WO2019235456A1 - Agent liquide aqueux - Google Patents

Agent liquide aqueux Download PDF

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Publication number
WO2019235456A1
WO2019235456A1 PCT/JP2019/022091 JP2019022091W WO2019235456A1 WO 2019235456 A1 WO2019235456 A1 WO 2019235456A1 JP 2019022091 W JP2019022091 W JP 2019022091W WO 2019235456 A1 WO2019235456 A1 WO 2019235456A1
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WO
WIPO (PCT)
Prior art keywords
salt
aqueous liquid
chlorobutanol
acid
brimonidine
Prior art date
Application number
PCT/JP2019/022091
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English (en)
Japanese (ja)
Inventor
涼香 家本
Original Assignee
千寿製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication of WO2019235456A1 publication Critical patent/WO2019235456A1/fr

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Classifications

    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an aqueous liquid agent that can suppress a decrease in pH over time while containing chlorobutanol.
  • preservatives such as benzalkonium chloride and methylparaben are blended in order to prevent the growth of microorganisms.
  • these preservatives are known to be capable of preventing bacterial growth, while exhibiting irritation and cytotoxicity (see Non-Patent Document 1).
  • chlorobutanol has little irritation and cytotoxicity, and is considered to be suitable from the viewpoint of safety for aqueous preparations applied to mucous membranes such as eye drops and eyewashes.
  • Various aqueous preparations containing chlorobutanol have been proposed (for example, see Patent Document 1).
  • An object of the present invention is to provide a preparation technique relating to an aqueous liquid preparation containing chlorobutanol.
  • the present inventor has found that an aqueous liquid preparation containing chlorobutanol and brimonidine and / or a salt thereof can suppress a decrease in pH over time and can have excellent formulation stability.
  • the present invention has been completed by further studies based on this finding.
  • aqueous liquid preparation As one aspect of the present invention, the following aqueous liquid preparation is provided.
  • the aqueous liquid preparation according to any one of Items 1-1 to 1-5 which is an eye drop.
  • An aqueous solution comprising chlorobutanol and brimonidine and / or a salt thereof, Substantially free of preservatives other than chlorobutanol,
  • the concentration of chlorobutanol is 0.01 to 0.5 w / v%
  • the concentration of brimonidine and / or its salt is 0.05 to 0.5 w / v%
  • An aqueous solution comprising chlorobutanol and brimonidine and / or a salt thereof, Substantially free of preservatives other than chlorobutanol,
  • the concentration of chlorobutanol is 0.01 to 0.5 w / v%, Brimonidine and / or its salt is brimonidine tartrate;
  • the concentration of brimonidine and / or its salt is 0.1-0.2 w / v%, Including a citrate buffer, pH is 5-8,
  • the aqueous liquid preparation has a pH maintenance ratio determined from the pH of the aqueous liquid before and after storage of 93% or more and is an eye drop .
  • Item 2-1 A method for suppressing a decrease in pH over time in an aqueous liquid preparation containing chlorobutanol, A method for inhibiting pH reduction, comprising a step of preparing an aqueous liquid preparation containing chlorobutanol and brimonidine and / or a salt thereof.
  • Item 2-2. Item 2. The method for inhibiting pH decrease according to Item 2-1, wherein the aqueous liquid substantially does not contain a preservative other than chlorobutanol.
  • Item 2-3 Item 3.
  • Item 2-11. A method for suppressing a decrease in pH over time in an aqueous liquid preparation containing chlorobutanol, Preparing an aqueous solution comprising chlorobutanol and brimonidine and / or a salt thereof,
  • the aqueous liquid agent Substantially free of preservatives other than chlorobutanol,
  • the concentration of chlorobutanol is 0.01 to 0.5 w / v%, Brimonidine and / or its salt is brimonidine tartrate;
  • the concentration of brimonidine and / or its salt is 0.1-0.2 w / v%,
  • 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.
  • the “preservative” is a component having a preservative effect, and when the aqueous solution containing only the corresponding single component at a concentration allowed by eye drops, the aqueous solution is the 17th revised Japanese pharmacy. This refers to information judged to be “conforming” based on the criteria set forth in category “IA” in the policy reference information “Preservation Efficacy Test”.
  • substantially free of preservatives other than chlorobutanol means that the concentration of the preservative (other than chlorobutanol) cannot exert the preservative effect only with the preservative (other than chlorobutanol).
  • concentration of the preservative other than chlorobutanol
  • the aqueous solution is classified as “IA” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test”.
  • concentration of preservative that is “fit” based on the criteria set forth in.
  • pH refers to a value measured at room temperature (20 to 30 ° C.).
  • the notations such as “decrease in pH over time” and “decrease in pH over time” indicate that the pH of an aqueous solution decreases due to storage for a certain period of time, for example, according to the following calculation formula: When the required pH maintenance rate is less than 90%, it can be said that “decrease in pH over time” is observed.
