WO2018105681A1 - Composition ophtalmologique et son procédé de production - Google Patents

Composition ophtalmologique et son procédé de production Download PDF

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Publication number
WO2018105681A1
WO2018105681A1 PCT/JP2017/043924 JP2017043924W WO2018105681A1 WO 2018105681 A1 WO2018105681 A1 WO 2018105681A1 JP 2017043924 W JP2017043924 W JP 2017043924W WO 2018105681 A1 WO2018105681 A1 WO 2018105681A1
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WO
WIPO (PCT)
Prior art keywords
oil
tear
liquid paraffin
preferable
composition
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PCT/JP2017/043924
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English (en)
Japanese (ja)
Inventor
雅貴 吉田
裕美 高村
Original Assignee
ライオン株式会社
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Filing date
Publication date
Application filed by ライオン株式会社 filed Critical ライオン株式会社
Priority to KR1020197006611A priority Critical patent/KR102497952B1/ko
Priority to CN201780072357.2A priority patent/CN109996538B/zh
Priority to JP2018555057A priority patent/JP6962663B2/ja
Publication of WO2018105681A1 publication Critical patent/WO2018105681A1/fr

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Classifications

    • 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
    • A61K47/44—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 ophthalmic composition containing liquid paraffin and a method for producing the same.
  • the tear fluid layer is essential for maintaining the function of the eye in order to prevent evaporation of water from tears and to remove foreign substances, and it must be stable on the surface of the eye to fulfill its role. is necessary.
  • This tear oil layer is composed of lipids (meibum) secreted from the meibomian glands, and the main components are wax esters, cholesterol esters, phospholipids and the like. On the other hand, these components increase the ratio of saturated lipids due to aging and hormonal changes, affect the stabilization of the tear oil layer, increase evaporation of the tear water layer, and cause dry eye symptoms. Furthermore, it is said to have a deep relationship with eye fatigue.
  • the present invention has been made in view of the above circumstances, and an object thereof is to provide an ophthalmic composition that stabilizes a tear fluid layer and has a clear appearance, and a method for producing the same.
  • liquid paraffin can stabilize a tear oil layer in which saturated lipids due to aging or hormonal changes, meibomian gland dysfunction, etc. are increased. .
  • the ophthalmic composition containing liquid paraffin has a problem in appearance stability that the appearance of the composition is difficult to be clear and creams in several hours.
  • the ophthalmic composition is preferably clear from the viewpoint of facilitating the foreign matter test and needs to have a stable appearance.
  • the surfactant is blended up to the amount where the liquid paraffin is solubilized, clarification and appearance stabilization can be achieved, but the liquid paraffin solubilized with a large amount of the surfactant is A new problem has arisen that it becomes difficult to transfer to the tear oil layer and the effect of stabilizing the tear oil layer is lost.
  • the liquid paraffin and surfactant are separated by being diluted into tear fluid after instillation, and are released to the water surface by promoting the coalescence of the liquid paraffin.
  • the aim was to develop an ophthalmic composition. As a result, it was found that this can be realized by setting the blending amount of the nonionic surfactant as a surfactant to a specific ratio or less with respect to the liquid paraffin, and the tear oil layer stabilizing effect can be maintained. Moreover, it discovered that the clarity and the appearance stability were improved by setting the total blending amount of the nonionic surfactant to a specific ratio or more with respect to the liquid paraffin.
  • the present invention provides the following inventions. [1].
  • the blending mass ratio of nonionic surfactants other than (B-1) and (B-2) is 0.5 ⁇ ((B-1) + (B-2) + (B-3)) / (A), ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.2))/(A) ⁇ 10.0
  • An ophthalmic composition [2].
  • an ophthalmic composition having a clear appearance and a method for producing the same by transferring liquid paraffin to the tear oil layer by tear dilution and stabilizing the tear oil layer.
  • Liquid paraffin is a component that has a high effect of stabilizing the tear oil layer relative to the unstable tear oil layer with increased saturated lipids.
  • Liquid paraffin is an oil component having a low polarity compared to vegetable oils and hydrocarbons composed of triglycerides, such as squalane with a short carbon chain length.
