WO2019189720A1 - Aqueous liquid formulation - Google Patents

Aqueous liquid formulation Download PDF

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Publication number
WO2019189720A1
WO2019189720A1 PCT/JP2019/013921 JP2019013921W WO2019189720A1 WO 2019189720 A1 WO2019189720 A1 WO 2019189720A1 JP 2019013921 W JP2019013921 W JP 2019013921W WO 2019189720 A1 WO2019189720 A1 WO 2019189720A1
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WIPO (PCT)
Prior art keywords
salt
aqueous liquid
acid
buffer
brimonidine
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PCT/JP2019/013921
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French (fr)
Japanese (ja)
Inventor
涼香 家本
Original Assignee
千寿製薬株式会社
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Publication of WO2019189720A1 publication Critical patent/WO2019189720A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to an aqueous liquid preparation containing brimonidine and / or a salt thereof and having at least a preservative effect higher than a level at which bacteriostatic action is observed.
  • preservatives such as benzalkonium chloride and methylparaben are usually blended in order to prevent the growth of microorganisms.
  • preservatives can prevent bacterial growth while exhibiting irritation and cytotoxicity (see Non-Patent Document 1).
  • multi-dose type preservative-free container a mechanism for preventing intrusion into the container (hereinafter sometimes referred to as “multi-dose type preservative-free container”) having a mechanism for preventing intrusion into the container (for example, Patent Documents 1 to 4). Etc.).
  • Brimonidine and its salts known as adrenergic ⁇ 2 receptor agonists, reduce intraocular pressure by promoting aqueous humor outflow through the uveal sclera outflow tract along with suppression of aqueous humor production. It has been used to treat glaucoma and ocular hypertension.
  • An object of the present invention is to provide a preparation technique relating to an aqueous liquid preparation containing brimonidine and / or a salt thereof.
  • the present inventor has found that an aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof and a buffering agent at least exhibits a bacteriostatic action even if it does not substantially contain a preservative. It has been found that the above-mentioned preservation efficacy can be provided. The present invention has been completed by further studies based on this finding.
  • Item 1 An aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and substantially free of a preservative.
  • Item 2. Item 2. The aqueous liquid according to Item 1, wherein the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer.
  • Item 3. Item 3. The aqueous liquid according to Item 1 or 2, wherein the concentration of edetic acid and / or a salt thereof is 0.005 to 0.5 w / v%.
  • Item 4. Item 4.
  • Item 5. The aqueous liquid preparation according to any one of Items 1 to 4, wherein the pH is 6 to 8.
  • Item 6. The aqueous liquid preparation according to any one of Items 1 to 5, which is an ophthalmic solution.
  • Brimonidine and / or its salt is brimonidine tartrate;
  • the concentration of brimonidine and / or its salt is 0.05 to 0.2 w / v%
  • the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer;
  • Edetic acid and / or its salt is sodium edetate dihydrate,
  • the concentration of edetic acid and / or its salt is 0.005 to 0.5 w / v%, Housed in a multi-dose type container having a pH of 6 to 8 and having a mechanism for preventing the backflow of the aqueous liquid once leached to the outside into the container and / or a mechanism for preventing foreign substances from entering the container.
  • An aqueous solution An aqueous solution.
  • Item 9. A method for imparting storage efficacy to an aqueous solution containing brimonidine and / or a salt thereof, Preparing an aqueous solution substantially free of preservatives and containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer; How to give preservation efficacy.
  • Item 10. Item 10. The application method according to Item 9, wherein the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer.
  • Item 11. Item 11.
  • Items 9 to 10 are accommodated in a multi-dose type container having a mechanism for preventing the aqueous liquid agent from flowing back into the container once it has leached to the outside and / or a mechanism for preventing foreign substances from entering the container. 14. The applying method according to any one of 14. Item 16.
  • the concentration of brimonidine and / or its salt in the aqueous liquid is 0.05 to 0.2 w / v%
  • the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer; Edetic acid and / or its salt is sodium edetate dihydrate, The concentration of edetic acid and / or salt thereof in the aqueous liquid is 0.005 to 0.5 w / v%,
  • the pH of the aqueous solution is 6-8, and furthermore, a mechanism for preventing the aqueous solution that has been leached out of the aqueous solution from flowing back into the container and / or preventing foreign matter from entering the container.
  • a method for imparting storage efficacy comprising a step of storing in a multi-dose type container having a mechanism for performing the above-described operation.
  • Item 17 An aqueous solution containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and substantially free of a preservative, It is accommodated in a multi-dose type container having a mechanism for preventing the backflow of the aqueous liquid once leached to the outside into the container and / or a mechanism for preventing foreign substances from entering the container, A pharmaceutical product characterized by that.
  • the aqueous liquid preparation of the present invention at least a bacteriostatic action is observed even if substantially free of a preservative is contained by the synergistic action of brimonidine and / or a salt thereof and edetic acid and / or a salt thereof. It can have a preserving effect that exceeds the standard. Therefore, even when the aqueous liquid preparation of the present invention is used in a multi-dose type preservative-free container, it can prevent microbial contamination that may occur due to liquid residue on the outer surface of the nozzle, and is administered by eye drop operation or the like. The safety of the aqueous liquid preparation can be ensured to a higher degree.
  • an “aqueous liquid agent” is a preparation that contains water as a base and exhibits a liquid state.
  • brimonidine is a compound known as an adrenergic ⁇ 2 receptor agonist, and is 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine. Point to.
  • edetic acid is a known compound that is also called ethylenediaminetetraacetic acid.
  • buffering agent refers to a compound or mixture having an action of reducing fluctuations in the hydrogen ion concentration (pH) of an aqueous liquid agent.
  • preservative is a component having a preservative effect, and when the aqueous solution containing only the relevant component at a concentration allowed by eye drops, the aqueous solution is the 17th revised Japanese Pharmacopoeia. Refers to information judged to be “conforming” based on the criteria defined in the category “IA” in the reference information “Preservation Efficacy Test”. However, in the present invention, the preservative does not include a borate buffer.
  • substantially free of preservative means that the concentration of the preservative is a concentration that cannot exert the preservative effect only by the preservative, specifically, only the preservative.
  • the “multi-dose type container” refers to a container that is filled with a plurality of usage amounts of an aqueous liquid and is used repeatedly.
  • the multi-dose type container includes a multi-dose type container (that is, a multi-dose type preservative that has a mechanism for preventing the backflow of the aqueous liquid once leached to the outside into the container or a mechanism for preventing foreign substances from entering the container. Free containers) and multi-dose containers that do not have the mechanism.
  • Multi-dose type preservative-free containers are usually used as a mechanism to prevent the backflow of aqueous liquids that have been leached to the outside into the container or to prevent foreign substances from entering the container.
  • a double-structured bottle for example, Patent Documents 1 to 4).
  • the “unit dose container” refers to a container that is filled with a single use amount of an aqueous liquid agent and is used up after a single instillation.
  • pharmaceutical product refers to a product in which an aqueous liquid is contained in an arbitrary container.
  • the “method for imparting preservative efficacy” means an aqueous solution that does not become “conforming” based on the criteria defined in the category “IC” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Law”. It means a method of making an aqueous solution that is “conforming” based on the criteria defined in the category “IC” in the same test.
  • an effect determined to be “conforming” based on a standard defined by “IC” may be referred to as “Japan IC IC conforming preservation effect”.
  • bacteriostatic action means that the number of viable bacteria or fungi is not decreased, but at least not increased, in a test based on the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test” It is the action of. Further, “having at least a preservative effect at or above the level at which bacteriostatic action is recognized” is synonymous with determining “conforming” based on the criteria defined in the “IC”.
  • Aqueous solutions Conventional ophthalmic solutions contained in ordinary multi-dose containers that do not fall under multi-dose preservative-free containers are classified in category “IA” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Tests”. It is required to have a preservative effect that is “conforming” based on the established criteria, but ophthalmic solutions contained in multi-dose preservative-free containers must satisfy the same criteria. Efficacy is not required. However, if the aqueous liquid is stored in a multi-dose type preservative-free container and used frequently, the aqueous liquid may remain attached to the outer surface of the nozzle.
  • an aqueous preparation contained in a multi-dose type preservative-free container has a preservative efficacy at least equal to or higher than a level at which a bacteriostatic action is recognized even if no preservative is blended.
  • brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and an aqueous liquid substantially free of a preservative are brimonidine and / or a salt thereof.
  • Preservation efficacy is improved by the synergistic action of the salt and edetic acid and / or its salt, and category “IC” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test” without using preservatives. It has been found that it has a storage effect that is “conforming” based on the criteria set forth in (1).
  • the present invention provides an aqueous solution comprising brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and substantially free of a preservative.
  • the salt of brimonidine used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and specifically, an organic acid salt such as tartrate or acetate; an inorganic acid salt such as hydrochloride Etc.
  • Brimonidine or a salt thereof may be in the form of a solvate such as a hydrate.
  • brimonidine or its salt brimonidine tartrate is preferable.
  • either brimonidine or a salt thereof may be used alone, or a combination thereof may be used.
  • the concentration of brimonidine or a salt thereof is not particularly limited, and may be appropriately set according to the use of the aqueous liquid preparation, the degree of symptoms of the patient to be applied, the amount applied per time, and the like. Is, for example, 0.05 to 0.2 w / v%, preferably 0.1 to 0.2 w / v%, particularly preferably 0.1 w / v%.
  • the concentration of brimonidine or a salt thereof is a concentration converted to brimonidine tartrate.
  • the salt of edetic acid used in the present invention is not particularly limited as long as it is pharmaceutically acceptable.
  • edetic acid such as monosodium edetate, disodium edetate (EDTA), tetrasodium edetate, etc.
  • An acid sodium salt is mentioned.
  • the salt of edetic acid may be in the form of a solvate such as a hydrate.
  • 1 type may be selected from edetic acid or its salt, and it may be used independently, and may be used in combination of 2 or more type.
  • sodium edetate dihydrate is preferably used from the viewpoint of providing even better storage efficacy.
  • edetic acid or a salt thereof may be used alone or in combination.
  • the concentration of edetic acid or a salt thereof is usually 0.001 to 0.5 w / v%, preferably 0.005 to 0.00%, from the viewpoint of providing even better storage efficacy.
  • the concentration of edetic acid or a salt thereof is a concentration converted to disodium edetate dihydrate.
  • the buffer used in the present invention is not particularly limited as long as it is pharmaceutically acceptable.
  • borate buffer phosphate buffer, Tris buffer, citrate buffer, tartrate buffer , Acetate buffer, amino acid buffer and the like.
  • boric acid buffer examples include boric acid and / or a salt thereof.
  • the boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, and tetraboric acid. Among these boric acids, orthoboric acid and tetraboric acid are preferable. These boric acids may be used alone or in combination of two or more.
  • the salt of boric acid is not particularly limited as long as it is pharmaceutically acceptable, but alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; Examples thereof include organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine.
  • the boric acid / or salt thereof may be in the form of a hydrate such as borax.
  • boric acid buffer one type selected from boric acid and its salt may be used alone, or two or more types may be used in combination.
  • the boric acids and salts thereof at least one of boric acid and borax is preferable, and at least one of orthoboric acid and borax is preferable, from the viewpoint of providing more excellent preservation effect.
  • boric acid buffer a combination of boric acid and borax can be mentioned.
  • boric acid and borax the ratio thereof is not particularly limited. For example, 0-100 parts by mass of borax, preferably 20-80 parts by mass, more preferably 100 parts by mass of boric acid. 40 to 60 parts by mass.
  • the amount of the boric acid buffer used is usually 0.1 to 2 w / v%, more preferably 0.5 to 1.5 w / v% as the concentration of boric acid or a salt thereof from the viewpoint of buffer action. Preferably it is 0.7 to 1.0 w / v%, particularly preferably 0.4 to 0.6 w / v%.
  • the concentration of boric acid or a salt thereof is a concentration converted to boric acid.
  • the phosphate buffer include phosphoric acid and / or a salt thereof.
  • the salt of phosphoric acid is not particularly limited as long as it is pharmaceutically acceptable.
  • a dialkali metal phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate
  • sodium dihydrogen phosphate And alkali metal dihydrogen phosphates such as potassium dihydrogen phosphate
  • trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate.
  • the salt of phosphoric acid may be in the form of a solvate such as a hydrate.
  • a solvate such as a hydrate.