  • “suppressing the decrease in pH over time” means that the pH of the aqueous liquid is less or less decreased by storage for a certain period of time.
  • the aqueous liquid is stored at 60 ° C. for 1 week under light-shielding conditions, and the pH maintenance ratio obtained from the pH of the aqueous liquid before and after storage is 91% or more, preferably 93% or more, More preferably 94% or more, more preferably 95% or more, and particularly preferably 96% or more, it can be said that "the pH drop with time is suppressed”.
  • formulation stability refers to the degree to which the pH of an aqueous liquid preparation is stably maintained by storage for a certain period of time, and is excellent when it is possible to suppress a decrease in pH over time. It can be said that it has “formulation stability”.
  • the aqueous liquid agent chlorobutanol is unstable in the aqueous liquid agent, and is easily decomposed by heat, light exposure, etc. to generate hydrochloric acid. Therefore, although the aqueous liquid preparation containing chlorobutanol can have antiseptic effect, there is a problem that, when stored, the pH decreases with time due to decomposition of chlorobutanol. Therefore, development of the aqueous liquid agent which can suppress the fall of pH with time while containing chlorobutanol is desired.
  • an aqueous liquid preparation containing chlorobutanol and brimonidine and / or a salt thereof can suppress a decrease in pH over time and can have excellent formulation stability. That is, in one embodiment, the present invention provides an aqueous solution comprising chlorobutanol and brimonidine and / or a salt thereof.
  • the concentration of chlorobutanol may be appropriately set according to the degree of storage efficacy to be imparted, etc., for example, 0.005 to 1 w / v%, preferably 0.01 to 0 0.5 w / v%, more preferably 0.1 to 0.2 w / v%.
  • brimonidine and / or a salt thereof play a role of suppressing a decrease in pH over time in an aqueous liquid preparation containing chlorobutanol.
  • 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 tartrate is preferable.
  • brimonidine in the aqueous liquid preparation of the present invention, either brimonidine or a salt thereof may be used alone or in combination.
  • the concentration of brimonidine and / or a salt thereof is, for example, 0.05 to 0.5 w / v%.
  • the concentration of brimonidine and / or its salt is preferably 0.1 to 0.2 w / v%, more preferably 0.1 w / v%. Is mentioned.
  • the concentration of brimonidine and / or a salt thereof is a concentration converted to brimonidine tartrate unless otherwise specified.
  • aqueous liquid preparation of the present invention by containing chlorobutanol, it is possible to have a desired storage effect.
  • some preservatives other than chlorobutanol exhibit strong irritation and cytotoxicity, or attenuate the effect of suppressing the decrease in pH over time in the aqueous liquid preparation of the present invention. Therefore, one aspect of the aqueous liquid preparation of the present invention is that it contains substantially no preservative other than chlorobutanol.
  • preservatives other than chlorobutanol include chlorites such as sodium chlorite; quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; sorbic acid and potassium sorbate Examples include sorbic acid and salts thereof; paraoxybenzoic acid esters such as methyl paraben and propyl paraoxybenzoate; benzoic acid and salts thereof; chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, chlorhexidine, polyhexanide, and the like.
  • the concentration of the preservative (other than chlorobutanol) that is acceptable in the aqueous liquid preparation of the present invention varies depending on the type of preservative, but specifically, Is less than 0.001 w / v%, preferably 0.0005 w / v% or less, more preferably 0.0001 w / v% or less, and particularly preferably 0 w / v%.
  • the aqueous liquid preparation of the present invention may contain a buffering agent in order to provide a buffering action.
  • the buffer used in the present invention is not particularly limited as long as it is pharmaceutically acceptable.
  • citrate buffer, borate buffer, phosphate buffer, Tris buffer, tartrate buffer , Acetate buffer, amino acid buffer and the like are examples of the buffer used in the present invention.
  • 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.
  • citric acids and salts thereof from the viewpoint of more effectively suppressing a decrease in pH over time, preferably a salt of citric acid, more preferably an alkali metal salt of citric acid, particularly preferably sodium citrate. Can be mentioned.
  • the amount of citrate buffer used is usually 0.001 to 5 w / v%, preferably 0.01 to 1 w / v%, more preferably 0 as the concentration of citric acid or a salt thereof from the viewpoint of buffering action. 0.02 to 0.5 w / v%, particularly preferably 0.03 to 0.15 w / v%.
  • the concentration of citric acid or a salt thereof is a concentration converted to citric acid unless otherwise specified.
  • 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.
  • boric acids and salts thereof preferably at least one of boric acid and borax, more preferably at least one of orthoboric acid and borax.
