WO2019235456A1 - Aqueous liquid agent - Google Patents

Aqueous liquid agent Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
salt
aqueous liquid
chlorobutanol
acid
brimonidine
Prior art date
Application number
PCT/JP2019/022091
Other languages
French (fr)
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.)
Filing date
Publication date
Application filed by 千寿製薬株式会社 filed Critical 千寿製薬株式会社
Publication of WO2019235456A1 publication Critical patent/WO2019235456A1/en

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The purpose of the present invention is to provide a formulation technique that is related to an aqueous liquid agent containing chlorobutanol. According to the present invention, an aqueous liquid agent which contains chlorobutanol and brimonidine and/or a salt thereof is able to be suppressed in decrease of pH over time, thereby being able to achieve excellent formulation stability.

Description

水性液剤Aqueous liquid
　本発明は、クロロブタノールを含みながらも、経時的なｐＨの低下を抑制できる水性液剤に関する。 The present invention relates to an aqueous liquid agent that can suppress a decrease in pH over time while containing chlorobutanol.
　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、ベンザルコニウム塩化物、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、これらの保存剤では、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, usually preservatives such as benzalkonium chloride and methylparaben are blended in order to prevent the growth of microorganisms. However, these preservatives are known to be capable of preventing bacterial growth, while exhibiting irritation and cytotoxicity (see Non-Patent Document 1).
　一方、保存剤の中でも、クロロブタノールは、刺激性や細胞毒性が少なく、点眼液や洗眼液等の粘膜に適用される水性製剤には安全性の点から適していると考えられており、従来、クロロブタノールを含む水性製剤が種々提案されている（例えば、特許文献１参照）。 On the other hand, among the preservatives, 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).
特開２０１２－６７１２９号公報JP 2012-67129 A
　本発明の目的は、クロロブタノール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 chlorobutanol.
　本発明者は、クロロブタノールと、ブリモニジン及び／又はその塩とを含む水性液剤は、経時的なｐＨの低下を抑制でき、優れた製剤安定性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 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.
　本発明の一態様として、下記に掲げる水性液剤を提供する。
項1-1．クロロブタノール、並びにブリモニジン及び／又はその塩を含む、水性液剤。
項1-2．クロロブタノール以外の保存剤を実質的に含まない、項1-1に記載の水性液剤。
項1-3．クロロブタノールの濃度が０．００５～１ｗ/ｖ％である、項1-1又は1-2に記載の水性液剤。
項1-4．ブリモニジン及び／又はその塩の濃度が０．０５～０．５ｗ/ｖ％である、項1-1～1-3のいずれかに記載の水性液剤。
項1-5．ｐＨが５～８である、項1-1～1-4のいずれかに記載の水性液剤。
項1-6．点眼液である、項1-1～1-5のいずれかに記載の水性液剤。
項1-7．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る、項1-1～1-6のいずれかに記載の水性液剤。
項1-8．緩衝剤を含む、項1-1～1-7のいずれかに記載の水性液剤。
項1-9．緩衝剤がクエン酸緩衝剤である、項1-8に記載の水性液剤。
項1-10．緩衝剤がクエン酸ナトリウムである、項1-8又は1-9に記載の水性液剤。
項1-11．ベンザルコニウム塩化物を実質的に含まない、項1-1に記載の水性液剤。
項1-12．クロロブタノール、並びにブリモニジン及び／又はその塩を含む、水性液剤であって、
　クロロブタノール以外の保存剤を実質的に含まず、
　クロロブタノールの濃度が０．０１～０．５ｗ/ｖ％であり、
　ブリモニジン及び／又はその塩の濃度が０．０５～０．５ｗ／ｖ％であり、
　ｐＨが５～８である、水性液剤。
項1-13．クロロブタノール、並びにブリモニジン及び／又はその塩を含む、水性液剤であって、
　クロロブタノール以外の保存剤を実質的に含まず、
　クロロブタノールの濃度が０．０１～０．５ｗ/ｖ％であり、
　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０．１～０．２ｗ／ｖ％であり、
　クエン酸緩衝剤を含み、
　ｐＨが５～８であり、
　水性液剤を調製直後に遮光条件下６０℃で1週間保存したときの、保存前及び保存後の水性液剤のｐＨから求められるｐＨ維持率が９３％以上であり、且つ
　点眼液である、水性液剤。 As one aspect of the present invention, the following aqueous liquid preparation is provided.
Item 1-1. An aqueous solution containing chlorobutanol and brimonidine and / or a salt thereof.
Item 1-2. Item 11. The aqueous liquid preparation according to Item 1-1, which contains substantially no preservative other than chlorobutanol.
Item 1-3. Item 11. The aqueous liquid preparation according to Item 1-1 or 1-2, wherein the concentration of chlorobutanol is 0.005 to 1 w / v%.
Item 1-4. Item 4. The aqueous liquid preparation according to any one of Items 1-1 to 1-3, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%.
Item 1-5. Item 5. The aqueous liquid preparation according to any one of Items 1-1 to 1-4, which has a pH of 5 to 8.
Item 1-6. The aqueous liquid preparation according to any one of Items 1-1 to 1-5, which is an eye drop.
Item 1-7. Item 7. The aqueous liquid preparation according to any one of Items 1-1 to 1-6, wherein brimonidine and / or a salt thereof is brimonidine tartrate.
