WO2020138135A1 - Composition à usage ophtalmique - Google Patents

Composition à usage ophtalmique Download PDF

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Publication number
WO2020138135A1
WO2020138135A1 PCT/JP2019/050751 JP2019050751W WO2020138135A1 WO 2020138135 A1 WO2020138135 A1 WO 2020138135A1 JP 2019050751 W JP2019050751 W JP 2019050751W WO 2020138135 A1 WO2020138135 A1 WO 2020138135A1
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Prior art keywords
preferable
ophthalmic composition
oil
polyoxyethylene
salts
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PCT/JP2019/050751
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English (en)
Japanese (ja)
Inventor
草太 渡部
圭祐 渡邊
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ライオン株式会社
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Priority to KR1020217000919A priority Critical patent/KR20210107607A/ko
Priority to CN201980067557.8A priority patent/CN112839641A/zh
Priority to JP2020563334A priority patent/JPWO2020138135A1/ja
Publication of WO2020138135A1 publication Critical patent/WO2020138135A1/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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A61K31/125—Camphor; Nuclear substituted derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/534—Mentha (mint)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to an ophthalmic composition containing phenylephrine.
  • Dry eye is a disease or condition with a high prevalence.
  • the prevalence in Asia, including Japan has been reported to be higher than in the West.
  • it is expected that the number of suspects due to age factors, “wearing contact lenses”, and “long computer work”, which are risk factors for dry eye, will continue to increase in the future.
  • Destruction (instability) of the tear film is caused by an abnormality of the tear oil layer, a decrease in the water content of the fluid layer, an abnormality of secretory mucin, or a decrease in the wettability of the epithelium.
  • TFOD tissue film oriented diagnosis
  • TFOT tissue film oriented therapy
  • Phenylephrine is excellent in the tear layer stabilizing effect and the meibam secretion promoting effect.
  • Phenylephrine is excellent in tear layer stabilizing effect and meibam secretion promoting effect, and is useful as a preventive or therapeutic agent for dry eye.
  • Phenylephrine is used for medical purposes with 5 w/v% (mass/volume %, g/100 mL, the same applies hereinafter, and will be described as %) of eye drops for the purpose of mydriasis during fundus examination.
  • the maximum concentration for approval standard is 0.1%, and mydriasis hardly occurs in normal usage.
  • the present inventors have conducted extensive studies to achieve the above object, and as a result, (A) one or more selected from phenylephrine and salts thereof, (B) one or more selected from terpenoids, and preferably (C) It was found that the above problems can be solved by using in combination with one or more selected from quaternary ammonium salt, sorbic acid and its salt, polyhexanide and its salt, and paraoxybenzoic acid ester, and the present invention has been accomplished. It is a thing.
  • the present invention provides the following ophthalmic composition.
  • An ophthalmic composition containing (A) one or more selected from phenylephrine and a salt thereof, and (B) one or more selected from a terpenoid. 2.
  • an ophthalmic composition that enhances the tear film stabilizing effect of phenylephrine or a salt thereof, and further maintains the tear film stabilizing effect even with frequent use for a short time without causing mydriasis. You can provide things.
  • the component (A) is one or more selected from phenylephrine and salts thereof, and may be used alone or in combination of two or more.
  • phenylephrine salts include pharmaceutically acceptable salts such as phenylephrine hydrochloride.
  • the amount of the component (A) is 0.01 to 5% in the ophthalmic composition, preferably 0.025 to 5%, more preferably 0.1 to 5%. preferable. Further, from the viewpoint of the mydriasis suppressing effect, 0.01 to 1% is more preferable, and 0.1 to 0.5% is further preferable.
  • the component (B) is one or more selected from terpenoids, and may be used alone or in combination of two or more.
  • the terpenoid in the present invention has a structure having an isoprene unit as a constitutional unit, and examples thereof include terpene hydrocarbon, terpene alcohol, terpene aldehyde, terpene ketone and the like. Further, depending on the carbon number, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes.
