WO2021210646A1 - Composition aqueuse contenant de l'épinastine ou un sel de celle-ci - Google Patents

Composition aqueuse contenant de l'épinastine ou un sel de celle-ci Download PDF

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Publication number
WO2021210646A1
WO2021210646A1 PCT/JP2021/015601 JP2021015601W WO2021210646A1 WO 2021210646 A1 WO2021210646 A1 WO 2021210646A1 JP 2021015601 W JP2021015601 W JP 2021015601W WO 2021210646 A1 WO2021210646 A1 WO 2021210646A1
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Prior art keywords
aqueous composition
salt
epinastine
acid
present
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PCT/JP2021/015601
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English (en)
Japanese (ja)
Inventor
剛史 林
雄介 桃川
ひとみ 木村
剛一 河津
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参天製薬株式会社
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Application filed by 参天製薬株式会社 filed Critical 参天製薬株式会社
Priority to CN202180026833.3A priority Critical patent/CN115397430A/zh
Priority to KR1020227039244A priority patent/KR20230004582A/ko
Publication of WO2021210646A1 publication Critical patent/WO2021210646A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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

Definitions

  • the present invention is an aqueous composition containing epinastine or a salt thereof, more specifically, an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound (hereinafter, also referred to as "aqueous composition of the present invention"). Regarding.
  • Aqueous compositions containing a solvent such as water, which are intended for repeated use, are required to have a certain level of antiseptic measures in order to prevent the growth of fungi and the like. Therefore, such compositions are usually formulated with preservatives.
  • preservatives For example, in the case of eye drops, benzalkonium chloride is generally used. Benzalkonium chloride is water-soluble, chemically stable, and has a high antiseptic effect compared to other preservatives. However, benzalkonium chloride is cytotoxic, and as the exposure increases, the possibility of causing corneal epithelial damage increases, so it is desirable not to use it as much as possible.
  • Non-Patent Document 1 Currently, Alesion (registered trademark) ophthalmic solution 0.05% marketed in Japan is an ophthalmic solution containing epinastine hydrochloride as an active ingredient, and boric acid is used instead of adding benzalkonium chloride as a preservative. It has been added (Non-Patent Document 1). Furthermore, by setting the concentration of epinastine or a salt thereof in the eye drops to more than 0.075% (w / v), a sufficient antiseptic effect can be obtained without substantially containing a preservative or a component having an antiseptic action. It is also known that it can be obtained (Patent Document 1). As described above, in recent years, eye drops that do not use benzalkonium chloride have been developed, and there is a tendency to avoid using benzalkonium chloride in the aqueous composition.
  • the number of medications per day is small.
  • the effective concentration in the living tissue cannot be maintained and the drug effect may be reduced, and it is necessary to maintain the effective concentration in the living tissue in order to exert the drug effect.
  • a method of maintaining the effective concentration in the eye tissue a method of increasing the concentration of the active ingredient, a method of using an absorption promoter, or a method of adding a thickener is used to retain the active ingredient in the eye tissue. There are known methods for improving.
  • Patent Document 2 describes that adding a ⁇ -blocker to an aqueous solution containing alginic acid and adjusting the pH to 6 to 8 has an effect of prolonging the action time after administration.
  • Patent Document 3 describes that the intraocular transferability of a drug is improved by containing a sugar alcohol in a ⁇ -blocker.
  • a quaternary ammonium compound such as benzalkonium chloride improves the transfer of epinastine or its salt to the ocular tissue and maintains the effective concentration in the ocular tissue.
  • the present inventors have conducted intensive studies on an aqueous composition containing epinastine or a salt thereof, and found that an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound adjusted to a specific content. It was found that the transferability of epinastine to the ocular tissue was improved when the epinastine was instilled into the eye, and the present invention was completed.
  • the present invention provides: (1) An aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound, wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 1 part by weight of the content of epinastine or a salt thereof. An aqueous composition which is 0.1 part by weight or less based on the amount.
  • the quaternary ammonium compound is at least one selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and polydronium chloride, to any one of (1) to (5).
  • the aqueous composition according to one. The aqueous composition according to any one of (1) to (8), which is for ophthalmology.
