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WO2024135344A1 - Ophthalmic product - Google Patents

Ophthalmic product Download PDF

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Publication number
WO2024135344A1
WO2024135344A1 PCT/JP2023/043479 JP2023043479W WO2024135344A1 WO 2024135344 A1 WO2024135344 A1 WO 2024135344A1 JP 2023043479 W JP2023043479 W JP 2023043479W WO 2024135344 A1 WO2024135344 A1 WO 2024135344A1
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WO
WIPO (PCT)
Prior art keywords
ophthalmic
ophthalmic composition
sodium
acid
composition
Prior art date
Application number
PCT/JP2023/043479
Other languages
French (fr)
Japanese (ja)
Inventor
恭平 椛嶋
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
Publication of WO2024135344A1 publication Critical patent/WO2024135344A1/en

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • G—PHYSICS
    • G02—OPTICS
    • G02C—SPECTACLES; SUNGLASSES OR GOGGLES INSOFAR AS THEY HAVE THE SAME FEATURES AS SPECTACLES; CONTACT LENSES
    • G02C13/00—Assembling; Repairing; Cleaning
    • G—PHYSICS
    • G02—OPTICS
    • G02C—SPECTACLES; SUNGLASSES OR GOGGLES INSOFAR AS THEY HAVE THE SAME FEATURES AS SPECTACLES; CONTACT LENSES
    • G02C7/00—Optical parts
    • G02C7/02—Lenses; Lens systems ; Methods of designing lenses
    • G02C7/04—Contact lenses for the eyes

Definitions

  • the present invention relates to an ophthalmic product housed in a container that has been sterilized using electron beam or gamma radiation.
  • Ophthalmic compositions are required to remain sterile until they are opened.
  • Methods for sterilizing ophthalmic compositions include incorporating a preservative into the ophthalmic composition, but the containers used must also be sterilized, and a method for doing so has been proposed.
  • hyaluronic acid or a salt thereof is able to retain moisture on the surface of the eye for a long time due to its high water retention, and also has the effect of repairing damage to the surface of the eye.
  • Chlorhexidine is effective as a preservative. The inventors have found that when an ophthalmic composition containing these two components is stored in a container that has been sterilized with electron beams or gamma rays, insoluble matter is generated after freezing and thawing (freezing and then returning to room temperature), and the stability of the appearance is reduced. The objective of the present invention is to solve this problem.
  • the present invention provides an ophthalmic product comprising: 1. (A) hyaluronic acid or a salt thereof, An ophthalmic composition comprising (B) chlorhexidine and (C) epsilon aminocaproic acid or a salt thereof, An ophthalmic product housed in a container that has been sterilized by electron beam or gamma radiation. 2. The ophthalmic product according to 1, wherein the content mass ratio represented by (C)/(B) is 100 to 5,000. 3. The ophthalmic product according to 1 or 2, wherein the content of component (A) in the ophthalmic composition is 0.01 to 0.1 w/v %. 4.
  • the present invention provides an ophthalmic product that suppresses the generation of insoluble matter after freezing and thawing and has excellent appearance stability, and that contains an ophthalmic composition containing (A) hyaluronic acid or a salt thereof and (B) chlorhexidine, and that is housed in a container that has been sterilized with electron beams or gamma rays.
  • the hyaluronic acid or its salt of the present invention is not particularly limited, and any hyaluronic acid that is usually used in mucous membrane application preparations in the ophthalmic field can be used.
  • hyaluronic acids include hyaluronic acid, its derivatives, and their pharmacologic and physiologically acceptable salts. Those obtained by extraction from cockscomb, fermentation by microorganisms, etc. can be used, and the origin and manufacturing method are not particularly limited.
  • Hyaluronic acid or its salt can be used alone or in appropriate combination of two or more.
  • component (A) examples include hyaluronic acid, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, etc. Among them, sodium hyaluronate is preferred.
  • component (A) commercially available products can be used, such as purified sodium hyaluronate (manufactured by Seikagaku Corporation, Kewpie Corporation, Kikkoman Biochemifa Corporation, Iwaki Pharmaceutical Co., Ltd., and Blue Meiji Biotechnology Co., Ltd.).
  • the average molecular weight of component (A) is preferably 500,000 to 5,000,000, more preferably 500,000 to 4,000,000, even more preferably 500,000 to 2,500,000, particularly preferably 500,000 to 2,000,000, and most preferably 500,000 to 1,490,000.
  • the average molecular weight of component (A) is measured by the method for measuring average molecular weight described in the "Purified Sodium Hyaluronate" section of the Japanese Pharmacopoeia, 18th Edition, Pharmaceutical Articles. Note that multiple types of hyaluronic acid and/or salts with different average molecular weights can be used.
  • component (A) such as “Sodium Hyaluronate “Seikagaku”” (average molecular weight 500,000 to 1,200,000) and “Cosmetic Sodium Hyaluronate (HC)” (average molecular weight 530,000 to 1,330,000) manufactured by Seikagaku Corporation, “Hyaluronic Acid FCH-60” (average molecular weight 500,000 to 700,000), “Hyaluronic Acid FCH-80” (average molecular weight 600,000 to 1,000,000), “Hyaluronic Acid FCH-120” (average molecular weight 1,000,000 to 1,400,000), and “Hyaluronic Acid FCH-150” (average molecular weight 1,400,000 to 1,800,000) manufactured by Kikkoman Biochemifa Corporation.
  • HC Cosmetic Sodium Hyaluronate
  • “Hyaluronic acid FCH-151C” (average molecular weight 1.4 million to 1.8 million), “Hyaluronic acid FCH-200” (average molecular weight 1.8 million to 2.2 million), “Hyaluronic acid FCH-201C” (average molecular weight 1.8 million to 2.2 million), “Hyaluronic acid FCH-80LE” (average molecular weight 600,000 to 1.2 million), “Hyaluronic acid GS-100” (average molecular weight 500,000 to 1.49 million), “Hyaluronic acid HA-QA” (average molecular weight 600,000 to 1.2 million), “Hyaluronic acid HA-AM” (average molecular weight 600,000 to 1.2 million), “Hyaluronic acid HA-Q” (average molecular weight 530,000 to 1.13 million), “Hyaluronic Acid M5070” (average molecular weight 500,000 to 700,000), “Hyaluronic Acid HA-LQ” (average molecular weight 850,000
  • the content of component (A) in the ophthalmic composition is preferably 0.001 w/v% (mass/volume %, g/100 mL) or more, more preferably 0.005 w/v% or more, and even more preferably 0.001-0.3 w/v%, 0.005-0.2 w/v%, 0.01-0.15 w/v%, 0.01-0.1 w/v%, and 0.05-0.1 w/v% in that order. If the content of component (A) is too high, the viscosity of the ophthalmic composition may be too high, which may cause blurring, etc. By keeping the content at 0.1 w/v% or less, the occurrence of insoluble matter after freezing and thawing is further suppressed and the appearance stability is further improved.
  • the chlorhexidine is not particularly limited, and any chlorhexidine generally used in preparations for mucosal application in the ophthalmic field can be used, and one type can be used alone or two or more types can be used in combination.
  • Chlorhexidine may be in the form of a salt, and examples of the salt include chlorhexidine gluconate, chlorhexidine acetate, and chlorhexidine hydrochloride. Among these, chlorhexidine gluconate is preferred.
  • the content of component (B) in the ophthalmic composition is preferably 0.0001 to 0.01 w/v%, more preferably 0.0002 to 0.005 w/v%, even more preferably 0.0002 to 0.002 w/v%, and particularly preferably 0.0002 to 0.0005 w/v%.
  • the content of component (B) is preferably 0.0001 to 0.01 w/v%, more preferably 0.0002 to 0.005 w/v%, even more preferably 0.0002 to 0.002 w/v%, and particularly preferably 0.0002 to 0.0005 w/v%.
  • Component (C) In the present invention, by blending (C) epsilon aminocaproic acid or a salt thereof in an ophthalmic composition, the ophthalmic composition containing (A) hyaluronic acid or a salt thereof and (B) chlorhexidine suppresses the generation of insoluble matter after freezing and thawing, which is a problem specific to ophthalmic products contained in a container sterilized by electron beam or gamma ray, and improves the appearance stability.
  • Epsilon-aminocaproic acid is a known compound as a neutral amino acid also called 6-aminohexanoic acid.
  • the salt of epsilon aminocaproic acid used in the present invention is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable, and can be used alone or in combination of two or more.
  • Specific examples of salts of epsilon aminocaproic acid include organic acid salts [e.g., monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polycarboxylates (fumarates, maleates, succinates, malons, etc.), oxycarboxylates (lactates, tartrates, citrates, etc.), organic sulfonates (methanesulfonates, toluenesulfonates, tosylates, etc.)], inorganic acid salts (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates
  • epsilon aminocaproic acid is preferred.
  • component (C) a commercially available product can be used, for example, " ⁇ -amino-n-caproic acid EKD" manufactured by Sekisui Medical Co., Ltd.
  • the content of component (C) in the ophthalmic composition is preferably 0.005 to 3 w/v%, more preferably 0.015 to 2 w/v%, even more preferably 0.01 to 2 w/v%, even more preferably 0.1 to 1 w/v%, even more preferably 0.2 to 0.8 w/v%, particularly preferably 0.2 to 0.5 w/v%, and most preferably 0.3 to 0.5 w/v%.
  • Component (D) By further blending (D) propylene glycol in the ophthalmic composition of the present invention, the generation of insoluble matters after freezing and thawing can be further suppressed, and the appearance stability can be further improved.
  • the content of component (D) in the ophthalmic composition is preferably 0.01 to 1 w/v%, more preferably 0.03 to 0.5 w/v%, and even more preferably 0.05 to 0.4 w/v%.
  • Component (E) By further blending sodium chloride (E) in the ophthalmic composition of the present invention, the generation of insoluble matters after freezing and thawing can be further suppressed, and the appearance stability can be further improved.
  • the content of component (E) in the ophthalmic composition is preferably 1.0 w/v% or less, more preferably 0.9 w/v% or less, and even more preferably 0.7 w/v% or less. More specifically, it is preferably 0.1 to 1.0 w/v%, more preferably 0.2 to 0.9 w/v%, and even more preferably 0.3 to 0.7 w/v%.
  • the preferred range of the mass ratio of each component in the ophthalmic composition is shown below. Note that this ratio is a w/v % ratio, but is the same value as the mass ratio.
  • (C)/(B) is preferably 100 or more, and more preferably 200 or more. More specifically, (C)/(B) is preferably 100 to 5,000, more preferably 150 to 3,000, even more preferably 200 to 2,000, particularly preferably 350 to 2,000, and most preferably 400 to 2,000.
  • (D)/(C) is preferably 0.01 to 3.0, more preferably 0.1 to 2.0, even more preferably 0.2 to 1.2, and particularly preferably 0.3 to 1.0.