  • monoterpenes such as menthol, menthone, camphor, borneol, leno, geraniol, cineol, linalool, citronellol and limonene
  • diterpenes such as retinol and retinal
  • tetraterpenes such as carotenoids.
  • monoterpenes such as menthol, menthone, camphor, borneol, leno, geraniol, cineol, linalool, citronellol and limonene
  • diterpenes such as retinol and retinal
  • tetraterpenes such as carotenoids.
  • terpenoids can be used in any of d-form, l-form and dl-form.
  • an essential oil containing the above compound may be used as the terpenoid.
  • Such essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, and dipterocarp essential oil, rosmarinic oil, lavender oil, and the like. Of these, menthol, borneol, camphor, geraniol, peppermint oil, spearmint oil, and eucalyptus oil are preferable.
  • the amount of the component (B) is preferably 0.00005 to 0.3%, more preferably 0.0001 to 0.2% in the ophthalmic composition from the viewpoints of the tear layer stabilizing effect and the mydriasis suppressing effect.
  • the range of 0.0005 to 0.1 is more preferable.
  • the upper limit is particularly preferably 0.03% or less.
  • each component in the ophthalmic composition is as follows.
  • menthol is blended, it is preferably 0.00005 to 0.2%, more preferably 0.0001 to 0.1%, further preferably 0.0005 to 0.03%, and 0.001 to 0.03%.
  • 0.019 to 0.03% is most preferred.
  • borneol is added, it is preferably 0.00005 to 0.2%, more preferably 0.0001 to 0.1%, further preferably 0.0005 to 0.03%, and 0.001 to 0.03%.
  • Particularly preferred, 0.009 to 0.03% is most preferred.
  • camphor When camphor is added, 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, 0.001 to 0.01% is further preferable, and 0.002 to 0.01% is preferable. Particularly preferred.
  • 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, 0.001 to 0.03% is further preferable, and 0.009 to 0.03% is Particularly preferred.
  • 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, 0.001 to 0.03% is further preferable, and 0.009 to 0%. 0.03% is particularly preferable.
  • 0.0002 to 0.2% is preferable, 0.001 to 0.1% is more preferable, 0.002 to 0.03% is further preferable, 0.009 to 0.03% Is particularly preferable, and 0.009 to 0.02% is most preferable.
  • the content mass ratio represented by (B)/(A) is preferably 0.001 to 1 and more preferably 0.005 to 0.5 from the viewpoint of enhancing the tear layer stabilizing effect and suppressing the mydriasis.
  • the range of 0.01 to 0.3 is more preferable.
  • the above ratio is the w/v% ratio, but it is the same value as the mass ratio.
  • the component (C) is one or more selected from quaternary ammonium salts, sorbic acid and its salts, polyhexanide and its salts, and paraoxybenzoic acid esters, and they are used alone or in combination of two or more. be able to.
  • quaternary ammonium salts benzalkonium chloride, benzethonium chloride, etc.
  • sorbates potassium sorbate, etc.
  • paraoxybenzoic acid esters methyl paraoxybenzoate, paraoxybenzoate, etc.
  • Ethyl acid and the like can be mentioned.
  • the amount of the component (C) blended is preferably 0.00005 to 1%, more preferably 0.0001 to 1%, and even more preferably 0.0005 to 0.5% in the ophthalmic composition from the viewpoint of the mydriasis suppressing effect. More preferably, 0.001 to 0.3% is particularly preferable.
  • each component in the ophthalmic composition is as follows.
  • a quaternary ammonium salt is added, 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, and 0.001 to 0.01% is further preferable.
  • sorbic acid and its salt are blended, 0.005 to 1.0% is preferable, 0.01 to 0.5% is more preferable, and 0.05 to 0.3% is further preferable.
  • polyhexanide and its salt are blended, 0.00005 to 0.05% is preferable, 0.0001 to 0.02% is more preferable, and 0.0001 to 0.01% is further preferable.
  • the paraoxybenzoic acid ester is blended, 0.001 to 0.3% is preferable, 0.005 to 0.2% is more preferable, and 0.01 to 0.1% is further preferable.
