WO2021166274A1 - Produit pharmaceutique - Google Patents

Produit pharmaceutique Download PDF

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Publication number
WO2021166274A1
WO2021166274A1 PCT/JP2020/015338 JP2020015338W WO2021166274A1 WO 2021166274 A1 WO2021166274 A1 WO 2021166274A1 JP 2020015338 W JP2020015338 W JP 2020015338W WO 2021166274 A1 WO2021166274 A1 WO 2021166274A1
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Prior art keywords
salt
item
acid
brimonidine
aqueous solution
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PCT/JP2020/015338
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English (en)
Japanese (ja)
Inventor
柊也 増田
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千寿製薬株式会社
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Publication of WO2021166274A1 publication Critical patent/WO2021166274A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to a pharmaceutical product containing chlorous acid and / or a salt thereof, and an aqueous solution containing boric acid and / or a salt thereof, and capable of suppressing a decrease in the content of chlorous acid and / or a salt thereof.
  • preservatives are used in aqueous preparations such as eye drops and nasal drops to prevent microbial invasion and proliferation.
  • benzalkonium chloride has been widely used as a preservative in preparations in the field of ophthalmology. Benzalkonium chloride exhibits an excellent antiseptic effect by denaturing bacterial proteins, but on the other hand, it is known that it can also be a factor that induces damage to the corneal epithelium.
  • chlorous acid and its salt are safe as an alternative to benzalkonium chloride because they exist as chlorite ions (ClO 2 -ions) in aqueous preparations, exhibit excellent storage efficacy, and are highly safe. It is attracting attention as a preservative.
  • Patent Document 1 states that chlorite and at least one non-steroid selected from the group consisting of bromfenac, diclofenac, ketorolac, flurbiprofen, pharmaceutically acceptable salts thereof, and nepafenac. It is disclosed that an aqueous preparation containing a sex anti-inflammatory drug can improve the photostability of chlorite. Further, Patent Document 2 states that an aqueous composition for contact lenses containing chlorous acid and / or a salt thereof and menthol can enhance the bactericidal power and / or detergency of chlorous acid and / or a salt thereof. It is disclosed.
  • the present invention provides a technique for producing a pharmaceutical product in which an aqueous liquid containing chlorous acid and / or a salt thereof and boric acid and / or a salt thereof are contained in a sterilized container.
  • the present inventor describes the content of chlorous acid and / or its salt when an aqueous solution containing chlorous acid and / or a salt thereof and boric acid and / or a salt thereof are contained in a gas-sterilized container. It was found that there was a problem that the amount of gas decreased. Further, when an aqueous solution containing chlorous acid and / or a salt thereof, boric acid and / or a salt thereof, and brimonidine and / or a salt thereof is contained in a gas-sterilized container, chlorous acid and / or a salt thereof are contained. / Or found that the decrease in salt content can be suppressed.
  • the present inventor holds an aqueous solution containing brimonidine and / or a salt thereof, chlorous acid and / or a salt thereof, and boric acid and / or a salt thereof in a gas-sterilized container. It has been found that a decrease in the content of brimonidine and / or a salt thereof can also be suppressed.
  • the present invention has been completed by further studies based on these findings.
  • Item 1-1 A pharmaceutical product in which an aqueous solution containing chlorous acid and / or a salt thereof, boric acid and / or a salt thereof, and brimonidine and / or a salt thereof is contained in a gas-sterilized container.
  • Item 1-2. Item 2. The pharmaceutical product according to Item 1-1, wherein the chlorous acid and / or a salt thereof is sodium chlorite.
  • Item 2 The pharmaceutical product according to Item 1-1 or 1-2, wherein the concentration of the chlorous acid and / or a salt thereof is 0.0001 to 1 w / v%.
  • the pharmaceutical product according to any one of Items 1-1 to 1-5, wherein the brimonidine and / or a salt thereof is brimonidine tartrate.
  • the concentration of the sodium chloride is 0.01 to 2 w / v%
  • the concentration of the potassium chloride is 0.01 to 2 w / v%
  • the concentration of the magnesium chloride is 0.001 to 0.2 w / v%
  • the chloride is 0.01 to 2 w / v%
  • the pharmaceutical product according to Item 1-10 or 1-11, wherein the concentration of calcium is 0.001 to 0.2 w / v%.