Item 1-8. Item 8. The aqueous liquid preparation according to any one of Items 1-1 to 1-7, comprising a buffer.
Item 1-9. Item 9. The aqueous solution according to Item 1-8, wherein the buffer is a citrate buffer.
Item 1-10. Item 10. The aqueous liquid according to Item 1-8 or 1-9, wherein the buffer is sodium citrate.
Item 1-11. Item 10. The aqueous liquid preparation according to Item 1-1, which is substantially free of benzalkonium chloride.
Item 1-12. 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 having a pH of 5-8.
Item 1-13. 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,
When the aqueous liquid is stored for 1 week at 60 ° C. under light-shielding conditions immediately after preparation, 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 .
　また、本発明の他の態様として、下記に掲げるｐＨ低下抑制方法を提供する。
項2-1．クロロブタノールを含む水性液剤において経時的なｐＨの低下を抑制する方法であって、
　クロロブタノール、並びにブリモニジン及び／又はその塩を含む水性液剤を調製する工程を含む、ｐＨ低下抑制方法。
項2-2．前記水性液剤がクロロブタノール以外の保存剤を実質的に含まない、項2-1に記載のｐＨ低下抑制方法。
項2-3．水性液剤におけるクロロブタノールの濃度が０．００５～１ｗ/ｖ％である、項2-1又は2-2に記載のｐＨ低下抑制方法。
項2-4．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％である、項2-1～2-3のいずれかに記載のｐＨ低下抑制方法。
項2-5．水性液剤のｐＨが５～８である、項2-1～2-4のいずれかに記載のｐＨ低下抑制方法。
項2-6．水性液剤が点眼液である、項2-1～2-5のいずれかに記載のｐＨ低下抑制方法。
項2-7．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る、項2-1～2-6のいずれかに記載のｐＨ低下抑制方法。
項2-8．水性液剤が緩衝剤を含む、項2-1～2-7のいずれかに記載のｐＨ低下抑制方法。
項2-9．緩衝剤がクエン酸緩衝剤である、項2-8に記載のｐＨ低下抑制方法。
項2-10．緩衝剤がクエン酸ナトリウムである、項2-8又は2-9に記載のｐＨ低下抑制方法。
項2-11．クロロブタノールを含む水性液剤において経時的なｐＨの低下を抑制する方法であって、
　クロロブタノール、並びにブリモニジン及び／又はその塩を含む水性液剤を調製する工程を含み、
　ここで、水性液剤において、
　　クロロブタノール以外の保存剤を実質的に含まず、
　　クロロブタノールの濃度が０．０１～０．５ｗ/ｖ％であり、
　　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０．１～０．２ｗ／ｖ％であり、
　　クエン酸緩衝剤を含み、且つ
　　ｐＨが５～８であり、
　水性液剤が点眼液である、ｐＨ低下抑制方法。 Moreover, the pH fall suppression method hung up below is provided as another aspect of this invention.
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. The method for inhibiting pH decrease according to Item 2-1 or 2-2, wherein the concentration of chlorobutanol in the aqueous liquid is 0.005 to 1 w / v%.
Item 2-4. Item 4. The method for inhibiting pH decrease according to any one of Items 2-1 to 2-3, wherein the concentration of brimonidine and / or a salt thereof in the aqueous liquid is 0.05 to 0.2 w / v%.
Item 2-5. Item 5. The method for inhibiting pH decrease according to any one of Items 2-1 to 2-4, wherein the pH of the aqueous liquid preparation is 5 to 8.
Item 2-6. Item 6. The method for inhibiting pH decrease according to any one of Items 2-1 to 2-5, wherein the aqueous liquid preparation is an ophthalmic solution.
Item 2-7. Item 7. The method for inhibiting pH decrease according to any one of Items 2-1 to 2-6, wherein brimonidine and / or a salt thereof is brimonidine tartrate.
Item 2-8. Item 8. The method for suppressing pH decrease according to any one of Items 2-1 to 2-7, wherein the aqueous liquid preparation contains a buffer.
Item 2-9. Item 9. The method for inhibiting pH decrease according to Item 2-8, wherein the buffer is a citrate buffer.
Item 2-10. Item 10. The method for inhibiting pH decrease according to Item 2-8 or 2-9, wherein the buffer is sodium citrate.
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,
Here, in 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%,
A citrate buffer and a pH of 5-8,
A method for inhibiting pH reduction, wherein the aqueous liquid preparation is an ophthalmic solution.
　本発明によれば、クロロブタノールを含む水性液剤において、経時的なｐＨの低下を抑制できるので、優れた製剤安定性を備えさせることができる。 According to the present invention, in an aqueous liquid preparation containing chlorobutanol, it is possible to suppress a decrease in pH over time, so that excellent formulation stability can be provided.
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、「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単独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。 In this specification, 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”.