  • the amount of boric acid buffer used is usually 0.1 to 2 w / v%, preferably 0.5 to 1.5 w / v%, more preferably as the concentration of boric acid or a salt thereof from the viewpoint of buffering action. 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 unless otherwise specified.
  • 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.
  • 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 preferably a phosphate, more preferably at least one of dibasic metal hydrogen phosphate and alkali metal dihydrogen phosphate, particularly preferably disodium hydrogen phosphate and dihydrogen phosphate.
  • the at least 1 sort (s) of sodium is mentioned.
  • 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 phosphate unless otherwise specified.
  • 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.
  • the tris acid buffer one kind selected from trometamol and a salt thereof may be used alone, or two or more kinds may be used in combination. Of the trometamol and salts thereof, trometamol is preferable.
  • 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 unless otherwise specified.
  • 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.
  • citrate buffering agent is preferable from the viewpoint of more effectively suppressing the decrease in pH over time.
  • aqueous liquid preparation of the present invention in addition to the above components, as required, isotonic agents, polyhydric alcohols, surfactants, thickeners, chelating agents, cooling agents, stabilizers, pH adjusters Etc. You may contain additives, such as.
  • 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, water-soluble 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 is not particularly limited as long as it is pharmaceutically acceptable.
  • edetic acid citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1
  • examples thereof include 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.
  • 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.
  • examples of the stabilizer include polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, and dibutylhydroxytoluene. 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 may contain a pharmacological component other than brimonidine and / or a salt thereof as necessary.
  • 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.
  • ⁇ 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. What is necessary is just to set the density
  • the pH of the aqueous liquid preparation of the present invention is not particularly limited, and examples thereof include pH 5 to 8, preferably pH 5 to 7.
  • examples thereof include pH 5 to 8, preferably pH 5 to 7.
  • the pH of an aqueous solution containing chlorobutanol is 5 to 8
  • the pH tends to decrease with time, but the aqueous solution of the present invention contains brimonidine and / or a salt thereof.
  • it is possible to suppress a decrease in pH over time even in the pH range.
  • 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 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 brimonidine and / or salt thereof contained in the aqueous liquid preparation of the present invention has the effect of suppressing intraocular pressure by suppressing the production of aqueous humor as well as the effect of suppressing the decrease in pH over time. Therefore, the aqueous liquid preparation of the present invention is provided as an eye drop and can be suitably used as an aqueous liquid for treating glaucoma or ocular hypertension.
  • 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.
  • One aspect of the present invention is a method for suppressing a decrease in pH over time in an aqueous liquid preparation containing chlorobutanol, and a step of preparing an aqueous liquid preparation containing chlorobutanol and brimonidine and / or a salt thereof.
  • a method for inhibiting pH decrease is a method for suppressing a decrease in pH over time in an aqueous liquid preparation containing chlorobutanol, and a step of preparing an aqueous liquid preparation containing chlorobutanol and brimonidine and / or a salt thereof.
  • the concentration of chlorobutanol, the type and concentration of brimonidine and / or its salt, the types of other additives and pharmacological components incorporated in the aqueous solution, the pH of the aqueous solution, the pharmaceutical form, and the use And the like are as described in the column of “2. Aqueous solution”.
  • Test example 1 An aqueous solution was prepared according to the formulation shown in Table 1. Specifically, each aqueous solution is adjusted to pH 5 using hydrochloric acid or sodium hydroxide in an aqueous solution containing a predetermined amount of brimonidine tartrate, chlorobutanol, sodium citrate dihydrate and benzalkonium chloride. It was prepared by. Note that 0.1 g of sodium citrate dihydrate corresponds to 0.065 g of citric acid.
  • the results obtained are shown in Table 1.
  • the aqueous liquid preparations containing chlorobutanol and not containing brimonidine tartrate (Comparative Examples 1 and 2) had a pH maintenance rate of less than 90% when stored at 60 ° C. for 1 week, and the preparation stability was insufficient.
  • the aqueous liquid preparations (Examples 1 to 5) containing chlorobutanol and brimonidine tartrate all had a pH maintenance rate of 91% or more and had excellent formulation stability.
  • the aqueous solution containing chlorobutanol and brimonidine tartrate and containing no benzalkonium chloride further improved the pH maintenance rate.

