WO2019131517A1 - Ophthalmic product and masking method - Google Patents

Ophthalmic product and masking method Download PDF

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Publication number
WO2019131517A1
WO2019131517A1 PCT/JP2018/047270 JP2018047270W WO2019131517A1 WO 2019131517 A1 WO2019131517 A1 WO 2019131517A1 JP 2018047270 W JP2018047270 W JP 2018047270W WO 2019131517 A1 WO2019131517 A1 WO 2019131517A1
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WIPO (PCT)
Prior art keywords
container
preferable
component
ophthalmic
volume
Prior art date
Application number
PCT/JP2018/047270
Other languages
French (fr)
Japanese (ja)
Inventor
香菜 内藤
奥村　隆
石井　玲子
Original Assignee
ライオン株式会社
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Publication date
Application filed by ライオン株式会社 filed Critical ライオン株式会社
Priority to JP2019561653A priority Critical patent/JP7117017B2/en
Priority to KR1020207001132A priority patent/KR102658489B1/en
Priority to CN201880083844.3A priority patent/CN111526892B/en
Publication of WO2019131517A1 publication Critical patent/WO2019131517A1/en
Priority to JP2022117682A priority patent/JP7380772B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • 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
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L9/00—Disinfection, sterilisation or deodorisation of air
    • A61L9/015—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone
    • A61L9/04—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone using substances evaporated in the air without heating
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
    • B65D81/02—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents specially adapted to protect contents from mechanical damage
    • B65D81/05—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents specially adapted to protect contents from mechanical damage maintaining contents at spaced relation from package walls, or from other contents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
    • Y02W90/00—Enabling technologies or technologies with a potential or indirect contribution to greenhouse gas [GHG] emissions mitigation
    • Y02W90/10—Bio-packaging, e.g. packing containers made from renewable resources or bio-plastics

Definitions

  • the present invention relates to an ophthalmic product and a masking method in which the odor of an oxygen absorbent is suppressed.
  • oxygen absorbers is known as a method of stabilizing easily oxidizable components. Also in the eye drop field, it is known that oxygen in the container can be absorbed and the easily oxidizable substance in the eye drop can be stabilized by enclosing the eye drop and the oxygen absorbent contained in the container in the enclosure. (Unexamined-Japanese-Patent No. 6-40907).
  • fat-soluble active ingredients such as vitamin A have attracted attention as effective ingredients for the treatment of the cornea, conjunctiva, nasal mucosa and pharynx, but these active ingredients have distinctive odors, and further over time The smell is amplified.
  • an iron-based oxygen absorbent (hereinafter also referred to as an iron-based oxygen absorbent) is placed in the enclosure for a long period of time, a specific offensive odor such as charring produced by the deoxygenation action is generated. It has been found that, by adhering to or filling the enclosure, a problem arises that an offensive odor is felt at the time of opening.
  • fat-soluble active ingredients such as vitamin A have attracted attention as effective ingredients for treating cornea, conjunctiva, nasal mucosa and pharynx. However, these active ingredients have a distinctive odor, and the odor is further amplified over time.
  • the present inventors contain an ophthalmic composition containing an easy oxide such as vitamin A in a container provided with a main body and a cap, and further contain iron as a main component.
  • the volume of the body, the oxygen permeability of the body, and the volume of the space formed between the enclosure and the container within a specific range.
  • the refreshing agent volatilizes from the inside of the container, and from the ophthalmic composition to the inside of the container, and further from the inside of the container to the inside of the surrounding body was found to be easy and inexpensive to mask.
  • the present invention provides the following ophthalmic product and masking method.
  • (A) easy oxides, (B) refreshing agent, An ophthalmic composition comprising (C) a nonionic surfactant and (D) one or more components selected from dibutyl hydroxytoluene, dibutyl hydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol,
  • An ophthalmic product contained in a container comprising a body containing an ophthalmic composition and a cap, the container being enclosed with an iron-based oxygen absorbent and enclosed with an enclosure,
  • the volume of the above body is 1 to 25 mL,
  • the ophthalmic product whose volume of the space formed between the said enclosure and the said container is 200 V / V% or less with respect to the volume of the said container.
  • Component (C) is at least one selected from polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene (20) sorbitan oleate, and polyoxyethylene polyoxypropylene glycol [1 ]
  • the ophthalmic product in any one of-[4]. [6].
  • An ophthalmic composition comprising (C) a nonionic surfactant and (D) one or more components selected from dibutyl hydroxytoluene, dibutyl hydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol,
  • An ophthalmic product contained in a container comprising a body containing an ophthalmic composition and a cap, the container being enclosed with an iron-based oxygen absorbent and enclosed in an enclosure;
  • the volume of the above body is 1 to 25 mL,
  • the odor masking method at the time of envelope opening which the volume of the space formed between the said enclosure and the said container shall be 200 V / V% or less with respect to the volume of the said container.
  • the specific offensive odor when the enclosure is opened is suppressed Provided an ophthalmic product and a masking method.
  • the ophthalmic composition of the present invention comprises (A) an easy oxide, (B) a refreshing agent, (C) a nonionic surfactant, and (D) dibutylhydroxytoluene, dibutylhydroxyanisole, propyl parahydroxybenzoate, It contains one or more components selected from butyl parahydroxybenzoate and chlorobutanol.
  • any of a water-soluble easy oxide and a hydrophobic easy oxide can be used, and these can be used singly or in appropriate combination of two or more.
  • water-soluble easily oxidized substances include sodium azulene sulfonate, vitamin B 2 (flavin adenine dinucleotide etc.), vitamin B 6 (pyridoxine hydrochloride etc.), vitamin B 12 (cyanocobalamin etc.), vitamin C (ascorbic acid etc.) Etc.
  • hydrophobic easy oxides among the ingredients listed in the Japanese Pharmacopoeia, Japanese Pharmacopoeia Extracorporeal Pharmaceutical Standards, Pharmaceutical Additives Convention, Pharmaceutical Additives Standards, Cosmetics Ingredient Standards, Cosmetic Type Compound Ingredient Standards and Food Additives Official Listing, It is possible to use substances that are "slightly soluble” to "poorly soluble” in water solubility, including all substances that undergo oxidative degradation.
  • Specific oxidizable substances include vitamin A, vitamin D, vitamin E, vitamin K, diphenhydramine, indomethacin, tacrolimus (FK506), macrolight antibiotics such as rifampicin, forskolin and the like, but are limited thereto It is not something to be done.
  • vitamin A promotes keratoconjunctival repair, mucin production, dry eye improvement effect, fatigue and haze improvement effect, and is easily decomposed and emits unique odor, so the effect of the present invention can be exhibited more .
  • vitamin A include vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid ester, and the like in addition to vitamin A itself.
  • vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid ester, and the like in addition to vitamin A itself.
  • vitamin A derivatives such as vitamin A fatty acid ester
  • retinol palmitate, retinol acetate, retinol, retinoic acid, retinoid, ⁇ -carotene and the like can be mentioned.
  • retinol palmitate and retinol acetate are preferable, and retinol palmitate is more preferable.
  • Retinol palmitate is generally commercially available in the range of 100 to 1.8 million international units / g (hereinafter sometimes abbreviated as IU / g). Specifically, DSM Nutrition Japan Co., Ltd. Examples thereof include retinol palmitate (1,740,000 I.U.), and retinoid palmitate retinoid.
  • vitamin D examples include cholecalciferol, 1 ⁇ , 25-dihydroxycholecalciferol and derivatives thereof.
  • vitamin E examples include ⁇ -tocopherol, d- ⁇ -tocopherol acetate and derivatives thereof
  • vitamin K includes phytilmenadione and derivatives thereof.
  • fat-soluble vitamins such as retinol palmitate and d- ⁇ -tocopherol acetate
  • macrolide antibiotics such as tacrolimus (FK506) and rifampicin
  • the blending amount of the component (A) in the ophthalmic composition is preferably 0.005 to 2 w / v% (mass / volume%, g / 100 mL, hereinafter the same), and more preferably 0.01 to 1 w / v% .
  • vitamin A is blended, 5,000 to 300,000 IU / 100 mL is preferable, 5,000 to 100,000 IU / 100 mL is more preferable, and 5,000 to 50,000 IU / 100 mL is further preferable.
  • concentration of vitamin A is high, the effects on the eye (stimulation of corneal and conjunctival repair, mucin production, dry eye improvement, fatigue and blurred eye improvement) are enhanced.
  • [(B) component] As the refreshing agent, l-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus oil, bergamot oil, geraniol, linalool, cineole, fennel oil, spearmint oil, peppermint oil, rose oil, coolmint oil and There may be mentioned peppermint oil and the like, which may be used singly or in appropriate combination of two or more. Among them, l-menthol, dl-camphor, d-camphor, d-borneol, geraniol and eucalyptus oil are preferable.
  • 0.0001 w / v% or more is preferable, and, as for the compounding quantity in the ophthalmic composition of (B) component, 0.0001-0.5 w / v% is more preferable, 0.00015-0. 2 w / v% is more preferable, and 0.0002 to 0.1 w / v% is particularly preferable. If the amount is too large, the irritation at the time of instillation may be strong, and the feeling of use may be impaired.
  • (B-1) 1-menthol is blended as the refreshing agent of the present invention
  • 0.005 to 0.5 w / v% is preferable, 0.01 to 0.2 w / v% is more preferable, and 0 .02 to 0.1 w / v% is more preferable, 0.03 to 0.1 w / v% is particularly preferable, and 0.04 to 0.05 W / V% is most preferable. If the compounding amount is too large, the irritation at the time of instillation may be strong and the feeling of use may be impaired, and if too small, the masking effect may be insufficient.
  • camphor When (B-2) camphor is blended as the refreshing agent of the present invention, 0.002 to 0.5 w / v% is preferable, 0.005 to 0.2 w / v% is more preferable, and 0.01 More preferably, it is at most 0.1 w / v%. If the compounding amount is too large, the irritation at the time of instillation may be strong and the feeling of use may be impaired, and if too small, the masking effect may be insufficient.
  • (B-3) d-borneol and geraniol are blended as the refreshing agent of the present invention, 0.002 to 0.5 w / v% is preferable, and 0.003 to 0.2 w / v% is more preferable. And 0.005 to 0.1 w / v% is more preferable. If the compounding amount is too large, the irritation at the time of instillation may be strong and the feeling of use may be impaired, and if too small, the masking effect may be insufficient.
  • blended as a refreshing agent of this invention 0.0005-0.5 w / v% is preferable, 0.001-0.2 w / v% is more preferable, 0. More preferably, 0015 to 0.1 w / v%. If the compounding amount is too large, the irritation at the time of instillation may be strong and the feeling of use may be impaired, and if too small, the masking effect may be insufficient.
  • the nonionic surfactant is not particularly limited as long as it is used in an ophthalmic composition, and may be used singly or in appropriate combination of two or more.
  • polyoxyethylene castor oil polyoxyethylene hydrogenated castor oil
  • polyoxyethylene sorbitan fatty acid ester POE sorbitan fatty acid ester
  • polyoxyethylene (20) sorbitan oleic acid ester polysorbate 80
  • poloxamer And polyoxyethylene polyoxypropylene glycol polyoxyethylene polyoxypropylene block copolymer, POEPOP glycol
  • polyethylene glycol monostearate represented by polyethylene glycol monostearate (10), and the like.
  • Polyoxyethylene castor oil is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and several types having different average addition mole number of ethylene oxide are known. .
  • the average addition mole number of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles are exemplified.
  • polyoxyethylene castor oil 3 (EO average addition mole number 3), polyoxyethylene castor oil 10 (EO average addition mole number 10), polyoxyethylene castor oil 20 (EO average addition mole number 20), poly Oxyethylene castor oil 35 (EO average added mole number 35), polyoxyethylene castor oil 40 (EO average added mole number 40), polyoxyethylene castor oil 50 (EO average added mole number 50), polyoxyethylene castor oil 60 (EO average added mole number 60) and the like.
  • Polyoxyethylene hydrogenated castor oil is a compound obtained by addition-polymerizing ethylene oxide to hydrogenated castor oil, and several types having different average addition mole number of ethylene oxide are known. ing.
  • the average addition mole number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, and 5 to 100 moles are exemplified.
  • polyoxyethylene hydrogenated castor oil 5 (EO average addition mole number 5), polyoxyethylene hydrogenated castor oil 10 (EO average addition mole number 10), polyoxyethylene hydrogenated castor oil 20 (EO average addition mole number 20) ), Polyoxyethylene hydrogenated castor oil 30 (EO average addition mole number 30), polyoxyethylene hydrogenated castor oil 40 (EO average addition mole number 40), polyoxyethylene hydrogenated castor oil 50 (EO average addition mole number 50), Examples include polyoxyethylene hydrogenated castor oil 60 (EO average added mole number 60), polyoxyethylene cured castor oil 80 (EO average added mole number 80), polyoxyethylene cured castor oil 100 (EO average added mole number 100), etc. Be
  • POE sorbitan fatty acid ester examples include polyoxyethylene monolaurate (20) sorbitan (polysorbate 20), monopalmitate polyoxyethylene (20) sorbitan (polysorbate 40), and monostearate polyoxyethylene (20) Sorbitan (polysorbate 60), polyoxyethylene tristearate (20) sorbitan (polysorbate 65), polyoxyethylene monooleate (20) sorbitan (polysorbate 80).
  • Polyoxyethylene polyoxypropylene glycol is a block copolymer consisting of polyoxyethylene chain (POE) and polyoxypropylene chain (POP), and is an average of ethylene oxide (EO) and propylene oxide (PO) Several types with different addition moles are known.
  • the average addition mole number of ethylene oxide and propylene oxide in polyoxyethylene polyoxypropylene glycol is not particularly limited, but an average addition mole number of 5 to 200 moles is exemplified.
  • polyoxyethylene (200) polyoxypropylene (70) glycol (average EOL addition mole number 200, PO average addition mole number 70), polyoxyethylene (196) polyoxypropylene (67) glycol (EO average addition Mol number 196, PO average addition mol number 67), polyoxyethylene (160) polyoxypropylene (30) glycol (EO average addition mol number 160, PO average addition mol number 30), polyoxyethylene (120) polyoxypropylene (40) Glycol (EO average addition mole number 120, PO average addition mole number 40), polyoxyethylene (42) polyoxypropylene (67) glycol (EO average addition mole number 42, PO average addition mole number 67), poly Oxyethylene (54) polyoxypropylene (39) glycol EO average addition molar number: 54, PO average addition mole number 39), polyoxyethylene (20) polyoxypropylene (20) glycol (EO average addition mole number of 20, PO average addition mole number of 20), and the like.
  • polyoxyethylene hydrogenated castor oil 60 polyoxyethylene hydrogenated castor oil 40, polyoxyethylene (20) sorbitan oleate and polyoxyethylene polyoxypropylene glycol are preferable.
  • the blending amount of the component (C) in the ophthalmic composition is preferably 0.001 to 5.0 w / v%, and 0.001 to 2.0 w / v% Is more preferable, and 0.001 to 1.0 w / v% is more preferable.
  • blending except polyoxyethylene polyoxypropylene glycol 0.001-0.5 w / v% is preferable, 0.001-0.3 w / v% is more preferable, 0.001-0.2 w / v% Is more preferred.
  • the refreshing agent may be encapsulated in the active agent micelles and volatilization may be suppressed. If the blending amount is too small, the refreshing agent or the easily soluble oxide may be separated. There is.
  • the component (D) is one or more components selected from dibutyl hydroxytoluene (BHT), dibutyl hydroxyanisole (BHA), propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol. Among them, dibutyl hydroxytoluene is preferred. As (D) component, it can be used individually by 1 type or in combination of 2 or more types suitably.
  • the component (D) has lower solubility than the component (B) and is easily contained in the active agent micelles, so the volatilization of the refreshing agent (B) is further promoted and the odor masking effect by the refreshing agent is enhanced (B) .
  • the amount of the component (D) to be incorporated in the ophthalmic composition is preferably 0.001 w / v% or more, 0.002 w / v% or more from the viewpoint of the masking effect when dibutyl hydroxytoluene and dibutyl hydroxyanisole are blended. Is more preferable, and 0.003 w / v% or more is more preferable.
  • the upper limit is not particularly limited, but can be 0.01 w / v% or less.
  • 0.03 w / v% or more is preferable, 0.05 w / v% or more is more preferable, and 0.1 w / v% or more is more preferable.
  • the upper limit is not particularly limited, but can be 3 w / v% or less.
  • the preferable range of the compounding ratio (mass ratio) represented by (B) / (D) is as follows. In addition, although this ratio is w / v% ratio, it is the same as mass ratio (following same).
  • component (D) is (D-I) dibutyl hydroxytoluene or dibutyl hydroxy anisole, when it is (D-II) propyl parahydroxybenzoate or butyl parahydroxybenzoate, when it is (D-III) chlorobutanol I will divide and explain.
  • component (I) (D) is dibutylhydroxytoluene (BHT) or dibutylhydroxyanisole (BHA), it is preferably 0.05 to 500, more preferably 0.1 to 200, and further preferably 0.1 to 100 preferable.
  • 1.0 to 200 is preferable, 2.0 to 100 is more preferable, 3.0 to 50 is more preferable, and 4.0 to 50 is particularly preferable.
