WO2019107569A1 - Ophthalmic product - Google Patents

Ophthalmic product Download PDF

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Publication number
WO2019107569A1
WO2019107569A1 PCT/JP2018/044307 JP2018044307W WO2019107569A1 WO 2019107569 A1 WO2019107569 A1 WO 2019107569A1 JP 2018044307 W JP2018044307 W JP 2018044307W WO 2019107569 A1 WO2019107569 A1 WO 2019107569A1
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WO
WIPO (PCT)
Prior art keywords
ophthalmic
product according
silver
zirconium phosphate
ophthalmic product
Prior art date
Application number
PCT/JP2018/044307
Other languages
French (fr)
Japanese (ja)
Inventor
文孝 田坂
直人 三好
隆司 森本
雄介 桃川
Original Assignee
参天製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 参天製薬株式会社 filed Critical 参天製薬株式会社
Priority to JP2019556768A priority Critical patent/JP7317714B2/en
Publication of WO2019107569A1 publication Critical patent/WO2019107569A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D1/00—Containers having bodies formed in one piece, e.g. by casting metallic material, by moulding plastics, by blowing vitreous material, by throwing ceramic material, by moulding pulped fibrous material, by deep-drawing operations performed on sheet material
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
    • Y02W90/00—Enabling technologies or technologies with a potential or indirect contribution to greenhouse gas [GHG] emissions mitigation
    • Y02W90/10—Bio-packaging, e.g. packing containers made from renewable resources or bio-plastics