  • disodium hydrogen phosphate the form of dodecahydrate, sodium dihydrogen phosphate, In some cases, it may be in the form of a dihydrate.
  • the phosphate buffer one kind selected from phosphoric acid and its salt may be used alone, or two or more kinds may be used in combination.
  • phosphoric acid and its salts from the viewpoint of providing more excellent storage efficacy, it is preferably a phosphate, more preferably at least one of hydrogen alkali metal dihydrogen phosphate and alkali metal dihydrogen phosphate, particularly Preferably, at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate is used.
  • a combination of a dibasic metal phosphate and an alkali metal dihydrogen phosphate can be given.
  • a combination of a dihydrogen alkali metal phosphate and an alkali metal dihydrogen phosphate in combination it becomes possible to provide a more excellent storage effect.
  • these ratios are not particularly limited.
  • diphosphoric acid phosphate per 100 parts by mass of the hydrogen dihydrogen alkali metal salt.
  • An alkali metal hydrogen salt is 1 to 120 parts by mass, preferably 5 to 80 parts by mass, and more preferably 10 to 40 parts by mass.
  • the concentration of phosphoric acid or a salt thereof is usually 0.1 to 5 w / v%, preferably 1 to 3 w / v%, more preferably 1.5. Up to 2.0 w / v%.
  • the concentration of the phosphate buffer is a concentration converted to phosphoric acid.
  • Tris buffer examples include trometamol and / or a salt thereof.
  • the salt of trometamol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as acetate; organic acid salts such as hydrochloride and sulfonate.
  • trometamol As the tris acid buffer, one kind selected from trometamol and salts thereof may be used alone, or two or more kinds may be used in combination. Of the trometamol and salts thereof, trometamol is preferably used from the viewpoint of providing more excellent storage efficacy.
  • the amount of Tris buffer used is usually 0.1 to 2 w / v%, preferably 0.3 to 1.75 w / v%, more preferably 0.5 to 1.5 w / v from the viewpoint of buffer action. %.
  • the concentration of the Tris buffer is a concentration converted to trometamol.
  • citrate buffer examples include citric acid and / or a salt thereof.
  • the salt of citric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt, and the like. It is done.
  • the salt of citric acid may be in the form of a solvate such as a hydrate.
  • As the citrate buffer one kind selected from citric acid and its salt may be used alone, or two or more kinds may be used in combination.
  • the tartaric acid buffer include tartaric acid and / or a salt thereof.
  • the tartaric acid salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. .
  • the salt of tartaric acid may be in the form of a solvate such as a hydrate.
  • As the tartaric acid buffer one kind selected from tartaric acid and salts thereof may be used alone, or two or more kinds may be used in combination.
  • the acetate buffer include acetic acid and / or a salt thereof.
  • the salt of acetic acid is not particularly limited as long as it is pharmaceutically acceptable.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • ammonium salt and the like Is mentioned.
  • the salt of acetic acid may be in the form of a solvate such as a hydrate.
  • the acetate buffer one kind selected from acetic acid and its salt may be used alone, or two or more kinds may be used in combination.
  • amino acid buffer examples include acidic amino acids and / or salts thereof.
  • acidic amino acid include aspartic acid and glutamic acid.
  • the salt of the acidic amino acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt.
  • the amino acid buffer one kind selected from acidic amino acids and salts thereof may be used alone, or two or more kinds may be used in combination.
  • These buffering agents may be used alone or in combination of two or more.
  • boric acid buffering agents phosphate buffering agents, and tris buffering agents are preferably used from the viewpoint of providing further excellent storage efficacy.
  • the aqueous liquid preparation of the present invention does not substantially contain a preservative, but when it is made into an aqueous solution containing only the preservative, the aqueous solution is classified in the category “IC” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Method”.
  • An amount of preservative may be included that is less than the minimum concentration of preservative that is “fit” based on the criteria defined in
  • preservatives include chlorite such as sodium chlorite; quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; sorbic acid such as sorbic acid and potassium sorbate and salts thereof; Paraoxybenzoic acid esters such as methyl paraben and propyl paraoxybenzoate; benzoic acid and its salts; chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, chlorobutanol, chlorhexidine, polyhexanide and the like.
  • chlorite such as sodium chlorite
  • quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride
  • sorbic acid such as sorbic acid and potassium sorbate and salts thereof
  • Paraoxybenzoic acid esters such as methyl paraben and propyl paraoxybenzoate
  • benzoic acid and its salts chlorcresol, phenethyl alcohol, polydronium
  • the concentration of the preservative allowed in the aqueous liquid preparation of the present invention varies depending on the type of storage, etc., but specifically, less than 0.001 w / v%, preferably 0.0005 w / v% or less, Preferably it is 0.0001 w / v% or less, Most preferably, it is 0 w / v%.
  • aqueous liquid preparation of the present invention by containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffering agent, it is possible to have at least a preservative effect that is at least a level at which bacteriostatic action is recognized. It has become. Therefore, in the aqueous liquid preparation of the present invention, in addition to the above-described components, components that improve the storage efficacy in the presence of brimonidine and / or a salt thereof may not be substantially contained.
  • dorzolamide and / or a salt thereof can improve storage efficacy when coexisting with brimonidine and / or a salt thereof in an aqueous solution having a pH of 6.0 or more.
  • dorzolamide and / or a salt thereof is substantially free.
  • the salt of dorzolamide include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid And salts with organic acids such as malic acid, citric acid and tartaric acid; salts with alkali metals, salts with alkaline earth metals, salts with organic amines, halides and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid
  • organic acids such as malic acid, citric acid and tartaric acid
  • salts with alkali metals, salts with alkaline earth metals, salts with organic amines, halides and the like such as malic acid, cit
  • substantially free of dorzolamide and / or a salt thereof specifically means that the concentration of dorzolamide and / or a salt thereof is less than 0.1 w / v%, preferably 0.05 w / v%. Hereinafter, it is more preferably 0.01 w / v% or less, particularly preferably 0 w / v%.
  • aqueous liquid preparation of the present invention in addition to the above components, an isotonic agent, a polyhydric alcohol, a surfactant, a thickening agent, a chelating agent (other than edetic acid and its salts), and a cooling agent as necessary. Further, additives such as stabilizers and pH adjusters may be contained.
  • the isotonic agent is not particularly limited as long as it is pharmaceutically acceptable.
  • polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol
  • metal salts such as magnesium, sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.
  • These isotonic agents may be used alone or in combination of two or more.
  • the polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, and glycerin. These polyhydric alcohols may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the surfactant is not particularly limited as long as it is pharmaceutically acceptable.
  • tyloxapol polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy Nonionic surfactants such as diols; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurates, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyls Anionic surfactants such as ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the thickening agent is not particularly limited as long as it is pharmaceutically acceptable, but for example, it has a high water solubility such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, etc.
  • Molecule Celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and the like. These thickeners may be used alone or in combination of two or more.
  • the chelating agent (other than edetic acid and its salt) is not particularly limited as long as it is pharmaceutically acceptable.
  • the form of the salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt.
  • These chelating agents may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the refreshing agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include l-menthol, borneol, camphor, and eucalyptus oil. These refreshing agents may be used alone or in combination of two or more.
  • the stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, dibutylhydroxytoluene and the like. Can be mentioned. These stabilizers may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the pH adjuster is not particularly limited as long as it is pharmaceutically acceptable.
  • acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide , Alkali such as borax, triethanolamine, monoethanolamine, sodium hydrogencarbonate, sodium carbonate.
  • alkali such as borax, triethanolamine, monoethanolamine, sodium hydrogencarbonate, sodium carbonate.
  • concentration of these additives may be set as appropriate according to the type of additive to be used and the characteristics to be imparted to the aqueous liquid.
  • the aqueous liquid preparation of the present invention contains, in addition to brimonidine and / or a salt thereof, a pharmacological component exhibiting a therapeutic effect on glaucoma or ocular hypertension as necessary, as long as the effects of the present invention are not hindered. It may be.
  • Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetic drugs such as pilocarpine hydrochloride; anticholinesterase drugs such as distigmine bromide; and sympathetic nerves such as dipivefrin hydrochloride.
  • Stimulants ⁇ 1 blockers such as betaxolol hydrochloride; ⁇ blockers such as timolol maleate; ⁇ 1 / ⁇ blockers such as nipradilol and levobanolol hydrochloride; ⁇ 1 blockers such as bunazosin hydrochloride .
  • These pharmacological components may be used alone or in combination of two or more.
  • concentration of these pharmacological components may be appropriately set according to the type of pharmacological component to be used and the medicinal effect to be imparted.
  • the pH of the aqueous liquid preparation of the present invention is not particularly limited, and examples thereof include pH 6 to 8.
  • the pH of the aqueous liquid preparation of the present invention is preferably pH 7 to 8, more preferably pH 7, from the viewpoint of providing further excellent storage efficacy.
  • the osmotic pressure ratio of the aqueous liquid preparation of the present invention is not particularly limited, and examples thereof include 0.5 to 4, preferably 0.7 to 1.3, and more preferably 0.9 to 1.1.
  • the osmotic pressure ratio is a ratio to the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution, and the osmotic pressure is in accordance with the “osmotic pressure method (osmolarity measurement method)” defined in the 17th revision Japanese Pharmacopoeia. Measured.
  • the aqueous liquid preparation of the present invention can have a preservative effect at least higher than a level at which bacteriostatic action is observed by including the above-described components.
  • the preservative efficacy of the aqueous preparation of the present invention is determined to be “conforming” based on the criteria defined in the category “IC” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Law”. Is. JP-Compliant Preservative Efficacy can be determined by a test method based on the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Method”, and the specific test method is as shown in the column of Test Examples described later.
  • the preparation form of the aqueous liquid preparation of the present invention is not particularly limited and may be any of aqueous solution, suspension, emulsion, etc., preferably an aqueous solution.
  • the aqueous liquid preparation of the present invention can be used as ophthalmic preparations such as eye drops and eyewashes.
  • the aqueous liquid preparation of the present invention is provided as an ophthalmic solution because it can suppress the production of aqueous humor and reduce intraocular pressure by the action of brimonidine and / or a salt thereof. It can be suitably used as an aqueous liquid for treating the above.
  • aqueous liquid preparation of the present invention may be produced according to a known preparation method according to its use, for example, using the method described in the 17th revised Japanese Pharmacopoeia General Rules for Preparations.
  • an eye drop container, an eye wash container, or the like may be used depending on the use of the aqueous preparation.
  • the aqueous liquid preparation of the present invention may be a multi-dose type container or a unit dose type container.
  • a multi-dose type preservative-free container in order to maintain the aseptic state of the aqueous liquid agent stored during storage.
  • a conventional aqueous solution containing no preservative even if a multi-dose type preservative-free container is used, there is a concern about microbial contamination of the aqueous solution remaining on the outer surface of the nozzle, but in the aqueous solution of the present invention, at least Since it has a preservative effect higher than the level at which bacteriostatic action is recognized, the microbial contamination can be suppressed even if it remains on the outer surface of the nozzle of the multi-dose type preservative-free container.
  • the present invention relates to a method for imparting storage efficacy to an aqueous liquid preparation containing brimonidine and / or a salt thereof, wherein the aqueous liquid preparation is substantially free of a preservative and contains brimonidine and / or a salt thereof.
  • a method for imparting storage efficacy comprising the step of preparing an aqueous solution containing edetic acid and / or a salt thereof and a buffer.
  • the type and concentration of brimonidine and / or its salt to be used the type and concentration of edetic acid and / or its salt, the type and concentration of a buffering agent, and other components incorporated in an aqueous liquid preparation
  • the types of additives and pharmacological components, the pH of the aqueous liquid preparation, the preparation form, the use, and the like are as described in the column “1.
  • Test Example 1 Evaluation of Preservative Efficacy According to the 17th revision Japanese Pharmacopoeia Reference Information "Preservation Efficacy Test Method", the preservative efficacy of eye drops having the composition shown in Table 1 was evaluated. Specific test methods and the like are as shown below.
  • Test material and test method 1-1 Sample Preparation An aqueous solution (eye drops) having the composition shown in Tables 1 to 3 was prepared and filtered through a 0.22 ⁇ m filter. The total amount of boric acid and borax in Example 1 was 0.72 g (concentration: 0.72 w / v%) in terms of boric acid, and disodium hydrogen phosphate hydrate in Example 2. The total amount of sodium dihydrogen phosphate is 1.8 g (concentration: 1.8 w / v%) in terms of phosphoric acid.
