WO2018235935A1 - Composition pharmaceutique comprenant un épaississant hydrosoluble - Google Patents

Composition pharmaceutique comprenant un épaississant hydrosoluble 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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Prior art keywords
pharmaceutical composition
water
ethylene oxide
container
oxide gas
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PCT/JP2018/023762
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English (en)
Japanese (ja)
Inventor
隆司 森本
Original Assignee
参天製薬株式会社
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Priority claimed from JP2017244738A external-priority patent/JP7037349B2/ja
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/fr

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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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  • Health & Medical Sciences (AREA)
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Abstract

L'invention fournit une composition pharmaceutique comprenant un épaississant hydrosoluble dans laquelle une baisse de viscosité est inhibée. La composition pharmaceutique comprenant un épaississant hydrosoluble de l'invention est admise dans un réceptacle de stérilisation par l'oxyde d'éthylène.
PCT/JP2018/023762 2017-06-23 2018-06-22 Composition pharmaceutique comprenant un épaississant hydrosoluble WO2018235935A1 (fr)

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JP2017-123072 2017-06-23
JP2017123072 2017-06-23
JP2017244738A JP7037349B2 (ja) 2017-06-23 2017-12-21 水溶性粘稠化剤を含有する医薬組成物
JP2017-244738 2017-12-21

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Publication number Priority date Publication date Assignee Title
JP7245383B1 (ja) 2022-09-20 2023-03-23 参天製薬株式会社 ジクアホソルまたはその塩を含有する眼科用組成物のｐＨの低下を抑制する方法
EP4230193A1 (fr) * 2022-02-22 2023-08-23 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Composition pharmaceutique ophtalmique
EP4309644A1 (fr) * 2022-07-22 2024-01-24 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Composition ophtalmique sans conservateur comprenant un agent antiglaucomatique

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JP2004516099A (ja) * 2000-12-22 2004-06-03 ノバルティス アクチエンゲゼルシャフト 医薬組成物の安定性の改善方法
JP2004536096A (ja) * 2001-06-27 2004-12-02 アルコン，インコーポレイテッド 局所投与のためのオロパタジン処方物
JP2006187602A (ja) * 2004-12-09 2006-07-20 Santen Pharmaceut Co Ltd 分子内にフッ素原子を有するプロスタグランジン含有製品
WO2007123193A1 (fr) * 2006-04-21 2007-11-01 Toko Yakuhin Kogyo Kabushiki Kaisha Préparation en gel vaporisable pour adhésion à la peau ou aux muqueuses et système d'administration utilisant la préparation
WO2014050301A1 (fr) * 2012-09-27 2014-04-03 千寿製薬株式会社 Médicament liquide aqueux
JP2017066033A (ja) * 2015-09-28 2017-04-06 参天製薬株式会社 水性医薬組成物

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Publication number Priority date Publication date Assignee Title
JP2004516099A (ja) * 2000-12-22 2004-06-03 ノバルティス アクチエンゲゼルシャフト 医薬組成物の安定性の改善方法
JP2004536096A (ja) * 2001-06-27 2004-12-02 アルコン，インコーポレイテッド 局所投与のためのオロパタジン処方物
JP2006187602A (ja) * 2004-12-09 2006-07-20 Santen Pharmaceut Co Ltd 分子内にフッ素原子を有するプロスタグランジン含有製品
WO2007123193A1 (fr) * 2006-04-21 2007-11-01 Toko Yakuhin Kogyo Kabushiki Kaisha Préparation en gel vaporisable pour adhésion à la peau ou aux muqueuses et système d'administration utilisant la préparation
WO2014050301A1 (fr) * 2012-09-27 2014-04-03 千寿製薬株式会社 Médicament liquide aqueux
JP2017066033A (ja) * 2015-09-28 2017-04-06 参天製薬株式会社 水性医薬組成物

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4230193A1 (fr) * 2022-02-22 2023-08-23 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Composition pharmaceutique ophtalmique
EP4309644A1 (fr) * 2022-07-22 2024-01-24 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Composition ophtalmique sans conservateur comprenant un agent antiglaucomatique
WO2024018090A1 (fr) * 2022-07-22 2024-01-25 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Composition ophtalmique sans conservateur comprenant un agent anti-glaucome
JP7245383B1 (ja) 2022-09-20 2023-03-23 参天製薬株式会社 ジクアホソルまたはその塩を含有する眼科用組成物のｐＨの低下を抑制する方法
JP2024044960A (ja) * 2022-09-20 2024-04-02 参天製薬株式会社 ジクアホソルまたはその塩を含有する眼科用組成物のｐＨの低下を抑制する方法

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