  • camphor (dl-camphor, d-camphor) is blended as the component (B), 0.4 to 200 is preferable, 1.0 to 100 is more preferable, and 2.0 to 50 is more preferable.
  • component (B) When d-borneol or geraniol is blended as the component (B), 0.4 to 200 is preferable, 0.6 to 100 is more preferable, and 1.0 to 50 is more preferable.
  • eucalyptus oil is blended as the component (B), 0.1 to 200 is preferable, 0.2 to 100 is more preferable, and 0.3 to 50 is more preferable.
  • component (II) (D) is propyl parahydroxybenzoate or butyl parahydroxybenzoate, it is preferably 0.001 to 200, more preferably 0.003 to 100, and still more preferably 0.01 to 50.
  • l-menthol When l-menthol is blended as the component (B), 0.1 to 100 is preferable, 0.2 to 50 is more preferable, and 0.4 to 10 is more preferable.
  • camphor (dl-camphor, d-camphor) is blended as the component (B), 0.05 to 100 is preferable, 0.15 to 50 is more preferable, and 0.2 to 10 is more preferable.
  • 0.05 to 100 is preferable, 0.1 to 50 is more preferable, and 0.15 to 10 is more preferable.
  • eucalyptus oil When eucalyptus oil is blended as the component (B), 0.01 to 100 is preferable, 0.02 to 50 is more preferable, and 0.05 to 10 is more preferable.
  • component (D) is chlorobutanol
  • 0.0001 to 100 is preferable, 0.0003 to 50 is more preferable, and 0.0005 to 20 or more is more preferable.
  • camphor (dl-camphor, d-camphor) is blended as the component (B), 0.05 to 50 is preferable, 0.15 to 20 is more preferable, and 0.2 to 10 is more preferable.
  • d-borneol or geraniol is blended as the component (B), 0.0005 to 50 is preferable, 0.001 to 20 is more preferable, and 0.0015 to 10 is more preferable.
  • 0.001 to 50 is preferable, 0.002 to 20 is more preferable, and 0.005 to 10 is more preferable.
  • component (A) is vitamin A
  • component (C) is (C-I) polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester
  • C-II polyoxyethylene polyoxypropylene glycol
  • the blending ratio (mass ratio) represented by ((B) + (D)) / (C) is preferably 0.01-30, more preferably 0.02-10. preferable. If ((B) + (D)) / (C) is too small, the refreshing agent may be included in the micelles and volatilization may be suppressed. If it is too large, the cooling agent or an easily soluble oxide may be contained. May separate.
  • component (C) is (CI) polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, or polyoxyethylene sorbitan fatty acid ester, 1-menthol is blended as component (B), and component (D) is incorporated as component (D)
  • component (D) is incorporated as component (D)
  • dibutylhydroxytoluene or dibutylhydroxyanisole is blended, 0.05 to 15 is preferable, 0.1 to 10 is more preferable, and 0.15 to 5 is more preferable.
  • camphor d-camphor, dl-camphor
  • component (B) dibutyl hydroxytoluene or dibutyl hydroxy anisole
  • it is preferably 0.04 to 5, and 0.05 to 5 4 is more preferable, and 0.08 to 3 is more preferable.
  • d-borneol or geraniol is blended as the component (B) and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as the component (D), 0.03 to 5 is preferable, and 0.04 to 4 is more preferable, 0.05 to 3 is more preferable, and 0.06 to 3 is particularly preferable.
  • eucalyptus oil is blended as the component (B) and dibutyl hydroxytoluene or dibutyl hydroxyanisole is blended as the component (D), 0.02 to 5 is preferable, 0.03 to 3 is more preferable, and 0.04 To 3 is more preferable, and 0.045 to 3 is particularly preferable.
  • camphor d-camphor, dl-camphor
  • component (B) dibutyl hydroxytoluene or dibutyl hydroxy anisole
  • 0.007 to 0.5 is preferable, and 0. 01 to 0.4 is more preferable, and 0.015 to 0.3 is more preferable.
  • 0.007 to 0.5 is preferable, and 0.008 to 0.4 is preferable. Is more preferable, and 0.01 to 0.3 is more preferable.
  • component (B) When eucalyptus oil is blended as component (B) and dibutyl hydroxytoluene or dibutyl hydroxy anisole is blended as component (D), 0.005 to 0.5 is preferable, and 0.006 to 0.4 is more preferable. And 0.007 to 0.3 are more preferable.
  • the compounding ratio represented by the (B) / (D) ratio and ((B) + (D)) / (C) above when a plurality of (B) components are compounded, the total amount of the (B) components is Treat as the concentration of each component. Since the masking effect is higher in the order of eucalyptus oil, geraniol, d-borneol, camphor (d-camphor, dl-camphor) and l-menthol, the above ratio is the component with the highest masking effect among the components blended.
  • the above ratio is in accordance with the range of the component with a large amount.
  • Optional ingredient The various components used for an ophthalmic composition can be mix
  • Preferred ingredients include drugs, buffers, stabilizers, thickeners, tonicity agents, antioxidants, preservatives, pH adjusters, polyhydric alcohols and the like.
  • a decongestant component for example, a decongestant component, an ocular muscle modulator component, an antiinflammatory component or an astringent drug component, an antihistamine component or an antiallergic component, an amino acid, an antibacterial component or a bactericidal component, a saccharide, a polysaccharide or The derivative, a local anesthetic ingredient, a steroid ingredient, a glaucoma treatment ingredient, a cataract treatment ingredient, a mydriasis ingredient etc. are mentioned. A specific example is shown below.
  • Decongestant components for example, ⁇ -adrenergic agents such as imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), ⁇ -phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and their pharmacologically or physiologically acceptable Salts (eg, Naphazoline hydrochloride, Naphazoline nitrate, Tetrahydrozoline hydrochloride, Tetrahydrozoline nitrate, Phenylephrine hydrochloride, Epinephrine hydrochloride, Ephedrine hydrochloride, Inorganic acid salts such as methylephedrine hydrochloride, etc .; Organic acid salts such as epinephrine hydrogen tartrate, etc. Etc.).
  • imidazoline derivatives naphazoline, tetrahydrozoline, etc.
  • Eye muscle modulator component For example, cholinesterase inhibitors having an active center similar to acetylcholine (eg, neostigmine methyl sulfate etc.), tropicamide, atropine sulfate etc. may be mentioned.
  • Anti-inflammatory or astringent ingredients eg pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemetacin, ibuprofen, tiaprofenic acid, loxoprofen sodium, tiaramide hydrochloride Zinc salts (eg, zinc sulfate, zinc lactate etc.), lysozyme, lysozyme, methyl salicylate, allantoin, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, glycyrrhizinic acid and pharmacologically acceptable salts (eg, glycyrrhizin) Dipotassium acid, ammonium glycyrrhi
  • Antihistamine drug component or antiallergic drug component for example, ketotifen, alitazanolast, chlorpheniramine, diphenhydramine, levocabastine, cromoglycic acid, tranilast, ibudilast, anlexanox, pemirolast, and their pharmaceutically or physiologically acceptable salts (Diphenhydramine hydrochloride, ketotifen fumarate, sodium cromoglycate etc.) and the like.
  • Amino acid for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, serine, glycine, serine, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine, glycylglycine, ⁇ -aminobutyric acid
  • Glutamic acid sodium aspartate, potassium aspartate, magnesium aspartate, aminoethyl sulfonic acid (taurine) or salts thereof (eg, cysteine hydrochloride etc.) and the like can be mentioned.
  • Antimicrobial or microbicidal components eg sulfonamides (eg sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine) Sodium etc), acrinol, alkyl polyaminoethyl glycine, new quinolone agent (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, etc), ⁇ -lactam antibacterial (sulbenicillin, cefmenoxim etc), aminoglycosides Antibacterial drugs (Kanamycin, Gentamycin, Tobramycin, Shisomycin, Dibekacin, Bekanamycin, Micronomycin etc.), Tetracyclines (Oxytetracycline etc.), Macrolide Antibiotics Drugs (erythromycin etc.), chlorampheni
  • antiviral agents idoxuridine, acyclovir, adenine arabino
  • ganciclovir phoscarnet
  • valacyclovir trifluorothymidine
  • cidofovir carbocyclic oxetanocin G, etc.
  • antifungal agents primaricin, fluconazole, itraconazole, miconazole, flucytosine, amphotericin B etc.
  • Sugars For example, lactulose, raffinose, pullulan, glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, mannitol, sorbitol and the like can be mentioned.
  • Polysaccharides or derivatives thereof for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac fat, quince seed, dammar gum, traganto, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin Collagen, pectin, starch, polygalacturonic acid (alginic acid), chitin and derivatives thereof, chitosan and derivatives thereof, elastin, hyaluronic acid, chondroitin sulfate or salts thereof (sodium alginate, sodium chondroitin sulfate etc.) and the like can be mentioned.
  • Local anesthetic components for example, lidocaine, oxybuprocaine, dipkine, procaine, ethyl aminobenzoate, meprilcaine, mepivacaine, bupivacaine, ***e, and salts thereof (such as lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) .
  • Steroid component For example, hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, paramethasone, betamethasone, salts thereof and the like can be mentioned.
  • Glaucoma therapeutic ingredients for example, distigmine bromide, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, isopropyl unoprostone, dipivefrine hydrochloride, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide , Methazolamide, salts thereof and the like.
  • ingredients for treating cataract for example, pyrenoxine, glutathione, salivary gland hormone, thiopronine, dihydro azapentacene disulphonate and salts thereof (for example, sodium 5,12-dihydro azapentacene disulphonate etc.) and the like.
  • Mydriatic component For example, cyclopentolate hydrochloride, tropicamide and the like can be mentioned.
  • the blending amount can be selected as an effective appropriate amount of each drug, but from the viewpoint of eye irritation, stability of the composition, etc., 0.001 in the ophthalmic composition. It is preferably in the range of ⁇ 5 w / v%.
  • a buffer for example, citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, acetic acid, sodium acetate, glacial acetic acid, trometamol, Sodium carbonate, sodium hydrogen carbonate and the like can be mentioned.
  • the amount thereof is preferably in the range of 0.003 to 4 w / v% in the ophthalmic composition.
  • the stabilizer examples include ethylenediamine acetic acid derivatives or salts thereof (eg, edetic acid (such as ethylenediaminetetraacetic acid), sodium edetate (such as sodium ethylenediaminetetraacetate), ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ - Cyclodextrin etc. are mentioned.
  • edetic acid such as ethylenediaminetetraacetic acid
  • sodium edetate such as sodium ethylenediaminetetraacetate
  • ⁇ -cyclodextrin ⁇ -cyclodextrin
  • ⁇ - Cyclodextrin ⁇ - Cyclodextrin etc.
  • the blending amount thereof is preferably in the range of 0.003 to 2 w / v% in the ophthalmic composition.
  • the thickening agent examples include cellulose-based polymer compounds such as methyl cellulose, hypromellose and hydroxyethyl cellulose, polyvinyl-based polymer compounds such as povidone and polyvinyl alcohol, liquid paraffin, carboxyvinyl polymer, polyethylene glycol and the like.
  • the blending amount thereof is preferably in the range of 0.003 to 3 w / v% in the ophthalmic composition.
  • tonicity agents examples include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium carbonate, sodium carbonate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen sulfite and the like. It can be mentioned.
  • the blending amount thereof is preferably in the range of 0.001 to 3 w / v% in the ophthalmic composition.
  • antioxidants examples include hydroquinone, propyl gallate, sodium bisulfite and the like.
  • the blending amount thereof is preferably in the range of 0.001 to 1 w / v% in the ophthalmic composition.
  • the preservative examples include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, polydronium chloride, alkyldiaminoethylglycine hydrochloride, polyhexamethylene biguanide and the like.
  • the blending amount is preferably in the range of 0.001 to 0.5 w / v% in the ophthalmic composition.
  • pH adjusters examples include hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like.
  • the pH (20 ° C.) of the ophthalmic composition of the present invention is 3.5 to 8.0, preferably 5.0 to 7.5, more preferably 6.0 to 7.3. If the pH is too low or too high, the feeling of irritation may be strong.
  • the pH is measured at 20 ° C. using a pH osmometer (HSMO-1, Toa DKK Co., Ltd.).
  • HSMO-1 pH osmometer
  • As a pH adjuster sodium hydroxide, potassium hydroxide, hydrochloric acid and the like are preferable.
  • polyhydric alcohols examples include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like.
  • the ophthalmic composition of the present invention can be produced, for example, by using the remaining portion as water, by a known production method. For example, after dissolving each of the above components in a mixed solvent with water such as sterile purified water, ion-exchanged water, etc., adjust the pH, and if necessary, adjust the osmotic pressure etc. with a pH adjuster or isotonizing agent. It can be obtained by adjusting.
  • the ophthalmic product of the present invention is contained in a container comprising a main body containing the ophthalmic composition and a cap, and the container is sealed together with an iron-based oxygen absorbent and enclosed in an enclosure.
  • the volume of the above body is 1 to 25 mL,
  • the volume of the space formed between the enclosure and the container is 200 V / V% or less with respect to the volume of the container.
  • the container comprises a body for containing the ophthalmic composition and a cap. More specifically, the main body is provided with an eyedrop opening, and has a cap of a screw type, one touch type or the like which seals the main body.
  • the inside plug which has an eye drop opening may be provided in the main body, the eye drop opening may be provided in a cap, and a cap may be directly installed in a container and sealed. It is preferable that the main body is provided with an inside plug having an eye drop opening.
  • the term "container" refers to a container in which a cap is attached to the main body.
  • the main body containing the ophthalmic composition volatilizes the refreshing agent in the ophthalmic composition into the enclosure, its oxygen permeability is 10 cc / (m 2 ⁇ 24 hr ⁇ atm) or more.
  • the upper limit is not particularly limited, but may be 200 cc / (m 2 ⁇ 24 hr ⁇ atm) or less.
  • Specific examples of the main body having such oxygen permeability include main bodies made of materials such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, and vinyl chloride. More specifically, a multi-dose container made of polyethylene terephthalate and the like is more preferable because of its high stability.
  • the oxygen permeability can be measured by the method according to JIS-K7126-2 plastic film and sheet-gas permeability test method B (Appendix B).
  • the volume of the main body (volume when the main body is filled with the ophthalmic composition) is 1 to 25 mL, preferably 5 to 20 mL.
  • the amount of the ophthalmic composition to be contained can be appropriately selected according to the product and its method of use, and is, for example, 1 to 25 mL, preferably 1 to 20 mL, and 5 to 20 mL for multidose eye drops. Is more preferred. If the amount of the ophthalmic composition is too small, the volatilization amount of the refreshing agent in the eye drop container may be insufficient, and the odor masking effect may be insufficient.
  • the plug and the cap can use a cap made of a material used for a container of a known ophthalmic product.
  • the material of the inside plug is preferably polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8.
  • polyethylene and polypropylene are preferable.
  • the oxygen permeability of the container is preferably 0.01% or more, more preferably 0.1% or more, and still more preferably 0.2% or more.
  • the upper limit is not particularly limited, but can be, for example, 5% or less.
  • the measuring method of oxygen permeability is a method as described in the Example mentioned later. If the oxygen permeability is high, the refreshing agent is easily volatilized and an odor masking effect can be obtained more.
  • the filling ratio of the ophthalmic composition with respect to the container volume (cap ratio of the empty wall of the main body to the container fullness in a container equipped with a cap and a stopper). The above is more preferable. If the storage rate is too low, the refreshing agent may fill the empty wall, and the effect of masking odors in the enclosure may be insufficient.
  • the oxygen absorbent of the present invention is an iron-based oxygen absorbent, and specifically, Ageless (FX, SA, Z-PT, GL, G) manufactured by Mitsubishi Gas Chemical Co., Ltd., Tokiwa Sangyo Co., Ltd. Commercially available Vitalon and the like. Use a spec that sufficiently absorbs oxygen in the enclosure. In general, oxygen absorbers are widely used in the pharmaceutical and food industries, and can be used at low cost. As the oxygen absorbent, one having an ability to absorb all the oxygen present in the pillow is used. If it is less than the capacity, oxygen can not be absorbed sufficiently, and the oxide easily decomposes, and if it is more than the capacity, the pillow may shrink and the container may be dented.
  • the ophthalmic composition is enclosed and sealed in an enclosure with an oxygen absorber.
  • the material of the enclosure is, for example, polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, polyvinyl alcohol film with aluminum foil or aluminum vapor deposited, polyamide film, alumina vapor deposited And polyethylene terephthalate on which silicon oxide is vapor-deposited, a film coated with polyvinylidene chloride or a laminate film, etc., and composites thereof, multilayer films and the like.
  • the oxygen permeability is preferably 10 cc / (m 2 ⁇ 24 hr ⁇ atm) or less (that is, 0 to 10 cc / (m 2 ⁇ 24 hr ⁇ atm)).