Definitions

  • the present invention relates to an ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate.
  • the eye drop containers include a multi-dose type drop container which can be used multiple times and a single use unit dose type drop container. Since the multi-dose type eye dropper container is used for a plurality of times for a fixed period, a preservative such as benzalkonium chloride is generally added to the ophthalmic composition in order to prevent the growth of fungi and the like. However, for example, benzalkonium chloride, which is a preservative, is cytotoxic, and it is more desirable not to include a preservative because it may cause corneal epithelial disorder if the exposure dose is increased. Therefore, the above-mentioned unit dose eye drop container is used as an eye drop container for containing an ophthalmic composition which does not contain a preservative.
  • a preservative such as benzalkonium chloride
  • the container has a preservative effect by having a backflow prevention valve in the outlet hole, and a container that exerts a preservative effect by making it a delamination bottle with a filter.
  • Multi-dose eye dropper PFMD (Preservative Free) Multi-Dose containers
  • PFMD Preservative Free Multi-Dose containers
  • Patent Document 2 discloses a unit dose type eye drop container in which antibacterial zeolite is dispersed and held on the entire surface or a required portion of the container (Technical field, claims 1, 22 etc.) Has been confirmed (Test Example 1).
  • unit dose type eye drop containers generally have high cost because they are used up once, and also have use disadvantages such as being bulky or difficult to open.
  • An object of one aspect of the present invention is to provide an ophthalmic product that can be used multiple times for a certain period of time without performing physical structures such as the above-described check valve and the delamination bottle with a filter.
  • an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container made of a resin containing silver-loaded zirconium phosphate.
  • the present invention has been completed by finding that the obtained ophthalmic products have excellent preservation efficacy.
  • the ophthalmic product according to an aspect of the present invention has a configuration in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate. .
  • an ophthalmic product is a multi-dose eye drop formed of a resin containing silver-loaded zirconium phosphate at a concentration of 0.08 to 10% (w / w) based on the resin.
  • the silver-loaded zirconium phosphate contains silver in an ion concentration of 0.001 to 20% (w / w), and the ophthalmic composition is substantially free of a preservative.
  • the ophthalmic composition which concerns on the further another aspect of this invention is an ophthalmic composition whose pH is less than 7,
  • the said ophthalmic composition was formed by resin containing a silver carrying
  • An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate has excellent storage efficacy. According to the aspect of the present invention, it is useful because it can be used multiple times for a fixed period without physical structure such as the above-mentioned backflow prevention valve or filter-attached delamination bottle, and there is no defect of the above unit dose type eye drop container is there.
  • a to B or “A to B” representing a numerical range are “A or more (including A and greater than A), B or less (including B and B) Means small. Also, “A to B” means “more than A (greater than A) and B or less (including B and less than B)”.
  • One embodiment of the present invention is an ophthalmic composition having a pH of less than 7 (hereinafter referred to as “the present eye container”) formed of a resin containing silver-loaded zirconium phosphate (hereinafter referred to as “the present eye container”). And an ophthalmic product (hereinafter, also referred to as a "present product”) containing the "present composition”.
  • the "present product” for example, an eye drop preparation product (also referred to as “eye drop preparation product”) can be mentioned.
  • ophthalmic composition refers to a composition for use in the prevention and / or treatment of ocular diseases and the like.
  • examples of the dosage form include eye drops.
  • eye drops are synonymous with eye drops or eye drops, and eye drops for contact lenses are also included in the definition of eye drops.
  • the form of the present composition is not particularly limited, and includes, for example, an aqueous solution, a suspension, an emulsion, a gel and the like.
  • the composition is an eye drop, particularly an aqueous eye drop
  • water examples include sterile purified water, water for injection, and the like.
  • the water content is, for example, preferably 80% (w / v) or more and less than 100% (w / v), and is 85% (w / v) or more and 99.5% (w / v)% or less Is more preferably 90% (w / v) or more and 99.2% (w / v) or less.
  • the present composition may contain a preservative as an additive in order to exert the storage efficacy more, but as shown in the following examples, the present product has a high storage efficacy, so it can be used in an ophthalmic composition. It does not have to contain a commonly used preservative.
  • preservatives include, for example, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzododecinium bromide, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, Chlorhexidine and the like can be mentioned.
  • the composition is substantially free of preservatives.
  • substantially free of preservatives is meant that it contains no preservatives or contains a limited amount of preservatives.
  • containing a limited amount of preservative means an amount which does not exert the preservative efficacy of the preservative.
  • the term “preservative alone” means an amount which does not exert the efficacy as a medicine.
  • it preferably contains, for example, about 0.01% (w / w) or less of preservative, more preferably about 0.005% (w / w).
  • w) containing the following preservatives, more preferably containing about 0.001% (w / w) or less, still more preferably about 0.0005% (w / w) )
  • preservatives more preferably containing about 0.0001% (w / w) or less of preservatives.
  • a “multi-dose type eye drop container” comprises a container body for containing the composition, a pouring portion having a pouring outlet for pouring the composition contained in the container body, and a pouring outlet.
  • an inner plug that can be attached to the main body of the container may be used as a pouring portion, or a storage portion (container main body) for containing the present composition and the pouring portion are integrally molded. It may be composed of a container body and a cap for closing the spout.
  • the shape and size of the container are not particularly limited, and can be appropriately set according to the content, type, properties, etc. of the present composition to be contained.
  • the multi-dose container usually contains a plurality of ophthalmic compositions for use for a fixed period of time.
  • the volume of the container body of the multi-dose eye drop container is not particularly limited as long as it is within the range acceptable for the ophthalmic product, but 5 to 20 mL is preferable, 5 to 15 mL is more preferable, and 5 -10 mL is more preferred.
  • the total volume of the ophthalmic composition contained in the multi-dose eye drop container is not particularly limited as long as it is within the range allowed for the ophthalmic product, but 2 to 20 mL is preferable, 2 -10 mL is more preferred, and 2-5 mL is more preferred.
  • the multi-dose eyedropper is formed of resin, but the material is not particularly limited.
  • resins such as polyethylene (PE; high density polyethylene (HDPE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE), polypropylene (PP), polyethylene terephthalate (PET) and the like.
  • the silver-loaded zirconium phosphate is not particularly limited as long as it is contained in the resin of the multi-dose type eye drop container, but in order to exert the storage efficacy of the ophthalmic composition, the resin of the container main body It is preferable that at least a part or all of the resin in contact with the composition is contained. Further, that the silver-loaded zirconium phosphate is contained in the resin of the multi-dose type eye drop container means that the silver-loaded zirconium phosphate is dispersed and held in the resin of the multi-dose type eye drop container.
  • a “unit dose type container” is used in which the cap is fusion-sealed at the mouth portion, and the fusion portion between the cap and the bottle-shaped main body is broken and opened at the time of use.
  • the unit dose container generally contains a single-use aqueous composition for single use.
  • the volume of the container body of the unit dose type eye drop container is 0.1 to 1 mL, and usually 0.1 mL to 0.5 mL of the ophthalmic composition is accommodated.
  • the total contact area to the container body per unit volume of the ophthalmic composition is smaller in the multi-dose type eye drop container than in the unit dose type eye drop container.
  • the multi-dose type eye drop container is formed of a resin containing zirconium phosphate (hereinafter, also simply referred to as "silver-loaded zirconium phosphate”) on which silver is supported as an antibacterial agent.
  • a resin containing zirconium phosphate hereinafter, also simply referred to as "silver-loaded zirconium phosphate”
  • the silver-supported zirconium phosphate is one in which silver ion is supported on an inorganic ion exchanger, hexagonal zirconium phosphate using an ion exchange method.
  • Silver-loaded zirconium phosphate is commercially available from Toagosei Co., Ltd. as Novaron® AG.
  • a multi-dose type eye dropper container made of a resin containing silver-loaded zirconium phosphate can be produced by molding a heat-melted resin into which silver-loaded zirconium phosphate is blended and kneaded.
  • the silver-loaded zirconium phosphate is preferably contained at a concentration of 0.08 to 10% (w / w), more than 0.08 to 10% (w / w) relative to the resin. w) It is more preferably contained in the following concentration, still more preferably in the concentration of more than 0.08 to 5% (w / w), more than 0.08 to 1% (w / w) It is particularly preferred to include in concentration.
  • silver in silver-supported zirconium phosphate is preferably contained in an ion concentration of 0.001 to 20% (w / w), preferably 0.01 to 20% (w / w) Is more preferably 0.1 to 20% (w / w), still more preferably 0.5 to 15% (w / w), still more preferably 1 to 15% (w / w) It is particularly preferred to contain 5 to 15% (w / w).
  • the average particle diameter of the silver-loaded zirconium phosphate is preferably 0.01 to 3 ⁇ m, and more preferably 0.1 to 2 ⁇ m.
  • the present composition may contain appropriate amounts of various drugs singly or in combination as appropriate.
  • the drug is not particularly limited as long as it is a pharmaceutically acceptable drug.
  • drugs used for the prevention and / or treatment of eye diseases are mentioned.
  • drug is synonymous with the "active ingredient" of a drug.
  • the drug also includes a salt of a drug, and is not particularly limited as long as it is a pharmaceutically acceptable salt, and hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphorus Salts with inorganic acids such as acids, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1 , 2-Ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, la
  • inorganic acids such
  • Salts with halogen ions such as bromine ion, chloride ion and iodine ion; salts with alkali metals such as lithium, sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; with iron, zinc etc Metal salts of: salts with ammonia; triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- ( And salts with organic amines such as hydroxymethyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
  • halogen ions such as bromine ion, chloride ion and iodine ion
  • salts with alkali metals such as lithium, sodium and potassium
  • salts with alkaline earth metals such as calcium and magnesium
  • the drug or salt thereof contained in the present composition may be in the form of a hydrate or a solvate.
  • composition pharmaceutically acceptable additives can be blended as needed using widely used techniques.
  • surfactants for example, surfactants, buffers, tonicity agents, stabilizers, antioxidants, high molecular weight polymers and the like can be blended.
  • the composition further comprises at least one selected from the group consisting of surfactants and tonicity agents.
  • a cationic surfactant As surfactant, a cationic surfactant, an anionic surfactant, and a nonionic surfactant can be mix
  • anionic surfactants include sulfate surfactants, phospholipids and the like, and examples of sulfate surfactants include sodium alkyl sulfate, alkyl benzene sulfate and the like.
  • phospholipids include lecithin and the like.
  • cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkyl imidazolines, 1-acylaminoethyl- 2-alkyl imidazoline, 1-hydroxy ethyl 2-alkyl imidazoline etc. are mentioned.
  • nonionic surfactants include polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, Vitamin E TPGS etc. are mentioned.
  • polyoxyethylene fatty acid esters examples include polyoxyl 40 stearate and the like.
  • polyoxyethylene sorbitan fatty acid ester examples include polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 and the like.
  • Polysorbate 80 is particularly preferred.
  • polyoxyethylene hydrogenated castor oil various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used.
  • the polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, and 40 -70 are particularly preferred, 60 is most preferred.
  • Specific examples of polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 and the like.
  • polyoxyethylene castor oil various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 5 to 100, more preferably 20 to 50, and 30 to 40. Is particularly preferred and 35 is most preferred.
  • Specific examples of polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil and the like.
  • polyoxyethylene polyoxypropylene glycol polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) Examples thereof include glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol.
  • sucrose fatty acid ester sucrose stearic acid ester etc. are mentioned.
  • Vitamin E TPGS is also referred to as tocopherol polyethylene glycol 1000 succinate.
  • the content of the surfactant in the case of incorporating the surfactant into the present composition can be appropriately adjusted depending on the type of the surfactant and the like, but preferably 0.001 to 10% (w / v), 0 .01-5% (w / v) is more preferred, 0.01-3% (w / v) is more preferred, and 0.01-1% (w / v) is even more preferred.
  • surfactants may be used alone or in any combination of two or more.
  • the composition can be incorporated with a buffer that can be used as an additive of a pharmaceutical.
  • a buffer that can be used as an additive of a pharmaceutical.
  • phosphoric acid or a salt thereof citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ⁇ -aminocaproic acid, trometamol and the like can be mentioned.
  • the phosphate examples include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and the like, and as the citrate, citric acid Sodium, disodium citrate and the like can be mentioned, as acetate, sodium acetate, potassium acetate and the like can be mentioned, as carbonate, sodium carbonate, sodium hydrogencarbonate and the like can be mentioned, and as tartrate, sodium tartrate, Potassium tartrate and the like can be mentioned.
  • the content of the buffer in the case of incorporating the buffer into the present composition can be appropriately adjusted depending on the type of the buffer etc., but preferably 0.001 to 10% (w / v), 0.01 to 10%. 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.2 to 2% (w / v) is most preferable.
  • These buffers may be used alone or in any combination of two or more.
  • an isotonic agent which can be used as a pharmaceutical additive can be appropriately blended.
  • tonicity agents include ionic tonicity agents, non-ionic tonicity agents, and the like.
  • examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, boric acid, borax and the like, and non-ionic tonicity agents such as glycerin, propylene glycol, sorbitol, mannitol and the like It can be mentioned.
  • the content of the tonicity agent in the case of incorporating the tonicity agent into the present composition can be appropriately adjusted depending on the type of the tonicity agent etc., but 0.01 to 10% (w / v) Preferably, 0.1 to 5% (w / v) is more preferable, and 0.5 to 3% (w / v) is most preferable.
  • tonicity agents may be used alone or in any combination of two or more.
  • a stabilizer which can be used as an additive of a medicine can be appropriately blended.
  • examples thereof include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, and disodium edetate is preferred, and disodium edetate dihydrate is particularly preferred.
  • the content of the stabilizer in the case of incorporating the stabilizer into the present composition can be appropriately adjusted depending on the kind of the stabilizer etc., but preferably 0.0001 to 0.5% (w / v).
  • 0.0005 to 0.3% (w / v) is more preferable, 0.001 to 0.1% (w / v) is more preferable, and 0.002 to 0.08% (w / v) is more preferable
  • 0.003 to 0.07% (w / v) is more preferable, 0.005 to 0.06% (w / v) is particularly preferable, and 0.007 to 0.05% (w / v) is preferable.
  • 0.001 to 0.1% (w / v) is more preferable
  • 0.002 to 0.08% (w / v) is more preferable
  • 0.003 to 0.07% (w / v) is more preferable
  • 0.005 to 0.06% (w / v) is particularly preferable
  • 0.007 to 0.05% (w / v) is preferable.
  • These stabilizers may be used alone or in any combination of two or more.
  • an antioxidant which can be used as an additive of a medicine can be appropriately blended.
  • antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
  • the content of the antioxidant in the case of incorporating the antioxidant into the present composition can be appropriately adjusted according to the type of the antioxidant etc., but preferably 0.0001 to 1% (w / v), 0 .001 to 0.1% (w / v) is more preferable, and 0.005 to 0.01% (w / v) is most preferable.
  • antioxidants may be used alone or in any combination of two or more.
  • a high molecular weight polymer which can be used as an additive of a medicine can be appropriately blended.
  • high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, Carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol and the like can be mentioned.
  • the content of the high molecular weight polymer in the case of incorporating the high molecular weight polymer into the present composition can be appropriately adjusted depending on the type of the high molecular weight polymer and the like, but 0.001 to 5% (w / v) Preferably, 0.01 to 3% (w / v) is more preferable, and 0.1 to 1% (w / v) is most preferable.
  • These high molecular weight polymers may be used alone or in any combination of two or more.
  • the osmotic pressure of the present composition is not limited to a specific value, but is in a range acceptable to the living body.
  • the osmotic pressure of the aqueous composition of the present invention is, for example, 100 to 1000 mOsm, preferably 200 to 500 mOsm, more preferably 250 to 350 mOsm.
  • the osmotic pressure of the aqueous composition is affected to some extent by the amount of drug and additive in the aqueous composition.
  • the osmotic pressure can be adjusted to be in the above range by appropriately adjusting the amount of these substances that can affect the osmotic pressure.
  • the osmotic pressure of the aqueous composition of the present invention can be measured in a conventional manner.
  • the osmotic pressure of the aqueous composition of the present invention can be measured according to the method described in “Osmometry (Osmolality measurement)” of the fifteenth revision Japanese Pharmacopoeia.
  • the pH of the composition is not particularly limited as long as it is within the range acceptable for ophthalmic products, but less than 7 is preferable, 3 or more and less than 7 is more preferable, 3 or more and 6 or less is more preferable, and 4 or more and 6 or less is more More preferably, the vicinity of 5 is particularly preferred. More specifically, for example, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4. 0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8. 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6. 5, 6.6, 6.7, 6.8 or 6.9.
  • the pH of the present composition can be adjusted by blending a pH regulator such as hydrochloric acid, sulfuric acid, nitric acid, boric acid and / or sodium hydroxide as an additive.
  • An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-supported zirconium phosphate.
  • An ophthalmic composition having a pH of less than 7 in a multi-dose eyedropper formed of a resin containing silver-loaded zirconium phosphate at a concentration of 0.08 to 10% (w / w) relative to the resin
  • An ophthalmic product comprising 0.001 to 20% (w / w), wherein the ophthalmic composition is substantially free of preservatives.
  • ophthalmic product according to any one of [1] to [10], wherein the ophthalmic composition further comprises at least one selected from the group consisting of a surfactant and a tonicity agent. .
  • the nonionic surfactant is polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester
  • the ophthalmic product according to [12] which is at least one selected from the group consisting of and vitamin E TPGS.
  • ⁇ Silver-loaded zirconium phosphate blend plate> A polypropylene plate (height 2 mm; height of plate; plate table with silver-loaded zirconium phosphate (Manufacturer: Toagosei Co., Ltd., product name: Novalon (registered trademark) AG1100) at a concentration of 0.5% (w / w) The total surface area of the back is 120 cm 2 ).
  • ⁇ Silver-loaded zeolite blended plate Polyethylene plate (height 2 mm; surface area of the front and back of the plate is 120 cm 2 in total) mixed with 0.5% (w / w) concentration of silver-loaded zeolite (by: Cinamin Zeomic, product name: DAW 502) Is created.
  • the prepared plastic plate was placed in a sterilized glass Pyrex bottle, and then 15 mL of physiological saline was added, and the plastic plate was immersed to prepare a sample to be used for the test.
  • the contact area of the plastic plate with saline is 8 cm 2 / mL.
  • the preservation efficacy test was conducted with reference to the preservation efficacy test method of the 15th Amended Japanese Pharmacopoeia.
  • the test bacteria were inoculated, and the number of bacteria was measured after 14 and 28 days.
  • Esherichia Coli E. coli
  • Pseudomonas aeruginosa P. aeruginosa
  • Test results The test results are shown in Table 1.
  • the test result (initial value, 14 days after, 28 days after) of Table 1 has shown a microbe number time-dependent change (piece / mL).
  • ⁇ Silver-loaded zirconium phosphate blend plate Polypropylene blended with silver supported zirconium phosphate (Manufacturer: Toagosei Co., Ltd., product name: Novalon (registered trademark) AG1100) at a concentration of 0.5% (w / w) or 1.0% (w / w) Each plate was made.
  • ⁇ Silver-loaded glass blend plate> The polypropylene plate which the silver carrying glass (maker: Ishizuka glass, product name: JN) of the density
  • JP JCAB General Test Method “Plastic Drug Container Test Method” 1 Ashing Test 1 ⁇ 2 Heavy Metals (Standards and Test Methods of Plastic Containers for Eye Drops (Drug 336 (March 28, 1996)) If the color of the test solution is not darker (20 ppm or less) than that of the comparison solution when the test is conducted according to the method of However, the container section collection amount is 1.0 g.
  • Constant efficacy test-2 A storage efficacy test was conducted using a multi-dose type eye dropper container made of a resin containing silver-loaded zirconium phosphate.
  • Eye drops 1 The eye drop 1 was prepared according to the formulation shown in Table 3. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent: 0.01 g) and concentrated glycerin (tonicity agent; 1.4 g) are dissolved in water, diluted hydrochloric acid (pH regulator) ) To bring the pH to around 5, and then an appropriate amount of water was added to make the total volume 100 mL.
  • API diquafosol sodium
  • sodium edetate chelating agent: 0.01 g
  • concentrated glycerin tonicity agent
  • Eye drops 2 were prepared according to the formulation shown in Table 3. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent: 0.01 g), boric acid (tonicity agent; 1.1 g) is dissolved in water, sodium hydroxide (pH A regulator was added to adjust the pH to around 5, and an appropriate amount of water was then added to make the total volume 100 mL.
  • API diquafosol sodium
  • sodium edetate chelating agent: 0.01 g
  • boric acid tonicity agent
  • pH sodium hydroxide
  • Eye drop 3 An eye drop 3 was prepared according to the formulation shown in Table 3. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent: 0.01 g) and concentrated glycerin (tonicity agent; 1.4 g) are dissolved in water, diluted hydrochloric acid (pH regulator) ) To bring the pH to around 5, and then an appropriate amount of water was added to make the total volume 100 mL.
  • API diquafosol sodium
  • sodium edetate chelating agent: 0.01 g
  • concentrated glycerin tonicity agent
  • Eye drop 4 An eye drop 4 was prepared according to the formulation shown in Table 3. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent: 0.01 g), boric acid (tonicity agent; 1.1 g) is dissolved in water, sodium hydroxide (pH A regulator was added to adjust the pH to around 5, and an appropriate amount of water was then added to make the total volume 100 mL.
  • API diquafosol sodium
  • sodium edetate chelating agent: 0.01 g
  • boric acid tonicity agent; 1.1 g
  • pH A regulator was added to adjust the pH to around 5, and an appropriate amount of water was then added to make the total volume 100 mL.
  • diquafosol sodium was used as an API, when stored in eye drops, there is a possibility that a visible insoluble precipitate may be generated, and sodium edetate which is a chelating agent is added (International Publication WO 2012-090994) See brochure).
  • Eye drop container To the heat-melted polyethylene resin, add 0.08% (w / w) or 1% (w / w) of silver-supported zirconium phosphate having an average particle diameter of 1 ⁇ m containing 10% (w / w) of silver as ion concentration The mixture was uniformly mixed to prepare a container body (volume 7.9 mL, height 45.2 mm, body type 19.45 mm) of the eye drop container.
  • a silver-based inorganic antibacterial agent "Novaron (registered trademark) AG" 1100 manufactured by Toagosei Co., Ltd. was used.
  • the preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 17th revised Japanese Pharmacopoeia.
  • Esherichia Coli E. coli
  • Pseudomonas aeruginosa P. aeruginosa
  • Staphylococcus aureus S. aureus
  • Candida albicans C. albicans
  • Aspergillus brasiliensis A. brasiliensis
  • a soy bean / casein / digest agar medium was used in the case of bacteria, and a Sabouraud's glucose medium was used in the case of fungi.
  • a soy bean / casein / digest agar medium was used in the case of bacteria, and a Sabouraud's glucose medium was used in the case of fungi.
  • 18 to 24 hours at 30 to 35 ° C. Candida albicans for 44 to 52 hours at 20 to 25 ° C.
  • Aspergillus brasiliensis was precultured at 20 to 25 ° C. for 1 week or until sufficient spores were formed.
  • Eye drops 1 to 4 were dispensed in 5 mL each into the 5 sterilized eye drop containers, and the inside plug was attached and sealed with a cap. After 1-month dark storage at 60 ° C., the precultured test bacteria were inoculated at 10 5 to 10 6 cells / mL. The test bacteria were not mixed, and each sample was inoculated alone. The liquid sampled 0.5 mL from each mixed sample after 1 week, 2 weeks and 4 weeks of storage start was cultured, and the viable cell count was measured.
  • Test results The test results are shown in Table 5.
  • the test results in Table 5 show by log reduction how much the number of viable bacteria at the time of examination decreased compared to the number of inoculated bacteria. For example, in the case of “1”, the number of viable bacteria at the time of examination Shows a reduction to 10% of the inoculum count.
  • the total contact area to the container body per unit volume of the ophthalmic composition is smaller in the multi-dose type eye drop container than in the unit dose type eye drop container. It was shown that this product has excellent storage efficacy even with a multi-dose type eye drop container.
  • Eye drops An eye drop 5 was prepared according to the formulation shown in Table 6. Specifically, concentrated glycerin (1.3 g) and sodium hydrogen phosphate hydrate (1.0 g) are dissolved in water, a pH regulator (1 N sodium hydroxide solution / sulfuric acid) is added, and the pH is adjusted to 5 After adjusting to 0, an appropriate amount of water was added to make the total volume 100 mL.
  • the eye drops 6 to 8 were also prepared in the same manner as the eye drop 5 according to the formulation shown in Table 6.
  • Eye drop container Add 0.5% (w / w) of silver-loaded zirconium phosphate with an average particle diameter of 1 ⁇ m containing 10% (w / w) of silver in an ion concentration to the heat-melted polyethylene resin and mix uniformly.
  • a container body (volume 7.9 mL, height 45.2 mm, barrel type 19.45 mm) was produced.
  • As silver-supported zirconium phosphate a silver-based inorganic antibacterial agent "Novaron (registered trademark) AG" 1100 manufactured by Toagosei Co., Ltd. was used.
  • the preservation efficacy test was conducted with reference to the preservation efficacy test method of the 17th revised Japanese Pharmacopoeia.
  • Esherichia Coli E. coli
  • Pseudomonas aeruginosa P. aeruginosa
  • Staphylococcus aureus S. aureus
  • Each of these strains was inoculated on the surface of agar slant medium and precultured.
  • a soy bean / casein / digest agar medium was used as the agar medium for pre-culture. It was precultured at 30 to 35 ° C. for 18 to 24 hours.
  • the eye drops 5 to 8 were dispensed in 5 mL portions into each of five sterilized eye drop containers, and the inside plug was attached and sealed with a cap. After 1 month dark storage at 60 ° C., the precultured test bacteria were inoculated at 10 5 to 10 6 cells / mL. The test bacteria were not mixed, and each sample was inoculated alone. The liquid which sampled 0.5 mL from each mixed sample after 1 week and 2 weeks of storage start was culture
  • Test results The test results are shown in Table 8.
  • the test results in Table 8 show how much the number of viable bacteria at the time of examination decreased compared to the number of inoculated bacteria, and in the case of “1”, for example, the number of viable bacteria at the time of examination Shows a reduction to 10% of the inoculum count.
  • Example 8 the storage efficacy of the product containing an eye drop near neutral pH was low (Comparative Example 1), but the product containing an eye drop near an acidic pH was 60 ° C. It was shown to have high preservation efficacy even after storage for 1 month (Examples 1 to 3). In particular, the product containing an eye drop containing polysorbate 80, which has a pH near acidic, was shown to have excellent storage efficacy (Example 3).
  • Formulation Example 1 Aqueous ophthalmic solution Sodium hydrogen phosphate 0.2 g in 100 mL Concentrated glycerin 2.4g Edetate sodium 0.01g pH adjuster Appropriate amount Water Appropriate amount Sodium hydrogen phosphate (0.2 g), concentrated glycerin (2.4 g), sodium edetate (0.01 g) are dissolved in water, pH adjuster (hydrochloric acid or sodium hydroxide solution) In addition, after the pH is adjusted to 5.0, an appropriate amount of water is added to adjust the total volume to 100 mL, and the eye drop can be prepared by sufficiently stirring.
  • pH adjuster hydroochloric acid or sodium hydroxide solution
  • Formulation Example 2 Aqueous Eye Drop 100g of concentrated glycerin 1.2g 1.0 g of boric acid pH adjuster Appropriate amount of water Appropriate amount After dissolving concentrated glycerin (1.2 g) and boric acid (1.0 g) in water and adding a pH adjuster (hydrochloric acid or sodium hydroxide solution) to adjust the pH to 5.0 An eye drop can be prepared by adding an appropriate amount of water to make the total volume 100 mL and sufficiently stirring.
  • a pH adjuster hydroochloric acid or sodium hydroxide solution
  • An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate has excellent storage efficacy.
  • the present invention is useful because it can be used for a plurality of times for a fixed period without physical structure such as the above-mentioned anti-return valve or filter-attached delamination bottle, and there is no disadvantage of the above unit dose type eye drop container.