  • Item 1-13 The pharmaceutical product according to any one of Items 1-1 to 1-12, wherein the aqueous solution is an eye drop.
  • Item 1-18. Item 2.
  • Item 1-20. A pharmaceutical product in which an aqueous solution containing sodium chlorite, boric acid and / or borax, and brimonidine tartrate is contained in a container sterilized with ethylene oxide gas.
  • the concentration of the sodium chlorite is 0.0001 to 1 w / v%, and the concentration is 0.0001 to 1 w / v%.
  • the concentration of boric acid and / or borax is 0.01 to 10 w / v%.
  • the concentration of the brimonidine tartrate is 0.05 to 0.5 w / v%.
  • the concentration of the sodium chlorite is 0.005 to 0.02 w / v%, and the concentration is 0.005 to 0.02 w / v%.
  • the concentration of boric acid and / or borax is 0.1 to 0.5 w / v%.
  • the concentration of the brimonidine tartrate is 0.05 to 0.2 w / v%.
  • the concentration of the sodium chlorite is 0.005 to 0.02 w / v%, and the concentration is 0.005 to 0.02 w / v%.
  • the concentration of boric acid and / or borax is 0.1 to 0.5 w / v%.
  • the concentration of the brimonidine tartrate is 0.05 to 0.2 w / v%.
  • the present invention provides, as another embodiment, a method for stabilizing the content of chlorous acid and / or a salt thereof, as described below.
  • Item 2-1 A method for stabilizing the content of chlorous acid and / or its salt in an aqueous solution containing chlorous acid and / or its salt and boric acid and / or its salt. The method comprising the step of accommodating an aqueous solution containing chlorous acid and / or a salt thereof, borate and / or a salt thereof, and brimonidine and / or a salt thereof in a gas-sterilized container.
  • Item 2-2. Item 2. The method according to Item 2-1. The chlorous acid and / or a salt thereof is sodium chlorite.
  • Item 2 The method according to any one of Items 2-1 to 2-6, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%. Item 2-8. Item 2. The method according to any one of Items 2-1 to 2-7, wherein the aqueous liquid agent contains a metal chloride. Item 2-9. Item 2. The method according to Item 2-8, wherein the metal chloride contains at least sodium chloride. Item 2-10. Item 2. The method according to Item 2-8 or 2-9, wherein the metal chloride is sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. Item 2-11. Item 2.
  • concentration of the sodium chlorite is 0.005 to 0.02 w / v%, and the concentration is 0.005 to 0.02 w / v%.
  • concentration of boric acid and / or borax is 0.1 to 0.5 w / v%.
  • the concentration of the brimonidine tartrate is 0.05 to 0.2 w / v%.
  • the present invention provides, as another embodiment, a method for stabilizing the content of brimonidine and / or a salt thereof, as described below.
  • Item 3-1 A method for stabilizing the content of brimonidine and / or a salt thereof in an aqueous solution containing brimonidine and / or a salt thereof and a borate and / or a salt thereof, wherein the content of brimonidine and / or a salt thereof, chlorous acid and / or The method comprising the step of accommodating the salt and an aqueous solution containing chlorous acid and / or the salt in a gas-sterilized container.
  • Item 3-2 Item 3. The method according to Item 3-1. The method according to Item 3-1.
  • the brimonidine and / or a salt thereof is brimonidine tartrate.
  • Item 6. The method according to any one of Items 3-8 to 3-10, wherein the concentration of the total amount of the metal chloride is 0.01 to 2 w / v%.
  • Item 3-12. The concentration of the sodium chloride is 0.01 to 2 w / v%, the concentration of the potassium chloride is 0.01 to 2 w / v%, the concentration of the magnesium chloride is 0.001 to 0.2 w / v%, and the chloride.
  • Item 3. The method according to Item 3-10 or 3-11, wherein the concentration of calcium is 0.001 to 0.2 w / v%.
  • Item 3-13 Item 2. The method according to any one of Items 3-1 to 3-12, wherein the aqueous solution is an eye drop. Item 3-14. Item 8. The method according to any one of Items 3-1 to 3-13, wherein the container is made of polyolefin. Item 3-15. Item 3. The method according to Item 3-14, wherein the polyolefin is polypropylene or polyethylene. Item 3-16. Item 8. The method according to any one of Items 3-1 to 3-15, wherein the container is a multi-dose type container. Item 3-17. Item 4. The pharmaceutical product according to any one of Items 3-1 to 3-16, wherein the gas sterilization is ethylene oxide gas sterilization. Item 3-18.