  • Liquid paraffin is a mixture of hydrocarbons obtained from crude oil and is liquid at room temperature. For example, the crude oil is produced by a method of performing distillation under reduced pressure and solvent history using raw material of atmospheric distillation residue, followed by solvent refining or hydrocracking.
  • the liquid paraffin used for this invention can use individually by 1 type or in combination of 2 or more types.
  • the carbon chain length of the hydrocarbon is not particularly limited, but those of 15 to 45 are preferably used.
  • the hydrocarbon structure may include any of linear, branched and cyclic structures, and any paraffinic liquid paraffin can be used.
  • liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia are suitable.
  • An appropriate type of tocopherol may be included as a stabilizer.
  • the viscosity of liquid paraffin correlates with its molecular weight.
  • a viscosity of 30-100 mm 2 / s is preferable, and a viscosity of 37-88 mm More preferable is 2 / s, and more preferable is 74 to 88 mm 2 / s. You may mix 2 or more types within the said viscosity range.
  • a tear oil layer stabilization effect can be obtained more, and by setting it to 100 mm 2 / s or less, the clarity (transmittance) of the composition is enhanced, Eye irritation peculiar to liquid paraffin can be further reduced.
  • the blending amount of component (A) is preferably 0.001 to 25.0 W / V% (mass / volume%, g / 100 mL or less) in the composition, more preferably 0.001 to 2.5 W / V%. 0.001 to 1.0 W / V% is more preferable, 0.01 to 0.5 W / V% is particularly preferable, and 0.05 to 0.25 W / V% is most preferable.
  • the amount is 0.001 W / V% or more, the tear oil layer stabilization effect can be further obtained, and when the amount is 25.0 W / V% or less, the clarity of the composition is further improved and at the same time, an eye peculiar to liquid paraffin Stimulation can be further reduced.
  • composition containing liquid paraffin has problems in the clarity and appearance stability of the composition as described above, and there is a problem in blending the surfactant. However, liquid paraffin solubilized with a large amount of surfactant loses the tear oil layer stabilizing effect.
  • Nonionic surfactants other than (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil (B-3) (B-1) and (B-2) The blending mass ratio of the active agent is 0.5 ⁇ ((B-1) + (B-2) + (B-3)) / (A), ((B-1) /0.75+ (B-2 ) / 2 + (B-3) /0.2)) / (A) ⁇ 10.0 so that the appearance of the composition is clear, but the liquid paraffin and the nonionic surfactant are diluted by tear dilution. Separating, promoting the coalescence of liquid paraffins, promoting the release to the water surface, and exhibiting a tear oil layer stabilizing effect.
  • the component (B-1) and the component (B-2) can maintain the tear oil layer stabilizing effect even when blended at a relatively high concentration, one or more components are advantageous from the viewpoint of clarity of the composition. It is preferable that it is blended. Furthermore, it is more preferable that two or more kinds of nonionic surfactants are blended from the viewpoint of clarity of the composition and appearance stability. Moreover, regarding HLB, since there is a possibility of affecting the tear oil layer stabilization effect, it is preferable to use 10 or more nonionic surfactants, more preferably 12.8 or more, and even more preferably 13 or more.
  • Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide to castor oil. The type of is known. The average added mole number of ethylene oxide in the polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles are exemplified. Specifically, polyoxyethylene castor oil 3 (the number is the average number of moles of ethylene oxide added, hereinafter the same), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor Examples include oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, and the like. These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. From the viewpoint of the effect of stabilizing the tear fluid layer, it is preferable to use polyoxyethylene castor oil 35.
  • the blending amount of the component (B-1) is not particularly limited as long as it satisfies the above ratio, but is preferably 0.0005 to 25.0 W / V%, preferably 0.0005 to 20.0 W / V% in the composition. More preferably, 0.001 to 10.0 W / V% is further more preferable, and 0.0025 to 6.0 W / V% is particularly preferable. From the viewpoint of the effect of stabilizing the tear fluid layer, 5.0 W / V% or less is preferable, 2.5 W / V% or less is more preferable, and 1.0 W / V% or less is more preferable.
  • Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil. Several types with different numbers of moles are known. The average added mole number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified by 5 to 100 moles.
  • polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 30, Examples include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, and polyoxyethylene hydrogenated castor oil 100.
  • These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. From the viewpoint of the effect of stabilizing the tear fluid layer, polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 are preferably used.
  • the blending amount of the component (B-2) is not particularly limited as long as the above ratio is satisfied, but 0.0005 to 20.0 W / V% is preferable in the composition, and 0.0010 to 10.0 W / V% is preferable. More preferred is 0.0025 to 6.0 W / V%. From the viewpoint of the effect of stabilizing the tear fluid layer, 5.0 W / V% or less is preferable, 2.5 W / V% or less is more preferable, and 1.0 W / V% or less is more preferable.
  • Nonionic surfactants other than (B-1) and (B-2) Polysorbate 80 polyoxyethylene (20) sorbitan monolaurate) (numbers in parentheses are average addition moles of ethylene oxide, The same shall apply hereinafter) polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester), polyoxyethylene-polyoxypropylene block copolymer (POEPOP glycol) typified by poloxamer, polyethylene glycol monostearate (4), monostearin Examples thereof include polyethylene glycol monostearate (10), polyethylene glycol monostearate (40), and polyethylene glycol monostearate typified by polyethylene glycol monostearate (100).
  • POE sorbitan fatty acid ester polyoxyethylene-polyoxypropylene block copolymer
  • POEPOP glycol polyoxyethylene-polyoxypropylene block copolymer
  • Examples thereof include polyethylene glycol monostearate (10), polyethylene glycol monostearate (
  • lecithin, hydrogenated lecithin, phospholipids such as phosphatidylcholine and phosphatidylglycerol that are difficult to desorb from the interface are not separated from the liquid paraffin by dilution of the tear, and the liquid paraffin is hardly transferred to the tear oil layer. It is preferable that it is not contained in.
  • the blending amount of the component (B-3) is not particularly limited as long as the following ratio is satisfied. From the viewpoint of the effect of stabilizing the tear film, 1.0 W / V% or less is preferable, 0.5 W / V% or less is more preferable, and 0.4 or less is more preferable.
  • the blending lower limit of the component (B) can be defined by ((B-1) + (B-2) + (B-3)) / (A), and 0.5 ⁇ ((B-1) + (B-2) + (B-3)) / (A), more preferably 1.0 or more, and even more preferably 2.5 or more. If it is less than the mixing lower limit, the clarity of the composition is deteriorated.
  • the upper limit of ((B-1) + (B-2) + (B-3)) / (A) is not particularly limited, but is usually 20 or less.
  • the upper limit of compounding can be defined by ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.2)) / (A), ((B-1 ) /0.75+ (B-2) / 2 + (B-3) /0.2)) / (A) ⁇ 10.0, more preferably 8.0 or less, and even more preferably 3.3 or less.
  • the lower limit value of ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.2)) / (A) is not particularly limited, but is usually 0.25 or more. .
  • “((B-1) + (B-2) + (B-3)) / (A)” defines the amount of (B) nonionic surfactant relative to component (A). ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.2)) / (A) provides the effects of the present invention (B-1), (B- 2) The amount of (B-3) is specified. These differ depending on the type of component (B). For example, when component (A) is 1.0 W / V%, (B-1) alone is 0.5 W / W% or more and 7.5 W / V% or less, and (B-2) is alone 0.
  • Cationic surfactants typified by benzalkonium chloride and benzethonium chloride, anionic surfactants typified by sodium lauryl sulfate and sorbic acid or salts thereof, and amphoteric surfactants typified by lauramine oxide.
  • the agent inhibits separation of the liquid paraffin and the surfactant by dilution of the tear, and the liquid paraffin is less likely to be transferred to the tear oil layer. Therefore, the content is preferably 0.1 W / V% or less in the composition. More preferably, the content is 0.01 W / V% or less, and it is more preferable that the content is not substantially contained.
  • the ophthalmic composition of the present invention may further contain a terpenoid.
  • a terpenoid By blending the terpenoid, liberty can be adjusted, for example, by increasing the liberation of liquid paraffin to the water surface by dilution of the composition with tear fluid, and the tear oil layer stabilization effect can be enhanced.