Abstract

The purpose of the present invention is to provide an ophthalmic product that can be used a plurality of times during a certain period of time even without using a physical structure. The ophthalmic product according to the present invention comprises an ophthalmic composition having a pH less than 7 that is held in a multidose eyedrop container formed of a resin containing a silver-loaded zirconium phosphate.

Description

眼科用製品Ophthalmic products
　本発明は、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品に関する。 The present invention relates to an ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate.
　点眼容器には、複数回使用可能なマルチドーズ型点眼容器と１回使い切りユニットドーズ型点眼容器がある。マルチドーズ型点眼容器は、一定期間複数回使用することから菌類等の繁殖を防止するために眼科用組成物に塩化ベンザルコニウムなどの防腐剤が配合されるのが一般的である。しかし、例えば、防腐剤である塩化ベンザルコニウムには細胞障害性があり、曝露量が増えると角膜上皮障害を引き起こす可能性があることから防腐剤を含まないことがより望ましい。そのため、防腐剤を含まない眼科用組成物を収容する点眼容器として、上述のユニットドーズ点眼容器が使用されている。また、近年では、導出孔に逆流防止弁を有することで防腐効果を発揮する容器やフィルター付きのデラミボトルとすることで防腐効果を発揮する容器など、物理的な構造によって防腐剤を含まずとも防腐効果を発揮するマルチドーズ型点眼容器（ＰＦＭＤ（Ｐｒｅｓｅｒｖａｔｉｖｅ　Ｆｒｅｅ
　Ｍｕｌｔｉ　Ｄｏｓｅ）容器）も使用されている（例えば特許文献１など）。 The eye drop containers include a multi-dose type drop container which can be used multiple times and a single use unit dose type drop container. Since the multi-dose type eye dropper container is used for a plurality of times for a fixed period, a preservative such as benzalkonium chloride is generally added to the ophthalmic composition in order to prevent the growth of fungi and the like. However, for example, benzalkonium chloride, which is a preservative, is cytotoxic, and it is more desirable not to include a preservative because it may cause corneal epithelial disorder if the exposure dose is increased. Therefore, the above-mentioned unit dose eye drop container is used as an eye drop container for containing an ophthalmic composition which does not contain a preservative. Also, in recent years, the container has a preservative effect by having a backflow prevention valve in the outlet hole, and a container that exerts a preservative effect by making it a delamination bottle with a filter. Multi-dose eye dropper (PFMD (Preservative Free)
Multi-Dose containers) are also used (for example, Patent Document 1).
　ところで、特許文献２には、容器の全面または所要部分に抗菌性ゼオライトが分散保持されたユニットドーズ型点眼容器が開示されており（技術分野、請求項１、２２など）、点眼容器の抗菌力が確認されたことが示されている（試験例－１）。しかし、一般にユニットドーズ型点眼容器は１回使い切りのためコストが高く、かさばる、あるいは開封がしにくいといった使用上の欠点もある。 Patent Document 2 discloses a unit dose type eye drop container in which antibacterial zeolite is dispersed and held on the entire surface or a required portion of the container (Technical field, claims 1, 22 etc.) Has been confirmed (Test Example 1). However, unit dose type eye drop containers generally have high cost because they are used up once, and also have use disadvantages such as being bulky or difficult to open.
特開２００２－８００５５号公報JP 2002-80055 A 国際公開ＷＯ９７／０１４９３号パンフレットInternational Publication WO 97/01493 Brochure
　本発明の一態様の課題は、上述の逆流防止弁やフィルター付きデラミボトルなど物理的な構造を施さなくても、一定期間複数回使用できる眼科用製品を提供することである。 An object of one aspect of the present invention is to provide an ophthalmic product that can be used multiple times for a certain period of time without performing physical structures such as the above-described check valve and the delamination bottle with a filter.
　本発明者は、上記課題を解決するために鋭意研究を行った結果、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品が優れた保存効力を有することを見出し、本発明を完成させた。 As a result of intensive studies to solve the above problems, the inventor of the present invention has found that an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container made of a resin containing silver-loaded zirconium phosphate. The present invention has been completed by finding that the obtained ophthalmic products have excellent preservation efficacy.
　すなわち、本発明の一態様に係る眼科用製品は、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された構成である。 That is, the ophthalmic product according to an aspect of the present invention has a configuration in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate. .
　また、本発明の他の態様に係る眼科用製品は、樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品であって、前記眼科用組成物と接触している前記樹脂の一部または全部が銀担持リン酸ジルコニウムを含み、前記銀担持リン酸ジルコニウムが、銀をイオン濃度で０．００１～２０％（ｗ／ｗ）含み、前記眼科用組成物が防腐剤を実質的に含有しない、構成である。 In addition, an ophthalmic product according to another aspect of the present invention is a multi-dose eye drop formed of a resin containing silver-loaded zirconium phosphate at a concentration of 0.08 to 10% (w / w) based on the resin. An ophthalmic product containing an ophthalmic composition having a pH of less than 7 in a container, wherein part or all of said resin in contact with said ophthalmic composition comprises silver-loaded zirconium phosphate, The silver-loaded zirconium phosphate contains silver in an ion concentration of 0.001 to 20% (w / w), and the ophthalmic composition is substantially free of a preservative.
　さらに、本発明のさらに他の態様に係る眼科用組成物は、ｐＨが７未満である眼科用組成物であって、前記眼科用組成物が、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に収容されている。 Furthermore, the ophthalmic composition which concerns on the further another aspect of this invention is an ophthalmic composition whose pH is less than 7, Comprising: The said ophthalmic composition was formed by resin containing a silver carrying | support zirconium phosphate. It is housed in a multi-dose type eye drop container.
　銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品は、優れた保存効力を有する。本発明の態様によれば、上述の逆流防止弁やフィルター付きデラミボトルなど物理的な構造を施さなくても、一定期間複数回使用でき、上述のユニットドーズ型点眼容器の欠点もないことから有用である。 An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate has excellent storage efficacy. According to the aspect of the present invention, it is useful because it can be used multiple times for a fixed period without physical structure such as the above-mentioned backflow prevention valve or filter-attached delamination bottle, and there is no defect of the above unit dose type eye drop container is there.
　以下、本発明の一実施形態に関してさらに詳しく説明する。なお、本明細書において特記しない限り、数値範囲を表す「Ａ～Ｂ」または「Ａ乃至Ｂ」は、「Ａ以上（Ａを含みかつＡよりも大きい）、Ｂ以下（Ｂを含みかつＢよりも小さい）」を意味する。また、「Ａ超乃至Ｂ」は、「Ａを超え（Ａより大きい）、Ｂ以下（Ｂを含みかつＢより小さい）」を意味する。 Hereinafter, one embodiment of the present invention will be described in more detail. In the present specification, unless otherwise specified, “A to B” or “A to B” representing a numerical range are “A or more (including A and greater than A), B or less (including B and B) Means small. Also, “A to B” means “more than A (greater than A) and B or less (including B and less than B)”.
　本発明の一実施形態は、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器（以下、「本点眼容器」ともいう）に、ｐＨが７未満である眼科用組成物（以下、「本組成物」ともいう）が収容された眼科用製品（以下、「本製品」ともいう）を提供する。ここで、「本製品」としては、例えば、点眼剤の製品（「点眼剤製品」ともいう）が挙げられる。 One embodiment of the present invention is an ophthalmic composition having a pH of less than 7 (hereinafter referred to as “the present eye container”) formed of a resin containing silver-loaded zirconium phosphate (hereinafter referred to as “the present eye container”). And an ophthalmic product (hereinafter, also referred to as a "present product") containing the "present composition". Here, as the "present product", for example, an eye drop preparation product (also referred to as "eye drop preparation product") can be mentioned.
　本発明の一実施形態において、「眼科用組成物」とは、眼疾患などの予防および／または治療に使用するための組成物のことをいう。その剤型としては、例えば、点眼剤が挙げられる。ここで点眼剤とは点眼液または点眼薬と同義であり、コンタクトレンズ用点眼剤も点眼剤の定義に含まれる。 In one embodiment of the present invention, "ophthalmic composition" refers to a composition for use in the prevention and / or treatment of ocular diseases and the like. Examples of the dosage form include eye drops. Here, eye drops are synonymous with eye drops or eye drops, and eye drops for contact lenses are also included in the definition of eye drops.
　本組成物の形態としては、特に制限されないが、例えば、水溶液、懸濁液、乳濁液、ゲルなどが挙げられる。 The form of the present composition is not particularly limited, and includes, for example, an aqueous solution, a suspension, an emulsion, a gel and the like.
　本組成物が点眼剤、特に水性点眼剤である場合、溶媒として水を含有することが好ましい。水の例としては、滅菌精製水、注射用水等を挙げることができる。水の含有量としては、例えば、８０％（ｗ／ｖ）以上１００％（ｗ／ｖ）未満であることが好ましく、８５％（ｗ／ｖ）以上９９．５％（ｗ／ｖ）％以下であることがより好ましく、９０％（ｗ／ｖ）以上９９．２％（ｗ／ｖ）以下であることがさらに好ましい。 When the composition is an eye drop, particularly an aqueous eye drop, it is preferable to contain water as a solvent. Examples of water include sterile purified water, water for injection, and the like. The water content is, for example, preferably 80% (w / v) or more and less than 100% (w / v), and is 85% (w / v) or more and 99.5% (w / v)% or less Is more preferably 90% (w / v) or more and 99.2% (w / v) or less.
　本組成物は、保存効力をより発揮するために、添加物として防腐剤を含んでもよいが、後述の実施例に示すように、本製品は高い保存効力を有することから、眼科用組成物に一般に使用される防腐剤を含有しなくてもよい。防腐剤の例としては、例えば、ベンザルコニウム塩化物、ベンザルコニウム臭化物、ベンゼトニウム塩化物、ベンゾドデシニウム臭化物、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、クロロブタノール、クロルヘキシジンなどが挙げられる。 The present composition may contain a preservative as an additive in order to exert the storage efficacy more, but as shown in the following examples, the present product has a high storage efficacy, so it can be used in an ophthalmic composition. It does not have to contain a commonly used preservative. Examples of preservatives include, for example, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzododecinium bromide, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, Chlorhexidine and the like can be mentioned.
　本発明の一実施形態において、本組成物が防腐剤を実質的に含有しないことが好ましい。「防腐剤を実質的に含有しない」とは、防腐剤を全く含有しないか、または限られた量の防腐剤を含有することを意味する。ここで、「限られた量の防腐剤を含有する」とは、防腐剤の防腐効力を発揮しない量を意味する。例えば、防腐剤単独で医薬としての防腐効力を発揮しない量を意味することが挙げられる。具体的には、防腐剤の種類によっても異なるが、例えば、好ましくは約０．０１％（ｗ／ｗ）以下の防腐剤を含有することをいい、より好ましくは約０．００５％（ｗ／ｗ）以下の防腐剤を含有することをいい、さらに好ましくは約０．００１％（ｗ／ｗ）以下の防腐剤を含有することをいい、よりさらに好ましくは約０．０００５％（ｗ／ｗ）以下の防腐剤を含有することをいい、特に好ましくは約０．０００１％（ｗ／ｗ）以下の防腐剤を含有することをいう。 In one embodiment of the present invention, it is preferred that the composition is substantially free of preservatives. By "substantially free of preservatives" is meant that it contains no preservatives or contains a limited amount of preservatives. Here, "containing a limited amount of preservative" means an amount which does not exert the preservative efficacy of the preservative. For example, the term “preservative alone” means an amount which does not exert the efficacy as a medicine. Specifically, although it varies depending on the type of preservative, it preferably contains, for example, about 0.01% (w / w) or less of preservative, more preferably about 0.005% (w / w). w) containing the following preservatives, more preferably containing about 0.001% (w / w) or less, still more preferably about 0.0005% (w / w) ) Refers to containing the following preservatives, particularly preferably containing about 0.0001% (w / w) or less of preservatives.
　本発明の一実施形態において、「マルチドーズ型点眼容器」は、本組成物を収容する容器本体、容器本体に収容された本組成物を注出する注出口を有する注出部、および注出口をふさぐキャップを備えた点眼容器であって、キャップの開封、再封を自由に行うことができる点眼容器のことをいう。ここで、マルチドーズ型点眼容器は、容器本体に装着可能な中栓を注出部として使用してもよいし、本組成物を収容する収容部（容器本体）と注出部が一体成型された容器本体および注出口をふさぐキャップから構成されていてもよい。当該容器の形状、大きさについては特に制限されるものではなく、収容する本組成物の含量、種類、性質等に応じて適宜設定することができる。 In one embodiment of the present invention, a “multi-dose type eye drop container” comprises a container body for containing the composition, a pouring portion having a pouring outlet for pouring the composition contained in the container body, and a pouring outlet. An eye drop container equipped with a cap for closing the cap, which can be freely opened and resealed. Here, in the multi-dose type eye drop container, an inner plug that can be attached to the main body of the container may be used as a pouring portion, or a storage portion (container main body) for containing the present composition and the pouring portion are integrally molded. It may be composed of a container body and a cap for closing the spout. The shape and size of the container are not particularly limited, and can be appropriately set according to the content, type, properties, etc. of the present composition to be contained.
　当該マルチドーズ型容器には、通常一定期間使用するために複数回分の眼科用組成物が収容されている。 The multi-dose container usually contains a plurality of ophthalmic compositions for use for a fixed period of time.
　本発明の一実施形態において、マルチドーズ型点眼容器の容器本体の容量は眼科用製品に許容される範囲内にあれば特に制限されないが、５～２０ｍＬが好ましく、５～１５ｍＬがより好ましく、５～１０ｍＬがさらに好ましい。 In one embodiment of the present invention, the volume of the container body of the multi-dose eye drop container is not particularly limited as long as it is within the range acceptable for the ophthalmic product, but 5 to 20 mL is preferable, 5 to 15 mL is more preferable, and 5 -10 mL is more preferred.
　本発明の一実施形態において、マルチドーズ型点眼容器に収容される眼科用組成物の総容量は、眼科用製品に許容される範囲内にあれば特に制限されないが、２～２０ｍＬが好ましく、２～１０ｍＬがより好ましく、２～５ｍＬがさらに好ましい。 In the embodiment of the present invention, the total volume of the ophthalmic composition contained in the multi-dose eye drop container is not particularly limited as long as it is within the range allowed for the ophthalmic product, but 2 to 20 mL is preferable, 2 -10 mL is more preferred, and 2-5 mL is more preferred.
　本発明の一実施形態において、マルチドーズ型点眼容器は樹脂で形成されるが、その材質は特に限定されない。例えば、ポリエチレン（ＰＥ；高密度ポリエチレン（ＨＤＰＥ）、低密度ポリエチレン（ＬＤＰＥ）、直鎖状低密度ポリエチレン（ＬＬＤＰＥ））、ポリプロピレン（ＰＰ）、ポリエチレンテレフタレート（ＰＥＴ）などの樹脂を挙げることができる。 In one embodiment of the present invention, the multi-dose eyedropper is formed of resin, but the material is not particularly limited. Examples thereof include resins such as polyethylene (PE; high density polyethylene (HDPE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE), polypropylene (PP), polyethylene terephthalate (PET) and the like.
　本発明の一実施形態において、銀担持リン酸ジルコニウムはマルチドーズ型点眼容器の樹脂に含まれていれば特に制限されないが、眼科用組成物の保存効力を発揮させるためには、容器本体の樹脂に含まれていることが好ましく、本組成物と接触している樹脂の一部または全部に少なくとも含まれていることがより好ましい。また、銀担持リン酸ジルコニウムがマルチドーズ型点眼容器の樹脂に含まれるとは、銀担持リン酸ジルコニウムがマルチドーズ型点眼容器の樹脂に分散保持されていることを意味する。 In one embodiment of the present invention, the silver-loaded zirconium phosphate is not particularly limited as long as it is contained in the resin of the multi-dose type eye drop container, but in order to exert the storage efficacy of the ophthalmic composition, the resin of the container main body It is preferable that at least a part or all of the resin in contact with the composition is contained. Further, that the silver-loaded zirconium phosphate is contained in the resin of the multi-dose type eye drop container means that the silver-loaded zirconium phosphate is dispersed and held in the resin of the multi-dose type eye drop container.
　なお、本発明の一実施形態において、「ユニットドーズ型容器」とは、瓶口部にキャップが融着封止され、使用時に当該キャップと瓶形本体との融着部を破断開封して使用することを目的とした点眼容器のことをいう。当該ユニットドーズ型容器には、１回使い切りのために１回使用分の水性組成物が収容されているのが一般的である。また、一般に、ユニットドーズ型点眼容器の容器本体の容量は０．１～１ｍＬであり、通常０．１ｍＬ～０．５ｍＬの眼科用組成物が収容される。 In one embodiment of the present invention, a “unit dose type container” is used in which the cap is fusion-sealed at the mouth portion, and the fusion portion between the cap and the bottle-shaped main body is broken and opened at the time of use. Refers to an eye drop container intended to The unit dose container generally contains a single-use aqueous composition for single use. In general, the volume of the container body of the unit dose type eye drop container is 0.1 to 1 mL, and usually 0.1 mL to 0.5 mL of the ophthalmic composition is accommodated.