  • (A)/(E) is preferably 0.05 to 0.70, more preferably 0.10 to 0.50, and even more preferably 0.13 to 0.30.
  • ((C)+(D))/(B) is preferably 100 to 5,000, more preferably 150 to 4,000, and even more preferably 200 to 3,000.
  • the ophthalmic composition of the present invention may contain other components in appropriate amounts within the range that does not impair the effects of the present invention.
  • other components include drugs, surfactants, buffers, local anesthetics or soothing agents, pH adjusters, stabilizers, sugars, polyhydric alcohols, thickeners, cooling agents, other inorganic compounds, oily components, etc. These components may be used alone or in appropriate combinations of two or more. The contents of the components shown below are the preferred ranges when they are used, and are the amounts in the composition.
  • Drugs include, for example, congestion relief ingredients (vasoconstrictors) (e.g., epinephrine, epinephrine hydrochloride, methylnorepinephrine, norepinephrine, ephedrine, methylephedrine, pseudoephedrine, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, oxymetazoline, methoxamine, phenylpropanolamine, etilefrine, midodrine, tramazoline, synephrine ...
  • congestion relief ingredients e.g., epinephrine, epinephrine hydrochloride, methylnorepinephrine, norepinephrine, ephedrine, methylephedrine, pseudoe
  • the amount can be selected based on the effective amount of each drug, but it is preferably 0.001 to 5.0 w/v% in the ophthalmic composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
  • Surfactants include nonionic surfactants (e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene polyoxypropylene glycol, polyethylene glycol monostearate, etc.), amphoteric surfactants (e.g., glycine-type amphoteric surfactants such as alkyl diaminoethyl glycine and alkyl polyaminoethyl glycine, betaine-type amphoteric surfactants such as lauryl dimethyl amino acetate betaine and imidazolium betaine), and cationic surfactants (e.g., benzalkonium chloride, benzethonium chloride, etc.).
  • nonionic surfactants e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene polyoxypropylene glycol, polyethylene glycol monoste
  • the amount in the ophthalmic composition is preferably 0.0001 to 5 w/v%, more preferably 0.0003 to 3 w/v%, and even more preferably 0.003 to 1 w/v%.
  • buffering agents include boric acid or its salts (e.g., borax), trometamol, citric acid or its salts (e.g., sodium citrate), phosphoric acid or its salts (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate), tartaric acid or its salts (e.g., sodium tartrate), gluconic acid or its salts (e.g., sodium gluconate), acetic acid or its salts (e.g., sodium acetate), glacial acetic acid, carbonic acid or its salts (e.g., sodium carbonate, sodium bicarbonate), various amino acids (potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), etc.
  • boric acid or its salts e.g., borax
  • phosphoric acid or its salts e.g., sodium hydrogen phosphate, sodium
  • the amount is preferably 0.001 to 5.0 w/v % in the ophthalmic composition, more preferably 0.001 to 2 w/v %, and even more preferably 0.001 to 1 w/v %.
  • isotonicity agents examples include potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, etc.
  • the amount thereof in the ophthalmic composition is preferably 0.00001 to 3 w/v%, more preferably 0.0001 to 2 w/v%, and even more preferably 0.005 to 1.5 w/v%.
  • Local anesthetics or soothing agents include, for example, chlorobutanol, oxybuprocaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride, etc.
  • the amount thereof in the ophthalmic composition is preferably 0.001 to 1.0 w/v %, more preferably 0.01 to 0.5 w/v %.
  • pH adjusters include inorganic acids and inorganic alkali agents.
  • an example of an inorganic acid is (dilute) hydrochloric acid.
  • examples of inorganic alkali agents include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.
  • Examples of monoethanolamine and diethanolamine are also included.
  • the pH of the composition can be set to 3.5 to 13.0, and is preferably 3.5 to 8.0, and more preferably 5.5 to 8.0, from the viewpoint of further improving the various symptoms caused by destabilization of the tear lipid layer.
  • the pH is measured at 25°C using a pH meter (HM-25R, manufactured by DKK-TOA Corporation).
  • stabilizers examples include sodium edetate, sodium edetate hydrate, cyclodextrin, monoethanolamine, etc.
  • stabilizers (antioxidants) include fat-soluble antioxidants such as dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), and vitamin E (e.g., tocopherol acetate, tocopherol nicotinate, tocopherol succinate, etc.).
  • water-soluble stabilizers examples include sulfites such as sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogensulfite, and potassium hydrogensulfite, ascorbic acid, sodium ascorbate, etc.
  • a stabilizer When a stabilizer is to be incorporated into an ophthalmic composition for soft contact lenses, it is preferable to use one that has low lens adsorption and accumulation properties, and examples of such stabilizers include sodium edetate, sodium edetate hydrate, cyclodextrin, vitamin E, vitamin A, sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogensulfite, and potassium hydrogensulfite, ascorbic acid, sodium ascorbate, etc.
  • the amount is preferably 0.001 to 5.0 w/v% in the ophthalmic composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
  • sugars examples include glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc. These may be in the d-, l- or dl-form.
  • Sugars have moisturizing properties and are effective in increasing moisture when applied to the eye, and can also be used as isotonicity agents. When sugars are added, their amount in the ophthalmic composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
  • polyhydric alcohols examples include glycerin, butylene glycol, polyethylene glycol, xylitol, mannitol, and sorbitol.
  • Polyhydric alcohols have moisturizing properties and can increase the moisture content of the eye when applied, and can also be used as isotonicity agents.
  • Glycerin can also be used as a solubilizer for cooling agents.
  • their amount in the ophthalmic composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
  • Thickening agents include water-soluble polymeric compounds, such as polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, dextran, alginic acid, sodium alginate, and xanthan gum.
  • thickening agents When thickening agents are added, they can be added to an extent that does not impair the feeling of use, such as stickiness or blurring.
  • the amount is preferably 0.001 to 5.0 w/v% in the ophthalmic composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
  • the refreshing agent may be, for example, menthol, camphor, borneol, geraniol, cineole, linalool, anethole, eugenol, limonene, ryunou, etc. Any of the d-, l- or dl-isomers may be used.
  • essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, eucalyptus oil, rose oil, fennel oil, bergamot oil, and cinnamon oil may be used.
  • the refreshing agent can enhance the feeling of the effect of sustained moisture.
  • the amount thereof in the ophthalmic composition is preferably 0.0001 to 1 w/v%, more preferably 0.0005 to 0.2 w/v%, and even more preferably 0.001 to 0.1 w/v%.
  • inorganic compounds include sodium thiosulfate, titanium oxide, zinc chloride, etc. When these are added, the amount is preferably 0.001 to 5 w/v% in the ophthalmic composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
  • the ophthalmic 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 content of water in the composition is preferably 90.0 to 99.5 w/v %, and more preferably 95.0 to 99.0 w/v %.
  • the transmittance of the ophthalmic composition at 600 nm is preferably 98.0 to 100.0%, and more preferably 99.0 to 100.0%.
  • the transmittance of the ophthalmic composition at 600 nm after freezing and thawing is preferably 98.0% or more, more preferably 98.5% or more, and even more preferably 99.0% or more.
  • the formulation of the composition of the present invention is not particularly limited, and can be suitably used, for example, as eye drops (including eye drops that can be applied while wearing contact lenses), eyewash, contact lens application solution, contact lens removal solution, etc. It can be particularly suitably used as eye drops and contact lens application solution, with eye drops being particularly preferred. Among these, it is suitable as an ophthalmic composition for contact lenses used by contact lens wearers, such as eye drops that can be applied while wearing contact lenses, contact lens application solution, contact lens removal solution, etc.
  • Contact lenses include, but are not limited to, hard contact lenses (including O2 hard contact lenses), soft contact lenses (including both ionic and non-ionic), silicone hydrogel contact lenses, colored contact lenses, etc. When no preservative is added, the composition is particularly suitable for soft contact lenses and silicone hydrogel contact lenses.
  • the method for producing the composition of the present invention is not particularly limited, but for example, the composition can be obtained by pre-dissolving (A), then mixing the solution with a solution containing an aqueous component such as component (B), adjusting the pH, and then adjusting the total volume with water.
  • the method for mixing each liquid may be a general method, and is appropriately carried out using a pulsator, propeller blade, paddle blade, turbine blade, etc., but the rotation speed is not particularly limited, and it is preferable to set it to a level that does not cause vigorous foaming.
  • the mixing temperature of each liquid is not particularly limited, but it is preferable that it is not high from the viewpoint of the stability of component (A), and is appropriately selected from the range of 20 to 60°C.
  • the present invention is an ophthalmic product comprising the above-mentioned ophthalmic composition contained in a container that has been sterilized with electron beams or gamma rays.
  • the container is preferably a plastic container, and may be made of materials such as polyethylene (PE), polyethylene terephthalate (PET), polypropylene (PP), polybutylene, polycarbonate, polyarylate, vinyl chloride, or a composite of these materials. Among these, polyethylene, polyethylene terephthalate, and polypropylene are preferred.
  • the amount of the ophthalmic composition in the product can be appropriately selected depending on the product and its method of use. For example, in the case of eye drops, 2 to 20 mL is preferred, and 5 to 20 mL is more preferred.
  • the container for the ophthalmic composition is not particularly limited, and may be a multi-dose (multi-unit) container or a single-use unit-dose container. A multi-dose (multi-unit) container is preferred.
  • the method of sterilization using electron beams or gamma rays is not particularly limited, and can be carried out according to conventionally known sterilization conditions.
  • the ophthalmic composition may be contained in a container that has been sterilized with electron beams or gamma rays, and an inert gas such as nitrogen may be sealed in the space formed between the container and the packaging body, or the ophthalmic composition may be filled into the container, and then sealed in the packaging body together with an oxygen scavenger.
  • the inner stopper and cap may be made of a material used for known containers of ophthalmic products.
  • the material of the inner stopper is preferably polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8.
  • the material of the cap is preferably polyethylene or polypropylene.
  • the method of the present invention is a method for stabilizing the appearance of the ophthalmic composition, which comprises (A) hyaluronic acid or its salt and (B) chlorhexidine, and is contained in a container that is sterilized by electron beam or gamma ray, and (C) epsilon aminocaproic acid or its salt is added to the ophthalmic composition.
  • the preferred components and amounts are the same as above.
  • this appearance stabilization method refers to suppressing the deterioration of the appearance of the ophthalmic product after freezing and thawing (freezing and then returning to room temperature).Specifically, the appearance stability after freezing and thawing is evaluated by the method described in Examples.
  • the 600 nm transmittance of the ophthalmic composition product of the present invention is preferably 99.0 to 100.0%, and the transmittance after three repeated freezing and thawing operations is preferably 97.5 to 100.0%, more preferably 98.0 to 100.0%.
  • the present invention will be described in detail below with examples and comparative examples, but the present invention is not limited to the following examples.
