WO2016181998A1 - Composition ophtalmologique - Google Patents

Composition ophtalmologique Download PDF

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Publication number
WO2016181998A1
WO2016181998A1 PCT/JP2016/064032 JP2016064032W WO2016181998A1 WO 2016181998 A1 WO2016181998 A1 WO 2016181998A1 JP 2016064032 W JP2016064032 W JP 2016064032W WO 2016181998 A1 WO2016181998 A1 WO 2016181998A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
ester
acid
carboxylic acid
branched
Prior art date
Application number
PCT/JP2016/064032
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English (en)
Japanese (ja)
Inventor
雅貴 吉田
Original Assignee
ライオン株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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 JP2017517968A priority Critical patent/JP6760275B2/ja
Priority to KR1020177031335A priority patent/KR20180003548A/ko
Publication of WO2016181998A1 publication Critical patent/WO2016181998A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K9/08—Solutions

Definitions

  • the present invention relates to an ophthalmic composition.
  • the tear film is composed of lipids secreted from the meibomian glands. It is known that saturated lipids increase in the oil film due to aging and changes in hormone balance. The tear film oil film with increased saturated lipids has poor stability and contributes to dry eye and eyestrain.
  • Patent Document 1 It has been reported that lecithin is used to stabilize the tear film oil film (Patent Document 1). However, there has been a problem that separation such as creaming occurs during storage of the preparation and the usability is significantly reduced.
  • the present invention has been made in view of the above problems, and an object thereof is to provide an ophthalmic composition that can stabilize a tear film oil film and has good storage stability.
  • the present inventor contains at least one selected from branched aliphatic carboxylic acids having 12 to 20 carbon atoms and esters having a branched alkyl chain having 12 to 20 carbon atoms.
  • the present inventors have found that the ophthalmic composition can stabilize the tear film oil film in which the saturated lipid is increased and that the storage stability is also good, and the present invention has been completed.
  • Ophthalmology containing one or more selected from (A) (A-1) a branched aliphatic carboxylic acid having 12 to 20 carbon atoms and (A-2) an ester having at least one branched alkyl chain having 12 to 20 carbon atoms Composition. [2].
  • the (A-2) ester is an ester of a branched aliphatic carboxylic acid having 12 to 20 carbon atoms and a polyhydric alcohol or ascorbic acid, or an ester of a branched alcohol having 12 to 20 carbon atoms and a polyvalent carboxylic acid.
  • the ophthalmic composition according to [1]. [3].
  • a method for stabilizing a tear film oil film comprising eye-dropping a composition containing at least one selected from a branched aliphatic carboxylic acid having 12 to 20 carbon atoms and an ester having a branched alkyl chain having 12 to 20 carbon atoms .
  • the ophthalmic composition of the present invention can stabilize a tear film oil film in which saturated lipids are increased, and has good storage stability.
  • the ophthalmic composition of the present invention contains one or more selected from the group consisting of the following (A-1) and (A-2).
  • (A-1) Branched aliphatic carboxylic acid having 12 to 20 carbon atoms
  • Examples of the branched aliphatic carboxylic acid having 12 to 20 carbon atoms include isopalmitic acid, isostearic acid, isomyristic acid, and isolauric acid. Of these, isostearic acid is preferred.
  • the number of carbon atoms of the branched aliphatic carboxylic acid is preferably 16-18.
  • An ester having at least one branched alkyl chain having 12 to 20 carbon atoms The number of branched alkyl chains per molecule of an ester having at least one branched alkyl chain having 12 to 20 carbon atoms is 1 to 5 Preferably, 1 to 3 is more preferable, and 2 is most preferable.
  • the branched alkyl chain preferably has 16 to 18 carbon atoms.
  • the number of branched chains (side chains) in the branched alkyl chain is preferably 1 to 4, more preferably 1 to 3, still more preferably 1 or 2, and most preferably 1.
  • the number of carbon atoms in the branched chain (side chain) in the branched alkyl chain is preferably 1 to 8, more preferably 1 to 6, and still more preferably 1 to 4.
  • ester examples include esters of a branched aliphatic carboxylic acid having 12 to 20 carbon atoms and alcohol or ascorbic acid.
  • Examples of the branched aliphatic carboxylic acid having 12 to 20 carbon atoms include isolauric acid, isomyristic acid, isopalmitic acid, and isostearic acid.
  • Examples of the alcohol include monohydric alcohols having 1 to 18 carbon atoms such as methanol, ethanol, propanol and stearyl alcohol; polyhydric alcohols such as ethylene glycol, polyethylene glycol, glycerin, polyglycerin and sorbitan; and saccharides such as dextrin. .
  • the ester of a branched aliphatic carboxylic acid having 12 to 20 carbon atoms and an alcohol or ascorbic acid is preferably an ester of a branched aliphatic carboxylic acid having 12 to 20 carbon atoms and a polyhydric alcohol or ascorbic acid.
  • an ester of a branched alcohol having 12 to 20 carbon atoms and a carboxylic acid may be mentioned, and an ester of a branched alcohol having 12 to 20 carbon atoms and a polyvalent carboxylic acid is more preferable.
  • Examples of the branched alcohol having 12 to 20 carbon atoms include isopalmityl alcohol, isostearyl alcohol, isomyristyl alcohol, and isolauryl alcohol.
  • carboxylic acid examples include monovalent carboxylic acids having 1 to 18 carbon atoms such as myristic acid, palmitic acid, stearic acid, and acetic acid; and polyvalent carboxylic acids such as sebacic acid, adipic acid, malic acid, and citric acid. Of these, polyvalent carboxylic acids are preferable, and divalent carboxylic acids such as sebacic acid, adipic acid, malic acid, and the like are particularly preferable.
  • component (A) examples include isostearic acid, polyglyceryl pentaisostearate such as polyglyceryl pentaisostearate, diisostearyl malate, ascorbyl tetraisopalmitate, propylene glycol isostearate, cholesteryl isostearate, and dextrin isostearate. Sorbitan isostearate, polyglyceryl-2 diisostearate and the like. Of these, diisostearyl malate is preferred.
  • the blending amount of the component (A) is preferably 0.01 to 1.0 w / v% (g / 100 mL) in the composition, more preferably 0.05 to 0.5 w / v%, and 0.05 to 0.5. 2 w / v% is more preferable, and 0.05 to 0.1 w / v% is most preferable.