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Abstract

Le but de la présente invention est de fournir une technique de formulation qui est liée à un agent liquide aqueux contenant du chlorobutanol. Selon la présente invention, un agent liquide aqueux qui contient du chlorobutanol et de la brimonidine et/ou un sel de celui-ci peut être supprimé par une réduction progressive du pH au cours du temps, ce qui permet d'obtenir une excellente stabilité de la formulation.
PCT/JP2019/022091 2018-06-05 2019-06-04 Agent liquide aqueux WO2019235456A1 (fr)

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JP2018-108045 2018-06-05
JP2018108045 2018-06-05

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Citations (6)

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JP2004256519A (ja) * 2003-02-07 2004-09-16 Senju Pharmaceut Co Ltd クロロブタノール含有人工涙液
WO2016093344A1 (fr) * 2014-12-12 2016-06-16 興和株式会社 Nouvelle composition aqueuse
WO2017057434A1 (fr) * 2015-09-28 2017-04-06 参天製薬株式会社 Composition aqueuse pharmaceutique
JP2017226652A (ja) * 2016-06-15 2017-12-28 興和株式会社 水性の組成物
JP2019006776A (ja) * 2017-06-28 2019-01-17 千寿製薬株式会社 水溶性高分子を含む点眼剤
WO2019112030A1 (fr) * 2017-12-08 2019-06-13 千寿製薬株式会社 Solution aqueuse contenant un polymère hydrosoluble

Patent Citations (6)

* Cited by examiner, † Cited by third party
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JP2004256519A (ja) * 2003-02-07 2004-09-16 Senju Pharmaceut Co Ltd クロロブタノール含有人工涙液
WO2016093344A1 (fr) * 2014-12-12 2016-06-16 興和株式会社 Nouvelle composition aqueuse
WO2017057434A1 (fr) * 2015-09-28 2017-04-06 参天製薬株式会社 Composition aqueuse pharmaceutique
JP2017226652A (ja) * 2016-06-15 2017-12-28 興和株式会社 水性の組成物
JP2019006776A (ja) * 2017-06-28 2019-01-17 千寿製薬株式会社 水溶性高分子を含む点眼剤
WO2019112030A1 (fr) * 2017-12-08 2019-06-13 千寿製薬株式会社 Solution aqueuse contenant un polymère hydrosoluble

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