  • the present invention will be described in detail below with examples and comparative examples, but the present invention is not limited to the following examples.
  • the "%" of the composition is "w/v % (g/100 mL)" and the ratio is w/v % ratio, which is the same value as the mass ratio.
  • Examples and Comparative Examples In order to obtain the composition shown in the table, the components other than purified water and the pH adjuster were dissolved in 90 mL of purified water and mixed by stirring at room temperature (25°C) for 18 hours. Next, the pH of the ophthalmic composition was adjusted with a pH adjuster as necessary so that the pH of the ophthalmic composition at 25°C would be 6.5, and the remaining purified water was added to make the total volume 100 mL to obtain an ophthalmic composition. A pH meter (manufactured by DKK-TOA Corporation, product name "HM-25R”) was used to measure the pH. The obtained composition was evaluated as follows. The results are also shown in the table. The pH of the composition was in the range of 6.0 to 7.0.
  • Propylene glycol Japanese Pharmacopoeia Propylene Glycol, manufactured by ADEKA Corporation
  • Sodium chloride Japanese Pharmacopoeia Sodium Chloride SG, manufactured by Tomita Pharmaceutical Co., Ltd.
  • Sodium edetate Sodium edetate hydrate "For manufacturing only", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.

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Abstract

This ophthalmic product is a composition for ophthalmic use held in a container that has been sterilized by electron beams or gamma rays. The composition contains (A) hyaluronic acid or a salt thereof, (B) chlorhexidine, and (C) an epsilon-aminocaproic acid or a salt thereof.

Description

眼科用製品Ophthalmic Products
　本発明は、電子線又はガンマ線にて滅菌処理された容器に収容された眼科用製品に関するものである。 The present invention relates to an ophthalmic product housed in a container that has been sterilized using electron beam or gamma radiation.
　眼科用組成物は、開封時までは無菌状態を保つことが求められている。眼科用組成物の滅菌方法としては、眼科用組成物への防腐剤の配合等が挙げられるが、その容器も滅菌処理されたものを用いる必要があり、その方法が提案されている。 Ophthalmic compositions are required to remain sterile until they are opened. Methods for sterilizing ophthalmic compositions include incorporating a preservative into the ophthalmic composition, but the containers used must also be sterilized, and a method for doing so has been proposed.
特開２０１９－６７５３号公報JP 2019-6753 A
　眼科用組成物の成分の中で、（Ａ）ヒアルロン酸又はその塩は、その保水性の高さから水分を長く目の表面に保つことができ、また、それ自体に目の表面の傷を修復する効果を有する。（Ｂ）クロルヘキシジンは、防腐剤として効果を有する。本発明者は、この２成分を含有する眼科用組成物を、電子線又はガンマ線にて滅菌処理された容器に収容すると、凍結融解（凍結させた後再び室温に戻す）後に不溶物が発生し、外観安定性が低下することを知見した。そして、これを解決することを課題とする。 Among the components of ophthalmic compositions, (A) hyaluronic acid or a salt thereof is able to retain moisture on the surface of the eye for a long time due to its high water retention, and also has the effect of repairing damage to the surface of the eye. (B) Chlorhexidine is effective as a preservative. The inventors have found that when an ophthalmic composition containing these two components is stored in a container that has been sterilized with electron beams or gamma rays, insoluble matter is generated after freezing and thawing (freezing and then returning to room temperature), and the stability of the appearance is reduced. The objective of the present invention is to solve this problem.
　本発明者は、眼科用組成物に、（Ｃ）イプシロンアミノカプロン酸を配合することで、上記課題を解決できることを知見し、本発明をなすに至ったものである。 The inventors discovered that the above problems could be solved by adding (C) epsilon aminocaproic acid to the ophthalmic composition, and thus came up with the present invention.
　従って、本発明は、下記眼科用製品を提供する。
１．（Ａ）ヒアルロン酸又はその塩、
（Ｂ）クロルヘキシジン、及び
（Ｃ）イプシロンアミノカプロン酸又はその塩
を含有する眼科用組成物が、
　電子線又はガンマ線にて滅菌処理された容器に収容された眼科用製品。
２．（Ｃ）／（Ｂ）で表される含有質量比が１００～５，０００である、１記載の眼科用製品。
３．（Ａ）成分の眼科用組成物中の含有量が、０．０１～０．１ｗ／ｖ％である１又は２記載の眼科用製品。
４．眼科用組成物が、（Ｄ）プロピレングリコールをさらに含有する１～３のいずれかに記載の眼科用製品。
５．眼科用組成物が、（Ｅ）塩化ナトリウムをさらに含有し、その眼科用組成物中の含有量が０．１～１．０ｗ／ｖ％である１～４のいずれかに記載の眼科用製品。
６．容器の材質が、ポリエチレン、ポリエチレンテレフタレート及びポリプロピレンから選ばれる１種以上である、１～５のいずれかに記載の眼科用製品。 Accordingly, the present invention provides an ophthalmic product comprising:
1. (A) hyaluronic acid or a salt thereof,
An ophthalmic composition comprising (B) chlorhexidine and (C) epsilon aminocaproic acid or a salt thereof,
An ophthalmic product housed in a container that has been sterilized by electron beam or gamma radiation.
2. The ophthalmic product according to 1, wherein the content mass ratio represented by (C)/(B) is 100 to 5,000.
3. The ophthalmic product according to 1 or 2, wherein the content of component (A) in the ophthalmic composition is 0.01 to 0.1 w/v %.
4. The ophthalmic product according to any one of 1 to 3, wherein the ophthalmic composition further contains (D) propylene glycol.
5. The ophthalmic product according to any one of 1 to 4, wherein the ophthalmic composition further contains (E) sodium chloride, the content of which in the ophthalmic composition is 0.1 to 1.0 w/v %.
6. The ophthalmic product according to any one of 1 to 5, wherein the material of the container is one or more selected from the group consisting of polyethylene, polyethylene terephthalate, and polypropylene.
　本発明によれば、凍結融解後における不溶物の発生を抑制し、外観安定性に優れた、（Ａ）ヒアルロン酸又はその塩及び（Ｂ）クロルヘキシジンを含有する眼科用組成物が、電子線又はガンマ線にて滅菌処理された容器に収容された眼科用製品を提供することができる。 The present invention provides an ophthalmic product that suppresses the generation of insoluble matter after freezing and thawing and has excellent appearance stability, and that contains an ophthalmic composition containing (A) hyaluronic acid or a salt thereof and (B) chlorhexidine, and that is housed in a container that has been sterilized with electron beams or gamma rays.
　以下、本発明について詳細に説明する。
［（Ａ）成分］
　本発明のヒアルロン酸又はその塩は特に限定されるものではなく、眼科用領域等における粘膜適用製剤に通常用いられる任意のヒアルロン酸類を用いることができる。ヒアルロン酸類の例として、ヒアルロン酸、その誘導体、これらの薬学的生理学的に許容される塩類が挙げられる。鶏冠から抽出する方法、微生物による発酵法等により得たものを使用でき、由来や製造法は特に限定されない。ヒアルロン酸又はその塩は、１種単独で又は２種以上を適宜組み合わせて用いることができる。（Ａ）成分の具体例として、ヒアルロン酸、ヒアルロン酸ナトリウム、ヒアルロン酸カリウム、ヒアルロン酸マグネシウム、ヒアルロン酸カルシウム等が挙げられる。中でも、ヒアルロン酸ナトリウムが好ましい。（Ａ）成分としては市販品を用いることができ、例えば、精製ヒアルロン酸ナトリウム（生化学工業（株）製、キユーピー（株）製、キッコーマンバイオケミファ（株）製、岩城製薬（株）製、ブルーメイジバイオテクノロジー（株）製）等が挙げられる。 The present invention will be described in detail below.
[Component (A)]
The hyaluronic acid or its salt of the present invention is not particularly limited, and any hyaluronic acid that is usually used in mucous membrane application preparations in the ophthalmic field can be used. Examples of hyaluronic acids include hyaluronic acid, its derivatives, and their pharmacologic and physiologically acceptable salts. Those obtained by extraction from cockscomb, fermentation by microorganisms, etc. can be used, and the origin and manufacturing method are not particularly limited. Hyaluronic acid or its salt can be used alone or in appropriate combination of two or more. Specific examples of component (A) include hyaluronic acid, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, etc. Among them, sodium hyaluronate is preferred. As component (A), commercially available products can be used, such as purified sodium hyaluronate (manufactured by Seikagaku Corporation, Kewpie Corporation, Kikkoman Biochemifa Corporation, Iwaki Pharmaceutical Co., Ltd., and Blue Meiji Biotechnology Co., Ltd.).
　（Ａ）成分の平均分子量は、５００，０００～５，０００，０００が好ましく、５００，０００～４，０００，０００がより好ましく、５００，０００～２，５００，０００がさらに好ましく、５００，０００～２，０００，０００が特に好ましく、５００，０００～１，４９０，０００が最も好ましい。（Ａ）成分の平均分子量は、第１８改正日本薬局方医薬品各条に記載の「精製ヒアルロン酸ナトリウム」に記載の平均分子量の測定方法で測定する。なお、平均分子量が異なる複数種のヒアルロン酸及び／又は塩を使用することができる。 The average molecular weight of component (A) is preferably 500,000 to 5,000,000, more preferably 500,000 to 4,000,000, even more preferably 500,000 to 2,500,000, particularly preferably 500,000 to 2,000,000, and most preferably 500,000 to 1,490,000. The average molecular weight of component (A) is measured by the method for measuring average molecular weight described in the "Purified Sodium Hyaluronate" section of the Japanese Pharmacopoeia, 18th Edition, Pharmaceutical Articles. Note that multiple types of hyaluronic acid and/or salts with different average molecular weights can be used.