  • (11) A method for improving the transferability of epinastine or a salt thereof to eye tissue by blending a quaternary ammonium compound with an aqueous composition containing epinastine or a salt thereof as an active ingredient.
  • (12) The method according to (11), wherein the quaternary ammonium compound is at least one selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and polydronium chloride.
  • (13) The method according to (11) or (12), wherein the quaternary ammonium compound is benzalkonium chloride.
  • the present invention also provides: (15) A method for treating an allergic disease, which comprises administering a therapeutically effective amount of the aqueous composition according to any one of (1) to (10) to a patient in need of treatment. (16) The aqueous composition according to any one of (1) to (10), which is used for treating an allergic disease. (17) Use of the aqueous composition according to any one of (1) to (10) for producing a drug for treating an allergic disease.
  • the present invention is an aqueous composition containing epinastine or a salt thereof, which can improve the transferability of epinastine or a salt thereof to an ocular tissue and bring about an excellent medicinal effect by blending a quaternary ammonium compound.
  • the composition is provided.
  • epinastine is a compound represented by the chemical name ( ⁇ ) -3-Amino-9,13b-dihydro-1H-divenz [c, f] imidazo [1,5-a] azepine. , And the following formula: It is a compound represented by.
  • the epinastine contained may be a racemate or an optical isomer.
  • the epinastine contained may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • the salt include a salt with an inorganic acid, a salt with an organic acid, and the like.
  • the salt with the inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydrobromic 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, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, and alanine.
  • Lactic acid horse uric acid, 1,2-ethanedisulfonic acid, isetioic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluene sulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid and the like.
  • epinastine monohydrochloride (epinastine hydrochloride) is particularly preferable.
  • the contained epinastine or a salt thereof may take the form of a hydrate or a solvate.
  • the content of epinastine or a salt thereof is preferably 0.01% (w / v) or more, more preferably 0.05% (w / v) or more, and 0.1% (w). / V) or more is more preferable, and the upper limit thereof may be any concentration acceptable for ophthalmic preparations, for example, 5% (w / v).
  • the content of epinastine or a salt thereof is preferably 0.01 to 5% (w / v), more preferably 0.05 to 1% (w / v), and more preferably 0.05 to 0.2% (w / v). v) is more preferable, and 0.05 to 0.1% (w / v) is particularly preferable. For example, its content is 0.1% (w / v).
  • % (w / v) means the mass (g) of the target component contained in 100 mL of the aqueous composition of the present invention.
  • a salt of epinastine is contained in the present invention, the value is the content of the salt of epinastine.
  • epinastine or a salt thereof is blended in the form of a hydrate or a solvate, the value is the content of the hydrate or solvate of epinastine or a salt thereof.
  • the "quaternary ammonium compound” is a salt of a quaternary ammonium cation and another anion, and is also referred to as a quaternary ammonium salt.
  • the quaternary ammonium compound contained is, for example, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, polydronium chloride, cetylpyridinium chloride, benzalkonium bromide, benzethonium bromide, odor.
  • benzalkonium chloride examples include methylbenzethonium chloride and cetrimid, preferably benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, polydronium chloride, and more preferably benzalkonium chloride.
  • the quaternary ammonium compound also acts as an additive for pharmaceuticals, for example, a preservative, a surfactant, a stabilizer, an isotonic agent, a buffer, and the like. Therefore, the quaternary ammonium compound can also be used as an additive for pharmaceutical products. Further, in the aqueous composition of the present invention, one or more quaternary ammonium compounds may be used together.
  • the content of the quaternary ammonium compound can be appropriately adjusted depending on the type, and is, for example, 0.0001 to 1% (w / v) and 0.0001 to 0.1% (w / v).
  • w / v) is preferable, 0.0001 to 0.01% (w / v) is more preferable, and 0.0001 to 0.005% (w / v) is even more preferable.
  • the quaternary ammonium compound is benzalkonium chloride
  • the upper limit of its content is 0.01% (w / v) or less because the possibility of causing corneal epithelial damage increases as the exposure amount increases.
