WO2018235935A1 - Medicinal composition containing water-soluble thickening agent - Google Patents

Medicinal composition containing water-soluble thickening agent Download PDF

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Publication number
WO2018235935A1
WO2018235935A1 PCT/JP2018/023762 JP2018023762W WO2018235935A1 WO 2018235935 A1 WO2018235935 A1 WO 2018235935A1 JP 2018023762 W JP2018023762 W JP 2018023762W WO 2018235935 A1 WO2018235935 A1 WO 2018235935A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
water
ethylene oxide
container
oxide gas
Prior art date
Application number
PCT/JP2018/023762
Other languages
French (fr)
Japanese (ja)
Inventor
隆司 森本
Original Assignee
参天製薬株式会社
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Filing date
Publication date
Priority claimed from JP2017244738A external-priority patent/JP7037349B2/en
Application filed by 参天製薬株式会社 filed Critical 参天製薬株式会社
Publication of WO2018235935A1 publication Critical patent/WO2018235935A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to a pharmaceutical composition containing a water-soluble thickener, which is contained in an ethylene oxide gas sterilization container.
  • the container for storing the aqueous liquid preparation is a resin-made container in which most of the containers are made of a synthetic resin such as polyethylene, polypropylene, propylene-ethylene copolymer, etc., unlike injections and the like filled in a glass container. Since these resin containers are poor in heat resistance, for example, it is difficult to heat sterilize after filling an aqueous solution into a resin container, and therefore, the resin container itself should be sterile before filling of the aqueous solution. Is required.
  • Known sterilization methods for resin-made containers include gamma ray sterilization, electron beam sterilization, ethylene oxide gas (EOG) sterilization, hydrogen peroxide solution sterilization and the like.
  • a thickening agent is used for the purpose of adjusting the viscosity and keeping it on the surface of the eye for a long time to enhance the efficacy of efficacy and transferability to the eye.
  • water-soluble thickening agents are commonly added to eye drops, it is known that the viscosity of the solution often decreases during long-term storage by being combined with an aqueous solution.
  • the present invention contains a pharmaceutical composition containing a water-soluble thickener.
  • the method of sterilizing the container affects the viscosity reduction of the pharmaceutical composition, and further, containing the water-soluble thickening agent-containing pharmaceutical composition in a container sterilized with ethylene oxide gas. It discovered that the viscosity fall of a pharmaceutical composition was suppressed, and came to this invention.
  • the present invention provides the following.
  • a pharmaceutical composition containing a water-soluble thickening agent which is contained in an ethylene oxide gas sterilization container.
  • the water-soluble thickening agent is one or more water-soluble thickening agents selected from the group consisting of cellulosic polymers, polyvinyl pyrrolidone, carboxyvinyl polymers and polyhydric alcohols, Pharmaceutical composition as described.
  • the pharmaceutical composition according to (2), wherein the cellulose-based polymer is one or more cellulose-based polymers selected from the group consisting of hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methyl cellulose.
  • a pharmaceutical composition comprising dorzolamide or a salt thereof and timolol or a salt thereof as an active ingredient, and hydroxyethyl cellulose as a water-soluble thickening agent, wherein the pharmaceutical composition is contained in a container made of ethylene oxide gas sterilization resin .
  • a method for suppressing the decrease in viscosity of a pharmaceutical composition by housing the pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.
  • a method of improving the stability of a pharmaceutical composition by storing the pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.
  • the invention further relates to the following.
  • a pharmaceutical composition for treatment and / or prevention of eye diseases which contains a water-soluble thickening agent and is contained in an ethylene oxide gas sterilization container.
  • a method for treating and / or preventing ocular diseases which method is effective for a subject in need of a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container A method comprising administering a dose.
  • a pharmaceutical product comprising a pharmaceutical composition containing a water-soluble thickening agent contained in an ethylene oxide gas sterilization container.
  • each structure of said (1) to (18) can select 2 or more arbitrarily, and can combine them.
  • the water-soluble thickening agent in the present invention may be any water-soluble thickening agent that can be used as a pharmaceutical additive, and examples thereof include cellulose polymers, polyvinyl pyrrolidone, carboxyvinyl polymers, mucopolysaccharides and the like Polyhydric alcohols may be mentioned, and furthermore, their hydrates or solvates.
  • nonionic cellulose As cellulose type polymer, nonionic cellulose, anionic cellulose, etc. are mentioned, for example.
  • examples of the nonionic cellulose include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose and the like
  • examples of the anionic cellulose include carboxymethylcellulose, hydroxypropyl methylcellulose acetate and so forth.
  • hydroxypropyl methylcellulose phthalate carboxymethylethylcellulose, cellulose acetate phthalate and the like, preferably nonionic cellulose, more preferably hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylmethylcellulose, and still more preferably Hydro Shi is ethyl cellulose or hydroxypropyl methylcellulose.
  • mucopolysaccharides examples include hyaluronic acid, chondroitin sulfate, heparin and the like.
  • polyhydric alcohol examples include polyethylene glycol and polyvinyl alcohol.
  • a cellulose-based polymer, polyvinyl pyrrolidone or a polyhydric alcohol is preferable, a cellulose-based polymer or polyvinyl pyrrolidone is more preferable, and hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose or polyvinyl pyrrolidone is further preferable.
  • Preferred is hydroxyethyl cellulose, hydroxypropyl methylcellulose or polyvinyl pyrrolidone.
  • one or more water-soluble thickening agents may be used together.
  • the content of the water-soluble thickening agent incorporated in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of water-soluble thickening agent, etc., but it is 0.001 to 10% (w / v) Is preferably 0.01% to 5% (w / v), more preferably 0.1 to 2% (w / v), and particularly preferably 0.2 to 1% (w / v).
  • % (w / v) means the mass (g) of the object component contained in 100 mL of the pharmaceutical composition of the present invention.
  • the ethylene oxide gas sterilization in the present invention is not particularly limited as long as it is a method of sterilizing using ethylene oxide gas, but for example, the container may be treated for a sufficient time to sterilize under a predetermined temperature and a predetermined humidity. It is exposed to ethylene oxide gas, sterilized, and then aerated to remove ethylene oxide gas.
  • the temperature of ethylene oxide gas sterilization can be appropriately selected according to the characteristics of the container, but is preferably 30 to 60 ° C.
  • the humidity (relative humidity) of ethylene oxide gas sterilization can be appropriately selected according to the characteristics of the container, but is preferably 30 to 80%.
  • the time of ethylene oxide gas sterilization is, for example, 1 to 10 hours, preferably 2 to 5 hours.
  • the gas used in ethylene oxide gas sterilization may be only ethylene oxide gas or a mixed gas with carbon dioxide or the like.
  • the ratio of ethylene oxide gas to other gases is, for example, 5:95 to 50:50 in volume ratio, preferably 10:90 to 40:60, and 20:80 to 30:70. More preferable.
  • the concentration of gas used in ethylene oxide gas sterilization can be appropriately selected according to the characteristics of the container, but is preferably 120 to 1200 mg / L.
  • aeration for removing ethylene oxide gas is not necessarily performed, but when aeration is performed, for example, air, nitrogen, argon, carbon dioxide, etc. can be used, and the aeration time is 8 hours or more are preferable, 12 hours or more are more preferable, and 24 hours or more are more preferable.
  • the ethylene oxide gas sterilization container refers to a container sterilized with ethylene oxide gas.
  • the container used may be any container that can be sterilized with ethylene oxide gas, but is preferably a resin container.
  • the material of the resin container include polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, and polycyclic olefin copolymer.
  • polyethylene is classified according to its density and includes low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE) and the like.
  • the resin container in the present invention is preferably made of polyethylene, polypropylene, polyethylene terephthalate, polypropylene-polyethylene copolymer or polycyclic olefin copolymer, more preferably made of polyethylene or polypropylene.
  • the eye drop container may be formed of a single member or a plurality of members, and any of a 1 piece eye drop container, a 2 piece eye drop container or a 3 piece eye drop container May be housed in
  • a three-piece eye drop container it is formed of three members, a container main body holding the pharmaceutical composition of the present invention, an inner plug and a cap, and an integral molding type simultaneously performing blow molding and drug solution filling.
  • a container is also included in the above-mentioned eyedrop container according to the number of members.
  • a container is formed from several members, it may be formed by the member by the same material, and may be formed by the member by a different material.
  • the material may constitute or coat a part or all of the member.
  • materials include the materials listed above, ie, polyethylene (including LDPE, MDPE, HDPE), polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, poly cyclic Refers to olefin copolymers and the like.
  • the ethylene oxide gas sterilization container has a residual ethylene oxide gas concentration of, for example, 0 to 10 ppm, preferably 0 to 5 ppm, more preferably 0 to 1 ppm, and most preferably not detected.
  • the residual ethylene oxide gas concentration can be measured in accordance with the Japan Medical Plastics Association "Quantification Method of Residual Ethylene Oxide in Medical Devices".
  • the pharmaceutical composition of the present invention is contained in an ethylene oxide gas sterilization container.
  • the present invention provides a pharmaceutical product comprising a pharmaceutical composition comprising a water soluble thickener, contained in an ethylene oxide gas sterilization container.
  • the present invention also provides a pharmaceutical product comprising a pharmaceutical composition containing a water-soluble thickener and an ethylene oxide gas sterilization container containing the pharmaceutical composition.
  • the present invention also provides a pharmaceutical product, wherein the pharmaceutical composition containing a water-soluble thickener is contained in an ethylene oxide gas sterilization container.
  • the present invention also provides a pharmaceutical product wherein a pharmaceutical composition containing a water soluble thickener is contained in an ethylene oxide gas sterilization container.
  • the pharmaceutical product of the present invention is one in which a pharmaceutical composition containing a water soluble thickener is contained in an ethylene oxide gas sterilization container.
  • the pharmaceutical product is preferably an ophthalmic product, an otolaryngological product, or a dermatological product, and more preferably an ophthalmic product.
  • ophthalmic products include products such as eye drops, injections, eye ointments, inserts and the like.
  • the pharmaceutical composition of the present invention can be orally or parenterally administered to a patient, and the administration mode is orally, topically to the eye, topically to the ear nose, inhaled, nebulized And intravenous administration, subcutaneous administration, transdermal administration and the like, and topical administration to the eye is more preferable.
  • topical administration to the eye refers to eye drop administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, subtenon administration and the like.
  • the pharmaceutical composition of the present invention can be formulated into a dosage form suitable for administration, if necessary, together with pharmaceutically acceptable additives.
  • a dosage form suitable for parenteral administration is preferred, and examples include eye drops, nasal drops, ear drops, inhalants, injections, eye ointments, inserts, transdermal preparations, external solutions, sprays, etc.
  • eye drops or injections are more preferable, eye drops are more preferable, and aqueous eye drops are particularly preferable.
  • the pharmaceutical composition of the present invention may contain an active ingredient of a medicine.
  • the active ingredient is not particularly limited and may be appropriately selected according to the purpose. For example, if it is used for eye drops, isopropyl unoprostone, carteolol, distigmine, dipibefrin, tafluprost, for the treatment of glaucoma , Timolol, travoprost, dolzolamide, nipatomilol, bimatoprost, pilocarpine, bunazosin, brimonidine, brinzolamide, betaxolol, betaxolol, latanoprost, ripasil, levobanolol or salts thereof are preferable, and as a antibacterial and antiviral treatment, acyclovir, erythromycin, ofloxacin, gatifloxax Syn, chloramphenicol, gentamicin, dibekacin, cefmenoxime, tosuf
  • Isopropyl unoprostone carteolol, distigmine, dipibefrin, tafluprost, timolol, travoprost, dorzolamide, nipradilol, bimatoprost, pilocarpine, bunazosin, brimonidin, betaxolol, latanoprost ripasil, levobnolol or their salts for the treatment of glaucoma More preferred is timolol, dorzolamide or a salt thereof.
  • the active ingredients contained in the pharmaceutical composition of the present invention may be used alone or in combination of two or more.
  • the active ingredient contained in the pharmaceutical composition of the present invention may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • salts include salts with inorganic acids, salts with organic acids, quaternary ammonium salts, salts with halogen ions, salts with alkali metals, salts with alkaline earth metals, salts with metal salts, organic amines Salt etc. are mentioned.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid Alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples thereof include salts with p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.
  • quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like.
  • Examples of the salt with a halogen ion include salts with a chloride ion, a bromide ion, an iodide ion and the like.
  • salts with alkali metals include salts with lithium, sodium, potassium and the like.
  • salts with alkaline earth metals include salts with calcium, magnesium and the like.