  • the oxygen permeability of the enclosure is preferably lower than that of the main body, more preferably less than 10 cc / (m 2 ⁇ 24 hr ⁇ atm), 0 to 3 cc / (m 2 ⁇ 24 hr ⁇ atm), 0 ⁇ 1cc / (m 2 ⁇ 24hr ⁇ atm), preferably 0.01 ⁇ 0.3cc / (m 2 ⁇ 24hr ⁇ atm) further, 0.01 ⁇ 0.1cc / (m 2 ⁇ 24hr ⁇ atm) particularly Preferably, 0.01 to 0.02 cc / (m 2 ⁇ 24 hr ⁇ atm) is most preferable.
  • the volume of the space (inner space) formed between the enclosure and the container (with the cap attached to the main body) is 200 V / V% or less and 150 V / V% or less with respect to the volume of the container Is preferable, and 120 V / V% or less is more preferable. If it exceeds 200 V / V%, the masking effect of the smell in an enclosure is not fully obtained.
  • the lower limit is not particularly limited, but can be 20 V / V% or more.
  • the present invention (A) easy oxides, (B) refreshing agent, An ophthalmic composition comprising (C) a nonionic surfactant and (D) one or more components selected from dibutyl hydroxytoluene, dibutyl hydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, An ophthalmic product contained in a container comprising a body containing an ophthalmic composition and a cap, the container being enclosed with an iron-based oxygen absorbent and enclosed in an enclosure; The volume of the above body is 1 to 25 mL, The oxygen permeability of the body above 10 cc / (m 2 ⁇ 24 hr ⁇ atm), The odor masking method is provided, wherein the volume of the space formed between the enclosure and the container is 200 V / V% or less with respect to the volume of the container. Preferred components, ranges and the like are the same as described above.
  • An ophthalmic composition having the composition shown in the following table is manufactured according to a conventional method and housed in the following container, and then an oxygen absorbent (Ageless (Model No .: Z-PT15), manufactured by Mitsubishi Gas Chemical Co., Ltd.) is enclosed, A film package was applied by an enclosure and sealed to obtain an ophthalmic product.
  • This ophthalmic product was stored for 1 month in an environment of 40 ° C. and 75% RH. After storage, the film package was opened, and the sensory evaluation of the following odor was carried out.
  • Example 2 Comparative Example 3
  • Comparative Example 4 Comparative Example 5.
  • ⁇ container> -Body Material polyethylene terephthalate: oxygen permeability 10cc / (m 2 ⁇ 24 hr ⁇ atm)
  • Body volume 17 mL
  • Cap screw type Inside plug
  • Material Alumina-deposited polyethylene terephthalate / polyethylene multilayer film (oxygen permeability 0.2 cc / (m 2 ⁇ 24 hr ⁇ atm)) Size: W 9.0 ⁇ L 6.5 (cm)
  • Example 2 and Comparative Example 4 the size of the enclosure is changed so that the inner space ratio to the container volume in the table is obtained, and in Comparative Example 3, the amount of composition in the table (mL) / body volume (mL) The space ratio was made to be the same, and Comparative Example 5 used a non-oxygen permeable one as the main body.
  • oxygen concentration in the space of the enclosure without the container was measured and used as the initial value.
  • the oxygen concentration used the residual oximeter (Iijima Electronics Co., Ltd.).
  • the oxygen concentration in the enclosure was measured. The value calculated by the following formula is defined as oxygen permeability.
  • Oxygen permeability (%) oxygen concentration in the enclosure after storage (%)-oxygen concentration in the initial enclosure (%)
  • Retinol palmitate ester (trade name: Retinol palmitate, manufactured by DSM Nutrition Japan KK, 1.74 million I.U / g)
  • l-menthol (Brand name: l-menthol (lightly charged brain), manufactured by Suzuki Taikari Co., Ltd.)
  • dl-Camphor (trade name: Japanese Pharmacopoeia dl-Camphor, manufactured by Nippon Seika Co., Ltd.)
  • d-Camphor (trade name: Japanese Pharmacopoeia d-Camphor, manufactured by Nippon Seika Co., Ltd.)
  • d-Borneol (brand name: special boiling dragon brain (d-Borneol), manufactured by Yanagisawa Shogoten)
  • Eucalyptus oil (trade name: Japan Pharmacopoeia Eucalyptus oil, Ogawa Aroma

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Abstract

Provided is an ophthalmic product obtained by: housing, in a container, an ophthalmological composition comprising (A) an easily-oxidizable substance, (B) a refreshing agent, (C) a non-ionic surfactant, and (D) at least one component selected from dibutyl hydroxytoluene, dibutyl hydroxyanisole, propyl para-hydroxybenzoate, butyl para-hydroxybenzoate, and chlorobutanol; and enclosing and sealing, by an enclosing body, the container together with an iron-based oxygen absorber. Regarding the ophthalmic product, the capacity of the main body thereof is 1-25 mL, the oxygen permeability of the main body is at least 10 cc/(m2·24 hr·atm), and the volume of space formed between the enclosing body and the container is at most 200 V/V% with respect to the volume of the container.

Description

眼科用製品及びマスキング方法Ophthalmic product and masking method
　本発明は、酸素吸収剤の臭いが抑制された眼科用製品及びマスキング方法に関するものである。 The present invention relates to an ophthalmic product and a masking method in which the odor of an oxygen absorbent is suppressed.
　易酸化成分を安定化する方法として、酸素吸収剤の使用が知られている。点眼剤分野においても、容器に収容された点眼剤と酸素吸収剤を包囲体内に封入することにより、容器内の酸素が吸収され、点眼剤中の易酸化物質を安定化できることが知られている（特開平６－４０９０７号公報）。一方、脂溶性であるビタミンＡ等の有効成分は、角膜・結膜、鼻粘膜や咽頭の治療に有効な成分として注目されているが、これらの有効成分は特有の臭いが存在し、さらに経時で臭いが増幅する。 The use of oxygen absorbers is known as a method of stabilizing easily oxidizable components. Also in the eye drop field, it is known that oxygen in the container can be absorbed and the easily oxidizable substance in the eye drop can be stabilized by enclosing the eye drop and the oxygen absorbent contained in the container in the enclosure. (Unexamined-Japanese-Patent No. 6-40907). On the other hand, fat-soluble active ingredients such as vitamin A have attracted attention as effective ingredients for the treatment of the cornea, conjunctiva, nasal mucosa and pharynx, but these active ingredients have distinctive odors, and further over time The smell is amplified.
特開平６－４０９０７号公報Japanese Patent Laid-Open No. 6-40907
　しかしながら、包囲体内に鉄を主成分とした酸素吸収剤(以下、鉄系の酸素吸収剤ともいう)を入れて長期間保存すると、脱酸素作用により生じる焦げたような特異的な異臭が発生し、包囲体に付着もしくは包囲体内に充満することによって、開封時に異臭を感じるという問題が生じることが判明した。一方、脂溶性であるビタミンＡ等の有効成分は、角膜・結膜、鼻粘膜や咽頭の治療に有効な成分として注目されている。しかしながら、これらの有効成分は特有の臭いが存在し、さらに経時で臭いが増幅する。ビタミンＡを含む眼科用製品における酸素吸収剤の使用は、開封時の臭いの改善という点では不十分であった。以上の点から、ビタミンＡ等の易酸化物を含有する眼科用組成物が、容器に収容され、さらに鉄を主成分とした酸素吸収剤と共に、包囲体で包囲して密封された眼科用製品において、脱酸素作用により生じる、包囲体開封時の特異的な異臭を抑制するマスキング方法が望まれていた。 However, if an iron-based oxygen absorbent (hereinafter also referred to as an iron-based oxygen absorbent) is placed in the enclosure for a long period of time, a specific offensive odor such as charring produced by the deoxygenation action is generated. It has been found that, by adhering to or filling the enclosure, a problem arises that an offensive odor is felt at the time of opening. On the other hand, fat-soluble active ingredients such as vitamin A have attracted attention as effective ingredients for treating cornea, conjunctiva, nasal mucosa and pharynx. However, these active ingredients have a distinctive odor, and the odor is further amplified over time. The use of oxygen absorbers in ophthalmic products containing vitamin A has been inadequate in terms of improving the odor upon opening. From the above points, an ophthalmic composition containing an easily-oxidizable compound such as vitamin A is contained in a container, and further enclosed with an iron-based oxygen absorbent and sealed by an enclosure. In the above, a masking method has been desired which suppresses the specific off-flavor at the time of opening the enclosure, which is generated by the deoxygenation action.
　本発明者らは、上記目的を達成するため鋭意検討した結果、ビタミンＡ等の易酸化物を含有する眼科用組成物が、本体とキャップとを備えた容器に収容され、さらに鉄を主成分とした酸素吸収剤と共に包囲体で包囲して密封された眼科用製品において、本体の容量、本体の酸素透過度、上記包囲体と上記容器との間に形成される空間の体積を特定範囲にすることで、容器内から清涼化剤が揮発し、眼科用組成物から容器内へ、さらには容器内から包囲体内へ揮発・滞留し、開封時に生じる異臭（酸素吸収剤由来及び易酸化物由来）を、簡便かつ低コストでマスキングできることを見出した。 As a result of intensive investigations to achieve the above object, the present inventors contain an ophthalmic composition containing an easy oxide such as vitamin A in a container provided with a main body and a cap, and further contain iron as a main component. The volume of the body, the oxygen permeability of the body, and the volume of the space formed between the enclosure and the container within a specific range. As a result, the refreshing agent volatilizes from the inside of the container, and from the ophthalmic composition to the inside of the container, and further from the inside of the container to the inside of the surrounding body Was found to be easy and inexpensive to mask.
　従って、本発明は、下記眼科用製品及びマスキング方法を提供する。
[１]．（Ａ）易酸化物、
（Ｂ）清涼化剤、
（Ｃ）非イオン性界面活性剤、及び
（Ｄ）ジブチルヒドロキシトルエン、ジブチルヒドロキシアニソール、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及びクロロブタノールから選ばれる１種以上の成分を含む眼科用組成物が、眼科用組成物を収容する本体とキャップとを備えた容器に収容され、この容器が鉄系の酸素吸収剤と共に、包囲体で包囲して密封された眼科用製品であって、
上記本体の容量が１～２５ｍＬ、
上記本体の酸素透過度が１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以上、
上記包囲体と上記容器との間に形成される空間の体積が、上記容器の体積に対し２００Ｖ／Ｖ％以下
である眼科用製品。
[２]．（Ａ）成分が、ビタミンＡである[１]記載の眼科用製品。
[３]．（Ｂ）成分が、ｌ－メントール、ｄｌ－カンフル、ｄ－カンフル、ｄ－ボルネオール、ゲラニオール及びユーカリ油から選ばれる１種以上である[１]又は[２]記載の眼科用製品。
[４]．（Ｂ）成分の眼科用組成物中の配合量が、０．０００１ｗ／ｖ％以上である[１]～[３]のいずれかに記載の眼科用製品。
[５]．（Ｃ）成分が、ポリオキシエチレン硬化ヒマシ油６０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン（２０）ソルビタンオレイン酸エステル及びポリオキシエチレンポリオキシプロピレングリコールから選ばれる１種以上である[１]～[４]のいずれかに記載の眼科用製品。
[６]．（Ａ）易酸化物、
（Ｂ）清涼化剤、
（Ｃ）非イオン性界面活性剤、及び
（Ｄ）ジブチルヒドロキシトルエン、ジブチルヒドロキシアニソール、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及びクロロブタノールから選ばれる１種以上の成分を含む眼科用組成物が、眼科用組成物を収容する本体とキャップとを備えた容器に収容され、この容器が鉄系の酸素吸収剤と共に、包囲体で包囲して密封された眼科用製品において、
上記本体の容量を１～２５ｍＬ、
上記本体の酸素透過度を１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以上、
上記包囲体と上記容器との間に形成される空間の体積が、上記容器の体積に対し２００Ｖ／Ｖ％以下
とする、包囲体開封時の臭いマスキング方法。 Accordingly, the present invention provides the following ophthalmic product and masking method.
[1]. (A) easy oxides,
(B) refreshing agent,
An ophthalmic composition comprising (C) a nonionic surfactant and (D) one or more components selected from dibutyl hydroxytoluene, dibutyl hydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, An ophthalmic product contained in a container comprising a body containing an ophthalmic composition and a cap, the container being enclosed with an iron-based oxygen absorbent and enclosed with an enclosure,
The volume of the above body is 1 to 25 mL,
The oxygen permeability of the body above 10 cc / (m 2 · 24 hr · atm),
The ophthalmic product whose volume of the space formed between the said enclosure and the said container is 200 V / V% or less with respect to the volume of the said container.
[2]. The ophthalmic product according to [1], wherein the component (A) is vitamin A.
[3]. The ophthalmic product according to [1] or [2], wherein the component (B) is at least one selected from l-menthol, dl-camphor, d-camphor, d-borneol, geraniol and eucalyptus oil.
[4]. The ophthalmic product according to any one of [1] to [3], wherein the compounding amount of the component (B) in the ophthalmic composition is 0.0001 w / v% or more.
[5]. Component (C) is at least one selected from polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene (20) sorbitan oleate, and polyoxyethylene polyoxypropylene glycol [1 ] The ophthalmic product in any one of-[4].
[6]. (A) easy oxides,
(B) refreshing agent,
An ophthalmic composition comprising (C) a nonionic surfactant and (D) one or more components selected from dibutyl hydroxytoluene, dibutyl hydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, An ophthalmic product contained in a container comprising a body containing an ophthalmic composition and a cap, the container being enclosed with an iron-based oxygen absorbent and enclosed in an enclosure;
The volume of the above body is 1 to 25 mL,
The oxygen permeability of the body above 10 cc / (m 2 · 24 hr · atm),
The odor masking method at the time of envelope opening which the volume of the space formed between the said enclosure and the said container shall be 200 V / V% or less with respect to the volume of the said container.
　本発明によれば、易酸化物を含有する眼科用組成物を、鉄を主成分とした酸素吸収剤と共に、包囲体で包装した眼科用製品において、包囲体開封時の特異的な異臭が抑制された眼科用製品、及びマスキング方法を提供することができる。 According to the present invention, in the ophthalmic product in which the ophthalmic composition containing the easy oxide is packaged in the enclosure together with the iron-based oxygen absorbent, the specific offensive odor when the enclosure is opened is suppressed Provided an ophthalmic product and a masking method.
　以下、本発明について詳細に説明する。
［眼科用組成物］
　本発明の眼科用組成物は、（Ａ）易酸化物、（Ｂ）清涼化剤、（Ｃ）非イオン性界面活性剤、及び（Ｄ）ジブチルヒドロキシトルエン、ジブチルヒドロキシアニソール、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及びクロロブタノールから選ばれる１種以上の成分を含むものである。 Hereinafter, the present invention will be described in detail.
[Ophthalmic composition]
The ophthalmic composition of the present invention comprises (A) an easy oxide, (B) a refreshing agent, (C) a nonionic surfactant, and (D) dibutylhydroxytoluene, dibutylhydroxyanisole, propyl parahydroxybenzoate, It contains one or more components selected from butyl parahydroxybenzoate and chlorobutanol.
[（Ａ）成分]
　（Ａ）易酸化物としては、水溶性易酸化物、疎水性易酸化物のいずれも用いることができ、１種単独で又は２種以上を適宜組み合わせて用いることができる。水溶性易酸化物として、例えば、アズレンスルホン酸ナトリウム、ビタミンＢ2（フラビンアデニンジヌクレオチド等）、ビタミンＢ6（ピリドキシン塩酸塩等）、ビタミンＢ12（シアノコバラミン等）、ビタミンＣ（アスコルビン酸等）等が挙げられる。 [(A) component]
As the easy oxide (A), any of a water-soluble easy oxide and a hydrophobic easy oxide can be used, and these can be used singly or in appropriate combination of two or more. Examples of water-soluble easily oxidized substances include sodium azulene sulfonate, vitamin B 2 (flavin adenine dinucleotide etc.), vitamin B 6 (pyridoxine hydrochloride etc.), vitamin B 12 (cyanocobalamin etc.), vitamin C (ascorbic acid etc.) Etc.
　疎水性易酸化物としては、日本薬局方、日本薬局方外医薬品規格、医薬品添加物事典、医薬品添加物規格、化粧品原料基準、化粧品種別配合成分規格及び食品添加物公定所収載の成分のうち、水に対する溶解性が「やや溶けにくい」から「ほとんど溶けない」物質を用いることができ、酸化分解を受ける全ての物質が含まれる。具体的な易酸化物質としては、ビタミンＡ、ビタミンＤ、ビタミンＥ、ビタミンＫ、ジフェンヒドラミン、インドメタシン、タクロリムス（ＦＫ５０６）、リファンピシン等のマクロライト系抗生物質、フォルスコリン等が挙げられるが、これらに限定されるものではない。 As hydrophobic easy oxides, among the ingredients listed in the Japanese Pharmacopoeia, Japanese Pharmacopoeia Extracorporeal Pharmaceutical Standards, Pharmaceutical Additives Convention, Pharmaceutical Additives Standards, Cosmetics Ingredient Standards, Cosmetic Type Compound Ingredient Standards and Food Additives Official Listing, It is possible to use substances that are "slightly soluble" to "poorly soluble" in water solubility, including all substances that undergo oxidative degradation. Specific oxidizable substances include vitamin A, vitamin D, vitamin E, vitamin K, diphenhydramine, indomethacin, tacrolimus (FK506), macrolight antibiotics such as rifampicin, forskolin and the like, but are limited thereto It is not something to be done.