  • Bacteria ⁇ Staphylococcus aureus, S.aureus / ATCC 6538 ⁇ Escherichia coli (E.coli / ATCC 8739) ⁇ Pseudomonas aeruginosa (Pseudomonas aeruginosa, P.aeruginosa / ATCC 9027) (fungus) ⁇ Candida (Candida albicans, C. albicans / ATCC 10231) Black mold (Aspergillus brasiliensis, A. brasiliensis / ATCC 16404)
  • agar medium for preculture a soy bean / casein / digest agar medium was used in the case of bacteria, and a Sabouraud dextrose agar medium was used in the case of fungi.
  • the culture was performed at 30 to 35 ° C. for 18 to 24 hours, Candida was cultured at 20 to 25 ° C. for 44 to 52 hours, and black mold was cultured at 20 to 25 ° C. for 6 to 10 days.
  • the number of generated colonies was measured, and the number of viable bacteria per 1 mL of the mixed sample (cfu / mL) and the logarithmic decrease value (log) of the viable cell count.
  • Judgment of preservation efficacy The preservation efficacy of each test solution is determined according to Category 1C described in "Table 3. Judgment Criteria by Formulation" in “4. Evaluation was made according to criteria. Specifically, (1) In all three types of bacteria, the log reduction value (log) is 1.0 log or more compared to the number of inoculated bacteria after 14 days, and the number of viable bacteria after 28 days does not increase after 14 days, And (2) In all two types of fungi, the case where the number of viable bacteria after 14 days and 28 days did not increase from the number of inoculated bacteria was judged as “conforming”, and other cases were judged as “nonconforming” .
  • the aqueous solution (Example 1) containing brimonidine tartrate and sodium edetate dihydrate together with the boric acid buffer has improved storage efficacy and has JP-Japan IC compatible storage efficacy. It was.
  • an aqueous solution containing brimonidine tartrate and sodium edetate dihydrate improves the storage efficacy, and the JP IC compatible storage efficacy is achieved. It was equipped.
  • Test Example 2 Evaluation of thermal stability An aqueous liquid (ophthalmic solution) having the composition shown in Table 5 was prepared. After filtration with a 0.22 ⁇ m filter, 5 mL of each aqueous solution was filled into a 5 mL colorless glass ampoule. These were placed in a desktop thermostat (NST-80, Nagano Science Co., Ltd.) and stored at 60 ° C. for 4 weeks under light shielding conditions. The brimonidine tartrate content before and after storage was measured according to the following conditions using a high performance liquid chromatograph system (Shimadzu Corporation).
  • Detector UV absorptiometer (measurement wavelength: 230 nm) Column: Symmetry C18, 4.6mm ID ⁇ 150mm, 3.5 ⁇ m, Waters Column temperature: Constant temperature around 40 ° C Mobile phase A: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 84/8/8) Mixed mobile phase B: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio) : 40/30/30) Mixed liquid Flow rate: 1.0 mL / min Autosampler internal temperature: 5 °C Mobile phase liquid feed: The linear concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 4.
  • the residual rate of brimonidine in the aqueous liquid was calculated.
  • Table 5 shows the obtained results.
  • an aqueous solution containing no preservative (Comparative Example 9) was an aqueous solution (Comparative Examples 7 and 8) containing a preservative generally blended into eye drops. )
  • the residual rate of brimonidine was reduced.
  • the stability of brimonidine can be improved by blending preservatives such as sodium bisulfite and benzalkonium chloride.
  • preservatives such as sodium bisulfite and benzalkonium chloride.
  • the stability of brimonidine tartrate was further improved in the aqueous liquid preparation containing sodium edetate dihydrate without adding a preservative.
  • the aqueous solution containing substantially no preservative and containing brimonidine and / or a salt thereof and edetic acid and / or a salt thereof is excellent in terms of stability of brimonidine and / or a salt thereof. It became clear that.

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Abstract

The purpose of the present invention is to provide pharmaceutical technology that makes it possible to obtain at least preservation efficacy equal to or exceeding a level at which bacteriostatic action is observed in an aqueous liquid formulation containing brimonidine and/or a salt thereof without mixing preservatives into said aqueous liquid formulation. An aqueous liquid formulation containing brimonidine and/or a salt thereof, edetic acid and/or a salt thereof, and a buffer agent makes it possible to obtain at least preservation efficacy at a level at which bacteriostatic action is observed despite said aqueous liquid formulation containing substantially no preservatives.

Description

水性液剤Aqueous liquid
　本発明は、ブリモニジン及び／又はその塩を含み、少なくとも静菌作用が認められる水準以上の保存効力を備えた水性液剤に関する。 The present invention relates to an aqueous liquid preparation containing brimonidine and / or a salt thereof and having at least a preservative effect higher than a level at which bacteriostatic action is observed.
　点眼液や洗眼液等の水性液剤には、微生物の繁殖を防止するために、通常、塩化ベンザルコニウム、メチルパラベン等の保存剤が配合されている。しかしながら、保存剤は、細菌の繁殖を防止できる一方、刺激性や細胞毒性を示すことがあることが知られている（非特許文献１参照）。 In aqueous solutions such as eye drops and eye wash solutions, preservatives such as benzalkonium chloride and methylparaben are usually blended in order to prevent the growth of microorganisms. However, it is known that preservatives can prevent bacterial growth while exhibiting irritation and cytotoxicity (see Non-Patent Document 1).
　従来、保存剤を含まない水性液剤において保存時の細菌の繁殖を防止するために、一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物（微生物等の）の容器内への侵入を防止する機構を有するマルチドーズ型容器（以下、「マルチドーズ型保存剤フリー容器」と表記することがある）に収容して使用されている（例えば、特許文献１～４等参照）。 Conventionally, in order to prevent bacterial growth during storage in an aqueous solution containing no preservative, a mechanism for preventing backflow of the aqueous solution once leached out into the container and / or foreign matter (such as microorganisms) Used in a multi-dose type container (hereinafter sometimes referred to as “multi-dose type preservative-free container”) having a mechanism for preventing intrusion into the container (for example, Patent Documents 1 to 4). Etc.).
　一方、ブリモニジン及びその塩は、アドレナリンα２受容体作動薬として知られており、眼房水産生抑制と共にぶどう膜強膜流出路を介した眼房水の流出を促進することによって、眼圧を低下させる作用があり、従来、緑内障や高眼圧症の治療に使用されている。 Brimonidine and its salts, known as adrenergic α2 receptor agonists, reduce intraocular pressure by promoting aqueous humor outflow through the uveal sclera outflow tract along with suppression of aqueous humor production. It has been used to treat glaucoma and ocular hypertension.
特開２０１６－１３２４６５号公報Japanese Unexamined Patent Publication No. 2016-132465 特開２００５－３４３５４９号公報JP 2005-343549 A 特開２００４－５１１７０号公報JP 2004-51170 A 特開２００２－８００５５号公報Japanese Patent Laid-Open No. 2002-80055
　本発明の目的は、ブリモニジン及び／又はその塩を含む水性液剤に関する製剤技術を提供することである。 An object of the present invention is to provide a preparation technique relating to an aqueous liquid preparation containing brimonidine and / or a salt thereof.
　本発明者は、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含む水性液剤は、保存剤を実質的に含まなくても、少なくとも静菌作用が認められる水準以上の保存効力を備え得ることを見出した。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。 The present inventor has found that an aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof and a buffering agent at least exhibits a bacteriostatic action even if it does not substantially contain a preservative. It has been found that the above-mentioned preservation efficacy can be provided. The present invention has been completed by further studies based on this finding.
　即ち、本発明は、下記に掲げる態様の発明を提供する。
項１．　ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含み、保存剤を実質的に含まない、水性液剤。
項２．　緩衝剤が、ホウ酸緩衝剤、リン酸緩衝剤、及びトリス緩衝剤よりなる群から選択される少なくとも１種である、項１に記載の水性液剤。
項３．　エデト酸及び／又はその塩の濃度が０．００５～０．５ｗ／ｖ％である、項１又は２に記載の水性液剤。
項４．　ブリモニジン及び／又はその塩の濃度が０．０５～０．２ｗ／ｖ％である、項１～３のいずれかに記載の水性液剤。
項５．　ｐＨが６～８である、項１～４のいずれかに記載の水性液剤。
項６．　点眼液である、項１～５のいずれかに記載の水性液剤。
項７．　一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、項１～６のいずれかに記載の水性液剤。
項８．　ブリモニジン及び／又はその塩がブリモニジン酒石酸塩であり、
　ブリモニジン及び／又はその塩の濃度が０．０５～０．２ｗ／ｖ％であり、
　緩衝剤が、ホウ酸緩衝剤、リン酸緩衝剤、及びトリス緩衝剤よりなる群から選択される少なくとも１種であり、
　エデト酸及び／又はその塩がエデト酸ナトリウム二水和物であり、
　エデト酸及び／又はその塩の濃度が０．００５～０．５ｗ／ｖ％であり、
　ｐＨが６～８であり、且つ
　一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、水性液剤。
項９．　ブリモニジン及び／又はその塩を含む水性液剤に保存効力を付与する方法であって、
　保存剤を実質的に含まず、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤を含む水性液剤を調製する工程を含む、
保存効力の付与方法。
項１０．　緩衝剤が、ホウ酸緩衝剤、リン酸緩衝剤、及びトリス緩衝剤よりなる群から選択される少なくとも１種である、項９に記載の付与方法。
項１１．　水性液剤におけるエデト酸及び／又はその塩の濃度が０．００５～０．５ｗ／ｖ％である、項９又は１０に記載の付与方法。
項１２．　ブリモニジン及び／又はその塩の濃度が０．０５～０．２ｗ／ｖ％である、項９～１１のいずれかに記載の付与方法。
項１３．　水性液剤のｐＨが６～８である、項９～１２のいずれかに記載の付与方法。
項１４．　水性液剤が点眼液である、項９～１３のいずれかに記載の付与方法。
項１５．　水性液剤が一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、項９～１４のいずれかに記載の付与方法。
項１６．　水性液剤におけるブリモニジン及び／又はその塩の濃度が０．０５～０．２ｗ／ｖ％であり、
　緩衝剤が、ホウ酸緩衝剤、リン酸緩衝剤、及びトリス緩衝剤よりなる群から選択される少なくとも１種であり、
　エデト酸及び／又はその塩がエデト酸ナトリウム二水和物であり、
　水性液剤におけるエデト酸及び／又はその塩の濃度が０．００５～０．５ｗ／ｖ％であり、
　水性液剤のｐＨが６～８であり、且つ
　更に、調製した水性液剤を、一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容する工程を含む、保存効力の付与方法。
項１７．　ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含み、保存剤を実質的に含まない、水性液剤が、
　一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、
　ことを特徴とする、医薬製品。 That is, this invention provides the invention of the aspect hung up below.
Item 1. An aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and substantially free of a preservative.
Item 2. Item 2. The aqueous liquid according to Item 1, wherein the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer.
Item 3. Item 3. The aqueous liquid according to Item 1 or 2, wherein the concentration of edetic acid and / or a salt thereof is 0.005 to 0.5 w / v%.
Item 4. Item 4. The aqueous liquid preparation according to any one of Items 1 to 3, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%.
Item 5. Item 5. The aqueous liquid preparation according to any one of Items 1 to 4, wherein the pH is 6 to 8.
Item 6. Item 6. The aqueous liquid preparation according to any one of Items 1 to 5, which is an ophthalmic solution.
Item 7. Any one of Items 1 to 6, which is accommodated in a multi-dose container having a mechanism for preventing the back flow of the aqueous liquid once leached to the outside into the container and / or a mechanism for preventing foreign substances from entering the container. An aqueous liquid preparation according to the above.
Item 8. Brimonidine and / or its salt is brimonidine tartrate;
The concentration of brimonidine and / or its salt is 0.05 to 0.2 w / v%,
The buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer;
Edetic acid and / or its salt is sodium edetate dihydrate,
The concentration of edetic acid and / or its salt is 0.005 to 0.5 w / v%,
Housed in a multi-dose type container having a pH of 6 to 8 and having a mechanism for preventing the backflow of the aqueous liquid once leached to the outside into the container and / or a mechanism for preventing foreign substances from entering the container. An aqueous solution.