  • metal salts examples include salts with iron, zinc and the like.
  • salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- Examples thereof include salts with (hydroxymethyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
  • the active ingredient or a salt thereof contained in the pharmaceutical composition of the present invention may be in the form of a hydrate or a solvate.
  • the amount of the active ingredient contained in the pharmaceutical composition of the present invention is preferably 0.01% (w / v) or more, more preferably 0.05% (w / v) or more, 0.1% (w / v) v) or more is more preferable, and the upper limit thereof may be an acceptable concentration as an ophthalmic preparation, for example, 5% (w / v). 0.01 to 5% (w / v) is preferable, 0.05 to 4% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, 0.5 to 1. 5% (w / v) is particularly preferred.
  • these values are content of the salt of an active ingredient.
  • the active ingredient or a salt thereof is contained in the form of a hydrate or a solvate in the pharmaceutical composition of the present invention, these values indicate the hydrate or the solvate of the active ingredient or a salt thereof. It is content.
  • additives acceptable for incorporation into medicines can be blended as long as the effects of the present invention are not impaired.
  • a buffer, a preservative, a surfactant, a tonicity agent, a stabilizer, an anti-drug An oxidant, a pH adjuster, etc. can be added. These can be used singly or in combination of two or more as appropriate, and an appropriate amount can be blended.
  • the buffer in the case of incorporating a buffer into the pharmaceutical composition of the present invention may be a buffer that can be used as an additive of pharmaceuticals, and for example, phosphoric acid or a salt thereof, boric acid or a salt thereof And borax, carbonic acid or salts thereof or organic acids or salts thereof, etc., and may be hydrates or solvates thereof.
  • phosphoric acid or salts thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and the like. It may be a hydrate of
  • boric acid or a salt thereof examples include boric acid, sodium borate, potassium borate and the like, and may be a hydrate of them.
  • Examples of carbonic acid or a salt thereof include sodium carbonate, sodium hydrogen carbonate and the like, and may be a hydrate thereof.
  • organic acids or salts thereof include citric acid, acetic acid, ⁇ -aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acids or their sodium salts, potassium salts And the like, and may be hydrates thereof.
  • a buffer When a buffer is incorporated into the pharmaceutical composition of the present invention, an organic acid or a salt thereof is preferred, citric acid or a salt thereof is more preferred, and sodium citrate is particularly preferred.
  • the content of the buffer in the case of incorporating the buffer into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of buffer etc., but preferably 0.001 to 10% (w / v), 0 .01-5% (w / v) is more preferable, 0.1-5% (w / v) is more preferable, and 0.1-1% (w / v) is particularly preferable.
  • the preservative in the case of incorporating a preservative into the pharmaceutical composition of the present invention may be a preservative that can be used as an additive of pharmaceuticals as appropriate, for example, reverse soaps, parabens, alcohols, And organic acids or salts thereof.
  • examples of inverse soaps include benzalkonium chloride, benzalkonium bromide, benzethonium chloride and benzethonium bromide.
  • parabens are, for example, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate.
  • the alcohol is, for example, chlorobutanol.
  • the organic acid or a salt thereof is, for example, sorbic acid or a salt thereof, sodium dehydroacetate, and among them, sorbic acid or a salt thereof is, for example, sodium sorbate or potassium sorbate.
  • the content of the preservative in the case of incorporating the preservative into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of preservative and the like, but it may be an amount that does not adversely affect safety.
  • the upper limit thereof is, for example, 1% (w / v) or less, preferably 0.5% (w / v) or less, more preferably 0.1% (w / v) or less, and 0.05% (w / v). v) or less is more preferable, and 0.01% (w / v) or less is particularly preferable.
  • the amount may be such that the preservative action can be exhibited, and the lower limit thereof is preferably 0.0001% (w / v) or more, and more preferably 0.001% (w / v) or more.
  • the content of the preservative is preferably 0.0001 to 1% (w / v), more preferably 0.001 to 0.5% (w / v), and 0.001 to 0.1% (w / v). v) is more preferred.
  • the surfactant in the case where the surfactant is added to the pharmaceutical composition of the present invention may be a surfactant which can be used appropriately as an additive for pharmaceuticals, but, for example, cationic surfactant may be used. Agents, anionic surfactants, nonionic surfactants and the like.
  • alkylamine salt for example, alkylamine salt, alkylamine polyoxyethylene adduct, fatty acid triethanolamine monoester salt, acylaminoethyl diethylamine salt, fatty acid polyamine condensate, alkyl imidazoline, 1-acylaminoethyl -2-alkyl imidazoline, 1-hydroxy ethyl 2-alkyl imidazoline and the like.
  • anionic surfactant examples include phosphoric acid lipids such as lecithin and the like.
  • nonionic surfactant examples include polyoxyethylene fatty acid esters such as polyoxyl stearate and the like; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 60; polyoxyl Polyoxyl castor oil such as 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, etc .; polyoxyethylene 160) Polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) Polyoxyethylene polyoxypropylene (
  • a surfactant When a surfactant is added to the pharmaceutical composition of the present invention, a nonionic surfactant is more preferred, polyethylene sorbitan fatty acid ester is more preferred, and polysorbate 80 is particularly preferred.
  • the content of the surfactant in the case of incorporating the surfactant into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant, etc. v) is preferable, 0.05 to 0.5% (w / v) is more preferable, and 0.05% to 0.2% (w / v) is more preferable.
  • the isotonizing agent in the case of incorporating an isotonizing agent into the pharmaceutical composition of the present invention may be an isotonizing agent which can be used as an additive for pharmaceuticals, and may be, for example, ionic isotonizing. Agents and nonionic tonicity agents.
  • ionic tonicity agent examples include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
  • nonionic tonicity agent examples include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol and the like.
  • the content of the tonicity agent in the case of incorporating the tonicity agent into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of tonicity agent etc., but it is 0.001 to 10% (w / w). v) is preferable, 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is further preferable, and 0.5 to 2% (w / v) is particularly preferable .
  • blending a stabilizer with the pharmaceutical composition of this invention can be suitably mix
  • edetic acid or its salt etc. are mentioned.
  • edetic acid or salts thereof examples include edetic acid, disodium edetate, tetrasodium edetate and the like.
  • the content of the stabilizer in the case of incorporating the stabilizer into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer etc., but 0.001 to 5% (w / v) Preferably, 0.01% to 1% (w / v) is more preferable, and 0.01 to 0.1% (w / v) is more preferable.
  • the antioxidant in the case of incorporating an antioxidant into the pharmaceutical composition of the present invention may be an antioxidant which can be suitably used as an additive of a pharmaceutical, and examples thereof include ascorbic acid, tocopherol, dibutyl hydroxytoluene Sodium sulfite and the like.
  • the content of the antioxidant in the case of incorporating the antioxidant into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the antioxidant etc., 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 more preferable.
  • the pH regulator in the case of incorporating a pH regulator into the pharmaceutical composition of the present invention may be a pH regulator which can be used as an additive of pharmaceuticals as appropriate, and is, for example, an acid or a base as an acid
  • the base include hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like
  • examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
  • the pH of the pharmaceutical composition of the present invention may be in the pharmaceutically acceptable range, preferably in the range of 4.0 to 8.5 or 4.0 to 8.0, and more preferably 5.0 to 8.0. Is more preferable, and 5.5 to 7.5 is more preferable. Particularly preferred pHs are 5.5 to 7.0, but 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, 6.9, 7.0 are even more preferred.
  • the osmotic pressure ratio of the pharmaceutical composition of the present invention may be in the pharmaceutically acceptable range, for example, 0.5 to 2.0, preferably 0.7 to 1.6, and 0.8 to 1. 4 is more preferable, and 0.9 to 1.2 is more preferable.
  • the viscosity of the pharmaceutical composition of the present invention may be measured by a widely used method, and can be measured using, for example, a capillary viscometer, a rotational viscometer, a falling ball viscometer, etc., and in particular, using an Ostwald viscometer , Can be measured.
  • the viscosity of the pharmaceutical composition of the present invention may be in the pharmaceutically acceptable range, preferably 2 to 700 (mPa ⁇ s) at 25 ° C., more preferably 50 to 500 (mPa ⁇ s), and 65 to 200 (mPa ⁇ s) is more preferable.
  • the viscosity at 25 ° C. is a value (relative viscosity) measured using an Ostwald viscometer.
  • the number of hydration waters can usually be coordinated, for example, a monohydrate. Dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, decahydrate, It is 12 hydrate, 1/2 hydrate, 3/2 hydrate etc.
  • the solvent or dispersion medium is preferably water, most preferably an aqueous solution.
  • the pharmaceutical composition of the present invention when used as an eye drop, it may be contained in any of a multi-dose container, a single-use unit dose container or a PFMD (Preservative Free Multi Dose) container.
  • PFMD Preservative Free Multi Dose
  • the pharmaceutical composition of the present invention may be, for example, a pharmaceutical composition for treatment and / or prevention of eye diseases, and examples of eye diseases to be treated and / or prevented include, for example, glaucoma, infectious eyes Diseases, inflammatory eye diseases, dry eyes, corneal diseases, allergic eye diseases, cataracts, eye strain and the like can be mentioned, with preference given to glaucoma.
  • the suppression of the viscosity decrease of the pharmaceutical composition means that the temporal decrease of the viscosity of the pharmaceutical composition is suppressed, and the temporal decrease of the viscosity is, for example, the composition of the pharmaceutical composition.
  • This can be shown by comparing the viscosity immediately after preparation (or immediately after filling) with the viscosity after a certain period of time.
  • the degree of suppression of the viscosity drop in the present invention can be shown, for example, by comparison with the viscosity drop when stored in a container subjected to electron beam sterilization, and in this case, the suppression of the viscosity drop in the present invention It can be said that the improvement of the viscosity decrease.
  • the viscosity is measured by a predetermined viscosity measurement method.
  • composition of the present invention also applies to the method for suppressing the viscosity reduction of the pharmaceutical composition of the present invention and the method for improving the stability of the pharmaceutical composition.
  • the method for suppressing the viscosity reduction of the pharmaceutical composition of the present invention comprises containing a pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.
  • the method of improving the stability of the pharmaceutical composition of the present invention comprises containing a pharmaceutical composition containing a water soluble thickener in an ethylene oxide gas sterilization container.
  • the improvement of the stability of the pharmaceutical composition means that the temporal change of the pharmaceutical composition is suppressed, and, for example, the suppression of the temporal decrease of the viscosity of the pharmaceutical composition is included.
  • One aspect of the present invention is a pharmaceutical composition for treatment and / or prevention of eye diseases, which contains a water-soluble thickener and is contained in an ethylene oxide gas sterilization container.
  • One aspect of the present invention is a pharmaceutical composition containing a water soluble thickener and contained in an ethylene oxide gas sterilization container, for use in the treatment and / or prevention of ocular diseases.
  • One aspect of the present invention is the use of a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container for the manufacture of a medicament for treating and / or preventing ocular diseases It is.
  • One aspect of the present invention is a method for the treatment and / or prevention of ocular diseases, which comprises a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container, which requires the pharmaceutical composition. Administering an effective amount to the subject.
  • One aspect of the present invention is a method of producing a pharmaceutical product comprising housing a pharmaceutical composition containing a water soluble thickener in an ethylene oxide gas sterilization container.
  • test preparation 1 In a polyethylene container which has been subjected to ethylene oxide gas (EOG) sterilization treatment (ethylene oxide concentration: 480 mg / L, temperature: 40 ° C., relative humidity: 45%, treatment time: 3 hours) (1) The test preparation 1 prepared in the above was filled. The test preparation 1 (Example 1) housed in the ethylene oxide gas sterilization container was stored at a temperature of 40 ° C. or 60 ° C. for up to 3 months. The viscosity of the test preparation 1 was measured immediately after filling and after the start of storage over time. The viscosity of the test preparation at 25 ° C. ⁇ 0.1 ° C. was measured using Micro Ostwald (manufactured by SI Analytics GmbH, Type No. 51623) for measurement of viscosity.
  • EOG ethylene oxide gas
  • test preparation 1 prepared in (1) was filled in a polyethylene container which was subjected to electron beam sterilization (50 kGy) instead of EOG sterilization (Comparative Example 1).
  • the test preparation 1 was tested in the same manner as in Example 1 to measure the viscosity.
  • Test Results and Discussion The test results for Test preparation 1 are shown in Table 1.
  • Example 1 in which the test preparation 1 is filled in a container treated with ethylene oxide gas sterilization is compared with Comparative Example 1 in which the test preparation 1 is filled in a container treated with electron beam sterilization, The effect of suppressing the viscosity reduction of the test preparation 1 was shown.