　一般に、眼科用組成物の単位容量あたりの容器本体への全接触面積は、マルチドーズ型点眼容器の方がユニットドーズ型点眼容器よりも小さい。 Generally, the total contact area to the container body per unit volume of the ophthalmic composition is smaller in the multi-dose type eye drop container than in the unit dose type eye drop container.
　本発明の一実施形態におけるマルチドーズ型点眼容器は、抗菌剤として銀が担持されたリン酸ジルコニウム（以下、単に「銀担持リン酸ジルコニウム」ともいう）を含む樹脂で形成されている。 The multi-dose type eye drop container according to one embodiment of the present invention is formed of a resin containing zirconium phosphate (hereinafter, also simply referred to as "silver-loaded zirconium phosphate") on which silver is supported as an antibacterial agent.
　銀担持リン酸ジルコニウムは、無機イオン交換体である六方晶リン酸ジルコニウムに、イオン交換法を用いて銀イオンを担持させたものである。 The silver-supported zirconium phosphate is one in which silver ion is supported on an inorganic ion exchanger, hexagonal zirconium phosphate using an ion exchange method.
　銀担持リン酸ジルコニウムは、ノバロン（登録商標）ＡＧとして東亞合成株式会社から販売されている。 Silver-loaded zirconium phosphate is commercially available from Toagosei Co., Ltd. as Novaron® AG.
　銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器は、銀担持リン酸ジルコニウムを配合して練り込んだ加熱融解状の樹脂を成形することによって製造することができる。 A multi-dose type eye dropper container made of a resin containing silver-loaded zirconium phosphate can be produced by molding a heat-melted resin into which silver-loaded zirconium phosphate is blended and kneaded.
　本発明の一実施形態において、銀担持リン酸ジルコニウムは、樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度で含まれることが好ましく、０．０８超乃至１０％（ｗ／ｗ）以下の濃度で含まれることがより好ましく、０．０８超乃至５％（ｗ／ｗ）以下の濃度で含まれることがさらに好ましく、０．０８超乃至１％（ｗ／ｗ）以下の濃度で含まれることが特に好ましい。 In one embodiment of the present invention, the silver-loaded zirconium phosphate is preferably contained at a concentration of 0.08 to 10% (w / w), more than 0.08 to 10% (w / w) relative to the resin. w) It is more preferably contained in the following concentration, still more preferably in the concentration of more than 0.08 to 5% (w / w), more than 0.08 to 1% (w / w) It is particularly preferred to include in concentration.
　本発明の一実施形態において、銀担持リン酸ジルコニウム中の銀はイオン濃度で、０．００１～２０％（ｗ／ｗ）含むことが好ましく、０．０１～２０％（ｗ／ｗ）含むことがより好ましく、０．１～２０％（ｗ／ｗ）含むことがさらに好ましく、０．５～１５％（ｗ／ｗ）含むことがよりさらに好ましく、１～１５％（ｗ／ｗ）含むことがことさら好ましく、５～１５％（ｗ／ｗ）含むことが特に好ましい。 In one embodiment of the present invention, silver in silver-supported zirconium phosphate is preferably contained in an ion concentration of 0.001 to 20% (w / w), preferably 0.01 to 20% (w / w) Is more preferably 0.1 to 20% (w / w), still more preferably 0.5 to 15% (w / w), still more preferably 1 to 15% (w / w) It is particularly preferred to contain 5 to 15% (w / w).
　本発明の一実施形態において、点眼容器は薄肉であることから、銀担持リン酸ジルコニウムの平均粒径は０．０１～３μｍであることが好ましく、０．１～２μｍであることがより好ましい。 In one embodiment of the present invention, since the eye drop container is thin, the average particle diameter of the silver-loaded zirconium phosphate is preferably 0.01 to 3 μm, and more preferably 0.1 to 2 μm.
　本組成物は、種々の薬物を単独または適宜組み合わせて適当量含有してもよい。当該薬物は、医薬として許容される薬物であれば特に限定されない。例えば、眼疾患の予防及び／又は治療に使用される薬物が挙げられる。なお、ここで「薬物」は、薬の「有効成分」と同義である。 The present composition may contain appropriate amounts of various drugs singly or in combination as appropriate. The drug is not particularly limited as long as it is a pharmaceutically acceptable drug. For example, drugs used for the prevention and / or treatment of eye diseases are mentioned. Here, "drug" is synonymous with the "active ingredient" of a drug.
　本発明の一実施形態において、薬物としては、薬物の塩も含まれ、医薬として許容される塩であれば特に制限はなく、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸などの無機酸との塩、酢酸、フマル酸、マレイン酸、コハク酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、乳酸、馬尿酸、１，２－エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、硫酸ラウリルエステル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸などの有機酸との塩；臭化メチル、ヨウ化メチルなどとの四級アンモニウム塩；臭素イオン、塩素イオン、ヨウ素イオンなどのハロゲンイオンとの塩；リチウム、ナトリウム、カリウムなどのアルカリ金属との塩；カルシウム、マグネシウムなどのアルカリ土類金属との塩；鉄、亜鉛などとの金属塩；アンモニアとの塩；トリエチレンジアミン、２－アミノエタノール、２，２－イミノビス（エタノール）、１－デオキシ－１－（メチルアミノ）－２－Ｄ－ソルビトール、２－アミノ－２－（ヒドロキシメチル）－１，３－プロパンジオール、プロカイン、Ｎ，Ｎ－ビス（フェニルメチル）－１，２－エタンジアミンなどの有機アミンとの塩などが挙げられる。 In one embodiment of the present invention, the drug also includes a salt of a drug, and is not particularly limited as long as it is a pharmaceutically acceptable salt, and hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphorus Salts with inorganic acids such as acids, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1 , 2-Ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate Salts with organic acids such as naphthalenesulfonic acid and sulfosalicylic acid; quaternary ammonium salts with methyl bromide, methyl iodide, etc. Salts with halogen ions such as bromine ion, chloride ion and iodine ion; salts with alkali metals such as lithium, sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; with iron, zinc etc Metal salts of: salts with ammonia; triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- ( And salts with organic amines such as hydroxymethyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
　本組成物に含有される薬物またはその塩は、水和物または溶媒和物の形態をとってもよい。 The drug or salt thereof contained in the present composition may be in the form of a hydrate or a solvate.
　本組成物には、汎用されている技術を用い、必要に応じて製薬学的に許容される添加物を配合することができる。例えば、界面活性剤、緩衝剤、等張化剤、安定化剤、抗酸化剤、高分子量重合体等を配合することができる。好ましくは、本組成物は、界面活性剤および等張化剤からなる群から選択される少なくとも１種をさらに含む。 In the present composition, pharmaceutically acceptable additives can be blended as needed using widely used techniques. For example, surfactants, buffers, tonicity agents, stabilizers, antioxidants, high molecular weight polymers and the like can be blended. Preferably, the composition further comprises at least one selected from the group consisting of surfactants and tonicity agents.
　界面活性剤としては、例えば、カチオン性界面活性剤、アニオン性界面活性剤、非イオン性界面活性剤を配合することができる。 As surfactant, a cationic surfactant, an anionic surfactant, and a nonionic surfactant can be mix | blended, for example.
　アニオン性界面活性剤の例としては、硫酸塩系界面活性剤、リン脂質等が挙げられ、硫酸塩系界面活性剤としては、例えば、アルキル硫酸ナトリウム塩、アルキルベンゼン硫酸塩等が挙げられる。リン脂質としては、例えば、レシチン等が挙げられる。 Examples of anionic surfactants include sulfate surfactants, phospholipids and the like, and examples of sulfate surfactants include sodium alkyl sulfate, alkyl benzene sulfate and the like. Examples of phospholipids include lecithin and the like.
　カチオン性界面活性剤の例としては、アルキルアミン塩、アルキルアミンポリオキシエチレン付加物、脂肪酸トリエタノールアミンモノエステル塩、アシルアミノエチルジエチルアミン塩、脂肪酸ポリアミン縮合物、アルキルイミダゾリン、１－アシルアミノエチル－２－アルキルイミダゾリン、１－ヒドロキシルエチル－２－アルキルイミダゾリン等が挙げられる。 Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkyl imidazolines, 1-acylaminoethyl- 2-alkyl imidazoline, 1-hydroxy ethyl 2-alkyl imidazoline etc. are mentioned.
　非イオン性界面活性剤の例としては、ポリオキシエチレン脂肪酸エステル、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硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、ショ糖脂肪酸エステル、ビタミンＥ　ＴＰＧＳ等が挙げられる。 Examples of nonionic surfactants include polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, Vitamin E TPGS etc. are mentioned.
　ポリオキシエチレン脂肪酸エステルとしては、ステアリン酸ポリオキシル４０等が挙げられる。 Examples of polyoxyethylene fatty acid esters include polyoxyl 40 stearate and the like.
　ポリオキシエチレンソルビタン脂肪酸エステルとしては、ポリソルベート８０、ポリソルベート６０、ポリソルベート４０、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンソルビタントリオレート、ポリソルベート６５等が挙げられる。ポリソルベート８０が特に好ましい。 Examples of polyoxyethylene sorbitan fatty acid ester include polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 and the like. Polysorbate 80 is particularly preferred.
　ポリオキシエチレン硬化ヒマシ油としては、酸化エチレンの重合数の異なる種々のポリオキシエチレン硬化ヒマシ油を用いることができ、酸化エチレンの重合数は１０～１００が好ましく、２０～８０がより好ましく、４０～７０が特に好ましく、６０が最も好ましい。ポリオキシエチレン硬化ヒマシ油の具体例としては、ポリオキシエチレン硬化ヒマシ油１０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０等が挙げられる。 As polyoxyethylene hydrogenated castor oil, various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used. The polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, and 40 -70 are particularly preferred, 60 is most preferred. Specific examples of polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 and the like.
　ポリオキシエチレンヒマシ油としては、酸化エチレンの重合数の異なる種々のポリオキシエチレンヒマシ油を用いることができ、酸化エチレンの重合数は５～１００が好ましく、２０～５０がより好ましく、３０～４０が特に好ましく、３５が最も好ましい。ポリオキシエチレンヒマシ油の具体例としては、ポリオキシル５ヒマシ油、ポリオキシル９ヒマシ油、ポリオキシル１５ヒマシ油、ポリオキシル３５ヒマシ油、ポリオキシル４０ヒマシ油等が挙げられる。 As polyoxyethylene castor oil, various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 5 to 100, more preferably 20 to 50, and 30 to 40. Is particularly preferred and 35 is most preferred. Specific examples of polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil and the like.
　ポリオキシエチレンポリオキシプロピレングリコールとしては、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリオキシエチレン（４２）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（５４）ポリオキシプロピレン（３９）グリコール、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール等が挙げられる。 As polyoxyethylene polyoxypropylene glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) Examples thereof include glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol.
　ショ糖脂肪酸エステルとしては、ショ糖ステアリン酸エステル等が挙げられる。 As sucrose fatty acid ester, sucrose stearic acid ester etc. are mentioned.
　ビタミンＥ　ＴＰＧＳは、トコフェロールポリエチレングリコール１０００コハク酸エステルともいう。 Vitamin E TPGS is also referred to as tocopherol polyethylene glycol 1000 succinate.
　本組成物に界面活性剤を配合する場合の界面活性剤の含有量は、界面活性剤の種類等により適宜調整することができるが、０．００１～１０％（ｗ／ｖ）が好ましく、０．０１～５％（ｗ／ｖ）がより好ましく、０．０１～３％（ｗ／ｖ）がさらに好ましく、０．０１～１％（ｗ／ｖ）がよりさらに好ましい。 The content of the surfactant in the case of incorporating the surfactant into the present composition can be appropriately adjusted depending on the type of the surfactant and the like, but preferably 0.001 to 10% (w / v), 0 .01-5% (w / v) is more preferred, 0.01-3% (w / v) is more preferred, and 0.01-1% (w / v) is even more preferred.
　これらの界面活性剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These surfactants may be used alone or in any combination of two or more.
　本組成物には、医薬品の添加物として使用可能な緩衝剤を配合することができる。例えば、リン酸又はその塩、クエン酸又はその塩、酢酸又はその塩、炭酸又はその塩、酒石酸又はその塩、ε－アミノカプロン酸、トロメタモール等が挙げられる。 The composition can be incorporated with a buffer that can be used as an additive of a pharmaceutical. For example, phosphoric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol and the like can be mentioned.
　リン酸塩としては、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられ、クエン酸塩としては、クエン酸ナトリウム、クエン酸二ナトリウム等が挙げられ、酢酸塩としては、酢酸ナトリウム、酢酸カリウム等が挙げられ、炭酸塩としては、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、酒石酸塩としては、酒石酸ナトリウム、酒石酸カリウム等が挙げられる。 Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and the like, and as the citrate, citric acid Sodium, disodium citrate and the like can be mentioned, as acetate, sodium acetate, potassium acetate and the like can be mentioned, as carbonate, sodium carbonate, sodium hydrogencarbonate and the like can be mentioned, and as tartrate, sodium tartrate, Potassium tartrate and the like can be mentioned.
　本組成物に緩衝剤を配合する場合の緩衝剤の含有量は、緩衝剤の種類等により適宜調整することができるが、０．００１～１０％（ｗ／ｖ）が好ましく、０．０１～５％（ｗ／ｖ）がより好ましく、０．１～３％（ｗ／ｖ）がさらに好ましく、０．２～２％（ｗ／ｖ）が最も好ましい。 The content of the buffer in the case of incorporating the buffer into the present composition can be appropriately adjusted depending on the type of the buffer etc., but preferably 0.001 to 10% (w / v), 0.01 to 10%. 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.2 to 2% (w / v) is most preferable.
　これらの緩衝剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These buffers may be used alone or in any combination of two or more.
　本組成物には、医薬品の添加物として使用可能な等張化剤を適宜配合することができる。等張化剤の例としては、イオン性等張化剤、非イオン性等張化剤等が挙げられる。イオン性等張化剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、ホウ酸、ホウ砂などが挙げられ、非イオン性等張化剤としてはグリセリン、プロピレングリコール、ソルビトール、マンニトール等が挙げられる。本組成物に等張化剤を配合する場合の等張化剤の含有量は、等張化剤の種類等により適宜調整することができるが、０．０１～１０％（ｗ／ｖ）が好ましく、０．１～５％（ｗ／ｖ）がより好ましく、０．５～３％（ｗ／ｖ）が最も好ましい。 In the present composition, an isotonic agent which can be used as a pharmaceutical additive can be appropriately blended. Examples of tonicity agents include ionic tonicity agents, non-ionic tonicity agents, and the like. Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, boric acid, borax and the like, and non-ionic tonicity agents such as glycerin, propylene glycol, sorbitol, mannitol and the like It can be mentioned. The content of the tonicity agent in the case of incorporating the tonicity agent into the present composition can be appropriately adjusted depending on the type of the tonicity agent etc., but 0.01 to 10% (w / v) Preferably, 0.1 to 5% (w / v) is more preferable, and 0.5 to 3% (w / v) is most preferable.
　これらの等張化剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These tonicity agents may be used alone or in any combination of two or more.
　本組成物には、医薬品の添加物として使用可能な安定化剤を適宜配合することができる。例えば、エデト酸、エデト酸一ナトリウム、エデト酸二ナトリウム、エデト酸四ナトリウム、クエン酸ナトリウム等が挙げられ、エデト酸二ナトリウムが好ましく、エデト酸二ナトリウム二水和物が特に好ましい。本組成物に安定化剤を配合する場合の安定化剤の含有量は、安定化剤の種類等により適宜調整することができるが、０．０００１～０．５％（ｗ／ｖ）が好ましく、０．０００５～０．３％（ｗ／ｖ）がより好ましく、０．００１～０．１％（ｗ／ｖ）がさらに好ましく、０．００２～０．０８％（ｗ／ｖ）がもっと好ましく、０．００３～０．０７％（ｗ／ｖ）が一層好ましく、０．００５～０．０６％（ｗ／ｖ）が特に好ましく、０．００７～０．０５％（ｗ／ｖ）が最も好ましい。 In the present composition, a stabilizer which can be used as an additive of a medicine can be appropriately blended. Examples thereof include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, and disodium edetate is preferred, and disodium edetate dihydrate is particularly preferred. The content of the stabilizer in the case of incorporating the stabilizer into the present composition can be appropriately adjusted depending on the kind of the stabilizer etc., but preferably 0.0001 to 0.5% (w / v). 0.0005 to 0.3% (w / v) is more preferable, 0.001 to 0.1% (w / v) is more preferable, and 0.002 to 0.08% (w / v) is more preferable Preferably, 0.003 to 0.07% (w / v) is more preferable, 0.005 to 0.06% (w / v) is particularly preferable, and 0.007 to 0.05% (w / v) is preferable. Most preferred.
　これらの安定化剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These stabilizers may be used alone or in any combination of two or more.
　本組成物には、医薬品の添加物として使用可能な抗酸化剤を適宜配合することができる。抗酸化剤の例としては、アスコルビン酸、トコフェロール、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム等が挙げられる。本組成物に抗酸化剤を配合する場合の抗酸化剤の含有量は、抗酸化剤の種類等により適宜調整することができるが、０．０００１～１％（ｗ／ｖ）が好ましく、０．００１～０．１％（ｗ／ｖ）がより好ましく、０．００５～０．０１％（ｗ／ｖ）が最も好ましい。 In the present composition, an antioxidant which can be used as an additive of a medicine can be appropriately blended. Examples of antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like. The content of the antioxidant in the case of incorporating the antioxidant into the present composition can be appropriately adjusted according to the type of the antioxidant etc., but preferably 0.0001 to 1% (w / v), 0 .001 to 0.1% (w / v) is more preferable, and 0.005 to 0.01% (w / v) is most preferable.