  • eye irritation is favorable and a tear film oil film can be stabilized effectively.
  • the ophthalmic composition of the present invention can be blended with other components in appropriate amounts within a range not impairing the effects of the present invention.
  • other components include surfactants, polyhydric alcohols, thickeners, sugars, buffers, pH adjusters, tonicity agents, cooling agents, drugs, and the like.
  • Surfactants include polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, glycine-type amphoteric surfactants such as alkyldiaminoethylglycine, alkyl quaternary ammonium salts (specifically Are cationic surfactants such as benzalkonium chloride and benzethonium chloride.
  • the blending amount of the surfactant is preferably 0.0001 to 10 w / v% in the composition.
  • 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 w / v% in the ophthalmic composition.
  • 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 of the thickening agent is preferably 0.003 to 3 w / v% in the composition.
  • sugars examples include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. These may be any of d-form, l-form, and dl-form.
  • the blending amount of the saccharide is preferably 0.001 to 5 w / v% in the composition.
  • 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 buffer is preferably 0.003 to 4 w / v% in the composition.
  • an inorganic acid or an inorganic alkali agent can be used as the pH adjusting agent.
  • (diluted) hydrochloric acid etc. are mentioned as an inorganic acid.
  • the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
  • the pH is measured at 20 ° C. using a pH osmometer (HSMO-1, Toa DKK).
  • the isotonic agent examples include sodium chloride and potassium chloride.
  • the blending amount of the isotonizing agent is preferably 0.001 to 3 w / v% in the composition.
  • the stabilizer examples include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like.
  • the blending amount of the stabilizer is preferably 0.003 to 2 w / v% in the composition.
  • the refreshing agent examples include menthol, camphor, borneol, geraniol, cineol, linalool and the like.
  • the blending amount of the refreshing agent is preferably 0.0001 to 0.2 w / v% in the composition.
  • drugs pharmaceutical active ingredients
  • decongestants eg, naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate
  • anti-inflammatory / astringent agents For example, neostigmine methyl sulfate, ⁇ -aminocaproic acid, allantoin, berberine chloride, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, sodium azulene sulfonate) , Antihistamine
  • the effective content of each drug can be selected as the content of the drug, but is preferably 0.001 to 5 w / v% in the composition from the viewpoint of irritation to the eye and stability of the composition. .
  • the other components can be blended singly or in appropriate combination of two or more.
  • the pH of the ophthalmic composition of the present invention is preferably 3.8 to 8.0, more preferably 5.0 to 7.5 from the viewpoint of eye irritation.
  • the osmotic pressure of the ophthalmic composition of the present invention is preferably 200 to 800 mOsm, more preferably 200 to 500 mOsm from the viewpoint of eye irritation.
  • each component is mixed in water at 50 to 90 ° C. using a propeller blade, a homomixer, a high-pressure emulsifier, or the like, and the pH is adjusted.
  • the final volume can be obtained by adding water (amount of water: balance).
  • the ester having at least one branched aliphatic carboxylic acid having 12 to 20 carbon atoms and branched alkyl chain having 12 to 20 carbon atoms has a function of stabilizing the tear film oil film. Therefore, a branched aliphatic carboxylic acid having 12 to 20 carbon atoms and an ester having at least one branched alkyl chain having 12 to 20 carbon atoms can be used as a tear film oil film stabilizer. When using these as a tear film oil film stabilizer, it can be used individually by 1 type or in combination of 2 or more types.
  • the ophthalmic composition of the present invention can be suitably used as an eye drop, an eye drop for contact lenses, an eye wash, and the like, but can be particularly preferably used as an eye drop.
  • the effect of the present invention can be further exerted by instilling 30 to 60 ⁇ L per time and 3 to 6 times per day.
  • the effect of the present invention can be further exerted by washing the eyes 3 to 6 mL per time and 3 to 6 times per day.
  • the present invention relates to one kind selected from (A) (A-1) a branched aliphatic carboxylic acid having 12 to 20 carbon atoms and (A-2) an ester having at least one branched alkyl chain having 12 to 20 carbon atoms.
  • a tear film oil film stabilizer containing the above as an active ingredient is provided. It is also effective as a dry eye prevention agent and dry eye improving agent.
  • a suitable thing, a range, etc. are the same as that of the above.
  • the effective amount is preferably 0.009 to 3.6 mg / day per adult.
  • Examples 1 to 10 Comparative Examples 1 to 4
  • Ophthalmic compositions (eye drops) having the compositions shown in Tables 1 to 3 below were prepared and evaluated as follows. The results are also shown in the table. Moreover, the image used for the oil film stability evaluation result of Example 3, 4 and 9 is shown in FIG. 1, and the image used for the oil film stability evaluation result of Comparative Examples 1 and 4 is shown in FIG.
  • the tear film oil film mainly contains wax ester (oleyl oleate, etc.), cholesterol ester (cholesterol oleate, etc.), and phosphatidylcholine.
  • wax ester oleyl oleate, etc.
  • cholesterol ester cholesterol ester
  • phosphatidylcholine a group consisting of C16F1, C18F1 fatty acids.
  • C16F0, C18F0 saturated lipids
  • oleyl oleate 3.8 ⁇ g, cholesterol oleate 5.8 ⁇ g, phosphatidylcholine (C18F0 / C18F0) 0.2 ⁇ g, phosphatidylcholine (C18F0 / C18F1) 0.2 ⁇ g and perylene 0.1 ⁇ g was dissolved in 1,000 ⁇ L chloroform, and an oil film prepared by the procedure of spreading 10 ⁇ L of the solution on a water film prepared with 1 mL of water in a 35 mm plastic dish was used. After allowing the oil film to stand at room temperature for 10 minutes, 50 ⁇ L of the prepared eye drop was added, placed on a 37 ° C. hot plate, and allowed to stand for 30 minutes.
  • Oil film stability evaluation ⁇ : Uniform oil film ⁇ : Uneven but water film is not exposed ⁇ : Uneven water film is not exposed ⁇ : Water film is exposed

