WO2019111917A1 - Aqueous ophthalmic composition and method for micronizing emulsion particles - Google Patents

Aqueous ophthalmic composition and method for micronizing emulsion particles Download PDF

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Publication number
WO2019111917A1
WO2019111917A1 PCT/JP2018/044633 JP2018044633W WO2019111917A1 WO 2019111917 A1 WO2019111917 A1 WO 2019111917A1 JP 2018044633 W JP2018044633 W JP 2018044633W WO 2019111917 A1 WO2019111917 A1 WO 2019111917A1
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component
ophthalmic composition
composition
aqueous ophthalmic
preferable
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PCT/JP2018/044633
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French (fr)
Japanese (ja)
Inventor
愛美 田中
雅貴 吉田
昌利 栗岡
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ライオン株式会社
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Priority to KR1020207007324A priority Critical patent/KR102665630B1/en
Priority to JP2019558236A priority patent/JP7230825B2/en
Publication of WO2019111917A1 publication Critical patent/WO2019111917A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions

Definitions

  • the present invention relates to an aqueous ophthalmic composition containing liquid paraffin and a method for atomizing emulsion particles thereof.
  • Liquid paraffin is a cold liquid hydrocarbon and is characterized by having low polarity.
  • an ophthalmic composition it is widely used as a base of eye ointment.
  • an aqueous ophthalmic composition it is necessary to uniformly disperse liquid paraffin in water, but liquid paraffin becomes turbid even when using a surfactant or the like because of its low polarity, and it transmits It was difficult to raise the rate.
  • a preparation having a cloudy appearance has a problem that it is difficult to determine whether or not foreign matter is mixed at the time of production or use.
  • the present invention has been made in view of the above problems, and it is possible to increase the permeability of the composition by making the emulsion particles in the composition into fine particles, even without high-pressure emulsification and high concentration of surfactant. It is an object of the present invention to provide an aqueous ophthalmic composition containing liquid paraffin which can suppress creaming by storage and is excellent in appearance storage stability and can stabilize a tear liquid oil layer.
  • the tear fluid oil layer is composed of lipids secreted from the meibomian glands. It is known that aging of the lipid in the oil reservoir proceeds with aging and hormonal balance change. It is further known that it is facilitated by contact lens wear. The progress of lipid saturation leads to destabilization of the tear fluid oil layer, development of dry eye and further contributing to eyestrain.
  • the present inventors have found that an aqueous composition containing liquid paraffin is effective in stabilizing this tear oil layer.
  • the present inventors contain (A) liquid paraffin and (B) a nonionic surfactant (B (C) terpenoid is added to the aqueous ophthalmic composition in which the blending mass ratio of the component (A) to the component (B) represented by (A) is 3 ⁇ (B) / (A) ⁇ 25.
  • the emulsion particles are finely divided without high-pressure emulsification or blending of surfactant at a high concentration, so the permeability of the composition is increased, and creaming by long-term storage It has been found that the present invention can be achieved.
  • the present invention provides the following invention.
  • (A) Liquid paraffin, (B) non-ionic surfactant, and (C) terpenoid are contained, and the compounding mass of (A) component and (B) component represented by (B) / (A) An aqueous ophthalmic composition having a ratio of 3 ⁇ (B) / (A) ⁇ 25 and a blending amount of the component (C) of 0.0001 to 0.5 w / v%. [2].
  • (D) Retinol palmitic acid ester, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyloxyethyl phosphoryl choline, at least one selected from sesame oil and castor oil according to [1].
  • Ophthalmic composition [3].
  • the blending mass ratio of the component (A) to the component (B) containing (A) liquid paraffin and (B) a nonionic surfactant and represented by (B) / (A) is 3 ⁇
  • a method for atomizing emulsion particles in an aqueous ophthalmic composition wherein the aqueous ophthalmic composition contains 0.0001 to 0.5 w / v% of (C) terpenoid in the aqueous ophthalmic composition. Method of atomizing emulsion particles.
  • the transmittance of the composition is increased, and creaming due to long-term storage can be suppressed, and appearance preservation is stable. It is possible to provide an aqueous ophthalmic composition containing liquid paraffin which is excellent in sex and stabilizes a tear oil layer.
  • Liquid paraffin is a component having a high effect of stabilizing the tear film formation on an unstable tear solution formation with increased saturated lipid.
  • Liquid paraffin is an oil having low polarity as compared with vegetable oils and hydrocarbons composed of triglyceride and squalane having a short carbon chain length among the hydrocarbons.
  • liquid paraffin is a mixture of hydrocarbons obtained from crude oil, and is liquid at normal temperature.
  • the crude oil is manufactured by a method such as vacuum distillation and solvent degassing treatment using atmospheric residual oil of crude oil as a raw material, and thereafter, a method of solvent purification method or hydrocracking method treatment.
  • liquid paraffin used for this invention It can be used individually by 1 type or in combination of 2 or more types suitably.
  • the carbon chain length of the hydrocarbon is not particularly limited, but those of 15 to 45 are preferably used.
  • limiting in particular about the presence or absence of the double bond in a hydrocarbon is used suitably.
  • the hydrocarbon structure may contain any of linear, branched and cyclic structures, and liquid paraffin of any specific gravity can be used.
  • liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia are suitable.
  • the viscosity of liquid paraffin is correlated with its molecular weight, and the kinematic viscosity is preferably 30 to 100 mm 2 / s, preferably 37 to 88 mm in the measurement method of the 16th revised Japanese Pharmacopoeia, Method 1 (37.8 ° C). More preferable is 2 / s, and more preferable is 74 to 88 mm 2 / s. Two or more of the above viscosity ranges may be mixed. By setting it as said 30 mm ⁇ 2 > / s or more, the tear fluid oil layer stabilization effect can be acquired more.
  • one having a diameter of 74 to 88 mm 2 / s is preferable. Further, by setting the thickness to 100 mm 2 / s or less, the transmittance of the appearance can be enhanced, and at the same time, the eye irritation specific to liquid paraffin can be further reduced. From the viewpoint of appearance transmittance and reduction of eye irritation, those of 37 to 88 mm 2 / s are preferable.
  • the blending amount of the component (A) is 0.001 to 2 w / v% (mass / volume%) in the aqueous ophthalmic composition (hereinafter sometimes referred to as a composition) from the viewpoint of stabilization of the tear fluid oil layer.
  • G / 100 mL is preferable, 0.001 to 1 w / v% is more preferable, 0.01 to 1 w / v% is more preferable, and 0.05 to 1 W / V% is most preferable.
  • the nonionic surfactant (B) is not particularly limited, and nonionic surfactants used in ophthalmic compositions may be used singly or in appropriate combination of two or more. Specifically, nonionic surfactant other than (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, and (B-3) (B-1) and (B-2) Agents and the like.
  • the component (B) preferably contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil.
  • Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and the average addition mole number of ethylene oxide is Several different types 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.
  • These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. It is preferable to use polyoxyethylene castor oil 35 from the viewpoint of reducing the feeling of irritation when instilled.
  • polyoxyethylene hydrogenated castor oil polyoxyethylene hydrogenated castor oil is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and the average addition of ethylene oxide Several types with different numbers of moles are known.
  • 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.
  • polyoxyethylene hydrogenated castor oils can be used singly or in appropriate combination of two or more. It is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 from the viewpoint of reducing the feeling of irritation when instilled.
  • Nonionic surfactants other than (B-1) and (B-2) polyoxyethylene sorbitan fatty acid ester POE sorbitan represented by polysorbate 80 (polyoxyethylene (20) sorbitan oleate) Fatty acid ester), polyoxyethylene polyoxypropylene glycol (POEPOP glycol) represented by poloxamer, polyethylene glycol monostearate (10), polyethylene glycol monostearate represented by polyethylene glycol monostearate (40), etc.
  • the compounding amount of the component (B) is appropriately selected by the compounding mass ratio with the component (A), and the compounding mass ratio of the component (A) to the component (B) represented by (B) / (A) is 3 ⁇ (B) / (A) ⁇ 25.
  • This ratio is less than 3, the atomization of the emulsion particles is insufficient, and when it exceeds 25, the surfactant which does not form an emulsion is present in excess, and foaming tends to occur.
  • the blending mass ratio is preferably 4 ⁇ (B) / (A), and more preferably 5 ⁇ (B) / (A).
  • permeability of a composition will be 50% or more.
  • the transmittance of the composition becomes 70% or more.
  • the said ratio is w / v% ratio, it becomes the same value as mass ratio.
  • the blending amount of the component (B) is not particularly limited as long as the above ratio is satisfied, but 0.0001 to 10 w / v% in the composition is preferable, and 0.0001 to 5 w / v% is more preferable.
  • the terpenoid in the present invention has a structure having an isoprene unit as a constituent unit, and examples thereof include terpene hydrocarbon, terpene alcohol, terpene aldehyde, terpene ketone and the like. Also, depending on the carbon number, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes and tetraterpenes.
  • monoterpenes such as menthol, menthol, camphor, borneol, leunow, geraniol, cineole, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoid.
  • diterpenes such as retinol and retinal
  • tetraterpenes such as carotenoid.
  • terpenoids can be used either in d form, l form or dl form.
  • menthol menthol, menthol, camphor, borneol, geraniol, cineole and linalool are preferable, and menthol, camphor, borneol, geraniol, cineole and linalool are more preferable. More preferably, menthol is used because the effect of atomization of the emulsion particles is large.
  • an essential oil containing the above-mentioned compound may be used as a terpenoid.
  • oils examples include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, and essential oils of Dipterocarpus plants, rosmarinic oil, lavender oil and the like.
  • the compounding amount of the component (C) is 0.0001 to 0.5 w / v% in the composition, and is appropriately selected from the kind of the component (C), other compounding components such as the component (B), and the compounding amount thereof Be done. Preferably, it is 0.0001 to 0.2 w / v%. In this compounding concentration range, there is little possibility that (C) terpenoid precipitates regardless of the types and compounding amounts of other compounding components. Further, from the viewpoint of making the emulsion particles fine, 0.0001 w / v% or more is preferable, and from the viewpoint of reducing the feeling of irritation, 0.075 w / v% or less is more preferable.
  • menthol When menthol is blended, it is particularly preferably 0.0001 to 0.075 w / v%, most preferably 0.001 to 0.075 w / v%, when menthol is blended, from the viewpoint of remarkable increase in atomization.
  • 0.001 to 0.075 w / v% in the composition is preferable, and 0.005 to 0.075 w / v% is more preferable.
  • cineole, linalool or geraniol it is preferably 0.0005 to 0.075 w / v%, more preferably 0.0025 to 0.075 w / v% in the composition, from the viewpoint of increasing the fineness of the composition. .
  • the compounding amount of the component (D) in the composition is preferably in the following range from the viewpoint of enhancing atomization of the composition.
  • 0.001 to 5.0 w / v% is preferable, 0.01 to 3.0 w / v% is more preferable, and 0.01 to 1.0 w / v% Is more preferred.
  • glycerin, propylene glycol, benzododecinium bromide, sesame oil and castor oil are blended, 0.005 to 5.0 w / v% is preferable, 0.05 to 3.0 w / v% is more preferable, and 0 1 to 1.0 w / v% is more preferable.