　本明細書において、「クロロブタノール以外の保存剤を実質的に含まない」とは、保存剤（クロロブタノール以外）の濃度が、当該保存剤（クロロブタノール以外）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（クロロブタノール以外）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 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). Specifically, when an aqueous solution containing only a preservative (other than chlorobutanol) is used, the aqueous solution is classified as “IA” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test”. Less than the minimum concentration of preservative that is “fit” based on the criteria set forth in.
　本明細書において、「ｐＨ」は、室温（２０～３０℃）で測定される値を指す。 In this specification, “pH” refers to a value measured at room temperature (20 to 30 ° C.).
　本明細書において、「経時的なｐＨの低下」、「経時的にｐＨが低下する」等の表記は、一定期間の保存によって水性液剤のｐＨが低下することを指し、例えば、下記算出式に従って求められるｐＨ維持率が９０％未満である場合には、「経時的なｐＨの低下」が認められるといえる。
Figure JPOXMLDOC01-appb-M000001
 In the present specification, 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.
Figure JPOXMLDOC01-appb-M000001
　本明細書において、「経時的なｐＨの低下を抑制」とは、一定期間の保存によって水性液剤のｐＨの低下が少ない若しくは無いことを指す。例えば、水性液剤を調製直後に遮光条件下６０℃で１週間保存し、保存前及び保存後の水性液剤のｐＨから前記算出式に従って求められるｐＨ維持率が９１％以上、好ましくは９３％以上、更に好ましくは９４％以上、より好ましくは９５％以上、特に好ましくは９６％以上である場合には、「経時的なｐＨの低下を抑制」できているといえる。 In the present specification, “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. For example, immediately after preparation, 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".
　本明細書において、「製剤安定性」とは、一定期間の保存によって水性液剤のｐＨが安定に維持されている度合を指し、経時的なｐＨの低下を抑制できている場合には、優れた「製剤安定性」を備えているといえる。 In the present specification, “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”.
２．水性液剤
　クロロブタノールは、水性液剤中では不安定であり、熱や光暴露等によって分解され塩酸を生じ易いことが知られている。そのため、クロロブタノールを含む水性液剤では、防腐効力を具備できるものの、保存すると、クロロブタノールの分解に起因して経時的にｐＨが低下するという課題がある。そのため、クロロブタノールを含みながらも、経時的なｐＨの低下を抑制できる水性液剤の開発が望まれている。 2. It is known that 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.
　本発明者は、クロロブタノールと、ブリモニジン及び／又はその塩とを含む水性液剤は、経時的なｐＨの低下を抑制でき、優れた製剤安定性を備え得ることを見出した。
　即ち、一つの態様において、本発明は、クロロブタノール、並びにブリモニジン及び／又はその塩を含む水性液剤を提供する。 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.
That is, in one embodiment, the present invention provides an aqueous solution comprising chlorobutanol and brimonidine and / or a salt thereof.
　本発明の水性液剤において、クロロブタノールの濃度については、付与すべき保存効力の程度等に応じて適宜設定すればよいが、例えば、０．００５～１ｗ/ｖ％、好ましくは０．０１～０．５ｗ/ｖ％、更に好ましくは０．１～０．２ｗ/ｖ％が挙げられる。 In the aqueous liquid preparation of the present invention, 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%.
　本発明の水性液剤において、ブリモニジン及び／又はその塩は、クロロブタノールを含む水性液剤において、経時的なｐＨの低下を抑制させる役割を果たす。 In the aqueous liquid preparation of the present invention, brimonidine and / or a salt thereof play a role of suppressing a decrease in pH over time in an aqueous liquid preparation containing chlorobutanol.
　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。 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.
　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。 In the aqueous liquid preparation of the present invention, either brimonidine or a salt thereof may be used alone or in combination.
　本発明の水性液剤において、ブリモニジン及び／又はその塩の濃度としては、例えば０．０５～０．５ｗ/ｖ％が挙げられる。経時的なｐＨの低下をより一層効果的に抑制するという観点から、ブリモニジン及び／又はその塩の濃度として、好ましくは０．１～０．２ｗ/ｖ％、更に好ましくは０．１ｗ/ｖ％が挙げられる。本明細書において、ブリモニジン及び／又はその塩の濃度は、特に明記しない限り、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 and / or a salt thereof is, for example, 0.05 to 0.5 w / v%. From the viewpoint of more effectively suppressing the decrease in pH over time, 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. In the present specification, the concentration of brimonidine and / or a salt thereof is a concentration converted to brimonidine tartrate unless otherwise specified.
　本発明の水性液剤では、クロロブタノールを含むことによって、所望の保存効力を備えることが可能になっている。一方、クロロブタノール以外の保存剤には、強い刺激性や細胞毒性を呈したり、本発明の水性液剤において経時的なｐＨの低下を抑制する効果を減弱させたりするものがある。そのため、本発明の水性液剤の一態様として、クロロブタノール以外の保存剤を実質的に含まないことが挙げられる。クロロブタノール以外の保存剤としては、具体的には、亜塩素酸ナトリウム等の亜塩素酸塩；ベンザルコニウム塩化物、ベンゼトニウム塩化物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、クロルヘキシジン、ポリヘキサニド等が該当する。クロロブタノール以外の保存剤を実質的に含まない態様において、本発明の水性液剤において許容される保存剤（クロロブタノール以外）の濃度については、保存剤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。 In the aqueous liquid preparation of the present invention, by containing chlorobutanol, it is possible to have a desired storage effect. On the other hand, 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. Specific examples of 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. In an embodiment that does not substantially contain a preservative other than chlorobutanol, 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%.