　これらの抗酸化剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These antioxidants may be used alone or in any combination of two or more.
　本組成物には、医薬品の添加物として使用可能な高分子量重合体を適宜配合することができる。高分子量重合体の例としては、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリエチレングリコール等が挙げられる。本組成物に高分子量重合体を配合する場合の高分子量重合体の含有量は、高分子量重合体の種類等により適宜調整することができるが、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．１～１％（ｗ／ｖ）が最も好ましい。 In the present composition, a high molecular weight polymer which can be used as an additive of a medicine can be appropriately blended. Examples of high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, Carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol and the like can be mentioned. The content of the high molecular weight polymer in the case of incorporating the high molecular weight polymer into the present composition can be appropriately adjusted depending on the type of the high molecular weight polymer and the like, but 0.001 to 5% (w / v) Preferably, 0.01 to 3% (w / v) is more preferable, and 0.1 to 1% (w / v) is most preferable.
　これらの高分子量重合体は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These high molecular weight polymers may be used alone or in any combination of two or more.
　更に、本組成物の浸透圧は特定の値に制限されないが、生体に許容される範囲とされる。本発明の水性組成物の浸透圧は、例えば、１００～１０００ｍＯｓｍ、好ましくは２００～５００ｍＯｓｍ、より好ましくは２５０～３５０ｍＯｓｍである。一般的に、水性組成物の浸透圧は少なからず水性組成物中の薬物や添加剤の量に影響を受ける。本発明において、浸透圧は浸透圧に影響を与え得るこれらの物質の量を適当に調整して、上記の範囲になるよう調整され得る。本発明の水性組成物の浸透圧は、通常の方法で測定されできることに留意すべきである。例えば、本発明の水性組成物の浸透圧は、第十五改正日本薬局方第の「浸透圧測定法（オスモル濃度測定法）」に記載の方法に従って測定できる。 Furthermore, the osmotic pressure of the present composition is not limited to a specific value, but is in a range acceptable to the living body. The osmotic pressure of the aqueous composition of the present invention is, for example, 100 to 1000 mOsm, preferably 200 to 500 mOsm, more preferably 250 to 350 mOsm. Generally, the osmotic pressure of the aqueous composition is affected to some extent by the amount of drug and additive in the aqueous composition. In the present invention, the osmotic pressure can be adjusted to be in the above range by appropriately adjusting the amount of these substances that can affect the osmotic pressure. It should be noted that the osmotic pressure of the aqueous composition of the present invention can be measured in a conventional manner. For example, the osmotic pressure of the aqueous composition of the present invention can be measured according to the method described in “Osmometry (Osmolality measurement)” of the fifteenth revision Japanese Pharmacopoeia.
　本組成物のｐＨは眼科用製品に許容される範囲内にあれば特に制限されないが、７未満が好ましく、３以上７未満がより好ましく、３以上６以下がさらに好ましく、４以上６以下がよりさらに好ましく、５の近傍が特に好ましい。より具体的には、例えば、３．０、３．１、３．２、３．３、３．４、３．５、３．６、３．７、３．８、３．９、４．０、４．１、４．２、４．３、４．４、４．５、４．６、４．７、４．８、４．９、５．０、５．１、５．２、５．３、５．４、５．５、５．６、５．７、５．８．５．９、６．０、６．１、６．２、６．３、６．４、６．５、６．６、６．７、６．８または６．９が挙げられる。本組成物のｐＨは、適宜、塩酸、硫酸、硝酸、ホウ酸および／または水酸化ナトリウムなどのｐＨ調節剤を添加物として配合して調節することができる。 The pH of the composition is not particularly limited as long as it is within the range acceptable for ophthalmic products, but less than 7 is preferable, 3 or more and less than 7 is more preferable, 3 or more and 6 or less is more preferable, and 4 or more and 6 or less is more More preferably, the vicinity of 5 is particularly preferred. More specifically, for example, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4. 0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8. 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6. 5, 6.6, 6.7, 6.8 or 6.9. The pH of the present composition can be adjusted by blending a pH regulator such as hydrochloric acid, sulfuric acid, nitric acid, boric acid and / or sodium hydroxide as an additive.
　本発明は上述した実施形態に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。 The present invention is not limited to the embodiments described above, and various modifications can be made within the scope of the claims, and embodiments obtained by appropriately combining the technical means disclosed in the embodiments are also possible. It is included in the technical scope of the present invention.
　〔まとめ〕
　以上のように、本発明の一態様は、以下に関する。 [Summary]
As mentioned above, one aspect of the present invention relates to the following.
　〔１〕銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品。 [1] An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-supported zirconium phosphate.
　〔２〕前記眼科用組成物と接触している前記樹脂の一部または全部が銀担持リン酸ジルコニウムを含む、〔１〕に記載の眼科用製品。 [2] The ophthalmic product according to [1], wherein a part or all of the resin in contact with the ophthalmic composition contains silver-loaded zirconium phosphate.
　〔３〕前記樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウムを含む、〔１〕または〔２〕に記載の眼科用製品。 [3] The ophthalmic product according to [1] or [2], containing silver-loaded zirconium phosphate at a concentration of 0.08 to 10% (w / w) based on the resin.
　〔４〕前記樹脂に対して、０．０８超乃至１０％（ｗ／ｗ）以下の濃度の銀担持リン酸ジルコニウムを含む、〔１〕または〔２〕に記載の眼科用製品。 [4] The ophthalmic product according to [1] or [2], which comprises a silver-loaded zirconium phosphate at a concentration of more than 0.08 and 10% (w / w) relative to the resin.
　〔５〕前記樹脂に対して、０．０８超乃至５％（ｗ／ｗ）以下の濃度の銀担持リン酸ジルコニウムを含む、〔１〕または〔２〕に記載の眼科用製品。 [5] The ophthalmic product according to [1] or [2], which comprises a silver-loaded zirconium phosphate at a concentration of more than 0.08 and 5% (w / w) relative to the resin.
　〔６〕前記樹脂に対して、０．０８超乃至１％（ｗ／ｗ）以下の濃度の銀担持リン酸ジルコニウムを含む、〔１〕または〔２〕に記載の眼科用製品。 [6] The ophthalmic product according to [1] or [2], which comprises silver-supported zirconium phosphate at a concentration of more than 0.08 and 1% (w / w) relative to the resin.
　〔７〕前記銀担持リン酸ジルコニウムが、銀をイオン濃度で０．００１～２０％（ｗ／ｗ）含む、〔１〕～〔６〕のいずれかに記載の眼科用製品。 [7] The ophthalmic product according to any one of [1] to [6], wherein the silver-supported zirconium phosphate contains silver in an ion concentration of 0.001 to 20% (w / w).
　〔８〕前記眼科用組成物が防腐剤を実質的に含有しない、〔１〕～〔７〕のいずれかに記載の眼科用製品。 [8] The ophthalmic product according to any one of [1] to [7], wherein the ophthalmic composition contains substantially no preservative.
　〔９〕樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品であって、前記眼科用組成物と接触している前記樹脂の一部または全部が銀担持リン酸ジルコニウムを含み、前記銀担持リン酸ジルコニウムが、銀をイオン濃度で０．００１～２０％（ｗ／ｗ）含み、前記眼科用組成物が防腐剤を実質的に含有しない、眼科用製品。 [9] An ophthalmic composition having a pH of less than 7 in a multi-dose eyedropper formed of a resin containing silver-loaded zirconium phosphate at a concentration of 0.08 to 10% (w / w) relative to the resin An ophthalmic product containing a substance, wherein part or all of the resin in contact with the ophthalmic composition contains silver-loaded zirconium phosphate, and the silver-loaded zirconium phosphate has an ion concentration of silver An ophthalmic product comprising 0.001 to 20% (w / w), wherein the ophthalmic composition is substantially free of preservatives.
　〔１０〕前記眼科用組成物のｐＨが３以上、７未満である、〔１〕～〔９〕のいずれかに記載の眼科用製品。 [10] The ophthalmic product according to any one of [1] to [9], wherein the pH of the ophthalmic composition is 3 or more and less than 7.
　〔１１〕前記眼科用組成物が、界面活性剤および等張化剤からなる群から選択される少なくとも１種をさらに含む、〔１〕～〔１０〕のいずれか１項に記載の眼科用製品。 [11] The ophthalmic product according to any one of [1] to [10], wherein the ophthalmic composition further comprises at least one selected from the group consisting of a surfactant and a tonicity agent. .
　〔１２〕前記界面活性剤が、非イオン性界面活性剤である、〔１１〕に記載の眼科用製品。 [12] The ophthalmic product according to [11], wherein the surfactant is a nonionic surfactant.
　〔１３〕前記非イオン性界面活性剤が、ポリオキシエチレン脂肪酸エステル、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硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、ショ糖脂肪酸エステルおよびビタミンＥ　ＴＰＧＳからなる群から選択される少なくとも１種である、〔１２〕に記載の眼科用製品。 [13] The nonionic surfactant is polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester The ophthalmic product according to [12], which is at least one selected from the group consisting of and vitamin E TPGS.
　〔１４〕前記等張化剤が、イオン性等張化剤および／または非イオン性等張化剤である、〔１１〕に記載の眼科用製品。 [14] The ophthalmic product according to [11], wherein the tonicity agent is an ionic tonicity agent and / or a nonionic tonicity agent.
　〔１５〕前記イオン性等張化剤が、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、ホウ酸およびホウ砂からなる群から選択される少なくとも１種である、〔１４〕に記載の眼科用製品。 [15] The ophthalmology according to [14], wherein the ionic tonicity agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, boric acid and borax. Product.
　〔１６〕前記非イオン性等張化剤が、グリセリン、プロピレングリコール、ソルビトールおよびマンニトールからなる群から選択される少なくとも１種である、〔１４〕に記載の眼科用製品。 [16] The ophthalmic product according to [14], wherein the non-ionic tonicity agent is at least one selected from the group consisting of glycerin, propylene glycol, sorbitol and mannitol.
　〔１７〕前記マルチドーズ型点眼容器の容器本体の容量が５～２０ｍＬである、〔１〕～〔１６〕のいずれかに記載の眼科用製品。 [17] The ophthalmic product according to any one of [1] to [16], wherein the volume of the container body of the multi-dose type eye drop container is 5 to 20 mL.
　〔１８〕前記眼科用組成物の総容量が２～２０ｍＬである、〔１〕～〔１７〕のいずれかに記載の眼科用製品。 [18] The ophthalmic product according to any one of [1] to [17], wherein the total volume of the ophthalmic composition is 2 to 20 mL.
　〔１９〕前記眼科用組成物が点眼剤である、〔１〕～〔１８〕のいずれかに記載の眼科用製品。 [19] The ophthalmic product according to any one of [1] to [18], wherein the ophthalmic composition is an eye drop.
　〔２０〕前記眼科用製品が点眼剤製品である、〔１〕～〔１９〕のいずれかに記載の眼科用製品。 [20] The ophthalmic product according to any one of [1] to [19], wherein the ophthalmic product is an eye drop product.
　〔２１〕ｐＨが７未満である眼科用組成物であって、前記眼科用組成物が、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に収容されていることを特徴とする眼科用組成物。 [21] An ophthalmic composition having a pH of less than 7, wherein the ophthalmic composition is accommodated in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate. Ophthalmic composition.
　以下に、試験結果および製剤例を示すが、これらの例は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。 The following shows test results and formulation examples, but these examples are for the purpose of better understanding the present invention, and do not limit the scope of the present invention.
　［保存効力試験－１］
　銀担持体の種類が抗菌性能に及ぼす影響を検討した。 [Conservative efficacy test-1]
The influence of the type of silver carrier on the antibacterial performance was investigated.
　（試料作製）
　銀担持体が配合されたプラスチックプレートを作成した。 (Sample preparation)
A plastic plate was prepared in which a silver carrier was blended.
　＜銀担持リン酸ジルコニウム配合プレート＞
　０．５％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウム（メーカー：東亞合成株式会社、製品名：ノバロン（登録商標）ＡＧ１１００）が配合されたポリプロピレンプレート（高さ２ｍｍ；プレートの表と裏の表面積の合計は１２０ｃｍ２である）を作成した。 <Silver-loaded zirconium phosphate blend plate>
A polypropylene plate (height 2 mm; height of plate; plate table with silver-loaded zirconium phosphate (Manufacturer: Toagosei Co., Ltd., product name: Novalon (registered trademark) AG1100) at a concentration of 0.5% (w / w) The total surface area of the back is 120 cm 2 ).
　＜銀担持ゼオライト配合プレート＞
　０．５％（ｗ／ｗ）の濃度の銀担持ゼオライト（メーカー：シナミンゼオミック、製品名：ＤＡＷ５０２）が配合されたポリエチレンプレート（高さ２ｍｍ；プレートの表と裏の表面積の合計は１２０ｃｍ２である）を作成した。 <Silver-loaded zeolite blended plate>
Polyethylene plate (height 2 mm; surface area of the front and back of the plate is 120 cm 2 in total) mixed with 0.5% (w / w) concentration of silver-loaded zeolite (by: Cinamin Zeomic, product name: DAW 502) Is created.
　（サンプル作成）
　滅菌済みガラスパイレックス（登録商標）瓶に、作成したプラスチックプレートを入れ、次いで生理食塩水１５ｍＬを加え、当該プラスチックプレートを浸漬させて、試験に用いるサンプルを作成した。この場合、プラスチックプレートの生理食塩水との接液面積は８ｃｍ２／ｍＬである。 (Sample creation)
The prepared plastic plate was placed in a sterilized glass Pyrex bottle, and then 15 mL of physiological saline was added, and the plastic plate was immersed to prepare a sample to be used for the test. In this case, the contact area of the plastic plate with saline is 8 cm 2 / mL.
　（試験方法）
　保存効力試験は、第十五改正日本薬局方の保存効力試験法を参考に行った。試験菌を接種し、１４日後、２８日後に菌数を測定した。本試験では、試験菌として、Ｅｓｈｅｒｉｃｈｉａ　Ｃｏｌｉ（Ｅ．ｃｏｌｉ）、Ｐｓｅｕｄｏｍｏｎａｓ　ａｅｒｕｇｉｎｏｓａ（Ｐ．ａｅｒｕｇｉｎｏｓａ）を用いた。 (Test method)
The preservation efficacy test was conducted with reference to the preservation efficacy test method of the 15th Amended Japanese Pharmacopoeia. The test bacteria were inoculated, and the number of bacteria was measured after 14 and 28 days. In this test, Esherichia Coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) were used as test bacteria.
　（試験結果）
　試験結果を表１に示す。なお、表１の試験結果（初期値、１４日後、２８日後）は、菌数経時変化（個／ｍＬ）を示している。 (Test results)
The test results are shown in Table 1. In addition, the test result (initial value, 14 days after, 28 days after) of Table 1 has shown a microbe number time-dependent change (piece / mL).
Figure JPOXMLDOC01-appb-T000001
 　（考察）
　表１に示すように、銀担持リン酸ジルコニウムは、銀担持ゼオライトよりも高い抗菌力を有することが示された。
Figure JPOXMLDOC01-appb-T000001
 (Discussion)
As shown in Table 1, silver supported zirconium phosphate was shown to have higher antibacterial activity than silver supported zeolite.
　［重金属評価試験］
　試料中の重金属を評価した。 [Heavy metal evaluation test]
Heavy metals in the sample were evaluated.
　（試料調製）
　銀担持体が配合されたプラスチックプレートを作成した。 (Sample preparation)
A plastic plate was prepared in which a silver carrier was blended.
　＜銀担持リン酸ジルコニウム配合プレート＞
　０．５％（ｗ／ｗ）または１．０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウム（メーカー：東亞合成株式会社、製品名：ノバロン（登録商標）ＡＧ１１００）が配合されたポリプロピレンプレートをそれぞれ作成した。 <Silver-loaded zirconium phosphate blend plate>
Polypropylene blended with silver supported zirconium phosphate (Manufacturer: Toagosei Co., Ltd., product name: Novalon (registered trademark) AG1100) at a concentration of 0.5% (w / w) or 1.0% (w / w) Each plate was made.
　＜銀担持ゼオライト配合プレート＞
　１％（ｗ／ｗ）、２％（ｗ／ｗ）または３％（ｗ／ｗ）の濃度の銀担持ゼオライト（メーカー：カネボウ、製品名：ＢＭ－１０２ＴＧ）が配合されたポリプロピレンプレートをそれぞれ作成した。 <Silver-loaded zeolite blended plate>
Produced polypropylene plates containing 1% (w / w), 2% (w / w) or 3% (w / w) concentration of silver-loaded zeolite (Manufacturer: Kanebo, Product name: BM-102TG) did.
　＜銀担持ガラス配合プレート＞
　１％（ｗ／ｗ）の濃度の銀担持ガラス（メーカー：石塚ガラス、製品名：ＪＮ）が配合されたポリプロピレンプレートを作成した。 <Silver-loaded glass blend plate>
The polypropylene plate which the silver carrying glass (maker: Ishizuka glass, product name: JN) of the density | concentration of 1% (w / w) was mix | blended was created.
　（試験方法）
　日局一般試験法「プラスチック製医薬品容器試験法」１灰化試験１・２重金属（点眼剤用プラスチック容器の規格及び試験法について（薬発３３６号（平成８年３月２８日））の別添、重金属）に準じて試料中の重金属を評価した。 (Test method)
JP JCAB General Test Method “Plastic Drug Container Test Method” 1 Ashing Test 1 ・ 2 Heavy Metals (Standards and Test Methods of Plastic Containers for Eye Drops (Drug 336 (March 28, 1996)) The heavy metals in the sample were evaluated according to
　（判定基準）
　日局一般試験法「プラスチック製医薬品容器試験法」１灰化試験１・２重金属（点眼剤用プラスチック容器の規格及び試験法について（薬発３３６号（平成８年３月２８日））の別添、重金属）に準じて試験したとき、検液の色が比較液より濃くない（２０ｐｐｍ以下）場合を合格とする。ただし、容器切片採取量は１．０ｇとする。 (Judgment criteria)