  • the content mass ratio represented by ((B)+(C))/(A) is preferably 0.001 to 3, and more preferably 0.005 to 2 from the viewpoint of the mydriasis suppressing effect and the eye irritation suppressing effect. It is preferably 0.01 to 1, more preferably 0.02 to 0.7.
  • the above ratio is the w/v% ratio, but it is the same value as the mass ratio.
  • Component (D) is polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol, chlorpheniramine maleate, epsilon aminocaproic acid, aspartic acid and its salts, and edetic acid and its salts.
  • One or more selected from salts can be used alone or in appropriate combination of two or more. By mixing these, the mydriasis suppressing effect is further enhanced, and the mydriasis suppressing effect can be further obtained even when the blending amount of the component (A) is high.
  • polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene polyoxypropylene glycol are preferable.
  • Polyoxyethylene hydrogenated castor oil is a compound obtained by addition-polymerizing ethylene oxide to hydrogenated castor oil, and several types with different average addition mole numbers of ethylene oxide are known. ing.
  • the average number of moles of added ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, but may be 5 to 100 moles.
  • 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), Polyoxyethylene hydrogenated castor oil 60 (EO average addition mole number 60), polyoxyethylene hydrogenated castor oil 80 (EO average addition mole number 80), polyoxyethylene hydrogenated castor oil 100 (EO average addition mole number 100), etc. To be Among them, polyoxyethylene hydrogenated castor oil 60 is preferable.
  • polyoxyethylene sorbitan fatty acid ester examples include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), and polyoxyethylene monostearate.
  • polyoxyethylene (20) sorbitan monooleate (polysorbate 80) is preferable.
  • the polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is not particularly limited, and those described in the pharmaceutical additive standard (medical additive regulation) can be used.
  • the average degree of polymerization of ethylene oxide is preferably 4 to 200, more preferably 20 to 200, and the average degree of polymerization of propylene oxide is preferably 5 to 100, more preferably 20 to 70, and may be a block copolymer or a random polymer.
  • Glycol Pluronic F-87 (manufactured by BASF), Polyoxyethylene (160) Polyoxypropylene (30) Glycol: Pluronic F-68 (manufactured by BASF), Pronone #188P (manufactured by NOF Corporation) Etc., polyoxyethylene (42) polyoxypropylene (67) glycol: Pluronic P123 (manufactured by BASF), polyoxyethylene (54) polyoxypropylene (39) glycol: Pluronic P85 (manufactured by BASF), Pronone #235P ( Polyoxyethylene (20) polyoxypropylene (20) glycol: Pluronic L-44, Tetronic (manufactured by BASF) and the like, such as NOF CORPORATION.
  • polyoxyethylene (200) polyoxypropylene (70) glycol is preferable.
  • Chlorpheniramine maleate is known as an antihistamine.
  • Epsilon aminocaproic acid is known as an anti-inflammatory astringent.
  • Examples of the aspartic acid salt of aspartic acid and its salt include potassium aspartate.
  • Examples of edetic acid and edetate salts thereof include sodium edetate and sodium edetate hydrate.
  • the blending amount of the component (D) is preferably 0.0001 to 20%, more preferably 0.0005 to 10%, further preferably 0.001 to 2% in the ophthalmic composition.
  • each component in the ophthalmic composition is as follows.
  • polyoxyethylene hydrogenated castor oil 0.001 to 1% is preferable, 0.005 to 0.5% is more preferable, and 0.01 to 0.2% is further preferable.
  • polyoxyethylene sorbitan fatty acid ester 0.001 to 0.5% is preferable, 0.005 to 0.4% is more preferable, and 0.01 to 0.2% is further preferable.
  • polyoxyethylene polyoxypropylene glycol 0.01 to 20% is preferable, 0.05 to 10% is more preferable, and 0.1 to 1% is further preferable.
  • chlorpheniramine maleate When chlorpheniramine maleate is added, 0.0001 to 0.1% is preferable, 0.0005 to 0.05% is more preferable, and 0.001 to 0.03 is further preferable.