Item 9. A method for imparting storage efficacy to an aqueous solution containing brimonidine and / or a salt thereof,
Preparing an aqueous solution substantially free of preservatives and containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer;
How to give preservation efficacy.
Item 10. Item 10. The application method according to Item 9, wherein the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer.
Item 11. Item 11. The applying method according to Item 9 or 10, wherein the concentration of edetic acid and / or a salt thereof in the aqueous liquid is 0.005 to 0.5 w / v%.
Item 12. Item 12. The application method according to any one of Items 9 to 11, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%.
Item 13. Item 13. The applying method according to any one of Items 9 to 12, wherein the pH of the aqueous liquid preparation is 6 to 8.
Item 14. Item 14. The application method according to any one of Items 9 to 13, wherein the aqueous liquid preparation is an ophthalmic solution.
Item 15. Items 9 to 10 are accommodated in a multi-dose type container having a mechanism for preventing the aqueous liquid agent from flowing back into the container once it has leached to the outside and / or a mechanism for preventing foreign substances from entering the container. 14. The applying method according to any one of 14.
Item 16. The concentration of brimonidine and / or its salt in the aqueous liquid is 0.05 to 0.2 w / v%,
The buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer;
Edetic acid and / or its salt is sodium edetate dihydrate,
The concentration of edetic acid and / or salt thereof in the aqueous liquid is 0.005 to 0.5 w / v%,
The pH of the aqueous solution is 6-8, and furthermore, a mechanism for preventing the aqueous solution that has been leached out of the aqueous solution from flowing back into the container and / or preventing foreign matter from entering the container. A method for imparting storage efficacy, comprising a step of storing in a multi-dose type container having a mechanism for performing the above-described operation.
Item 17. An aqueous solution containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and substantially free of a preservative,
It is accommodated in a multi-dose type container having a mechanism for preventing the backflow of the aqueous liquid once leached to the outside into the container and / or a mechanism for preventing foreign substances from entering the container,
A pharmaceutical product characterized by that.
　本発明の水性液剤によれば、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩との相乗作用によって、保存剤を実質的に含んでいなくても、少なくとも静菌作用が認められる水準以上の保存効力を備えることができる。そのため、本発明の水性液剤は、マルチドーズ型保存剤フリー容器に収容して使用しても、ノズルの外側表面での液残りによって生じ得る微生物汚染を防ぐことができ、点眼操作等によって投与される水性液剤の安全性をより高度に確保することができる。 According to the aqueous liquid preparation of the present invention, at least a bacteriostatic action is observed even if substantially free of a preservative is contained by the synergistic action of brimonidine and / or a salt thereof and edetic acid and / or a salt thereof. It can have a preserving effect that exceeds the standard. Therefore, even when the aqueous liquid preparation of the present invention is used in a multi-dose type preservative-free container, it can prevent microbial contamination that may occur due to liquid residue on the outer surface of the nozzle, and is administered by eye drop operation or the like. The safety of the aqueous liquid preparation can be ensured to a higher degree.
１．定義
　本明細書において、「水性液剤」とは、水を基剤として含み液状を呈する製剤である。 1. Definitions In the present specification, an “aqueous liquid agent” is a preparation that contains water as a base and exhibits a liquid state.
　本明細書において、「ブリモニジン」とは、アドレナリンα２受容体作動薬として公知の化合物であり、５－ブロモ－Ｎ－（４，５－ジヒドロ－１Ｈ－イミダゾール－２－イル）キノキサリン－６－アミンを指す。 In the present specification, “brimonidine” is a compound known as an adrenergic α2 receptor agonist, and is 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine. Point to.
　本明細書において、「エデト酸」とは、別名エチレンジアミン四酢酸とも称される公知の化合物である。 In this specification, “edetic acid” is a known compound that is also called ethylenediaminetetraacetic acid.
　本明細書において、「緩衝剤」とは、水性液剤の水素イオン濃度（ｐＨ）の変動を和らげる作用を持つ化合物又は混合物のことを指す。 In the present specification, “buffering agent” refers to a compound or mixture having an action of reducing fluctuations in the hydrogen ion concentration (pH) of an aqueous liquid agent.
　本明細書において、「保存剤」とは、保存効力を有する成分であって、点眼剤で許容される濃度で該当の成分のみを含む水溶液にした場合、当該水溶液が第十七改正日本薬局方参考情報「保存効力試験法」においてカテゴリー「ＩＡ」で定められた判定基準に基づいて「適合」と判断されるものを指す。但し、本発明において、保存剤には、ホウ酸緩衝剤は包含されない。 In this specification, “preservative” is a component having a preservative effect, and when the aqueous solution containing only the relevant component at a concentration allowed by eye drops, the aqueous solution is the 17th revised Japanese Pharmacopoeia. Refers to information judged to be “conforming” based on the criteria defined in the category “IA” in the reference information “Preservation Efficacy Test”. However, in the present invention, the preservative does not include a borate buffer.
　本明細書において、「保存剤を実質的に含まない」とは、保存剤の濃度が、保存剤のみでは保存効力を発揮し得ない濃度であることを指し、具体的には、保存剤のみを含む水溶液にした場合、当該水溶液が第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」となる保存剤の最小濃度よりも少ないことを指す。 In the present specification, “substantially free of preservative” means that the concentration of the preservative is a concentration that cannot exert the preservative effect only by the preservative, specifically, only the preservative. When the aqueous solution contains a preservative that is “conforming” based on the criteria set forth in the category “IC” in the 17th revised Japanese Pharmacopoeia Reference Information “Conservation Efficacy Test” Point to less.
　本明細書において、「マルチドーズ型容器」とは、複数回分の使用量の水性液剤が充填され、繰返し使用される容器を指す。マルチドーズ型容器には、一旦外側に浸出した水性液剤の容器内への逆流を防止する機構又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器（即ち、マルチドーズ型保存剤フリー容器）と、当該機構を有していないマルチドーズ型容器がある。マルチドーズ型保存剤フリー容器は、一旦外側に浸出した水性液剤の容器内への逆流を防止する機構又は異物の容器内への混入を防止する機構として、通常、逆流防止弁、マイクロフィルター、特殊な二重構造ボトル等の構造を有している（例えば、特許文献１～４）。 In this specification, the “multi-dose type container” refers to a container that is filled with a plurality of usage amounts of an aqueous liquid and is used repeatedly. The multi-dose type container includes a multi-dose type container (that is, a multi-dose type preservative that has a mechanism for preventing the backflow of the aqueous liquid once leached to the outside into the container or a mechanism for preventing foreign substances from entering the container. Free containers) and multi-dose containers that do not have the mechanism. Multi-dose type preservative-free containers are usually used as a mechanism to prevent the backflow of aqueous liquids that have been leached to the outside into the container or to prevent foreign substances from entering the container. Such as a double-structured bottle (for example, Patent Documents 1 to 4).
　本明細書において、「ユニットドーズ型容器」とは、単回分の使用量の水性液剤が充填され、１回の点眼で使い終わる容器を指す。 In this specification, the “unit dose container” refers to a container that is filled with a single use amount of an aqueous liquid agent and is used up after a single instillation.
　本明細書において、「医薬製品」とは、水性液剤が任意の容器に収容されている状態にある製品を指す。 In this specification, “pharmaceutical product” refers to a product in which an aqueous liquid is contained in an arbitrary container.
　本明細書において、「保存効力を付与する方法」とは、第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」とならない水性液剤に、同試験においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」となる水性液剤にする方法を意味する。また、「ＩＣ」で定められた基準に基づいて「適合」と判断された効力のことを「日局ＩＣ適合保存効力」と表記することがある。 In this specification, the “method for imparting preservative efficacy” means an aqueous solution that does not become “conforming” based on the criteria defined in the category “IC” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Law”. It means a method of making an aqueous solution that is “conforming” based on the criteria defined in the category “IC” in the same test. In addition, an effect determined to be “conforming” based on a standard defined by “IC” may be referred to as “Japan IC IC conforming preservation effect”.
　本明細書において、「静菌作用」とは、第十七改正日本薬局方 参考情報「保存効力試験法」に基づく試験において、細菌又は真菌の生菌数を減少させないが、少なくとも増加もさせない程度の作用である。また、「少なくとも静菌作用が認められる水準以上の保存効力を備える」とは、前記の「ＩＣ」で定められた基準に基づいて「適合」と判断されることと同義である。 In the present specification, “bacteriostatic action” means that the number of viable bacteria or fungi is not decreased, but at least not increased, in a test based on the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test” It is the action of. Further, “having at least a preservative effect at or above the level at which bacteriostatic action is recognized” is synonymous with determining “conforming” based on the criteria defined in the “IC”.
２．水性液剤
　従来、マルチドーズ型保存剤フリー容器には該当しない通常のマルチドーズ型容器に収容する点眼液については、第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＡ」で定められた判定基準に基づいて「適合」とされる保存効力を有していることが必要とされているが、マルチドーズ型保存剤フリー容器に収容する点眼液では、同判定基準を満たす保存効力は必要とされていない。しかしながら、水性液剤をマルチドーズ型保存剤フリー容器に収容して頻回使用すると、ノズルの外側表面に水性液剤が付着したまま残存することがある。ノズルの外側表面に残存した水性液剤は、微生物に汚染される場合があり、このような状態で頻回使用すると、点眼操作等によって投与される水性液剤の無菌状態を確保できなくなる。そのため、マルチドーズ型保存剤フリー容器に収容する水性製剤では、保存剤を配合していなくても、少なくとも静菌作用が認められる水準以上の保存効力を有していることが望ましい。 2. Aqueous solutions Conventional ophthalmic solutions contained in ordinary multi-dose containers that do not fall under multi-dose preservative-free containers are classified in category “IA” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Tests”. It is required to have a preservative effect that is “conforming” based on the established criteria, but ophthalmic solutions contained in multi-dose preservative-free containers must satisfy the same criteria. Efficacy is not required. However, if the aqueous liquid is stored in a multi-dose type preservative-free container and used frequently, the aqueous liquid may remain attached to the outer surface of the nozzle. The aqueous liquid remaining on the outer surface of the nozzle may be contaminated with microorganisms, and if it is used frequently in such a state, it becomes impossible to ensure the aseptic state of the aqueous liquid administered by eye drop operation or the like. Therefore, it is desirable that an aqueous preparation contained in a multi-dose type preservative-free container has a preservative efficacy at least equal to or higher than a level at which a bacteriostatic action is recognized even if no preservative is blended.
　しかしながら、従来、ブリモニジン及び／又はその塩を含む水性液剤において、保存剤を配合することなく保存効力を高める製剤技術については報告されておらず、従来技術では、マルチドーズ型保存剤フリー容器に収容した際にノズルの外側表面に水性液剤が残存することによって生じる微生物汚染の懸念を払拭できていない。 However, conventionally, there has been no report on a formulation technique for enhancing the storage efficacy without blending a preservative in an aqueous liquid preparation containing brimonidine and / or a salt thereof, and the conventional technique accommodates in a multi-dose type preservative-free container. In this case, the concern about microbial contamination caused by the aqueous liquid remaining on the outer surface of the nozzle cannot be eliminated.
　これに対して、本発明者は、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含み、保存剤を実質的に含まない水性液剤は、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩との相乗作用により保存効力が向上し、保存剤を使用しなくても、第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた判定基準に基づいて「適合」とされる保存効力を有することを見出した。 In contrast, the present inventor considered that brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and an aqueous liquid substantially free of a preservative are brimonidine and / or a salt thereof. Preservation efficacy is improved by the synergistic action of the salt and edetic acid and / or its salt, and category “IC” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test” without using preservatives. It has been found that it has a storage effect that is “conforming” based on the criteria set forth in (1).
　１つの態様において、本発明は、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含み、保存剤を実質的に含まない、水性液剤を提供する。 In one aspect, the present invention provides an aqueous solution comprising brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and substantially free of a preservative.
　本発明で使用されるブリモニジンの塩としては、薬学的に許容されることを限度として特に制限されないが、具体的には、酒石酸塩、酢酸塩等の有機酸塩；塩酸塩等の無機酸塩等が挙げられる。また、ブリモニジン又はその塩は、水和物等の溶媒和物の形態であってもよい。ブリモニジン又はその塩の中でも、好ましくはブリモニジン酒石酸塩が挙げられる。
　本発明の水性液剤において、ブリモニジン又はその塩のいずれか一方を単独で使用してもよく、またこれらを組み合わせて使用してもよい。 The salt of brimonidine used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and specifically, an organic acid salt such as tartrate or acetate; an inorganic acid salt such as hydrochloride Etc. Brimonidine or a salt thereof may be in the form of a solvate such as a hydrate. Among brimonidine or its salt, brimonidine tartrate is preferable.