JP JCAB General Test Method “Plastic Drug Container Test Method” 1 Ashing Test 1 ・ 2 Heavy Metals (Standards and Test Methods of Plastic Containers for Eye Drops (Drug 336 (March 28, 1996)) If the color of the test solution is not darker (20 ppm or less) than that of the comparison solution when the test is conducted according to the method of However, the container section collection amount is 1.0 g.
　（試験結果）
　表２に試験結果を示す。 (Test results)
Table 2 shows the test results.
Figure JPOXMLDOC01-appb-T000002
 　表２に示すように、銀担持リン酸ジルコニウムが配合されたプレートでは、検液の色は比較液より濃くならず、上記判定基準を満たした。一方、銀担持ゼオライトや銀担持ガラスが配合されたプレートでは、分析不能で、上記判定基準を満たすか判定できなかった。
Figure JPOXMLDOC01-appb-T000002
 As shown in Table 2, in the plate containing the silver-loaded zirconium phosphate, the color of the test solution did not become darker than that of the comparison solution, and the above judgment criteria were satisfied. On the other hand, in the plate in which the silver-supporting zeolite and the silver-supporting glass were blended, it was impossible to analyze and it could not be determined whether the above judgment criteria were satisfied.
　（考察）
　以上の重金属評価試験の結果から、銀担持リン酸ジルコニウムが点眼剤用プラスチック容器に好ましいことが示された。 (Discussion)
From the results of the above heavy metal evaluation tests, it was shown that silver-loaded zirconium phosphate is preferable for plastic containers for eye drops.
　［保存効力試験－２］
　銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器を用いて、保存効力試験を行った。 [Conservative efficacy test-2]
A storage efficacy test was conducted using a multi-dose type eye dropper container made of a resin containing silver-loaded zirconium phosphate.
　（試料調製）
　点眼液１：
　表３に示す処方に従って、点眼液１を調製した。具体的には、ジクアホソルナトリウム（ＡＰＩ；３ｇ）、エデト酸ナトリウム（キレート剤；０．０１ｇ）、濃グリセリン（等張化剤；１．４ｇ）を水に溶解し、希塩酸（ｐＨ調節剤）を加えて、ｐＨを５付近とした後、水を適量加えて全量を１００ｍＬとした。 (Sample preparation)
Eye drops 1:
The eye drop 1 was prepared according to the formulation shown in Table 3. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent: 0.01 g) and concentrated glycerin (tonicity agent; 1.4 g) are dissolved in water, diluted hydrochloric acid (pH regulator) ) To bring the pH to around 5, and then an appropriate amount of water was added to make the total volume 100 mL.
　点眼液２：
　表３に示す処方に従って、点眼液２を調製した。具体的には、ジクアホソルナトリウム（ＡＰＩ；３ｇ）、エデト酸ナトリウム（キレート剤；０．０１ｇ）、ホウ酸（等張化剤；１．１ｇ）を水に溶解し、水酸化ナトリウム（ｐＨ調節剤）を加えて、ｐＨを５付近とした後、水を適量加えて全量を１００ｍＬとした。 Eye drops 2:
Eye drops 2 were prepared according to the formulation shown in Table 3. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent: 0.01 g), boric acid (tonicity agent; 1.1 g) is dissolved in water, sodium hydroxide (pH A regulator was added to adjust the pH to around 5, and an appropriate amount of water was then added to make the total volume 100 mL.
　点眼液３：
　表３に示す処方に従って、点眼液３を調製した。具体的には、ジクアホソルナトリウム（ＡＰＩ；３ｇ）、エデト酸ナトリウム（キレート剤；０．０１ｇ）、濃グリセリン（等張化剤；１．４ｇ）を水に溶解し、希塩酸（ｐＨ調節剤）を加えて、ｐＨを５付近とした後、水を適量加えて全量を１００ｍＬとした。 Eye drop 3:
An eye drop 3 was prepared according to the formulation shown in Table 3. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent: 0.01 g) and concentrated glycerin (tonicity agent; 1.4 g) are dissolved in water, diluted hydrochloric acid (pH regulator) ) To bring the pH to around 5, and then an appropriate amount of water was added to make the total volume 100 mL.
　点眼液４：
　表３に示す処方に従って、点眼液４を調製した。具体的には、ジクアホソルナトリウム（ＡＰＩ；３ｇ）、エデト酸ナトリウム（キレート剤；０．０１ｇ）、ホウ酸（等張化剤；１．１ｇ）を水に溶解し、水酸化ナトリウム（ｐＨ調節剤）を加えて、ｐＨを５付近とした後、水を適量加えて全量を１００ｍＬとした。 Eye drop 4:
An eye drop 4 was prepared according to the formulation shown in Table 3. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent: 0.01 g), boric acid (tonicity agent; 1.1 g) is dissolved in water, sodium hydroxide (pH A regulator was added to adjust the pH to around 5, and an appropriate amount of water was then added to make the total volume 100 mL.
　なお、ＡＰＩとしてジクアホソルナトリウムを用いたが、点眼液中で保存すると目視可能な不溶性析出物が発生するおそれがあることからキレート剤であるエデト酸ナトリウムを添加した（国際公開ＷＯ２０１２－０９０９９４号パンフレット参照）。 In addition, although diquafosol sodium was used as an API, when stored in eye drops, there is a possibility that a visible insoluble precipitate may be generated, and sodium edetate which is a chelating agent is added (International Publication WO 2012-090994) See brochure).
　点眼容器：
　加熱溶解したポリエチレン樹脂に、銀をイオン濃度で１０％（ｗ／ｗ）含む平均粒径１μｍの銀担持リン酸ジルコニウムを０．０８％（ｗ／ｗ）または１％（ｗ／ｗ）添加して均一に練り込み、点眼容器の容器本体（容積７．９ｍＬ、高さ４５．２ｍｍ、胴型１９．４５ｍｍ）を製造した。銀担持リン酸ジルコニウムは、東亞合成株式会社製の銀系無機抗菌剤「ノバロン（登録商標）ＡＧ」１１００を使用した。 Eye drop container:
To the heat-melted polyethylene resin, add 0.08% (w / w) or 1% (w / w) of silver-supported zirconium phosphate having an average particle diameter of 1 μm containing 10% (w / w) of silver as ion concentration The mixture was uniformly mixed to prepare a container body (volume 7.9 mL, height 45.2 mm, body type 19.45 mm) of the eye drop container. As silver-supported zirconium phosphate, a silver-based inorganic antibacterial agent "Novaron (registered trademark) AG" 1100 manufactured by Toagosei Co., Ltd. was used.
Figure JPOXMLDOC01-appb-T000003
 　（試験方法）
　保存効力試験は、第十七改正日本薬局方の保存効力試験法に準拠して行なった。本試験では、試験菌株として、Ｅｓｈｅｒｉｃｈｉａ Ｃｏｌｉ（Ｅ．ｃｏｌｉ）、Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏｓａ（Ｐ．ａｅｒｕｇｉｎｏｓａ）、Ｓｔａｐｈｙｌｏｃｏｃｃｕｓ ａｕｒｅｕｓ（Ｓ．ａｕｒｅｕｓ）、Ｃａｎｄｉｄａ ａｌｂｉｃａｎｓ（Ｃ．ａｌｂｉｃａｎｓ）およびＡｓｐｅｒｇｉｌｌｕｓ ｂｒａｓｉｌｉｅｎｓｉｓ（Ａ．ｂｒａｓｉｌｉｅｎｓｉｓ）を用いた。これらの菌株をそれぞれカンテン斜面培地の表面に接種して前培養した。前培養用のカンテン培地としては、細菌の場合はソイビーン・カゼイン・ダイジェストカンテン培地を、真菌の場合はサブロー・ブドウ糖カンテン培地を用いた。細菌の場合は３０～３５℃で１８～２４時間、Ｃａｎｄｉｄａ　ａｌｂｉｃａｎｓは２０～２５℃で４４～５２時間、Ａｓｐｅｒｇｉｌｌｕｓ　ｂｒａｓｉｌｉｅｎｓｉｓは２０～２５℃で１週間又は十分な胞子が形成されるまで前培養した。
Figure JPOXMLDOC01-appb-T000003
 (Test method)
The preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 17th revised Japanese Pharmacopoeia. In this test, Esherichia Coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans) and Aspergillus brasiliensis (A. brasiliensis) were used as test strains. . Each of these strains was inoculated on the surface of agar slant medium and precultured. As the agar medium for pre-culture, a soy bean / casein / digest agar medium was used in the case of bacteria, and a Sabouraud's glucose medium was used in the case of fungi. In the case of bacteria, 18 to 24 hours at 30 to 35 ° C., Candida albicans for 44 to 52 hours at 20 to 25 ° C., Aspergillus brasiliensis was precultured at 20 to 25 ° C. for 1 week or until sufficient spores were formed.
　点眼液１～４を５本の滅菌済みの上記点眼容器に５ｍＬずつ分注し、中栓を装着し、キャップで密封した。６０℃で１か月遮光保存した後、前培養した試験菌を１０５～１０６個／ｍＬとなるよう接種した。なお、試験菌は混合せず、それぞれ単独に各検体に接種した。保存開始から１週、２週及び４週保存後に各混合試料から０．５ｍＬをサンプリングした液を培養し、生菌数の測定を行った。 Eye drops 1 to 4 were dispensed in 5 mL each into the 5 sterilized eye drop containers, and the inside plug was attached and sealed with a cap. After 1-month dark storage at 60 ° C., the precultured test bacteria were inoculated at 10 5 to 10 6 cells / mL. The test bacteria were not mixed, and each sample was inoculated alone. The liquid sampled 0.5 mL from each mixed sample after 1 week, 2 weeks and 4 weeks of storage start was cultured, and the viable cell count was measured.
　表４に従い、保存効力を判定した。 Storage efficacy was determined according to Table 4.
Figure JPOXMLDOC01-appb-T000004
 　（試験結果）
　試験結果を表５に示す。なお、表５の試験結果は検査時の生菌数が接種した菌数に比べてどの程度減少したかをｌｏｇ ｒｅｄｕｃｔｉｏｎで示しており、たとえば「１」の場合には、検査時の生菌数が接種菌数の１０％に減少したことを示している。
Figure JPOXMLDOC01-appb-T000004
 (Test results)
The test results are shown in Table 5. The test results in Table 5 show by log reduction how much the number of viable bacteria at the time of examination decreased compared to the number of inoculated bacteria. For example, in the case of “1”, the number of viable bacteria at the time of examination Shows a reduction to 10% of the inoculum count.
Figure JPOXMLDOC01-appb-T000005
 　表５に示された通り、製品３、４は、６０℃１か月保存後においても、保存効力を有することが示された。
Figure JPOXMLDOC01-appb-T000005
 As shown in Table 5, the products 3 and 4 were shown to have storage efficacy even after storage at 60 ° C. for 1 month.
　一般に、眼科用組成物の単位容量あたりの容器本体への全接触面積は、マルチドーズ型点眼容器の方がユニットドーズ型点眼容器よりも小さい。マルチドーズ型点眼容器であっても本製品が優れた保存効力を有することが示された。 Generally, the total contact area to the container body per unit volume of the ophthalmic composition is smaller in the multi-dose type eye drop container than in the unit dose type eye drop container. It was shown that this product has excellent storage efficacy even with a multi-dose type eye drop container.
　［保存効力試験－３］
　銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器を用いて、保存効力試験を行った。 [Conservative efficacy test-3]
A storage efficacy test was conducted using a multi-dose type eye dropper container made of a resin containing silver-loaded zirconium phosphate.
　（試料調製）
　点眼液：
　表６に示す処方に従って、点眼液５を調製した。具体的には、濃グリセリン（１．３ｇ）、リン酸水素ナトリウム水和物（１．０ｇ）を水に溶解し、ｐＨ調節剤（１Ｎ水酸化ナトリウム溶液／硫酸）を加えて、ｐＨを５．０とした後、水を適量加えて全量を１００ｍＬとした。点眼液６～８も表６に示す処方に従って、点眼液５と同様に調製した。 (Sample preparation)
Eye drops:
An eye drop 5 was prepared according to the formulation shown in Table 6. Specifically, concentrated glycerin (1.3 g) and sodium hydrogen phosphate hydrate (1.0 g) are dissolved in water, a pH regulator (1 N sodium hydroxide solution / sulfuric acid) is added, and the pH is adjusted to 5 After adjusting to 0, an appropriate amount of water was added to make the total volume 100 mL. The eye drops 6 to 8 were also prepared in the same manner as the eye drop 5 according to the formulation shown in Table 6.
　点眼容器：
　加熱溶解したポリエチレン樹脂に、銀をイオン濃度で１０％（ｗ／ｗ）含む平均粒径１μｍの銀担持リン酸ジルコニウムを０．５％（ｗ／ｗ）添加して均一に練り込み、点眼容器の容器本体（容積７．９ｍＬ、高さ４５．２ｍｍ、胴型１９．４５ｍｍ）を製造した。銀担持リン酸ジルコニウムは、東亞合成株式会社製の銀系無機抗菌剤「ノバロン（登録商標）ＡＧ」１１００を使用した。 Eye drop container:
Add 0.5% (w / w) of silver-loaded zirconium phosphate with an average particle diameter of 1 μm containing 10% (w / w) of silver in an ion concentration to the heat-melted polyethylene resin and mix uniformly. A container body (volume 7.9 mL, height 45.2 mm, barrel type 19.45 mm) was produced. As silver-supported zirconium phosphate, a silver-based inorganic antibacterial agent "Novaron (registered trademark) AG" 1100 manufactured by Toagosei Co., Ltd. was used.
Figure JPOXMLDOC01-appb-T000006
 　（試験方法）
　保存効力試験は、第十七改正日本薬局方の保存効力試験法を参考に行なった。本試験では、試験菌株として、Ｅｓｈｅｒｉｃｈｉａ Ｃｏｌｉ（Ｅ．ｃｏｌｉ）、Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏｓａ（Ｐ．ａｅｒｕｇｉｎｏｓａ）およびＳｔａｐｈｙｌｏｃｏｃｃｕｓ ａｕｒｅｕｓ（Ｓ．ａｕｒｅｕｓ）を用いた。これらの菌株をそれぞれカンテン斜面培地の表面に接種して前培養した。前培養用のカンテン培地としては、ソイビーン・カゼイン・ダイジェストカンテン培地を用いた。３０～３５℃で１８～２４時間前培養した。
Figure JPOXMLDOC01-appb-T000006
 (Test method)
The preservation efficacy test was conducted with reference to the preservation efficacy test method of the 17th revised Japanese Pharmacopoeia. In this test, Esherichia Coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) were used as test strains. Each of these strains was inoculated on the surface of agar slant medium and precultured. A soy bean / casein / digest agar medium was used as the agar medium for pre-culture. It was precultured at 30 to 35 ° C. for 18 to 24 hours.
　点眼液５～８を５本の滅菌済みの上記点眼容器に５ｍＬずつ分注し、中栓を装着し、キャップで密封した。６０℃で１か月遮光保存後、前培養した試験菌を１０５～１０６個／ｍＬとなるよう接種した。なお、試験菌は混合せず、それぞれ単独に各検体に接種した。保存開始から１週及び２週保存後に各混合試料から０．５ｍＬをサンプリングした液を培養し、生菌数の測定を行った。 The eye drops 5 to 8 were dispensed in 5 mL portions into each of five sterilized eye drop containers, and the inside plug was attached and sealed with a cap. After 1 month dark storage at 60 ° C., the precultured test bacteria were inoculated at 10 5 to 10 6 cells / mL. The test bacteria were not mixed, and each sample was inoculated alone. The liquid which sampled 0.5 mL from each mixed sample after 1 week and 2 weeks of storage start was culture | cultivated, and viable count was measured.
　表７に従い、保存効力を判定した。 Storage efficacy was determined according to Table 7.
Figure JPOXMLDOC01-appb-T000007
 　（試験結果）
　試験結果を表８に示す。なお、表８の試験結果は検査時の生菌数が接種した菌数に比べてどの程度減少したかをｌｏｇ ｒｅｄｕｃｔｉｏｎで示しており、たとえば「１」の場合には、検査時の生菌数が接種菌数の１０％に減少したことを示している。
Figure JPOXMLDOC01-appb-T000007
 (Test results)
The test results are shown in Table 8. The test results in Table 8 show how much the number of viable bacteria at the time of examination decreased compared to the number of inoculated bacteria, and in the case of “1”, for example, the number of viable bacteria at the time of examination Shows a reduction to 10% of the inoculum count.
Figure JPOXMLDOC01-appb-T000008
 　表８に示された通り、ｐＨが中性付近の点眼液を収容する本製品の保存効力は低かったが（比較例１）、ｐＨが酸性付近の点眼液を収容する本製品は、６０℃１か月保存後においても高い保存効力を有することが示された（実施例１～３）。特に、ｐＨが酸性付近であって、ポリソルベート８０を含有する点眼液を収容する本製品は優れた保存効力を有することが示された（実施例３）。
Figure JPOXMLDOC01-appb-T000008
 As shown in Table 8, the storage efficacy of the product containing an eye drop near neutral pH was low (Comparative Example 1), but the product containing an eye drop near an acidic pH was 60 ° C. It was shown to have high preservation efficacy even after storage for 1 month (Examples 1 to 3). In particular, the product containing an eye drop containing polysorbate 80, which has a pH near acidic, was shown to have excellent storage efficacy (Example 3).
　［製剤例］
　製剤例を挙げて本発明をさらに具体的に説明するが、本発明はこれらの製剤例にのみに限定されるものでない。 [Formulation example]
Although the present invention will be more specifically described by way of formulation examples, the present invention is not limited to only these formulation examples.
　（製剤例１：水性点眼液）
１００ｍＬ中
　リン酸水素ナトリウム ０．２ｇ
　濃グリセリン ２．４ｇ
　エデト酸ナトリウム ０．０１ｇ
　ｐＨ調節剤 適量
　水 適量
　リン酸水素ナトリウム（０．２ｇ）、濃グリセリン（２．４ｇ）、エデト酸ナトリウム（０．０１ｇ）を水に溶解し、ｐＨ調節剤（塩酸または水酸化ナトリウム溶液）を加えて、ｐＨを５．０とした後、水を適量加えて全量を１００ｍＬとし、十分に撹拌することで点眼液を調製できる。 Formulation Example 1: Aqueous ophthalmic solution
Sodium hydrogen phosphate 0.2 g in 100 mL
Concentrated glycerin 2.4g
Edetate sodium 0.01g
pH adjuster Appropriate amount Water Appropriate amount Sodium hydrogen phosphate (0.2 g), concentrated glycerin (2.4 g), sodium edetate (0.01 g) are dissolved in water, pH adjuster (hydrochloric acid or sodium hydroxide solution) In addition, after the pH is adjusted to 5.0, an appropriate amount of water is added to adjust the total volume to 100 mL, and the eye drop can be prepared by sufficiently stirring.
　（製剤例２：水性点眼液）
１００ｍＬ中
　濃グリセリン １．２ｇ
　ホウ酸 １．０ｇ
　ｐＨ調節剤 適量
　水 適量
　濃グリセリン（１．２ｇ）、ホウ酸（１．０ｇ）を水に溶解し、ｐＨ調節剤（塩酸または水酸化ナトリウム溶液）を加えて、ｐＨを５．０とした後、水を適量加えて全量を１００ｍＬとし、十分に撹拌することで点眼液を調製できる。 Formulation Example 2 Aqueous Eye Drop
100g of concentrated glycerin 1.2g
1.0 g of boric acid
pH adjuster Appropriate amount of water Appropriate amount After dissolving concentrated glycerin (1.2 g) and boric acid (1.0 g) in water and adding a pH adjuster (hydrochloric acid or sodium hydroxide solution) to adjust the pH to 5.0 An eye drop can be prepared by adding an appropriate amount of water to make the total volume 100 mL and sufficiently stirring.
　銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品が優れた保存効力を有する。本発明は、上述の逆流防止弁やフィルター付きデラミボトルなど物理的な構造を施さなくても、一定期間複数回使用でき、上述のユニットドーズ型点眼容器の欠点もないことから有用である。 An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate has excellent storage efficacy. The present invention is useful because it can be used for a plurality of times for a fixed period without physical structure such as the above-mentioned anti-return valve or filter-attached delamination bottle, and there is no disadvantage of the above unit dose type eye drop container.

