　ＴＲＰＡ１発現細胞は、安定的にｈＴＲＰＡ１遺伝子を保持することが出来る細胞であれば特に限定されないが、例えば、T-REｘ－293細胞、HEK293T細胞等が好ましい。
　上記方法における、細胞内カルシウムイオン濃度の変化は、例えば、公知のＣａ２＋濃度指示薬、Fluo-4、Fluo-8又はFluo-2等を用いて、市販のマイクロプレートリーダーや、蛍光顕微鏡等により測定、観察することが出来る。
　本発明においては、細胞内カルシウムイオン濃度の変化量を測定することで、眼刺激の有無、眼刺激の強さ等の情報を得ることが出来る。また、被験試料や対照試料をＴＲＰＡ１発現細胞と接触させる時間を調整すること等により、細胞内カルシウムイオン濃度を経時観察して、被験試料の、ＴＲＰＡ１発現細胞に対する親和性に関する情報（例えば、被験試料のＬｏｇＰ値（分配係数）等との相関）等も得ることが出来る。
　また、被験試料を、ＴＲＰＡ１発現細胞と接触させる方法としては、例えば、被験試料又はその希釈液、あるいは、被験試料を含む人工涙液等を、培養されたＴＲＰＡ１発現細胞やヒト等の動物に添加、点眼する方法等が挙げられる。 [Evaluation method of eye stimulation]
The present invention also provides a method for evaluating eye irritation. For example, a method for evaluating eye irritation by a test sample, which comprises contacting a test sample with TRPA1-expressing cells and measuring the amount of change in intracellular calcium ion concentration caused by the test sample via TRPA1. is there.
As the test sample used in the evaluation method of the present invention, for example, a combination of (B) TRPA1 agonist and a component usually used in the field of ophthalmic composition can be used. For example, such a component may be the above-mentioned (A-1) component, (A-2) component, (A-3) component, or (A-4) component, and is a surfactant. Thickeners, buffers, isotonic agents, carriers, chelating agents, bases, pH regulators, stabilizers, preservatives, bactericides or antibacterial agents, sugars, sugar alcohols, eye muscle regulators, vitamins, It may be an amino acid, an antibacterial agent, an astringent agent or the like.
Moreover, (B) TRPA1 agonist may be used as a control (control sample) with a test sample.
The TRPA1-expressing cells are not particularly limited as long as they can stably carry the hTRPA1 gene, but for example, T-REx-293 cells, HEK293T cells and the like are preferable.
The change in intracellular calcium ion concentration in the above method is measured with a commercially available microplate reader, a fluorescence microscope, or the like using, for example, a known Ca 2+ concentration indicator, Fluo-4, Fluo-8, or Fluo-2. , Can be observed.
In the present invention, by measuring the amount of change in the intracellular calcium ion concentration, it is possible to obtain information such as the presence or absence of eye irritation and the intensity of eye irritation. In addition, the intracellular calcium ion concentration is observed over time by adjusting the time for contacting the test sample or the control sample with the TRPA1-expressing cells, and information on the affinity of the test sample for the TRPA1-expressing cells (for example, the test sample). Correlation with the LogP value (partition coefficient) and the like) can also be obtained.
As a method for bringing the test sample into contact with TRPA1-expressing cells, for example, the test sample or a diluted solution thereof, or artificial tears containing the test sample is added to cultured TRPA1-expressing cells or animals such as humans. , The method of instilling, etc.
　以下に実施例を示し、本発明をより具体的に説明するが、本発明は実施例に何ら限定されるものではない。 Examples are shown below to explain the present invention more specifically, but the present invention is not limited to the examples.