  • blending 2-methacryloyl oxyethyl phosphoryl choline 0.01-5.0 w / v% is preferable, 0.03-2.0 w / v% is more preferable, 0.05-1.0 w / v% is More preferable.
  • composition of the present invention other components to be blended in the ophthalmic composition can be blended in appropriate amounts as long as the effects of the present invention are not impaired.
  • Other components include preservatives, saccharides, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, drugs and the like. These components may be blended singly or in appropriate combination of two or more.
  • the compounding quantity of the component shown below is a preferable range in the case of mix
  • preservatives thimerosal, phenylethyl alcohol, alkylaminoethyl glycine, chlorhexidine gluconic acid, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, etc. may be mentioned as preservatives having a hydrophobic moiety such as alkyl chain or benzene ring.
  • 0.1 w / v% or less is preferable, 0.01 w / v% or less is more preferable, and 0.001 w / v% or less is more preferable, because paraffin is less likely to be transferred to the tear oil layer. More preferably, they are not contained in
  • sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like.
  • any of D body, L body, or DL body may be sufficient as these.
  • the blending amount thereof is preferably 0.001 to 5.0 w / v% in the composition, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v%. More preferable.
  • the buffer examples include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, sodium hydrogen carbonate and the like.
  • the blending amount thereof is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 2 w / v%, and further preferably 0.001 to 1 w / v% in the composition. preferable.
  • an inorganic acid or an inorganic alkali agent is mentioned.
  • the inorganic acid includes (dilute) hydrochloric acid.
  • the inorganic alkali agent sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like can be mentioned.
  • the pH of the composition may be 3.5 to 13.0, preferably 3.5 to 8.0, more preferably 5.5 to 8 from the viewpoint of further improving various conditions caused by tear film instability. .0 is more preferred.
  • the pH is measured at 25 ° C. using a pH meter (HM-25R, Toa DKK Co., Ltd.).
  • tonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium hydrogencarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogenphosphate, sodium dihydrogenphosphate, potassium dihydrogenphosphate and the like. It can be mentioned. From the viewpoint of further improving the various conditions caused by the tear liquid layer destabilization, it is preferable that at least one of sodium chloride and potassium chloride be blended to be isotonic.
  • the osmotic pressure ratio of the composition to saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and more preferably 0.83 from the viewpoint of further improving the various conditions caused by the tear fluid layer destabilization. Most preferred is 1.20.
  • the osmotic pressure is measured at 25 ° C. using an automatic osmometer (A2O, Advanced Instruments).
  • the stabilizer examples include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like.
  • the blending amount thereof is preferably 0.001 to 5.0 w / v% in the composition, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v % Is more preferred.
  • polyhydric alcohols examples include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like.
  • the blending amount of the polyhydric alcohol is preferably 0.001 to 5.0 w / v% in the composition, more preferably 0.001 to 1 w / v%, and 0.001 to 0. 1 w / v% is more preferable.
  • thickener examples include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer and the like.
  • blending a viscosity agent 0.001-5.0 w / v% in a composition is preferable, 0.001-1 w / v% is more preferable, 0.001-0.1 w / v is preferable. % Is more preferred.
  • oil components other than (A) liquid paraffin and (D) soybean oil, olive oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglyceride, acetic acid-d- ⁇ -tocopherol, retinol palmitate, white petrolatum , Purified lanolin, cholesterol, mixed tocopherols and the like.
  • the blending amount thereof is preferably 0.001 to 1.0 w / v%, more preferably 0.001 to 0.5 w / v%, and 0.001 to 0.25 w / v% is most preferred.
  • Examples of the drug include decongestion components (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride etc.), Anti-inflammatory and astringent agents (eg neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride Salts, etc., antihistamines (eg, diphenhydramine hydrochloride, chlorphenir
  • the compounding amount of the drug can be selected from the effective appropriate amount of each drug, but 0.001 to 5.0 w / v% in the composition is preferable, 0.001 to 1 w / v% Is more preferable, and 0.001 to 0.1 w / v% is more preferable.
  • the method for producing the composition of the present invention is not particularly limited, and the composition can be obtained by mixing the components (A), (B) and (C) and optional components as needed.
  • a mixed solution of oily components such as (A), part or all of (B) and (C) components is mixed with an aqueous solution containing an aqueous component and emulsified, and after adjusting the pH, the total volume is adjusted with water
  • the mixing method of each liquid may be a general method, and is appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, etc., but the number of rotations is not particularly limited. Is preferred.
  • each liquid is not particularly limited, but it is preferable that both the oil component and the surfactant component be at the melting temperature or higher, and specifically, it is appropriately selected from the range of 40 to 95 ° C.
  • the permeability of the composition can be increased and the creaming due to long-term storage can be suppressed by atomizing the emulsion particles in the composition.
  • the composition may be further sealed by a package, and inert gas in the space formed between the container and the package may be enclosed;
  • the substance may be filled in a resin container and sealed by a package together with an oxygen scavenger.
  • the composition of the present invention is an "aqueous ophthalmic composition".
  • the "aqueous ophthalmic composition” refers to an ophthalmic composition in which the medium is water.
  • the content of water is preferably 90.0 to 99.5 w / v% in the composition, from the viewpoint of facilitating mixing with tear fluid and obtaining a tear oil layer stabilization effect, and 95.0 to 97%. .5 w / v% is more preferred.
  • the particle diameter of the emulsion particles (the association of the (A) component and the (B) component) contained in the composition of the present invention can be 800 nm or less, preferably 500 nm or less, and more preferably 300 nm or less.
  • the lower limit is not particularly limited, but may be 1 nm.
  • the particle diameter refers to the average diameter (median diameter nm) of the volume-based particle size distribution calculated from the scattered light intensity.
  • the particle diameter is measured by a constant temperature bath at a constant temperature of 25 ° C. using a constant temperature bath by various measuring devices to which the principle of light scattering or the like is applied.
  • a particle size measuring apparatus ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.
  • the transmittance of the composition of the present invention is 30 to 100% at a wavelength of 600 nm measured using a spectrophotometer (for example, UV-1800, Shimadzu Corporation). 50 to 100% is preferable, and 70 to 100% is more preferable.
  • a spectrophotometer for example, UV-1800, Shimadzu Corporation
  • the composition of the present invention is preferably a liquid from the viewpoint of facilitating application to the eye, and the viscosity at 25 ° C. facilitates mixing with tear fluid, and from the point of achieving a tear oil layer stabilization effect, 20 mPa ⁇ s
  • the following is preferable, 10 mPa ⁇ s or less is more preferable, and 5 mPa ⁇ s or less is more preferable.
  • the measuring method of a viscosity is performed using a cone-plate viscometer (DV2T, Eiko Seiki Co., Ltd.).
  • composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye wash etc.
  • tear dilution ratio is high, release of surfactant from liquid paraffin is further promoted, and liquid paraffin delivery Can be suitably used as an eye drop and an eye drop for contact lens (eye drop for contact lens wearer).
  • the contact lenses include, but are not limited to, hard contact lenses, O 2 hard contact lenses, soft contact lenses, silicone hydrogel soft contact lenses, and the like.
  • the tear fluid oil layer stabilizing effect 1 to 3 drops of 10 to 50 ⁇ L at a time, and more preferably 1 to 6 times a day. More preferably, 1 to 3 drops of 10 to 30 ⁇ L at a time, and 1 to 6 times a day.
  • the present invention contains (A) liquid paraffin and (B) a nonionic surfactant, and the blending mass ratio of the (A) component to the (B) component represented by (B) / (A) is A method for atomizing emulsion particles in an aqueous ophthalmic composition, wherein 3 ⁇ (B) / (A) ⁇ 25, wherein the aqueous ophthalmic composition comprises (C) terpenoid in an amount of 0.0001 to 0.5 w / w.
  • a method for atomizing emulsion particles containing v% Preferred components and amounts are the same as described above.
  • the composition can be made transparent, and the appearance storage stability can be improved.
  • “Appearance storage stability” means that when the composition is stored over time, aggregation, creaming, coalescence, floating and the like of the association of the (A) component and the (B) component are suppressed. .
  • the atomization effect by the component (C) can not be obtained.
  • Example, Comparative Example Each aqueous component in the following table was dissolved in 90 mL of purified water, and heated and mixed at 90 ° C. for 15 minutes. Separately, a preliminary mixture of (A) liquid paraffin, (B) nonionic surfactant and (C) terpenoid was prepared, and heated and mixed at 90 ° C. for 15 minutes. Next, a predetermined amount of the pre-mixture was added to the aqueous solution, and heated and mixed at 90 ° C. for 15 minutes. After that, the reaction solution was cooled to room temperature, pH was adjusted, and purified water was added to 100 mL. The viscosity of each example was in the range of 0.5 to 2.0 mPa ⁇ s. The following evaluation was performed about the obtained composition. The results are shown in the table.
  • the particle diameter of the emulsion particles in the composition immediately after production was measured using ELSZ-200ZS (manufactured by Otsuka Electronics Co., Ltd.). From the particle diameter obtained, atomization of emulsion particles in the composition is shown by the following evaluation criteria.
  • the particle diameter is the average diameter (median diameter nm) of the volume-based particle size distribution calculated from the scattered light intensity, and the measurement was carried out under a constant temperature condition of 25 ° C.
  • composition Permeability (%)] ⁇ : 70% or more and 100% or less 70: 50% or more and less than 70% ⁇ : 30% or more and less than 50% x: less than 30% “O” or more is accepted.
  • compositions of the examples were all "o" in the following appearance storage stability evaluation.
  • DR-1 is an apparatus capable of measuring an interference image of light reflected at the interface between the surface of the tear fluid oil layer and the tear fluid water layer. In a normal eye, a uniform gray or white interference image is observed, and when the tear fluid oil layer collapses, the interference image disappears.
  • each composition was instilled in a subject, and after 10 minutes, it blinked several times, and the time from the blink to the collapse of the tear fluid oil layer (oil layer BUT) was measured.
  • the subjects selected 13 eyes of 7 people who had oil reservoir BUT less than 10 seconds before instillation. The results are shown by the following evaluation criteria from the average value of 7 eyes and 13 eyes.
  • the oil layer BUT which was less than 10 seconds, did not fluctuate more than 10 seconds in intraday and inter-day variations, in compositions without liquid paraffin, and improvement to 10 seconds or more was acceptable as having sufficient utility. It was judged.
  • Oil layer BUT is 60 seconds or more ⁇ : Oil layer BUT is 30 seconds to 60 seconds ⁇ : Oil layer BUT is 10 seconds to 30 seconds x (not good): Oil layer BUT is less than 10 seconds " ⁇ " or more is accepted.
  • the aqueous ophthalmic composition of the present invention was confirmed to have a tear oil layer stabilizing effect.
  • Liquid paraffin 16th Amended Japanese Pharmacopoeia Method 1 (37.8 ° C) Dynamic viscosity 76.6 mm 2 / s (KAYDOL, manufactured by Shima Trading Co., Ltd.)
  • Liquid paraffin 16th Amended Japanese Pharmacopoeia Method 1 (37.8 ° C) Dynamic viscosity 34.8 mm 2 / s (Hycor M-172, Kaneda Co., Ltd.)