　中でも、ビタミンＡは、角結膜修復促進、ムチン産生促進、ドライアイ改善効果、疲れ目・かすみ目改善効果を有すると共に、分解し易く、独特の臭気を発するので、本発明の効果がより発揮できる。上記ビタミンＡとしては、例えば、ビタミンＡそれ自体の他に、ビタミンＡ油等のビタミンＡ含有混合物、ビタミンＡ脂肪酸エステル等のビタミンＡ誘導体等が挙げられる。具体的には、レチノールパルミチン酸エステル、レチノール酢酸エステル、レチノール、レチノイン酸、レチノイド、β－カロテン等が挙げられる。中でも、レチノールパルミチン酸エステル、レチノール酢酸エステルが好ましく、レチノールパルミチン酸エステルがより好ましい。 Among them, vitamin A promotes keratoconjunctival repair, mucin production, dry eye improvement effect, fatigue and haze improvement effect, and is easily decomposed and emits unique odor, so the effect of the present invention can be exhibited more . Examples of vitamin A include vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid ester, and the like in addition to vitamin A itself. Specifically, retinol palmitate, retinol acetate, retinol, retinoic acid, retinoid, β-carotene and the like can be mentioned. Among them, retinol palmitate and retinol acetate are preferable, and retinol palmitate is more preferable.
　レチノールパルミチン酸エステルは、通常、１００～１８０万国際単位／ｇ（以下、ＩＵ／ｇと略記する場合がある。）のものが市販されており、具体的には、ＤＳＭニュートリションジャパン(株)製レチノールパルミチン酸エステル（１７４万Ｉ．Ｕ．）、シグマアルドリッチ製パルミチン酸レチノール等が挙げられる。 Retinol palmitate is generally commercially available in the range of 100 to 1.8 million international units / g (hereinafter sometimes abbreviated as IU / g). Specifically, DSM Nutrition Japan Co., Ltd. Examples thereof include retinol palmitate (1,740,000 I.U.), and retinoid palmitate retinoid.
　ビタミンＤとしては、例えば、コレカルシフェロ－ル、１α，２５－ジヒドロキシコレカルシフェロール及びこれらの誘導体等が挙げられる。ビタミンＥとしては、例えば、α－トコフェロ－ル、酢酸ｄ－α－トコフェロール及びこれらの誘導体等が挙げられ、ビタミンＫとしては、フィチルメナジオン及びその誘導体等が挙げられる。中でも、眼科用物質として有用である点から、（Ａ）成分としては、パルミチン酸レチノール、酢酸ｄ－α－トコフェロール等の脂溶性ビタミン、タクロリムス（ＦＫ５０６）、リファンピシン等のマクロライド系抗生物質、フォルスコリン等が好ましい。 Examples of vitamin D include cholecalciferol, 1α, 25-dihydroxycholecalciferol and derivatives thereof. Examples of vitamin E include α-tocopherol, d-α-tocopherol acetate and derivatives thereof, and vitamin K includes phytilmenadione and derivatives thereof. Among them, fat-soluble vitamins such as retinol palmitate and d-α-tocopherol acetate, macrolide antibiotics such as tacrolimus (FK506) and rifampicin, and falses as the component (A) from the viewpoint of being useful as ophthalmic substances. Choline etc. are preferred.
　（Ａ）成分の眼科用組成物中の配合量は、０．００５～２ｗ／ｖ％（質量／体積％，ｇ／１００ｍＬ、以下同じ）が好ましく、０．０１～１ｗ／ｖ％がより好ましい。なお、ビタミンＡを配合する場合は、５，０００～３００，０００ＩＵ／１００ｍＬが好ましく、５，０００～１００，０００ＩＵ／１００ｍＬがより好ましく、５，０００～５０，０００ＩＵ／１００ｍＬがさらに好ましい。ビタミンＡが高濃度であると、より眼に対する効果（角結膜修復促進、ムチン産生促進、ドライアイ改善効果、疲れ目・かすみ眼改善効果）が高まる。 The blending amount of the component (A) in the ophthalmic composition is preferably 0.005 to 2 w / v% (mass / volume%, g / 100 mL, hereinafter the same), and more preferably 0.01 to 1 w / v% . When vitamin A is blended, 5,000 to 300,000 IU / 100 mL is preferable, 5,000 to 100,000 IU / 100 mL is more preferable, and 5,000 to 50,000 IU / 100 mL is further preferable. When the concentration of vitamin A is high, the effects on the eye (stimulation of corneal and conjunctival repair, mucin production, dry eye improvement, fatigue and blurred eye improvement) are enhanced.
[（Ｂ）成分]
　清涼化剤としては、ｌ－メントール、ｄｌ－カンフル、ｄ－カンフル、ｄ－ボルネオール、ユーカリ油、ベルガモット油、ゲラニオール、リナロール、シネオール、ウイキョウ油、スペアミント油、ペパーミント油、ローズ油、クールミント油及びハッカ油等が挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。中でも、ｌ－メントール、ｄｌ－カンフル、ｄ－カンフル、ｄ－ボルネオール、ゲラニオール、ユーカリ油が好ましい。 [(B) component]
As the refreshing agent, l-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus oil, bergamot oil, geraniol, linalool, cineole, fennel oil, spearmint oil, peppermint oil, rose oil, coolmint oil and There may be mentioned peppermint oil and the like, which may be used singly or in appropriate combination of two or more. Among them, l-menthol, dl-camphor, d-camphor, d-borneol, geraniol and eucalyptus oil are preferable.
　（Ｂ）成分の眼科用組成物中の配合量は、マスキングの点から、０．０００１ｗ／ｖ％以上が好ましく、０．０００１～０．５ｗ／ｖ％がより好ましく、０．０００１５～０．２ｗ／ｖ％がさらに好ましく、０．０００２～０．１ｗ／ｖ％が特に好ましい。配合量が多すぎると、点眼時の刺激が強く、使用感が損なわれるおそれがある。 From the point of masking, 0.0001 w / v% or more is preferable, and, as for the compounding quantity in the ophthalmic composition of (B) component, 0.0001-0.5 w / v% is more preferable, 0.00015-0. 2 w / v% is more preferable, and 0.0002 to 0.1 w / v% is particularly preferable. If the amount is too large, the irritation at the time of instillation may be strong, and the feeling of use may be impaired.
　本発明の清涼化剤として、（Ｂ－１）ｌ－メントールを配合する場合は、０．００５～０．５ｗ／ｖ％が好ましく、０．０１～０．２ｗ／ｖ％がより好ましく、０．０２～０．１ｗ／ｖ％がさらに好ましく、０．０３～０．１ｗ／ｖ％が特に好ましく、０．０４～０．０５Ｗ／Ｖ％が最も好ましい。配合量が多すぎると、点眼時の刺激が強く、使用感が損なわれるおそれがあり、少なすぎると、マスキング効果が不十分となる。 When (B-1) 1-menthol is blended as the refreshing agent of the present invention, 0.005 to 0.5 w / v% is preferable, 0.01 to 0.2 w / v% is more preferable, and 0 .02 to 0.1 w / v% is more preferable, 0.03 to 0.1 w / v% is particularly preferable, and 0.04 to 0.05 W / V% is most preferable. If the compounding amount is too large, the irritation at the time of instillation may be strong and the feeling of use may be impaired, and if too small, the masking effect may be insufficient.
　本発明の清涼化剤として、（Ｂ－２）カンフルを配合する場合は、０．００２～０．５ｗ／ｖ％が好ましく、０．００５～０．２ｗ／ｖ％がより好ましく、０．０１～０．１ｗ／ｖ％がさらに好ましい。配合量が多すぎると、点眼時の刺激が強く、使用感が損なわれるおそれがあり、少なすぎると、マスキング効果が不十分となる。 When (B-2) camphor is blended as the refreshing agent of the present invention, 0.002 to 0.5 w / v% is preferable, 0.005 to 0.2 w / v% is more preferable, and 0.01 More preferably, it is at most 0.1 w / v%. If the compounding amount is too large, the irritation at the time of instillation may be strong and the feeling of use may be impaired, and if too small, the masking effect may be insufficient.
　本発明の清涼化剤として、（Ｂ－３）ｄ－ボルネオール、ゲラニオールを配合する場合は、０．００２～０．５ｗ／ｖ％が好ましく、０．００３～０．２ｗ／ｖ％がより好ましく、０．００５～０．１ｗ／ｖ％がさらに好ましい。配合量が多すぎると、点眼時の刺激が強く、使用感が損なわれるおそれがあり、少なすぎると、マスキング効果が不十分となる。 When (B-3) d-borneol and geraniol are blended as the refreshing agent of the present invention, 0.002 to 0.5 w / v% is preferable, and 0.003 to 0.2 w / v% is more preferable. And 0.005 to 0.1 w / v% is more preferable. If the compounding amount is too large, the irritation at the time of instillation may be strong and the feeling of use may be impaired, and if too small, the masking effect may be insufficient.
　本発明の清涼化剤として、（Ｂ－４）ユーカリ油を配合する場合は、０．０００５～０．５ｗ／ｖ％が好ましく、０．００１～０．２ｗ／ｖ％がより好ましく、０．００１５～０．１ｗ／ｖ％がさらに好ましい。配合量が多すぎると、点眼時の刺激が強く、使用感が損なわれるおそれがあり、少なすぎると、マスキング効果が不十分となる。 When (B-4) eucalyptus oil is mix | blended as a refreshing agent of this invention, 0.0005-0.5 w / v% is preferable, 0.001-0.2 w / v% is more preferable, 0. More preferably, 0015 to 0.1 w / v%. If the compounding amount is too large, the irritation at the time of instillation may be strong and the feeling of use may be impaired, and if too small, the masking effect may be insufficient.
[（Ｃ）成分]
　非イオン性界面活性剤としては眼科用組成物に用いられるものであれば特に限定されず、１種単独で又は２種以上を適宜組み合わせて用いることができる。例えば、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレン（２０）ソルビタンオレイン酸エステル（ポリソルベート８０）に代表されるポリオキシエチレンソルビタン脂肪酸エステル（ＰＯＥソルビタン脂肪酸エステル）、ポロクサマーに代表されるポリオキシエチレンポリオキシプロピレングリコール（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，ＰＯＥＰＯＰグリコール）、モノステアリン酸ポリエチレングリコール（１０）に代表されるモノステアリン酸ポリエチレングリコール等が挙げられる。 [(C) ingredient]
The nonionic surfactant is not particularly limited as long as it is used in an ophthalmic composition, and may be used singly or in appropriate combination of two or more. For example, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester) typified by polyoxyethylene (20) sorbitan oleic acid ester (polysorbate 80), poloxamer And polyoxyethylene polyoxypropylene glycol (polyoxyethylene polyoxypropylene block copolymer, POEPOP glycol), polyethylene glycol monostearate represented by polyethylene glycol monostearate (10), and the like.
　ポリオキシエチレンヒマシ油（ＰＯＥヒマシ油）は、ヒマシ油に酸化エチレン（ＥＯ）を付加重合することによって得られる化合物であり、酸化エチレンの平均付加モル数が異なるいくつかの種類が知られている。ポリオキシエチレンヒマシ油における酸化エチレンの平均付加モル数については、特に限定はないが、３～６０モルが例示される。具体的にはポリオキシエチレンヒマシ油３（ＥＯ平均付加モル数３）、ポリオキシエチレンヒマシ油１０（ＥＯ平均付加モル数１０）、ポリオキシエチレンヒマシ油２０（ＥＯ平均付加モル数２０）、ポリオキシエチレンヒマシ油３５（ＥＯ平均付加モル数３５）、ポリオキシエチレンヒマシ油４０（ＥＯ平均付加モル数４０）、ポリオキシエチレンヒマシ油５０（ＥＯ平均付加モル数５０）、ポリオキシエチレンヒマシ油６０（ＥＯ平均付加モル数６０）等が挙げられる。 Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and several types having different average addition mole number of ethylene oxide are known. . The average addition mole number of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles are exemplified. Specifically, polyoxyethylene castor oil 3 (EO average addition mole number 3), polyoxyethylene castor oil 10 (EO average addition mole number 10), polyoxyethylene castor oil 20 (EO average addition mole number 20), poly Oxyethylene castor oil 35 (EO average added mole number 35), polyoxyethylene castor oil 40 (EO average added mole number 40), polyoxyethylene castor oil 50 (EO average added mole number 50), polyoxyethylene castor oil 60 (EO average added mole number 60) and the like.
　ポリオキシエチレン硬化ヒマシ油（ＰＯＥ硬化ヒマシ油）は、水添したヒマシ油に酸化エチレンを付加重合することによって得られる化合物であり、酸化エチレンの平均付加モル数が異なるいくつかの種類が知られている。ポリオキシエチレン硬化ヒマシ油における酸化エチレンの平均付加モル数については、特に限定はないが、５～１００モルが例示される。具体的にはポリオキシエチレン硬化ヒマシ油５（ＥＯ平均付加モル数５）、ポリオキシエチレン硬化ヒマシ油１０（ＥＯ平均付加モル数１０）、ポリオキシエチレン硬化ヒマシ油２０（ＥＯ平均付加モル数２０）、ポリオキシエチレン硬化ヒマシ油３０（ＥＯ平均付加モル数３０）、ポリオキシエチレン硬化ヒマシ油４０（ＥＯ平均付加モル数４０）、ポリオキシエチレン硬化ヒマシ油５０（ＥＯ平均付加モル数５０）、ポリオキシエチレン硬化ヒマシ油６０（ＥＯ平均付加モル数６０）、ポリオキシエチレン硬化ヒマシ油８０（ＥＯ平均付加モル数８０）、ポリオキシエチレン硬化ヒマシ油１００（ＥＯ平均付加モル数１００）等が挙げられる。 Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition-polymerizing ethylene oxide to hydrogenated castor oil, and several types having different average addition mole number of ethylene oxide are known. ing. The average addition mole number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, and 5 to 100 moles are exemplified. Specifically, polyoxyethylene hydrogenated castor oil 5 (EO average addition mole number 5), polyoxyethylene hydrogenated castor oil 10 (EO average addition mole number 10), polyoxyethylene hydrogenated castor oil 20 (EO average addition mole number 20) ), Polyoxyethylene hydrogenated castor oil 30 (EO average addition mole number 30), polyoxyethylene hydrogenated castor oil 40 (EO average addition mole number 40), polyoxyethylene hydrogenated castor oil 50 (EO average addition mole number 50), Examples include polyoxyethylene hydrogenated castor oil 60 (EO average added mole number 60), polyoxyethylene cured castor oil 80 (EO average added mole number 80), polyoxyethylene cured castor oil 100 (EO average added mole number 100), etc. Be
　ポリオキシエチレンソルビタン脂肪酸エステル（ＰＯＥソルビタン脂肪酸エステル）としては、モノラウリン酸ポリオキシエチレン（２０）ソルビタン（ポリソルベート２０）、モノパルミチン酸ポリオキシエチレン（２０）ソルビタン（ポリソルベート４０）、モノステアリン酸ポリオキシエチレン（２０）ソルビタン（ポリソルベート６０）、トリステアリン酸ポリオキシエチレン（２０）ソルビタン（ポリソルベート６５）、モノオレイン酸ポリオキシエチレン（２０）ソルビタン（ポリソルベート８０）が挙げられる。 Examples of polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester) include polyoxyethylene monolaurate (20) sorbitan (polysorbate 20), monopalmitate polyoxyethylene (20) sorbitan (polysorbate 40), and monostearate polyoxyethylene (20) Sorbitan (polysorbate 60), polyoxyethylene tristearate (20) sorbitan (polysorbate 65), polyoxyethylene monooleate (20) sorbitan (polysorbate 80).
　ポリオキシエチレンポリオキシプロピレングリコール（ＰＯＥＰＯＰグリコール）は、ポリオキシエチレン鎖（ＰＯＥ）とポリオキシプロピレン鎖（ＰＯＰ）からなるブロック共重合体であり、酸化エチレン（ＥＯ）と酸化プロピレン（ＰＯ）の平均付加モル数が異なるいくつかの種類が知られている。ポリオキシエチレンポリオキシプロピレングリコールにおける酸化エチレンと酸化プロピレンの平均付加モル数については、特に限定はないが、平均付加モル数５～２００モルが例示される。具体的にはポリオキシエチレン（２００）ポリオキシプロピレン（７０）グリコール（ＥＯ平均付加モル数２００、ＰＯ平均付加モル数７０）、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール（ＥＯ平均付加モル数１９６、ＰＯ平均付加モル数６７）、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール（ＥＯ平均付加モル数１６０、ＰＯ平均付加モル数３０）、ポリオキシエチレン(１２０）ポリオキシプロピレン(４０)グリコール（ＥＯ平均付加モル数１２０、ＰＯ平均付加モル数４０）、ポリオキシエチレン（４２）ポリオキシプロピレン（６７）グリコール（ＥＯ平均付加モル数４２、ＰＯ平均付加モル数６７）、ポリオキシエチレン（５４）ポリオキシプロピレン（３９）グリコール（ＥＯ平均付加モル数５４、ＰＯ平均付加モル数３９）、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール（ＥＯ平均付加モル数２０、ＰＯ平均付加モル数２０）等が挙げられる。 Polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is a block copolymer consisting of polyoxyethylene chain (POE) and polyoxypropylene chain (POP), and is an average of ethylene oxide (EO) and propylene oxide (PO) Several types with different addition moles are known. The average addition mole number of ethylene oxide and propylene oxide in polyoxyethylene polyoxypropylene glycol is not particularly limited, but an average addition mole number of 5 to 200 moles is exemplified. Specifically, polyoxyethylene (200) polyoxypropylene (70) glycol (average EOL addition mole number 200, PO average addition mole number 70), polyoxyethylene (196) polyoxypropylene (67) glycol (EO average addition Mol number 196, PO average addition mol number 67), polyoxyethylene (160) polyoxypropylene (30) glycol (EO average addition mol number 160, PO average addition mol number 30), polyoxyethylene (120) polyoxypropylene (40) Glycol (EO average addition mole number 120, PO average addition mole number 40), polyoxyethylene (42) polyoxypropylene (67) glycol (EO average addition mole number 42, PO average addition mole number 67), poly Oxyethylene (54) polyoxypropylene (39) glycol EO average addition molar number: 54, PO average addition mole number 39), polyoxyethylene (20) polyoxypropylene (20) glycol (EO average addition mole number of 20, PO average addition mole number of 20), and the like.