＜使用細胞＞
　ｈＴＲＰＡ１遺伝子を保持するＴ－ＲＥｘ－２９３細胞株の調製
　ｈＴＲＰＡ１のｍＲＮＡを、ヒトＷＩ３８細胞から抽出した。安定的にｈＴＲＰＡ１を発現させたＨＥＫ細胞は、Ｉｎｖｉｔｒｏｇｅｎ社のテトラサイクリン制御Ｔ－ＲＥｘ発現システムを用いて作成した。ｈＴＲＰＡ１　ｍＲＮＡを鋳型としてＲＴ－ＰＣＲにより増幅させたｈＴＲＰＡ１のｃＤＮＡを、哺乳類細胞用遺伝子発現ベクターであるｐｃＤＮＡ４／ＴＯ（ｉｎｖｉｔｒｏｇｅｎ社製）へ組み込み、ｉｎｖｉｔｒｏｇｅｎ社の遺伝子導入試薬であるＬｉｐｏｆｅｃｔａｍｉｎ ２０００ ｒｅａｇｅｎｔを用いてＴ－ＲＥｘ－２９３細胞に導入した。ｐｃＤＮＡ４／ＴＯにはＺｅｏｃｉｎが組み込まれており、Ｔ－ＲＥｘ－２９３細胞にＴ－Ｒｅｘシステムを維持するためのプラスミド（ブラストサイジン耐性遺伝子）が保持されている。抗生物質であるＺｅｏｃｉｎ５００μｇ／ｍＬ及びブラストサイジン１０μｇ／ｍＬを用いて安定的にｈＴＲＰＡ１遺伝子を保持するＴ－ＲＥｘ－２９３細胞株を樹立した。 <Cells used>
Preparation of 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 μg / mL and Blasticidin 10 μg / mL.
＜細胞培養＞
　ｈＴＲＰＡ１を保持するＴ－ＲＥｘ－２９３細胞は１０％ＦＢＳ，１００ｕｎｉｔ／ｍＬ ｐｅｎｉｃｉｌｌｉｎ，１００ｍｇ／ｍＬ ｓｔｒｅｐｔｏｍｙｓｉｎ，２５０ｎｇ／ｍＬ ａｍｐｈｏｔｅｒｉｃｉｎ Ｂを含むＤＭＥＭ培地を用いて、５％二酸化炭素存在下で培養した。継代の際には２００μｇ／ｍＬ Ｚｅｏｃｉｎ，５μｇ／ｍＬ ブラストサイジンを加え、最大継代数は５０以下で行った。
　具体的には前培養として６０ ｍｍ　ｄｉｓｈにセミコンフルエントになるようにＴ－ＲＥｘ－２９３細胞を培養した後、ＰＢＳ（－）で洗浄した。１×Ｔｒｙｐｓｉｎ／ＥＤＴＡ処理によりｄｉｓｈから細胞を剥がし、ＤＭＥＭ培地を加えた。その後、１５ ｍＬチューブに移し、８００ ｒｐｍにて室温で４分間、遠心分離した。ＤＭＥＭ培地のみを吸引除去し、タッピングにより細胞をほぐした後、新たなＤＭＥＭ培地を加え、約４０×１０４～５０×１０４ｃｅｌｌ／ｍＬになるように細胞数を調整した細胞懸濁液を作成した。この時、受容体発現のために１μｇ／ｍＬｔｅｔｒａｃｙｃｌｉｎｅを加えた。作成した細胞懸濁液を９６ウェルプレートに１００μＬずつ分注し、３７℃、５％ＣＯ２インキュベーターで一晩インキュベートして試験に使用した。 <Cell culture>
T-REx-293 cells carrying hTRPA1 were cultured in DMEM medium containing 10% FBS, 100 unit / mL penicillin, 100 mg / mL streptomysin, 250 ng / mL amphotericin B in the presence of 5% carbon dioxide. At the time of passage, 200 μg / mL Zeocin and 5 μg / mL Blasticidin were added, and the maximum number of passages was 50 or less.