  • Polyoxyethylene (POE) castor oil polyoxyethylene castor oil 35: Uniox C 35, manufactured by NOF Corporation
  • Polyoxyethylene (POE) hydrogenated castor oil Polyoxyethylene hydrogenated castor oil (Polyoxyethylene hydrogenated castor oil 60: HCO60, HCO40, manufactured by Nippon Surfactant Industries Co., Ltd.) Monostearate PEG (polyethylene glycol monostearate (10): MYS 10 V,

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Abstract

An aqueous ophthalmic composition containing (A) liquid paraffin, (B) a non-ionic surfactant, and (C) a terpenoid; the mass ratio of component (A) and component (B) as represented by (B)/(A) being 3 ≤ (B)/(A) ≤ 25; and the amount of component (C) being 0.0001–0.5 w/v%.

Description

水性眼科用組成物及びエマルション粒子の微粒化方法Aqueous ophthalmic composition and method of atomizing emulsion particles
　本発明は、流動パラフィンを含有する水性眼科用組成物及びそのエマルション粒子の微粒化方法に関するものである。 The present invention relates to an aqueous ophthalmic composition containing liquid paraffin and a method for atomizing emulsion particles thereof.
　流動パラフィンは、常温液体の炭化水素で極性が低いことが特徴である。従来、眼科用組成物としては眼軟膏の基剤として広く用いられている。一方、水性眼科用組成物として配合する場合、流動パラフィンを水中に均一に分散させる必要があるが、流動パラフィンは、その極性の低さゆえに界面活性剤等を用いても白濁してしまい、透過率を高めることは困難だった。また、外観が白濁した製剤は、製造時や使用時において異物混入の有無の判断が困難になるという課題を有する。そのため、従来、流動パラフィンを配合した水性製剤の透過率を改善するには、高圧乳化の工程や、界面活性剤の高濃度配合が必要であった。しかしながら、高圧乳化には製造設備の導入が必要であり、界面活性剤を高濃度配合すると眼科用組成物として眼刺激性が生じる課題があった。 Liquid paraffin is a cold liquid hydrocarbon and is characterized by having low polarity. Heretofore, as an ophthalmic composition, it is widely used as a base of eye ointment. On the other hand, when formulated as an aqueous ophthalmic composition, it is necessary to uniformly disperse liquid paraffin in water, but liquid paraffin becomes turbid even when using a surfactant or the like because of its low polarity, and it transmits It was difficult to raise the rate. In addition, a preparation having a cloudy appearance has a problem that it is difficult to determine whether or not foreign matter is mixed at the time of production or use. Therefore, conventionally, in order to improve the permeability of an aqueous preparation containing liquid paraffin, it has been necessary to carry out a high pressure emulsification process and high concentration of surfactant. However, introduction of a production facility is necessary for high-pressure emulsification, and there is a problem that when the surfactant is incorporated in a high concentration, eye irritation occurs as an ophthalmic composition.
特表２００４－５３４７３２号公報Japanese Patent Publication No. 2004-534732
　本発明は上記課題に鑑みなされたもので、高圧乳化や界面活性剤を高濃度配合しなくても、組成物中のエマルション粒子を微粒化することで、組成物の透過率を高めるとともに、長期保存によるクリーミングの抑制が可能で、外観保存安定性に優れる、涙液油層を安定化することができる流動パラフィンを含有する水性眼科用組成物を提供することを目的とする。 The present invention has been made in view of the above problems, and it is possible to increase the permeability of the composition by making the emulsion particles in the composition into fine particles, even without high-pressure emulsification and high concentration of surfactant. It is an object of the present invention to provide an aqueous ophthalmic composition containing liquid paraffin which can suppress creaming by storage and is excellent in appearance storage stability and can stabilize a tear liquid oil layer.
　涙液油層は、マイボーム腺から分泌される脂質から構成される。加齢やホルモンバランス変化により、前記油層中の脂質の飽和化が進行することが知られている。それはコンタクトレンズ装用により助長されることが、さらに知られている。脂質の飽和化が進行することにより、涙液油層が不安定化し、ドライアイを発症し、さらには眼精疲労を引き起こす一因となる。本発明者らは、この涙液油層の安定化に流動パラフィンを含む水性組成物が有効であることを見出した。 The tear fluid oil layer is composed of lipids secreted from the meibomian glands. It is known that aging of the lipid in the oil reservoir proceeds with aging and hormonal balance change. It is further known that it is facilitated by contact lens wear. The progress of lipid saturation leads to destabilization of the tear fluid oil layer, development of dry eye and further contributing to eyestrain. The present inventors have found that an aqueous composition containing liquid paraffin is effective in stabilizing this tear oil layer.
　本発明者らは、上記流動パラフィンを含有する水性眼科用組成物を提供するため、さらに鋭意検討した結果、（Ａ）流動パラフィンと、（Ｂ）非イオン界面活性剤とを含有し、（Ｂ）／（Ａ）で表される（Ａ）成分と（Ｂ）成分の配合質量比が３≦（Ｂ）／（Ａ）≦２５である水性眼科用組成物に、（Ｃ）テルペノイドを０．０００１～０．５ｗ／ｖ％配合することによって、高圧乳化や界面活性剤を高濃度配合しなくても、エマルション粒子が微粒化されることで、組成物の透過率が上がり、長期保存によるクリーミングの抑制が可能であることを見出し、本発明をなすに至ったものである。 As a result of further intensive studies to provide an aqueous ophthalmic composition containing the above liquid paraffin, the present inventors contain (A) liquid paraffin and (B) a nonionic surfactant (B (C) terpenoid is added to the aqueous ophthalmic composition in which the blending mass ratio of the component (A) to the component (B) represented by (A) is 3 ≦ (B) / (A) ≦ 25. By blending 0001 to 0.5 w / v%, the emulsion particles are finely divided without high-pressure emulsification or blending of surfactant at a high concentration, so the permeability of the composition is increased, and creaming by long-term storage It has been found that the present invention can be achieved.
　従って、本発明は下記発明を提供する。
[１]．（Ａ）流動パラフィンと、（Ｂ）非イオン界面活性剤と、（Ｃ）テルペノイドとを含有し、（Ｂ）／（Ａ）で表される（Ａ）成分と（Ｂ）成分との配合質量比が３≦（Ｂ）／（Ａ）≦２５であり、（Ｃ）成分の配合量が０．０００１～０．５ｗ／ｖ％である水性眼科用組成物。
[２]．さらに、（Ｄ）レチノールパルミチン酸エステル、酢酸トコフェロール、グリセリン、プロピレングリコール、臭化ベンゾドデシニウム、２－メタクリロイルオキシエチルホスホリルコリン、ゴマ油及びヒマシ油から選ばれる１種以上を含む[１]記載の水性眼科用組成物。
[３]．（Ｂ）成分が、（Ｂ－１）ポリオキシエチレンヒマシ油及び（Ｂ－２）ポリオキシエチレン硬化ヒマシ油から選ばれる１種以上を含む[１]又は[２]記載の水性眼科用組成物。
[４]．（Ｃ）成分が、メントール、メントン、カンフル、ボルネオール、ゲラニオール、シネオール及びリナロールの中から選ばれる１種以上である[１]～[３]のいずれかに記載の水性眼科用組成物。
[５]．（Ｃ）成分がメントールである[４]記載の水性眼科用組成物。
[６]．透過率が５０％以上である[１]～[５]のいずれかに記載の水性眼科用組成物。
[７]．（Ａ）流動パラフィンと、（Ｂ）非イオン界面活性剤とを含有し、（Ｂ）／（Ａ）で表される（Ａ）成分と（Ｂ）成分との配合質量比が３≦（Ｂ）／（Ａ）≦２５である水性眼科用組成物中のエマルション粒子の微粒化方法であって、上記水性眼科用組成物に（Ｃ）テルペノイドを０．０００１～０．５ｗ／ｖ％配合するエマルション粒子の微粒化方法。 Accordingly, the present invention provides the following invention.
[1]. (A) Liquid paraffin, (B) non-ionic surfactant, and (C) terpenoid are contained, and the compounding mass of (A) component and (B) component represented by (B) / (A) An aqueous ophthalmic composition having a ratio of 3 ≦ (B) / (A) ≦ 25 and a blending amount of the component (C) of 0.0001 to 0.5 w / v%.
[2]. Furthermore, (D) Retinol palmitic acid ester, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyloxyethyl phosphoryl choline, at least one selected from sesame oil and castor oil according to [1]. Ophthalmic composition.
[3]. The aqueous ophthalmic composition according to [1] or [2], wherein the component (B) contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil .
[4]. The aqueous ophthalmic composition according to any one of [1] to [3], wherein the component (C) is at least one selected from menthol, menthol, camphor, borneol, geraniol, cineol and linalool.
[5]. The aqueous ophthalmic composition according to [4], wherein the component (C) is menthol.
[6]. The aqueous ophthalmic composition according to any one of [1] to [5], which has a transmittance of 50% or more.
[7]. The blending mass ratio of the component (A) to the component (B) containing (A) liquid paraffin and (B) a nonionic surfactant and represented by (B) / (A) is 3 ≦ (B) A method for atomizing emulsion particles in an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition contains 0.0001 to 0.5 w / v% of (C) terpenoid in the aqueous ophthalmic composition. Method of atomizing emulsion particles.
　高圧乳化や界面活性剤を高濃度配合しなくても、組成物中のエマルション粒子が微粒化されることで、組成物の透過率が上がり、長期保存によるクリーミングの抑制が可能で、外観保存安定性に優れ、涙液油層を安定化させる流動パラフィンを含有する水性眼科用組成物を提供することができる。 By making the emulsion particles in the composition fine-grained without high-pressure emulsification or high concentration blending of surfactant, the transmittance of the composition is increased, and creaming due to long-term storage can be suppressed, and appearance preservation is stable. It is possible to provide an aqueous ophthalmic composition containing liquid paraffin which is excellent in sex and stabilizes a tear oil layer.
　以下、本発明について詳細に説明する。
［（Ａ）成分］
　流動パラフィンは、飽和脂質が増加した不安定な涙液油層に対して、涙液油層安定化効果が高い成分である。流動パラフィンは、トリグリセリドからなる植物油や炭化水素の中でも炭素鎖長の短いスクワラン等と比較して極性が低い油分である。また、流動パラフィンは原油から得られる炭化水素類の混合物であり、常温で液体である。原油の常圧蒸留残油を原料に減圧蒸留，溶剤脱歴処理を行い、その後、溶剤精製法又は水素化分解法処理を行う方法等により製造される。本発明に用いられる流動パラフィンに特に制限はなく、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。炭化水素の炭素鎖長に特に制限はないが、１５～４５のものが好適に用いられる。また、炭化水素における二重結合の有無について特に制限はないが、飽和炭化水素を多く含むものが好適に用いられる。さらに、炭化水素の構造としては、直鎖、分岐鎖及び環状構造のいずれを含んでいてもよく、いずれの比重の流動パラフィンであっても用いることができる。特に、日本薬局方に収載された流動パラフィン及び軽質流動パラフィン等が好適である。なお、安定剤として適当な型のトコフェロールを含んでいてもよい。 Hereinafter, the present invention will be described in detail.