  • Test preparation 2-5 (1) Preparation of Test Preparation
  • the test preparations 2 to 5 shown in Table 2 were prepared using the same method as the test preparation 1.
  • Example 2 Polyethylene oxide to which ethylene oxide gas (EOG) sterilization treatment (ethylene oxide concentration: 480 mg / L, temperature: 40 ° C., relative humidity: 45%, treatment time: 3 hours) was applied
  • the test preparations 2 to 5 prepared in (1) were filled in respective containers.
  • the test preparation (Examples 2 to 5) contained in this ethylene oxide gas sterilization container was stored at a temperature of 50 ° C. for up to 8 weeks.
  • the viscosities of the test formulations 2 to 5 were measured in the same manner as in Example 1 immediately after filling and after the start of storage over time.
  • test preparations 2 to 5 prepared in (1) were respectively filled in polyethylene containers which were subjected to electron beam sterilization (50 kGy) instead of EOG sterilization (Comparative Examples 2 to 5).
  • the test preparations 2 to 5 were tested in the same manner as in Examples 2 to 5 to measure the viscosity.
  • test preparations 2 to 5 As shown in Table 3, for any of the test preparations 2 to 5, when the test preparation is filled in a container treated with ethylene oxide gas sterilization, compared to the case where the container treated with electron beam sterilization is filled, The effect of suppressing the viscosity reduction of the test preparation was shown.
  • the present invention provides a pharmaceutical composition containing a water-soluble thickener, which is contained in an ethylene oxide gas sterilization container.

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Abstract

Provided is a medicinal composition containing a water-soluble thickening agent, wherein a decrease in the viscosity of the medicinal composition is prevented. The medicinal composition according to the present invention, which contains a water-soluble thickening agent, is housed in an ethylene oxide gas-sterilized container.

Description

水溶性粘稠化剤を含有する医薬組成物Pharmaceutical composition containing a water soluble thickener
　本発明は、水溶性粘稠化剤を含有する医薬組成物であって、エチレンオキサイドガス滅菌容器に収容された、医薬組成物に関する。 The present invention relates to a pharmaceutical composition containing a water-soluble thickener, which is contained in an ethylene oxide gas sterilization container.
　点眼液のような水性液剤は、人体における特に鋭敏な器官である眼に直接投与されるため、点眼容器の開封時までは無菌状態を保つことが厳しく求められている。水性液剤を保存する容器は、ガラス製容器に充填される注射剤等とは異なり、その多くがポリエチレン、ポリプロピレン、プロピレン－エチレンコポリマー等の合成樹脂を成形した樹脂製容器である。これらの樹脂製容器は耐熱性に劣ることから、例えば、水性液剤を樹脂製容器に充填後に加熱滅菌を施すことは難しく、従って、水性液剤の充填前に樹脂製容器自体を無菌状態にすることが求められる。樹脂製容器の滅菌方法としては、ガンマ線滅菌、電子線滅菌、エチレンオキサイドガス（ＥＯＧ）滅菌、過酸化水素水滅菌等が知られている。 Since an aqueous solution such as an eye drop is directly administered to the eye, which is a particularly sensitive organ in the human body, it is strictly required to maintain sterility until the eye drop container is opened. The container for storing the aqueous liquid preparation is a resin-made container in which most of the containers are made of a synthetic resin such as polyethylene, polypropylene, propylene-ethylene copolymer, etc., unlike injections and the like filled in a glass container. Since these resin containers are poor in heat resistance, for example, it is difficult to heat sterilize after filling an aqueous solution into a resin container, and therefore, the resin container itself should be sterile before filling of the aqueous solution. Is required. Known sterilization methods for resin-made containers include gamma ray sterilization, electron beam sterilization, ethylene oxide gas (EOG) sterilization, hydrogen peroxide solution sterilization and the like.
　他方、点眼液には、その粘度を調整して眼表面に長時間滞留させることにより薬効の持続性や眼内移行性を高める目的で、粘稠化剤が使用されている。しかし、水溶性粘稠化剤は点眼液に汎用的に添加される一方で、水性液剤と配合することにより長期間の保存中にしばしば液剤の粘度低下が起きることが知られている。水溶性粘稠化剤を含む水性液剤における粘度低下を抑制する方法としては、例えば、特許文献１では、ヒプロメロース及び／又はヒドロキシエチルセルロースを含む水性液剤に、ポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシルを配合すること、特許文献２では、セルロース系粘稠化剤に非イオン性界面活性剤及び特定の植物油を配合すること、特許文献３では、水溶性高分子化合物に、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、アスコルビン酸またはその塩及び／又は亜硫酸またはその塩を配合すること、さらには容器周囲を不活性ガス雰囲気とする包装とし、あるいは脱酸素剤を使用することにより、特に優れた粘度低下防止効果が得られること等が記載されている。 On the other hand, in the eye drop solution, a thickening agent is used for the purpose of adjusting the viscosity and keeping it on the surface of the eye for a long time to enhance the efficacy of efficacy and transferability to the eye. However, while water-soluble thickening agents are commonly added to eye drops, it is known that the viscosity of the solution often decreases during long-term storage by being combined with an aqueous solution. As a method of suppressing the viscosity decrease in the aqueous solution containing the water-soluble thickening agent, for example, in Patent Document 1, polyoxyethylene hardened castor oil and / or stearic acid is added to the aqueous solution containing hypromellose and / or hydroxyethyl cellulose. Compounding polyoxyl, compounding nonionic surfactant and specific vegetable oil to the cellulose-based thickening agent in patent document 2, dibutyl hydroxytoluene, butyl as compounding water-soluble polymer compound in patent document 3 Particularly excellent prevention of viscosity drop by blending hydroxyanisole, ascorbic acid or its salt and / or sulfurous acid or its salt, and by using a package with an inert gas atmosphere around the container, or using an oxygen scavenger It describes that the effect can be obtained.
　しかし、容器の滅菌方法が、水溶性粘稠化剤を含有する医薬組成物の粘度低下に影響を及ぼすことはこれまでに知られていない。 However, it has not previously been known that the method of sterilizing the container affects the viscosity reduction of a pharmaceutical composition containing a water soluble thickener.
国際ＷＯ２０１４－０５０３０１号International WO 2014-050301 特開２０１１－０６８６８４号JP, 2011-068684, No. 特開２００４－１２３６３４号JP 2004-123634
　水溶性粘稠化剤を含有する医薬組成物であって、前記医薬組成物の粘度低下が抑制された医薬組成物を提供することは興味深い課題である。 It is an interesting subject to provide a pharmaceutical composition containing a water-soluble thickening agent, wherein the viscosity reduction of the pharmaceutical composition is suppressed.
　本発明者らは、水溶性粘稠化剤を含有する医薬組成物の粘度低下を抑制すべく鋭意研究を行ったところ、意外にも水溶性粘稠化剤を含有する医薬組成物を収容する容器の滅菌方法が、前記医薬組成物の粘度低下に影響を及ぼすこと、さらには水溶性粘稠化剤を含有する医薬組成物を、エチレンオキサイドガスで滅菌された容器に収容することによって、前記医薬組成物の粘度低下が抑制されることを見出し、本発明に至った。具体的に、本発明は以下を提供する。 The inventors of the present invention have conducted intensive studies to suppress the decrease in viscosity of a pharmaceutical composition containing a water-soluble thickener, and surprisingly, the present invention contains a pharmaceutical composition containing a water-soluble thickener. The method of sterilizing the container affects the viscosity reduction of the pharmaceutical composition, and further, containing the water-soluble thickening agent-containing pharmaceutical composition in a container sterilized with ethylene oxide gas. It discovered that the viscosity fall of a pharmaceutical composition was suppressed, and came to this invention. Specifically, the present invention provides the following.
（１）水溶性粘稠化剤を含有する医薬組成物であって、エチレンオキサイドガス滅菌容器に収容された、医薬組成物。
（２）水溶性粘稠化剤が、セルロース系高分子、ポリビニルピロリドン、カルボキシビニルポリマー及び多価アルコールよりなる群から選択される１又は複数の水溶性粘稠化剤である、（１）に記載の医薬組成物。
（３）セルロース系高分子が、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース及びヒドロキシプロピルメチルセルロースよりなる群から選択される１又は複数のセルロース系高分子である、（２）に記載の医薬組成物。
（４）水溶性粘稠化剤の含有量が０．００１～１０％（ｗ／ｖ）である、（１）～（３）のいずれかに記載の医薬組成物。
（５）容器が樹脂製容器である、（１）～（４）のいずれかに記載の医薬組成物。
（６）樹脂製容器がポリエチレン製、ポリプロピレン製、またはポリエチレンテレフタレート製である、（５）に記載の医薬組成物。
（７）水溶性粘稠化剤としてセルロース系高分子を含有する医薬組成物であって、エチレンオキサイドガス滅菌樹脂製容器に収容された、医薬組成物。
（８）水性点眼剤である、（１）～（７）のいずれかに記載の医薬組成物。
（９）緑内障治療剤である、（１）～（８）のいずれかに記載の医薬組成物。
（１０）有効成分としてドルゾラミド又はその塩を含有する、（１）～（９）のいずれかに記載の医薬組成物。
（１１）有効成分としてドルゾラミド又はその塩及びチモロール又はその塩、水溶性粘稠化剤としてヒドロキシエチルセルロースを含有する医薬組成物であって、エチレンオキサイドガス滅菌樹脂製容器に収容された、医薬組成物。
（１２）水溶性粘稠化剤を含有する医薬組成物を、エチレンオキサイドガス滅菌容器に収容することによって、医薬組成物の粘度低下を抑制する方法。
（１３）水溶性粘稠化剤を含有する医薬組成物を、エチレンオキサイドガス滅菌容器に収容することによって、医薬組成物の安定性を向上する方法。 (1) A pharmaceutical composition containing a water-soluble thickening agent, which is contained in an ethylene oxide gas sterilization container.
(2) The water-soluble thickening agent is one or more water-soluble thickening agents selected from the group consisting of cellulosic polymers, polyvinyl pyrrolidone, carboxyvinyl polymers and polyhydric alcohols, Pharmaceutical composition as described.
(3) The pharmaceutical composition according to (2), wherein the cellulose-based polymer is one or more cellulose-based polymers selected from the group consisting of hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methyl cellulose.
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the content of the water-soluble thickening agent is 0.001 to 10% (w / v).
(5) The pharmaceutical composition according to any one of (1) to (4), wherein the container is a resin container.
(6) The pharmaceutical composition according to (5), wherein the resin container is made of polyethylene, polypropylene or polyethylene terephthalate.
(7) A pharmaceutical composition comprising a cellulose-based polymer as a water-soluble thickening agent, which is contained in a container made of ethylene oxide gas sterilization resin.
(8) The pharmaceutical composition according to any one of (1) to (7), which is an aqueous eye drop.
(9) The pharmaceutical composition according to any one of (1) to (8), which is a therapeutic agent for glaucoma.
(10) The pharmaceutical composition according to any one of (1) to (9), which comprises dorzolamide or a salt thereof as an active ingredient.
(11) A pharmaceutical composition comprising dorzolamide or a salt thereof and timolol or a salt thereof as an active ingredient, and hydroxyethyl cellulose as a water-soluble thickening agent, wherein the pharmaceutical composition is contained in a container made of ethylene oxide gas sterilization resin .
(12) A method for suppressing the decrease in viscosity of a pharmaceutical composition by housing the pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.
(13) A method of improving the stability of a pharmaceutical composition by storing the pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.
　本発明は、更に以下にも関する。
（１４）水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、眼疾患の治療及び／又は予防のための医薬組成物。
（１５）眼疾患の治療及び／又は予防における使用のための、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、医薬組成物。
（１６）眼疾患の治療及び／又は予防するための医薬の製造のための、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、医薬組成物の使用。
（１７）眼疾患の治療及び／又は予防する方法であって、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、医薬組成物を、それを必要とする対象に有効量投与することを含む、方法。
（１８）エチレンオキサイドガス滅菌容器に収容された、水溶性粘稠化剤を含有する医薬組成物を含む、医薬用製品。 The invention further relates to the following.
(14) A pharmaceutical composition for treatment and / or prevention of eye diseases, which contains a water-soluble thickening agent and is contained in an ethylene oxide gas sterilization container.
(15) A pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container, for use in the treatment and / or prevention of ocular diseases.
(16) Use of a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container for the manufacture of a medicament for treating and / or preventing ocular diseases.
(17) A method for treating and / or preventing ocular diseases, which method is effective for a subject in need of a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container A method comprising administering a dose.