Claims (21)

  1. 　銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品。 An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate.
  2. 　前記眼科用組成物と接触している前記樹脂の一部または全部が銀担持リン酸ジルコニウムを含む、請求項１に記載の眼科用製品。 The ophthalmic product according to claim 1, wherein part or all of the resin in contact with the ophthalmic composition comprises silver supported zirconium phosphate.
  3. 　前記樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウムを含む、請求項１または２に記載の眼科用製品。 An ophthalmic product according to claim 1 or 2, comprising silver-loaded zirconium phosphate at a concentration of 0.08-10% (w / w) relative to the resin.
  4. 　前記樹脂に対して、０．０８超乃至１０％（ｗ／ｗ）以下の濃度の銀担持リン酸ジルコニウムを含む、請求項１または２に記載の眼科用製品。 An ophthalmic product according to claim 1 or 2 comprising silver supported zirconium phosphate at a concentration greater than 0.08 and up to 10% (w / w) relative to the resin.
  5. 　前記樹脂に対して、０．０８超乃至５％（ｗ／ｗ）以下の濃度の銀担持リン酸ジルコニウムを含む、請求項１または２に記載の眼科用製品。 An ophthalmic product according to claim 1 or 2 comprising silver supported zirconium phosphate at a concentration greater than 0.08 and up to 5% (w / w) relative to the resin.
  6. 　前記樹脂に対して、０．０８超乃至１％（ｗ／ｗ）以下の濃度の銀担持リン酸ジルコニウムを含む、請求項１または２に記載の眼科用製品。 An ophthalmic product according to claim 1 or 2 comprising silver supported zirconium phosphate at a concentration greater than 0.08 and up to 1% (w / w) relative to the resin.
  7. 　前記銀担持リン酸ジルコニウムが、銀をイオン濃度で０．００１～２０％（ｗ／ｗ）含む、請求項１～６のいずれか１項に記載の眼科用製品。 The ophthalmic product according to any one of claims 1 to 6, wherein the silver-loaded zirconium phosphate contains silver in an ion concentration of 0.001 to 20% (w / w).
  8. 　前記眼科用組成物が防腐剤を実質的に含有しない、請求項１～７のいずれか１項に記載の眼科用製品。 The ophthalmic product according to any one of the preceding claims, wherein the ophthalmic composition is substantially free of preservatives.
  9. 　樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品であって、
    　前記眼科用組成物と接触している前記樹脂の一部または全部が銀担持リン酸ジルコニウムを含み、
    　前記銀担持リン酸ジルコニウムが、銀をイオン濃度で０．００１～２０％（ｗ／ｗ）含み、
    　前記眼科用組成物が防腐剤を実質的に含有しない、眼科用製品。     An ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate at a concentration of 0.08 to 10% (w / w) relative to the resin An ophthalmic product that has been
    Some or all of the resin in contact with the ophthalmic composition comprises silver supported zirconium phosphate,
    The silver-supported zirconium phosphate contains silver in an ion concentration of 0.001 to 20% (w / w),
    An ophthalmic product, wherein the ophthalmic composition is substantially free of preservatives.
  10. 　前記眼科用組成物のｐＨが３以上、７未満である、請求項１～９のいずれか１項に記載の眼科用製品。 The ophthalmic product according to any one of claims 1 to 9, wherein the pH of the ophthalmic composition is 3 or more and less than 7.
  11. 　前記眼科用組成物が、界面活性剤および等張化剤からなる群から選択される少なくとも１種をさらに含む、請求項１～１０のいずれか１項に記載の眼科用製品。 The ophthalmic product according to any one of claims 1 to 10, wherein the ophthalmic composition further comprises at least one selected from the group consisting of a surfactant and a tonicity agent.
  12. 　前記界面活性剤が、非イオン性界面活性剤である、請求項１１に記載の眼科用製品。 The ophthalmic product according to claim 11, wherein the surfactant is a non-ionic surfactant.
  13. 　前記非イオン性界面活性剤が、ポリオキシエチレン脂肪酸エステル、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硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、ショ糖脂肪酸エステルおよびビタミンＥ　ＴＰＧＳからなる群から選択される少なくとも１種である、請求項１２に記載の眼科用製品。 The nonionic surfactant is polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and vitamin E The ophthalmic product according to claim 12, which is at least one selected from the group consisting of TPGS.
  14. 　前記等張化剤が、イオン性等張化剤および／または非イオン性等張化剤である、請求項１１に記載の眼科用製品。 The ophthalmic product according to claim 11, wherein the tonicity agent is an ionic tonicity agent and / or a non-ionic tonicity agent.
  15. 　前記イオン性等張化剤が、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、ホウ酸およびホウ砂からなる群から選択される少なくとも１種である、請求項１４に記載の眼科用製品。 The ophthalmic product according to claim 14, wherein the ionic tonicity agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, boric acid and borax.
  16. 　前記非イオン性等張化剤が、グリセリン、プロピレングリコール、ソルビトールおよびマンニトールからなる群から選択される少なくとも１種である、請求項１４に記載の眼科用製品。 The ophthalmic product according to claim 14, wherein the non-ionic tonicity agent is at least one selected from the group consisting of glycerin, propylene glycol, sorbitol and mannitol.
  17. 　前記マルチドーズ型点眼容器の容器本体の容量が５～２０ｍＬである、請求項１～１６のいずれか１項に記載の眼科用製品。 The ophthalmic product according to any one of claims 1 to 16, wherein the volume of the container body of the multi-dose type eye drop container is 5 to 20 mL.
  18. 　前記眼科用組成物の総容量が２～２０ｍＬである、請求項１～１７のいずれか１項に記載の眼科用製品。 The ophthalmic product according to any of the preceding claims, wherein the total volume of the ophthalmic composition is 2 to 20 mL.
  19. 　前記眼科用組成物が点眼剤である、請求項１～１８のいずれか１項に記載の眼科用製品。 The ophthalmic product according to any one of claims 1 to 18, wherein the ophthalmic composition is an eye drop.
  20. 　前記眼科用製品が点眼剤製品である、請求項１～１９のいずれか１項に記載の眼科用製品。 The ophthalmic product according to any of the preceding claims, wherein the ophthalmic product is an eye drop product.
  21. 　ｐＨが７未満である眼科用組成物であって、
    　前記眼科用組成物が、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に収容されていることを特徴とする眼科用組成物。     An ophthalmic composition having a pH of less than 7;
    An ophthalmic composition characterized in that the ophthalmic composition is contained in a multi-dose type eye drop container formed of a resin containing silver-loaded zirconium phosphate.
PCT/JP2018/044307 2017-12-01 2018-11-30 Ophthalmic product WO2019107569A1 (en)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
JP2022103144A (en) * 2020-12-25 2022-07-07 参天製薬株式会社 Aqueous ophthalmic solution containing diquafosol or salt thereof, silver salt and ionic tonicity agent
EP4129341A4 (en) * 2020-03-31 2024-04-24 Santen Pharmaceutical Co Ltd Silver-salt-containing ophthalmic aqueous composition with which resin container is filled