[(A) component]
Liquid paraffin is a component having a high effect of stabilizing the tear film formation on an unstable tear solution formation with increased saturated lipid. Liquid paraffin is an oil having low polarity as compared with vegetable oils and hydrocarbons composed of triglyceride and squalane having a short carbon chain length among the hydrocarbons. In addition, liquid paraffin is a mixture of hydrocarbons obtained from crude oil, and is liquid at normal temperature. The crude oil is manufactured by a method such as vacuum distillation and solvent degassing treatment using atmospheric residual oil of crude oil as a raw material, and thereafter, a method of solvent purification method or hydrocracking method treatment. There is no restriction | limiting in particular in the liquid paraffin used for this invention, It can be used individually by 1 type or in combination of 2 or more types suitably. The carbon chain length of the hydrocarbon is not particularly limited, but those of 15 to 45 are preferably used. Moreover, there is no restriction | limiting in particular about the presence or absence of the double bond in a hydrocarbon, However, What contains many saturated hydrocarbons is used suitably. Furthermore, the hydrocarbon structure may contain any of linear, branched and cyclic structures, and liquid paraffin of any specific gravity can be used. In particular, liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia are suitable. In addition, you may contain the tocopherol of a suitable type as a stabilizer.
　流動パラフィンの粘度はその分子量と相関しており、第十六改正日本薬局法第１法（３７．８℃）の測定方法において、動粘度３０～１００ｍｍ2／ｓのものが好ましく、３７～８８ｍｍ2／ｓのものがより好ましく、７４～８８ｍｍ2／ｓのものがさらに好ましい。上記粘度範囲内の２種以上を混合してもよい。上記３０ｍｍ2／ｓ以上とすることで、涙液油層安定化効果をより得ることができる。涙液油層安定化効果をより高める点からは、７４～８８ｍｍ2／ｓのものが好ましい。また、１００ｍｍ2／ｓ以下とすることで、外観の透過率が高められると同時に、流動パラフィン特有の眼刺激をより軽減することができる。なお、外観の透過率と眼刺激軽減の点からは、３７～８８ｍｍ2／ｓのものが好ましい。 The viscosity of liquid paraffin is correlated with its molecular weight, and the kinematic viscosity is preferably 30 to 100 mm 2 / s, preferably 37 to 88 mm in the measurement method of the 16th revised Japanese Pharmacopoeia, Method 1 (37.8 ° C). More preferable is 2 / s, and more preferable is 74 to 88 mm 2 / s. Two or more of the above viscosity ranges may be mixed. By setting it as said 30 mm < 2 > / s or more, the tear fluid oil layer stabilization effect can be acquired more. From the viewpoint of further enhancing the effect of stabilizing the tear film formation, one having a diameter of 74 to 88 mm 2 / s is preferable. Further, by setting the thickness to 100 mm 2 / s or less, the transmittance of the appearance can be enhanced, and at the same time, the eye irritation specific to liquid paraffin can be further reduced. From the viewpoint of appearance transmittance and reduction of eye irritation, those of 37 to 88 mm 2 / s are preferable.
　（Ａ）成分の配合量は、涙液油層安定化の観点から、水性眼科用組成物（以下、組成物と記載する場合がある）中、０．００１～２ｗ／ｖ％（質量／体積％、ｇ／１００ｍＬ）が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．０１～１ｗ／ｖ％がさらに好ましく、０．０５～１Ｗ／Ｖ％が最も好ましい。 The blending amount of the component (A) is 0.001 to 2 w / v% (mass / volume%) in the aqueous ophthalmic composition (hereinafter sometimes referred to as a composition) from the viewpoint of stabilization of the tear fluid oil layer. , G / 100 mL) is preferable, 0.001 to 1 w / v% is more preferable, 0.01 to 1 w / v% is more preferable, and 0.05 to 1 W / V% is most preferable.
［（Ｂ）成分］
　（Ｂ）非イオン界面活性剤としては特に限定されず、眼科用組成物に用いられる非イオン界面活性剤を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。具体的には、（Ｂ－１）ポリオキシエチレンヒマシ油、（Ｂ－２）ポリオキシエチレン硬化ヒマシ油、（Ｂ－３）（Ｂ－１）及び（Ｂ－２）以外の非イオン界面活性剤等が挙げられる。（Ｂ）成分としては、（Ｂ－１）ポリオキシエチレンヒマシ油及び（Ｂ－２）ポリオキシエチレン硬化ヒマシ油から選ばれる１種以上を含むことが好ましい。 [(B) component]
The nonionic surfactant (B) is not particularly limited, and nonionic surfactants used in ophthalmic compositions may be used singly or in appropriate combination of two or more. Specifically, nonionic surfactant other than (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, and (B-3) (B-1) and (B-2) Agents and the like. The component (B) preferably contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil.
（Ｂ－１）ポリオキシエチレンヒマシ油
　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。これらのポリオキシエチレンヒマシ油は、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。点眼時の刺激感を低減する観点から、ポリオキシエチレンヒマシ油３５を用いることが好ましい。 (B-1) Polyoxyethylene castor oil Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and the average addition mole number of ethylene oxide is Several different types 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. These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. It is preferable to use polyoxyethylene castor oil 35 from the viewpoint of reducing the feeling of irritation when instilled.
（Ｂ－２）ポリオキシエチレン硬化ヒマシ油
　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。これらのポリオキシエチレン硬化ヒマシ油は、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。点眼時の刺激感を低減する観点から、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硬化ヒマシ油６０を用いることが好ましい。 (B-2) polyoxyethylene hydrogenated castor oil polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and the average addition of ethylene oxide Several types with different numbers of moles are known. 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 These polyoxyethylene hydrogenated castor oils can be used singly or in appropriate combination of two or more. It is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 from the viewpoint of reducing the feeling of irritation when instilled.
（Ｂ－３）（Ｂ－１）及び（Ｂ－２）以外の非イオン界面活性剤
　ポリソルベート８０（ポリオキシエチレン（２０）ソルビタンオレイン酸エステル）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（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）、モノステアリン酸ポリエチレングリコール（４０）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。 (B-3) Nonionic surfactants other than (B-1) and (B-2) polyoxyethylene sorbitan fatty acid ester (POE sorbitan represented by polysorbate 80 (polyoxyethylene (20) sorbitan oleate) Fatty acid ester), polyoxyethylene polyoxypropylene glycol (POEPOP glycol) represented by poloxamer, polyethylene glycol monostearate (10), polyethylene glycol monostearate represented by polyethylene glycol monostearate (40), etc. Be
　（Ｂ）成分の配合量は（Ａ）成分との配合質量比で適宜選択され、（Ｂ）／（Ａ）で表される（Ａ）成分と（Ｂ）成分との配合質量比が３≦（Ｂ）／（Ａ）≦２５である。この比率が３未満であると、エマルション粒子の微粒化が不十分であり、２５を超えると、エマルションを形成しない界面活性剤が過剰に存在することになり、泡立ちが生じやすくなる。この配合質量比は、４≦（Ｂ）／（Ａ）が好ましく、５≦（Ｂ）／（Ａ）がより好ましい。上記配合質量比を４以上とすることで、（Ｃ）成分にもよるが、組成物の透過率が５０％以上となる。上記配合質量比を５以上とすることで、組成物の透過率が７０％以上となる。組成物の泡立ちを抑制する観点から、（Ｂ）／（Ａ）≦２０が好ましく、（Ｂ）／（Ａ）≦１５がより好ましい。なお、上記比率はｗ／ｖ％比であるが、質量比と同じ値となる。 The compounding amount of the component (B) is appropriately selected by the compounding mass ratio with the component (A), and the compounding mass ratio of the component (A) to the component (B) represented by (B) / (A) is 3 ≦ (B) / (A) ≦ 25. When this ratio is less than 3, the atomization of the emulsion particles is insufficient, and when it exceeds 25, the surfactant which does not form an emulsion is present in excess, and foaming tends to occur. The blending mass ratio is preferably 4 ≦ (B) / (A), and more preferably 5 ≦ (B) / (A). By making the said combination mass ratio into 4 or more, although based also on (C) component, the transmittance | permeability of a composition will be 50% or more. By setting the above-mentioned blending mass ratio to 5 or more, the transmittance of the composition becomes 70% or more. From the viewpoint of suppressing foaming of the composition, (B) / (A) ≦ 20 is preferable, and (B) / (A) ≦ 15 is more preferable. In addition, although the said ratio is w / v% ratio, it becomes the same value as mass ratio.
　（Ｂ）成分の配合量は、上記比率を満たしていれば特に限定されないが、組成物中０．０００１～１０ｗ／ｖ％が好ましく、０．０００１～５ｗ／ｖ％がより好ましい。
　（Ｂ－１）ポリオキシエチレンヒマシ油を配合する場合は、組成物中０．００３～１０ｗ／ｖ％が好ましく、０．００３～５ｗ／ｖ％がより好ましく、０．０３～１ｗ／ｖ％がさらに好ましい。
　（Ｂ－２）ポリオキシエチレン硬化ヒマシ油を配合する場合は、組成物中０．００３～１０ｗ／ｖ％が好ましく、０．００３～５ｗ／ｖ％がより好ましく、０．０３～１ｗ／ｖ％がさらに好ましい。
　（Ｂ－３）（Ｂ－１）及び（Ｂ－２）以外の非イオン界面活性剤を配合する場合は、組成物中０．０００３～１ｗ／ｖ％が好ましく、０．０００３～０．５ｗ／ｖ％がより好ましく、０．００３～０．１ｗ／ｖ％がさらに好ましい。 The blending amount of the component (B) is not particularly limited as long as the above ratio is satisfied, but 0.0001 to 10 w / v% in the composition is preferable, and 0.0001 to 5 w / v% is more preferable.
(B-1) When mix | blending polyoxyethylene castor oil, 0.003 to 10 w / v% in a composition is preferable, 0.003 to 5 w / v% is more preferable, 0.03 to 1 w / v% Is more preferred.
(B-2) When mix | blending polyoxyethylene hydrogenated castor oil, 0.003-10 w / v% in a composition is preferable, 0.003-5 w / v% is more preferable, 0.03-1 w / v. % Is more preferred.
(B-3) When mix | blending nonionic surfactant other than (B-1) and (B-2), 0.0003 to 1 w / v% in a composition is preferable, 0.0003 to 0.5 w / V% is more preferable, and 0.003 to 0.1 w / v% is more preferable.