　中でも、ポリオキシエチレン硬化ヒマシ油６０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン（２０）ソルビタンオレイン酸エステル及びポリオキシエチレンポリオキシプロピレングリコールが好ましい。 Among them, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene (20) sorbitan oleate and polyoxyethylene polyoxypropylene glycol are preferable.
　（Ｃ）成分の眼科用組成物中の配合量は、ポリオキシエチレンポリオキシプロピレングリコールを配合する場合、０．００１～５．０ｗ／ｖ％が好ましく、０．００１～２．０ｗ／ｖ％がより好ましく、０．００１～１．０ｗ／ｖ％がさらに好ましい。ポリオキシエチレンポリオキシプロピレングリコール以外を配合する場合、０．００１～０．５ｗ／ｖ％が好ましく、０．００１～０．３ｗ／ｖ％がより好ましく、０．００１～０．２ｗ／ｖ％がさらに好ましい。（Ｃ）成分の配合量が多すぎると、清涼化剤が活性剤ミセル中に内包され、揮発が抑制されるおそれがあり、少なすぎると、清涼化剤や脂溶性易酸化物が分離するおそれがある。 When the polyoxyethylene polyoxypropylene glycol is blended, the blending amount of the component (C) in the ophthalmic composition is preferably 0.001 to 5.0 w / v%, and 0.001 to 2.0 w / v% Is more preferable, and 0.001 to 1.0 w / v% is more preferable. When mix | blending except polyoxyethylene polyoxypropylene glycol, 0.001-0.5 w / v% is preferable, 0.001-0.3 w / v% is more preferable, 0.001-0.2 w / v% Is more preferred. If the blending amount of the component (C) is too large, the refreshing agent may be encapsulated in the active agent micelles and volatilization may be suppressed. If the blending amount is too small, the refreshing agent or the easily soluble oxide may be separated. There is.
[（Ｄ）成分]
　（Ｄ）成分は、ジブチルヒドロキシトルエン（ＢＨＴ）、ジブチルヒドロキシアニソール（ＢＨＡ）、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及びクロロブタノールから選ばれる１種以上の成分である。中でも、ジブチルヒドロキシトルエンが好ましい。（Ｄ）成分としては、１種単独で又は２種以上を適宜組み合わせて用いることができる。（Ｄ）成分は、（Ｂ）成分より溶解度が低く、活性剤ミセル中に内包されやすいため、（Ｂ）清涼化剤の揮発がより促進され、（Ｂ）清涼化剤による臭いマスキング効果が高まる。 [(D) component]
The component (D) is one or more components selected from dibutyl hydroxytoluene (BHT), dibutyl hydroxyanisole (BHA), propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol. Among them, dibutyl hydroxytoluene is preferred. As (D) component, it can be used individually by 1 type or in combination of 2 or more types suitably. The component (D) has lower solubility than the component (B) and is easily contained in the active agent micelles, so the volatilization of the refreshing agent (B) is further promoted and the odor masking effect by the refreshing agent is enhanced (B) .
　（Ｄ）成分の眼科用組成物中の配合量は、ジブチルヒドロキシトルエン、ジブチルヒドロキシアニソールを配合する場合、マスキング効果の点から、０．００１ｗ／ｖ％以上が好ましく、０．００２ｗ／ｖ％以上がより好ましく、０．００３ｗ／ｖ％以上がさらに好ましい。上限は特に限定されないが、０．０１ｗ／ｖ％以下とすることができる。 The amount of the component (D) to be incorporated in the ophthalmic composition is preferably 0.001 w / v% or more, 0.002 w / v% or more from the viewpoint of the masking effect when dibutyl hydroxytoluene and dibutyl hydroxyanisole are blended. Is more preferable, and 0.003 w / v% or more is more preferable. The upper limit is not particularly limited, but can be 0.01 w / v% or less.
　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を配合する場合は、マスキング効果の点から、０．０３ｗ／ｖ％以上が好ましく、０．０５ｗ／ｖ％以上がより好ましく、０．１ｗ／ｖ％以上がさらに好ましい。上限は特に限定されないが、１ｗ／ｖ％以下とすることができる。 In the case of blending propyl parahydroxybenzoate and butyl parahydroxybenzoate, in view of the masking effect, 0.03 w / v% or more is preferable, 0.05 w / v% or more is more preferable, 0.1 w / v% or more More preferable. The upper limit is not particularly limited, but may be 1 w / v% or less.
　クロロブタノールを配合する場合、マスキング効果の点から、０．０３ｗ／ｖ％以上が好ましく、０．０５ｗ／ｖ％以上がより好ましく、０．１ｗ／ｖ％以上がさらに好ましい。上限は特に限定されないが、３ｗ／ｖ％以下とすることができる。 In the case of blending chlorobutanol, in view of the masking effect, 0.03 w / v% or more is preferable, 0.05 w / v% or more is more preferable, and 0.1 w / v% or more is more preferable. The upper limit is not particularly limited, but can be 3 w / v% or less.
　（Ｂ）／（Ｄ）で表される配合比（質量比）の好ましい範囲は、下記の通りである。なお、この比率はｗ／ｖ％比であるが、質量比と同じである（以下同様）。（Ｄ）成分が、（Ｄ－Ｉ）ジブチルヒドロキシトルエン又はジブチルヒドロキシアニソールである場合、（Ｄ－ＩＩ）パラオキシ安息香酸プロピル又はパラオキシ安息香酸ブチルである場合、（Ｄ－ＩＩＩ）クロロブタノールである場合に分けて説明する。 The preferable range of the compounding ratio (mass ratio) represented by (B) / (D) is as follows. In addition, although this ratio is w / v% ratio, it is the same as mass ratio (following same). When the component (D) is (D-I) dibutyl hydroxytoluene or dibutyl hydroxy anisole, when it is (D-II) propyl parahydroxybenzoate or butyl parahydroxybenzoate, when it is (D-III) chlorobutanol I will divide and explain.
（Ｉ）（Ｄ）成分が、ジブチルヒドロキシトルエン（ＢＨＴ）又はジブチルヒドロキシアニソール（ＢＨＡ）である場合、０．０５～５００が好ましく、０．１～２００がより好ましく、０．１～１００がさらに好ましい。 When the component (I) (D) is dibutylhydroxytoluene (BHT) or dibutylhydroxyanisole (BHA), it is preferably 0.05 to 500, more preferably 0.1 to 200, and further preferably 0.1 to 100 preferable.
　（Ｂ）成分として、ｌ－メントールを配合する場合、１．０～２００が好ましく、２．０～１００がより好ましく、３．０～５０がさらに好ましく、４．０～５０が特に好ましい。 When 1-menthol is blended as the component (B), 1.0 to 200 is preferable, 2.0 to 100 is more preferable, 3.0 to 50 is more preferable, and 4.0 to 50 is particularly preferable.
　（Ｂ）成分として、カンフル（ｄｌ-カンフル、ｄ－カンフル）を配合する場合、０．４～２００が好ましく、１．０～１００がより好ましく、２．０～５０がさらに好ましい。 When camphor (dl-camphor, d-camphor) is blended as the component (B), 0.4 to 200 is preferable, 1.0 to 100 is more preferable, and 2.0 to 50 is more preferable.
　（Ｂ）成分として、ｄ－ボルネオール又はゲラニオールを配合する場合、０．４～２００が好ましく、０．６～１００がより好ましく、１．０～５０がさらに好ましい。 When d-borneol or geraniol is blended as the component (B), 0.4 to 200 is preferable, 0.6 to 100 is more preferable, and 1.0 to 50 is more preferable.
　（Ｂ）成分として、ユーカリ油を配合する場合、０．１～２００が好ましく、０．２～１００がより好ましく、０．３～５０がさらに好ましい。 When eucalyptus oil is blended as the component (B), 0.1 to 200 is preferable, 0.2 to 100 is more preferable, and 0.3 to 50 is more preferable.
（ＩＩ）（Ｄ）成分が、パラオキシ安息香酸プロピル又はパラオキシ安息香酸ブチルである場合、０．００１～２００が好ましく、０．００３～１００がより好ましく、０．０１～５０がさらに好ましい。 When the component (II) (D) is propyl parahydroxybenzoate or butyl parahydroxybenzoate, it is preferably 0.001 to 200, more preferably 0.003 to 100, and still more preferably 0.01 to 50.
　（Ｂ）成分として、ｌ－メントールを配合する場合は、０．１～１００が好ましく、０．２～５０がより好ましく、０．４～１０がさらに好ましい。 When l-menthol is blended as the component (B), 0.1 to 100 is preferable, 0.2 to 50 is more preferable, and 0.4 to 10 is more preferable.
　（Ｂ）成分として、カンフル（ｄｌ-カンフル、ｄ－カンフル）を配合する場合、０．０５～１００が好ましく、０．１５～５０がより好ましく、０．２～１０がさらに好ましい。 When camphor (dl-camphor, d-camphor) is blended as the component (B), 0.05 to 100 is preferable, 0.15 to 50 is more preferable, and 0.2 to 10 is more preferable.
　（Ｂ）成分として、ｄ－ボルネオール又はゲラニオールを配合する場合、０．０５～１００が好ましく、０．１～５０がより好ましく、０．１５～１０がさらに好ましい。 When d-borneol or geraniol is blended as the component (B), 0.05 to 100 is preferable, 0.1 to 50 is more preferable, and 0.15 to 10 is more preferable.
　（Ｂ）成分として、ユーカリ油を配合する場合、０．０１～１００が好ましく、０．０２～５０がより好ましく、０．０５～１０がさらに好ましい。 When eucalyptus oil is blended as the component (B), 0.01 to 100 is preferable, 0.02 to 50 is more preferable, and 0.05 to 10 is more preferable.
（ＩＩＩ）（Ｄ）成分がクロロブタノールである場合、０．０００１～１００が好ましく、０．０００３～５０がより好ましく、０．０００５～２０以上がさらに好ましい。 (III) When the component (D) is chlorobutanol, 0.0001 to 100 is preferable, 0.0003 to 50 is more preferable, and 0.0005 to 20 or more is more preferable.
　（Ｂ）成分として、ｌ－メントールを配合する場合、０．０１～５０が好ましく、０．０２～２０がより好ましく、０．０４～１０がさらに好ましい。 When 1-menthol is blended as the component (B), 0.01 to 50 is preferable, 0.02 to 20 is more preferable, and 0.04 to 10 is more preferable.
　（Ｂ）成分として、カンフル（ｄｌ－カンフル、ｄ－カンフル）を配合する場合、０．０５～５０が好ましく、０．１５～２０がより好ましく、０．２～１０がさらに好ましい。 When camphor (dl-camphor, d-camphor) is blended as the component (B), 0.05 to 50 is preferable, 0.15 to 20 is more preferable, and 0.2 to 10 is more preferable.
　（Ｂ）成分として、ｄ－ボルネオール又はゲラニオールを配合する場合、０．０００５～５０が好ましく、０．００１～２０がより好ましく、０．００１５～１０がさらに好ましい。 When d-borneol or geraniol is blended as the component (B), 0.0005 to 50 is preferable, 0.001 to 20 is more preferable, and 0.0015 to 10 is more preferable.
　（Ｂ）成分として、ユーカリ油を配合する場合、０．００１～５０が好ましく、０．００２～２０がより好ましく、０．００５～１０がさらに好ましい。 When eucalyptus oil is blended as the component (B), 0.001 to 50 is preferable, 0.002 to 20 is more preferable, and 0.005 to 10 is more preferable.
　（（Ｂ）＋（Ｄ））／（Ｃ）で表される配合比（質量比）の好ましい範囲は、下記の通りである。なお、（Ａ）成分がビタミンＡの場合、（Ｃ）成分が、（Ｃ－Ｉ）ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油又はポリオキシエチレンソルビタン脂肪酸エステルの場合、（Ｃ－ＩＩ）ポリオキシエチレンポリオキシプロピレングリコールの場合に分けて記載する。 The preferable range of the compounding ratio (mass ratio) represented by ((B) + (D)) / (C) is as follows. When component (A) is vitamin A, component (C) is (C-I) polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester, (C-II) The case of polyoxyethylene polyoxypropylene glycol is described separately.
　（Ａ）成分がビタミンＡの場合、（（Ｂ）＋（Ｄ））／（Ｃ）で表される配合比（質量比）は、０．０１～３０が好ましく、０．０２～１０がより好ましい。（（Ｂ）＋（Ｄ））／（Ｃ）が小さすぎると、清涼化剤がミセル中に包含し、揮発が抑制されるおそれがあり、大きすぎると、清涼化剤や脂溶性易酸化物が分離するおそれがある。 When the component (A) is vitamin A, the blending ratio (mass ratio) represented by ((B) + (D)) / (C) is preferably 0.01-30, more preferably 0.02-10. preferable. If ((B) + (D)) / (C) is too small, the refreshing agent may be included in the micelles and volatilization may be suppressed. If it is too large, the cooling agent or an easily soluble oxide may be contained. May separate.
　（Ｃ）成分が、（Ｃ－Ｉ）ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油又はポリオキシエチレンソルビタン脂肪酸エステルの場合
　（Ｂ）成分として、ｌ－メントールを配合し、（Ｄ）成分として、ジブチルヒドロキシトルエン又はジブチルヒドロキシアニソールを配合する場合、０．０５～１５が好ましく、０．１～１０がより好ましく、０．１５～５がさらに好ましい。 When component (C) is (CI) polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, or polyoxyethylene sorbitan fatty acid ester, 1-menthol is blended as component (B), and component (D) is incorporated as component (D) When dibutylhydroxytoluene or dibutylhydroxyanisole is blended, 0.05 to 15 is preferable, 0.1 to 10 is more preferable, and 0.15 to 5 is more preferable.
　（Ｂ）成分として、カンフル（ｄ－カンフル、ｄｌ－カンフル）を配合し、（Ｄ）成分として、ジブチルヒドロキシトルエン又はジブチルヒドロキシアニソールを配合する場合、０．０４～５が好ましく、０．０５～４がより好ましく、０．０８～３がさらに好ましい。 When camphor (d-camphor, dl-camphor) is blended as the component (B) and dibutyl hydroxytoluene or dibutyl hydroxy anisole is blended as the component (D), it is preferably 0.04 to 5, and 0.05 to 5 4 is more preferable, and 0.08 to 3 is more preferable.
　（Ｂ）成分として、ｄ－ボルネオール又はゲラニオールを配合し、（Ｄ）成分として、ジブチルヒドロキシトルエン又はジブチルヒドロキシアニソールを配合する場合、０．０３～５が好ましく、０．０４～４がより好ましく、０．０５～３がさらに好ましく、０．０６～３が特に好ましい。 When d-borneol or geraniol is blended as the component (B) and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as the component (D), 0.03 to 5 is preferable, and 0.04 to 4 is more preferable, 0.05 to 3 is more preferable, and 0.06 to 3 is particularly preferable.
　（Ｂ）成分として、ユーカリ油を配合し、（Ｄ）成分として、ジブチルヒドロキシトルエン又はジブチルヒドロキシアニソールを配合する場合、０．０２～５が好ましく、０．０３～３がより好ましく、０．０４～３がさらに好ましく、０．０４５～３が特に好ましい。 When eucalyptus oil is blended as the component (B) and dibutyl hydroxytoluene or dibutyl hydroxyanisole is blended as the component (D), 0.02 to 5 is preferable, 0.03 to 3 is more preferable, and 0.04 To 3 is more preferable, and 0.045 to 3 is particularly preferable.
（Ｃ－ＩＩ）ポリオキシエチレンポリオキシプロピレングリコールの場合
　（Ｂ）成分として、ｌ－メントールを配合し、（Ｄ）成分として、ジブチルヒドロキシトルエン又はジブチルヒドロキシアニソールを配合する場合、０．００５～１．５が好ましく、０．０１５～１．０がより好ましく、０．０２５～０．５がさらに好ましい。 (C-II) In the case of polyoxyethylene polyoxypropylene glycol When 1-menthol is blended as the component (B) and dibutyl hydroxytoluene or dibutyl hydroxyanisole is blended as the component (D), 0.005 to 1 Is preferable, 0.015 to 1.0 is more preferable, and 0.025 to 0.5 is more preferable.