　本発明の水性液剤には、緩衝作用を備えさせるために、緩衝剤が含まれていてもよい。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、クエン酸緩衝剤、ホウ酸緩衝剤、リン酸緩衝剤、トリス緩衝剤、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 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. For example, citrate buffer, borate buffer, phosphate buffer, Tris buffer, tartrate buffer , Acetate buffer, amino acid buffer and the like.
　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。クエン酸及びその塩の中でも、経時的なｐＨの低下をより一層効果的に抑制するという観点から、好ましくはクエン酸の塩、更に好ましくはクエン酸のアルカリ金属塩、特に好ましくはクエン酸ナトリウムが挙げられる。 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. Among 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.
　クエン酸緩衝剤の使用量については、緩衝作用の観点から、クエン酸又はその塩の濃度として、通常０．００１～５ｗ/ｖ％、好ましくは０．０１～１ｗ/ｖ％、更に好ましくは０．０２～０．５ｗ/ｖ％、特に好ましくは０．０３～０．１５ｗ/ｖ％が挙げられる。本明細書において、クエン酸又はその塩の濃度は、特に明記しない限り、クエン酸に換算された濃度である。 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%. In the present specification, the concentration of citric acid or a salt thereof is a concentration converted to citric acid unless otherwise specified.
　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。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、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。 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. As the 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 boric acids and salts thereof, preferably at least one of boric acid and borax, more preferably at least one of orthoboric acid and borax.
　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％、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、特に明記しない限り、ホウ酸に換算された濃度である。 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%. In the present specification, the concentration of boric acid or a salt thereof is a concentration converted to boric acid unless otherwise specified.
　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。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、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。 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. 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, 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.
　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、特に明記しない限り、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 the present specification, the concentration of the phosphate buffer is a concentration converted to phosphate unless otherwise specified.
　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。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、好ましくはトロメタモールが挙げられる。 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. As 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.
　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、特に明記しない限り、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 the present specification, the concentration of the Tris buffer is a concentration converted to trometamol unless otherwise specified.
　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、経時的なｐＨの低下をより一層効果的に抑制するという観点から、好ましくはクエン酸緩衝剤が挙げられる。 Among these buffering agents, a citrate buffering agent is preferable from the viewpoint of more effectively suppressing the decrease in pH over time.
　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、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, as required, isotonic agents, polyhydric alcohols, surfactants, thickeners, chelating agents, cooling agents, stabilizers, pH adjusters Etc. You may contain additives, such as.
　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, 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.
　キレート剤としては、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、エデト酸、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 is not particularly limited as long as it is pharmaceutically acceptable. For example, 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.