　（Ａ）成分としては市販品を用いることができ、例えば、生化学工業（株）製の「ヒアルロン酸ナトリウム「生化学」」（平均分子量５０万～１２０万）、「化粧用ヒアルロン酸ナトリウム（ＨＣ）」（平均分子量５３万～１３３万）、キッコーマンバイオケミファ（株）製の「ヒアルロン酸ＦＣＨ－６０」（平均分子量５０万～７０万）、「ヒアルロン酸ＦＣＨ－８０」（平均分子量６０万～１００万）、「ヒアルロン酸ＦＣＨ－１２０」（平均分子量１００万～１４０万）、「ヒアルロン酸ＦＣＨ－１５０」（平均分子量１４０万～１８０万）、「ヒアルロン酸ＦＣＨ－１５１Ｃ」（平均分子量１４０万～１８０万）、「ヒアルロン酸ＦＣＨ－２００」（平均分子量１８０万～２２０万）、「ヒアルロン酸ＦＣＨ－２０１Ｃ」（平均分子量１８０万～２２０万）、「ヒアルロン酸ＦＣＨ－８０ＬＥ」（平均分子量６０万～１２０万）、「ヒアルロン酸ＧＳ－１００」（平均分子量５０万～１４９万）、キユーピー（株）製の「ヒアルロンサンＨＡ－ＱＡ」（平均分子量６０万～１２０万）、「ヒアルロンサンＨＡ－ＡＭ」（平均分子量６０万～１２０万）、「ヒアルロンサンＨＡ－Ｑ」（平均分子量５３万～１１３万）、「ヒアルロンサンＭ５０７０」（平均分子量５０万～７０万）、「ヒアルロンサンＨＡ－ＬＱ」（平均分子量８５万～１６０万）、「ヒアルロンサンＨＡ－ＬＱＨ」（平均分子量１２０万～２２０万）、「ヒアルロンサンＨＡ－ＡＭＬ」（平均分子量５０万～１２０万）「ヒアルロンサンＨＡ－ＳＨＬ」（平均分子量１６０万～２４０万）、岩城製薬（株）製の「ヒアルロン酸ＩＷ９０」（平均分子量８０万～１１７万）、「ヒアルロン酸ＩＷ１２０」（平均分子量１１０万～１６０万）、「ヒアルロン酸ＩＷ２００」（平均分子量１９０万～２７０万）、ブルーメイジバイオテクノロジー（株）製の「精製ヒアルロン酸ナトリウムＪＰ－ＡＥ」（平均分子量５０万～１４９万）、「精製ヒアルロン酸ナトリウムＪＰ－Ｅ」（平均分子量５０万～１４９万）、「Ｓｏｄｉｕｍ　Ｈｙａｌｕｒｏｎａｔｅ　ＭＷ８０／１１０」（平均分子量８０万～１１０万）、「Ｓｏｄｉｕｍ　Ｈｙａｌｕｒｏｎａｔｅ　ＭＷ１１０／１６０」（平均分子量１１０万～１６０万）、「Ｓｏｄｉｕｍ　Ｈｙａｌｕｒｏｎａｔｅ　ＭＷ１９０／２４０」（平均分子量１９０万～２４０万）等が挙げられる。 Commercially available products can be used as component (A), such as "Sodium Hyaluronate "Seikagaku"" (average molecular weight 500,000 to 1,200,000) and "Cosmetic Sodium Hyaluronate (HC)" (average molecular weight 530,000 to 1,330,000) manufactured by Seikagaku Corporation, "Hyaluronic Acid FCH-60" (average molecular weight 500,000 to 700,000), "Hyaluronic Acid FCH-80" (average molecular weight 600,000 to 1,000,000), "Hyaluronic Acid FCH-120" (average molecular weight 1,000,000 to 1,400,000), and "Hyaluronic Acid FCH-150" (average molecular weight 1,400,000 to 1,800,000) manufactured by Kikkoman Biochemifa Corporation. "Hyaluronic acid FCH-151C" (average molecular weight 1.4 million to 1.8 million), "Hyaluronic acid FCH-200" (average molecular weight 1.8 million to 2.2 million), "Hyaluronic acid FCH-201C" (average molecular weight 1.8 million to 2.2 million), "Hyaluronic acid FCH-80LE" (average molecular weight 600,000 to 1.2 million), "Hyaluronic acid GS-100" (average molecular weight 500,000 to 1.49 million), "Hyaluronic acid HA-QA" (average molecular weight 600,000 to 1.2 million), "Hyaluronic acid HA-AM" (average molecular weight 600,000 to 1.2 million), "Hyaluronic acid HA-Q" (average molecular weight 530,000 to 1.13 million), "Hyaluronic Acid M5070" (average molecular weight 500,000 to 700,000), "Hyaluronic Acid HA-LQ" (average molecular weight 850,000 to 1.6 million), "Hyaluronic Acid HA-LQH" (average molecular weight 1.2 million to 2.2 million), "Hyaluronic Acid HA-AML" (average molecular weight 500,000 to 1.2 million), "Hyaluronic Acid HA-SHL" (average molecular weight 1.6 million to 2.4 million), and "Hyaluronic Acid IW90" (average molecular weight 800,000 to 1.17 million), "Hyaluronic Acid IW120" (average molecular weight 1.1 million to 1.6 million), "Hyaluronic Acid IW200" (average molecular weight 1.9 million to 2.7 million), Blue Meiji Biotechnology Co., Ltd.'s "Purified Sodium Hyaluronate JP-AE" (average molecular weight 500,000 to 1.49 million), "Purified Sodium Hyaluronate JP-E" (average molecular weight 500,000 to 1.49 million), "Sodium Hyaluronate MW80/110" (average molecular weight 800,000 to 1.1 million), "Sodium Hyaluronate MW110/160" (average molecular weight 1.1 million to 1.6 million), and "Sodium Hyaluronate MW190/240" (average molecular weight 1.9 million to 2.4 million).
　（Ａ）成分の含有量は、眼科用組成物中０．００１ｗ／ｖ％（質量／体積％，ｇ／１００ｍＬ）以上が好ましく、０．００５ｗ／ｖ％以上がより好ましく、０．００１～０．３ｗ／ｖ％、０．００５～０．２ｗ／ｖ％、０．０１～０．１５ｗ／ｖ％、０．０１～０．１ｗ／ｖ％、０．０５～０．１ｗ／ｖ％の順でさらに好ましい。（Ａ）成分の含有量が多すぎると、眼科用組成物の粘度が高すぎて、ぼやけ等が生じるおそれがあり、特に０．１ｗ／ｖ％以下とすることで、凍結融解後における不溶物の発生をより抑制し、外観安定性がより向上する。 The content of component (A) in the ophthalmic composition is preferably 0.001 w/v% (mass/volume %, g/100 mL) or more, more preferably 0.005 w/v% or more, and even more preferably 0.001-0.3 w/v%, 0.005-0.2 w/v%, 0.01-0.15 w/v%, 0.01-0.1 w/v%, and 0.05-0.1 w/v% in that order. If the content of component (A) is too high, the viscosity of the ophthalmic composition may be too high, which may cause blurring, etc. By keeping the content at 0.1 w/v% or less, the occurrence of insoluble matter after freezing and thawing is further suppressed and the appearance stability is further improved.
［（Ｂ）成分］
　クロルヘキシジンは特に限定されるものではなく、眼科用領域等における粘膜適用製剤に通常用いられる任意のクロルヘキシジンを用いることができ、１種単独で又は２種以上組み合わせて用いることができる。クロルヘキシジンは塩であってもよく、例えば、クロルヘキシジングルコン酸塩、クロルヘキシジン酢酸塩、クロルヘキシジン塩酸塩等が挙げられる。中でも、クロルヘキシジングルコン酸塩が好ましい。 [Component (B)]
The chlorhexidine is not particularly limited, and any chlorhexidine generally used in preparations for mucosal application in the ophthalmic field can be used, and one type can be used alone or two or more types can be used in combination. Chlorhexidine may be in the form of a salt, and examples of the salt include chlorhexidine gluconate, chlorhexidine acetate, and chlorhexidine hydrochloride. Among these, chlorhexidine gluconate is preferred.
　（Ｂ）成分の含有量は、眼科用組成物中０．０００１～０．０１ｗ／ｖ％が好ましく、０．０００２～０．００５ｗ／ｖ％がより好ましく、０．０００２～０．００２ｗ／ｖ％がさらに好ましく、０．０００２～０．０００５ｗ／ｖ％が特に好ましい。（Ｂ）成分の含有量を上記下限値以上とすることで、眼科用組成物の保存効力がより向上する。含有量が上記上限値以下とすることで、凍結融解後における不溶物の発生をより抑制し、外観安定性がより向上する。 The content of component (B) in the ophthalmic composition is preferably 0.0001 to 0.01 w/v%, more preferably 0.0002 to 0.005 w/v%, even more preferably 0.0002 to 0.002 w/v%, and particularly preferably 0.0002 to 0.0005 w/v%. By making the content of component (B) equal to or greater than the above lower limit, the preservative effectiveness of the ophthalmic composition is further improved. By making the content equal to or less than the above upper limit, the occurrence of insoluble matter after freezing and thawing is further suppressed, and the appearance stability is further improved.
［（Ｃ）成分］
　本発明において、（Ｃ）イプシロンアミノカプロン酸又はその塩を眼科用組成物に配合することで、（Ａ）ヒアルロン酸又はその塩及び（Ｂ）クロルヘキシジンを含有する眼科用組成物が、電子線又はガンマ線にて滅菌処理された容器に収容された眼科用製品の特有の課題である、凍結融解後における不溶物の発生を抑制し、外観安定性を向上させる。イプシロン－アミノカプロン酸は、６－アミノヘキサン酸とも称される中性アミノ酸として公知の化合物である。本発明で用いられるイプシロンアミノカプロン酸の塩としては、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されず、１種単独で又は２種以上組み合わせて用いることができる。イプシロンアミノカプロン酸の塩として、具体的には、有機酸塩［例えば、モノカルボン酸塩（酢酸塩、トリフルオロ酢酸塩、酪酸塩、パルミチン酸塩、ステアリン酸塩等）、多価カルボン酸塩（フマル酸塩、マレイン酸塩、コハク酸塩、マロン酸塩等）、オキシカルボン酸塩（乳酸塩、酒石酸塩、クエン酸塩等）、有機スルホン酸塩（メタンスルホン酸塩、トルエンスルホン酸塩、トシル酸塩等）等］、無機酸塩（例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩等）、有機塩基との塩（例えば、メチルアミン、トリエチルアミン、トリエタノールアミン、モルホリン、ピペラジン、ピロリジン、トリピリジン、ピコリン等の有機アミンとの塩等）、無機塩基との塩［例えば、アンモニウム塩；アルカリ金属（ナトリウム、カリウム等）、アルカリ土類金属（カルシウム、マグネシウム等）、アルミニウム等の金属との塩等］等が挙げられる。これらの中でも、イプシロンアミノカプロン酸が好ましい。（Ｃ）成分としては市販品を用いることができ、例えば、積水メディカル（株）製の「ε－アミノ－ｎ－カプロン酸　ＥＫＤ」等が挙げられる。 [Component (C)]
In the present invention, by blending (C) epsilon aminocaproic acid or a salt thereof in an ophthalmic composition, the ophthalmic composition containing (A) hyaluronic acid or a salt thereof and (B) chlorhexidine suppresses the generation of insoluble matter after freezing and thawing, which is a problem specific to ophthalmic products contained in a container sterilized by electron beam or gamma ray, and improves the appearance stability. Epsilon-aminocaproic acid is a known compound as a neutral amino acid also called 6-aminohexanoic acid. The salt of epsilon aminocaproic acid used in the present invention is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable, and can be used alone or in combination of two or more. Specific examples of salts of epsilon aminocaproic acid include organic acid salts [e.g., monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polycarboxylates (fumarates, maleates, succinates, malons, etc.), oxycarboxylates (lactates, tartrates, citrates, etc.), organic sulfonates (methanesulfonates, toluenesulfonates, tosylates, etc.)], inorganic acid salts (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [e.g., ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), and aluminum, etc.], etc. Among these, epsilon aminocaproic acid is preferred. As the component (C), a commercially available product can be used, for example, "ε-amino-n-caproic acid EKD" manufactured by Sekisui Medical Co., Ltd.