  • the terpenoid in the present invention has a structure having an isoprene unit as a structural unit, and examples thereof include terpene hydrocarbon, terpene alcohol, terpene aldehyde, and terpene ketone.
  • monoterpenes sesquiterpenes, diterpenes, triterpenes, and tetraterpenes.
  • monoterpenes such as menthol, menthone, camphor, borneol, rünou, geraniol, cineole, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids.
  • terpenoids can be used in any of d-form, l-form or dl-form.
  • an essential oil containing the above compound may be used as the terpenoid.
  • essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, mint oil, peppermint oil, spearmint oil, and essential oils of dipterocarpaceae, rosmarin oil, and lavender oil. Bergamot oil and eucalyptus oil are preferred from the viewpoint of enhancing the effect of stabilizing the tear fluid layer.
  • the blending amount of the component (C) is 0.0001 to 0.2 W / V% in the composition, and is appropriately selected from the other blending components such as the type of the component (C), the component (B) and the blending amount thereof. Is done. 0.001 to 0.1 W / V% is preferable. In this blending concentration range, (C) terpenoids are less likely to precipitate regardless of the type and blending amount of other blending components. Further, 0.005 W / V% or more is more preferable from the viewpoint of the tear oil layer stabilization effect, and 0.075 W / V% or less is more preferable from the viewpoint of reducing irritation.
  • composition of the present invention An appropriate amount of other components can be blended in the composition of the present invention as long as the effects of the present invention are not impaired.
  • other components include oil components other than liquid paraffin, preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, drugs, and the like. These components can 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
  • oil components other than liquid paraffin castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium chain fatty acid triglyceride, acetic acid-d- ⁇ -tocopherol, retinol palmitate, white petrolatum, refined lanolin , Cholesterol, mixed tocopherol and the like.
  • the amount of oil components other than liquid paraffin is preferably 0.001 to 1.0 W / V%, more preferably 0.001 to 0.5 W / V%, and most preferably 0.001 to 0.25 W / V%. .
  • examples of the preservative having a hydrophobic portion such as an alkyl chain or a benzene ring include tyromesal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconic acid, methyl paraoxybenzoate, ethyl paraoxybenzoate, etc. Since it becomes difficult for paraffin to be transferred to the tear fluid layer, 0.1 W / V% or less is preferable in the composition, and it is more preferable that the composition is not substantially contained.
  • sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. In addition, these may be any of d-form, l-form, or dl-form.
  • the blending amount of the saccharide is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 1 W / V%, and still more preferably 0.001 to 0.1 W / V%.
  • 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 of the buffering agent is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 2 W / V%, and still more preferably 0.001 to 1 W / V%.
  • an inorganic acid or an inorganic alkali agent can be used as the pH adjusting agent.
  • (diluted) hydrochloric acid is mentioned as an inorganic acid.
  • the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
  • the pH of the composition may be 3.5 to 13.0, and is preferably 3.5 to 8.0 from the viewpoint of further improving various symptoms caused by tear fluid layer destabilization. 0.0 is more preferable.
  • the pH is measured at 25 ° C. using a pH meter (HM-25R, Toa DKK).
  • tonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. Can be mentioned. From the viewpoint of further improving various symptoms caused by the tear fluid layer destabilization, it is preferable that at least one sodium chloride and potassium chloride are blended to make it isotonic.
  • the osmotic pressure ratio of the composition to physiological saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, more preferably 0.83 from the viewpoint of further improving various symptoms caused by tear fluid layer instability. Most preferred is ⁇ 1.20.
  • the osmotic pressure is measured using an automatic osmometer (A2O, Advanced Instruments) at 25 ° C.
  • the stabilizer examples include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like.
  • the blending amount of the stabilizer is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 1 W / V%, and still more preferably 0.001 to 0.1 W / V%.
  • Dibutylhydroxytoluene inhibits separation of liquid paraffin and surfactant due to dilution of tears, and liquid paraffin is less likely to be transferred to the tear oil layer.
  • the polyhydric alcohol examples include glycerin, propylene glycol, butylene glycol, and polyethylene glycol.