  • epsilon aminocaproic acid When epsilon aminocaproic acid is added, it is preferably 0.01 to 5%, more preferably 0.05 to 4%, still more preferably 0.1 to 2%.
  • aspartic acid or a salt thereof it is preferably 0.01 to 3%, more preferably 0.03 to 2%, still more preferably 0.05 to 1%.
  • edetic acid or a salt thereof When adding edetic acid or a salt thereof, 0.0001 to 1.5% is preferable, 0.0005 to 1% is more preferable, and 0.001 to 0.1% is further preferable.
  • the ophthalmic composition of the present invention may contain other components in appropriate amounts within a range that does not impair the effects of the present invention.
  • Other components include water, oily components, surfactants other than component (D), preservatives other than component (C), sugars, buffers, pH adjusters, tonicity agents, other than component (D).
  • examples include stabilizers, polyhydric alcohols, thickeners, drugs other than the component (A) and the component (D), and the like. These components may be blended alone or in an appropriate combination of two or more. The blending amounts of the components shown below are preferable ranges when blended.
  • the water content may be the balance of the ophthalmic composition.
  • oily ingredients include liquid paraffin, castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium chain fatty acid triglyceride, white petrolatum, mixed tocopherols, lanolin and the like.
  • the blending amount thereof in the ophthalmic composition is preferably 0.001 to 1.0%, more preferably 0.001 to 0.5%, and further preferably 0.001 to 0.25%. ..
  • surfactant examples include the following nonionic surfactants.
  • Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition-polymerizing ethylene oxide to castor oil, and several types of ethylene oxide having different average addition mole numbers are known.
  • the average number of moles of ethylene oxide added to the polyoxyethylene castor oil is not particularly limited, but may be 3 to 60 moles.
  • polyoxyethylene castor oil 3 numbererical value is the average number of moles of ethylene oxide added, the same applies hereinafter
  • polyoxyethylene castor oil 10 polyoxyethylene castor oil 20
  • polyoxyethylene castor oil 35 polyoxyethylene castor.
  • Oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, etc. are mentioned.
  • polyethylene glycol fatty acid ester examples include polyethylene glycol 25 stearate, polyethylene glycol 40 stearate, and the like, among which polyethylene glycol 40 stearate is preferable.
  • the blending amount thereof in the ophthalmic composition is preferably 0.01 to 2.0%, more preferably 0.05 to 1.5%, and 0.1 to 1.2% is more preferable.
  • preservatives other than the component (C) thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconic acid and the like can be mentioned as preservatives having a hydrophobic portion such as an alkyl chain or a benzene ring.
  • the preservative When the preservative is added, its amount is preferably 0.0001 to 0.5% in the ophthalmic composition. However, when blended, it is preferably 0.1% or less, more preferably 0.01% or less in the ophthalmic composition.
  • sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. It should be noted that these may be any of d body, l body and dl body.
  • the amount of the saccharide added is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, even more preferably 0.001 to 0.1% in the ophthalmic 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 thereof is preferably 0.001 to 5.0%, more preferably 0.001 to 2%, and further preferably 0.001 to 1% in the ophthalmic composition.
  • an inorganic acid or an inorganic alkaline agent can be mentioned.
  • the inorganic acid may be (dilute) hydrochloric acid.
  • the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
  • the pH of the ophthalmic composition is preferably 3.5 to 8.0, more preferably 5.5 to 8.0. The pH is measured at 25° C. using a pH meter (HM-25R, Toa DKK Co., Ltd.).
  • the tonicity agent examples include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, 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 improving various symptoms caused by destabilization of the tear oil layer, it is preferable to add sodium chloride or potassium chloride to make it isotonic.
  • the osmotic pressure ratio of the ophthalmic composition to physiological saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and most preferably 0.83 to 1.20. The osmotic pressure is measured at 25° C. using an automatic osmometer (A2O, Advanced Instruments Co.).
  • the stabilizer other than the component (D) examples include cyclodextrin, sulfite, dibutylhydroxytoluene and the like.
  • the blending amount thereof in the ophthalmic composition is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, and further preferably 0.001 to 0.1%.