(18) A pharmaceutical product comprising a pharmaceutical composition containing a water-soluble thickening agent contained in an ethylene oxide gas sterilization container.
　なお、前記（１）から（１８）の各構成は、任意に２以上を選択して組み合わせることができる。 In addition, each structure of said (1) to (18) can select 2 or more arbitrarily, and can combine them.
　本発明により、水溶性粘稠化剤を含有する医薬組成物であって、前記医薬組成物の粘度低下が抑制された医薬組成物を得ることができる。 According to the present invention, it is possible to obtain a pharmaceutical composition containing a water-soluble thickening agent, wherein the reduction in viscosity of the pharmaceutical composition is suppressed.
　以下に、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
　本発明における水溶性粘稠化剤とは、医薬品の添加物として使用可能な水溶性の粘稠化剤であればよく、例えば、セルロース系高分子、ポリビニルピロリドン、カルボキシビニルポリマー、ムコ多糖類又は多価アルコールが挙げられ、さらにそれらの水和物又は溶媒和物であってもよい。 The water-soluble thickening agent in the present invention may be any water-soluble thickening agent that can be used as a pharmaceutical additive, and examples thereof include cellulose polymers, polyvinyl pyrrolidone, carboxyvinyl polymers, mucopolysaccharides and the like Polyhydric alcohols may be mentioned, and furthermore, their hydrates or solvates.
　セルロース系高分子としては、例えば、ノニオン性セルロース、アニオン性セルロース等が挙げられる。ノニオン性セルロースとしては、例えば、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等が挙げられ、アニオン性セルロースとしては、例えば、カルボキシメチルセルロース、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等が挙げられるが、好ましくは、ノニオン性セルロースであり、より好ましくは、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又はヒドロキシプロピルメチルセルロースであり、さらに好ましくは、ヒドロキシエチルセルロース又はヒドロキシプロピルメチルセルロースである。 As cellulose type polymer, nonionic cellulose, anionic cellulose, etc. are mentioned, for example. Examples of the nonionic cellulose include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose and the like, and examples of the anionic cellulose include carboxymethylcellulose, hydroxypropyl methylcellulose acetate and so forth. And hydroxypropyl methylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate and the like, preferably nonionic cellulose, more preferably hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylmethylcellulose, and still more preferably Hydro Shi is ethyl cellulose or hydroxypropyl methylcellulose.
　ムコ多糖類としては、例えば、ヒアルロン酸、コンドロイチン硫酸、ヘパリン等が挙げられる。 Examples of mucopolysaccharides include hyaluronic acid, chondroitin sulfate, heparin and the like.
　多価アルコールとしては、例えば、ポリエチレングリコール、ポリビニルアルコール等が挙げられる。 Examples of the polyhydric alcohol include polyethylene glycol and polyvinyl alcohol.
　本発明における水溶性粘稠化剤として、セルロース系高分子、ポリビニルピロリドン又は多価アルコールが好ましく、セルロース系高分子又はポリビニルピロリドンがより好ましく、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルメチルセルロース又はポリビニルピロリドンがさらに好ましく、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース又はポリビニルピロリドンが特に好ましい。 As the water-soluble thickening agent in the present invention, a cellulose-based polymer, polyvinyl pyrrolidone or a polyhydric alcohol is preferable, a cellulose-based polymer or polyvinyl pyrrolidone is more preferable, and hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose or polyvinyl pyrrolidone is further preferable. Preferred is hydroxyethyl cellulose, hydroxypropyl methylcellulose or polyvinyl pyrrolidone.
　本発明における医薬組成物には、水溶性粘稠化剤を１種または２種以上一緒に用いてもよい。 In the pharmaceutical composition of the present invention, one or more water-soluble thickening agents may be used together.
　本発明の医薬組成物に配合される水溶性粘稠化剤の含有量は、水溶性粘稠化剤の種類など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、０．１～２％（ｗ／ｖ）がさらに好ましく、０．２～１％（ｗ／ｖ）が特に好ましい。 The content of the water-soluble thickening agent incorporated in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of water-soluble thickening agent, etc., but it is 0.001 to 10% (w / v) Is preferably 0.01% to 5% (w / v), more preferably 0.1 to 2% (w / v), and particularly preferably 0.2 to 1% (w / v).
　なお、「％（ｗ／ｖ）」は、本発明の医薬組成物１００ｍＬ中に含まれる対象成分の質量（ｇ）を意味する。以下、特に断りがない限り同様とする。 In addition, "% (w / v)" means the mass (g) of the object component contained in 100 mL of the pharmaceutical composition of the present invention. Hereinafter, the same applies unless otherwise noted.
　本発明におけるエチレンオキサイドガス滅菌とは、エチレンオキサイドガスを用いて滅菌処理する方法であれば特に制限されないが、例えば、所定の温度、所定の湿度の下、滅菌するのに十分な時間、容器をエチレンオキサイドガスに曝し、滅菌を行い、その後、エチレンオキサイドガスを除去するためにエアレーションをする手順で行われる。 The ethylene oxide gas sterilization in the present invention is not particularly limited as long as it is a method of sterilizing using ethylene oxide gas, but for example, the container may be treated for a sufficient time to sterilize under a predetermined temperature and a predetermined humidity. It is exposed to ethylene oxide gas, sterilized, and then aerated to remove ethylene oxide gas.
　本発明において、エチレンオキサイドガス滅菌の温度は、容器の特性に応じて適宜選択できるが、好ましくは３０～６０℃である。 In the present invention, the temperature of ethylene oxide gas sterilization can be appropriately selected according to the characteristics of the container, but is preferably 30 to 60 ° C.
　本発明において、エチレンオキサイドガス滅菌の湿度（相対湿度）は、容器の特性に応じて適宜選択できるが、好ましくは３０～８０％である。 In the present invention, the humidity (relative humidity) of ethylene oxide gas sterilization can be appropriately selected according to the characteristics of the container, but is preferably 30 to 80%.
　本発明において、エチレンオキサイドガス滅菌の時間は、例えば、１～１０時間、好ましくは２～５時間である。 In the present invention, the time of ethylene oxide gas sterilization is, for example, 1 to 10 hours, preferably 2 to 5 hours.
　本発明において、エチレンオキサイドガス滅菌で使用されるガスは、エチレンオキサイドガスのみであっても、二酸化炭素等との混合ガスであってもよい。混合ガスを用いる場合のエチレンオキサイドガスとその他のガスの割合は、例えば、体積比で５：９５～５０：５０であり、１０：９０～４０：６０が好ましく、２０：８０～３０：７０がより好ましい。 In the present invention, the gas used in ethylene oxide gas sterilization may be only ethylene oxide gas or a mixed gas with carbon dioxide or the like. When using a mixed gas, the ratio of ethylene oxide gas to other gases is, for example, 5:95 to 50:50 in volume ratio, preferably 10:90 to 40:60, and 20:80 to 30:70. More preferable.
　本発明において、エチレンオキサイドガス滅菌で使用されるガスの濃度は、容器の特性に応じて適宜選択できるが、好ましくは１２０～１２００ｍｇ／Ｌである。 In the present invention, the concentration of gas used in ethylene oxide gas sterilization can be appropriately selected according to the characteristics of the container, but is preferably 120 to 1200 mg / L.
　本発明において、エチレンオキサイドガスを除去するためのエアレーションは必ずしも実施する必要はないが、エアレーションを実施する場合は、例えば、空気、窒素、アルゴン、二酸化炭素等を使用することができ、エアレーション時間は、８時間以上が好ましく、１２時間以上がより好ましく、２４時間以上がさらに好ましい。 In the present invention, aeration for removing ethylene oxide gas is not necessarily performed, but when aeration is performed, for example, air, nitrogen, argon, carbon dioxide, etc. can be used, and the aeration time is 8 hours or more are preferable, 12 hours or more are more preferable, and 24 hours or more are more preferable.
　本発明において、エチレンオキサイドガス滅菌容器とは、エチレンオキサイドガスで滅菌された容器をいう。使用される容器は、エチレンオキサイドガスで滅菌処理ができる容器であればよいが、好ましくは樹脂製容器である。樹脂製容器の材質は、例えば、ポリエチレン、ポリプロピレン、ポリエチレンテレフタレート、ポリブチレンテレフタレート、ポリプロピレン－ポリエチレンコポリマー、ポリ塩化ビニル、アクリル樹脂、ポリスチレン、ポリ環状オレフィンコポリマー等が挙げられる。さらにポリエチレンは、その密度によって分類され、低密度ポリエチレン（ＬＤＰＥ）、中密度ポリエチレン（ＭＤＰＥ）、高密度ポリエチレン（ＨＤＰＥ）等が挙げられる。 In the present invention, the ethylene oxide gas sterilization container refers to a container sterilized with ethylene oxide gas. The container used may be any container that can be sterilized with ethylene oxide gas, but is preferably a resin container. Examples of the material of the resin container include polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, and polycyclic olefin copolymer. Furthermore, polyethylene is classified according to its density and includes low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE) and the like.
　本発明における樹脂製容器として、ポリエチレン製、ポリプロピレン製、ポリエチレンテレフタレート製、ポリプロピレン－ポリエチレンコポリマー製又はポリ環状オレフィンコポリマー製が好ましく、ポリエチレン製又はポリプロピレン製がより好ましい。 The resin container in the present invention is preferably made of polyethylene, polypropylene, polyethylene terephthalate, polypropylene-polyethylene copolymer or polycyclic olefin copolymer, more preferably made of polyethylene or polypropylene.
　本発明の医薬組成物を点眼剤として使用する場合、その点眼容器は１部材または複数の部材から形成されてもよく、１ピース型点眼容器、２ピース型点眼容器又は３ピース型点眼容器のいずれに収容されていてもよい。なお、例えば、３ピース型点眼容器であれば、本発明の医薬組成物を保持する容器本体と中栓、キャップの３部材から形成されるし、またブロー成形と薬液充填を同時に行う一体成型型容器もその部材数に即して前記の点眼容器に含まれる。また、容器が複数の部材から形成される場合には、同一の材質による部材で形成されてもよく、異なる材質による部材で形成されてもよい。さらに、材質が部材の一部又は全部を構成し、またはコーティングしている場合であってもよい。これらの材質とは、前記で挙げた材質、すなわち、ポリエチレン（ＬＤＰＥ、ＭＤＰＥ、ＨＤＰＥを含む）、ポリプロピレン、ポリエチレンテレフタレート、ポリブチレンテレフタレート、ポリプロピレン－ポリエチレンコポリマー、ポリ塩化ビニル、アクリル樹脂、ポリスチレン、ポリ環状オレフィンコポリマー等を指す。 When the pharmaceutical composition of the present invention is used as an eye drop, the eye drop container may be formed of a single member or a plurality of members, and any of a 1 piece eye drop container, a 2 piece eye drop container or a 3 piece eye drop container May be housed in For example, in the case of a three-piece eye drop container, it is formed of three members, a container main body holding the pharmaceutical composition of the present invention, an inner plug and a cap, and an integral molding type simultaneously performing blow molding and drug solution filling. A container is also included in the above-mentioned eyedrop container according to the number of members. Moreover, when a container is formed from several members, it may be formed by the member by the same material, and may be formed by the member by a different material. Furthermore, the material may constitute or coat a part or all of the member. These materials include the materials listed above, ie, polyethylene (including LDPE, MDPE, HDPE), polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, poly cyclic Refers to olefin copolymers and the like.
　本発明において、エチレンオキサイドガス滅菌容器は、残留エチレンオキサイドガス濃度が、例えば０～１０ｐｐｍであり、０～５ｐｐｍが好ましく、０～１ｐｐｍがより好ましく、検出されないのが最も好ましい。なお、残留エチレンオキサイドガス濃度は、日本医療用プラスチック協会「医療用具の残留エチレンオキサイドの定量法」に従って測定することができる。 In the present invention, the ethylene oxide gas sterilization container has a residual ethylene oxide gas concentration of, for example, 0 to 10 ppm, preferably 0 to 5 ppm, more preferably 0 to 1 ppm, and most preferably not detected. The residual ethylene oxide gas concentration can be measured in accordance with the Japan Medical Plastics Association "Quantification Method of Residual Ethylene Oxide in Medical Devices".