Specifically, as a preculture, T-REx-293 cells were cultured in 60 mm dish so as to be semi-confluent, and then washed with PBS (-). Cells were stripped from the dish by 1 × Trypsin / EDTA treatment and DMEM medium was added. Then, it was transferred to a 15 mL tube and centrifuged at 800 rpm at room temperature for 4 minutes. After removing only the DMEM medium by suction and loosening the cells by tapping, a new DMEM medium is added, and a cell suspension adjusted to have a cell number of about 40 × 10 4 to 50 × 10 4 cells / mL is prepared. Created. At this time, 1 μg / mL telecycline was added for receptor expression. The prepared cell suspension was dispensed into 96-well plates in 100 μL portions and incubated overnight in a 5% CO 2 incubator at 37 ° C. for use in the test.
［試験例１］ｌ－メントールによる刺激感抑制確認試験
　メントールは、刺激受容体ＴＲＰＡ１を活性化して刺激を与えることが知られている。そこでｌ－メントールと被験試料（実施例）を上記した細胞に投与し、被験試料によって、ｌ－メントールによるＴＲＰＡ１活性が阻害されるかどうかを確認した。
　Ｃａ２＋濃度指示薬（Ｆｌｕｏ－４若しくはＦｌｕｏ－８（ＡＡＴ Ｂｉｏｑｕｅｓｔ, Ｉｎｃ.社製）を用いて、ＴＲＰ活性が変化するかを観察した。Ｃａ２＋濃度指示薬を予めｈＴＲＰＡ１を保持したＴ－ＲＥｘ－２９３細胞内に取り込ませておき、マイクロプレートリーダーにて蛍光量を測定した。
　具体的には以下のプロトコールに従って実施した。前日に準備（上記した細胞培養）を行っていた９６ウェルプレートをインキュベーターより取り出し、ＤＭＥＭ培地をデカンテーションで除去した。１００μＬ／ウェルの緩衝液（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、残余　精製水）で優しく洗浄し、１．５μＭ Ｆｌｕｏ－８で溶解した同上の緩衝液を５０μＬずつウェルに添加した後、３７℃、５％ＣＯ2インキュベーターで１時間処理した。インキュベーター処理後、Ｆｌｕｏ－８が入った同上の緩衝液をデカンテーションで除去し、１００μＬ／ウェルの同上の緩衝液で優しく洗浄した。さらに、１８０μＬ／ウェルの同上の緩衝液を添加して、Ｆｌｅｘｓｔａｔｉｏｎ II (レジスタードトレードマーク) 又はＦｌｅｘｓｔａｔｉｏｎ III (レジスタードトレードマーク) マイクロプレートリーダー（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ、Ｓｕｎｎｙｖａｌｅ、ＣＡ、ＵＳＡ）で測定を開始した。マイクロプレートリーダー測定開始３０秒後に被験試料を２０μＬ／ウェル添加し、添加後５秒～１２０秒間における蛍光量の最大値を測定し、この値を蛍光量とした。 [Test Example 1] Confirmation test for suppression of irritation by l-menthol Menthol is known to activate the stimulus receptor TRPA1 to stimulate it. Therefore, l-menthol and a test sample (Example) were administered to the above-mentioned cells, and it was confirmed whether the test sample inhibited TRPA1 activity by l-menthol.
Using a Ca 2+ concentration indicator (Fluor-4 or Fluor-8 (manufactured by AAT Bioquest, Inc.), it was observed whether the TRP activity was changed. The Ca 2+ concentration indicator was T-REx-293 that previously held hTRPA1. It was taken up into cells, and the amount of fluorescence was measured with a microplate reader.