In the aqueous liquid preparation of the present invention, either brimonidine or a salt thereof may be used alone, or a combination thereof may be used.
　本発明の水性液剤において、ブリモニジン又はその塩の濃度は、特に制限されず、水性液剤の用途、適用対象となる患者の症状の程度、１回当たりの適用量等に応じて適宜設定すればよいが、例えば０．０５～０．２ｗ/ｖ％、好ましくは０．１～０．２ｗ/ｖ％、特に好ましくは０．１ｗ/ｖ％が挙げられる。本明細書において、ブリモニジン又はその塩の濃度は、ブリモニジン酒石酸塩に換算された濃度である。 In the aqueous liquid preparation of the present invention, the concentration of brimonidine or a salt thereof is not particularly limited, and may be appropriately set according to the use of the aqueous liquid preparation, the degree of symptoms of the patient to be applied, the amount applied per time, and the like. Is, for example, 0.05 to 0.2 w / v%, preferably 0.1 to 0.2 w / v%, particularly preferably 0.1 w / v%. In this specification, the concentration of brimonidine or a salt thereof is a concentration converted to brimonidine tartrate.
　本発明で使用されるエデト酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、エデト酸一ナトリウム、エデト酸二ナトリウム（ＥＤＴＡ）、エデト酸四ナトリウム等のエデト酸ナトリウム塩が挙げられる。また、エデト酸の塩は、水和物等の溶媒和物の形態であってもよい。また、エデト酸又はその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。エデト酸又はその塩の中でも、より一層優れた保存効力を備えさせるという観点から、好ましくはエデト酸ナトリウム二水和物が挙げられる。 The salt of edetic acid used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, edetic acid such as monosodium edetate, disodium edetate (EDTA), tetrasodium edetate, etc. An acid sodium salt is mentioned. The salt of edetic acid may be in the form of a solvate such as a hydrate. Moreover, 1 type may be selected from edetic acid or its salt, and it may be used independently, and may be used in combination of 2 or more type. Among the edetic acids or salts thereof, sodium edetate dihydrate is preferably used from the viewpoint of providing even better storage efficacy.
　本発明の水性液剤において、エデト酸又はその塩のいずれか一方を単独で使用してもよく、またこれらを組み合わせて使用してもよい。 In the aqueous liquid preparation of the present invention, either edetic acid or a salt thereof may be used alone or in combination.
　本発明の水性液剤において、エデト酸又はその塩の濃度としては、より一層優れた保存効力を備えさせるという観点から、通常０．００１～０．５ｗ/ｖ％、好ましくは０．００５～０．０５ｗ/ｖ％、更に好ましくは０．００３～０．０２ｗ/ｖ％、特に好ましくは０．００５～０．０１ｗ/ｖ％が挙げられる。本明細書において、エデト酸又はその塩の濃度は、エデト酸二ナトリウム二水和物に換算された濃度である。 In the aqueous liquid preparation of the present invention, the concentration of edetic acid or a salt thereof is usually 0.001 to 0.5 w / v%, preferably 0.005 to 0.00%, from the viewpoint of providing even better storage efficacy. 05 w / v%, more preferably 0.003 to 0.02 w / v%, particularly preferably 0.005 to 0.01 w / v%. In the present specification, the concentration of edetic acid or a salt thereof is a concentration converted to disodium edetate dihydrate.
　本発明で使用される緩衝剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、ホウ酸緩衝剤、リン酸緩衝剤、トリス緩衝剤、クエン酸緩衝剤、酒石酸緩衝剤、酢酸緩衝剤、アミノ酸緩衝剤等が挙げられる。 The buffer used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, borate buffer, phosphate buffer, Tris buffer, citrate buffer, tartrate buffer , Acetate buffer, amino acid buffer and the like.
　ホウ酸緩衝剤としては、具体的には、ホウ酸及び／又はその塩が挙げられる。ホウ酸としては、薬学的に許容されることを限度として特に制限されないが、例えば、オルトホウ酸、メタホウ酸、テトラホウ酸等が挙げられる。これらのホウ酸の中でも、好ましくはオルトホウ酸及びテトラホウ酸が挙げられる。これらのホウ酸は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。ホウ酸の塩としては、薬学的に許容されることを限度として、特に制限されないが、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アルミニウム塩；トリエチルアミン、トリエタノールアミン、モルホリン、ピペラジン、ピロリジン等の有機アミン塩等が挙げられる。また、ホウ酸／又はその塩は、ホウ砂等のように、水和物の形態であってもよい。 Specific examples of the boric acid buffer include boric acid and / or a salt thereof. The boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, and tetraboric acid. Among these boric acids, orthoboric acid and tetraboric acid are preferable. These boric acids may be used alone or in combination of two or more. The salt of boric acid is not particularly limited as long as it is pharmaceutically acceptable, but alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; Examples thereof include organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. The boric acid / or salt thereof may be in the form of a hydrate such as borax.
　ホウ酸緩衝剤として、ホウ酸及びその塩の中から、１種を選択して単独で使用してもよく、２種以上を組み合わせて使用してもよい。ホウ酸及びその塩の中でも、より優れた保存効力を備えさせるという観点から、好ましくはホウ酸及びホウ砂の少なくとも１種、更に好ましくはオルトホウ酸及びホウ砂の少なくとも１種が挙げられる。 As a boric acid buffer, one type selected from boric acid and its salt may be used alone, or two or more types may be used in combination. Among the boric acids and salts thereof, at least one of boric acid and borax is preferable, and at least one of orthoboric acid and borax is preferable, from the viewpoint of providing more excellent preservation effect.
　また、ホウ酸緩衝剤の好適な一態様として、ホウ酸とホウ砂を組み合わせが挙げられる。このようにホウ酸とホウ砂を組み合わせて使用することによって、より一層優れた保存効力を備えさせることが可能になる。ホウ酸とホウ砂を組み合わせて使用する場合、これらの比率については、特に制限されないが、例えば、ホウ酸１００質量部当たり、ホウ砂が０～１００質量部、好ましく２０～８０質量部、更に好ましくは４０～６０質量部が挙げられる。 Moreover, as a preferred embodiment of the boric acid buffer, a combination of boric acid and borax can be mentioned. Thus, by using a combination of boric acid and borax, it becomes possible to provide a more excellent preservation effect. When boric acid and borax are used in combination, the ratio thereof is not particularly limited. For example, 0-100 parts by mass of borax, preferably 20-80 parts by mass, more preferably 100 parts by mass of boric acid. 40 to 60 parts by mass.
　ホウ酸緩衝剤の使用量については、緩衝作用の観点から、ホウ酸又はその塩の濃度として、通常０．１～２ｗ/ｖ％、更に好ましくは０．５～１．５ｗ/ｖ％、更に好ましくは０．７～１．０ｗ/ｖ％、特に好ましくは０．４～０．６ｗ/ｖ％が挙げられる。本明細書において、ホウ酸又はその塩の濃度は、ホウ酸に換算された濃度である。 The amount of the boric acid buffer used is usually 0.1 to 2 w / v%, more preferably 0.5 to 1.5 w / v% as the concentration of boric acid or a salt thereof from the viewpoint of buffer action. Preferably it is 0.7 to 1.0 w / v%, particularly preferably 0.4 to 0.6 w / v%. In this specification, the concentration of boric acid or a salt thereof is a concentration converted to boric acid.
　リン酸緩衝剤としては、具体的には、リン酸及び／又はその塩が挙げられる。リン酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、リン酸水素二ナトリウム、リン酸水素二カリウム等のリン酸水素二アルカリ金属塩；リン酸二水素ナトリウム、リン酸二水素カリウム等のリン酸二水素アルカリ金属塩；リン酸三ナトリウム、リン酸三カリウム等のリン酸三アルカリ金属塩等が挙げられる。また、リン酸の塩は、水和物等の溶媒和物の形態であってもよく、例えば、リン酸水素二ナトリウムの場合であれば十二水和物の形態、リン酸二水素ナトリウムの場合であれば二水和物の形態等であってもよい。 Specific examples of the phosphate buffer include phosphoric acid and / or a salt thereof. The salt of phosphoric acid is not particularly limited as long as it is pharmaceutically acceptable. For example, a dialkali metal phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium dihydrogen phosphate And alkali metal dihydrogen phosphates such as potassium dihydrogen phosphate; trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. The salt of phosphoric acid may be in the form of a solvate such as a hydrate. For example, in the case of disodium hydrogen phosphate, the form of dodecahydrate, sodium dihydrogen phosphate, In some cases, it may be in the form of a dihydrate.
　リン酸緩衝剤として、リン酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。リン酸及びその塩の中でも、より優れた保存効力を備えさせるという観点から、好ましくはリン酸塩、更に好ましくはリン酸水素二アルカリ金属塩及びリン酸二水素アルカリ金属塩の少なくとも１種、特に好ましくはリン酸水素二ナトリウム及びリン酸二水素ナトリウムの少なくとも１種が挙げられる。 As the phosphate buffer, one kind selected from phosphoric acid and its salt may be used alone, or two or more kinds may be used in combination. Among phosphoric acid and its salts, from the viewpoint of providing more excellent storage efficacy, it is preferably a phosphate, more preferably at least one of hydrogen alkali metal dihydrogen phosphate and alkali metal dihydrogen phosphate, particularly Preferably, at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate is used.
　また、リン酸緩衝剤の好適な一態様として、リン酸水素二アルカリ金属塩とリン酸二水素アルカリ金属塩を組み合わせが挙げられる。このようにリン酸水素二アルカリ金属塩とリン酸二水素アルカリ金属塩を組み合わせて使用することによって、より一層優れた保存効力を備えさせることが可能になる。リン酸水素二アルカリ金属塩とリン酸二水素アルカリ金属塩を組み合わせて使用する場合、これらの比率については、特に制限されないが、例えば、リン酸水素二アルカリ金属塩１００質量部当たり、リン酸二水素アルカリ金属塩が１～１２０質量部、好ましく５～８０質量部、更に好ましくは１０～４０質量部が挙げられる。 In addition, as a preferable embodiment of the phosphate buffer, a combination of a dibasic metal phosphate and an alkali metal dihydrogen phosphate can be given. As described above, by using a combination of a dihydrogen alkali metal phosphate and an alkali metal dihydrogen phosphate in combination, it becomes possible to provide a more excellent storage effect. When a dihydrogen alkali metal phosphate and an alkali metal dihydrogen phosphate are used in combination, these ratios are not particularly limited. For example, per 100 parts by mass of the hydrogen dihydrogen alkali metal salt, diphosphoric acid phosphate is used. An alkali metal hydrogen salt is 1 to 120 parts by mass, preferably 5 to 80 parts by mass, and more preferably 10 to 40 parts by mass.
　リン酸緩衝剤の使用量については、緩衝作用の観点から、リン酸又はその塩の濃度が、通常０．１～５ｗ/ｖ％、好ましくは１～３ｗ/ｖ％、更に好ましくは１．５～２．０ｗ/ｖ％が挙げられる。本明細書において、リン酸緩衝剤の濃度は、リン酸に換算された濃度である。 Regarding the amount of the phosphate buffer used, from the viewpoint of buffer action, the concentration of phosphoric acid or a salt thereof is usually 0.1 to 5 w / v%, preferably 1 to 3 w / v%, more preferably 1.5. Up to 2.0 w / v%. In this specification, the concentration of the phosphate buffer is a concentration converted to phosphoric acid.
　トリス緩衝剤としては、具体的には、トロメタモール及び／又はその塩が挙げられる。トロメタモールの塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、酢酸塩等の有機酸塩；塩酸塩、スルホン酸塩等の有機酸塩が挙げられる。 Specific examples of the Tris buffer include trometamol and / or a salt thereof. The salt of trometamol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as acetate; organic acid salts such as hydrochloride and sulfonate.
　トリス酸緩衝剤として、トロメタモール及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。トロメタモール及びその塩の中でも、より優れた保存効力を備えさせるという観点から、好ましくはトロメタモールが挙げられる。 As the tris acid buffer, one kind selected from trometamol and salts thereof may be used alone, or two or more kinds may be used in combination. Of the trometamol and salts thereof, trometamol is preferably used from the viewpoint of providing more excellent storage efficacy.