　本発明における医薬組成物は、エチレンオキサイドガス滅菌容器に収容される。本発明は、エチレンオキサイドガス滅菌容器に収容された、水溶性粘稠化剤を含有する医薬組成物を含む、医薬用製品を提供する。また、本発明は、水溶性粘稠化剤を含有する医薬組成物と、前記医薬組成物を収容したエチレンオキサイドガス滅菌容器とを含む、医薬用製品を提供する。また、本発明は、水溶性粘稠化剤を含有する医薬組成物が、エチレンオキサイドガス滅菌容器に収容された、医薬用製品を提供する。また、本発明は、水溶性粘稠化剤を含有する医薬組成物が、エチレンオキサイドガス滅菌容器に収容されてなる、医薬用製品を提供する。ここで、本発明の医薬用製品は、水溶性粘稠化剤を含有する医薬組成物が、エチレンオキサイドガス滅菌容器に収容された状態にあるものである。医薬用製品は、眼科用製品、耳鼻咽喉科用製品、皮膚用製品であることが好ましく、眼科用製品であることがより好ましい。眼科用製品としては、例えば、点眼剤、注射剤、眼軟膏、挿入剤等の製品が挙げられる。 The pharmaceutical composition of the present invention is contained in an ethylene oxide gas sterilization container. The present invention provides a pharmaceutical product comprising a pharmaceutical composition comprising a water soluble thickener, contained in an ethylene oxide gas sterilization container. The present invention also provides a pharmaceutical product comprising a pharmaceutical composition containing a water-soluble thickener and an ethylene oxide gas sterilization container containing the pharmaceutical composition. The present invention also provides a pharmaceutical product, wherein the pharmaceutical composition containing a water-soluble thickener is contained in an ethylene oxide gas sterilization container. The present invention also provides a pharmaceutical product wherein a pharmaceutical composition containing a water soluble thickener is contained in an ethylene oxide gas sterilization container. Here, the pharmaceutical product of the present invention is one in which a pharmaceutical composition containing a water soluble thickener is contained in an ethylene oxide gas sterilization container. The pharmaceutical product is preferably an ophthalmic product, an otolaryngological product, or a dermatological product, and more preferably an ophthalmic product. Examples of ophthalmic products include products such as eye drops, injections, eye ointments, inserts and the like.
　本発明における医薬組成物は、患者に対して経口的又は非経口的に投与することができ、投与形態としては、経口投与、眼への局所投与、耳鼻への局所投与、吸入投与、噴霧投与、静脈内投与、皮下投与、経皮投与等が挙げられ、眼への局所投与がより好ましい。 The pharmaceutical composition of the present invention can be orally or parenterally administered to a patient, and the administration mode is orally, topically to the eye, topically to the ear nose, inhaled, nebulized And intravenous administration, subcutaneous administration, transdermal administration and the like, and topical administration to the eye is more preferable.
　本発明において、眼への局所投与とは、点眼投与、結膜嚢内投与、硝子体内投与、結膜下投与、テノン嚢下投与等を指す。 In the present invention, topical administration to the eye refers to eye drop administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, subtenon administration and the like.
　本発明における医薬組成物は、必要に応じて、製薬学的に許容され得る添加剤と共に、投与に適した剤型に製剤化することができる。非経口投与に適した剤型が好ましく、例えば、点眼剤、点鼻剤、点耳剤、吸入剤、注射剤、眼軟膏、挿入剤、経皮吸収型製剤、外用液剤、スプレー剤等が挙げられるが、点眼剤又は注射剤がより好ましく、点眼剤がさらに好ましく、水性点眼剤が特に好ましい。 The pharmaceutical composition of the present invention can be formulated into a dosage form suitable for administration, if necessary, together with pharmaceutically acceptable additives. A dosage form suitable for parenteral administration is preferred, and examples include eye drops, nasal drops, ear drops, inhalants, injections, eye ointments, inserts, transdermal preparations, external solutions, sprays, etc. However, eye drops or injections are more preferable, eye drops are more preferable, and aqueous eye drops are particularly preferable.
　本発明の医薬組成物には、薬の有効成分を含んでもよい。有効成分は、特に限定されず、目的に応じて適宜選択することができるが、例えば点眼剤に用いられる場合であれば、緑内障治療用として、イソプロピルウノプロストン、カルテオロール、ジスチグミン、ジピベフリン、タフルプロスト、チモロール、トラボプロスト、ドルゾラミド、ニプラジロール、ビマトプロスト、ピロカルピン、ブナゾシン、ブリモニジン、ブリンゾラミド、ベタキソロール、ラタノプロスト、リパスジル、レボブノロール又はそれらの塩が好ましく、抗菌・抗ウイルス治療用として、アシクロビル、エリスロマイシン、オフロキサシン、ガチフロキサシン、クロラムフェニコール、ゲンタマイシン、ジベカシン、セフメノキシム、トスフロキサシン、トブラマイシン、ノルフロキサシン、バンコマイシン、ピマリシン、モキシフロキサシン、レボフロキサシン、ロメフロキサシン又はそれらの塩が好ましく、抗炎症治療用として、デキサメタゾン、デキサメタゾンメタスルホ安息香酸エステル、デキサメタゾンリン酸エステル、ヒドロコルチゾン酢酸エステル、フラジオマイシン、フルオロメトロン、プレドニゾロン酢酸エステル、ベタメタゾンリン酸エステル、アズレンスルホン酸、グリチルリチン酸、ジクロフェナク、ネパフェナク、プラノプロフェン、ブロムフェナク又はそれらの塩が好ましく、ドライアイ・角膜治療用として、コンドロイチン硫酸、ジクアホソル、ヒアルロン酸、フラビンアデニンジヌクレオチド、レバミピド又はそれらの塩が好ましく、抗アレルギー治療用として、アシタザノラスト、アンレキサノクス、イブジラスト、エピナスチン、オロパタジン、クロモグリク酸、ケトチフェン、シクロスポリン、タクロリムス、トラニラスト、ペミロラスト、レボカバスチン又はそれらの塩が好ましく、白内障・眼精疲労・その他の治療用として、アトロピン、オキシブプロカイン、オキシメタゾリン、グルタチオン、シアノコバラミン、シクロペントラート、トロピカミド、ナファゾリン、ネオスチグミン、ピレノキシン、フェニレフリン、リゾチーム、硫酸亜鉛又はそれらの塩が好ましい。緑内障治療用として、イソプロピルウノプロストン、カルテオロール、ジスチグミン、ジピベフリン、タフルプロスト、チモロール、トラボプロスト、ドルゾラミド、ニプラジロール、ビマトプロスト、ピロカルピン、ブナゾシン、ブリモニジン、ブリンゾラミド、ベタキソロール、ラタノプロスト、リパスジル、レボブノロール又はそれらの塩がより好ましく、チモロール、ドルゾラミド又はそれらの塩がさらに好ましい。 The pharmaceutical composition of the present invention may contain an active ingredient of a medicine. The active ingredient is not particularly limited and may be appropriately selected according to the purpose. For example, if it is used for eye drops, isopropyl unoprostone, carteolol, distigmine, dipibefrin, tafluprost, for the treatment of glaucoma , Timolol, travoprost, dolzolamide, nipatomilol, bimatoprost, pilocarpine, bunazosin, brimonidine, brinzolamide, betaxolol, betaxolol, latanoprost, ripasil, levobanolol or salts thereof are preferable, and as a antibacterial and antiviral treatment, acyclovir, erythromycin, ofloxacin, gatifloxax Syn, chloramphenicol, gentamicin, dibekacin, cefmenoxime, tosufloxacin, tobramycin, norfloxacin, vancomycin, pimarisi , Moxifloxacin, levofloxacin, lomefloxacin or salts thereof are preferred, and for anti-inflammatory treatment, dexamethasone, dexamethasone metasulfobenzoate, dexamethasone phosphate, hydrocortisone acetate, fradiomycin, fluorometholone, prednisolone acetate, Betamethasone phosphate, azulene sulfonic acid, glycyrrhizinic acid, diclofenac, nepafenac, pranoprofen, bromfenac or salts thereof are preferred, and chondroitin sulfate, diquafosol, hyaluronic acid, flavin adenine dinucleotide, rebamipide for the treatment of dry eye and cornea Or salts thereof are preferred, and for the treatment of anti-allergy, alitazanolast, anlexanox, ibudilast, epi Stin, olopatadine, cromoglycic acid, ketotifen, cyclosporin, tacrolimus, tranilast, pemirolast, levocavastine or salts thereof are preferred, and for treatment of cataract, eye fatigue, and others, atropine, oxybuprocaine, oxymetazoline, glutathione, cyanocobalamin Cyclopentolate, tropicamide, naphazoline, neostigmine, pyrenoxine, phenylephrine, lysozyme, zinc sulfate or salts thereof are preferred. Isopropyl unoprostone, carteolol, distigmine, dipibefrin, tafluprost, timolol, travoprost, dorzolamide, nipradilol, bimatoprost, pilocarpine, bunazosin, brimonidin, betaxolol, latanoprost ripasil, levobnolol or their salts for the treatment of glaucoma More preferred is timolol, dorzolamide or a salt thereof.
　本発明の医薬組成物に含有される有効成分は、１種又は２種以上一緒に用いてもよい。 The active ingredients contained in the pharmaceutical composition of the present invention may be used alone or in combination of two or more.
　本発明の医薬組成物に含有される有効成分は塩であってもよく、医薬として許容される塩であれば特に制限はない。塩としては、例えば、無機酸との塩、有機酸との塩、四級アンモニウム塩、ハロゲンイオンとの塩、アルカリ金属との塩、アルカリ土類金属との塩、金属塩、有機アミンとの塩等が挙げられる。 The active ingredient contained in the pharmaceutical composition of the present invention may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of salts include salts with inorganic acids, salts with organic acids, quaternary ammonium salts, salts with halogen ions, salts with alkali metals, salts with alkaline earth metals, salts with metal salts, organic amines Salt etc. are mentioned.
　無機酸との塩としては、例えば、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。 Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
　有機酸との塩としては、例えば、酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、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、アラニン、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、没食子酸、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、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸等との塩が挙げられる。 Examples of salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid Alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples thereof include salts with p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.
　四級アンモニウム塩としては、例えば、臭化メチル、ヨウ化メチル等との塩が挙げられる。 Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like.
　ハロゲンイオンとの塩としては、例えば、塩化物イオン、臭化物イオン、ヨウ化物イオン等との塩が挙げられる。 Examples of the salt with a halogen ion include salts with a chloride ion, a bromide ion, an iodide ion and the like.
　アルカリ金属との塩としては、例えば、リチウム、ナトリウム、カリウム等との塩が挙げられる。 Examples of salts with alkali metals include salts with lithium, sodium, potassium and the like.
　アルカリ土類金属との塩としては、例えば、カルシウム、マグネシウム等との塩が挙げられる。 Examples of salts with alkaline earth metals include salts with calcium, magnesium and the like.
　金属塩としては、例えば、鉄、亜鉛等との塩が挙げられる。 Examples of metal salts include salts with iron, zinc and the like.
　有機アミンとの塩としては、例えば、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－エタンジアミン等との塩が挙げられる。 Examples of salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- Examples thereof include salts with (hydroxymethyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
　本発明の医薬組成物に含有される有効成分又はその塩は、水和物又は溶媒和物の形態をとってもよい。 The active ingredient or a salt thereof contained in the pharmaceutical composition of the present invention may be in the form of a hydrate or a solvate.
　本発明の医薬組成物に含有される有効成分の量は、０．０１％（ｗ／ｖ）以上が好ましく、０．０５％（ｗ／ｖ）以上がより好ましく、０．１％（ｗ／ｖ）以上がさらに好ましく、その上限は眼科製剤として許容される濃度でよく、例えば、５％（ｗ／ｖ）である。０．０１～５％（ｗ／ｖ）が好ましく、０．０５～４％（ｗ／ｖ）がより好ましく、０．１～３％（ｗ／ｖ）がさらに好ましく、０．５～１．５％（ｗ／ｖ）が特に好ましい。なお、本発明の医薬組成物に有効成分の塩が含有される場合、これらの値は有効成分の塩の含有量である。本発明の医薬組成物に有効成分又はその塩が、水和物又は溶媒和物の形態をとって含有される場合、これらの値は有効成分又はその塩の、水和物又は溶媒和物の含有量である。 The amount of the active ingredient contained in the pharmaceutical composition of the present invention is preferably 0.01% (w / v) or more, more preferably 0.05% (w / v) or more, 0.1% (w / v) v) or more is more preferable, and the upper limit thereof may be an acceptable concentration as an ophthalmic preparation, for example, 5% (w / v). 0.01 to 5% (w / v) is preferable, 0.05 to 4% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, 0.5 to 1. 5% (w / v) is particularly preferred. In addition, when the salt of an active ingredient is contained in the pharmaceutical composition of this invention, these values are content of the salt of an active ingredient. When the active ingredient or a salt thereof is contained in the form of a hydrate or a solvate in the pharmaceutical composition of the present invention, these values indicate the hydrate or the solvate of the active ingredient or a salt thereof. It is content.