Specifically, it was carried out according to the following protocol. The 96-well plate prepared the day before (the above-mentioned cell culture) was taken out from the incubator, and the DMEM medium was removed by decantation. 100 μL / well buffer (pH 7.4, 5.37 mM KCl, 0.44 mM KH 2 PO 4 , 137 mM NaCl, 0.34 mM Na 2 HPO 4 , 5.56 mM D-glucose, 20 mM Gently washed with HEPES, 1 mM CaCl 2 , 0.1% chloride serum albumin, 2.5 mM pH probecid, residual purified water), and 50 μL of the same buffer solution dissolved in 1.5 μM Fluo-8 was added to the wells. After that, it was treated with a 5% CO 2 incubator at 37 ° C. for 1 hour. After incubator treatment, the same buffer containing Fluo-8 was decanted and gently washed with 100 μL / well of the same buffer. In addition, 180 μL / well of the same buffer was added and measurements were initiated on a Flexstation II (registered trademark) or Flexstation III (registered trademark) microplate reader (Molecular Devices, Sunnyvale, CA, USA). .. 20 μL / well of the test sample was added 30 seconds after the start of the microplate reader measurement, and the maximum value of the fluorescence amount was measured from 5 seconds to 120 seconds after the addition, and this value was taken as the fluorescence amount.
　なお、ＴＲＰ活性（％）は以下の式に基づき、算出した。
Figure JPOXMLDOC01-appb-M000001
 The TRP activity (%) was calculated based on the following formula.
Figure JPOXMLDOC01-appb-M000001
　比較例２（ｌ－メントール単独投与時）は１００％となる。
　下記表１に記載の被験試料のＴＲＰ活性の算出結果を図１に示す。なお、比較例１はコントロール（ｌ－メントール非添加緩衝液（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、残余　精製水））であり、比較例２は、比較例１と同様の緩衝液にｌ－メントール（ＴＲＰＡ１アゴニスト）を６６．７μＭの濃度で溶解させたものである。そして、実施例は、比較例１と同様の緩衝液に、ｌ－メントール（６６．７μＭ）と表１に記載の成分を、表２に記載の濃度で溶解させたものである。 Comparative Example 2 (when l-menthol alone is administered) is 100%.
The calculation results of the TRP activity of the test samples shown in Table 1 below are shown in FIG. In Comparative Example 1, 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)), and 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 μM. Then, in the example, l-menthol (66.7 μM) and the components shown in Table 1 were dissolved in the same buffer solution as in Comparative Example 1 at the concentrations shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　図１の結果から、本発明の（Ａ－１）充血除去成分である、テトラヒドロゾリン塩酸塩、ナファゾリン塩酸塩、（Ａ－２）抗ヒスタミン成分である、クロルフェニラミンマレイン酸塩、ジフェンヒドラミン塩酸塩、（Ａ－３）成分であるｄ－カンフル、ｄｌ－カンフル、（－）－メントン、（＋）－イソメントール、１，８－シネオール、メントフラン、α-ピネン、β-ピネン、（Ｒ）－（＋）－リモネン、（Ｓ）－（－）－リモネン、ネオメントール、メチルアセテート、及び（Ａ－４）成分である、クロロブタノールを含む眼科組成物は、ＴＲＰＡ１アゴニストによる刺激感を抑制できた。また、（Ａ－３）成分を含む精油である、ペパーミントオイル及びユーカリ油を含む眼科組成物においても、同様にＴＲＰＡ１アゴニストによる刺激感を抑制できた。 From the results of FIG. 1, the (A-1) decongestant component of the present invention, tetrahydrozoline hydrochloride, nafazoline hydrochloride, and (A-2) antihistamine component, chlorpheniramine maleate, diphenhydramine hydrochloride, (A-3) Ingredients d-camphor, dl-camphor, (-)-menthol, (+)-isomenthol, 1,8-cineole, mentoflan, α-pinene, β-pinene, (R)- 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. .. 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.