　（Ｂ）成分として、カンフル（ｄ－カンフル、ｄｌ－カンフル）を配合し、（Ｄ）成分として、ジブチルヒドロキシトルエン又はジブチルヒドロキシアニソールを配合する場合、０．００７～０．５が好ましく、０．０１～０．４がより好ましく、０．０１５～０．３がさらに好ましい。 When camphor (d-camphor, dl-camphor) is blended as the component (B) and dibutyl hydroxytoluene or dibutyl hydroxy anisole is blended as the component (D), 0.007 to 0.5 is preferable, and 0. 01 to 0.4 is more preferable, and 0.015 to 0.3 is more preferable.
　（Ｂ）成分として、ｄ－ボルネオール又はゲラニオールを配合し、（Ｄ）成分として、ジブチルヒドロキシトルエン又はジブチルヒドロキシアニソールを配合する場合、０．００７～０．５が好ましく、０．００８～０．４がより好ましく、０．０１～０．３がさらに好ましい。 When d-borneol or geraniol is blended as the component (B) and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as the component (D), 0.007 to 0.5 is preferable, and 0.008 to 0.4 is preferable. Is more preferable, and 0.01 to 0.3 is more preferable.
　（Ｂ）成分として、ユーカリ油を配合し、（Ｄ）成分として、ジブチルヒドロキシトルエン又はジブチルヒドロキシアニソールを配合する場合、０．００５～０．５が好ましく、０．００６～０．４がより好ましく、０．００７～０．３がさらに好ましい。 When eucalyptus oil is blended as component (B) and dibutyl hydroxytoluene or dibutyl hydroxy anisole is blended as component (D), 0.005 to 0.5 is preferable, and 0.006 to 0.4 is more preferable. And 0.007 to 0.3 are more preferable.
　上記（Ｂ）／（Ｄ）比、（（Ｂ）＋（Ｄ））／（Ｃ）で表される配合比において、（Ｂ）成分が複数配合される場合は、（Ｂ）成分の総量を各成分の濃度として扱う。マスキング効果は、ユーカリ油、ゲラニオール、ｄ－ボルネオール、カンフル（ｄ－カンフル、ｄｌ－カンフル）、ｌ－メントールの順に高いため、上記比は、配合されている成分のうち、マスキング効果の高い成分の範囲に従う。（Ｃ）及び（Ｄ）成分が複数配合される場合は、各成分の総量を各成分の濃度として扱う。上記比は、配合量の多い成分の範囲に従う。 In the compounding ratio represented by the (B) / (D) ratio and ((B) + (D)) / (C) above, when a plurality of (B) components are compounded, the total amount of the (B) components is Treat as the concentration of each component. Since the masking effect is higher in the order of eucalyptus oil, geraniol, d-borneol, camphor (d-camphor, dl-camphor) and l-menthol, the above ratio is the component with the highest masking effect among the components blended. Follow the range. When multiple components (C) and (D) are blended, the total amount of each component is treated as the concentration of each component. The above ratio is in accordance with the range of the component with a large amount.
[任意成分]
　本発明の眼科用組成物には、眼科用組成物に用いられる各種成分を、必要に応じて、本発明の効果を損なわない範囲で配合することができる。好ましい配合成分としては、薬物、緩衝剤、安定化剤、粘稠化剤、等張化剤、抗酸化剤、防腐剤、ｐＨ調整剤、多価アルコール等が挙げられる。 [Optional ingredient]
The various components used for an ophthalmic composition can be mix | blended with the ophthalmic composition of this invention in the range which does not impair the effect of this invention as needed. Preferred ingredients include drugs, buffers, stabilizers, thickeners, tonicity agents, antioxidants, preservatives, pH adjusters, polyhydric alcohols and the like.
　薬物としては、例えば、充血除去成分、眼筋調節薬成分、抗炎症薬成分又は収斂薬成分、抗ヒスタミン薬成分又は抗アレルギー薬成分、アミノ酸、抗菌薬成分又は殺菌薬成分、糖類、多糖類又はその誘導体、局所麻酔薬成分、ステロイド成分、緑内障治療成分、白内障治療成分、散瞳成分等が挙げられる。具体例を下記に示す。 As the drug, for example, a decongestant component, an ocular muscle modulator component, an antiinflammatory component or an astringent drug component, an antihistamine component or an antiallergic component, an amino acid, an antibacterial component or a bactericidal component, a saccharide, a polysaccharide or The derivative, a local anesthetic ingredient, a steroid ingredient, a glaucoma treatment ingredient, a cataract treatment ingredient, a mydriasis ingredient etc. are mentioned. A specific example is shown below.
　充血除去成分：例えば、α－アドレナリン作動薬、例えば、イミダゾリン誘導体（ナファゾリン、テトラヒドロゾリン等）、β－フェニルエチルアミン誘導体（フェニレフリン、エピネフリン、エフェドリン、メチルエフェドリン等）、及びそれらの薬学上又は生理的に許容される塩（例えば、ナファゾリン塩酸塩、ナファゾリン硝酸塩、塩酸テトラヒドロゾリン、硝酸テトラヒドロゾリン、フェニレフリン塩酸塩、エピネフリン塩酸塩、エフェドリン塩酸塩、メチルエフェドリン塩酸塩等の無機酸塩；酒石酸水素エピネフリン等の有機酸塩等）等が挙げられる。 Decongestant components: for example, α-adrenergic agents such as imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and their pharmacologically or physiologically acceptable Salts (eg, Naphazoline hydrochloride, Naphazoline nitrate, Tetrahydrozoline hydrochloride, Tetrahydrozoline nitrate, Phenylephrine hydrochloride, Epinephrine hydrochloride, Ephedrine hydrochloride, Inorganic acid salts such as methylephedrine hydrochloride, etc .; Organic acid salts such as epinephrine hydrogen tartrate, etc. Etc.).
　眼筋調節薬成分：例えば、アセチルコリンと類似した活性中心を有するコリンエステラーゼ阻害剤（例えば、ネオスチグミンメチル硫酸塩等）、トロピカミド、アトロピン硫酸塩等が挙げられる。 Eye muscle modulator component: For example, cholinesterase inhibitors having an active center similar to acetylcholine (eg, neostigmine methyl sulfate etc.), tropicamide, atropine sulfate etc. may be mentioned.
　抗炎症薬成分又は収斂薬成分：例えば、プラノプロフェン、セレコキシブ、ロフェコキシブ、インドメタシン、ジクロフェナク、ジクロフェナクナトリウム、ピロキシカム、メロキシカム、アスピリン、メフェナム酸、インドメタシンファルネシル、アセメタシン、イブプロフェン、チアプロフェン酸、ロキソプロフェンナトリウム、塩酸チアラミド、亜鉛塩（例えば、硫酸亜鉛、乳酸亜鉛等）、リゾチーム、塩化リゾチーム、サリチル酸メチル、アラントイン、イプシロン－アミノカプロン酸、塩化ベルベリン、硫酸ベルベリン、グリチルリチン酸及び薬理学的に許容される塩（例えば、グリチルリチン酸二カリウム、グリチルリチン酸アンモニウム等）等が挙げられる。 Anti-inflammatory or astringent ingredients: eg pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemetacin, ibuprofen, tiaprofenic acid, loxoprofen sodium, tiaramide hydrochloride Zinc salts (eg, zinc sulfate, zinc lactate etc.), lysozyme, lysozyme, methyl salicylate, allantoin, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, glycyrrhizinic acid and pharmacologically acceptable salts (eg, glycyrrhizin) Dipotassium acid, ammonium glycyrrhizinate and the like) and the like.
　抗ヒスタミン薬成分又は抗アレルギー薬成分：例えば、ケトチフェン、アシタザノラスト、クロルフェニラミン、ジフェンヒドラミン、レボカバスチン、クロモグリク酸、トラニラスト、イブジラスト、アンレキサノクス、ペミロラスト、及びそれらの薬学上又は生理的に許容される塩（ジフェンヒドラミン塩酸塩、ケトチフェンフマル酸塩、クロモグリク酸ナトリウム等）等が挙げられる。 Antihistamine drug component or antiallergic drug component: for example, ketotifen, alitazanolast, chlorpheniramine, diphenhydramine, levocabastine, cromoglycic acid, tranilast, ibudilast, anlexanox, pemirolast, and their pharmaceutically or physiologically acceptable salts (Diphenhydramine hydrochloride, ketotifen fumarate, sodium cromoglycate etc.) and the like.
　アミノ酸：例えば、ロイシン、イソロイシン、バリン、メチオニン、トレオニン、アラニン、フェニルアラニン、トリプトファン、リジン、グリシン、セリン、プロリン、チロシン、システイン、ヒスチジン、オルニチン、ヒドロキシプロリン、ヒドロキシリジン、グリシルグリシン、γ－アミノ酪酸、グルタミン酸、アスパラギン酸ナトリウム、アスパラギン酸カリウム、アスパラギン酸マグネシウム、アミノエチルスルホン酸（タウリン）又はその塩（例えば塩酸システイン等）等が挙げられる。 Amino acid, for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, serine, glycine, serine, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine, glycylglycine, γ-aminobutyric acid Glutamic acid, sodium aspartate, potassium aspartate, magnesium aspartate, aminoethyl sulfonic acid (taurine) or salts thereof (eg, cysteine hydrochloride etc.) and the like can be mentioned.
　抗菌薬成分又は殺菌薬成分：例えば、スルホンアミド類（例えば、スルファメトキサゾール、スルフイソキサゾール、スルフイソミジン及び薬理学的に許容される塩（スルファメトキサゾールナトリウム、スルフイソミジンナトリウム等）、アクリノール、アルキルポリアミノエチルグリシン、ニューキノロン剤（ロメフロキサシン、レボフロキサシン、シプロフロキサシン、オフロキサシン、ノルフロキサシン、シプロフロキサシン塩酸塩等）、βラクタム系抗菌薬（スルベニシリン、セフメノキシム等）、アミノグリコシド系抗菌薬（カナマイシン、ゲンタマイシン、トブラマイシン、シソマイシン、ジベカシン、ベカナマイシン、ミクロノマイシン等）、テトラサイクリン系抗菌薬（オキシテトラサイクリン等）、マクロライド系抗菌薬（エリスロマイシン等）、クロラムフェニコール系抗菌薬（クロラムフェニコール等）、ポリペプチド系抗菌薬（コリスチン等）等が挙げられる。また、抗ウイルス薬（イドクスウリジン、アシクロビル、アデニンアラビノシド、ガンシクロビル、ホスカルネット、バラシクロビル、トリフルオロチミジン、シドフォビル、カルボサイクリック・オキセタノシンＧ等）、抗真菌薬（ピマリシン、フルコナゾール、イトラコナゾール、ミコナゾール、フルシトシン、アムホテリシンＢ等）等が挙げられる。 Antimicrobial or microbicidal components: eg sulfonamides (eg sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine) Sodium etc), acrinol, alkyl polyaminoethyl glycine, new quinolone agent (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, etc), β-lactam antibacterial (sulbenicillin, cefmenoxim etc), aminoglycosides Antibacterial drugs (Kanamycin, Gentamycin, Tobramycin, Shisomycin, Dibekacin, Bekanamycin, Micronomycin etc.), Tetracyclines (Oxytetracycline etc.), Macrolide Antibiotics Drugs (erythromycin etc.), chloramphenicol antibiotics (chloramphenicol etc.), polypeptide antibiotics (eg colistin etc.) etc. Also, antiviral agents (idoxuridine, acyclovir, adenine arabino) Sid, ganciclovir, phoscarnet, valacyclovir, trifluorothymidine, cidofovir, carbocyclic oxetanocin G, etc., antifungal agents (pimaricin, fluconazole, itraconazole, miconazole, flucytosine, amphotericin B etc.) and the like.
　糖類：例えば、ラクツロース、ラフィノース、プルラン、グルコース、マルトース、トレハロース、スクロース、シクロデキストリン、キシリトール、マンニトール、ソルビトール等が挙げられる。 Sugars: For example, lactulose, raffinose, pullulan, glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, mannitol, sorbitol and the like can be mentioned.
　多糖類又はその誘導体：例えば、アラビアゴム、カラヤガム、キサンタンガム、キャロブガム、グアーガム、グアヤク脂、クインスシード、ダンマルゴム、トラガント、ベンゾインゴム、ローカストビーンガム、カゼイン、寒天、アルギン酸、デキストリン、デキストラン、カラギーナン、ゼラチン、コラーゲン、ペクチン、デンプン、ポリガラクツロン酸（アルギン酸）、キチン及びその誘導体、キトサン及びその誘導体、エラスチン、ヒアルロン酸、コンドロイチン硫酸又はその塩（アルギン酸ナトリウム、コンドロイチン硫酸ナトリウム等）等が挙げられる。 Polysaccharides or derivatives thereof: for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac fat, quince seed, dammar gum, traganto, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin Collagen, pectin, starch, polygalacturonic acid (alginic acid), chitin and derivatives thereof, chitosan and derivatives thereof, elastin, hyaluronic acid, chondroitin sulfate or salts thereof (sodium alginate, sodium chondroitin sulfate etc.) and the like can be mentioned.
　局所麻酔薬成分：例えば、リドカイン、オキシブプロカイン、ジプカイン、プロカイン、アミノ安息香酸エチル、メプリルカイン、メピバカイン、ブピバカイン、コカイン、及びそれらの塩（リドカイン塩酸塩、オキシブプロカイン塩酸塩等）等が挙げられる。 Local anesthetic components: for example, lidocaine, oxybuprocaine, dipkine, procaine, ethyl aminobenzoate, meprilcaine, mepivacaine, bupivacaine, ***e, and salts thereof (such as lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) .
　ステロイド成分：例えば、ヒドロコルチゾン、プレドニゾロン、コルチゾール、メチルプレドニゾロン、トリアムシノロン、パラメタゾン、ベタメタゾン、及びそれらの塩等が挙げられる。 Steroid component: For example, hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, paramethasone, betamethasone, salts thereof and the like can be mentioned.
　緑内障治療成分：例えば、ジスチグミン臭化物、チモロールマレイン酸塩、カルテオロール塩酸塩、ベタキソロール塩酸塩、ラタノプロスト、イソプロピルウノプロストン、ジピベフリン塩酸塩、アプラクロニジン塩酸塩、ピロカルピン塩酸塩、カルバコール、ドルゾラミド塩酸塩、アセタゾラミド、メタゾラミド、及びそれらの塩等が挙げられる。 Glaucoma therapeutic ingredients: for example, distigmine bromide, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, isopropyl unoprostone, dipivefrine hydrochloride, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide , Methazolamide, salts thereof and the like.
　白内障治療成分：例えば、ピレノキシン、グルタチオン、唾液腺ホルモン、チオプロニン、Ｄｉｈｙｄｒｏ ａｚａｐｅｎｔａｃｅｎｅ ｄｉｓｕｌｆｏｎａｔｅ及びそれらの塩（例えばＳｏｄｉｕｍ５，１２－ｄｉｈｙｄｒｏ ａｚａｐｅｎｔａｃｅｎｅ ｄｉｓｕｌｆｏｎａｔｅ等）等が挙げられる。 Ingredients for treating cataract: for example, pyrenoxine, glutathione, salivary gland hormone, thiopronine, dihydro azapentacene disulphonate and salts thereof (for example, sodium 5,12-dihydro azapentacene disulphonate etc.) and the like.
　散瞳成分：例えば、シクロペントラート塩酸塩、トロピカミド等が挙げられる。 Mydriatic component: For example, cyclopentolate hydrochloride, tropicamide and the like can be mentioned.
　薬物を配合する場合、その配合量は、各薬物の有効な適性量を選択することができるが、眼への刺激性、組成物の安定性等の点から、眼科用組成物中０．００１～５ｗ／ｖ％の範囲であることが好ましい。 When a drug is blended, the blending amount can be selected as an effective appropriate amount of each drug, but from the viewpoint of eye irritation, stability of the composition, etc., 0.001 in the ophthalmic composition. It is preferably in the range of ̃5 w / v%.
　緩衝剤としては、例えば、クエン酸、クエン酸ナトリウム、ホウ酸、ホウ砂、リン酸、リン酸水素ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、酢酸、酢酸ナトリウム、氷酢酸、トロメタモール、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。緩衝剤を配合する場合、その配合量は、眼科用組成物中０．００３～４ｗ／ｖ％の範囲であることが好ましい。 As a buffer, for example, citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, acetic acid, sodium acetate, glacial acetic acid, trometamol, Sodium carbonate, sodium hydrogen carbonate and the like can be mentioned. When a buffer is added, the amount thereof is preferably in the range of 0.003 to 4 w / v% in the ophthalmic composition.