　（Ｃ）成分の含有量は、眼科用組成物中０．００５～３ｗ／ｖ％が好ましく、０．０１５～２ｗ／ｖ％がより好ましく、０．０１～２ｗ／ｖ％がさらに好ましく、０．１～１ｗ／ｖ％が一層好ましく、０．２～０．８ｗ／ｖ％がより一層好ましく、０．２～０．５ｗ／ｖ％が特に好ましく、０．３～０．５ｗ／ｖ％が最も好ましい。（Ｃ）成分の含有量を上記下限値以上とすることで、凍結融解後における不溶物の発生をより抑制し、外観安定性がより向上する。含有量が上記上限値以下とすることで、眼科用組成物の保存効力がより向上する。 The content of component (C) in the ophthalmic composition is preferably 0.005 to 3 w/v%, more preferably 0.015 to 2 w/v%, even more preferably 0.01 to 2 w/v%, even more preferably 0.1 to 1 w/v%, even more preferably 0.2 to 0.8 w/v%, particularly preferably 0.2 to 0.5 w/v%, and most preferably 0.3 to 0.5 w/v%. By making the content of component (C) equal to or greater than the above lower limit, the occurrence of insoluble matter after freezing and thawing is further suppressed, and the appearance stability is further improved. By making the content equal to or less than the above upper limit, the preservation effectiveness of the ophthalmic composition is further improved.
［（Ｄ）成分］
　本発明の眼科用組成物に、（Ｄ）プロピレングリコールをさらに配合することで、凍結融解後における不溶物の発生をさらに抑制し、外観安定性をより向上させることができる。 [Component (D)]
By further blending (D) propylene glycol in the ophthalmic composition of the present invention, the generation of insoluble matters after freezing and thawing can be further suppressed, and the appearance stability can be further improved.
　（Ｄ）成分の含有量は、眼科用組成物中０．０１～１ｗ／ｖ％が好ましく、０．０３～０．５ｗ／ｖ％がより好ましく、０．０５～０．４ｗ／ｖ％がさらに好ましい。（Ｄ）成分の含有量を上記下限値以上とすることで、凍結融解後における不溶物の発生をより抑制し、外観安定性がより向上する。含有量が上記上限値以下とすることで、点眼時のぼやけがより生じにくくなる。 The content of component (D) in the ophthalmic composition is preferably 0.01 to 1 w/v%, more preferably 0.03 to 0.5 w/v%, and even more preferably 0.05 to 0.4 w/v%. By making the content of component (D) equal to or greater than the above lower limit, the occurrence of insoluble matter after freezing and thawing is further suppressed, and the stability of the appearance is further improved. By making the content equal to or less than the above upper limit, blurring is less likely to occur when the composition is applied to the eye.
［（Ｅ）成分］
　本発明の眼科用組成物に、（Ｅ）塩化ナトリウムをさらに配合することで、凍結融解後における不溶物の発生をさらに抑制し、外観安定性をより向上させることができる。 [Component (E)]
By further blending sodium chloride (E) in the ophthalmic composition of the present invention, the generation of insoluble matters after freezing and thawing can be further suppressed, and the appearance stability can be further improved.
　（Ｅ）成分の含有量は、眼科用組成物中１．０ｗ／ｖ％以下が好ましく、０．９ｗ／ｖ％以下がより好ましく、０．７ｗ／ｖ％以下がさらに好ましい。より具体的には、０．１～１．０ｗ／ｖ％が好ましく、０．２～０．９ｗ／ｖ％がより好ましく、０．３～０．７ｗ／ｖ％がさらに好ましい。（Ｅ）成分の含有量を上記下限値以上とすることで、凍結融解後における不溶物の発生をより抑制し、外観安定性がより向上する。含有量を上記上限値以下とすることで、眼科用組成物の粘度、点眼時のうるおい感がより得られやすくなる。 The content of component (E) in the ophthalmic composition is preferably 1.0 w/v% or less, more preferably 0.9 w/v% or less, and even more preferably 0.7 w/v% or less. More specifically, it is preferably 0.1 to 1.0 w/v%, more preferably 0.2 to 0.9 w/v%, and even more preferably 0.3 to 0.7 w/v%. By making the content of component (E) equal to or greater than the above lower limit, the occurrence of insoluble matter after freezing and thawing is further suppressed, and the appearance stability is further improved. By making the content equal to or less than the above upper limit, the viscosity of the ophthalmic composition and the feeling of moisture when applied to the eye are improved.
　各成分の眼科用組成物中の含有質量比の好ましい範囲を下記に示す。なお、この比率はｗ／ｖ％比であるが、質量比と同じ値となる。（Ｃ）／（Ｂ）は、１００以上が好ましく、２００以上がより好ましい。より具体的には、（Ｃ）／（Ｂ）は、１００～５，０００が好ましく、１５０～３，０００がより好ましく、２００～２，０００がさらに好ましく、３５０～２，０００が特に好ましく、４００～２，０００が最も好ましい。上記比率を下限以上とすることで、凍結融解後の外観安定性がより向上し、上限以下とすることで、凍結融解後における不溶物の発生をより抑制し、眼科用組成物の保存効力がより向上する。 The preferred range of the mass ratio of each component in the ophthalmic composition is shown below. Note that this ratio is a w/v % ratio, but is the same value as the mass ratio. (C)/(B) is preferably 100 or more, and more preferably 200 or more. More specifically, (C)/(B) is preferably 100 to 5,000, more preferably 150 to 3,000, even more preferably 200 to 2,000, particularly preferably 350 to 2,000, and most preferably 400 to 2,000. By setting the above ratio at or above the lower limit, the appearance stability after freezing and thawing is further improved, and by setting it at or below the upper limit, the generation of insoluble matter after freezing and thawing is further suppressed, and the preservation effectiveness of the ophthalmic composition is further improved.
　（Ｄ）／（Ｃ）は、０．０１～３．０が好ましく、０．１～２．０がより好ましく、０．２～１．２がさらに好ましく、０．３～１．０が特に好ましい。上記比率とすることで、凍結融解後の外観安定性がより向上する。 (D)/(C) is preferably 0.01 to 3.0, more preferably 0.1 to 2.0, even more preferably 0.2 to 1.2, and particularly preferably 0.3 to 1.0. By setting the ratio at the above levels, the appearance stability after freezing and thawing is further improved.
　（Ａ）／（Ｅ）は、０．０５～０．７０が好ましく、０．１０～０．５０がより好ましく、０．１３～０．３０がさらに好ましい。上記比率を下限以上とすることで、凍結融解後の外観安定性がより向上し、上限以下とすることで、ぼやけ等をより抑制することができる。 (A)/(E) is preferably 0.05 to 0.70, more preferably 0.10 to 0.50, and even more preferably 0.13 to 0.30. By setting the above ratio at or above the lower limit, the appearance stability after freezing and thawing can be further improved, and by setting it at or below the upper limit, blurring and the like can be further suppressed.
　（（Ｃ）＋（Ｄ））／（Ｂ）は、１００～５，０００が好ましく、１５０～４，０００がより好ましく、２００～３，０００がさらに好ましい。上記比率を下限以上とすることで、凍結融解後の外観安定性がより向上し、上限以下とすることで、眼科用組成物の保存効力がより向上する。 ((C)+(D))/(B) is preferably 100 to 5,000, more preferably 150 to 4,000, and even more preferably 200 to 3,000. By setting the above ratio to the lower limit or higher, the appearance stability after freezing and thawing is further improved, and by setting it to the upper limit or lower, the preservative effectiveness of the ophthalmic composition is further improved.
［その他の成分］
　本発明の眼科用組成物には、本発明の効果を損なわない範囲で、その他の成分を適量配合することができる。その他の成分としては、薬物、界面活性剤、緩衝剤、局所麻酔剤又は無痛化剤、ｐＨ調整剤、安定化剤、糖類、多価アルコール、粘稠剤、清涼化剤、その他の無機化合物、油性成分等が挙げられる。これらの成分は、１種単独で又は２種以上を適宜組み合わせて配合することができる。下記に示す成分の含有量は、配合する場合の好ましい範囲であり、組成物中の量である。 [Other ingredients]
The ophthalmic composition of the present invention may contain other components in appropriate amounts within the range that does not impair the effects of the present invention. Examples of other components include drugs, surfactants, buffers, local anesthetics or soothing agents, pH adjusters, stabilizers, sugars, polyhydric alcohols, thickeners, cooling agents, other inorganic compounds, oily components, etc. These components may be used alone or in appropriate combinations of two or more. The contents of the components shown below are the preferred ranges when they are used, and are the amounts in the composition.
　薬物（薬学的有効成分）としては、例えば、充血除去成分（血管収縮剤）（例えば、エピネフリン、塩酸エピネフリン、メチルノルエピネフリン、ノルエピネフリン、エフェドリン、メチルエフェドリン、シュードエフェドリン、エフェドリン塩酸塩、塩酸テトラヒドロゾリン、ナファゾリン硝酸塩、フェニレフリン塩酸塩、ｄｌ－メチルエフェドリン塩酸塩、オキシメタゾリン、メトキサミン、フェニルプロパノラミン、エチレフリン、ミドドリン、トラマゾリン、シネフリン、シラゾリン、キシロメタゾリン及びこれらの薬学的に許容される塩等）、消炎剤（イプシロン－アミノカプロン酸、アラントイン、ベルベリン塩化物水和物、ベルベリン硫酸塩水和物、アズレンスルホン酸ナトリウム、グリチルリチン酸二カリウム、リゾチーム塩酸塩、プラノプロフェン等）、収斂剤（例えば、ネオスチグミンメチル硫酸塩（毛様体筋等に対する眼筋調節作用を有する）、硫酸亜鉛、乳酸亜鉛）、抗ヒスタミン剤（例えば、ジフェンヒドラミン塩酸塩、クロルフェニラミンマレイン酸塩、フマル酸ケトチフェン、塩酸オロパタジン等）、抗アレルギー剤（例えば、クロモグリク酸ナトリウム、アシタザノラスト、イブジラスト、トラニラスト、ペミロラストカリウム、アンレキサノクス等）、水溶性ビタミン類（フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、ピリドキシン塩酸塩、パンテノール、パントテン酸カルシウム、パントテン酸ナトリウム、アスコルビン酸ナトリウム等）、脂溶性ビタミン類（例えば、レチノールパルミチン酸エステル、酢酸トコフェロール、コハク酸トコフェロール、ニコチン酸トコフェロール）、アミノ酸類（例えば、Ｌ－アスパラギン酸カリウム、Ｌ－アスパラギン酸マグネシウム、Ｌ－アスパラギン酸カリウム・マグネシウム（等量混合物）、アミノエチルスルホン酸、コンドロイチン硫酸エステルナトリウム等）、抗菌成分（例えば、サルファ剤（スルファメトキサゾール、スルファメトキサゾールナトリウム、スルフイソキサゾール、スルフイソミジンナトリウム等）等が挙げられる。 Drugs (pharmaceutical active ingredients) include, for example, congestion relief ingredients (vasoconstrictors) (e.g., epinephrine, epinephrine hydrochloride, methylnorepinephrine, norepinephrine, ephedrine, methylephedrine, pseudoephedrine, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, oxymetazoline, methoxamine, phenylpropanolamine, etilefrine, midodrine, tramazoline, synephrine ... lazoline, xylometazoline and pharma- ceutical acceptable salts thereof, etc.), anti-inflammatory agents (epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, lysozyme hydrochloride, pranoprofen, etc.), astringents (e.g., neostigmine methylsulfate (has an ocular muscle adjusting effect on the ciliary muscle, etc.), zinc sulfate, zinc lactate), antihistamines (e.g., diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, olopatadine hydrochloride, etc.), antiallergic agents (e.g., sodium cromoglycate, azadazanolast, ibudilast, tranilast, pemirolast potassium, amlexanox, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, sodium ascorbate, etc.), fat-soluble vitamins (e.g., retinol palmitate, ester, tocopherol acetate, tocopherol succinate, tocopherol nicotinate), amino acids (e.g., potassium L-aspartate, magnesium L-aspartate, potassium and magnesium L-aspartate (mixture of equal parts), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), antibacterial components (e.g., sulfa drugs (sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, etc.) etc.).