［（Ｃ）成分］
　（Ｃ）テルペノイドの配合により、高圧乳化や界面活性剤の増量を行わなくても、エマルション粒子が微粒化されることで、組成物の透過率が上がり、長期保存によるクリーミングの抑制が可能となる。本発明におけるテルペノイドとは、イソプレンユニットを構成単位とする構造を有するもので、例えば、テルペン炭化水素、テルペンアルコール、テルペンアルデヒド、テルペンケトン等が挙げられる。また、炭素数により、モノテルペン、セスキテルペン、ジテルペン、トリテルペン、テトラテルペンがある。具体的には、メントール、メントン、カンフル、ボルネオール、リュウノウ、ゲラニオール、シネオール、リナロール、シトロネロール及びリモネン等のモノテルペン、レチノール及びレチナール等のジテルペン、カロチノイド等のテトラテルペン等が挙げられる。中でも、モノテルペンを使用することが好ましい。これらのテルペノイドは、ｄ体、ｌ体又はｄｌ体のいずれでも使用することができる。中でも、メントール、メントン、カンフル、ボルネオール、ゲラニオール、シネオール、リナロールが好ましく、メントール、カンフル、ボルネオール、ゲラニオール、シネオール、リナロールがより好ましい。さらに好ましくは、エマルション粒子の微粒化効果が大きい点から、メントールである。なお、本発明において、テルペノイドとして、上記化合物を含有する精油を使用してもよい。このような精油としては、例えば、ユーカリ油、ベルガモット油、ウイキョウ油、ローズ油、ハッカ油、ペパーミント油、スペアミント油、及びフタバガキ科植物の精油、ロズマリン油、ラベンダー油等が挙げられる。 [(C) ingredient]
(C) By blending the terpenoid, the emulsion particles are made into fine particles without high-pressure emulsification and surfactant amount increase, so the permeability of the composition is increased, and it is possible to suppress creaming due to long-term storage . The terpenoid in the present invention has a structure having an isoprene unit as a constituent unit, and examples thereof include terpene hydrocarbon, terpene alcohol, terpene aldehyde, terpene ketone and the like. Also, depending on the carbon number, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes and tetraterpenes. Specific examples thereof include monoterpenes such as menthol, menthol, camphor, borneol, leunow, geraniol, cineole, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoid. Among them, it is preferable to use a monoterpene. These terpenoids can be used either in d form, l form or dl form. Among them, menthol, menthol, camphor, borneol, geraniol, cineole and linalool are preferable, and menthol, camphor, borneol, geraniol, cineole and linalool are more preferable. More preferably, menthol is used because the effect of atomization of the emulsion particles is large. In the present invention, an essential oil containing the above-mentioned compound may be used as a terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, and essential oils of Dipterocarpus plants, rosmarinic oil, lavender oil and the like.
　（Ｃ）成分の配合量は、組成物中０．０００１～０．５ｗ／ｖ％であり、（Ｃ）成分の種類、（Ｂ）成分等の他の配合成分及びその配合量等から適宜選定される。好ましくは、０．０００１～０．２ｗ／ｖ％である。この配合濃度範囲では、他の配合成分の種類や配合量に関わらず、（Ｃ）テルペノイドが析出するおそれが少ない。また、エマルション粒子の微粒化の観点から、０．０００１ｗ／ｖ％以上が好ましく、刺激感を低減する観点から０．０７５ｗ／ｖ％以下がさらに好ましい。 The compounding amount of the component (C) is 0.0001 to 0.5 w / v% in the composition, and is appropriately selected from the kind of the component (C), other compounding components such as the component (B), and the compounding amount thereof Be done. Preferably, it is 0.0001 to 0.2 w / v%. In this compounding concentration range, there is little possibility that (C) terpenoid precipitates regardless of the types and compounding amounts of other compounding components. Further, from the viewpoint of making the emulsion particles fine, 0.0001 w / v% or more is preferable, and from the viewpoint of reducing the feeling of irritation, 0.075 w / v% or less is more preferable.
　メントールは微粒化が顕著に高まるという観点から、メントールを配合する場合、組成物中０．０００１～０．０７５ｗ／ｖ％が特に好ましく、０．００１～０．０７５ｗ／ｖ％が最も好ましい。 When menthol is blended, it is particularly preferably 0.0001 to 0.075 w / v%, most preferably 0.001 to 0.075 w / v%, when menthol is blended, from the viewpoint of remarkable increase in atomization.
　ボルネオールやカンフルを配合する場合、組成物の微粒化を高めるという観点から、組成物中０．００１～０．０７５ｗ／ｖ％が好ましく、０．００５～０．０７５ｗ／ｖ％がより好ましい。シネオールやリナロールやゲラニオールを配合する場合、組成物の微粒化を高めるという観点から、組成物中０．０００５～０．０７５ｗ／ｖ％が好ましく、０．００２５～０．０７５ｗ／ｖ％がより好ましい。 When borneol and camphor are blended, from the viewpoint of enhancing the atomization of the composition, 0.001 to 0.075 w / v% in the composition is preferable, and 0.005 to 0.075 w / v% is more preferable. In the case of blending cineole, linalool or geraniol, it is preferably 0.0005 to 0.075 w / v%, more preferably 0.0025 to 0.075 w / v% in the composition, from the viewpoint of increasing the fineness of the composition. .
　本発明の組成物には、（Ｃ）成分によるエマルション粒子の微粒化をより高める観点から、（Ｄ）レチノールパルミチン酸エステル、酢酸トコフェロール、グリセリン、プロピレングリコール、臭化ベンゾドデシニウム、２－メタクリロイルオキシエチルホスホリルコリン、ゴマ油及びヒマシ油から選ばれる１種以上を配合することが好ましい。これらは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。中でも、レチノールパルミチン酸エステル、酢酸トコフェロール、グリセリン、プロピレングリコールが好ましい。 In the composition of the present invention, (D) retinol palmitic acid ester, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyl ester, from the viewpoint of further enhancing micronization of emulsion particles by the component (C). It is preferable to blend one or more selected from oxyethyl phosphoryl choline, sesame oil and castor oil. These can be used singly or in appropriate combination of two or more. Among them, retinol palmitate, tocopherol acetate, glycerin and propylene glycol are preferable.
　（Ｄ）成分の組成物中の配合量は、組成物の微粒化を高める観点から、以下の範囲が好ましい。レチノールパルミチン酸エステル、酢酸トコフェロールを配合する場合は、０．００１～５．０ｗ／ｖ％が好ましく、０．０１～３．０ｗ／ｖ％がより好ましく、０．０１～１．０ｗ／ｖ％がさらに好ましい。グリセリン、プロピレングリコール、臭化ベンゾドデシニウム、ゴマ油、ヒマシ油を配合する場合は、０．００５～５．０ｗ／ｖ％が好ましく、０．０５～３．０ｗ／ｖ％がより好ましく、０．１～１．０ｗ／ｖ％がさらに好ましい。２－メタクリロイルオキシエチルホスホリルコリンを配合する場合は、０．０１～５．０ｗ／ｖ％が好ましく、０．０３～２．０ｗ／ｖ％がより好ましく、０．０５～１．０ｗ／ｖ％がさらに好ましい。 The compounding amount of the component (D) in the composition is preferably in the following range from the viewpoint of enhancing atomization of the composition. When retinol palmitic acid ester and tocopherol acetate are blended, 0.001 to 5.0 w / v% is preferable, 0.01 to 3.0 w / v% is more preferable, and 0.01 to 1.0 w / v% Is more preferred. When glycerin, propylene glycol, benzododecinium bromide, sesame oil and castor oil are blended, 0.005 to 5.0 w / v% is preferable, 0.05 to 3.0 w / v% is more preferable, and 0 1 to 1.0 w / v% is more preferable. When mix | blending 2-methacryloyl oxyethyl phosphoryl choline, 0.01-5.0 w / v% is preferable, 0.03-2.0 w / v% is more preferable, 0.05-1.0 w / v% is More preferable.
［その他の成分］
　本発明の組成物には、本発明の効果を損なわない範囲で、眼科用組成物に配合されるその他の成分を適量配合することができる。その他の成分としては、防腐剤、糖類、緩衝剤、ｐＨ調整剤、等張化剤、安定化剤、多価アルコール、粘稠剤、薬物等が挙げられる。これらの成分は、１種単独で又は２種以上を適宜組み合わせて配合することができる。下記に示す成分の配合量は、配合する場合の好ましい範囲であり、組成物中の量である。 [Other ingredients]
In the composition of the present invention, other components to be blended in the ophthalmic composition can be blended in appropriate amounts as long as the effects of the present invention are not impaired. Other components include preservatives, saccharides, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, drugs and the like. These components may be blended singly or in appropriate combination of two or more. The compounding quantity of the component shown below is a preferable range in the case of mix | blending, and is the quantity in a composition.
　防腐剤の中でもアルキル鎖やベンゼン環等の疎水部を有する防腐剤として、チメロサール、フェニルエチルアルコール、アルキルアミノエチルグリシン、クロルヘキシジングルコン酸、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル等が挙げられるが、流動パラフィンが涙液油層へ移行されにくくなるため、組成物中に０．１ｗ／ｖ％以下が好ましく、０．０１Ｗ／Ｖ％以下がさらに好ましく、０．００１Ｗ／Ｖ％以下がより好ましく、実質的に含まないことがより好ましい。 Among preservatives, thimerosal, phenylethyl alcohol, alkylaminoethyl glycine, chlorhexidine gluconic acid, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, etc. may be mentioned as preservatives having a hydrophobic moiety such as alkyl chain or benzene ring. In the composition, 0.1 w / v% or less is preferable, 0.01 w / v% or less is more preferable, and 0.001 w / v% or less is more preferable, because paraffin is less likely to be transferred to the tear oil layer. More preferably, they are not contained in
　糖類としては、グルコース、シクロデキストリン、キシリトール、ソルビトール、マンニトール等が挙げられる。なお、これらは、Ｄ体、Ｌ体又はＤＬ体のいずれでもよい。糖類を配合する場合、その配合量は、組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 Examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. In addition, any of D body, L body, or DL body may be sufficient as these. When the saccharide is blended, the blending amount thereof is preferably 0.001 to 5.0 w / v% in the composition, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v%. More preferable.
　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、氷酢酸、トロメタモール、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、組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～２ｗ／ｖ％がより好ましく、０．００１～１ｗ／ｖ％がさらに好ましい。 Examples of the buffer include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, sodium hydrogen carbonate and the like. When the buffer is blended, the blending amount thereof is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 2 w / v%, and further preferably 0.001 to 1 w / v% in the composition. preferable.
　ｐＨ調整剤としては、無機酸又は無機アルカリ剤が挙げられる。例えば、無機酸としては（希）塩酸が挙げられる。無機アルカリ剤としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。組成物のｐＨは、３．５～１３．０とすることもでき、涙液油層不安定化が引き起こす諸症状をより改善する点から３．５～８．０が好ましく、５．５～８．０がより好ましい。なお、ｐＨの測定は、２５℃でｐＨメータ（ＨＭ－２５Ｒ、東亜ディーケーケー（株））を用いて行う。 As a pH adjuster, an inorganic acid or an inorganic alkali agent is mentioned. For example, the inorganic acid includes (dilute) hydrochloric acid. As the inorganic alkali agent, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like can be mentioned. The pH of the composition may be 3.5 to 13.0, preferably 3.5 to 8.0, more preferably 5.5 to 8 from the viewpoint of further improving various conditions caused by tear film instability. .0 is more preferred. The pH is measured at 25 ° C. using a pH meter (HM-25R, Toa DKK Co., Ltd.).