  • the content thereof is preferably 0.0001 to 0.01% (w / v), more preferably 0.001 to 0.005% (w / v), and 0.001 to 0.003%.
  • W / v) or 0.003 to 0.005% (w / v) is more preferable.
  • the content ratio of the quaternary ammonium compound can be appropriately adjusted depending on the type, but for example, the upper limit of the content ratio is 0.1 per 1 part by weight of the content of epinastine or a salt thereof. It is less than parts by weight or less than 0.1 parts by weight, preferably 0.05 parts by weight or less.
  • the lower limit of the content ratio is 0.0001 parts by weight or more, preferably 0.001 parts by weight or more, and 0.003 parts by weight or more and 0.005 parts by weight with respect to 1 part by weight of the content of epinastine or a salt thereof. More preferably, more than 0.01 parts by weight or more.
  • the content ratio is 0.0001 to 0.1 parts by weight, preferably 0.001 to 0.1 parts by weight, more preferably 0.003 to 0.1 parts by weight, and 0.005 parts by weight.
  • 0.05 parts by weight is more preferable, and 0.01 to 0.05 parts by weight is particularly preferable.
  • the content ratio is based on 1 part by weight of the content of epinastin or a salt thereof. It is 0.1 part by weight or less or less than 0.1 part by weight, preferably 0.05 part by weight or less or 0.03 part by weight or less.
  • the content ratio is 0.0001 to 0.1 parts by weight, preferably 0.001 to 0.1 parts by weight, more preferably 0.003 to 0.1 parts by weight, and 0.005 to 0.005 parts by weight.
  • 0.05 parts by weight is more preferable, 0.01 to 0.05 parts by weight is particularly preferable, and 0.03 to 0.05 parts by weight is particularly preferable.
  • an aqueous composition containing epinastine or a salt thereof at a certain concentration or higher can obtain a sufficient antiseptic effect without substantially containing a preservative or a component having an antiseptic action.
  • the quaternary ammonium compound is benzalkonium chloride commonly used as a preservative
  • the content of benzalkonium chloride is sufficient to exert an action as a preservative. It does not have to be, and may contain an amount that exerts the effect of the present invention.
  • the content of benzalkonium chloride may be an amount that exerts an action as a preservative as long as the effect of the present invention is exhibited.
  • the eye tissue includes, for example, conjunctiva, cornea, tear fluid, aqueous humor, anterior chamber and the like.
  • the amount of epinastine or a salt thereof transferred to the eye tissue can be increased (or also referred to as improvement).
  • the "aqueous composition” refers to a composition containing water.
  • the content of water contained in the aqueous composition of the present invention is not particularly limited, but is preferably 10% (w / v) or more, preferably 30% (w / v) or more, based on the total weight of the aqueous composition. More preferably, 50% (w / v) or more is further preferable. In particular, it is preferably 70% (w / v) or more, more preferably 90% (w / v) or more, and further preferably 95% (w / v) or more.
  • the "patient” means not only humans but also other animals such as dogs, cats and horses.
  • the patient is preferably a mammal, more preferably a human.
  • the "therapeutically effective amount” refers to an amount that brings about a therapeutic effect on a disease and its symptoms, or an amount that causes a delay in the progression of the disease and its symptoms, as compared with an untreated subject.
  • compositions of the present invention can be used in the aqueous composition of the present invention, if necessary, for example, buffers, thickeners, surfactants, tonicity agents, stabilizers, preservatives, etc.
  • Antioxidants, pH regulators and the like can be added. These may be used alone or in combination of two or more as appropriate, and an appropriate amount may be blended.
  • a buffer that can be used as an additive for pharmaceuticals can be appropriately added, and for example, citric acid or a salt thereof, boric acid or a salt thereof, etc.
  • examples thereof include carbonic acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, tartrate acid or a salt thereof, ⁇ -aminocaproic acid or a salt thereof, glutamic acid or a salt thereof, an organic amine, etc. It may be.
  • Examples of phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate (hereinafter, also referred to as sodium hydrogen phosphate), potassium phosphate, potassium dihydrogen phosphate, and hydrogen phosphate. Examples thereof include dipotassium, and these hydrates may be used.