　薬物を配合する場合、その量は、各薬物の有効な適性量を選択することができるが眼科用組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 When drugs are added, the amount can be selected based on the effective amount of each drug, but it is preferably 0.001 to 5.0 w/v% in the ophthalmic composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
　界面活性剤としては、非イオン界面活性剤（例えば、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、モノステアリン酸ポリエチレングリコール等）、両性界面活性剤（例えば、グリシン型両性界面活性剤として、アルキルジアミノエチルグリシン、アルキルポリアミノエチルグリシン等、ベタイン型両性界面活性剤として、ラウリルジメチルアミノ酢酸ベタイン、イミダゾリウムベタイン等）、陽イオン性界面活性剤（例えば、塩化ベンザルコニウム、塩化ベンゼトニウム等）が挙げられる。 Surfactants include nonionic surfactants (e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene polyoxypropylene glycol, polyethylene glycol monostearate, etc.), amphoteric surfactants (e.g., glycine-type amphoteric surfactants such as alkyl diaminoethyl glycine and alkyl polyaminoethyl glycine, betaine-type amphoteric surfactants such as lauryl dimethyl amino acetate betaine and imidazolium betaine), and cationic surfactants (e.g., benzalkonium chloride, benzethonium chloride, etc.).
　界面活性剤を配合する場合、眼科用組成物中０．０００１～５ｗ／ｖ％が好ましく、０．０００３～３ｗ／ｖ％がより好ましく、０．００３～１ｗ／ｖ％がさらに好ましい。 When a surfactant is added, the amount in the ophthalmic composition is preferably 0.0001 to 5 w/v%, more preferably 0.0003 to 3 w/v%, and even more preferably 0.003 to 1 w/v%.
　緩衝剤としては、例えば、ホウ酸又はその塩（ホウ砂等）、トロメタモール、クエン酸又はその塩（クエン酸ナトリウム等）、リン酸又はその塩（リン酸水素ナトリウム、リン酸二水素ナトリウム等）、酒石酸又はその塩（酒石酸ナトリウム等）、グルコン酸又はその塩（グルコン酸ナトリウム等）、酢酸又はその塩（酢酸ナトリウム等）、氷酢酸、炭酸又はその塩（炭酸ナトリウム、炭酸水素ナトリウム等）、各種アミノ酸類（アスパラギン酸カリウム、アミノエチルスルホン酸、グルタミン酸、グルタミン酸ナトリウム）等が挙げられる。なお、これらは水和物であってもよい。緩衝剤を配合する場合、その量は、眼科用組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～２ｗ／ｖ％がより好ましく、０．００１～１ｗ／ｖ％がさらに好ましい。 Examples of buffering agents include boric acid or its salts (e.g., borax), trometamol, citric acid or its salts (e.g., sodium citrate), phosphoric acid or its salts (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate), tartaric acid or its salts (e.g., sodium tartrate), gluconic acid or its salts (e.g., sodium gluconate), acetic acid or its salts (e.g., sodium acetate), glacial acetic acid, carbonic acid or its salts (e.g., sodium carbonate, sodium bicarbonate), various amino acids (potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), etc. These may be hydrates. When a buffering agent is added, the amount is preferably 0.001 to 5.0 w/v % in the ophthalmic composition, more preferably 0.001 to 2 w/v %, and even more preferably 0.001 to 1 w/v %.
　等張化剤としては、例えば、塩化カリウム、塩化カルシウム、炭酸水素ナトリウム、炭酸ナトリウム、乾燥炭酸ナトリウム、硫酸マグネシウム、リン酸水素ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、グリセリン等が挙げられる。等張化剤を配合する場合、その量は、眼科用組成物中０．００００１～３ｗ／ｖ％が好ましく、０．０００１～２ｗ／ｖ％がより好ましく、０．００５～１．５ｗ／ｖ％がさらに好ましい。 Examples of isotonicity agents include potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, etc. When an isotonicity agent is added, the amount thereof in the ophthalmic composition is preferably 0.00001 to 3 w/v%, more preferably 0.0001 to 2 w/v%, and even more preferably 0.005 to 1.5 w/v%.
　局所麻酔剤又は無痛化剤としては、例えば、クロロブタノール、塩酸オキシブプロカイン、塩酸ジブカイン、塩酸テトラカイン、塩酸ピペロカイン、塩酸プロカイン、塩酸プロパラカイン、塩酸ヘキソチオカイン、塩酸リドカイン等が挙げられる。局所麻酔剤又は無痛化剤を配合する場合、その量は、眼科用組成物中０．００１～１．０ｗ／ｖ％が好ましく、０．０１～０．５ｗ／ｖ％がより好ましい。 Local anesthetics or soothing agents include, for example, chlorobutanol, oxybuprocaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride, etc. When a local anesthetic or soothing agent is added, the amount thereof in the ophthalmic composition is preferably 0.001 to 1.0 w/v %, more preferably 0.01 to 0.5 w/v %.
　ｐＨ調整剤としては、例えば、無機酸又は無機アルカリ剤が挙げられる。具体的には、無機酸としては（希）塩酸が挙げられる。無機アルカリ剤としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。また、モノエタノールアミン、ジエタノールアミン等が挙げられる。組成物のｐＨは、３．５～１３．０とすることもでき、涙液油層不安定化が引き起こす諸症状をより改善する点から３．５～８．０が好ましく、５．５～８．０がより好ましい。なお、ｐＨの測定は、２５℃でｐＨメーター（ＨＭ－２５Ｒ、東亜ディーケーケー（株）製）を用いて行う。 Examples of pH adjusters include inorganic acids and inorganic alkali agents. Specifically, an example of an inorganic acid is (dilute) hydrochloric acid. Examples of inorganic alkali agents include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. Examples of monoethanolamine and diethanolamine are also included. The pH of the composition can be set to 3.5 to 13.0, and is preferably 3.5 to 8.0, and more preferably 5.5 to 8.0, from the viewpoint of further improving the various symptoms caused by destabilization of the tear lipid layer. The pH is measured at 25°C using a pH meter (HM-25R, manufactured by DKK-TOA Corporation).
　安定化剤としては、例えば、エデト酸ナトリウム、エデト酸ナトリウム水和物、シクロデキストリン、モノエタノールアミン等が挙げられる。安定化剤（抗酸化剤）としては、脂溶性の抗酸化剤として、ジブチルヒドロキシトルエン（ＢＨＴ）、ブチルヒドロキシアニソール（ＢＨＡ）、ビタミンＥ類（例えば、酢酸トコフェロール、ニコチン酸トコフェロール、コハク酸トコフェロール等）等が挙げられる。 Examples of stabilizers include sodium edetate, sodium edetate hydrate, cyclodextrin, monoethanolamine, etc. Examples of stabilizers (antioxidants) include fat-soluble antioxidants such as dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), and vitamin E (e.g., tocopherol acetate, tocopherol nicotinate, tocopherol succinate, etc.).
　水溶性の安定化剤（抗酸化剤）としては、亜硫酸ナトリウム、亜硫酸カリウム、乾燥亜硫酸ナトリウム（無水亜硫酸ナトリウム）、ピロ亜硫酸ナトリウム、ピロ亜硫酸カリウム、亜硫酸水素ナトリウム、亜硫酸水素カリウム等の亜硫酸塩、アスコルビン酸、アスコルビン酸ナトリウム等が挙げられる。なお、安定化剤をソフトコンタクトレンズ用眼科用組成物に配合する場合には、レンズ吸着性、蓄積性の低いものが好ましく、例えば、エデト酸ナトリウム、エデト酸ナトリウム水和物、シクロデキストリン、ビタミンＥ、ビタミンＡ、亜硫酸ナトリウム、亜硫酸カリウム、乾燥亜硫酸ナトリウム（無水亜硫酸ナトリウム）、ピロ亜硫酸ナトリウム、ピロ亜硫酸カリウム、亜硫酸水素ナトリウム、亜硫酸水素カリウム等の亜硫酸塩等、スコルビン酸、アスコルビン酸ナトリウム等が挙げられる。 Examples of water-soluble stabilizers (antioxidants) include sulfites such as sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogensulfite, and potassium hydrogensulfite, ascorbic acid, sodium ascorbate, etc. When a stabilizer is to be incorporated into an ophthalmic composition for soft contact lenses, it is preferable to use one that has low lens adsorption and accumulation properties, and examples of such stabilizers include sodium edetate, sodium edetate hydrate, cyclodextrin, vitamin E, vitamin A, sodium sulfite, potassium sulfite, dried sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogensulfite, and potassium hydrogensulfite, ascorbic acid, sodium ascorbate, etc.