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JPH0871124A (en) * 1994-08-31 1996-03-19 Shinotesuto:Kk Container containing antimicrobial material and storing method of the material
JP2002282338A (en) * 2001-03-23 2002-10-02 Terumo Corp Hook for intravenous drip
JP2005298448A (en) * 2004-04-15 2005-10-27 Rohto Pharmaceut Co Ltd Aqueous solution containing azulene

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JP4863589B2 (en) * 2001-09-28 2012-01-25 ロート製薬株式会社 Aqueous composition

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
JPH0871124A (en) * 1994-08-31 1996-03-19 Shinotesuto:Kk Container containing antimicrobial material and storing method of the material
JP2002282338A (en) * 2001-03-23 2002-10-02 Terumo Corp Hook for intravenous drip
JP2005298448A (en) * 2004-04-15 2005-10-27 Rohto Pharmaceut Co Ltd Aqueous solution containing azulene

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4129341A4 (en) * 2020-03-31 2024-04-24 Santen Pharmaceutical Co Ltd Silver-salt-containing ophthalmic aqueous composition with which resin container is filled
JP2022103144A (en) * 2020-12-25 2022-07-07 参天製薬株式会社 Aqueous ophthalmic solution containing diquafosol or salt thereof, silver salt and ionic tonicity agent
JP7230169B2 (en) 2020-12-25 2023-02-28 参天製薬株式会社 Aqueous ophthalmic solution containing diquafosol or its salt, silver salt and ionic tonicity agent

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