　本発明における医薬組成物には、水溶性粘稠化剤および有効成分の他に、医薬品への配合が許容される添加剤を、本発明の効果を損なわない範囲で配合することができる。特に、眼への局所投与を可能とする製剤である場合、水溶性粘稠化剤および有効成分の他に、緩衝剤、防腐剤、界面活性化剤、等張化剤、安定化剤、抗酸化剤、ｐＨ調節剤等を加えることができる。これらは、それぞれ１種単独又は２種以上を適宜組み合わせて用いることができ、適量を配合することができる。 In the pharmaceutical composition of the present invention, in addition to the water-soluble thickening agent and the active ingredient, additives acceptable for incorporation into medicines can be blended as long as the effects of the present invention are not impaired. In particular, when the preparation enables topical administration to the eye, in addition to the water-soluble thickening agent and the active ingredient, a buffer, a preservative, a surfactant, a tonicity agent, a stabilizer, an anti-drug An oxidant, a pH adjuster, etc. can be added. These can be used singly or in combination of two or more as appropriate, and an appropriate amount can be blended.
　本発明の医薬組成物に緩衝剤を配合する場合の緩衝剤は、医薬品の添加剤として使用可能な緩衝剤を適宜配合することができるが、例えば、リン酸又はその塩、ホウ酸又はその塩、ホウ砂、炭酸又はその塩或いは有機酸又はその塩等が挙げられ、それらの水和物又は溶媒和物であってもよい。 The buffer in the case of incorporating a buffer into the pharmaceutical composition of the present invention may be a buffer that can be used as an additive of pharmaceuticals, and for example, phosphoric acid or a salt thereof, boric acid or a salt thereof And borax, carbonic acid or salts thereof or organic acids or salts thereof, etc., and may be hydrates or solvates thereof.
　リン酸又はその塩としては、例えば、リン酸、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、それらの水和物であってもよい。 Examples of phosphoric acid or salts thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and the like. It may be a hydrate of
　ホウ酸又はその塩としては、例えば、ホウ酸、ホウ酸ナトリウム、ホウ酸カリウム等が挙げられ、それらの水和物であってもよい。 Examples of boric acid or a salt thereof include boric acid, sodium borate, potassium borate and the like, and may be a hydrate of them.
　炭酸又はその塩としては、例えば、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、それらの水和物であってもよい。 Examples of carbonic acid or a salt thereof include sodium carbonate, sodium hydrogen carbonate and the like, and may be a hydrate thereof.
　有機酸又はその塩としては、例えば、クエン酸、酢酸、ε－アミノカプロン酸、グルコン酸、フマル酸、乳酸、アスコルビン酸、コハク酸、マレイン酸、リンゴ酸、アミノ酸類又はそれらのナトリウム塩、カリウム塩等が挙げられ、それらの水和物であってもよい。 Examples of organic acids or salts thereof include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acids or their sodium salts, potassium salts And the like, and may be hydrates thereof.
　本発明の医薬組成物に緩衝剤を配合する場合、有機酸又はその塩が好ましく、クエン酸又はその塩がより好ましく、クエン酸ナトリウムが特に好ましい。 When a buffer is incorporated into the pharmaceutical composition of the present invention, an organic acid or a salt thereof is preferred, citric acid or a salt thereof is more preferred, and sodium citrate is particularly preferred.
　本発明の医薬組成物に緩衝剤を配合する場合の緩衝剤の含有量は、緩衝剤の種類など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、０．１～５％（ｗ／ｖ）がさらに好ましく、０．１～１％（ｗ／ｖ）が特に好ましい。 The content of the buffer in the case of incorporating the buffer into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of buffer etc., but preferably 0.001 to 10% (w / v), 0 .01-5% (w / v) is more preferable, 0.1-5% (w / v) is more preferable, and 0.1-1% (w / v) is particularly preferable.
　本発明の医薬組成物に防腐剤を配合する場合の防腐剤は、医薬品の添加剤として使用可能な防腐剤を適宜配合することができるが、例えば、逆性石鹸類、パラベン類、アルコール類、および有機酸又はその塩が挙げられる。 The preservative in the case of incorporating a preservative into the pharmaceutical composition of the present invention may be a preservative that can be used as an additive of pharmaceuticals as appropriate, for example, reverse soaps, parabens, alcohols, And organic acids or salts thereof.
　本発明において、逆性石鹸類としては、例えば、塩化ベンザルコニウム、臭化ベンザルコニウム、塩化ベンゼトニウム、臭化ベンゼトニウムである。 In the present invention, examples of inverse soaps include benzalkonium chloride, benzalkonium bromide, benzethonium chloride and benzethonium bromide.
　本発明において、パラベン類としては、例えば、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチルである。 In the present invention, parabens are, for example, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate.
　本発明において、アルコール類としては、例えば、クロロブタノールである。 In the present invention, the alcohol is, for example, chlorobutanol.
　本発明において、有機酸又はその塩としては、例えば、ソルビン酸又はその塩、デヒドロ酢酸ナトリウムであり、そのうちソルビン酸又はその塩としては、例えば、ソルビン酸ナトリウム、ソルビン酸カリウムである。 In the present invention, the organic acid or a salt thereof is, for example, sorbic acid or a salt thereof, sodium dehydroacetate, and among them, sorbic acid or a salt thereof is, for example, sodium sorbate or potassium sorbate.
　本発明の医薬組成物に防腐剤を配合する場合の防腐剤の含有量は、防腐剤の種類などにより適宜調整することができるが、安全性に悪影響を及ぼさない程度の量であればよく、その上限は、例えば１％（ｗ／ｖ）以下であり、０．５％（ｗ／ｖ）以下が好ましく、０．１％（ｗ／ｖ）以下がより好ましく、０．０５％（ｗ／ｖ）以下がさらに好ましく、０．０１％（ｗ／ｖ）以下が特に好ましい。また防腐作用が発揮できる量があればよく、その下限は、０．０００１％（ｗ／ｖ）以上が好ましく、０．００１％（ｗ／ｖ）以上がより好ましい。防腐剤の含有量としては、０．０００１～１％（ｗ／ｖ）が好ましく、０．００１～０．５％（ｗ／ｖ）がより好ましく、０．００１～０．１％（ｗ／ｖ）がさらに好ましい。 The content of the preservative in the case of incorporating the preservative into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of preservative and the like, but it may be an amount that does not adversely affect safety. The upper limit thereof is, for example, 1% (w / v) or less, preferably 0.5% (w / v) or less, more preferably 0.1% (w / v) or less, and 0.05% (w / v). v) or less is more preferable, and 0.01% (w / v) or less is particularly preferable. Further, the amount may be such that the preservative action can be exhibited, and the lower limit thereof is preferably 0.0001% (w / v) or more, and more preferably 0.001% (w / v) or more. The content of the preservative is preferably 0.0001 to 1% (w / v), more preferably 0.001 to 0.5% (w / v), and 0.001 to 0.1% (w / v). v) is more preferred.
　本発明の医薬組成物に界面活性化剤を配合する場合の界面活性化剤は、医薬品の添加剤として使用可能な界面活性化剤を適宜配合することができるが、例えば、カチオン性界面活性化剤、アニオン性界面活性化剤、非イオン性界面活性化剤等が挙げられる。 The surfactant in the case where the surfactant is added to the pharmaceutical composition of the present invention may be a surfactant which can be used appropriately as an additive for pharmaceuticals, but, for example, cationic surfactant may be used. Agents, anionic surfactants, nonionic surfactants and the like.
　カチオン性界面活性化剤としては、例えば、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。 As a cationic surfactant, for example, alkylamine salt, alkylamine polyoxyethylene adduct, fatty acid triethanolamine monoester salt, acylaminoethyl diethylamine salt, fatty acid polyamine condensate, alkyl imidazoline, 1-acylaminoethyl -2-alkyl imidazoline, 1-hydroxy ethyl 2-alkyl imidazoline and the like.
　アニオン性界面活性化剤としては、例えば、レシチン等のリン酸脂質等が挙げられる。 Examples of the anionic surfactant include phosphoric acid lipids such as lecithin and the like.
　非イオン性界面活性化剤としては、例えば、ステアリン酸ポリオキシル４０等のポリオキシエチレン脂肪酸エステル；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等の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等のポリオキシエチレン硬化ヒマシ油；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ヒマシ油等のポリオキシルヒマシ油；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）グリコール等のポリオキシエチレンポリオキシプロピレングリコール；ショ糖ステアリン酸エステル等のショ糖脂肪酸エステル；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（ビタミンＥ　ＴＰＧＳ）等が挙げられる。 Examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl stearate and the like; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 60; polyoxyl Polyoxyl castor oil such as 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, etc .; polyoxyethylene 160) Polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) Polyoxyethylene polyoxypropylene glycol such as glycol, polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid ester such as sucrose stearate; tocopherol polyethylene glycol 1000 succinic acid ester (vitamin E TPGS) etc Can be mentioned.
　本発明の医薬組成物に界面活性化剤を配合する場合、非イオン性界面活性化剤がより好ましく、ポリエチレンソルビタン脂肪酸エステルがさらに好ましく、ポリソルベート８０が特に好ましい。 When a surfactant is added to the pharmaceutical composition of the present invention, a nonionic surfactant is more preferred, polyethylene sorbitan fatty acid ester is more preferred, and polysorbate 80 is particularly preferred.
　本発明の医薬組成物に界面活性化剤を配合する場合の界面活性化剤の含有量は、界面活性化剤の種類などにより適宜調整することができるが、０．０１～１％（ｗ／ｖ）が好ましく、０．０５～０．５％（ｗ／ｖ）がより好ましく、０．０５％～０．２％（ｗ／ｖ）がさらに好ましい。 The content of the surfactant in the case of incorporating the surfactant into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant, etc. v) is preferable, 0.05 to 0.5% (w / v) is more preferable, and 0.05% to 0.2% (w / v) is more preferable.
　本発明の医薬組成物に等張化剤を配合する場合の等張化剤は、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が、例えば、イオン性等張化剤や非イオン性等張化剤等が挙げられる。 The isotonizing agent in the case of incorporating an isotonizing agent into the pharmaceutical composition of the present invention may be an isotonizing agent which can be used as an additive for pharmaceuticals, and may be, for example, ionic isotonizing. Agents and nonionic tonicity agents.
　イオン性等張化剤としては、例えば、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等が挙げられる。 Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
　非イオン性等張化剤としては、例えば、グリセリン、プロピレングリコール、ポリエチレングリコール、ソルビトール、マンニトール、トレハロース、マルトース、スクロース、キシリトール等が挙げられる。 Examples of the nonionic tonicity agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol and the like.
　本発明の医薬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、等張化剤の種類など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、０．５～２％（ｗ／ｖ）が特に好ましい。 The content of the tonicity agent in the case of incorporating the tonicity agent into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of tonicity agent etc., but it is 0.001 to 10% (w / w). v) is preferable, 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is further preferable, and 0.5 to 2% (w / v) is particularly preferable .
　本発明の医薬組成物に安定化剤を配合する場合の安定化剤は、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が、例えば、エデト酸又はその塩等が挙げられる。 Although the stabilizer in the case of mix | blending a stabilizer with the pharmaceutical composition of this invention can be suitably mix | blended the stabilizer which can be used as an additive of a pharmaceutical, For example, edetic acid or its salt etc. are mentioned. Be
　エデト酸又はその塩としては、例えば、エデト酸、エデト酸二ナトリウム、エデト酸四ナトリウム等が挙げられる。 Examples of edetic acid or salts thereof include edetic acid, disodium edetate, tetrasodium edetate and the like.
　本発明の医薬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、安定化剤の種類など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％～１％（ｗ／ｖ）がより好ましく、０．０１～０．１％（ｗ／ｖ）がさらに好ましい。 The content of the stabilizer in the case of incorporating the stabilizer into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer etc., but 0.001 to 5% (w / v) Preferably, 0.01% to 1% (w / v) is more preferable, and 0.01 to 0.1% (w / v) is more preferable.
　本発明の医薬組成物に抗酸化剤を配合する場合の抗酸化剤は、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が、例えば、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、亜硫酸ナトリウム等が挙げられる。 The antioxidant in the case of incorporating an antioxidant into the pharmaceutical composition of the present invention may be an antioxidant which can be suitably used as an additive of a pharmaceutical, and examples thereof include ascorbic acid, tocopherol, dibutyl hydroxytoluene Sodium sulfite and the like.