［試験例２］ｌ－メントールのＴＲＰＡ１活性化の可視化、経時観察及び結合能力評価
　上記試験例１と同様の原理に基づき、Ｃａ２＋濃度に応じて蛍光量が増すＣａ２＋濃度指示薬Ｆｌｕｏ－８を用いてＴＲＰの活性化度を測定した。Ｃａ２＋濃度指示薬を予めｈＴＲＰＡ１遺伝子を保持したＴ－ＲＥｘ－２９３細胞内に取り込ませておき、蛍光顕微鏡システム（Ｌｅｉｃａ, ＬＡＳ ＡＦ６０００）にて蛍光量を可視化した。 [Test Example 2] l-visualization of TRPA1 activation of menthol, based on the same principle as time-series observation and binding capacity evaluation in Test Example 1, the Ca 2+ concentration indicator Fluo-8 fluorescence amount is increased in accordance with the Ca 2+ concentration The degree of activation of TRP was measured using. The Ca 2+ concentration indicator was previously incorporated into T-REx-293 cells carrying the hTRPA1 gene, and the amount of fluorescence was visualized with a fluorescence microscope system (Leica, LAS AF6000).
　カバーガラス上に約６０×１０４ｃｅｌｌ／ｍＬのｈＴＲＰＡ１遺伝子を保持したＴ－ＲＥｘ－２９３細胞ＤＭＥＭ懸濁液をスライドガラス１枚あたり２０μＬ滴下して、３７℃、５％ＣＯ２インキュベーターで一晩インキュベートした。インキュベートしたカバーガラスをインキュベーターより取り出し、培地をデカンテーションで除去した。カバーガラスを緩衝液 (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、残余　精製水)で優しく洗浄した後、蛍光指示薬Ｆｌｕｏ－８／緩衝液を添加し、３７℃、５％ＣＯ2インキュベーターで１時間処理した。インキュベーター処理後、カバーガラスをチャンバー上に設置し、蛍光顕微鏡システム（Ｌｅｉｃａ, ＬＡＳ　ＡＦ６０００）にて蛍光量を可視化及び経時観察した。 20 μL of T-REx-293 cell DMEM suspension carrying the hTRPA1 gene of about 60 × 10 4 cell / mL was added dropwise to each slide glass on a cover glass, and overnight at 37 ° C. in a 5% CO 2 incubator. Incubated. The incubated cover glass was removed from the incubator and the medium was decanted. Buffer the cover glass (pH 7.4, 5.37 mM KCl, 0.44 mM KH 2 PO 4 , 137 mM NaCl, 0.34 mM Na 2 HPO 4 , 5.56 mM D-glucose, 20 mM HEPES. After gently washing with (1 mM NaCl 2 , residual purified water), 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).
　本試験の流れは以下の通りである。
（１）緩衝液中で蛍光試薬の発光量が安定しているのを確認した後に、緩衝液をｌ－メントール(６６．７μＭ)を含有する緩衝液に替え、ＴＲＰＡ１を活性させる。
（２）ＴＲＰＡ１の活性化が確認できた後に、ｌ－メントール(６６．７μＭ)を含有する緩衝液を、さらに同濃度のｌ－メントールと各被験試料(テトラヒドロゾリン塩酸塩　０．００３１２５ｗ／ｖ％、ペパーミントオイル０．０１５ｗ／ｖ％)との組み合わせに替え、ＴＲＰＡ１活性が阻害されるか確認を行う。
（３）ＴＲＰＡ１活性の阻害効果が確認できた後に、ｌ－メントールと各被験試料を含有する緩衝液を、(１)で用いたｌ－メントールを含有する緩衝液に戻し、ＴＲＰＡ１が再び活性化されるか確認を行う。 The flow of this test is as follows.
(1) After confirming that the amount of light emitted from the fluorescent reagent is stable in the buffer solution, the buffer solution is replaced with a buffer solution containing l-menthol (66.7 μM) to activate TRPA1.
(2) After the activation of TRPA1 was confirmed, a buffer solution containing l-menthol (66.7 μM) was added, and the same concentration of l-menthol and each test sample (tetrahydrozoline hydrochloride 0.003125 w / v%) were added. Instead of the combination with peppermint oil 0.015 w / v%), it is confirmed whether TRPA1 activity is inhibited.