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Une composition ophtalmologique, caractérisée en ce qu'elle contient au moins un type d'ester choisi parmi des esters qui ont au moins un acide carboxylique ramifié en C12-20 et une chaîne alkyle ramifiée en C12-20.
PCT/JP2016/064032 2015-05-12 2016-05-11 Composition ophtalmologique WO2016181998A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2017517968A JP6760275B2 (ja) 2015-05-12 2016-05-11 眼科用組成物
KR1020177031335A KR20180003548A (ko) 2015-05-12 2016-05-11 안과용 조성물

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015097340 2015-05-12
JP2015-097340 2015-05-12

Publications (1)

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WO2016181998A1 true WO2016181998A1 (fr) 2016-11-17

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KR (1) KR20180003548A (fr)
WO (1) WO2016181998A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002038149A1 (fr) * 2000-11-08 2002-05-16 Santen Pharmaceutical Co., Ltd. Médicaments à base de farnésyl-acétate contre des affections kératoconjonctivales
JP2010120856A (ja) * 2008-11-17 2010-06-03 Santen Pharmaceut Co Ltd 眼科用組成物
WO2011039638A2 (fr) * 2009-10-02 2011-04-07 Foamix Ltd. Compositions de tétracycline à usage topique
JP2016027039A (ja) * 2014-07-03 2016-02-18 ロート製薬株式会社 局所粘膜用水性組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002038149A1 (fr) * 2000-11-08 2002-05-16 Santen Pharmaceutical Co., Ltd. Médicaments à base de farnésyl-acétate contre des affections kératoconjonctivales
JP2010120856A (ja) * 2008-11-17 2010-06-03 Santen Pharmaceut Co Ltd 眼科用組成物
WO2011039638A2 (fr) * 2009-10-02 2011-04-07 Foamix Ltd. Compositions de tétracycline à usage topique
JP2016027039A (ja) * 2014-07-03 2016-02-18 ロート製薬株式会社 局所粘膜用水性組成物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AKIKO ARIMURA ET AL.: "Developments and applications of Vitamin A for eyedrops", BIOSCIENCE & INDUSTRY, vol. 58, no. 10, 1 October 2000 (2000-10-01), pages 716 - 719 *

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JP6760275B2 (ja) 2020-09-23
KR20180003548A (ko) 2018-01-09
JPWO2016181998A1 (ja) 2018-03-01

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