　トリス緩衝剤の使用量については、緩衝作用の観点から、通常０．１～２ｗ/ｖ％、好ましくは０．３～１．７５ｗ/ｖ％、更に好ましくは０．５～１．５ｗ/ｖ％が挙げられる。本明細書において、トリス緩衝剤の濃度は、トロメタモールに換算された濃度である。 The amount of Tris buffer used is usually 0.1 to 2 w / v%, preferably 0.3 to 1.75 w / v%, more preferably 0.5 to 1.5 w / v from the viewpoint of buffer action. %. In this specification, the concentration of the Tris buffer is a concentration converted to trometamol.
　クエン酸緩衝剤としては、具体的には、クエン酸及び／又はその塩が挙げられる。クエン酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられる。また、クエン酸の塩は、水和物等の溶媒和物の形態であってもよい。クエン酸緩衝剤として、クエン酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of the citrate buffer include citric acid and / or a salt thereof. The salt of citric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt, and the like. It is done. The salt of citric acid may be in the form of a solvate such as a hydrate. As the citrate buffer, one kind selected from citric acid and its salt may be used alone, or two or more kinds may be used in combination.
　酒石酸緩衝剤としては、具体的には、酒石酸及び／又はその塩が挙げられる。酒石酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられる。また、酒石酸の塩は、水和物等の溶媒和物の形態であってもよい。酒石酸緩衝剤として、酒石酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of the tartaric acid buffer include tartaric acid and / or a salt thereof. The tartaric acid salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. . The salt of tartaric acid may be in the form of a solvate such as a hydrate. As the tartaric acid buffer, one kind selected from tartaric acid and salts thereof may be used alone, or two or more kinds may be used in combination.
　酢酸緩衝剤としては、具体的には、酢酸及び／又はその塩が挙げられる。酢酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アンモニウム塩等が挙げられる。また、酢酸の塩は、水和物等の溶媒和物の形態であってもよい。酢酸緩衝剤として、酢酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of the acetate buffer include acetic acid and / or a salt thereof. The salt of acetic acid is not particularly limited as long as it is pharmaceutically acceptable. For example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt and the like Is mentioned. The salt of acetic acid may be in the form of a solvate such as a hydrate. As the acetate buffer, one kind selected from acetic acid and its salt may be used alone, or two or more kinds may be used in combination.
　アミノ酸緩衝剤としては、具体的には、酸性アミノ酸及び／又はそれらの塩が挙げられる。酸性アミノ酸としては、具体的には、アスパラギン酸、グルタミン酸が挙げられる。酸性アミノ酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩等が挙げられる。アミノ酸緩衝剤として、酸性アミノ酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of the amino acid buffer include acidic amino acids and / or salts thereof. Specific examples of the acidic amino acid include aspartic acid and glutamic acid. The salt of the acidic amino acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt. As the amino acid buffer, one kind selected from acidic amino acids and salts thereof may be used alone, or two or more kinds may be used in combination.
　これらの緩衝剤は、１種単独で使用してもよく、２種以上を組み合わせて使用してもよい。 These buffering agents may be used alone or in combination of two or more.
　これらの緩衝剤の中でも、より一層優れた保存効力を備えさせるという観点から、好ましくはホウ酸緩衝剤、リン酸緩衝剤、トリス緩衝剤が挙げられる。 Among these buffering agents, boric acid buffering agents, phosphate buffering agents, and tris buffering agents are preferably used from the viewpoint of providing further excellent storage efficacy.
　本発明の水性液剤では、保存剤を実質的に含まないが、保存剤のみを含む水溶液にした場合に、当該水溶液が第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」となる保存剤の最小濃度よりも少ない程度の量の保存剤を含んでいてもよい。 The aqueous liquid preparation of the present invention does not substantially contain a preservative, but when it is made into an aqueous solution containing only the preservative, the aqueous solution is classified in the category “IC” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Method”. An amount of preservative may be included that is less than the minimum concentration of preservative that is “fit” based on the criteria defined in
　保存剤としては、具体的には、亜塩素酸ナトリウム等の亜塩素酸塩；塩化ベンザルコニウム、塩化ベンゼトニウム等の第四級アンモニウム塩；ソルビン酸、ソルビン酸カリウム等のソルビン酸及びその塩；メチルパラベン、パラオキシ安息香酸プロピル等のパラオキシ安息香酸エステル；安息香酸及びその塩；クロルクレゾール、フェネチルアルコール、塩化ポリドロニウム、チメロサール、クロロブタノール、クロルヘキシジン、ポリヘキサニド等が該当する。 Specific examples of preservatives include chlorite such as sodium chlorite; quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; sorbic acid such as sorbic acid and potassium sorbate and salts thereof; Paraoxybenzoic acid esters such as methyl paraben and propyl paraoxybenzoate; benzoic acid and its salts; chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, chlorobutanol, chlorhexidine, polyhexanide and the like.
　本発明の水性液剤において許容される保存剤の濃度については、保存の種類等に応じて異なるが、具体的には、０．００１ｗ/ｖ％未満、好ましくは０．０００５ｗ/ｖ％以下、更に好ましくは０．０００１ｗ/ｖ％以下、特に好ましくは０ｗ/ｖ％が挙げられる。 The concentration of the preservative allowed in the aqueous liquid preparation of the present invention varies depending on the type of storage, etc., but specifically, less than 0.001 w / v%, preferably 0.0005 w / v% or less, Preferably it is 0.0001 w / v% or less, Most preferably, it is 0 w / v%.
　本発明の水性液剤では、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含むことによって、少なくとも静菌作用が認められる水準以上の保存効力を備えることが可能になっている。そのため、本発明の水性液剤では、前記成分以外に、ブリモニジン及び／又はその塩との共存下で保存効力を向上させる成分については、実質的に含んでなくてもよい。 In the aqueous liquid preparation of the present invention, by containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffering agent, it is possible to have at least a preservative effect that is at least a level at which bacteriostatic action is recognized. It has become. Therefore, in the aqueous liquid preparation of the present invention, in addition to the above-described components, components that improve the storage efficacy in the presence of brimonidine and / or a salt thereof may not be substantially contained.
　例えば、ドルゾラミド及び／又はその塩は、ｐＨが６．０以上の水性液剤においてブリモニジン及び／又はその塩と共存すると、保存効力を向上させ得ることが知られているので、本発明の水性液剤の一態様として、ドルゾラミド及び／又はその塩を実質的に含まないことが挙げられる。ドルゾラミドの塩としては、具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等の無機酸との塩；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、酒石酸等の有機酸との塩；アルカリ金属との塩、アルカリ土類金属との塩、有機アミンとの塩、ハロゲン化物等が該当する。また、「ドルゾラミド及び／又はその塩を実質的に含まない」とは、具体的には、ドルゾラミド及び／又はその塩の濃度が、０．１ｗ/ｖ％未満、好ましくは０．０５ｗ/ｖ％以下、更に好ましくは０．０１ｗ/ｖ％以下、特に好ましくは０ｗ/ｖ％が挙げられる。 For example, it is known that dorzolamide and / or a salt thereof can improve storage efficacy when coexisting with brimonidine and / or a salt thereof in an aqueous solution having a pH of 6.0 or more. As one aspect, dorzolamide and / or a salt thereof is substantially free. Specific examples of the salt of dorzolamide include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid And salts with organic acids such as malic acid, citric acid and tartaric acid; salts with alkali metals, salts with alkaline earth metals, salts with organic amines, halides and the like. Further, “substantially free of dorzolamide and / or a salt thereof” specifically means that the concentration of dorzolamide and / or a salt thereof is less than 0.1 w / v%, preferably 0.05 w / v%. Hereinafter, it is more preferably 0.01 w / v% or less, particularly preferably 0 w / v%.
　本発明の水性液剤には、前記成分の他に、必要に応じて、等張化剤、多価アルコール、界面活性剤、粘稠剤、キレート剤（エデト酸及びその塩以外）、清涼化剤、安定化剤、ｐＨ調整剤等の添加剤を含有してもよい。 In the aqueous liquid preparation of the present invention, in addition to the above components, an isotonic agent, a polyhydric alcohol, a surfactant, a thickening agent, a chelating agent (other than edetic acid and its salts), and a cooling agent as necessary. Further, additives such as stabilizers and pH adjusters may be contained.
　等張化剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、グリセリン、プロピレングリコール、ブチレングリコール、ポリエチレングリコール等の多価アルコール；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、酢酸ナトリウム、酢酸カリウム、亜硫酸水素ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、リン酸水素二ナトリウム、リン酸二水素ナトリウム等の金属塩等が挙げられる。これらの等張化剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The isotonic agent is not particularly limited as long as it is pharmaceutically acceptable. For example, polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; sodium chloride, potassium chloride, calcium chloride, chloride Examples thereof include metal salts such as magnesium, sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. These isotonic agents may be used alone or in combination of two or more.
　多価アルコールとしては、薬学的に許容されることを限度として特に制限されないが、例えば、プロピレングリコール、ブチレングリコール、ポリエチレングリコール、グリセリン等が挙げられる。これらの多価アルコールは、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, and glycerin. These polyhydric alcohols may be used individually by 1 type, and may be used in combination of 2 or more type.
　界面活性剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、チロキサポール、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンポリオキシプロピレンブロックコポリマー、ポリオキシエチレンソルビタン脂肪酸エステル、オクトキシノール等の非イオン性界面活性剤；アルキルジアミノエチルグリシン、ラウリルジメチルアミノ酢酸ベタイン等の両性界面活性剤；アルキル硫酸塩、Ｎ－アシルタウリン塩、ポリオキシエチレンアルキルエーテルリン酸塩、ポリオキシエチレンアルキルエーテル硫酸塩等の陰イオン界面活性剤；アルキルピリジニウム塩、アルキルアミン塩等の陽イオン界面活性剤等が挙げられる。これらの界面活性剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The surfactant is not particularly limited as long as it is pharmaceutically acceptable. For example, tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy Nonionic surfactants such as diols; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurates, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyls Anionic surfactants such as ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.
　粘稠剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、カルボキシビニルポリマー、ポリビニルピロリドン、ポリエチレングリコール、ポリビニルアルコール、キサンタンガム、コンドロイチン硫酸ナトリウム、ヒアルロン酸ナトリウム等の水溶性高分子；ヒドロキシエチルセルロース、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム等のセルロース類等が挙げられる。これらの粘稠剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The thickening agent is not particularly limited as long as it is pharmaceutically acceptable, but for example, it has a high water solubility such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, etc. Molecule: Celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and the like. These thickeners may be used alone or in combination of two or more.
　キレート剤（エデト酸及びその塩以外）としては、薬学的に許容されることを限度として特に制限されないが、例えば、クエン酸、コハク酸、アスコルビン酸、トリヒドロキシメチルアミノメタン、ニトリロトリ酢酸、１－ヒドロキシエタン－１，１－ジホスホン酸、ポリリン酸、メタリン酸、ヘキサメタリン酸、これら塩等が挙げられる。塩の形態としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩等が挙げられる。これらのキレート剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The chelating agent (other than edetic acid and its salt) is not particularly limited as long as it is pharmaceutically acceptable. For example, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1- Examples include hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, and salts thereof. The form of the salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt. These chelating agents may be used individually by 1 type, and may be used in combination of 2 or more type.
　清涼化剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、l－メントール、ボルネオール、カンフル、ユーカリ油等が挙げられる。これらの清涼化剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The refreshing agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include l-menthol, borneol, camphor, and eucalyptus oil. These refreshing agents may be used alone or in combination of two or more.
　安定化剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、ポリビニルピロリドン、亜硫酸塩、モノエタノールアミン、シクロデキストリン、デキストラン、アスコルビン酸、タウリン、トコフェロール、ジブチルヒドロキシトルエン等が挙げられる。これらの安定化剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, dibutylhydroxytoluene and the like. Can be mentioned. These stabilizers may be used individually by 1 type, and may be used in combination of 2 or more type.
　ｐＨ調整剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、塩酸、酢酸、ホウ酸、アミノエチルスルホン酸、イプシロン－アミノカプロン酸等の酸；水酸化ナトリウム、水酸化カリウム、ホウ砂、トリエタノールアミン、モノエタノールアミン、炭酸水素ナトリウム、炭酸ナトリウム等のアルカリが挙げられる。これらのｐＨ調整剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable. For example, acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide , Alkali such as borax, triethanolamine, monoethanolamine, sodium hydrogencarbonate, sodium carbonate. These pH adjusters may be used alone or in combination of two or more.