　等張化剤としては、例えば、塩化ナトリウム、塩化カリウム、塩化カルシウム、炭酸水素ナトリウム、炭酸ナトリウム、乾燥炭酸ナトリウム、硫酸マグネシウム、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等が挙げられる。涙液油層不安定化が引き起こす諸症状をより改善する点から、塩化ナトリウムと塩化カリウムを少なくとも１種以上配合し、等張化されていることが好ましい。組成物の対生理食塩水浸透圧比は涙液油層不安定化が引き起こす諸症状をより改善する点から０．６０～２．００が好ましく、０．６０～１．５５がより好ましく、０．８３～１．２０が最も好ましい。なお、浸透圧の測定は、２５℃で自動浸透圧計（Ａ２Ｏ、アドバンスインスツルメンツ社）を用いて行う。 Examples of tonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium hydrogencarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogenphosphate, sodium dihydrogenphosphate, potassium dihydrogenphosphate and the like. It can be mentioned. From the viewpoint of further improving the various conditions caused by the tear liquid layer destabilization, it is preferable that at least one of sodium chloride and potassium chloride be blended to be isotonic. The osmotic pressure ratio of the composition to saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and more preferably 0.83 from the viewpoint of further improving the various conditions caused by the tear fluid layer destabilization. Most preferred is 1.20. The osmotic pressure is measured at 25 ° C. using an automatic osmometer (A2O, Advanced Instruments).
　安定化剤としては、例えば、エデト酸ナトリウム、シクロデキストリン、亜硫酸塩、ジブチルヒドロキシトルエン等が挙げられる。安定化剤を配合する場合、その配合量は、組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like. When the stabilizer is blended, the blending amount thereof is preferably 0.001 to 5.0 w / v% in the composition, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v % Is more preferred.
　多価アルコールとしては、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。多価アルコールを配合する場合、多価アルコールの配合量は、組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like. When the polyhydric alcohol is blended, the blending amount of the polyhydric alcohol is preferably 0.001 to 5.0 w / v% in the composition, more preferably 0.001 to 1 w / v%, and 0.001 to 0. 1 w / v% is more preferable.
　粘稠剤としては、例えば、ポリビニルピロリドン、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリビニルアルコール、ヒアルロン酸ナトリウム、コンドロイチン硫酸ナトリウム、ポリアクリル酸、カルボキシビニルポリマー等が挙げられる。粘稠剤を配合する場合、その配合量は、組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 Examples of the thickener include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer and the like. When mix | blending a viscosity agent, 0.001-5.0 w / v% in a composition is preferable, 0.001-1 w / v% is more preferable, 0.001-0.1 w / v is preferable. % Is more preferred.
　（Ａ）流動パラフィン、及び（Ｄ）以外の油成分として、大豆油、オリーブ油、コーン油、ヤシ油、アーモンド油、中鎖脂肪酸トリグリセリド、酢酸－ｄ－α－トコフェロール、レチノールパルミチン酸エステル、白色ワセリン、精製ラノリン、コレステロール、ミックストコフェロール等が挙げられる。流動パラフィン以外の油成分を配合する場合、その配合量は０．００１～１．０ｗ／ｖ％が好ましく、０．００１～０．５ｗ／ｖ％がより好ましく、０．００１～０．２５ｗ／ｖ％が最も好ましい。 As oil components other than (A) liquid paraffin and (D), soybean oil, olive oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglyceride, acetic acid-d-α-tocopherol, retinol palmitate, white petrolatum , Purified lanolin, cholesterol, mixed tocopherols and the like. When blending oil components other than liquid paraffin, the blending amount thereof is preferably 0.001 to 1.0 w / v%, more preferably 0.001 to 0.5 w / v%, and 0.001 to 0.25 w / v% is most preferred.
　薬物（薬学的有効成分）としては、例えば、充血除去成分（例えば、エピネフリン、塩酸エピネフリン、エフェドリン塩酸塩、塩酸テトラヒドロゾリン、ナファゾリン塩酸塩、ナファゾリン硝酸塩、フェニレフリン塩酸塩、ｄｌ－メチルエフェドリン塩酸塩等）、消炎・収斂剤（例えば、ネオスチグミンメチル硫酸塩、イプシロン－アミノカプロン酸、アラントイン、ベルベリン塩化物水和物、ベルベリン硫酸塩水和物、アズレンスルホン酸ナトリウム、グリチルリチン酸二カリウム、硫酸亜鉛、乳酸亜鉛、リゾチーム塩酸塩等）、抗ヒスタミン剤（例えば、ジフェンヒドラミン塩酸塩、クロルフェニラミンマレイン酸塩等）、水溶性ビタミン類（フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、ピリドキシン塩酸塩、パンテノール、パントテン酸カルシウム、パントテン酸ナトリウム等）、アミノ酸類（例えば、Ｌ－アスパラギン酸カリウム、Ｌ－アスパラギン酸マグネシウム、Ｌ－アスパラギン酸カリウム・マグネシウム（等量混合物）、アミノエチルスルホン酸等）、サルファ剤等が挙げられる。薬物を配合する場合、薬物の配合量は、各薬物の有効な適性量を選択することができるが組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 Examples of the drug (pharmaceutically active ingredient) include decongestion components (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride etc.), Anti-inflammatory and astringent agents (eg neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride Salts, etc., antihistamines (eg, diphenhydramine hydrochloride, chlorpheniramine maleate etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, pa Tenol, calcium pantothenate, sodium pantothenate etc., amino acids (eg, potassium L-aspartate, magnesium L-aspartate, potassium magnesium magnesium L-aspartate (equivalent mixture), aminoethyl sulfonic acid etc.), sulfa drug Etc. When the drug is compounded, the compounding amount of the drug can be selected from the effective appropriate amount of each drug, but 0.001 to 5.0 w / v% in the composition is preferable, 0.001 to 1 w / v% Is more preferable, and 0.001 to 0.1 w / v% is more preferable.
［製造方法］
　本発明の組成物の製造方法は特に限定されず、（Ａ）、（Ｂ）、（Ｃ）成分、及び必要に応じて任意成分を混合することで得ることができる。例えば、（Ａ）、一部又は全部の（Ｂ）及び（Ｃ）成分等の油性成分の混合溶液を、水性成分を含む水溶液と混合して乳化させ、ｐＨ調整後、総体積を水により調整することにより得ることができる。各液体の混合方法は、一般的な方法でよく、パルセーター、プロペラ羽根、パドル羽根、タービン羽根等を用いて適宜行われるが、回転数は特に限定されず、激しく泡立たない程度に設定することが好ましい。各液体の混合温度は特に限定しないが、油性成分と界面活性剤成分が共に融解温度以上であることが好ましく、具体的には４０～９５℃の範囲から適宜選定される。なお、本発明においては、高圧乳化工程がなくても、組成物中のエマルション粒子を微粒化することで、組成物の透過率を高めるとともに、長期保存によるクリーミングの抑制が可能である。 [Production method]
The method for producing the composition of the present invention is not particularly limited, and the composition can be obtained by mixing the components (A), (B) and (C) and optional components as needed. For example, a mixed solution of oily components such as (A), part or all of (B) and (C) components is mixed with an aqueous solution containing an aqueous component and emulsified, and after adjusting the pH, the total volume is adjusted with water It can be obtained by The mixing method of each liquid may be a general method, and is appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, etc., but the number of rotations is not particularly limited. Is preferred. The mixing temperature of each liquid is not particularly limited, but it is preferable that both the oil component and the surfactant component be at the melting temperature or higher, and specifically, it is appropriately selected from the range of 40 to 95 ° C. In the present invention, even if there is no high-pressure emulsification step, the permeability of the composition can be increased and the creaming due to long-term storage can be suppressed by atomizing the emulsion particles in the composition.
　また、得られた組成物を樹脂製容器に充填後、さらに包装体により密封し、上記容器と上記包装体との間に形成された空間の不活性ガスを封入してもよく、眼科用組成物を樹脂製容器に充填し、脱酸素剤と共に包装体により密封してもよい。 In addition, after filling the obtained composition into a resin container, the composition may be further sealed by a package, and inert gas in the space formed between the container and the package may be enclosed; The substance may be filled in a resin container and sealed by a package together with an oxygen scavenger.
［眼科用組成物］
　本発明の組成物は、「水性眼科用組成物」である。本発明において、「水性眼科用組成物」とは、媒質が水である眼科用組成物をいう。なお、水の配合量は、涙液との混合を容易にし、涙液油層安定化効果をより得る点から、組成物中９０．０～９９．５ｗ／ｖ％が好ましく、９５．０～９７．５ｗ／ｖ％がより好ましい。 [Ophthalmic composition]
The composition of the present invention is an "aqueous ophthalmic composition". In the present invention, the "aqueous ophthalmic composition" refers to an ophthalmic composition in which the medium is water. The content of water is preferably 90.0 to 99.5 w / v% in the composition, from the viewpoint of facilitating mixing with tear fluid and obtaining a tear oil layer stabilization effect, and 95.0 to 97%. .5 w / v% is more preferred.
　本発明の組成物中に含有されるエマルション粒子（（Ａ）成分と（Ｂ）成分の会合体）の粒子径は、８００ｎｍ以下とすることができ、５００ｎｍ以下が好ましく、３００ｎｍ以下がより好ましい。下限は特に限定されないが、１ｎｍとすることもできる。なお、本発明において粒子径とは散乱光強度から算出した体積基準粒度分布の平均径（メディアン径ｎｍ）を指す。粒子径は光散乱等の原理を応用した各種測定装置により、恒温槽を用い、２５℃一定の温度条件のもと行う。このような装置としては例えば、粒子径測定装置（ＥＬＳＺ－２００ＺＳ、大塚電子（株）製）にて測定することができる。 The particle diameter of the emulsion particles (the association of the (A) component and the (B) component) contained in the composition of the present invention can be 800 nm or less, preferably 500 nm or less, and more preferably 300 nm or less. The lower limit is not particularly limited, but may be 1 nm. In the present invention, the particle diameter refers to the average diameter (median diameter nm) of the volume-based particle size distribution calculated from the scattered light intensity. The particle diameter is measured by a constant temperature bath at a constant temperature of 25 ° C. using a constant temperature bath by various measuring devices to which the principle of light scattering or the like is applied. As such an apparatus, for example, it can be measured by a particle size measuring apparatus (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.).
　本発明の組成物の透過率は、具体的には、分光光度計（例えば、ＵＶ－１８００、（株）島津製作所）を用いて測定した波長６００ｎｍの透過率が、３０～１００％とすることもでき、５０～１００％が好ましく、７０～１００％がより好ましい。 Specifically, the transmittance of the composition of the present invention is 30 to 100% at a wavelength of 600 nm measured using a spectrophotometer (for example, UV-1800, Shimadzu Corporation). 50 to 100% is preferable, and 70 to 100% is more preferable.
　本発明の組成物は眼への適応を容易にする点から液体が好ましく、２５℃における粘度は、涙液との混合を容易にし、涙液油層安定化効果をより得る点から、２０ｍＰａ・ｓ以下が好ましく、１０ｍＰａ・ｓ以下がより好ましく、５ｍＰａ・ｓ以下がさらに好ましい。なお、粘度の測定方法はコーンプレート型粘度計（ＤＶ２Ｔ、英弘精機（株））を用いて行う。 The composition of the present invention is preferably a liquid from the viewpoint of facilitating application to the eye, and the viscosity at 25 ° C. facilitates mixing with tear fluid, and from the point of achieving a tear oil layer stabilization effect, 20 mPa · s The following is preferable, 10 mPa · s or less is more preferable, and 5 mPa · s or less is more preferable. In addition, the measuring method of a viscosity is performed using a cone-plate viscometer (DV2T, Eiko Seiki Co., Ltd.).