　本発明の医薬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、抗酸化剤の種類など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）がさらに好ましい。 The content of the antioxidant in the case of incorporating the antioxidant into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the antioxidant etc., 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 more preferable.
　本発明の医薬組成物にｐＨ調節剤を配合する場合のｐＨ調節剤は、医薬品の添加物として使用可能なｐＨ調節剤を適宜配合することができるが、例えば、酸又は塩基であり、酸としては例えば、塩酸、リン酸、クエン酸、酢酸等、塩基としては例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。 The pH regulator in the case of incorporating a pH regulator into the pharmaceutical composition of the present invention may be a pH regulator which can be used as an additive of pharmaceuticals as appropriate, and is, for example, an acid or a base as an acid Examples of the base include hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
　本発明の医薬組成物のｐＨは、医薬品として許容される範囲内にあればよく、４．０～８．５又は４．０～８．０の範囲内が好ましく、５．０～８．０がより好ましく、５．５～７．５がさらに好ましい。特に好ましいｐＨは、５．５～７．０であるが、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、６．９、７．０もさらにより好ましい。 The pH of the pharmaceutical composition of the present invention may be in the pharmaceutically acceptable range, preferably in the range of 4.0 to 8.5 or 4.0 to 8.0, and more preferably 5.0 to 8.0. Is more preferable, and 5.5 to 7.5 is more preferable. Particularly preferred pHs are 5.5 to 7.0, but 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, 6.9, 7.0 are even more preferred.
　本発明の医薬組成物の浸透圧比は、医薬品として許容される範囲内にあればよく、例えば０．５～２．０であり、０．７～１．６が好ましく、０．８～１．４がより好ましく、０．９～１．２がさらに好ましい。 The osmotic pressure ratio of the pharmaceutical composition of the present invention may be in the pharmaceutically acceptable range, for example, 0.5 to 2.0, preferably 0.7 to 1.6, and 0.8 to 1. 4 is more preferable, and 0.9 to 1.2 is more preferable.
　本発明の医薬組成物の粘度は、汎用される手法により測定されてよく、例えば毛細管粘度計、回転粘度計、落球粘度計等を用いて、測定することができ、特にオストワルド粘度計を用いて、測定することができる。 The viscosity of the pharmaceutical composition of the present invention may be measured by a widely used method, and can be measured using, for example, a capillary viscometer, a rotational viscometer, a falling ball viscometer, etc., and in particular, using an Ostwald viscometer , Can be measured.
　本発明の医薬組成物の粘度は、医薬品として許容される範囲内にあればよく、２５℃において２～７００（ｍＰａ・ｓ）が好ましく、５０～５００（ｍＰａ・ｓ）がより好ましく、６５～２００（ｍＰａ・ｓ）がさらに好ましい。ここで、２５℃における粘度は、オストワルド粘度計を用いて、測定される値（相対粘度）である。 The viscosity of the pharmaceutical composition of the present invention may be in the pharmaceutically acceptable range, preferably 2 to 700 (mPa · s) at 25 ° C., more preferably 50 to 500 (mPa · s), and 65 to 200 (mPa · s) is more preferable. Here, the viscosity at 25 ° C. is a value (relative viscosity) measured using an Ostwald viscometer.
　本発明の医薬組成物において、水溶性粘稠化剤、有効成分または添加剤が水和物である場合は、その水和水は通常配位できる数であればよく、例えば１水和物、２水和物、３水和物、４水和物、５水和物、６水和物、７水和物、８水和物、９水和物、１０水和物、１１水和物、１２水和物、１／２水和物、３／２水和物等である。 In the pharmaceutical composition of the present invention, when the water-soluble thickening agent, the active ingredient or the additive is a hydrate, the number of hydration waters can usually be coordinated, for example, a monohydrate. Dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, decahydrate, It is 12 hydrate, 1/2 hydrate, 3/2 hydrate etc.
　本発明の医薬組成物において、その構成成分が全て溶解または一部懸濁していてもよいが、構成成分が全て溶解している液状がより好ましい。溶媒又は分散媒は水であることが好ましく、水溶液であることが最も好ましい。 In the pharmaceutical composition of the present invention, although all the components may be dissolved or partially suspended, a liquid in which all the components are dissolved is more preferable. The solvent or dispersion medium is preferably water, most preferably an aqueous solution.
　本発明の医薬組成物を点眼剤として使用する場合、マルチドーズ型容器、１回使い切りのユニットドーズ型容器又はＰＦＭＤ（Ｐｒｅｓｅｒｖａｔｉｖｅ　Ｆｒｅｅ　Ｍｕｌｔｉ　Ｄｏｓｅ）容器のいずれに収容されていてもよい。 When the pharmaceutical composition of the present invention is used as an eye drop, it may be contained in any of a multi-dose container, a single-use unit dose container or a PFMD (Preservative Free Multi Dose) container.
　本発明の医薬組成物は、例えば、眼疾患の治療及び／又は予防用の医薬組成物であってもよく、治療及び／又は予防の対象となる眼疾患としては、例えば、緑内障、感染性眼疾患、炎症性眼疾患、ドライアイ、角膜疾患、アレルギー性眼疾患、白内障、眼精疲労等が挙げられ、好ましくは、緑内障である。 The pharmaceutical composition of the present invention may be, for example, a pharmaceutical composition for treatment and / or prevention of eye diseases, and examples of eye diseases to be treated and / or prevented include, for example, glaucoma, infectious eyes Diseases, inflammatory eye diseases, dry eyes, corneal diseases, allergic eye diseases, cataracts, eye strain and the like can be mentioned, with preference given to glaucoma.
　本発明において、医薬組成物の粘度低下の抑制とは、医薬組成物の粘度の経時的な低下が抑制されることをいい、ここで、粘度の経時的な低下は、例えば、医薬組成物の調製直後（又は、充填直後）の粘度と一定期間経過後の粘度とを比較することによって示すことができる。また、本発明における粘度低下の抑制程度は、例えば、電子線滅菌処理された容器に収容された場合の粘度低下との比較によって示すことができ、この場合、本発明における粘度低下の抑制とは、粘度低下の改善ともいえる。なお、粘度は、所定の粘度測定方法によって測定される。 In the present invention, the suppression of the viscosity decrease of the pharmaceutical composition means that the temporal decrease of the viscosity of the pharmaceutical composition is suppressed, and the temporal decrease of the viscosity is, for example, the composition of the pharmaceutical composition. This can be shown by comparing the viscosity immediately after preparation (or immediately after filling) with the viscosity after a certain period of time. Further, the degree of suppression of the viscosity drop in the present invention can be shown, for example, by comparison with the viscosity drop when stored in a container subjected to electron beam sterilization, and in this case, the suppression of the viscosity drop in the present invention It can be said that the improvement of the viscosity decrease. The viscosity is measured by a predetermined viscosity measurement method.
　上記の本発明の医薬組成物の詳細な説明は、本発明の医薬組成物の粘度低下を抑制する方法、医薬組成物の安定性を向上する方法にも適用される。 The above detailed description of the pharmaceutical composition of the present invention also applies to the method for suppressing the viscosity reduction of the pharmaceutical composition of the present invention and the method for improving the stability of the pharmaceutical composition.
　本発明の医薬組成物の粘度低下を抑制する方法は、水溶性粘稠化剤を含有する医薬組成物を、エチレンオキサイドガス滅菌容器に収容することを含む。 The method for suppressing the viscosity reduction of the pharmaceutical composition of the present invention comprises containing a pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.
　本発明の医薬組成物の安定性を向上する方法は、水溶性粘稠化剤を含有する医薬組成物を、エチレンオキサイドガス滅菌容器に収容することを含む。 The method of improving the stability of the pharmaceutical composition of the present invention comprises containing a pharmaceutical composition containing a water soluble thickener in an ethylene oxide gas sterilization container.
　本発明において、医薬組成物の安定性の向上とは、医薬組成物の経時的な変化が抑制されることを意味し、例えば、医薬組成物の経時的な粘度低下の抑制が含まれる。 In the present invention, the improvement of the stability of the pharmaceutical composition means that the temporal change of the pharmaceutical composition is suppressed, and, for example, the suppression of the temporal decrease of the viscosity of the pharmaceutical composition is included.
　上記の本発明の医薬組成物の詳細な説明は、本発明の以下に示す態様にも適用される。 The above detailed description of the pharmaceutical composition of the present invention also applies to the following aspects of the present invention.
　本発明の一態様は、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、眼疾患の治療及び／又は予防のための医薬組成物である。 One aspect of the present invention is a pharmaceutical composition for treatment and / or prevention of eye diseases, which contains a water-soluble thickener and is contained in an ethylene oxide gas sterilization container.
　本発明の一態様は、眼疾患の治療及び／又は予防における使用のための、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、医薬組成物である。 One aspect of the present invention is a pharmaceutical composition containing a water soluble thickener and contained in an ethylene oxide gas sterilization container, for use in the treatment and / or prevention of ocular diseases.
　本発明の一態様は、眼疾患の治療及び／又は予防するための医薬の製造のための、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、医薬組成物の使用である。 One aspect of the present invention is the use of a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container for the manufacture of a medicament for treating and / or preventing ocular diseases It is.
　本発明の一態様は、眼疾患の治療及び／又は予防する方法であって、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、医薬組成物を、それを必要とする対象に有効量投与することを含む、方法である。 One aspect of the present invention is a method for the treatment and / or prevention of ocular diseases, which comprises a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container, which requires the pharmaceutical composition. Administering an effective amount to the subject.
　本発明の一態様は、エチレンオキサイドガス滅菌容器に、水溶性粘稠化剤を含有する医薬組成物を収容することを含む、医薬用製品の製造方法である。 One aspect of the present invention is a method of producing a pharmaceutical product comprising housing a pharmaceutical composition containing a water soluble thickener in an ethylene oxide gas sterilization container.
　以下に、製剤例および粘度経時変化測定試験の結果を示すが、これらは本発明をより良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 are formulation examples and results of viscosity aging test, but these are for the purpose of better understanding the present invention and do not limit the scope of the present invention.
［製剤例］
　以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は製剤１ｍＬ中の含量である。 [Formulation example]
The following are representative preparation examples of the present invention. In addition, the compounding quantity of each component is a content in 1 mL of formulation in the following formulation example.
製剤例１
　ドルゾラミド塩酸塩　　　　　　１０ｍｇ
　チモロールマレイン酸塩　　　　　５ｍｇ
　ヒドロキシエチルセルロース　　　５ｍｇ
　クエン酸ナトリウム水和物　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　６．５
製剤例２
　ドルゾラミド塩酸塩　　　　　　　　　１０ｍｇ
　ヒドロキシプロピルメチルセルロース　　５ｍｇ
　クエン酸ナトリウム水和物　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　６．５
製剤例３
　ドルゾラミド塩酸塩　　　　　　２０ｍｇ
　ポリビニルピロリドン　　　　　２０ｍｇ
　クエン酸ナトリウム水和物　　　１０ｍｇ
　希塩酸　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　６．５
製剤例４
　チモロールマレイン酸塩　　　　　５ｍｇ
　ヒドロキシエチルセルロース　　　５ｍｇ
　クエン酸ナトリウム水和物　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　６．５
製剤例５
　ドルゾラミド塩酸塩　　　　　　１０ｍｇ
　ヒドロキシエチルセルロース　　１０ｍｇ
　ホウ酸　　　　　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　６．５ Formulation example 1
Dorzolamide hydrochloride 10 mg
Timolol maleate 5 mg
Hydroxyethyl cellulose 5 mg
Sodium citrate hydrate 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 6.5
Formulation example 2
Dorzolamide hydrochloride 10 mg
Hydroxypropyl methylcellulose 5 mg
Sodium citrate hydrate 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 6.5
Formulation example 3
Dorzolamide hydrochloride 20 mg
Polyvinylpyrrolidone 20 mg
Sodium citrate hydrate 10 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 6.5
Formulation example 4
Timolol maleate 5 mg
Hydroxyethyl cellulose 5 mg
Sodium citrate hydrate 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 6.5
Formulation example 5
Dorzolamide hydrochloride 10 mg
Hydroxyethyl cellulose 10 mg
5 mg boric acid
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 6.5
［粘度経時変化測定試験］
＜被験製剤１＞
（１）被験製剤の調製
　ドルゾラミド塩酸塩（１９．７５９ｇ）、チモロールマレイン酸塩（１２．１２７ｇ）、クエン酸ナトリウム水和物（５．２１９ｇ）、エデト酸二ナトリウム（０．１７８ｇ）、ポリソルベート８０（１．７８ｇ）を精製水に溶解し、全量を７１０ｇとなるように精製水を添加した。この水溶液の一部（４１２．８ｇ）を取り出して０．８％ヒドロキシエチルセルロース溶液（６１２．７５ｇ）と混合し、ｐＨ調節剤（塩酸および／または水酸化ナトリウム）によりｐＨを５．６０～５．７０に調整した。全量を１０４２ｇとなるように精製水を添加して、被験製剤１とした。 [Viscosity Aging Test]
<Test preparation 1>
(1) Preparation of test preparation Dorzolamide hydrochloride (19.759 g), timolol maleate (12.127 g), sodium citrate hydrate (5.219 g), disodium edetate (0.178 g), polysorbate 80 (1.78 g) was dissolved in purified water, and purified water was added to a total amount of 710 g. A portion (412.8 g) of this aqueous solution is taken out and mixed with 0.8% hydroxyethyl cellulose solution (612.75 g), and the pH is adjusted to 5.60 to 5.5 with a pH adjuster (hydrochloric acid and / or sodium hydroxide). Adjusted to 70. Purified water was added to make the total amount 1042 g, and the test preparation 1 was obtained.