  • Examples of boric acid or a salt thereof include boric acid, sodium borate (borax), potassium borate and the like, and hydrates thereof may be used.
  • Examples of carbonic acid or a salt thereof include carbonic acid, sodium carbonate, sodium hydrogencarbonate and the like, and hydrates thereof may be used.
  • citric acid or a salt thereof examples include citric acid, monosodium citrate, disodium citrate, trisodium citrate and the like, and hydrates thereof may be used.
  • acetic acid or a salt thereof examples include acetic acid, sodium acetate and the like, and hydrates thereof may be used.
  • tartaric acid or a salt thereof examples include tartaric acid, monosodium tartaric acid, disodium tartrate and the like, and hydrates thereof may be used.
  • ⁇ -aminocaproic acid or a salt thereof examples include ⁇ -aminocaproic acid, sodium ⁇ -aminocaproate, ⁇ -aminocapronate salt and the like, and hydrates thereof may be used.
  • glutamic acid or a salt thereof examples include glutamic acid, monosodium glutamic acid, disodium glutamic acid, glutamic acid salt and the like, and hydrates thereof may be used.
  • the organic amine examples include tromethamole and the like, and these hydrates may be used.
  • the content of the buffer when the buffer is added to the aqueous composition of the present invention can be appropriately adjusted depending on the type of the buffer and the like, but is preferably 0.001 to 10% (w / v), and is 0. 0.01 to 5% (w / v) is more preferable, 0.1 to 5% (w / v) is further preferable, and 0.1 to 2% (w / v) is particularly preferable.
  • a buffer is added to the aqueous composition of the present invention, one or more buffers may be used together.
  • a thickening agent that can be used as an additive for pharmaceuticals can be appropriately blended, and for example, methyl cellulose, ethyl cellulose, and hydroxymethyl cellulose can be blended.
  • the content of the thickening agent when the thickening agent is added to the aqueous composition of the present invention can be appropriately adjusted depending on the type of the thickening agent and the like, but is 0.001 to 5% (w / w /). v) is preferable, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable. Further, when the thickening agent is blended in the aqueous composition of the present invention, one kind or two or more kinds of thickening agents may be used together.
  • the surfactant that can be used as an additive for pharmaceuticals can be appropriately blended, for example, a cationic surfactant.
  • Cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolin, 1-acylaminoethyl-2. -Alkyl imidazoline, 1-hydroxyethyl-2-alkyl imidazoline and the like can be mentioned.
  • quaternary ammonium cations such as benzalkonium chloride have the properties of a cationic surfactant, they are not included in the cationic surfactant in the present invention.
  • the anionic surfactant include phospholipids such as lecithin.
  • the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan triolate, and polysorbate 65.
  • Polyoxyethylene sorbitan fatty acid ester polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.
  • Oxyethylene polyoxypropylene glycol; sucrose fatty acid ester such as sucrose stearic acid ester; tocopherol polyethylene glycol 1000 succinic acid ester (vitamin E TPGS) and the like.
  • the content of the surfactant when the surfactant is blended in the aqueous composition of the present invention can be appropriately adjusted depending on the type of the surfactant and the like, but is 0.01 to 1% (w / w /). v) is preferable, 0.05 to 0.5% (w / v) is more preferable, and 0.05 to 0.2% (w / v) is even more preferable. Further, when a surfactant is blended in the aqueous composition of the present invention, one or more surfactants may be used together.
  • the isotonic agent that can be used as an additive of a pharmaceutical product can be appropriately blended, and for example, an ionic isotonic agent.
  • an ionic isotonic agent e.g., sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
  • the nonionic isotonic agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol and the like.
  • the content of the tonicity agent when the tonicity agent is blended in the aqueous composition of the present invention can be appropriately adjusted depending on the type of the tonicity agent and the like, but 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 0.2 to 1% (w / v) is particularly preferable.
  • the isotonic agent is blended in the aqueous composition of the present invention, one or two or more isotonic agents may be used together.
  • a stabilizer that can be used as an additive for pharmaceutical products can be appropriately added, and for example, edetic acid or a salt thereof, cyclodextrin, etc. Examples thereof include sodium thiosulfate.