(3) After confirming the inhibitory effect on TRPA1 activity, the buffer solution containing l-menthol and each test sample was returned to the buffer solution containing l-menthol used in (1), and TRPA1 was activated again. Check if it is done.
　ｌ－メントールによるＴＲＰＡ１活性化を蛍光顕微鏡にて可視化した結果を図２に示す。ボルネオールを被験試料として用いたものはＴＲＰＡ１活性阻害効果を示した後に、試験液をｌ－メントールに戻すと再度、ＴＲＰＡ１活性を示した（図２の参考例参照）。一方、（Ａ－１）充血除去成分であるテトラヒドロゾリン塩酸塩及び（Ａ－３）成分を含む精油であるペパーミントオイルを被験試料として用いたものは、ＴＲＰＡ１活性阻害効果を示した後に、試験液をメントールのみのものに戻すと阻害効果が見られないか、再活性化が弱かった（図２の実施例参照）。
　すなわち、本発明の（Ａ－１）成分及び（Ａ－３）成分は、それぞれ、ＴＲＰＡ１受容体に対する阻害効果をしばらくの間、持続出来たと考えられる。 The result of visualizing TRPA1 activation by l-menthol with a fluorescence microscope is shown in FIG. The sample using borneol as a test sample showed TRPA1 activity inhibitory effect, and then returned to l-menthol to show TRPA1 activity again (see the reference example in FIG. 2). On the other hand, those using tetrahydrozoline hydrochloride, which is a decongestant component (A-1), and peppermint oil, which is an essential oil containing the component (A-3), as test samples showed a TRPA1 activity inhibitory effect, and then the test solution was used. Returning to menthol-only ones showed no inhibitory effect or weak reactivation (see Examples in FIG. 2).
That is, it is considered that the components (A-1) and (A-3) of the present invention were able to sustain the inhibitory effect on the TRPA1 receptor for a while.
［試験例３］ヒトにおけるテトラヒドロゾリン塩酸塩による刺激感抑制確認試験
　人工涙液(ロート製薬(株)製　「ロート　ソフトワン点眼」　塩化カリウム０．１ｗ／ｖ％、塩化ナトリウム０．４ｗ／ｖ％、ホウ酸、ｐＨ調節剤含有)にｌ－メントール(０．０１ｗ／ｖ％)及びポリオキシエチレン硬化ヒマシ油(０．１ｗ／ｖ％)を溶解させたもの（比較例）、同上の人工涙液にｌ－メントール(０．０１ｗ／ｖ％)、ポリオキシエチレン硬化ヒマシ油(０．１ｗ／ｖ％)及びテトラヒドロゾリン塩酸塩(０．０５ｗ／ｖ％)を溶解させたもの（実施例）を同じ被験者の左右の眼にそれぞれ点眼し、清涼感及び刺激感を評価した結果を図３に示す。なお、被験者は裸眼若しくは眼鏡着用の８名の成人男性であり、評価はＶＡＳスケール（最大目盛：２０）を用いて数値化して行った。 [Test Example 3] Confirmation test of suppression of irritation by tetrahydrozoline hydrochloride in humans Artificial tears ("Rohto Soft One Eye Drops" manufactured by Rohto Pharmaceutical Co., Ltd. L-menthol (0.01 w / v%) and polyoxyethylene hydrogenated castor oil (0.1 w / v%) dissolved in boric acid (containing pH adjuster) (comparative example), artificial tears as above The same as in (Example) in which l-menthol (0.01 w / v%), polyoxyethylene hydrogenated castor oil (0.1 w / v%) and tetrahydrozoline hydrochloride (0.05 w / v%) were dissolved. FIG. 3 shows the results of evaluating the refreshing sensation and the stimulating sensation by instilling the left and right eyes of the subject. The subjects were eight adult males with naked eyes or wearing spectacles, and the evaluation was quantified using the VAS scale (maximum scale: 20).