　これらの添加剤の濃度は、使用する添加剤の種類や水性液剤に付与すべき特性等に応じて適宜設定すればよい。 The concentration of these additives may be set as appropriate according to the type of additive to be used and the characteristics to be imparted to the aqueous liquid.
　更に、本発明の水性液剤には、ブリモニジン及び／又はその塩以外に、本発明の効果を妨げない範囲で、必要に応じて、緑内障や高眼圧症に対して治療効果を示す薬理成分が含まれていてもよい。 Furthermore, the aqueous liquid preparation of the present invention contains, in addition to brimonidine and / or a salt thereof, a pharmacological component exhibiting a therapeutic effect on glaucoma or ocular hypertension as necessary, as long as the effects of the present invention are not hindered. It may be.
　このような薬理成分としては、例えば、タフルプロスト、ラタノプロスト、イソプロピルウノプロストン等のプロスタグランジン類；ピロカルピン塩酸塩等の副交感神経刺激薬；ジスチグミン臭化物等の抗コリンエステラーゼ薬；ジピベフリン塩酸塩等の交感神経刺激薬；ベタキソロール塩酸塩等のβ1遮断薬；チモロールマレイン酸塩等のβ遮断薬；ニプラジロール、レボブノロール塩酸塩等のα1・β遮断薬；ブナゾシン塩酸塩等のα1遮断薬等が挙げられる。これらの薬理成分は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetic drugs such as pilocarpine hydrochloride; anticholinesterase drugs such as distigmine bromide; and sympathetic nerves such as dipivefrin hydrochloride. Stimulants; β 1 blockers such as betaxolol hydrochloride; β blockers such as timolol maleate; α 1 / β blockers such as nipradilol and levobanolol hydrochloride; α 1 blockers such as bunazosin hydrochloride . These pharmacological components may be used alone or in combination of two or more.
　これらの薬理成分の濃度は、使用する薬理成分の種類や付与すべき薬効等に応じて適宜設定すればよい。 The concentration of these pharmacological components may be appropriately set according to the type of pharmacological component to be used and the medicinal effect to be imparted.
　本発明の水性液剤のｐＨについては、特に制限されないが、例えば、ｐＨ６～８が挙げられる。本発明の水性液剤のｐＨとして、より一層優れた保存効力を備えさせるという観点から、好ましくはｐＨ７～８、更に好ましくはｐＨ７が挙げられる。 The pH of the aqueous liquid preparation of the present invention is not particularly limited, and examples thereof include pH 6 to 8. The pH of the aqueous liquid preparation of the present invention is preferably pH 7 to 8, more preferably pH 7, from the viewpoint of providing further excellent storage efficacy.
　本発明の水性液剤の浸透圧比については、特に制限されないが、例えば、０．５～４、好ましくは０．７～１．３、更に好ましくは０．９～１．１が挙げられる。当該浸透圧比は、０．９ｗ／ｖ％塩化ナトリウム水溶液の浸透圧に対する比率であり、浸透圧は第十七改正日本薬局方に規定されている「浸透圧法（オスモル濃度測定法）」に準じて測定される。 The osmotic pressure ratio of the aqueous liquid preparation of the present invention is not particularly limited, and examples thereof include 0.5 to 4, preferably 0.7 to 1.3, and more preferably 0.9 to 1.1. The osmotic pressure ratio is a ratio to the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution, and the osmotic pressure is in accordance with the “osmotic pressure method (osmolarity measurement method)” defined in the 17th revision Japanese Pharmacopoeia. Measured.
　本発明の水性液剤は、前述する成分を含むことにより、少なくとも静菌作用が認められる水準以上の保存効力を有することが可能になっている。本発明の水性製剤が有する保存効力として、具体的には、第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」と判断されるものである。日局ＩＣ適合保存効力は、第十七改正日本薬局方 参考情報「保存効力試験法」に準拠した試験方法で判定でき、具体的な試験方法は後述する試験例の欄に示す通りである。 The aqueous liquid preparation of the present invention can have a preservative effect at least higher than a level at which bacteriostatic action is observed by including the above-described components. Specifically, the preservative efficacy of the aqueous preparation of the present invention is determined to be “conforming” based on the criteria defined in the category “IC” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Law”. Is. JP-Compliant Preservative Efficacy can be determined by a test method based on the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Method”, and the specific test method is as shown in the column of Test Examples described later.
　本発明の水性液剤の製剤形態については、特に制限されず、水溶液状、懸濁液状、乳液状等のいずれであってもよいが、好ましくは水溶液状が挙げられる。 The preparation form of the aqueous liquid preparation of the present invention is not particularly limited and may be any of aqueous solution, suspension, emulsion, etc., preferably an aqueous solution.
　本発明の水性液剤は、点眼液、洗眼液等の眼科用製剤等として使用することができる。特に、本発明の水性液剤は、ブリモニジン及び／又はその塩の作用によって、眼房水の産生を抑制して、眼圧を低下させることができるので、点眼液として提供され、緑内障又は高眼圧症の治療するための水性液剤として好適に使用できる。 The aqueous liquid preparation of the present invention can be used as ophthalmic preparations such as eye drops and eyewashes. In particular, the aqueous liquid preparation of the present invention is provided as an ophthalmic solution because it can suppress the production of aqueous humor and reduce intraocular pressure by the action of brimonidine and / or a salt thereof. It can be suitably used as an aqueous liquid for treating the above.
　本発明の水性液剤は、その用途に応じて、公知の調製法に従って製造すればよく、例えば、第十七改正日本薬局方 製剤総則に記載された方法を用いて製造することができる。 The aqueous liquid preparation of the present invention may be produced according to a known preparation method according to its use, for example, using the method described in the 17th revised Japanese Pharmacopoeia General Rules for Preparations.
　本発明の水性液剤を収容する容器については、当該水性製剤の用途に応じて、点眼容器、洗眼容器等を使用すればよい。 For the container for storing the aqueous liquid preparation of the present invention, an eye drop container, an eye wash container, or the like may be used depending on the use of the aqueous preparation.
　本発明の水性液剤は、マルチドーズ型容器であってもよく、ユニットドーズ型容器であってもよい。 The aqueous liquid preparation of the present invention may be a multi-dose type container or a unit dose type container.
　また、マルチドーズ型容器の場合、保存中に収容されている水性液剤の無菌状態を維持するために、マルチドーズ型保存剤フリー容器を使用することが特に好ましい。保存剤を含まない従来の水性液剤では、マルチドーズ型保存剤フリー容器を使用しても、ノズルの外側表面に残存した水性液剤の微生物汚染が懸念されるが、本発明の水性液剤では、少なくとも静菌作用が認められる水準以上の保存効力を備えているので、マルチドーズ型保存剤フリー容器のノズルの外側表面に残存しても、前記微生物汚染を抑制することができる。 In the case of a multi-dose type container, it is particularly preferable to use a multi-dose type preservative-free container in order to maintain the aseptic state of the aqueous liquid agent stored during storage. In a conventional aqueous solution containing no preservative, even if a multi-dose type preservative-free container is used, there is a concern about microbial contamination of the aqueous solution remaining on the outer surface of the nozzle, but in the aqueous solution of the present invention, at least Since it has a preservative effect higher than the level at which bacteriostatic action is recognized, the microbial contamination can be suppressed even if it remains on the outer surface of the nozzle of the multi-dose type preservative-free container.
３．保存効力の付与方法
　本発明は、ブリモニジン及び／又はその塩を含む水性液剤に保存効力を付与する方法であって、水性液剤において、保存剤を実質的に含まず、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含む水性液剤を調製する工程を含むことを特徴とする、保存効力の付与方法を提供する。 3. The present invention relates to a method for imparting storage efficacy to an aqueous liquid preparation containing brimonidine and / or a salt thereof, wherein the aqueous liquid preparation is substantially free of a preservative and contains brimonidine and / or a salt thereof. A method for imparting storage efficacy is provided, comprising the step of preparing an aqueous solution containing edetic acid and / or a salt thereof and a buffer.
　本発明の保存効力の付与方法によれば、ブリモニジン及び／又はその塩を含む水性液剤に日局ＩＣ適合保存効力を付与することが可能になる。 According to the method for imparting storage efficacy of the present invention, it becomes possible to impart JP-Japan IC compatible storage efficacy to an aqueous liquid preparation containing brimonidine and / or a salt thereof.
　本発明の保存効力の付与方法において、使用するブリモニジン及び／又はその塩の種類や濃度、エデト酸及び／又はその塩の種類や濃度、緩衝剤の種類や濃度、水性液剤に配合される他の添加剤や薬理成分の種類、水性液剤のｐＨ、製剤形態、用途等については、前記「１．水性液剤」の欄に記載の通りである。 In the method for imparting the preservative effect of the present invention, the type and concentration of brimonidine and / or its salt to be used, the type and concentration of edetic acid and / or its salt, the type and concentration of a buffering agent, and other components incorporated in an aqueous liquid preparation The types of additives and pharmacological components, the pH of the aqueous liquid preparation, the preparation form, the use, and the like are as described in the column “1.
　以下に、実施例を挙げて、本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。なお、以下の試験例において、ホウ酸は、全てオルトホウ酸を使用した。 Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. In the following test examples, all boric acid was orthoboric acid.
試験例１：保存効力の評価
　第十七改正日本薬局方 参考情報「保存効力試験法」に準拠して、表１に示す組成の点眼液の保存効力の評価を行った。具体的な試験方法等は以下に示す通りである。 Test Example 1: Evaluation of Preservative Efficacy According to the 17th revision Japanese Pharmacopoeia Reference Information "Preservation Efficacy Test Method", the preservative efficacy of eye drops having the composition shown in Table 1 was evaluated. Specific test methods and the like are as shown below.
１．試験材料及び試験方法
１－１．検体の調製
　表１～３に示す組成の水性液剤（点眼液）を調製し、０．２２μｍフィルターでろ過したものを検体とした。なお、実施例１のホウ酸及びホウ砂の総量は、ホウ酸に換算した量として０．７２ｇ（濃度として０．７２ｗ／ｖ％）であり、実施例２のリン酸水素二ナトリウム水和物及びリン酸二水素ナトリウムの総量は、リン酸に換算した量として１．８ｇ（濃度として１．８ｗ／ｖ％）である。 1. Test material and test method
1-1. Sample Preparation An aqueous solution (eye drops) having the composition shown in Tables 1 to 3 was prepared and filtered through a 0.22 μm filter. The total amount of boric acid and borax in Example 1 was 0.72 g (concentration: 0.72 w / v%) in terms of boric acid, and disodium hydrogen phosphate hydrate in Example 2. The total amount of sodium dihydrogen phosphate is 1.8 g (concentration: 1.8 w / v%) in terms of phosphoric acid.
１－２．試験菌
　以下に示す３種の細菌及び２種の真菌を使用した。
（細菌）
　・黄色ブドウ球菌（Staphylococcus aureus、S.aureus / ATCC 6538）
　・大腸菌（Escherichia coli、E.coli / ATCC 8739）
　・緑膿菌（Pseudomonas aeruginosa、P.aeruginosa / ATCC 9027）
（真菌）
　・カンジタ菌（Candida albicans、C.albicans / ATCC 10231）
　・黒麹かび（Aspergillus brasiliensis、A.brasiliensis / ATCC 16404） 1-2. The following three types of bacteria and two types of fungi were used.
(Bacteria)
・ Staphylococcus aureus, S.aureus / ATCC 6538
・ Escherichia coli (E.coli / ATCC 8739)
・ Pseudomonas aeruginosa (Pseudomonas aeruginosa, P.aeruginosa / ATCC 9027)
(fungus)
・ Candida (Candida albicans, C. albicans / ATCC 10231)
Black mold (Aspergillus brasiliensis, A. brasiliensis / ATCC 16404)
１－３．前培養
　前記試験菌をそれぞれカンテン斜面培地の表面に接種して前培養した。前培養用のカンテン培地としては、細菌の場合はソイビーン・カゼイン・ダイジェストカンテン培地を、真菌の場合はサブロー・ブドウ糖カンテン培地を用いた。前培養は、細菌の場合は３０～３５℃で１８～２４時間、カンジタ菌は２０～２５℃で４４～５２時間、黒麹かびは２０～２５℃で６～１０日間培養した。 1-3. Pre-culture Each of the test bacteria was inoculated on the surface of an agar slant medium and pre-cultured. As the agar medium for preculture, a soy bean / casein / digest agar medium was used in the case of bacteria, and a Sabouraud dextrose agar medium was used in the case of fungi. In the case of bacteria, the culture was performed at 30 to 35 ° C. for 18 to 24 hours, Candida was cultured at 20 to 25 ° C. for 44 to 52 hours, and black mold was cultured at 20 to 25 ° C. for 6 to 10 days.