（２）試験方法
　エチレンオキサイドガス（ＥＯＧ）滅菌処理（エチレンオキサイド濃度：４８０ｍｇ／Ｌ、温度：４０℃、相対湿度：４５％、処理時間：３時間）が施されたポリエチレン製容器に（１）で調製した被験製剤１を充填した。このエチレンオキサイドガス滅菌容器に収容された被験製剤１（実施例１）を、温度４０℃または６０℃で最長３か月間保存した。充填直後及び保存開始後経時的に被験製剤１の粘度を測定した。なお、粘度の測定にはマイクロオストワルド（ＳＩ　Ａｎａｌｙｔｉｃｓ　ＧｍｂＨ社製、Ｔｙｐｅ　Ｎｏ．５１６２３）を使用し、２５℃±０．１℃における被験製剤の粘度を測定した。 (2) Test method In a polyethylene container which has been subjected to ethylene oxide gas (EOG) sterilization treatment (ethylene oxide concentration: 480 mg / L, temperature: 40 ° C., relative humidity: 45%, treatment time: 3 hours) (1) The test preparation 1 prepared in the above was filled. The test preparation 1 (Example 1) housed in the ethylene oxide gas sterilization container was stored at a temperature of 40 ° C. or 60 ° C. for up to 3 months. The viscosity of the test preparation 1 was measured immediately after filling and after the start of storage over time. The viscosity of the test preparation at 25 ° C. ± 0.1 ° C. was measured using Micro Ostwald (manufactured by SI Analytics GmbH, Type No. 51623) for measurement of viscosity.
　また、ＥＯＧ滅菌処理に替えて電子線滅菌処理（５０ｋＧｙ）を施したポリエチレン製容器に（１）で調製した被験製剤１を充填した（比較例１）。この被験製剤１について、実施例１と同様にして、試験を行い、粘度を測定した。 In addition, the test preparation 1 prepared in (1) was filled in a polyethylene container which was subjected to electron beam sterilization (50 kGy) instead of EOG sterilization (Comparative Example 1). The test preparation 1 was tested in the same manner as in Example 1 to measure the viscosity.
（３）試験結果及び考察
　被験製剤１に関する試験結果を表１に示す。
Figure JPOXMLDOC01-appb-T000001
 (3) Test Results and Discussion The test results for Test preparation 1 are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
　表１に示されるように、エチレンオキサイドガス滅菌で処理した容器に被験製剤１を充填した実施例１は、電子線滅菌で処理した容器に被験製剤１を充填した比較例１と比較して、被験製剤１の粘度低下が抑制される効果を示した。 As shown in Table 1, Example 1 in which the test preparation 1 is filled in a container treated with ethylene oxide gas sterilization is compared with Comparative Example 1 in which the test preparation 1 is filled in a container treated with electron beam sterilization, The effect of suppressing the viscosity reduction of the test preparation 1 was shown.
＜被験製剤２～５＞
（１）被験製剤の調製
　表２に示す被験製剤２～５について、被験製剤１と同様の方法を用いて調製した。
Figure JPOXMLDOC01-appb-T000002
 <Test preparation 2-5>
(1) Preparation of Test Preparation The test preparations 2 to 5 shown in Table 2 were prepared using the same method as the test preparation 1.
Figure JPOXMLDOC01-appb-T000002
（２）試験方法
　実施例１と同様、エチレンオキサイドガス（ＥＯＧ）滅菌処理（エチレンオキサイド濃度：４８０ｍｇ／Ｌ、温度：４０℃、相対湿度：４５％、処理時間：３時間）が施されたポリエチレン製容器に（１）で調製した被験製剤２～５を、それぞれ充填した。このエチレンオキサイドガス滅菌容器に収容された被験製剤（実施例２～５）を、温度５０℃で最長８週間保存した。充填直後及び保存開始後経時的に被験製剤２～５の粘度を、実施例１と同様の方法で測定した。 (2) Test method As in Example 1, polyethylene oxide to which ethylene oxide gas (EOG) sterilization treatment (ethylene oxide concentration: 480 mg / L, temperature: 40 ° C., relative humidity: 45%, treatment time: 3 hours) was applied The test preparations 2 to 5 prepared in (1) were filled in respective containers. The test preparation (Examples 2 to 5) contained in this ethylene oxide gas sterilization container was stored at a temperature of 50 ° C. for up to 8 weeks. The viscosities of the test formulations 2 to 5 were measured in the same manner as in Example 1 immediately after filling and after the start of storage over time.
　また、ＥＯＧ滅菌処理に替えて電子線滅菌処理（５０ｋＧｙ）を施したポリエチレン製容器に（１）で調製した被験製剤２～５を、それぞれ充填した（比較例２～５）。この被験製剤２～５について、実施例２～５と同様にして、試験を行い、粘度を測定した。 Further, the test preparations 2 to 5 prepared in (1) were respectively filled in polyethylene containers which were subjected to electron beam sterilization (50 kGy) instead of EOG sterilization (Comparative Examples 2 to 5). The test preparations 2 to 5 were tested in the same manner as in Examples 2 to 5 to measure the viscosity.
（３）試験結果及び考察
　被験製剤２～５に関する試験結果を、粘度低下率として表３に示す。なお、粘度低下率は以下の式により算出した。
［粘度低下率（％）］＝１００×（［充填直後における粘度値］－［各測定ポイントにおける粘度値］）／［充填直後における粘度値］
Figure JPOXMLDOC01-appb-T000003
 (3) Test Results and Discussion The test results for the test formulations 2 to 5 are shown in Table 3 as viscosity reduction rates. The viscosity decrease rate was calculated by the following equation.
[Viscosity reduction rate (%)] = 100 × ([viscosity value immediately after filling]-[viscosity value at each measurement point]) / [viscosity value immediately after filling]
Figure JPOXMLDOC01-appb-T000003
　表３に示されるように、被験製剤２～５のいずれについても、被験製剤をエチレンオキサイドガス滅菌で処理した容器に充填した場合、電子線滅菌で処理した容器に充填した場合と比較して、被験製剤の粘度低下が抑制される効果を示した。 As shown in Table 3, for any of the test preparations 2 to 5, when the test preparation is filled in a container treated with ethylene oxide gas sterilization, compared to the case where the container treated with electron beam sterilization is filled, The effect of suppressing the viscosity reduction of the test preparation was shown.
　本発明は、水溶性粘稠化剤を含有する医薬組成物であって、エチレンオキサイドガス滅菌容器に収容された、医薬組成物を提供する。 The present invention provides a pharmaceutical composition containing a water-soluble thickener, which is contained in an ethylene oxide gas sterilization container.

Claims (18)

  1. 水溶性粘稠化剤を含有する医薬組成物であって、エチレンオキサイドガス滅菌容器に収容された、医薬組成物。 A pharmaceutical composition comprising a water-soluble thickener, which is contained in an ethylene oxide gas sterilization container.
  2. 水溶性粘稠化剤が、セルロース系高分子、ポリビニルピロリドン、カルボキシビニルポリマー及び多価アルコールよりなる群から選択される１又は複数の水溶性粘稠化剤である、請求項１に記載の医薬組成物。 The medicine according to claim 1, wherein the water soluble thickener is one or more water soluble thickeners selected from the group consisting of cellulosic polymers, polyvinyl pyrrolidone, carboxyvinyl polymers and polyhydric alcohols. Composition.
  3. セルロース系高分子が、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース及びヒドロキシプロピルメチルセルロースよりなる群から選択される１又は複数のセルロース系高分子である、請求項２に記載の医薬組成物。 The pharmaceutical composition according to claim 2, wherein the cellulose-based polymer is one or more cellulose-based polymers selected from the group consisting of hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methyl cellulose.
  4. 水溶性粘稠化剤の含有量が０．００１～１０％（ｗ／ｖ）である、請求項１～３のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3, wherein the content of the water-soluble thickening agent is 0.001 to 10% (w / v).
  5. 容器が樹脂製容器である、請求項１～４のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the container is a resin container.
  6. 樹脂製容器がポリエチレン製、ポリプロピレン製、またはポリエチレンテレフタレート製である、請求項５に記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the resin container is made of polyethylene, polypropylene or polyethylene terephthalate.
  7. 水溶性粘稠化剤としてセルロース系高分子を含有する医薬組成物であって、エチレンオキサイドガス滅菌樹脂製容器に収容された、医薬組成物。 A pharmaceutical composition comprising a cellulose-based polymer as a water-soluble thickening agent, which is contained in a container made of ethylene oxide gas sterilization resin.
  8. 水性点眼剤である、請求項１～７のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 7, which is an aqueous eye drop.
  9. 緑内障治療剤である、請求項１～８のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 8, which is a therapeutic agent for glaucoma.
  10. 有効成分としてドルゾラミド又はその塩を含有する、請求項１～９のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, which comprises dorzolamide or a salt thereof as an active ingredient.
  11. 有効成分としてドルゾラミド又はその塩及びチモロール又はその塩、水溶性粘稠化剤としてヒドロキシエチルセルロースを含有する医薬組成物であって、エチレンオキサイドガス滅菌樹脂製容器に収容された、医薬組成物。 A pharmaceutical composition comprising dorzolamide or a salt thereof and timolol or a salt thereof as an active ingredient, and hydroxyethyl cellulose as a water-soluble thickening agent, wherein the pharmaceutical composition is contained in a container made of ethylene oxide gas sterilization resin.
  12. 水溶性粘稠化剤を含有する医薬組成物を、エチレンオキサイドガス滅菌容器に収容することによって、医薬組成物の粘度低下を抑制する方法。 A method for suppressing the decrease in viscosity of a pharmaceutical composition by storing the pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.
  13. 水溶性粘稠化剤を含有する医薬組成物を、エチレンオキサイドガス滅菌容器に収容することによって、医薬組成物の安定性を向上する方法。 A method of improving the stability of a pharmaceutical composition by storing the pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.
  14. 水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、眼疾患の治療及び／又は予防のための医薬組成物。 Pharmaceutical composition for treatment and / or prevention of eye diseases, which contains a water-soluble thickening agent and is contained in an ethylene oxide gas sterilization container.
  15. 眼疾患の治療及び／又は予防における使用のための、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、医薬組成物。 A pharmaceutical composition containing a water soluble thickener and contained in an ethylene oxide gas sterilization container, for use in the treatment and / or prevention of ocular diseases.
  16. 眼疾患の治療及び／又は予防するための医薬の製造のための、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、医薬組成物の使用。 Use of a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container for the manufacture of a medicament for treating and / or preventing ocular diseases.
  17. 眼疾患の治療及び／又は予防する方法であって、水溶性粘稠化剤を含有し、エチレンオキサイドガス滅菌容器に収容された、医薬組成物を、それを必要とする対象に有効量投与することを含む、方法。 A method for treating and / or preventing eye diseases, which comprises administering an effective amount of a pharmaceutical composition containing a water-soluble thickener and contained in an ethylene oxide gas sterilization container to a subject in need thereof. How, including.
  18. エチレンオキサイドガス滅菌容器に収容された、水溶性粘稠化剤を含有する医薬組成物を含む、医薬用製品。 A pharmaceutical product comprising a pharmaceutical composition containing a water-soluble thickening agent contained in an ethylene oxide gas sterilization container.
PCT/JP2018/023762 2017-06-23 2018-06-22 Medicinal composition containing water-soluble thickening agent WO2018235935A1 (en)

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