　安定化剤を配合する場合、その量は、眼科用組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 When a stabilizer is added, the amount is preferably 0.001 to 5.0 w/v% in the ophthalmic composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
　糖類としては、グルコース、シクロデキストリン、キシリトール、ソルビトール、マンニトール等が挙げられる。なお、これらは、ｄ体、ｌ体又はｄｌ体のいずれでもよい。糖類は、湿潤性があるため点眼時のうるおいを高める効果を有し、また等張化剤としても使用できる。糖類を配合する場合、その量は、眼科用組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 Examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc. These may be in the d-, l- or dl-form. Sugars have moisturizing properties and are effective in increasing moisture when applied to the eye, and can also be used as isotonicity agents. When sugars are added, their amount in the ophthalmic composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
　多価アルコールとしては、例えば、グリセリン、ブチレングリコール、ポリエチレングリコール、キシリトール、マンニトール、ソルビトール等が挙げられる。多価アルコールは、湿潤性があるため点眼時のうるおいを高める効果を有し、また等張化剤としても使用できる。また、グリセリンは清涼化剤の可溶化剤としても使用できる。多価アルコールを配合する場合、その量は、眼科用組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 Examples of polyhydric alcohols include glycerin, butylene glycol, polyethylene glycol, xylitol, mannitol, and sorbitol. Polyhydric alcohols have moisturizing properties and can increase the moisture content of the eye when applied, and can also be used as isotonicity agents. Glycerin can also be used as a solubilizer for cooling agents. When polyhydric alcohols are added, their amount in the ophthalmic composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
　粘稠剤としては、水溶性高分子化合物等が挙げられ、例えば、ポリビニルピロリドン、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリビニルアルコール、コンドロイチン硫酸ナトリウム、ポリアクリル酸、カルボキシビニルポリマー、ポリエチレングリコール、デキストラン、アルギン酸、アルギン酸ナトリウム、キサンタンガム等が挙げられる。粘稠剤を配合する場合、べたつき、ぼやけ等の使用感を損なわない程度で配合することができる。粘稠剤を配合する場合、その量は、眼科用組成物中０．００１～５．０ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 Thickening agents include water-soluble polymeric compounds, such as polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, dextran, alginic acid, sodium alginate, and xanthan gum. When thickening agents are added, they can be added to an extent that does not impair the feeling of use, such as stickiness or blurring. When thickening agents are added, the amount is preferably 0.001 to 5.0 w/v% in the ophthalmic composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
　清涼化剤としては、例えば、メントール、カンフル、ボルネオール、ゲラニオール、シネオール、リナロール、アネトール、オイゲノール、リモネン、リュウノウ等が挙げられる。ｄ体、ｌ体又はｄｌ体のいずれでもよい。また、ハッカ油、クールミント油、スペアミント油、ペパーミント油、ユーカリ油、ローズ油、ウイキョウ油、ベルガモット油、ケイヒ油等の精油が挙げられる。清涼化剤は、うるおい持続の効果実感を高めることができる。清涼化剤、精油を配合する場合、その量は、眼科用組成物中０．０００１～１ｗ／ｖ％が好ましく、０．０００５～０．２ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 The refreshing agent may be, for example, menthol, camphor, borneol, geraniol, cineole, linalool, anethole, eugenol, limonene, ryunou, etc. Any of the d-, l- or dl-isomers may be used. In addition, essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, eucalyptus oil, rose oil, fennel oil, bergamot oil, and cinnamon oil may be used. The refreshing agent can enhance the feeling of the effect of sustained moisture. When a refreshing agent or essential oil is added, the amount thereof in the ophthalmic composition is preferably 0.0001 to 1 w/v%, more preferably 0.0005 to 0.2 w/v%, and even more preferably 0.001 to 0.1 w/v%.
　その他の無機化合物としては、チオ硫酸ナトリウム、酸化チタン、塩化亜鉛等挙げられる。これらを配合する場合、その量は、眼科用組成物中０．００１～５ｗ／ｖ％が好ましく、０．００１～１ｗ／ｖ％がより好ましく、０．００１～０．１ｗ／ｖ％がさらに好ましい。 Other inorganic compounds include sodium thiosulfate, titanium oxide, zinc chloride, etc. When these are added, the amount is preferably 0.001 to 5 w/v% in the ophthalmic composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.
［眼科用組成物］
　本発明の眼科用組成物は、「水性眼科用組成物」であることが好ましい。本発明において、「水性眼科用組成物」とは、媒質が水である眼科用組成物をいう。水の含有量は、組成物中９０．０～９９．５ｗ／ｖ％が好ましく、９５．０～９９．０ｗ／ｖ％がより好ましい。 [Ophthalmic Composition]
The ophthalmic composition of the present invention is preferably an "aqueous ophthalmic composition". In the present invention, the "aqueous ophthalmic composition" refers to an ophthalmic composition in which the medium is water. The content of water in the composition is preferably 90.0 to 99.5 w/v %, and more preferably 95.0 to 99.0 w/v %.
　眼科用組成物の６００ｎｍの透過率は、９８．０～１００．０が好ましく、９９．０～１００．０％がより好ましい。凍結融解後における眼科用組成物の６００ｎｍの透過率は、９８．０％以上が好ましく、９８．５％以上がより好ましく、９９．０％以上がさらに好ましい。 The transmittance of the ophthalmic composition at 600 nm is preferably 98.0 to 100.0%, and more preferably 99.0 to 100.0%. The transmittance of the ophthalmic composition at 600 nm after freezing and thawing is preferably 98.0% or more, more preferably 98.5% or more, and even more preferably 99.0% or more.
　本発明の組成物の剤型は特に限定されず、例えば、点眼剤（コンタクトレンズ装用中に点眼可能な点眼剤を含む）、洗眼剤、コンタクトレンズ装着液、コンタクトレンズ取り外し液等として好適に使用できる。特に点眼剤、コンタクトレンズ装着液として好適に使用でき、点眼剤が特に好ましい。中でも、コンタクトレンズ装用中に点眼可能な点眼剤、コンタクトレンズ装着液、コンタクトレンズ取り外し液等のコンタクトレンズ使用者が使用するコンタクトレンズ用眼科用組成物として好適である。 The formulation of the composition of the present invention is not particularly limited, and can be suitably used, for example, as eye drops (including eye drops that can be applied while wearing contact lenses), eyewash, contact lens application solution, contact lens removal solution, etc. It can be particularly suitably used as eye drops and contact lens application solution, with eye drops being particularly preferred. Among these, it is suitable as an ophthalmic composition for contact lenses used by contact lens wearers, such as eye drops that can be applied while wearing contact lenses, contact lens application solution, contact lens removal solution, etc.
　コンタクトレンズとしては、ハードコンタクトレンズ（Ｏ2ハードコンタクトレンズを含む）、ソフトコンタクトレンズ（イオン性及び非イオン性の双方を含む）、シリコーンハイドロゲルコンタクトレンズ、カラーコンタクトレンズ等特に限定されない。防腐剤を配合しない場合には、特にソフトコンタクトレンズ、シリコーンハイドロゲルコンタクトレンズ用として好適である。 Contact lenses include, but are not limited to, hard contact lenses (including O2 hard contact lenses), soft contact lenses (including both ionic and non-ionic), silicone hydrogel contact lenses, colored contact lenses, etc. When no preservative is added, the composition is particularly suitable for soft contact lenses and silicone hydrogel contact lenses.
［製造方法］
　本発明の組成物の製造方法は特に限定されないが、例えば、（Ａ）を予備溶解させ、その後、溶液と（Ｂ）成分等の水性成分を含む溶液と混合し、ｐＨ調整後、総体積を水により調整することにより得ることができる。各液体の混合方法は、一般的な方法でよく、パルセーター、プロペラ羽根、パドル羽根、タービン羽根等を用いて適宜行われるが、回転数は特に限定されず、激しく泡立たない程度に設定することが好ましい。各液体の混合温度は特に限定しないが、（Ａ）成分の安定性の観点から高温でないことが好ましく、２０～６０℃の範囲から適宜選定される。 [Production method]
The method for producing the composition of the present invention is not particularly limited, but for example, the composition can be obtained by pre-dissolving (A), then mixing the solution with a solution containing an aqueous component such as component (B), adjusting the pH, and then adjusting the total volume with water. The method for mixing each liquid may be a general method, and is appropriately carried out using a pulsator, propeller blade, paddle blade, turbine blade, etc., but the rotation speed is not particularly limited, and it is preferable to set it to a level that does not cause vigorous foaming. The mixing temperature of each liquid is not particularly limited, but it is preferable that it is not high from the viewpoint of the stability of component (A), and is appropriately selected from the range of 20 to 60°C.
［眼科用製品］
　本発明は、上記眼科用組成物が、電子線又はガンマ線にて滅菌処理された容器に収容された眼科用製品である。 [Ophthalmic products]
The present invention is an ophthalmic product comprising the above-mentioned ophthalmic composition contained in a container that has been sterilized with electron beams or gamma rays.
［容器］
　容器としては、プラスチック製容器が好ましく、ポリエチレン（ＰＥ）、ポリエチレンテレフタレート（ＰＥＴ）、ポリプロピレン（ＰＰ）、ポリブチレン、ポリカーボネート、ポリアリレート、塩化ビニル等の材質又はこれら材質の複合体からなるもの等を用いることができる。これらの中でもポリエチレン、ポリエチレンテレフタレート、ポリプロピレンが好ましい。製品中の眼科用組成物の量は、製品及びその使用方法に応じて適宜選択することができ、例えば点眼剤の場合、２～２０ｍＬが好ましく、５～２０ｍＬがより好ましい。眼科用組成物の容器は、特に限定されないがマルチドーズ型（マルチユニット型）容器でもよく、１回使い切りのユニットドーズ型容器でもよい。マルチドーズ型（マルチユニット型）容器が好ましい。 [container]
The container is preferably a plastic container, and may be made of materials such as polyethylene (PE), polyethylene terephthalate (PET), polypropylene (PP), polybutylene, polycarbonate, polyarylate, vinyl chloride, or a composite of these materials. Among these, polyethylene, polyethylene terephthalate, and polypropylene are preferred. The amount of the ophthalmic composition in the product can be appropriately selected depending on the product and its method of use. For example, in the case of eye drops, 2 to 20 mL is preferred, and 5 to 20 mL is more preferred. The container for the ophthalmic composition is not particularly limited, and may be a multi-dose (multi-unit) container or a single-use unit-dose container. A multi-dose (multi-unit) container is preferred.
　電子線又はガンマ線にて滅菌処理する方法としては、特に限定されるものではなく、従来公知の滅菌条件に従って行うことができる。例えば、滅菌効果の観点から５～８０ｋＧｙで行うのが好ましく、５～５０ｋＧｙがより好ましく、５～３０ｋＧｙで行うのがさらに好ましい。 The method of sterilization using electron beams or gamma rays is not particularly limited, and can be carried out according to conventionally known sterilization conditions. For example, from the viewpoint of sterilization effect, it is preferable to carry out the sterilization at 5 to 80 kGy, more preferably 5 to 50 kGy, and even more preferably 5 to 30 kGy.