  • polyhydric alcohols examples include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like.
  • the blending amount thereof in the ophthalmic composition is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, and further preferably 0.001 to 0.1%.
  • the thickener examples include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer and the like.
  • the amount added is preferably 0.001 to 5.0%, more preferably 0.001 to 1%, even more preferably 0.001 to 0.1% in the ophthalmic composition.
  • Examples of the drug (pharmaceutically active ingredient) other than the components (A) and (D) include decongestant components (eg, epinephrine, methylnorepinephrine, norepinephrine, epinephrine hydrochloride, ephedrine, methylephedrine, pseudoephedrine, ephedrine hydrochloride).
  • decongestant components eg, epinephrine, methylnorepinephrine, norepinephrine, epinephrine hydrochloride, ephedrine, methylephedrine, pseudoephedrine, ephedrine hydrochloride.
  • anti-inflammatory/astringent for example, neostigmine methyl sulfate, allantoin, berberine chloride hydrate,
  • antihistamines for example, diphenhydramine hydrochloride, etc.
  • water-soluble vitamins for example, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.
  • fat-soluble vitamins retinol acetate, Examples thereof include retinol palmitate, tocopherol acetate and the like
  • amino acids for example, aminoethyl sulfonic acid and the like
  • the compounding amount of the drug can be selected as an effective appropriate amount of each drug, but is preferably 0.001 to 5%, more preferably 0.001 to 1% in the ophthalmic composition. , 0.001 to 0.1% is more preferable.
  • the method for producing the ophthalmic composition of the present invention is not particularly limited. For example, it can be obtained by dissolving an aqueous component in purified water, adjusting the pH, and then adjusting the total volume with the purified water.
  • the mixing method may be a general method, and may be appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, or the like, but the number of revolutions is not particularly limited, and it is preferable to set it so that it does not foam violently.
  • the mixing temperature of each liquid is not particularly limited, but specifically, is appropriately selected from the range of 20 to 95°C.
  • the ophthalmic composition of the present invention is preferably a liquid from the viewpoint of facilitating adaptation to the eye, and the viscosity at 20° C. is preferably 20 mPa ⁇ s or less from the viewpoint of facilitating mixing with tear fluid, and 10 mPa ⁇ s. The following is more preferable, 5 mPa ⁇ s or less is further preferable, and 2 mPa ⁇ s or less is particularly preferable.
  • the viscosity is measured using a cone-plate type viscometer (DV2T, Eiko Seiki Co., Ltd.). The lower limit is not particularly limited, but may be 1 mPa ⁇ s.
  • the ophthalmic composition of the present invention can be preferably used as eye drops, eye drops for contact lenses, eye washes, etc., but from the viewpoint of the preventive or therapeutic effect on dry eye, eye drops, eye drops for contact lenses (contact lens wear) It can be suitably used as an eye drop such as a human eye drop).
  • the contact lens is not particularly limited, such as a hard contact lens and a soft contact lens, specifically, a silicon hydrogel soft contact lens, an O 2 hard contact lens, and a color contact lens. It has been reported that contact lenses affect morphological changes of meibomian glands and contribute to dry eye, and are particularly suitable as eye drops for contact lenses.
  • the ophthalmic composition of the present invention can suppress mydriasis due to frequent use (6 or more eye drops (or eye washes) per hour) in a short time, but the use method is not limited.
  • 1 to 6 drops preferably 1 to 3 drops
  • 10 to 100 ⁇ L each time, and 1 to 6 times per day preferably once.
  • When used as an eye wash it is preferable to wash 3 to 6 mL once and wash 3 to 6 times per day.
  • the container is further sealed with a package, and an inert gas such as nitrogen is sealed in the space formed between the container and the package.
  • an inert gas such as nitrogen is sealed in the space formed between the container and the package.
  • the container may be sealed with a deoxidizer.
  • the ophthalmic composition of the present invention has a tear film stabilizing effect and is suitable as a tear film stabilizing agent.