　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. 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.
　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、必要に応じて、ブリモニジン及び／又はその塩以外の薬理成分が含まれていてもよい。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。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。 Furthermore, the aqueous liquid preparation of the present invention may contain a pharmacological component other than brimonidine and / or a salt thereof as necessary. 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. What is necessary is just to set the density | concentration of these pharmacological components suitably according to the kind of pharmacological component to be used, the medicinal effect which should be provided, etc.
　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、ｐＨ５～８、好ましくはｐＨ５～７が挙げられる。従来技術において、クロロブタノールを含む水性液剤のｐＨが５～８の場合には経時的なｐＨの低下が生じ易い傾向があるが、本発明の水性液剤では、ブリモニジン及び／又はその塩を含むことにより、前記ｐＨ範囲でも、経時的なｐＨの低下を抑制することが可能になっている。 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. In the prior art, when 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. Thus, it is possible to suppress a decrease in pH over time even in the pH range.
　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、本発明の水性液剤に含まれるブリモニジン及び／又はその塩は、経時的なｐＨの低下を抑制する作用だけでなく、眼房水の産生を抑制して、眼圧を低下させる効果を奏し得るので、本発明の水性液剤は、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 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.
　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.
３．ｐＨ低下抑制方法
　本発明の一態様は、クロロブタノールを含む水性液剤において経時的なｐＨの低下を抑制する方法であって、クロロブタノール、並びにブリモニジン及び／又はその塩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、ｐＨ低下抑制方法である。 3. Method for inhibiting pH decrease 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.
　本発明のｐＨ低下抑制方法によれば、クロロブタノールを含む水性液剤において、経時的なｐＨ低下を抑制でき、製剤安定性を付与することが可能になる。 According to the method for suppressing pH decrease of the present invention, it is possible to suppress pH decrease with time in an aqueous liquid preparation containing chlorobutanol, and to impart formulation stability.
　本発明のｐＨ低下抑制方法において、クロロブタノールの濃度、ブリモニジン及び／又はその塩の種類や濃度、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「２．水性液剤」の欄に記載の通りである。 In the method for inhibiting pH reduction of the present invention, 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”.
　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。 Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
試験例１
　表１に示す処方に従って、水性液剤を調製した。具体的には、各水性液剤は、所定量のブリモニジン酒石酸塩、クロロブタノール、クエン酸ナトリウム二水和物及びベンザルコニウム塩化物を配合した水溶液に、塩酸又は水酸化ナトリウムを用いてｐＨ５に調整することによって調製した。なお、０．１ｇのクエン酸ナトリウム二水和物は０．０６５ｇのクエン酸に相当する。 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.
　調製直後の各水性液剤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））に入れ、遮光条件下で６０℃で１週間保存した。保存前後に水性液剤のｐＨを室温でｐＨメータ（株式会社堀場製作所）にて測定した。また、下記算出式に従って、各水性液剤のｐＨ維持率（％）を算出した。 5 mL of colorless aqueous glass ampule was filled with 5 mL of each aqueous solution immediately after preparation. These were placed in a desktop thermostat (NST-80, Nagano Science Co., Ltd.) and stored at 60 ° C. for 1 week under light-shielded conditions. Before and after storage, the pH of the aqueous liquid was measured at room temperature with a pH meter (Horiba, Ltd.). Moreover, according to the following calculation formula, the pH maintenance factor (%) of each aqueous liquid preparation was calculated.
Figure JPOXMLDOC01-appb-M000002
Figure JPOXMLDOC01-appb-M000002
　得られた結果を表１に示す。クロロブタノールを含み、且つブリモニジン酒石酸塩を含まない水性液剤（比較例１及び２）では、６０℃で１週間保存すると、ｐＨ維持率が９０％を下回り、製剤安定性が不十分であった。これに対して、クロロブタノール及びブリモニジン酒石酸塩を含む水性液剤（実施例１～５）では、いずれもｐＨ維持率が９１％以上であり、優れた製剤安定性を有していた。特に、実施例１と実施例３との対比から明らかなように、クロロブタノール及びブリモニジン酒石酸塩を含み、且つベンザルコニウム塩化物を含まない水性液剤では、ｐＨ維持率が更に向上していた。 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. On the other hand, 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. In particular, as is clear from the comparison between Example 1 and Example 3, the aqueous solution containing chlorobutanol and brimonidine tartrate and containing no benzalkonium chloride further improved the pH maintenance rate.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003