　本発明の組成物は、点眼剤、コンタクトレンズ用点眼剤、洗眼剤等として好適に使用できるが、涙液希釈倍率が高く、流動パラフィンからの界面活性剤の離脱がより促進され、流動パラフィン送達が効率的に行われる点から、点眼剤、コンタクトレンズ用点眼剤（コンタクトレンズ装着者用点眼剤）として好適に使用できる。コンタクトレンズとしては、ハードコンタクトレンズ、Ｏ2ハードコンタクトレンズ、ソフトコンタクトレンズ、シリコーンハイドロゲルソフトコンタクトレンズ等が挙げられ、特に限定されない。 The composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye wash etc. However, tear dilution ratio is high, release of surfactant from liquid paraffin is further promoted, and liquid paraffin delivery Can be suitably used as an eye drop and an eye drop for contact lens (eye drop for contact lens wearer). The contact lenses include, but are not limited to, hard contact lenses, O 2 hard contact lenses, soft contact lenses, silicone hydrogel soft contact lenses, and the like.
　点眼剤又はコンタクトレンズ用点眼剤として使用する場合、１回につき１０～１００μＬを１～３滴、１日につき１～６回点眼することが好ましく、目からあふれ出すことにより涙液油層安定化効果が減ずるおそれがあるため、１回につき１０～５０μＬを１～３滴、１日につき１～６回がより好ましい。１回につき１０～３０μＬを１～３滴、１日につき１～６回がさらに好ましい。洗眼剤として使用する場合、１回につき３～６ｍＬ、１日につき３～６回洗眼することが好ましい。 When used as eye drops or eye drops for contact lenses, it is preferable to instill 1 to 3 drops of 10 to 100 μL at a time, 1 to 6 times per day, and by spilling out of the eye, the tear fluid oil layer stabilizing effect 1 to 3 drops of 10 to 50 μL at a time, and more preferably 1 to 6 times a day. More preferably, 1 to 3 drops of 10 to 30 μL at a time, and 1 to 6 times a day. When used as an eye wash, it is preferable to wash 3 to 6 mL at a time, 3 to 6 times a day.
［微粒化方法］
　本発明は、（Ａ）流動パラフィンと、（Ｂ）非イオン界面活性剤とを含有し、（Ｂ）／（Ａ）で表される（Ａ）成分と（Ｂ）成分との配合質量比が３≦（Ｂ）／（Ａ）≦２５である水性眼科用組成物中のエマルション粒子の微粒化方法であって、上記水性眼科用組成物に（Ｃ）テルペノイドを０．０００１～０．５ｗ／ｖ％配合するエマルション粒子の微粒化方法を提供する。好ましい成分や、配合量は上記と同じである。なお、微粒化により、組成物の透明化を図ることができ、外観保存安定性を向上することができる。なお、「外観保存安定性」とは、組成物を経時保存した場合、（Ａ）成分と（Ｂ）成分との会合体の凝集、クリーミング、合一、浮遊等が抑制されることを意味する。微粒化方法において、（Ｂ）／（Ａ）が上記範囲外では、（Ｃ）成分による微粒化効果が得られない。 [Method of atomization]
The present invention contains (A) liquid paraffin and (B) a nonionic surfactant, and the blending mass ratio of the (A) component to the (B) component represented by (B) / (A) is A method for atomizing emulsion particles in an aqueous ophthalmic composition, wherein 3 ≦ (B) / (A) ≦ 25, wherein the aqueous ophthalmic composition comprises (C) terpenoid in an amount of 0.0001 to 0.5 w / w. Provided is a method for atomizing emulsion particles containing v%. Preferred components and amounts are the same as described above. In addition, by atomization, the composition can be made transparent, and the appearance storage stability can be improved. "Appearance storage stability" means that when the composition is stored over time, aggregation, creaming, coalescence, floating and the like of the association of the (A) component and the (B) component are suppressed. . In the atomization method, when (B) / (A) is outside the above range, the atomization effect by the component (C) can not be obtained.
　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％、比率は質量比（ｗ／ｖ％比と同じ値）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%, and the ratio indicates the mass ratio (the same value as the w / v% ratio).
　　［実施例、比較例］
　下記表の各水性成分を９０ｍＬの精製水に溶解し、９０℃・１５分間加温混合した。別途、（Ａ）流動パラフィンと（Ｂ）非イオン界面活性剤と（Ｃ）テルペノイドの予備混合物を作製し、９０℃・１５分間加熱混合した。次に、予備混合物を水溶液に所定量加え、さらに９０℃・１５分間加熱混合した。その後、室温まで冷却し、ｐＨ調整を行い、１００ｍＬになるように精製水を加えた。なお、各実施例の粘度は０．５～２．０ｍＰａ・ｓの範囲であった。得られた組成物について、下記評価を行った。結果を表中に併記する。 Example, Comparative Example
Each aqueous component in the following table was dissolved in 90 mL of purified water, and heated and mixed at 90 ° C. for 15 minutes. Separately, a preliminary mixture of (A) liquid paraffin, (B) nonionic surfactant and (C) terpenoid was prepared, and heated and mixed at 90 ° C. for 15 minutes. Next, a predetermined amount of the pre-mixture was added to the aqueous solution, and heated and mixed at 90 ° C. for 15 minutes. After that, the reaction solution was cooled to room temperature, pH was adjusted, and purified water was added to 100 mL. The viscosity of each example was in the range of 0.5 to 2.0 mPa · s. The following evaluation was performed about the obtained composition. The results are shown in the table.
［エマルション粒子の微粒化］
　製造直後の組成物中のエマルション粒子の粒子径を、ＥＬＳＺ－２００ＺＳ、大塚電子（株）製）を用いて測定した。得られた粒子径から、組成物中のエマルション粒子の微粒化を下記評価基準で示す。粒子径は散乱光強度から算出した体積基準粒度分布の平均径（メディアン径ｎｍ）であり、２５℃一定の温度条件のもとで行った。
［評価基準］
○：（Ｃ）成分（及び（Ｄ）成分）を含まない比較例と比較して、微粒化が認められる
×：（Ｃ）成分（及び（Ｄ）成分）を含まない比較例と比較して、微粒化が認められない [Pulverization of emulsion particles]
The particle diameter of the emulsion particles in the composition immediately after production was measured using ELSZ-200ZS (manufactured by Otsuka Electronics Co., Ltd.). From the particle diameter obtained, atomization of emulsion particles in the composition is shown by the following evaluation criteria. The particle diameter is the average diameter (median diameter nm) of the volume-based particle size distribution calculated from the scattered light intensity, and the measurement was carried out under a constant temperature condition of 25 ° C.
[Evaluation criteria]
○: Compared with the comparative example not containing the (C) component (and the (D) component), the atomization is recognized x: Compared with the comparative example not containing the (C) component (and the (D) component) , Atomization is not recognized
［透過率の測定］
　製造直後の組成物を、紫外可視近赤外分光光度計ＵＶ－１８００（株式会社島津製作所）を用いて、波長６００ｎｍの透過率（％）を測定した。 [Measurement of transmittance]
The composition immediately after production was measured for transmittance (%) at a wavelength of 600 nm using an ultraviolet-visible near-infrared spectrophotometer UV-1800 (Shimadzu Corporation).
［透過率向上］
　○：（Ｃ）成分（及び（Ｄ）成分）を含まない比較例と比較して、透過率が向上している
　×：（Ｃ）成分（及び（Ｄ）成分）を含まない比較例と比較して、透過率が向上していない [Improved transmittance]
○: The transmittance is improved as compared to the comparative example containing no (C) component (and (D) component) ×: Comparison with the comparative example containing no (C) component (and (D) component) And the transmittance has not improved
［組成物：透過率（％）］
◎：７０％以上１００％以下
〇：５０％以上７０％未満
△：３０％以上５０％未満
×：３０％未満
「〇」以上を合格とする。 [Composition: Permeability (%)]
◎: 70% or more and 100% or less 70: 50% or more and less than 70% Δ: 30% or more and less than 50% x: less than 30% “O” or more is accepted.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　サンプル１－１～１－２と比較サンプル１－１～１－２とを比較すると、（Ａ）成分である流動パラフィンと（Ｂ）成分であるＰＯＥヒマシ油とを、３≦（Ｂ）／（Ａ）≦２５の割合で含む水性組成物に、（Ｃ）ｌ－メントールを配合することで、６００ｎｍの光線透過率が高まり、粒子径が小さくなった。以上のことから、上記組成物に（Ｃ）ｌ－メントールを配合することで、エマルション粒子が微粒化され、組成物の透過率が向上した。一方、比較サンプル１－３と比較サンプル１－３’とを比較すると、（Ｂ）／（Ａ）が１であると、粒子径及び透過率がほぼ同じで、上記効果が得られなかった。 Comparing Samples 1-1 to 1-2 with Comparative Samples 1-1 to 1-2, the liquid paraffin which is the component (A) and the POE castor oil which is the component (B) satisfy 3 ≦ (B) / By adding (C) 1-menthol to the aqueous composition containing (A) ≦ 25, the light transmittance at 600 nm was increased and the particle size was decreased. From the above, by blending (C) 1-menthol with the above composition, the emulsion particles are atomized, and the transmittance of the composition is improved. On the other hand, when Comparative Sample 1-3 and Comparative Sample 1-3 'were compared, when (B) / (A) was 1, the particle diameter and the transmittance were almost the same, and the above effect was not obtained.
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
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
　実施例の組成物は下記外観保存安定性評価において、全て「〇」であった。
［外観保存安定性］
　組成物２０ｇをガラスビン（容量２０ｍＬ）に入れ、室温下でそれぞれ４８時間静置した。その後、保管品の外観保存安定性を目視により観察し、以下の基準により判定した。
［評価基準］
○：外観が調製直後と変わらない
×：クリーミング等が起こり、調製直後と比べてエマルションの外観に変化が見られる The compositions of the examples were all "o" in the following appearance storage stability evaluation.
[Appearance storage stability]
20 g of the composition was placed in a glass bottle (20 mL volume) and allowed to stand at room temperature for 48 hours. Thereafter, the appearance storage stability of the stored product was visually observed and judged according to the following criteria.
[Evaluation criteria]
○: The appearance does not change from that immediately after preparation ×: Creaming etc. occur, and the appearance of the emulsion changes compared to that immediately after preparation
　実施例の組成物は下記涙液油層安定性試験において、全て「◎」又は「〇」であった。
　実施例３－１、３－７、比較例Ａ，Ｂの結果を下記に示す。
［涙液油層安定性試験］
　涙液油層安定性の評価を、ドライアイ観察装置ＤＲ－１（興和株式会社製）を用いて涙液油層のＢＵＴ（ｂｒｅａｋ　ｕｐ　ｔｉｍｅ）を測定することで行った。ＤＲ－１は涙液油層表面と涙液水層との境界面で反射される光の干渉像を測定できる装置である。健常眼では、均一な灰色又は白色の干渉像が観察され、涙液油層が崩壊すると干渉像が消失する。被験者に各組成物３０μＬを点眼し１０分経過後、数度瞬目し、その瞬目から涙液油層の崩壊までの時間（油層ＢＵＴ）を測定した。被験者は点眼前の油層ＢＵＴが１０秒以下の人７名１３眼を選択した。結果を７名１３眼の平均値から、下記評価基準で示す。１０秒以下であった油層ＢＵＴは日内や日間変動、流動パラフィンを含まない組成物においては１０秒を超えることはなく、１０秒以上への改善は十分な有用性があるものとして可であると判断した。
［評価基準］
◎：油層ＢＵＴが６０秒以上
〇：油層ＢＵＴが３０秒以上６０秒未満
●：油層ＢＵＴが１０秒以上３０秒未満
×（不可）：油層ＢＵＴが１０秒未満
「●」以上を合格とする。 The compositions of the examples were all "◎" or "〇" in the following tear film stability test.