  • the tear layer stabilizing effect can be measured by, for example, NI (Non-invasive) BUT (non-invasive tear layer destruction time). Specifically, it is the method of the embodiment described later.
  • Dry eye is defined as "a disease or symptom in which the stability of the tear film is reduced due to various factors, which may cause eye discomfort or abnormal visual function and may be accompanied by damage to the ocular surface.”
  • the diagnostic criteria are two items with subjective symptoms and fluorescein BUT (breakdown time of tear film) of 5 seconds or less. Fluorescein is generally used for the measurement of BUT, but it is necessary to administer a staining reagent into the eye, and the tear volume may change slightly, and the staining reagent may adhere to the face or clothes. There is also a widely known method for non-invasively examining the time until the tear film is destroyed (non-invasive breakup time: NIBUT). NIBUT is generally considered to be longer than fluorescein BUT.
  • phenylephrine or its salt shows a remarkable effect on BUT shortened dry eye.
  • BUT shortened dry eye tear secretion and keratoconjunctival epithelium are almost normal, but shortened BUT is detected, which causes eye fatigue, dry eyes, discomfort when wearing contact lenses and Dry eye that causes symptoms such as blurred vision, foreign body sensation, eye pain, dazzling eyes, heavy eyes, eye discomfort, eye oil and tearing.
  • the tear film stabilizing agent of the present invention may or may not be accompanied by an increase in tear production, and may exhibit a prominent dry eye preventive or therapeutic effect even without an increase in tear production. it can.
  • the diseases or symptoms caused by destabilization of the tear film include the following symptoms, and the tear film stabilizer of the present invention is suitable as a preventive or therapeutic agent for the following diseases or symptoms.
  • Eye fatigue dry eyes, tired eyes, discomfort when wearing contact lenses, blurred vision, lid wiper epitheliopathy, keratoconjunctival epithelial disorder, corneal epithelial detachment, cornea due to dry eye
  • the diseases or symptoms caused by the destabilization of the tear film include the following symptoms, and the tear film stabilizer of the present invention is preferably used as a preventive or therapeutic agent for the following symptoms.
  • the tear film stabilizer of the present invention is preferably used as a preventive or therapeutic agent for the following symptoms. be able to. Eye fatigue, dry eyes, discomfort when wearing contact lenses and blurring of eyes, foreign body sensation, eye pain, dazzling eyes, heavy eyes, discomfort in eyes, eye oil and tearing.
  • Phenylephrine or a salt thereof has a meibum secretagogue effect, and thus the ophthalmic composition of the present invention has a meibum secretagogue effect and is suitable as a meibum secretagogue.
  • Meibum is a component secreted from the meibomian gland, and the tear oil layer increases by promoting the secretion of meibum. The effect of promoting mybam secretion is measured by measuring the thickness of the tear oil layer.
  • the meibomian glands in the eyelids secrete lipids and are important as a source of tear oil layer.
  • This tear fluid layer is important because the tear fluid is stable as a film, such as the reduction of the surface tension of the tear fluid and the prevention of evaporation of the tear fluid.
  • meibomian gland dysfunction As a disease or symptom caused by the inhibition of meibom secretion from the meibomian gland, in addition to the above dry eye, meibomian gland dysfunction, stye (hordeolum, chalazion) and the like can be mentioned.
  • Meibomian gland dysfunction is defined as tear and eye surface abnormalities caused by impaired secretion of the meibomian glands. It is diagnosed by subjective symptoms, abnormal findings around the meibomian gland opening, and meibomian gland obstruction. MGD patients have a variety of subjective symptoms, including a foreign body sensation, a feeling of dryness, an eye fatigue, and a burning sensation.
  • Ergot and chalazion are diseases or symptoms that occur in the meibomian glands.
  • Stye is an acute purulent inflammation caused by a bacterial infection.
  • Treatment includes drug therapy and surgical therapy.
  • an antibacterial agent is administered when self-destruction or drainage of pus is observed.
  • puncture/incision is performed using an injection needle or the like to promote drainage. That is, the treatment requires drainage from the meibomian glands, but until now, the only option was to wait for spontaneous drainage or forceful drainage.
