WO2019189720A1 - Solution aqueuse - Google Patents

Solution aqueuse 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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Prior art keywords
salt
aqueous liquid
acid
buffer
brimonidine
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PCT/JP2019/013921
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English (en)
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/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • 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

L'invention concerne une solution aqueuse qui contient une brimonidine et/ou un sel de celle-ci, et a pour objet de fournir une technique de préparation conférant une efficacité de conservation au moins égale ou supérieure à la norme permettant une action bactériostatique, sans mélange d'agent conservateur. La solution aqueuse de l'invention qui contient une brimonidine et/ou un sel de celle-ci, un acide éthylène-diamine-tétracétique et/ou un sel de celui-ci, et un agent tampon, peut comporter une efficacité de conservation de norme permettant une action bactériostatique, y compris dans le cas où elle ne contient substantiellement pas d'agent conservateur.
PCT/JP2019/013921 2018-03-30 2019-03-29 Solution aqueuse WO2019189720A1 (fr)

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JP2020033290A (ja) * 2018-08-29 2020-03-05 興和株式会社 水性組成物

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JP2002080055A (ja) * 2000-09-12 2002-03-19 Nippon Tenganyaku Kenkyusho:Kk フィルター付き吐出容器
JP2004051170A (ja) * 2002-07-22 2004-02-19 Nipro Corp 薬液容器
JP2005343549A (ja) * 2004-06-07 2005-12-15 Rohto Pharmaceut Co Ltd 容器の注出口構造、包装用容器および中栓構造体
JP2017525686A (ja) * 2014-07-28 2017-09-07 サン、ファーマ、アドバンスト、リサーチ、カンパニー、リミテッドＳｕｎ Ｐｈａｒｍａ Ａｄｖａｎｃｅｄ Ｒｅｓｅａｒｃｈ Ｃｏｍｐａｎｙ Ｌｉｍｉｔｅｄ 薬物のバイオアベイラビリティーの増加および／または眼作用の持続方法
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