［包装］
　眼科用組成物を電子線又はガンマ線にて滅菌処理された容器に収容し、上記容器と上記包装体との間に形成された空間に窒素等の不活性ガスを封入してもよく、眼科用組成物を上記容器に充填、収容後、脱酸素剤と共に包装体により密封してもよい。中栓、キャップは、公知の眼科用製品の容器に使用される材質のキャップを使用することができる。中栓の材質としては、メルトフローレート２．０以下、好ましくは１．２～１．８のポリエチレン、ポリプロピレンが好ましい。キャップの材質としては、ポリエチレン、ポリプロピレンが好ましい。 [Packaging]
The ophthalmic composition may be contained in a container that has been sterilized with electron beams or gamma rays, and an inert gas such as nitrogen may be sealed in the space formed between the container and the packaging body, or the ophthalmic composition may be filled into the container, and then sealed in the packaging body together with an oxygen scavenger. The inner stopper and cap may be made of a material used for known containers of ophthalmic products. The material of the inner stopper is preferably polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8. The material of the cap is preferably polyethylene or polypropylene.
［外観安定化方法］
　本発明の方法は、（Ａ）ヒアルロン酸又はその塩、及び（Ｂ）クロルヘキシジンを含有する眼科用組成物が、電子線又はガンマ線にて滅菌処理された容器に収容された眼科用製品において、（Ｃ）イプシロンアミノカプロン酸又はその塩を配合する、上記眼科用組成物の外観安定化方法である。これらの方法において、好適な成分、量は上記と同じである。なお、この外観安定化方法とは、上記眼科用製品を、凍結融解（凍結させた後再び室温に戻す）後に、外観が悪化することを抑制することをいう。具体的には実施例に記載の方法で凍結融解後の外観安定性を評価する。 [Appearance stabilization method]
The method of the present invention is a method for stabilizing the appearance of the ophthalmic composition, which comprises (A) hyaluronic acid or its salt and (B) chlorhexidine, and is contained in a container that is sterilized by electron beam or gamma ray, and (C) epsilon aminocaproic acid or its salt is added to the ophthalmic composition.In these methods, the preferred components and amounts are the same as above.Note that this appearance stabilization method refers to suppressing the deterioration of the appearance of the ophthalmic product after freezing and thawing (freezing and then returning to room temperature).Specifically, the appearance stability after freezing and thawing is evaluated by the method described in Examples.
　本発明の眼科用組成物製品の６００ｎｍの透過率は、９９．０～１００．０％が好ましく、凍結と融解の操作を３回繰り返した後の透過率は、９７．５～１００．０％が好ましく、９８．０～１００．０％がより好ましい。 The 600 nm transmittance of the ophthalmic composition product of the present invention is preferably 99.0 to 100.0%, and the transmittance after three repeated freezing and thawing operations is preferably 97.5 to 100.0%, more preferably 98.0 to 100.0%.
　以下、実施例及び比較例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。以下、実施例及び比較例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。なお、下記の例において特に明記のない場合は、組成の「％」は「ｗ／ｖ％（ｇ／１００ｍＬ）」、比率はｗ／ｖ％比であり、質量比と同じ値である。 The present invention will be described in detail below with examples and comparative examples, but the present invention is not limited to the following examples. The present invention will be described in detail below with examples and comparative examples, but the present invention is not limited to the following examples. In the following examples, unless otherwise specified, the "%" of the composition is "w/v % (g/100 mL)" and the ratio is w/v % ratio, which is the same value as the mass ratio.
［実施例、比較例］
　表に示す配合組成となるように、精製水及びｐＨ調整剤以外の成分を９０ｍＬの精製水に溶解し、室温（２５℃）で１８時間攪拌混合した。次いで、眼科用組成物の２５℃でのｐＨが６．５となるように、必要に応じてｐＨ調整剤でｐＨを調整した後、全量が１００ｍＬになるように残りの精製水を加えて、眼科用組成物を得た。ｐＨの測定には、ｐＨメーター（東亜ディーケーケー株式会（株）製、商品名「ＨＭ－２５Ｒ」）を用いた。得られた組成物について、下記評価を行った。結果を表中に併記する。なお、組成物のｐＨは６．０～７．０の範囲であった。 [Examples and Comparative Examples]
In order to obtain the composition shown in the table, the components other than purified water and the pH adjuster were dissolved in 90 mL of purified water and mixed by stirring at room temperature (25°C) for 18 hours. Next, the pH of the ophthalmic composition was adjusted with a pH adjuster as necessary so that the pH of the ophthalmic composition at 25°C would be 6.5, and the remaining purified water was added to make the total volume 100 mL to obtain an ophthalmic composition. A pH meter (manufactured by DKK-TOA Corporation, product name "HM-25R") was used to measure the pH. The obtained composition was evaluated as follows. The results are also shown in the table. The pH of the composition was in the range of 6.0 to 7.0.
［外観安定性試験方法］
　電子線にて滅菌した容器（照射量１８ｋＧｙ）及び滅菌していない容器（容量１０ｍＬ）に、調製した被験眼科用組成物（容量１０ｍＬ）を充填し収容した。得られた眼科用製品を－２０℃で凍結させ、眼科用組成物が凍結したことを確認した後に常温に取り出し、解凍させた。この凍結と融解の操作を３回繰り返した。
　初期と、凍結と融解の操作を３回繰り返した後の眼科用組成物について、６００ｎｍの透過率を、分光光度計（ＵＶ－１８００、（株）島津製作所）を用いて測定した。
　凍結と融解の操作を３回繰り返した後の眼科用製品の外観を、蛍光灯下で目視観察し、粒子の有無を確認した。結果を下記で示す。
　〇：粒子が認められない
　×：粒子が認められる [Appearance stability test method]
The prepared ophthalmic composition to be tested (volume 10 mL) was filled and stored in a container sterilized by electron beam (irradiation dose 18 kGy) and a non-sterilized container (volume 10 mL). The obtained ophthalmic product was frozen at -20°C, and after confirming that the ophthalmic composition was frozen, it was taken out at room temperature and thawed. This freezing and thawing operation was repeated three times.
The transmittance at 600 nm of the ophthalmic composition was measured using a spectrophotometer (UV-1800, Shimadzu Corporation) initially and after three cycles of freezing and thawing.
After the freezing and thawing process was repeated three times, the appearance of the ophthalmic product was visually observed under a fluorescent lamp to confirm the presence or absence of particles. The results are shown below.
◯: No particles found ×: Particles found
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　実施例及び比較例を調製する際に用いた原料を以下に示す。なお、特に明記がない限り、表中の各成分の量は純分換算量である。
ヒアルロン酸ナトリウム：ヒアルロンサンＨＡ－ＡＭＬ、キユーピー（株）製
クロルヘキシジングルコン酸塩：２０ｗ／ｖ％マスキン液、丸石製薬（株）製
イプシロンアミノカプロン酸：ε－アミノ－ｎ－カプロン酸　ＥＫＤ、積水メディカル（株）製
プロピレングリコール：日本薬局方プロピレングリコール、（株）ＡＤＥＫＡ製
塩化ナトリウム：日本薬局方塩化ナトリウムＳＧ、富田製薬（株）製
エデト酸ナトリウム：エデト酸ナトリウム水和物「製造専用」、富士フイルム和光純薬（株）製 The raw materials used in preparing the Examples and Comparative Examples are shown below. Note that unless otherwise specified, the amount of each component in the table is the pure amount.
Sodium hyaluronate: Hyaluronsan HA-AML, manufactured by Kewpie Corporation Chlorhexidine gluconate: 20 w/v% Maskin solution, manufactured by Maruishi Pharmaceutical Co., Ltd. Epsilon aminocaproic acid: ε-amino-n-caproic acid EKD, manufactured by Sekisui Medical Co., Ltd. Propylene glycol: Japanese Pharmacopoeia Propylene Glycol, manufactured by ADEKA Corporation Sodium chloride: Japanese Pharmacopoeia Sodium Chloride SG, manufactured by Tomita Pharmaceutical Co., Ltd. Sodium edetate: Sodium edetate hydrate "For manufacturing only", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.

Claims (6)

  1. 　（Ａ）ヒアルロン酸又はその塩、
    （Ｂ）クロルヘキシジン、及び
    （Ｃ）イプシロンアミノカプロン酸又はその塩
    を含有する眼科用組成物が、
    　電子線又はガンマ線にて滅菌処理された容器に収容された眼科用製品。     (A) hyaluronic acid or a salt thereof,
    An ophthalmic composition comprising (B) chlorhexidine and (C) epsilon aminocaproic acid or a salt thereof,
    An ophthalmic product housed in a container that has been sterilized by electron beam or gamma radiation.
  2. 　（Ｃ）／（Ｂ）で表される含有質量比が１００～５，０００である、請求項１記載の眼科用製品。 The ophthalmic product according to claim 1, in which the mass ratio of (C)/(B) is 100 to 5,000.
  3. 　（Ａ）成分の眼科用組成物中の含有量が、０．０１～０．１ｗ／ｖ％である請求項１又は２記載の眼科用製品。 The ophthalmic product according to claim 1 or 2, wherein the content of component (A) in the ophthalmic composition is 0.01 to 0.1 w/v %.
  4. 　眼科用組成物が、（Ｄ）プロピレングリコールをさらに含有する請求項１又は２記載の眼科用製品。 The ophthalmic product according to claim 1 or 2, wherein the ophthalmic composition further contains (D) propylene glycol.
  5. 　眼科用組成物が、（Ｅ）塩化ナトリウムをさらに含有し、その眼科用組成物中の含有量が０．１～１．０ｗ／ｖ％である請求項１又は２記載の眼科用製品。 The ophthalmic product according to claim 1 or 2, wherein the ophthalmic composition further contains (E) sodium chloride, the content of which in the ophthalmic composition is 0.1 to 1.0 w/v %.
  6. 　容器の材質が、ポリエチレン、ポリエチレンテレフタレート及びポリプロピレンから選ばれる１種以上である、請求項１又は２記載の眼科用製品。 The ophthalmic product according to claim 1 or 2, wherein the material of the container is one or more selected from polyethylene, polyethylene terephthalate, and polypropylene.
PCT/JP2023/043479 2022-12-21 2023-12-05 Ophthalmic product WO2024135344A1 (en)

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Publication number Priority date Publication date Assignee Title
JPH1160505A (en) * 1997-05-20 1999-03-02 Senju Pharmaceut Co Ltd Antiseptic composition
JPH115744A (en) * 1997-06-16 1999-01-12 Toa Yakuhin Kk Aqueous solution preparation for external use containing hyaluronic acid
JP2001302518A (en) * 2000-02-15 2001-10-31 Rohto Pharmaceut Co Ltd Method for improving action and agent for improving action
JP2003002837A (en) * 2001-06-21 2003-01-08 Lion Corp Composition for aqueous skin care preparation and method for preventing clouding of liquid composition
JP2009086619A (en) * 2007-09-14 2009-04-23 Rohto Pharmaceut Co Ltd Contact lens fitting liquid
JP2016166195A (en) * 2015-03-06 2016-09-15 参天製薬株式会社 Ophthalmic composition
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JP2022044701A (en) * 2022-01-24 2022-03-17 参天製薬株式会社 Aqueous suspension contained in injection blow molded multi-dose eye drop container
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