  • edetonic acid or a salt thereof include edetic acid, monosodium edetate, disodium edetate (hereinafter, also referred to as sodium edetate), trisodium edetate, tetrasodium edetate, and the like, and these hydrates There may be.
  • the content of the stabilizer when the stabilizer is blended in the aqueous composition of the present invention can be appropriately adjusted depending on the type of the stabilizer and the like, but is 0.001 to 5% (w / v). Preferably, 0.01 to 3% (w / v) is more preferable, and 0.01 to 1% (w / v) is even more preferable. Further, when a stabilizer is blended in the aqueous composition of the present invention, one or more stabilizers may be used together.
  • a preservative that can be used as an additive for pharmaceuticals can be appropriately blended.
  • a preservative that can be used as an additive for pharmaceuticals can be appropriately blended.
  • examples thereof include propyl paraoxybenzoate, sodium chlorite or chlorobutanol.
  • the content of the preservative when the preservative is added to the aqueous composition of the present invention can be appropriately adjusted depending on the type of the preservative and the like, but the amount should not adversely affect the safety, for example. It is preferably 0.0001 to 0.1% (w / v), more preferably 0.001 to 0.05% (w / v).
  • one or two or more preservatives may be used together.
  • an antioxidant that can be used as an additive for pharmaceutical products can be appropriately added.
  • ascorbic acid, tocopherol, dibutylhydroxytoluene, etc. examples thereof include sodium sulfite.
  • the content of the antioxidant when the antioxidant is added to the aqueous composition of the present invention can be appropriately adjusted depending on the type of the antioxidant and the like, but is 0.001 to 5% (w / v). Preferably, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is even more preferable.
  • one or more antioxidants may be used together.
  • the pH adjuster that can be used as an additive for pharmaceuticals can be appropriately added, and is, for example, an acid or a base, as an acid.
  • hydrochloric acid, phosphoric acid and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like.
  • the pH of the aqueous composition of the present invention may be in the range acceptable for pharmaceutical products, for example, in the range of 4.0 to 8.5 or 4.0 to 8.0, and 6.0 to 8.0. 0 is preferable, and 6.5 to 7.5 is more preferable.
  • Particularly preferred pH is 6.7 to 7.3, but 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 are even more preferred.
  • the osmotic pressure ratio of the aqueous composition of the present invention may be within the range acceptable for pharmaceutical products, 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 even more preferable.
  • the aqueous composition of the present invention is particularly preferably used as a pharmaceutical, and is suitable for parenteral (for example, topical) administration.
  • the parenteral route of administration of the aqueous composition of the present invention includes a locally acceptable route of administration as a pharmaceutical product, for example, topical administration to the eye (for example, eye drop administration), nasal drop (nasal) administration, and topical administration to the ear. (For example, ear drop administration), inhalation administration, spray administration, transdermal administration, intradermal administration, injection administration and the like can be mentioned. Topical administration to the eye is preferred.
  • the aqueous composition of the present invention can also be orally administered.
  • the aqueous composition of the present invention can be used as an ophthalmic preparation, an otolaryngological preparation, an inhalation preparation, and a transdermal absorption preparation, and the dosage form thereof is particularly limited as long as it can be used as a pharmaceutical product. It's not a thing.
  • Dosage forms include, for example, oral administrations such as liquids and suspensions, eye drops, nasal drops, ear drops, inhalants, (inhalation powders, inhalation solutions, inhalation aerosols), ointments, creams.
  • Topical administration agents such as injections (infusions, implantable injections, continuous injections) can be mentioned. It is preferably an eye drop, a transdermal preparation for ophthalmology, or an injection for ophthalmology, and more preferably an eye drop. These can be manufactured according to the usual methods in the art.
  • the aqueous composition of the present invention may have all the constituents dissolved or partially suspended, or may be in the form of an emulsion or a semi-solid.
  • the aqueous composition of the present invention is more preferably in a solution state in which all the constituent components are dissolved, and most preferably an aqueous solution.
  • eye drops eye drops
  • eye drops are particularly preferable for ophthalmology.