  • the blending amount of the polyhydric alcohol is preferably 0.001 to 5.0 W / V%, more preferably 0.001 to 1 W / V% in the composition, and 0.001 to 0.00%. 1 W / V% is more preferable.
  • the thickener examples include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, and the like.
  • the blending amount 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%. V% is more preferable.
  • drugs pharmaceutical active ingredients
  • decongestants eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.
  • Anti-inflammatory / astringent eg, neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride Salt
  • antihistamines eg, diphenhydramine hydrochloride, chlorpheniramine maleate
  • the effective content of each drug can be selected as the drug content, 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 still more preferable.
  • the production method of the composition of the present invention is not particularly limited.
  • a mixed solution of an oil component such as component (A) and a surfactant component such as component (B) is mixed with an aqueous solution containing an aqueous component.
  • the total volume can be obtained 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 rotation speed is not particularly limited and should be set to a level that does not cause intense foaming. Is preferred.
  • each liquid is not particularly limited, but it is preferable that both the oily component and the surfactant component are equal to or higher than the melting temperature, and specifically, appropriately selected from the range of 40 to 95 ° C. More preferably, a further refinement step by high-pressure emulsification is performed. From the viewpoint of improving the clarity of the composition, it is preferable to increase the number of passes at a high pressure, and from the viewpoint of improving production efficiency, it is preferable to reduce the number of passes at a low pressure. 100 to 245 MPa is preferable, 150 to 245 MPa is more preferable, and 200 to 245 MPa is more preferable. Further, it is preferable to apply a back pressure, preferably 1 to 10 MPa, more preferably 2 to 5 MPa. Further, the number of passes is preferably 1 to 10 times, and more preferably 1 to 5 times. The temperature during high-pressure emulsification is appropriately selected from the range of 20 to 90 ° C.
  • the obtained composition after filling the obtained composition into a resin container, it may be further sealed with a package, and the inert gas concentration in the space formed between the container and the package may be enclosed.
  • the composition may be filled in a resin container and sealed with a package together with an oxygen scavenger.
  • the composition of the present invention is preferably an “aqueous ophthalmic composition”.
  • the “aqueous ophthalmic composition” refers to an ophthalmic composition in which the medium is water.
  • the amount of water is preferably 90.0 to 99.5 W / V% in the composition from the viewpoint of facilitating mixing with tears, preventing delay in the transfer of liquid paraffin, and obtaining a tear oil layer stabilization effect. 95.0 to 98.0 W / V% is more preferable.
  • the composition of the present invention is preferably a liquid from the viewpoint of facilitating adaptation to the eyes, and the viscosity at 25 ° C. facilitates mixing with tear fluid, prevents delaying the transition to liquid paraffin, and further improves the effect of stabilizing the tear film. From the viewpoint, it is preferably 20 mPa ⁇ s or less, more preferably 10 mPa ⁇ s or less, further preferably 5 mPa ⁇ s or less, and particularly preferably 2 mPa ⁇ s or less.
  • the viscosity is measured using a cone plate viscometer (for example, DV2T, Eihiro Seiki Co., Ltd.).
  • the composition of the present invention is preferably clear from the viewpoint of facilitating discovery when foreign matter is mixed.
  • the transmittance at a wavelength of 600 nm measured using a spectrophotometer is preferably 50 to 100%, more preferably 75 to 100%, and further 90 to 100%. preferable.
  • the median diameter of the aggregate of the surfactant and the liquid paraffin contained in the composition of the present invention is measured by a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.), and the clarity of the composition From the viewpoint of appearance stability, it is preferably 1 to 200 nm, more preferably 1 to 100 nm, still more preferably 1 to 60 nm, and most preferably 1 to 40 nm.
  • composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye washes, etc., but has a high tear dilution ratio, facilitates the release of surfactant from liquid paraffin, and delivers liquid paraffin.
  • the contact lens is not particularly limited, such as a hard contact lens or a soft contact lens.