　結果、ｌ－メントールと（Ａ－１）充血除去成分であるテトラヒドロゾリン塩酸塩を組み合わせることで、ｌ－メントールの清涼感は維持しつつ、ｌ－メントールの刺激感を抑制出来ることが示された。すなわち本発明の（Ａ－１）充血除去成分によって、ＴＲＰＡ１アゴニストによる刺激感を抑制出来ることがヒトにおいても確認された。 As a result, it was shown that by combining l-menthol and tetrahydrozoline hydrochloride, which is a (A-1) decongestant component, the irritation sensation of l-menthol can be suppressed while maintaining the refreshing sensation of l-menthol. That is, it was confirmed in humans that the (A-1) decongestant component of the present invention can suppress the irritation sensation caused by the TRPA1 agonist.
［製剤例］
　下記表４及び表５に記載の処方例を調製した。精製水は各液剤の全量が１００ｍＬとなるよう加えられた。 [Formulation example]
The formulation examples shown in Tables 4 and 5 below were prepared. Purified water was added so that the total volume of each solution was 100 mL.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　本発明は、刺激感が抑制された眼科組成物、眼科組成物用の刺激抑制剤、眼科組成物の刺激を抑制する方法及び眼刺激の評価方法に関する。本発明の剤は、医薬品の分野において有用である。 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.

Claims (5)

  1. 　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有することを特徴とする、眼科組成物用の刺激抑制剤：
    （Ａ－１）充血除去成分、
    （Ａ－２）抗ヒスタミン成分、
    （Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
    （Ａ－４）局所麻酔成分。     Ophthalmology, which contains at least one selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4). Stimulation inhibitor for 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.
  2. 　（Ｂ）ｌ－メントールを含有する眼科組成物用であり、かつ、ｌ－メントールの刺激感を抑制するための剤であることを特徴とする、請求項１に記載の刺激抑制剤。 (B) The irritation inhibitor according to claim 1, which is for an ophthalmic composition containing l-menthol and is an agent for suppressing the irritation sensation of l-menthol.
  3. 　（Ｂ）ＴＲＰＡ１アゴニストを含有する眼科組成物に、さらに、以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有させることを特徴とする、(Ｂ)ＴＲＰＡ１アゴニストに由来する眼科組成物の刺激を抑制する方法：
    （Ａ－１）充血除去成分、
    （Ａ－２）抗ヒスタミン成分、
    （Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
    （Ａ－４）局所麻酔成分。     (B) An ophthalmic composition containing a TRPA1 agonist, further selected from the group consisting of the following components (A-1), (A-2), (A-3), and (A-4). (B) A method for suppressing irritation of an ophthalmic composition derived from a TRPA1 agonist, which comprises containing at least one of the above:
    (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.
  4. 　被験試料を、ＴＲＰＡ１発現細胞と接触させ、前記被験試料によりＴＲＰＡ１を介して引き起こされる細胞内カルシウムイオン濃度の変化量を測定することを特徴とする、被験試料による眼刺激の評価方法。 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.
  5. 　以下の（Ａ－１）成分、（Ａ－２）成分、（Ａ－３）成分、及び（Ａ－４）成分からなる群より選択される少なくとも１種を含有することを特徴とする、ドライアイやアレルギー等に由来する疼痛抑制用の眼科組成物：
    （Ａ－１）充血除去成分、
    （Ａ－２）抗ヒスタミン成分、
    （Ａ－３）カンフル、メントン、イソメントール、シネオール、メントフラン、ピネン、リモネン、ネオメントール、及びメチルアセテートからなる群より選択される少なくとも１種、及び
    （Ａ－４）局所麻酔成分。     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 for pain control derived from eye and allergies:
    (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.
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