　安定化剤としては、例えば、エチレンジアミン酢酸誘導体又はその塩（例えば、エデト酸（エチレンジアミン四酢酸等）、エデト酸ナトリウム（エチレンジアミン四酢酸ナトリウム）等）、α－シクロデキストリン、β－シクロデキストリン、γ－シクロデキストリン等が挙げられる。安定化剤を配合する場合、その配合量は、眼科用組成物中０．００３～２ｗ／ｖ％の範囲であることが好ましい。  Examples of the stabilizer include ethylenediamine acetic acid derivatives or salts thereof (eg, edetic acid (such as ethylenediaminetetraacetic acid), sodium edetate (such as sodium ethylenediaminetetraacetate), α-cyclodextrin, β-cyclodextrin, γ- Cyclodextrin etc. are mentioned. When a stabilizer is blended, the blending amount thereof is preferably in the range of 0.003 to 2 w / v% in the ophthalmic composition.
　粘稠化剤としては、例えば、メチルセルロース、ヒプロメロース、ヒドロキシエチルセルロース等のセルロース系高分子化合物、ポビドン、ポリビニルアルコール等のポリビニル系高分子化合物、流動パラフィン、カルボキシビニルポリマー、ポリエチレングリコール等が挙げられる。粘稠化剤を配合する場合、その配合量は、眼科用組成物中０．００３～３ｗ／ｖ％の範囲であることが好ましい。 Examples of the thickening agent include cellulose-based polymer compounds such as methyl cellulose, hypromellose and hydroxyethyl cellulose, polyvinyl-based polymer compounds such as povidone and polyvinyl alcohol, liquid paraffin, carboxyvinyl polymer, polyethylene glycol and the like. When a thickening agent is blended, the blending amount thereof is preferably in the range of 0.003 to 3 w / v% in the ophthalmic composition.
　等張化剤としては、例えば、塩化カリウム、塩化ナトリウム、塩化カルシウム、塩化マグネシウム、酢酸カリウム、酢酸ナトリウム、炭酸ナトリウム、硫酸マグネシウム、リン酸水素二ナトリウム、リン酸二水素ナトリウム、亜硫酸水素ナトリウム等が挙げられる。等張化剤を配合する場合、その配合量は、眼科用組成物中０．００１～３ｗ／ｖ％の範囲であることが好ましい。 Examples of tonicity agents include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium carbonate, sodium carbonate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen sulfite and the like. It can be mentioned. When a tonicity agent is blended, the blending amount thereof is preferably in the range of 0.001 to 3 w / v% in the ophthalmic composition.
　抗酸化剤としては、例えば、ヒドロキノン、没食子酸プロピル、亜硫酸水素ナトリウム等が挙げられる。抗酸化剤を配合する場合、その配合量は、眼科用組成物中０．００１～１ｗ／ｖ％の範囲であることが好ましい。 Examples of the antioxidant include hydroquinone, propyl gallate, sodium bisulfite and the like. When the antioxidant is blended, the blending amount thereof is preferably in the range of 0.001 to 1 w / v% in the ophthalmic composition.
　防腐剤としては、例えば、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、塩化ポリドロニウム、塩酸アルキルジアミノエチルグリシン、ポリヘキサメチレンビグアニド等が挙げられる。防腐剤を配合する場合、その配合量は、眼科用組成物中０．００１～０．５ｗ／ｖ％の範囲であることが好ましい。 Examples of the preservative include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, polydronium chloride, alkyldiaminoethylglycine hydrochloride, polyhexamethylene biguanide and the like. When a preservative is blended, the blending amount is preferably in the range of 0.001 to 0.5 w / v% in the ophthalmic composition.
　ｐＨ調整剤としては、例えば、塩酸、硫酸、リン酸、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、水酸化カルシウム等が挙げられる。本発明の眼科用組成物のｐＨ（２０℃）は、３．５～８．０であり、好ましくは、５．０～７．５、より好ましくは６．０～７．３である。ｐＨが低すぎても、高すぎても、刺激感が強くなる可能性がある。なお、ｐＨの測定は、２０℃でｐＨ浸透圧計（ＨＳＭＯ－１、東亜ディーケーケー（株））を用いて行う。ｐＨ調整剤としては、水酸化ナトリウム、水酸化カリウム、塩酸等が好ましい。 Examples of pH adjusters include hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like. The pH (20 ° C.) of the ophthalmic composition of the present invention is 3.5 to 8.0, preferably 5.0 to 7.5, more preferably 6.0 to 7.3. If the pH is too low or too high, the feeling of irritation may be strong. The pH is measured at 20 ° C. using a pH osmometer (HSMO-1, Toa DKK Co., Ltd.). As a pH adjuster, sodium hydroxide, potassium hydroxide, hydrochloric acid and the like are preferable.
　多価アルコールとしては、例えば、グリセリン、プロピレングリコール、ブチレングリコール、ポリエチレングリコール等が挙げられる。 Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like.
[製造方法]
　本発明の眼科用組成物は、例えば、残部を水とし、公知の製造方法で製造することができる。例えば上記各成分を滅菌精製水、イオン交換水等の水との混合溶媒等に溶解させた後、ｐＨを調整し、さらに必要に応じて浸透圧等をｐＨ調整剤、等張化剤により適宜調整することによって得ることができる。 [Production method]
The ophthalmic composition of the present invention can be produced, for example, by using the remaining portion as water, by a known production method. For example, after dissolving each of the above components in a mixed solvent with water such as sterile purified water, ion-exchanged water, etc., adjust the pH, and if necessary, adjust the osmotic pressure etc. with a pH adjuster or isotonizing agent. It can be obtained by adjusting.
[眼科用製品]
　本発明の眼科用製品は、眼科用組成物を収容する本体とキャップとを備えた容器に収容され、この容器が鉄系の酸素吸収剤と共に、包囲体で包囲して密封された眼科用製品であって、
上記本体の容量が１～２５ｍＬ、
上記本体の酸素透過度が１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以上、
上記包囲体と上記容器との間に形成される空間の体積が、上記容器の体積に対し２００Ｖ／Ｖ％以下
のものである。 [Ophthalmic products]
The ophthalmic product of the present invention is contained in a container comprising a main body containing the ophthalmic composition and a cap, and the container is sealed together with an iron-based oxygen absorbent and enclosed in an enclosure. And
The volume of the above body is 1 to 25 mL,
The oxygen permeability of the body above 10 cc / (m 2 · 24 hr · atm),
The volume of the space formed between the enclosure and the container is 200 V / V% or less with respect to the volume of the container.
　容器は、眼科用組成物を収容する本体とキャップとを備えたものである。より具体的には、本体には点眼口が設けられ、本体を密閉する、スクリュータイプ、ワンタッチタイプ等のキャップを有する。なお、本体には点眼口を有する中栓が設けられてもよく、点眼口はキャップに設けられていてもよく、キャップを容器に直接設置して密閉できるようにしてもよい。本体には点眼口を有する中栓が設けられていることが好ましい。本発明においては、容器という場合は、本体にキャップを装着した状態のものをいう。 The container comprises a body for containing the ophthalmic composition and a cap. More specifically, the main body is provided with an eyedrop opening, and has a cap of a screw type, one touch type or the like which seals the main body. In addition, the inside plug which has an eye drop opening may be provided in the main body, the eye drop opening may be provided in a cap, and a cap may be directly installed in a container and sealed. It is preferable that the main body is provided with an inside plug having an eye drop opening. In the present invention, the term "container" refers to a container in which a cap is attached to the main body.
〈本体〉
　眼科用組成物を収容する本体は、眼科用組成物中の清涼化剤を包囲体内に揮発させるため、その酸素透過度は１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以上である。上限は特に限定されないが、２００ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以下とすることもできる。このような酸素透過度を有する本体としては、具体的には、例えば、ポリエチレン、ポリエチレンテレフタレート、ポリプロピレン、ポリブチレン、ポリカーボネート、ポリアリレート、塩化ビニル等の材質からなる本体が挙げられる。より具体的にはポリエチレンテレフタレート製のマルチドーズの点眼用容器等が、安定性が高く、より好適である。酸素透過度は、ＪＩＳ－Ｋ７１２６－２プラスチックフィルム及びシート－ガス透過度試験方法Ｂ法（付属書Ｂ）に準じた方法で測定できる。 <Body>
Since the main body containing the ophthalmic composition volatilizes the refreshing agent in the ophthalmic composition into the enclosure, its oxygen permeability is 10 cc / (m 2 · 24 hr · atm) or more. The upper limit is not particularly limited, but may be 200 cc / (m 2 · 24 hr · atm) or less. Specific examples of the main body having such oxygen permeability include main bodies made of materials such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, and vinyl chloride. More specifically, a multi-dose container made of polyethylene terephthalate and the like is more preferable because of its high stability. The oxygen permeability can be measured by the method according to JIS-K7126-2 plastic film and sheet-gas permeability test method B (Appendix B).
　本体の容量（本体を眼科用組成物で満量にしたときの体積）は１～２５ｍＬであり、５～２０ｍＬが好ましい。さらに、収容する眼科用組成物の量は、製品及びその使用方法に応じて適宜選択することができ、例えばマルチドーズ点眼剤の場合、１～２５ｍＬであり、１～２０ｍＬが好ましく、５～２０ｍＬがより好ましい。眼科用組成物の量が少なすぎると、点眼剤容器内の清涼化剤の揮発量が不十分となり、臭いマスキング効果が不十分となるおそれがある。 The volume of the main body (volume when the main body is filled with the ophthalmic composition) is 1 to 25 mL, preferably 5 to 20 mL. Furthermore, the amount of the ophthalmic composition to be contained can be appropriately selected according to the product and its method of use, and is, for example, 1 to 25 mL, preferably 1 to 20 mL, and 5 to 20 mL for multidose eye drops. Is more preferred. If the amount of the ophthalmic composition is too small, the volatilization amount of the refreshing agent in the eye drop container may be insufficient, and the odor masking effect may be insufficient.
〈キャップ、中栓〉
　中栓、キャップは、公知の眼科用製品の容器に使用される材質のキャップを使用することができる。中栓の材質としては、メルトフローレート２．０以下、好ましくは１．２～１．８のポリエチレン、ポリプロピレンが好ましい。キャップの材質としては、ポリエチレン、ポリプロピレンが好ましい。 <Cap, inside plug>
The plug and the cap can use a cap made of a material used for a container of a known ophthalmic product. The material of the inside plug is preferably polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8. As a material of the cap, polyethylene and polypropylene are preferable.
　容器の酸素透過性は、０．０１％以上が好ましく、０．１％以上がより好ましく、０．２％以上がさらに好ましい。上限は特に限定されないが、例えば５％以下とすることができる。なお、酸素透過性の測定方法は後述する実施例記載の方法である。酸素透過性が高ければ、清涼化剤が揮発し易く、臭いマスキング効果がより得られる。 The oxygen permeability of the container is preferably 0.01% or more, more preferably 0.1% or more, and still more preferably 0.2% or more. The upper limit is not particularly limited, but can be, for example, 5% or less. In addition, the measuring method of oxygen permeability is a method as described in the Example mentioned later. If the oxygen permeability is high, the refreshing agent is easily volatilized and an odor masking effect can be obtained more.
　容器体積に対する眼科用組成物の充填率（キャップ、中栓を装着した容器において、本体の空壁の容器満量に対する体積率）は、５０％以上が好ましく、７０％以上がより好ましく、８０％以上がさらに好ましい。収容率が低すぎると、清涼化剤が空壁内に充満し、包囲体内の臭いのマスキング効果が不十分になるおそれがある。 50% or more is preferable, 70% or more is more preferable, and 80% or more is preferable for the filling ratio of the ophthalmic composition with respect to the container volume (cap ratio of the empty wall of the main body to the container fullness in a container equipped with a cap and a stopper). The above is more preferable. If the storage rate is too low, the refreshing agent may fill the empty wall, and the effect of masking odors in the enclosure may be insufficient.
[酸素吸収剤]
　本発明の酸素吸収剤は、鉄系の酸素吸収剤であり、具体的には、三菱ガス化学（株）製のエージレス（ＦＸ、ＳＡ、Ｚ－ＰＴ、ＧＬ、Ｇ）、（株）常盤産業製のバイタロン等が市販されている。包囲体内の酸素を十分に吸収するスペックのものを使用する。通常、酸素吸収剤は医薬品・食品業界で広く使用されているため、低コストで使用できる。なお、酸素吸収剤は、ピロー内に存在する酸素を全て吸収できる能力のものを用いる。能力以下だと酸素を十分に吸収できず、易酸化物が酸化分解し、能力以上だとピローがシュリンクし、容器がへこむおそれがある。 [Oxygen absorbent]
The oxygen absorbent of the present invention is an iron-based oxygen absorbent, and specifically, Ageless (FX, SA, Z-PT, GL, G) manufactured by Mitsubishi Gas Chemical Co., Ltd., Tokiwa Sangyo Co., Ltd. Commercially available Vitalon and the like. Use a spec that sufficiently absorbs oxygen in the enclosure. In general, oxygen absorbers are widely used in the pharmaceutical and food industries, and can be used at low cost. As the oxygen absorbent, one having an ability to absorb all the oxygen present in the pillow is used. If it is less than the capacity, oxygen can not be absorbed sufficiently, and the oxide easily decomposes, and if it is more than the capacity, the pillow may shrink and the container may be dented.
[包囲体]
　眼科用組成物は、酸素吸収剤と共に包囲体で包囲して密封される。包囲体の材料としては、例えば、ポリエチレン、ポリエチレンテレフタレート、ポリプロピレン、ポリブチレン、ポリカーボネート、ポリエステル、ナイロン、セロファン、ポリ塩化ビニルフィルム、アルミ箔又はアルミニウムを蒸着したポリビニルアルコール系フィルム、ポリアミド系フィルム、アルミナを蒸着したポリエチレンテレフタレート、酸化ケイ素を蒸着したポリエチレンテレフタレート、ポリ塩化ビニリデンをコートしたフィルム又はラミネートフィルム等、これらの複合、多層フィルム等が挙げられる。中でも、ポリエチレンテレフタレート／ポリエチレン多層フィルム、アルミナを蒸着したポリエチレンテレフタレート／ポリエチレン多層フィルムが好ましい。酸素透過度は、１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以下（即ち、０～１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ））が好ましい。なお、包囲体の酸素透過度は、本体の酸素透過度より低いことが望ましく、１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）未満がより好ましく、０～３ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）、０～１ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）、０．０１～０．３ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）がさらに好ましく、０．０１～０．１ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）が特に好ましく、０．０１～０．０２ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）が最も好ましい。 [Enclosure]
The ophthalmic composition is enclosed and sealed in an enclosure with an oxygen absorber. The material of the enclosure is, for example, polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, polyvinyl alcohol film with aluminum foil or aluminum vapor deposited, polyamide film, alumina vapor deposited And polyethylene terephthalate on which silicon oxide is vapor-deposited, a film coated with polyvinylidene chloride or a laminate film, etc., and composites thereof, multilayer films and the like. Among them, polyethylene terephthalate / polyethylene multilayer film, and polyethylene terephthalate / polyethylene multilayer film formed by vapor deposition of alumina are preferable. The oxygen permeability is preferably 10 cc / (m 2 · 24 hr · atm) or less (that is, 0 to 10 cc / (m 2 · 24 hr · atm)). The oxygen permeability of the enclosure is preferably lower than that of the main body, more preferably less than 10 cc / (m 2 · 24 hr · atm), 0 to 3 cc / (m 2 · 24 hr · atm), 0 ~ 1cc / (m 2 · 24hr · atm), preferably 0.01 ~ 0.3cc / (m 2 · 24hr · atm) further, 0.01 ~ 0.1cc / (m 2 · 24hr · atm) particularly Preferably, 0.01 to 0.02 cc / (m 2 · 24 hr · atm) is most preferable.
　上記包囲体と上記容器（本体にキャップを装着した状態）との間に形成される空間（インナースペース）の体積は、上記容器の体積に対し２００Ｖ／Ｖ％以下であり、１５０Ｖ／Ｖ％以下が好ましく、１２０Ｖ／Ｖ％以下がより好ましい。２００Ｖ／Ｖ％を超えると、包囲体内の臭いのマスキング効果が十分に得られない。下限は特に限定されないが、２０Ｖ／Ｖ％以上とすることができる。 The volume of the space (inner space) formed between the enclosure and the container (with the cap attached to the main body) is 200 V / V% or less and 150 V / V% or less with respect to the volume of the container Is preferable, and 120 V / V% or less is more preferable. If it exceeds 200 V / V%, the masking effect of the smell in an enclosure is not fully obtained. The lower limit is not particularly limited, but can be 20 V / V% or more.
[マスキング方法]
　本発明は、
（Ａ）易酸化物、
（Ｂ）清涼化剤、
（Ｃ）非イオン性界面活性剤、及び
（Ｄ）ジブチルヒドロキシトルエン、ジブチルヒドロキシアニソール、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及びクロロブタノールから選ばれる１種以上の成分を含む眼科用組成物が、眼科用組成物を収容する本体とキャップとを備えた容器に収容され、この容器が鉄系の酸素吸収剤と共に、包囲体で包囲して密封された眼科用製品において、
上記本体の容量を１～２５ｍＬ、
上記本体の酸素透過度を１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以上、
上記包囲体と上記容器との間に形成される空間の体積が、上記容器の体積に対し２００Ｖ／Ｖ％以下
とする、包囲体開封時の臭いマスキング方法を提供する。好ましい成分、範囲等は上記と同じである。 [Masking method]
The present invention
(A) easy oxides,
(B) refreshing agent,
An ophthalmic composition comprising (C) a nonionic surfactant and (D) one or more components selected from dibutyl hydroxytoluene, dibutyl hydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, An ophthalmic product contained in a container comprising a body containing an ophthalmic composition and a cap, the container being enclosed with an iron-based oxygen absorbent and enclosed in an enclosure;
The volume of the above body is 1 to 25 mL,
The oxygen permeability of the body above 10 cc / (m 2 · 24 hr · atm),
The odor masking method is provided, wherein the volume of the space formed between the enclosure and the container is 200 V / V% or less with respect to the volume of the container. Preferred components, ranges and the like are the same as described above.