  • 10 to 100 ⁇ L each time 1 to 3 drops 1 to 6 times a day, and overflowing from the eyes can stabilize the tear oil layer. Since there is a risk of reduction, 10 to 50 ⁇ L is preferably 1 to 3 drops per day, 1 to 6 times per day, more preferably 10 to 30 ⁇ L per time and 1 to 3 drops 1 to 6 times per day. When used as an eye wash, it is preferable to wash 3 to 6 mL per day and 3 to 6 times per day.
  • composition of the present invention does not merely replenish the tear oil layer or promote the production of oil components from the meibomian gland, but stabilizes the tear oil layer destabilized by meibomian gland dysfunction or the like Is. Simply promoting the production of the oil component will increase the saturated lipids and make the symptom worse, and it will not be possible to stabilize the depleted tear oil layer simply by replenishing the tear oil layer.
  • the composition of the present invention is effective as a tear fluid layer stabilization (tear fluid layer stabilizer), and further, dry eye symptoms (eye fatigue, blurred vision, blurred vision, dry eyes, foreign body sensation, eye (For pain in the eyes, dazzling eyes, heavy eyes, itchy eyes, discomfort in the eyes, greasy, lacrimation, hyperemia, etc.) and symptoms of eye fatigue (eye fatigue, fatigue, stiff shoulders, headache, etc.) It is effective as an agent for improving dry eye symptoms. In particular, it is effective for improving dry eye symptoms and eye fatigue symptoms caused by destabilization of the tear fluid layer (eye fatigue, blurring / haze of eyes, dryness of eyes or fatigue).
  • More effective symptoms are eye fatigue, blurred eyes and blurred vision, dry eyes, and tiredness, and more effective symptoms are eye fatigue and blurred eyes and blurred vision. It is blurry and blurred.
  • meibomian gland dysfunction patients dry eye patients, eye fatigue patients, especially for dry eye patients caused by tear oil layer destabilization or meibomian gland dysfunction, tear oil layer destabilization or meibom Useful for patients with eye fatigue caused by glandular dysfunction. Since contact lens wearing promotes meibomian gland dysfunction, it is preferably used for contact lens wearers, particularly for soft contact lens wearers.
  • Effective amount, administration method, preparation method, etc. are as described above. For example, as an amount of liquid paraffin, 0.01 to 1 mg per adult is divided into 1 to 6 times a day and administered to the eye.
  • each aqueous component was dissolved in 90 mL of water and heated and mixed at 90 ° C. for 15 minutes.
  • a premix of (A) liquid paraffin and (B) nonionic surfactant was prepared and heated and mixed at 90 ° C. for 15 minutes.
  • a predetermined amount of the premix was added to the aqueous solution, and further heated and mixed at 90 ° C. for 15 minutes. Then, it cooled to room temperature, pH adjustment was performed, and water was added so that it might become 100 mL with water.
  • a volumetric flask having a dilution ratio of 1.2 times when poured into the opening was used, and the area of the opening was 152 mm 2 .
  • the observation of the liquid paraffin on the water surface uses a fluorescent lamp as a light source, applies light to the liquid surface, observes the interference light of the oil floating on the liquid surface, calculates the ratio of the area of the oil interference light occupying the water surface, Evaluation was made according to the following criteria. In any of the examples and comparative examples, no oil interference light was observed in the undiluted case. [Evaluation criteria] ⁇ : Oil interference light is observed at 10% or more of the water surface ⁇ : Oil interference light is observed at less than 10% of the water surface ⁇ : Oil interference light is not observed
  • DR-1 dry eye observation device
  • Oil layer BUT which was 10 seconds or less does not exceed 10 seconds in intraocular and day-to-day fluctuations, and no ophthalmic solution containing liquid paraffin, and improvement to 10 seconds or more is considered to be sufficiently useful. It was judged. [Evaluation criteria] ⁇ (excellent): Oil layer BUT is 60 seconds or more ⁇ (good): Oil layer BUT is 30 seconds or more and less than 60 seconds ⁇ (possible): Oil layer BUT is 10 seconds or more and less than 30 seconds x (Not possible): Oil layer BUT is less than 10 seconds
  • liquid paraffin showed a stabilizing effect, but castor oil, sesame oil, medium-chain fatty acid triglyceride, and lecithin did not show a stabilizing effect.