Claims (8)

  1. 　クロロブタノール、並びにブリモニジン及び／又はその塩を含む、水性液剤。 An aqueous solution containing chlorobutanol and brimonidine and / or a salt thereof.
  2. 　クロロブタノール以外の保存剤を実質的に含まない、請求項１に記載の水性液剤。 The aqueous liquid preparation according to claim 1, which contains substantially no preservative other than chlorobutanol.
  3. 　クロロブタノールの濃度が０．００５～１ｗ/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 chlorobutanol is 0.005 to 1 w / v%.
  4. 　ブリモニジン及び／又はその塩の濃度が０．０５～０．５ｗ/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 brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%.
  5. 　ｐＨが５～８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, having a pH of 5 to 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. 　クロロブタノール、並びにブリモニジン及び／又はその塩を含む、水性液剤であって、
    　クロロブタノール以外の保存剤を実質的に含まず、
    　クロロブタノールの濃度が０．０１～０．５ｗ/ｖ％であり、
    　ブリモニジン及び／又はその塩の濃度が０．０５～０．５ｗ／ｖ％であり、
    　ｐＨが５～８である、水性液剤。     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 having a pH of 5-8.
  8. 　クロロブタノールを含む水性液剤において経時的なｐＨの低下を抑制する方法であって、
    　クロロブタノール、並びにブリモニジン及び／又はその塩を含む水性液剤を調製する工程を含む、ｐＨ低下抑制方法。     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.
PCT/JP2019/022091 2018-06-05 2019-06-04 Aqueous liquid agent WO2019235456A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018-108045 2018-06-05
JP2018108045 2018-06-05