　以下、実施例及び比較例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。なお、下記の例において特に明記のない場合は、組成の「％」はｗ／ｖ％（ｇ／１００ｍＬ）、比率は質量比を示す。 EXAMPLES The present invention will be specifically described below by showing Examples and Comparative Examples, but the present invention is not limited to the following Examples. In the following examples, unless otherwise specified, “%” of the composition indicates w / v% (g / 100 mL), and the ratio indicates a mass ratio.
　　［実施例，比較例］
　下記表に示す組成の眼科用組成物を常法に従って製造し、下記容器に収容した後、酸素吸収剤（エージレス(型番：Ｚ－ＰＴ１５)、三菱ガス化学株式会社製）を同梱し、下記包囲体でフィルム包装を施して密封して眼科用製品を得た。この眼科用製品を４０℃・７５％ＲＨ環境下で１ヶ月保存した。保存後、フィルム包装を開封、下記臭気の官能評価を実施した。 [Examples, Comparative Examples]
An ophthalmic composition having the composition shown in the following table is manufactured according to a conventional method and housed in the following container, and then an oxygen absorbent (Ageless (Model No .: Z-PT15), manufactured by Mitsubishi Gas Chemical Co., Ltd.) is enclosed, A film package was applied by an enclosure and sealed to obtain an ophthalmic product. This ophthalmic product was stored for 1 month in an environment of 40 ° C. and 75% RH. After storage, the film package was opened, and the sensory evaluation of the following odor was carried out.
　実施例２、比較例３、比較例４及び比較例５以外は、下記の容器・包囲体を用いた。
〈容器〉
・本体
　材質：ポリエチレンテレフタレート：酸素透過度１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）
　本体の容量：１７ｍＬ
・キャップ
　スクリュータイプ
・中栓
〈包囲体〉
　材質：アルミナを蒸着したポリエチレンテレフタレート／ポリエチレン多層フィルム（酸素透過度０．２ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ））
　大きさ：Ｗ９．０×Ｌ６．５（ｃｍ） The following containers and enclosures were used except for Example 2, Comparative Example 3, Comparative Example 4 and Comparative Example 5.
<container>
-Body Material: polyethylene terephthalate: oxygen permeability 10cc / (m 2 · 24 hr · atm)
Body volume: 17 mL
・ Cap screw type ・ Inside plug <Enclosure>
Material: Alumina-deposited polyethylene terephthalate / polyethylene multilayer film (oxygen permeability 0.2 cc / (m 2 · 24 hr · atm))
Size: W 9.0 × L 6.5 (cm)
　上記容器・包囲体を用いた場合の各条件は以下のようになる。
・眼科用組成物の量：１５ｍＬ
・容器酸素透過性：０．７％
・容器体積に対する眼科用組成物の充填率：８８％
・容器体積：２２ｍＬ
・上記包囲体と上記容器との間に形成される空間（インナースペース）：２３ｍＬ
・容器体積に対するインナースペース比：１０５％
　実施例２及び比較例４は、包囲体の大きさを変更して表中の容器体積に対するインナースペース比となるようにし、比較例３は表中の組成物量（ｍＬ）／本体容量（ｍＬ）とし、スペース比となるようにし、比較例５は、本体として非酸素透過性のものを用いた。 Each condition in the case of using the said container and enclosure becomes as follows.
-Amount of ophthalmic composition: 15 mL
-Container oxygen permeability: 0.7%
· Packing ratio of ophthalmic composition to container volume: 88%
・ Container volume: 22mL
・ Space (inner space) formed between the above enclosure and the above container: 23 mL
・ Inner space ratio to container volume: 105%
In Example 2 and Comparative Example 4, the size of the enclosure is changed so that the inner space ratio to the container volume in the table is obtained, and in Comparative Example 3, the amount of composition in the table (mL) / body volume (mL) The space ratio was made to be the same, and Comparative Example 5 used a non-oxygen permeable one as the main body.
［容器酸素透過性の測定方法］
（１）室温（２０～３０℃）で包囲体に空の容器を入れた。容器には、中栓・キャップを装着した。包囲体の酸素透過性は酸素透過度が０．２ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以下となる酸素透過性の低い包囲体を使用した。包囲体の大きさは１５０×６５ｍｍ（内寸）とした。
（２）容器と包囲体の間に窒素ガスを満たし、密封した。このときの窒素置換率は９０体積％以上（酸素濃度２体積％以下）とした。
（３）包囲体の大きさが８５×６５ｍｍ（内寸）となるよう、ヒートシールをして包囲体を２つの空間に区切った。容器のない側の包囲体の空間の酸素濃度を測定し、初期値とした。酸素濃度は残存酸素濃度計（飯島電子（株））を用いた。
（４）４０℃・７５％ＲＨ条件で３日間保存し、取出し室温に放置した後、包囲体内の酸素濃度を測定した。
以下の計算式で算出した値を、酸素透過性と定義する。
酸素透過性の計算式：
　酸素透過性（％）＝保存後の包囲体内酸素濃度（％）－初期の包囲体内酸素濃度（％） [Measurement method of container oxygen permeability]
(1) An empty container was placed in the enclosure at room temperature (20 to 30 ° C.). The container was fitted with a plug and cap. The oxygen permeability of the enclosure was a low oxygen permeability enclosure having an oxygen permeability of 0.2 cc / (m 2 · 24 hr · atm) or less. The size of the enclosure was 150 × 65 mm (inner size).
(2) The container was filled with nitrogen gas and sealed between the container and the enclosure. The nitrogen substitution rate at this time was 90 volume% or more (oxygen concentration 2 volume% or less).
(3) The enclosure was heat sealed to divide the enclosure into two spaces so that the size of the enclosure would be 85 × 65 mm (inner size). The oxygen concentration in the space of the enclosure without the container was measured and used as the initial value. The oxygen concentration used the residual oximeter (Iijima Electronics Co., Ltd.).
(4) After storing for 3 days under conditions of 40 ° C. and 75% RH and taking it out and leaving it at room temperature, the oxygen concentration in the enclosure was measured.
The value calculated by the following formula is defined as oxygen permeability.
Formula for oxygen permeability:
Oxygen permeability (%) = oxygen concentration in the enclosure after storage (%)-oxygen concentration in the initial enclosure (%)
[臭気の評価]
　臭気は下記４段階で、専門パネラーによる官能評価を行った（ｎ＝６）。
　０：とても異臭を感じる
　１：異臭を感じる
　２：少し異臭を感じる
　３：ほとんど異臭を感じない
　４：全く異臭を感じない
　５：異臭はせず、清涼化剤の匂いを感じる
　得られた結果（平均値）と、これに基づく下記評価基準を併記する。●、〇、◎を合格とする。
〈評価基準〉
　×：１．５未満
　●：１．５以上２．０未満
　〇：２．０以上３．０未満
　◎：３．０以上 [Evaluation of odor]
The odor was evaluated by a panel of experts at the following four stages (n = 6).
0: very offensive odor 1: offensive odor 2: slight offensive odor 3: hardly offensive offensive odor 4: no offensive offensive odor 5: offensive odor not on, smell of refreshing agent obtained result obtained ( The average value) and the following evaluation criteria based on this are written together. ●, 〇, ◎ pass.
<Evaluation criteria>
×: less than 1.5 ●: 1.5 or more and less than 2.0 ○: 2.0 or more and less than 3.0 ◎: 3.0 or more
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　なお、包囲体の材質をポリエチレン（酸素透過度３ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ））に変更した場合も上記と同様の結果が得られた。 The same result as described above was obtained when the material of the enclosure was changed to polyethylene (oxygen permeability: 3 cc / (m 2 · 24 hr · atm)).
　上記例で使用した原料を下記に示す。なお、特に明記がない限り、表中の各成分の量は純分換算量である。
レチノールパルミチン酸エステル：（商品名：パルミチン酸レチノール、ＤＳＭニュートリションジャパン（株）製、１７４万Ｉ．Ｕ／ｇ）
ｌ－メントール：（商品名：ｌ－メントール（薄荷脳）、鈴木薄荷（株）製）
ｄｌ－カンフル：（商品名：日本薬局方 dl-カンフル、日本精化（株）製）
ｄ－カンフル（商品名：日本薬局方 d-カンフル、日本精化（株）製）
ｄ－ボルネオール：（商品名：特沸龍脳（ｄ－ボルネオール）、（株）柳沢正巳商店製）
ユーカリ油：（商品名：日本薬局方ユーカリ油、小川香料（株））
ゲラニオール：（商品名：ゲラニオールＥＸ　ＭＩＸ、高砂香料工業（株）製）
ポリオキシエチレン硬化ヒマシ油６０：（商品名：ＨＣＯ－６０(医療用)、日本サーファクタント工業（株）製）
ポリオキシエチレン硬化ヒマシ油４０：（商品名：ＨＣＯ－４０(医療用)、日本サーファクタント工業（株）製）
ポリオキシエチレン（２０）ソルビタンオレイン酸エステル（ポリソルベート８０）：（商品名：レオドールＴＷ－Ｏ１２０Ｖ、花王（株）製）
ポリオキシエチレンポリオキシプロピレングリコール（ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール）：（商品名：Ｋｏｌｌｉｐｈｏｒ　Ｐ４０７、ＢＡＳＦジャパン（株）製）
モノステアリン酸ポリエチレングリコール（ステアリン酸ポリオキシル４０）：（商品名：ＮＩＫＫＯＬ　ＭＹＳ-４０ＭＶ、日本サーファクタント工業（株）製）
ジブチルヒドロキシトルエン：（商品名：ジブチルヒドロキシトルエン、和光純薬工業（株）製）
パラオキシ安息香酸プロピル：（商品名：メッキンス－Ｐ、上野製薬（株）製）
パラオキシ安息香酸ブチル：（商品名：メッキンス－Ｂ、上野製薬（株）製）
クロロブタノール：（商品名：クロロブタノール、ＪＳＣ　Ｏｌａｉｎｆａｒｍ） Raw materials used in the above example are shown below. In addition, the amount of each component in the table is a net equivalent amount unless otherwise specified.
Retinol palmitate ester: (trade name: Retinol palmitate, manufactured by DSM Nutrition Japan KK, 1.74 million I.U / g)
l-menthol: (Brand name: l-menthol (lightly charged brain), manufactured by Suzuki Taikari Co., Ltd.)
dl-Camphor: (trade name: Japanese Pharmacopoeia dl-Camphor, manufactured by Nippon Seika Co., Ltd.)
d-Camphor (trade name: Japanese Pharmacopoeia d-Camphor, manufactured by Nippon Seika Co., Ltd.)
d-Borneol: (brand name: special boiling dragon brain (d-Borneol), manufactured by Yanagisawa Shogoten)
Eucalyptus oil: (trade name: Japan Pharmacopoeia Eucalyptus oil, Ogawa Aroma Co., Ltd.)
Geraniol: (trade name: Geraniol EX MIX, manufactured by Takasago Fragrance Industry Co., Ltd.)
Polyoxyethylene hydrogenated castor oil 60: (trade name: HCO-60 (for medical use), manufactured by Nippon Surfactant Industries Co., Ltd.)
Polyoxyethylene hydrogenated castor oil 40: (trade name: HCO-40 (for medical use), manufactured by Nippon Surfactant Industries Co., Ltd.)
Polyoxyethylene (20) sorbitan oleic acid ester (polysorbate 80): (trade name: Reodor TW-O 120 V, manufactured by Kao Corporation)
Polyoxyethylene polyoxypropylene glycol (polyoxyethylene (196) polyoxypropylene (67) glycol): (trade name: Kolliphor P407, manufactured by BASF Japan Ltd.)
Polyethylene glycol monostearate (polyoxyl 40 stearate): (trade name: NIKKOL MYS-40MV, manufactured by Nippon Surfactant Industries Co., Ltd.)
Dibutylhydroxytoluene: (trade name: dibutylhydroxytoluene, manufactured by Wako Pure Chemical Industries, Ltd.)
Propyl parahydroxybenzoate: (trade name: Platings-P, manufactured by Ueno Pharmaceutical Co., Ltd.)
Butyl parahydroxybenzoate: (trade name: Platings-B, manufactured by Ueno Pharmaceutical Co., Ltd.)
Chlorobutanol: (trade name: Chlorobutanol, JSC Olainfarm)

Claims (6)

  1. 　（Ａ）易酸化物、
    （Ｂ）清涼化剤、
    （Ｃ）非イオン性界面活性剤、及び
    （Ｄ）ジブチルヒドロキシトルエン、ジブチルヒドロキシアニソール、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及びクロロブタノールから選ばれる１種以上の成分を含む眼科用組成物が、眼科用組成物を収容する本体とキャップとを備えた容器に収容され、この容器が鉄系の酸素吸収剤と共に、包囲体で包囲して密封された眼科用製品であって、
    上記本体の容量が１～２５ｍＬ、
    上記本体の酸素透過度が１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以上、
    上記包囲体と上記容器との間に形成される空間の体積が、上記容器の体積に対し２００Ｖ／Ｖ％以下
    である眼科用製品。     (A) easy oxides,
    (B) refreshing agent,
    An ophthalmic composition comprising (C) a nonionic surfactant and (D) one or more components selected from dibutyl hydroxytoluene, dibutyl hydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, An ophthalmic product contained in a container comprising a body containing an ophthalmic composition and a cap, the container being enclosed with an iron-based oxygen absorbent and enclosed with an enclosure,
    The volume of the above body is 1 to 25 mL,
    The oxygen permeability of the body above 10 cc / (m 2 · 24 hr · atm),
    The ophthalmic product whose volume of the space formed between the said enclosure and the said container is 200 V / V% or less with respect to the volume of the said container.
  2. 　（Ａ）成分が、ビタミンＡである請求項１記載の眼科用製品。 The ophthalmic product according to claim 1, wherein the component (A) is vitamin A.
  3. 　（Ｂ）成分が、ｌ－メントール、ｄｌ－カンフル、ｄ－カンフル、ｄ－ボルネオール、ゲラニオール及びユーカリ油から選ばれる１種以上である請求項１又は２記載の眼科用製品。 The ophthalmic product according to claim 1 or 2, wherein the component (B) is at least one selected from l-menthol, dl-camphor, d-camphor, d-borneol, geraniol and eucalyptus oil.
  4. 　（Ｂ）成分の眼科用組成物中の配合量が、０．０００１ｗ／ｖ％以上である請求項１～３のいずれか１項記載の眼科用製品。 The ophthalmic product according to any one of claims 1 to 3, wherein the blending amount of the component (B) in the ophthalmic composition is 0.0001 w / v% or more.
  5. 　（Ｃ）成分が、ポリオキシエチレン硬化ヒマシ油６０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン（２０）ソルビタンオレイン酸エステル及びポリオキシエチレンポリオキシプロピレングリコールから選ばれる１種以上である請求項１～４のいずれか１項記載の眼科用製品。 The component (C) is at least one selected from polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene (20) sorbitan oleate, and polyoxyethylene polyoxypropylene glycol. An ophthalmic product according to any one of 1 to 4 above.
  6. 　（Ａ）易酸化物、
    （Ｂ）清涼化剤、
    （Ｃ）非イオン性界面活性剤、及び
    （Ｄ）ジブチルヒドロキシトルエン、ジブチルヒドロキシアニソール、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及びクロロブタノールから選ばれる１種以上の成分を含む眼科用組成物が、眼科用組成物を収容する本体とキャップとを備えた容器に収容され、この容器が鉄系の酸素吸収剤と共に、包囲体で包囲して密封された眼科用製品において、
    上記本体の容量を１～２５ｍＬ、
    上記本体の酸素透過係度を１０ｃｃ／（ｍ2・２４ｈｒ・ａｔｍ）以上、
    上記包囲体と上記容器との間に形成される空間の体積が、上記容器の体積に対し２００Ｖ／Ｖ％以下
    とする、包囲体開封時の臭いマスキング方法。     (A) easy oxides,
    (B) refreshing agent,
    An ophthalmic composition comprising (C) a nonionic surfactant and (D) one or more components selected from dibutyl hydroxytoluene, dibutyl hydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, An ophthalmic product contained in a container comprising a body containing an ophthalmic composition and a cap, the container being enclosed with an iron-based oxygen absorbent and enclosed in an enclosure;
    The volume of the above body is 1 to 25 mL,
    The oxygen permeability of the body above 10 cc / (m 2 · 24 hr · atm),
    The odor masking method at the time of envelope opening which the volume of the space formed between the said enclosure and the said container shall be 200 V / V% or less with respect to the volume of the said container.
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