１－４．混合試料の調製及び菌数測定
　前記検体を１０ｍＬずつ５本の滅菌済みの共栓付試験管に分注し、前培養した各試験菌を１×１０5～１×１０6ＣＦＵ／ｍＬとなるよう接種し、これらを混合試料とした。混合試料を２０～２５℃、遮光保存した。なお、各試験菌は混合せず、菌種毎にそれぞれ単独に検体に接種して混合試料を調製した。 1-4. Preparation of mixed sample and measurement of bacterial count Each 10 mL of the sample is dispensed into 5 sterilized test tubes with a stopper, and each pre-cultured test bacteria is 1 × 10 5 to 1 × 10 6 CFU / mL. These were used as mixed samples. The mixed sample was stored at 20-25 ° C. protected from light. In addition, each test microbe was not mixed, but each specimen was inoculated into each specimen individually to prepare a mixed sample.
　試験開始時、並びに試験開始から７、１４、及び２８日目に、各混合試料から１ｍＬをサンプリングし、その液を生理食塩水９ｍＬで希釈した。必要に応じ、さらに同様の希釈を２～３回行い、各希釈液１ｍＬを滅菌シャーレに分注した。次に、細菌の場合は０．１％レシチン及び０．７％ポリソルベート８０を添加したソイビーン・カゼイン・ダイジェストカンテン培地を、真菌の場合は０．１％レシチン及び０．７％ポリソルベート８０を添加したサブロー・ブドウ糖カンテン培地を加えて混釈した。そして、細菌の場合は３０～３５℃で３～５日間、真菌の場合は２０～２５℃で５～７日間培養した後に、生成コロニー数を測定し、混合試料１ｍＬ当たりの生菌数（cfu/mL）及び生菌数の対数減少値（log）を算出した。
Figure JPOXMLDOC01-appb-M000001
 At the start of the test and on days 7, 14, and 28 after the start of the test, 1 mL was sampled from each mixed sample, and the solution was diluted with 9 mL of physiological saline. If necessary, the same dilution was further performed 2-3 times, and 1 mL of each diluted solution was dispensed into a sterile petri dish. Next, a soy bean casein digest agar medium supplemented with 0.1% lecithin and 0.7% polysorbate 80 in the case of bacteria, and 0.1% lecithin and 0.7% polysorbate 80 added in the case of fungi. Sabouraud dextrose medium was added and mixed. Then, after culturing at 30 to 35 ° C. for 3 to 5 days in the case of bacteria and 5 to 7 days at 20 to 25 ° C. in the case of fungi, the number of generated colonies was measured, and the number of viable bacteria per 1 mL of the mixed sample (cfu / mL) and the logarithmic decrease value (log) of the viable cell count.
Figure JPOXMLDOC01-appb-M000001
１－５．保存効力の判定
　各試験液の保存効力を、第十七改正日本薬局方 参考情報「保存効力試験法」の「４．判定」の「表３　製剤区分別判定基準」に記載されたカテゴリー１Ｃの基準に従って評価した。具体的には、（１）３種全ての細菌において、対数減少値（log）が１４日後に接種菌数に比べ１．０log以上、且つ２８日後の生菌数が１４日後から増加せず、且つ（２）２種全ての真菌において、１４日後及び２８日後の生菌数が接種菌数から増加しない、を全て満たした場合を「適合」と判定し、それ以外を「不適合」と判定した。 1-5. Judgment of preservation efficacy The preservation efficacy of each test solution is determined according to Category 1C described in "Table 3. Judgment Criteria by Formulation" in "4. Evaluation was made according to criteria. Specifically, (1) In all three types of bacteria, the log reduction value (log) is 1.0 log or more compared to the number of inoculated bacteria after 14 days, and the number of viable bacteria after 28 days does not increase after 14 days, And (2) In all two types of fungi, the case where the number of viable bacteria after 14 days and 28 days did not increase from the number of inoculated bacteria was judged as “conforming”, and other cases were judged as “nonconforming” .
２．試験結果
　得られた結果を表１～３に示す。ブリモニジン酒石酸塩及びエデト酸ナトリウム二水和物を含まず、且つホウ酸緩衝剤（ホウ酸及びホウ砂）を含む水性液剤（参考例１）では、日局ＩＣ適合保存効力を有していたが、ホウ酸緩衝剤と共にブリモニジン酒石酸塩又はエデト酸ナトリウム二水和物を配合した水性液剤では（比較例１及び２）では、保存効力が低下し、日局ＩＣ適合保存効力を具備できていなかった。これに対して、ホウ酸緩衝剤と共に、ブリモニジン酒石酸塩及びエデト酸ナトリウム二水和物を配合した水性液剤（実施例１）では、保存効力が向上し、日局ＩＣ適合保存効力を有していた。また、リン酸緩衝剤及びトリス緩衝剤を使用した場合であっても、ブリモニジン酒石酸塩及びエデト酸ナトリウム二水和物を配合した水性液剤では、保存効力が向上し、日局ＩＣ適合保存効力を具備できていた。 2. Test results The results obtained are shown in Tables 1 to 3. The aqueous solution (Reference Example 1) that does not contain brimonidine tartrate and sodium edetate dihydrate and contains a boric acid buffer (boric acid and borax) had preservative efficacy conforming to JP IC. In the case of an aqueous liquid preparation containing brimonidine tartrate or sodium edetate dihydrate together with a borate buffer (Comparative Examples 1 and 2), the preservative efficacy was lowered, and the JP IC compatible preservative efficacy was not achieved. . On the other hand, the aqueous solution (Example 1) containing brimonidine tartrate and sodium edetate dihydrate together with the boric acid buffer has improved storage efficacy and has JP-Japan IC compatible storage efficacy. It was. In addition, even when phosphate buffer and Tris buffer are used, an aqueous solution containing brimonidine tartrate and sodium edetate dihydrate improves the storage efficacy, and the JP IC compatible storage efficacy is achieved. It was equipped.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002

Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003

Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
試験例２：熱安定性の評価
　表５に示す組成の水性液剤（点眼液）を調製した。０．２２μｍフィルターでろ過した後に、各水性液剤５ｍＬを５ｍＬ容の無色ガラスアンプルに充填した。これらを卓上恒温恒湿器（NST-80、ナガノサイエンス株式会社）に入れ、遮光条件下、６０℃で４週間保管した。保管前後のブリモニジン酒石酸塩含量を、高速液体クロマトグラフシステム（株式会社島津製作所）を用いて下記の条件に従い測定した。 Test Example 2: Evaluation of thermal stability An aqueous liquid (ophthalmic solution) having the composition shown in Table 5 was prepared. After filtration with a 0.22 μm filter, 5 mL of each aqueous solution was filled into a 5 mL colorless glass ampoule. These were placed in a desktop thermostat (NST-80, Nagano Science Co., Ltd.) and stored at 60 ° C. for 4 weeks under light shielding conditions. The brimonidine tartrate content before and after storage was measured according to the following conditions using a high performance liquid chromatograph system (Shimadzu Corporation).
＜測定条件＞
　検出器：紫外吸光光度計（測定波長：230 nm）
　カラム： Symmetry C18, 4.6mm I.D.×150mm, 3.5μm, Waters
　カラム温度：40℃温付近の一定温度
　移動相A：4.3 mMリン酸水溶液/メタノール/アセトニトリル（容量比：84/8/8）混液
　移動相B：4.3 mMリン酸水溶液/メタノール/アセトニトリル（容量比：40/30/30）混液
　流量：1.0 mL/min
　オートサンプラ内温度：5℃
　移動相の送液：移動相A及び移動相Bの混合比率を表４に示すように変えて直線濃度勾配制御した。 <Measurement conditions>
Detector: UV absorptiometer (measurement wavelength: 230 nm)
Column: Symmetry C18, 4.6mm ID × 150mm, 3.5μm, Waters
Column temperature: Constant temperature around 40 ° C Mobile phase A: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 84/8/8) Mixed mobile phase B: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio) : 40/30/30) Mixed liquid Flow rate: 1.0 mL / min
Autosampler internal temperature: 5 ℃
Mobile phase liquid feed: The linear concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 4.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　次の算出式に従い、水性液剤中のブリモニジンの残存率を算出した。
Figure JPOXMLDOC01-appb-M000006
 According to the following calculation formula, the residual rate of brimonidine in the aqueous liquid was calculated.
Figure JPOXMLDOC01-appb-M000006
　得られた結果を表５に示す。エデト酸ナトリウム二水和物を配合していない場合では、保存剤を含まない水性液剤（比較例９）は、点眼液に一般的に配合される保存剤を含む水性液剤（比較例７及び８）に比べてブリモニジンの残存率が低下していた。亜硫酸水素ナトリウム及びベンザルコニウム塩化物といった保存剤を配合することでブリモニジンの安定性を向上することができる。しかしながら、保存剤を配合しなくとも、エデト酸ナトリウム二水和物を配合した水性液剤では、ブリモニジン酒石酸塩の安定性が更に向上していた。即ち、本結果から、保存剤を実質的に含まず、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩とを含む水性液剤は、ブリモニジン及び／又はその塩の安定性の点でも優れていることが明らかとなった。 Table 5 shows the obtained results. In the case where sodium edetate dihydrate was not blended, an aqueous solution containing no preservative (Comparative Example 9) was an aqueous solution (Comparative Examples 7 and 8) containing a preservative generally blended into eye drops. ), The residual rate of brimonidine was reduced. The stability of brimonidine can be improved by blending preservatives such as sodium bisulfite and benzalkonium chloride. However, the stability of brimonidine tartrate was further improved in the aqueous liquid preparation containing sodium edetate dihydrate without adding a preservative. That is, from this result, the aqueous solution containing substantially no preservative and containing brimonidine and / or a salt thereof and edetic acid and / or a salt thereof is excellent in terms of stability of brimonidine and / or a salt thereof. It became clear that.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007

Claims (8)

  1. 　ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含み、保存剤を実質的に含まない、水性液剤。 An aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and substantially free of a preservative.
  2. 　緩衝剤が、ホウ酸緩衝剤、リン酸緩衝剤、及びトリス緩衝剤よりなる群から選択される少なくとも１種である、請求項１に記載の水性液剤。 The aqueous liquid according to claim 1, wherein the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer.
  3. 　エデト酸及び／又はその塩の濃度が０．００１～０．５ｗ／ｖ％である、請求項１又は２に記載の水性液剤。 The aqueous liquid preparation according to claim 1 or 2, wherein the concentration of edetic acid and / or a salt thereof is 0.001 to 0.5 w / v%.
  4. 　ブリモニジン及び／又はその塩の濃度が０．０５～０．２ｗ／ｖ％である、請求項１又は２に記載の水性液剤。 The aqueous liquid preparation according to claim 1 or 2, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%.
  5. 　ｐＨが６～８である、請求項１又は２に記載の水性液剤。 The aqueous liquid preparation according to claim 1 or 2, wherein the pH is 6-8.
  6. 　点眼液である、請求項１又は２に記載の水性液剤。 The aqueous liquid preparation according to claim 1 or 2, which is an ophthalmic solution.
  7. 　一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、請求項１又は２に記載の水性液剤。 It is accommodated in the multi-dose type container which has the mechanism which prevents the back flow into the container of the aqueous liquid agent which leached outside once, and / or the mechanism which prevents mixing of the foreign material in the container. The aqueous liquid preparation described.
  8. 　ブリモニジン及び／又はその塩を含む水性液剤に保存効力を付与する方法であって、
    　水性液剤は保存剤を実質的に含まず、
    　ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含む水性液剤を調製する工程を含む、
    保存効力の付与方法。     A method for imparting storage efficacy to an aqueous solution containing brimonidine and / or a salt thereof,
    Aqueous solutions are substantially free of preservatives,
    Preparing an aqueous solution containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer;
    How to give preservation efficacy.
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