  • Chalazion is said to be a foreign body reaction to lipids and is not an infectious disease. Treatment is basically surgery. In other words, hordeolum and chalazion have not been available by any method other than surgery, although they require pus and lipid excretion from the meibomian glands.
  • the meibum secretagogue of the present invention can be preferably used as a preventive or therapeutic agent for the same symptoms as the tear film stabilizer. Furthermore, the agent for promoting secretion of mybam of the present invention can improve or prevent secretion of mebam, thereby preventing or treating MGD, dry eye, hordeolum and chalazion.
  • Examples and comparative examples After mixing the component (B) with propylene glycol and dissolving it in purified water, the components (A) to (D) and other water-soluble components are dissolved in purified water, and after adjusting the pH, the total volume is 100 mL with purified water. And The pH of the obtained ophthalmic composition at 25°C is shown in the table. The viscosity of the composition at 25° C. was in the range of 1 to 20 mPa ⁇ s. The following evaluations were performed on the obtained ophthalmic compositions. The results are also shown in the table.
  • ⁇ Test 1 Mydriasis suppressing effect> Three panelists instilled the sample 6 times in 1 hour (1 drop (50 ⁇ L) each time). The degree of mydriasis before and after the instillation was evaluated according to the following criteria. In order to evaluate the degree of mydriasis, a pre-light emission mode was set using a digital camera, and light adaptation (constriction of eyes) was induced immediately before the shooting, and the shooting was performed. The lower the mydriasis rate, the higher the mydriatic suppression effect.
  • D1 pupil diameter (mm) before instillation (initial state)
  • D2 pupil diameter after instillation (mm)
  • ⁇ and " ⁇ " are passed.
  • ⁇ Average value of mydriatic rate is less than 10%
  • ⁇ Average value of mydriatic rate is 10% or more and less than 20%
  • ⁇ Average value of mydriatic rate is 20% or more and less than 30%
  • ⁇ Average value of mydriatic rate Is over 30%
  • ⁇ Test 2 Evaluation of glare> Three panelists instilled each sample 6 times in 1 hour (1 drop (50 ⁇ L) each time). After instillation, the degree of glare was evaluated according to the following criteria. The lower the score, the less glare. " ⁇ " and " ⁇ " are passed.
  • NI Non-invasive
  • BUT Non-invasive tear film destruction time
  • DR-1 manufactured by Kowa
  • the tear interference pattern is observed using DR-1, and the time (seconds) until the tear layer is destroyed (the uniform gray or white interference pattern disappears) after opening the eyelid (NIBUT; non-invasive) Tear layer destruction time) was measured and the average value was calculated.
  • NIBUT was measured when the Examples and Comparative Examples were instilled, and the average value was obtained. Further, the tear layer stability effect was evaluated by the following criteria by calculating the difference between the average value of the examples and the average value of the comparative examples. It should be noted that when the phenylephrine hydrochloride concentration is 0.1%, it is a difference from Comparative Example 2, and when it is 1%, it is a difference from Comparative Example 3.
  • NIBUT non-invasive tear film destruction time is described. " ⁇ ”, " ⁇ ", “ ⁇ ” are passed.
  • ⁇ Difference in average value is 1.5 seconds or more
  • ⁇ Difference in average value is 1 second or more and less than 1.5 seconds
  • ⁇ Difference in average value is less than 1 second ⁇ : No tear film stability effect

Abstract

Cette composition pour utilisation ophtalmique contient (A) un ou plusieurs éléments sélectionnés parmi la phényléphrine et ses sels et (B) un ou plusieurs terpénoïdes choisis parmi les terpénoïdes, et, en conséquence, présente un effet de stabilisation de film lacrymal amélioré, et est capable de supprimer la mydriase tout en maintenant l'effet de stabilisation de film lacrymal de la phényléphrine, même lorsqu'il est fréquemment administré à des intervalles courts.
PCT/JP2019/050751 2018-12-26 2019-12-25 Composition à usage ophtalmique WO2020138135A1 (fr)

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