  • the aqueous composition of the present invention When used as an ophthalmic preparation, it is particularly useful as a therapeutic agent for allergic conjunctivitis. Further, unless otherwise specified, the aqueous composition of the present invention may contain a pharmaceutical active ingredient other than epinastine or a salt thereof, for example, an active ingredient used in other eye drops.
  • the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, but one drop at a time, preferably 1 to 10 times a day.
  • the eye drops can be instilled 1 to 6 times a day, more preferably 2 to 4 times a day, more preferably 2 times a day or 4 times a day, and particularly preferably 2 times a day.
  • the aqueous composition of the present invention When used as an eye drop, it may be contained in either a multi-dose container, a single-use unit-dose container, or a PFMD (Preservative Free Multi Dose) container.
  • the material of the container is not particularly limited, and any container for eye drops that is generally used may be used, but a resin container is preferable, and for example, polyethylene (PE), polypropylene (PP), or polyethylene terephthalate ( Containers made of PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer and the like can be used.
  • PE polyethylene
  • PP polypropylene
  • PBT polyethylene terephthalate
  • polypropylene-polyethylene copolymer Polyvinyl chloride
  • acrylic polystyrene
  • polyethylene is classified according to its density, and containers made of low-density polyethylene (LDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE), etc. are used. Can be used.
  • LDPE low-density polyethylene
  • MDPE medium-density polyethylene
  • HDPE high-density polyethylene
  • preparations Typical examples of preparations of the present invention are shown below.
  • the blending amount of each component is the content in 1 mL of the formulation.
  • Test example 1 Intraocular dynamics test (1) Preparation of test preparation Epinastine hydrochloride, benzalconium chloride, sodium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate hydrate are dissolved in water so as to have the concentrations shown in Table 1 below. Then, a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and water were added to make the total volume 10 mL, and filtration sterilization was performed to prepare the preparation of Example 1 (pH 7.0). In addition, the formulations of Example 2 and Comparative Example 1 in Table 1 below were prepared in the same manner as the preparation method of the formulation of Example 1.
  • Test method 50 ⁇ L of each test preparation was instilled into the eyes of rabbits three times at 15-minute intervals, 0.25 hours, 0.5 hours, 1 hour, 2 hours and 4 hours after the final instillation. At that time, the eye drops after slaughter were removed. At each time point, the epinastine concentration in the cornea and in the aqueous humor was measured, and the AUC (area under the blood concentration-time curve) was calculated. The AUC was calculated by a Sparse sampling analysis using Phoenix WinNonlin (registered trademark) V8.1.
  • Test results and discussion Table 2 shows the test results.
  • “Mean” is the average value
  • “SE” is the standard error
  • “N” is the number of samples, which are calculated by general-purpose statistical processing.
  • Examples 1 and 2 containing benzalkonium chloride, which is a quaternary ammonium compound, are in the cornea and aqueous humor as compared with Comparative Example 1 not containing benzalkonium chloride. It was confirmed that the amount of epinastine transferred was increased. Therefore, it was shown that the aqueous composition of the present invention remarkably improves the transferability to the ocular tissue.
  • the present invention is an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound, wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 1 weight by weight of the content of epinastine or a salt thereof.
  • an aqueous composition having an amount of 0.1 parts by weight or less based on parts.

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Abstract

La présente invention concerne une composition aqueuse pour améliorer la transférabilité dans un tissu oculaire, la composition aqueuse contenant de l'épinastine ou un sel de celle-ci et un composé d'ammonium quaternaire, le rapport de teneur du composé d'ammonium quaternaire par rapport à l'épinastine ou son sel étant de 0,1 partie en poids ou moins par rapport à 1 partie en poids de la teneur en épinastine ou sel de celle-ci.
PCT/JP2021/015601 2020-04-16 2021-04-15 Composition aqueuse contenant de l'épinastine ou un sel de celle-ci WO2021210646A1 (fr)

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CN202180026833.3A CN115397430A (zh) 2020-04-16 2021-04-15 含有依匹斯汀或其盐的水性组合物
KR1020227039244A KR20230004582A (ko) 2020-04-16 2021-04-15 에피나스틴 또는 그 염을 함유하는 수성 조성물

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JP2021169431A (ja) 2021-10-28

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