  • Polyoxyethylene hydrogenated castor oil * 1 Polyoxyethylene hydrogenated castor oil 60, HCO 60, Poly from Nippon Surfactant Co., Ltd.
  • Oxyethylene hydrogenated castor oil * 2 Polyoxyethylene hydrogenated castor oil 40, HCO 40, manufactured by Nippon Surfactant Industries, Ltd.
  • Polyethylene glycol monostearate * 3 Polyethylene glycol monostearate (4), MYS4V, Nippon Surfactant Industries, Ltd.
  • Polyethylene glycol monostearate * 4 Polyethylene glycol monostearate (10), MYS10V, polyethylene glycol monostearate manufactured by Nippon Surfactant Co., Ltd.

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Abstract

L'invention concerne une composition ophtalmologique qui stabilise la couche lipidique du film lacrymal et a un aspect externe clair. La composition ophtalmologique contient : (A) un paraffine liquide et (B) un tensioactif non ionique, le rapport de masse de mélange du composant (A), et de l'huile de ricin polyoxyéthylénée (B-1), de l'huile de ricin hydrogénée polyoxyéthylénée (B-2), et un tensioactif non ionique (B-3) autre que (B-1) et (B-2) satisfont aux expressions 0.5 ≤ ((B-1)+(B-2)+(B-3))/(A) et ((B-1)/0.75+(B-2)/2+(B-3)/0.05))/(A) ≤ 10.0.
PCT/JP2017/043924 2016-12-08 2017-12-07 Composition ophtalmologique et son procédé de production WO2018105681A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2019111917A1 (fr) * 2017-12-07 2019-06-13 ライオン株式会社 Composition ophtalmologique aqueuse, et procédé d'atomisation de particules en émulsion
WO2020085190A1 (fr) * 2018-10-24 2020-04-30 ライオン株式会社 Composition ophtalmique aqueuse et procédé pour améliorer la durée de conservation
CN112839641A (zh) * 2018-12-26 2021-05-25 狮王株式会社 眼科用组合物
JP2021102570A (ja) * 2019-12-25 2021-07-15 ライオン株式会社 眼科用組成物及び外観安定化方法
WO2022026805A1 (fr) * 2020-07-31 2022-02-03 Altaire Pharmaceuticals, Inc. Compositions ophtalmiques pour l'élimination de meibum ou l'inhibition de l'accumulation de meibum

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JP5722299B2 (ja) * 2012-12-07 2015-05-20 バイオアバイラビリティ，インク． 栄養学的に使用するための高濃度自己マイクロエマルジョン化コエンザイムｑ１０調製物
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JP2008094839A (ja) * 2006-09-14 2008-04-24 Taisho Pharmaceutical Co Ltd 眼科用剤
JP2008222638A (ja) * 2007-03-13 2008-09-25 Teika Seiyaku Kk 油成分含有眼用組成物
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019111917A1 (fr) * 2017-12-07 2019-06-13 ライオン株式会社 Composition ophtalmologique aqueuse, et procédé d'atomisation de particules en émulsion
WO2020085190A1 (fr) * 2018-10-24 2020-04-30 ライオン株式会社 Composition ophtalmique aqueuse et procédé pour améliorer la durée de conservation
JP2020066590A (ja) * 2018-10-24 2020-04-30 ライオン株式会社 水性眼科用組成物及び保存効力向上方法
CN112823024A (zh) * 2018-10-24 2021-05-18 狮王株式会社 水性眼科用组合物和提高保存效果的方法
JP7172438B2 (ja) 2018-10-24 2022-11-16 ライオン株式会社 水性眼科用組成物及び保存効力向上方法
CN112839641A (zh) * 2018-12-26 2021-05-25 狮王株式会社 眼科用组合物
JP2021102570A (ja) * 2019-12-25 2021-07-15 ライオン株式会社 眼科用組成物及び外観安定化方法
JP7467911B2 (ja) 2019-12-25 2024-04-16 ライオン株式会社 眼科用組成物及び外観安定化方法
WO2022026805A1 (fr) * 2020-07-31 2022-02-03 Altaire Pharmaceuticals, Inc. Compositions ophtalmiques pour l'élimination de meibum ou l'inhibition de l'accumulation de meibum

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