The results of Examples 3-1 and 3-7 and Comparative Examples A and B are shown below.
[Tear fluid layer stability test]
The evaluation of the tear liquid oil layer stability was performed by measuring BUT (break up time) of the tear liquid oil layer using a dry eye observation apparatus DR-1 (manufactured by Kowa Co., Ltd.). DR-1 is an apparatus capable of measuring an interference image of light reflected at the interface between the surface of the tear fluid oil layer and the tear fluid water layer. In a normal eye, a uniform gray or white interference image is observed, and when the tear fluid oil layer collapses, the interference image disappears. 30 μL of each composition was instilled in a subject, and after 10 minutes, it blinked several times, and the time from the blink to the collapse of the tear fluid oil layer (oil layer BUT) was measured. The subjects selected 13 eyes of 7 people who had oil reservoir BUT less than 10 seconds before instillation. The results are shown by the following evaluation criteria from the average value of 7 eyes and 13 eyes. The oil layer BUT, which was less than 10 seconds, did not fluctuate more than 10 seconds in intraday and inter-day variations, in compositions without liquid paraffin, and improvement to 10 seconds or more was acceptable as having sufficient utility. It was judged.
[Evaluation criteria]
:: Oil layer BUT is 60 seconds or more ○: Oil layer BUT is 30 seconds to 60 seconds ●: Oil layer BUT is 10 seconds to 30 seconds x (not good): Oil layer BUT is less than 10 seconds "●" or more is accepted.
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
　本発明の水性眼科用組成物には、涙液油層安定化効果が確認された。 The aqueous ophthalmic composition of the present invention was confirmed to have a tear oil layer stabilizing effect.
　実施例及び比較例を調製する際に用いた原料を以下に示す。表中の各成分の量は純分換算した量である。
流動パラフィン：第十六改正日本薬局法第１法（３７．８℃）動粘度７６．６ｍｍ2／ｓ（ＫＡＹＤＯＬ、島貿易（株）製）
流動パラフィン：第十六改正日本薬局法第１法（３７．８℃）動粘度３４．８ｍｍ2／ｓ（ハイコールＭ－１７２、カネダ（株）製）
ポリオキシエチレン（ＰＯＥ）ヒマシ油（ポリオキシエチレンヒマシ油３５：ユニオックスＣ３５、日油（株）製）
ポリオキシエチレン（ＰＯＥ）硬化ヒマシ油（ポリオキシエチレン硬化ヒマシ油６０：ＨＣＯ６０、ＨＣＯ４０、日本サーファクタント工業（株）製）
モノステアリン酸ＰＥＧ（モノステアリン酸ポリエチレングリコール（１０）：ＭＹＳ１０Ｖ、モノステアリン酸ポリエチレングリコール（４０）：ＭＹＳ４０ＭＶ、日本サーファクタント工業（株）製）
モノステアリン酸ＰＥＧ（モノステアリン酸ポリエチレングリコール（１００）：ＥＭＡＬＥＸ８１００、日本エマルション（株）製）
ＰＯＥソルビタン脂肪酸エステル（ポリオキシエチレン（２０）ソルビタンオレイン酸エステル：レオドールＴＷ－Ｏ１２０Ｖ、花王（株）製）
ＰＯＥＰＯＰグリコール（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）（ＬｕｔｒｏｌＦ１２７、ＢＡＳＦジャパン（株）製）
ｌ－メントール（鈴木薄荷（株）製）
ｄｌ－カンフル（日本精化（株）製）
ｄ－ボルネオール（柳沢正巳商店（株）製）
ゲラニオール（高砂香料工業（株）製）
シネオール（高砂香料工業（株）製）
リナロール（高砂香料工業（株）製）
ホウ酸（関東化学（株）製）
トロメタモール（関東化学（株）製）
エデト酸ナトリウム水和物（クレワットＮ、ナガセケムテックス（株）製）
塩化ナトリウム（富田製薬（株）製）
水酸化ナトリウム（和光純薬工業（株）製）
レチノールパルミチン酸エステル（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単位／ｇ）
酢酸ｄ－α－トコフェロール（理研Ｅアセテートα、理研ビタミン（株）製）
グリセリン（日本薬局方グリセリン、（株）ＡＤＥＫＡ製）
プロピレングリコール（日本薬局方プロピレングリコール、（株）ＡＤＥＫＡ製）
臭化ベンゾドデシニウム（ベンジルドデシルジメチルアンモニウムブロミド、和光純薬工業（株）製）
ゴマ油（日本薬局方ゴマ油、カネダ（株）製）
ヒマシ油（日本薬局方ヒマシ油、カネダ（株）製） The raw materials used in preparing the examples and comparative examples are shown below. The amount of each component in the table is a net amount.
Liquid paraffin: 16th Amended Japanese Pharmacopoeia Method 1 (37.8 ° C) Dynamic viscosity 76.6 mm 2 / s (KAYDOL, manufactured by Shima Trading Co., Ltd.)
Liquid paraffin: 16th Amended Japanese Pharmacopoeia Method 1 (37.8 ° C) Dynamic viscosity 34.8 mm 2 / s (Hycor M-172, Kaneda Co., Ltd.)
Polyoxyethylene (POE) castor oil (polyoxyethylene castor oil 35: Uniox C 35, manufactured by NOF Corporation)
Polyoxyethylene (POE) hydrogenated castor oil (Polyoxyethylene hydrogenated castor oil 60: HCO60, HCO40, manufactured by Nippon Surfactant Industries Co., Ltd.)
Monostearate PEG (polyethylene glycol monostearate (10): MYS 10 V, polyethylene glycol monostearate (40): MYS 40 MV, manufactured by Nippon Surfactant Industries Co., Ltd.)
Monostearate PEG (polyethylene glycol monostearate (100): EMALEX 8100, manufactured by Nippon Emulsion Co., Ltd.)
POE sorbitan fatty acid ester (polyoxyethylene (20) sorbitan oleic acid ester: Leodol TW-O 120 V, manufactured by Kao Corporation)
POEPOP glycol (polyoxyethylene (200) polyoxypropylene (70) glycol) (Lutrol F127, manufactured by BASF Japan Ltd.)
l-Menthol (made by Suzuki Taikan Co., Ltd.)
dl-Camphor (manufactured by Nippon Seika Co., Ltd.)
d-Borneol (Miyagi Yanagisawa store made)
Geraniol (made by Takasago Perfume Industry Co., Ltd.)
Cineole (made by Takasago perfume industry Co., Ltd.)
Linalool (manufactured by Takasago Aroma Kogyo Co., Ltd.)
Boric acid (Kanto Chemical Co., Ltd.)
Trometamol (Kanto Chemical Co., Ltd.)
Edetate sodium hydrate (Crewat N, Nagase ChemteX Co., Ltd.)
Sodium chloride (manufactured by Tomita Pharmaceutical Co., Ltd.)
Sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.)
Retinol palmitate (DSM Nutrition Japan KK, retinol palmitate, 174 units / g)
Acetic acid d-α-tocopherol (RIKEN E acetate α, manufactured by Riken Vitamin Co., Ltd.)
Glycerin (Japanese Pharmacopoeia glycerin, manufactured by ADEKA Co., Ltd.)
Propylene glycol (Japan Pharmacopoeia propylene glycol, manufactured by ADEKA Co., Ltd.)
Benzododecinium bromide (benzyldodecyldimethylammonium bromide, manufactured by Wako Pure Chemical Industries, Ltd.)
Sesame oil (Japanese Pharmacopoeia Sesame oil, Kaneda Co., Ltd. product)
Castor oil (Japanese Pharmacopoeia castor oil, manufactured by Kaneda Co., Ltd.)

Claims (7)

  1. 　（Ａ）流動パラフィンと、（Ｂ）非イオン界面活性剤と、（Ｃ）テルペノイドとを含有し、（Ｂ）／（Ａ）で表される（Ａ）成分と（Ｂ）成分との配合質量比が３≦（Ｂ）／（Ａ）≦２５であり、（Ｃ）成分の配合量が０．０００１～０．５ｗ／ｖ％である水性眼科用組成物。 (A) Liquid paraffin, (B) non-ionic surfactant, and (C) terpenoid are contained, and the compounding mass of (A) component and (B) component represented by (B) / (A) An aqueous ophthalmic composition having a ratio of 3 ≦ (B) / (A) ≦ 25 and a blending amount of the component (C) of 0.0001 to 0.5 w / v%.
  2. 　さらに、（Ｄ）レチノールパルミチン酸エステル、酢酸トコフェロール、グリセリン、プロピレングリコール、臭化ベンゾドデシニウム、２－メタクリロイルオキシエチルホスホリルコリン、ゴマ油及びヒマシ油から選ばれる１種以上を含む請求項１記載の水性眼科用組成物。 The aqueous solution according to claim 1, further comprising (D) at least one selected from retinol palmitate, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyloxyethyl phosphoryl choline, sesame oil and castor oil. Ophthalmic composition.
  3. 　（Ｂ）成分が、（Ｂ－１）ポリオキシエチレンヒマシ油及び（Ｂ－２）ポリオキシエチレン硬化ヒマシ油から選ばれる１種以上を含む請求項１又は２記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 1 or 2, wherein the component (B) contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil.
  4. 　（Ｃ）成分が、メントール、メントン、カンフル、ボルネオール、ゲラニオール、シネオール及びリナロールの中から選ばれる１種以上である請求項１～３のいずれか１項記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 3, wherein the component (C) is at least one selected from menthol, menthol, camphor, borneol, geraniol, cineol and linalool.
  5. 　（Ｃ）成分がメントールである請求項４記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 4, wherein the component (C) is menthol.
  6. 　透過率が５０％以上である請求項１～５のいずれか１項記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 5, which has a transmittance of 50% or more.
  7. 　（Ａ）流動パラフィンと、（Ｂ）非イオン界面活性剤とを含有し、（Ｂ）／（Ａ）で表される（Ａ）成分と（Ｂ）成分との配合質量比が３≦（Ｂ）／（Ａ）≦２５である水性眼科用組成物中のエマルション粒子の微粒化方法であって、上記水性眼科用組成物に（Ｃ）テルペノイドを０．０００１～０．５ｗ／ｖ％配合するエマルション粒子の微粒化方法。 The blending mass ratio of the component (A) to the component (B) containing (A) liquid paraffin and (B) a nonionic surfactant and represented by (B) / (A) is 3 ≦ (B) A method for atomizing emulsion particles in an aqueous ophthalmic composition, wherein the aqueous ophthalmic composition contains 0.0001 to 0.5 w / v% of (C) terpenoid in the aqueous ophthalmic composition. Method of atomizing emulsion particles.
PCT/JP2018/044633 2017-12-07 2018-12-05 Aqueous ophthalmic composition and method for micronizing emulsion particles WO2019111917A1 (en)

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