Publications (1)

Publication Number Publication Date
WO2019235456A1 true WO2019235456A1 (en) 2019-12-12

Family

ID=68769867

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/022091 WO2019235456A1 (en) 2018-06-05 2019-06-04 Aqueous liquid agent

Country Status (2)

Country Link
JP (1) JP6628924B2 (en)
WO (1) WO2019235456A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004256519A (en) * 2003-02-07 2004-09-16 Senju Pharmaceut Co Ltd Chlorobutanol-containing artificial tear liquid
WO2016093344A1 (en) * 2014-12-12 2016-06-16 興和株式会社 Novel aqueous composition
WO2017057434A1 (en) * 2015-09-28 2017-04-06 参天製薬株式会社 Aqueous pharmaceutical composition
JP2017226652A (en) * 2016-06-15 2017-12-28 興和株式会社 Aqueous composition
JP2019006776A (en) * 2017-06-28 2019-01-17 千寿製薬株式会社 Eye drop containing water-soluble polymer
WO2019112030A1 (en) * 2017-12-08 2019-06-13 千寿製薬株式会社 Aqueous liquid agent including water-soluble polymer

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004256519A (en) * 2003-02-07 2004-09-16 Senju Pharmaceut Co Ltd Chlorobutanol-containing artificial tear liquid
WO2016093344A1 (en) * 2014-12-12 2016-06-16 興和株式会社 Novel aqueous composition
WO2017057434A1 (en) * 2015-09-28 2017-04-06 参天製薬株式会社 Aqueous pharmaceutical composition
JP2017226652A (en) * 2016-06-15 2017-12-28 興和株式会社 Aqueous composition
JP2019006776A (en) * 2017-06-28 2019-01-17 千寿製薬株式会社 Eye drop containing water-soluble polymer
WO2019112030A1 (en) * 2017-12-08 2019-06-13 千寿製薬株式会社 Aqueous liquid agent including water-soluble polymer

Also Published As

Publication number Publication date
JP6628924B2 (en) 2020-01-15
JP2019210288A (en) 2019-12-12

Similar Documents

Publication Publication Date Title
JP6441087B2 (en) Pharmaceutical composition containing pyridylaminoacetic acid compound
JP6449205B2 (en) Pharmaceutical composition containing pyridylaminoacetic acid compound and polyoxyethylene castor oil
JP6621955B2 (en) Aqueous liquid
JP2024040421A (en) Aqueous liquid preparation
JP2022190022A (en) Eye drop containing water-soluble polymer
JP2012140459A (en) Method for preventing degradation of isopropylunoprostone
JP2023181428A (en) Ophthalmic composition
JP4757970B2 (en) Eye drop composition
JP2019178083A (en) Aqueous solution for eye drops
JP6628924B2 (en) Aqueous liquid
JP4314429B2 (en) Stable ophthalmic solution containing latanoprost as an active ingredient
JP6797992B1 (en) Aqueous solution
JP6901619B2 (en) Aqueous solution
JP7447072B2 (en) aqueous liquid
JP7269425B2 (en) aqueous solution
JP6802943B2 (en) Aqueous solution
JP5478680B2 (en) Stabilizer for composition containing water-soluble polymer thickener
JP2015044751A (en) Eye drop which contains latanoprost and timolol maleate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19814343

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19814343

Country of ref document: EP

Kind code of ref document: A1