  • a method for stabilizing the content of brimonidine tartrate in an aqueous solution containing brimonidine tartrate and boric acid and / or borax Including the step of containing an aqueous solution containing brimonidine tartrate, borate and / or borax, and sodium chlorite in a container sterilized with ethylene oxide gas.
  • the concentration of the brimonidine tartrate is 0.05 to 0.2 w / v%.
  • the concentration of boric acid and / or borax is 0.1 to 0.5 w / v%.
  • the concentration of the sodium chlorite is 0.005 to 0.02 w / v%, and the concentration is 0.005 to 0.02 w / v%.
  • the method, wherein the container is a polypropylene or polyethylene multi-dose container.
  • an aqueous solution containing chlorous acid and / or a salt thereof, boric acid and / or a salt thereof, and brimonidine and / or a salt thereof is contained in a gas-sterilized container.
  • the decrease in the content of chlorous acid and / or its salt can be suppressed, and the preservation effect of chlorous acid and / or its salt can be stably maintained.
  • not only the decrease in the content of chlorous acid and / or its salt can be suppressed, but also the decrease in the content of brimonidine and / or its salt can be suppressed, so that excellent formulation stability can be suppressed. Can be provided.
  • aqueous liquid agent refers to a liquid-containing preparation containing water as a base.
  • chlorous acid refers to an oxo acid (HClO 2 ) of chlorine, and is a compound that exists as a chlorite ion (ClO 2 -ion) in an aqueous solution.
  • boric acid refers to the oxo acid of boron.
  • 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.
  • metal chloride refers to a compound in which metal ions and chloride ions are ionically bonded.
  • osmotic pressure of aqueous solution is measured according to the method specified in “30. Osmotic pressure measurement method (osmolal concentration measurement method)" of “General test method” of the 17th revised Japanese Pharmacopoeia. Is the value to be.
  • the "osmotic pressure ratio of the aqueous solution” refers to the ratio of the osmotic pressure of the aqueous solution to the osmotic pressure of physiological saline (0.9 w / v% sodium chloride aqueous solution).
  • the "gas sterilized container” refers to a container that has been sterilized by being brought into contact with a gas such as ethylene oxide (ethylene oxide) gas or hydrogen peroxide gas.
  • a gas such as ethylene oxide (ethylene oxide) gas or hydrogen peroxide gas.
  • the container body including the accommodating portion for accommodating the aqueous liquid agent may be gas sterilized, and other members such as nozzles and lids provided as necessary may be sterilized by other methods. It may be given.
  • multi-dose type container refers to a container filled with an aqueous solution for a plurality of times and used repeatedly.
  • unit dose type container refers to a container filled with a single dose of an aqueous liquid agent and used after one instillation.
  • the "pharmaceutical product” refers to a product in which an aqueous liquid agent is contained in a container.
  • the notation such as "decrease in the content of chlorous acid and / or its salt” means that the content of chlorous acid and / or its salt in the aqueous solution decreases by storage for a certain period of time.
  • the residual ratio of chlorous acid and / or its salt measured under the following conditions is less than 95%, it can be said that "decrease in the content of chlorous acid and / or its salt” is observed.
  • ⁇ Measurement conditions for residual rate of chlorous acid and / or its salt> An aqueous solution containing chlorous acid and / or a salt thereof is prepared, and immediately after the preparation, it is stored at 60 ° C. for 2 weeks under light-shielded conditions.
  • the concentration of chlorine dioxide in the aqueous solution immediately after preparation and after storage for 2 weeks is measured by the iodine titration method, and the residual rate of chlorine dioxide is calculated according to the following formula.
  • the calculated residual rate of chlorine dioxide shall be the residual rate of chlorous acid and / or a salt thereof.
  • the notation such as "suppressing the decrease in the content of chlorous acid and / or its salt” means that the aqueous solution after storage for a certain period of time has chlorous acid and / or compared with the aqueous solution before storage. It means that the decrease in the salt content can be suppressed. For example, when the residual rate of the chlorous acid and / or its salt is 95% or more, it can be said that "the decrease in the content of the chlorous acid and / or its salt over time is suppressed".
  • a method for stabilizing the content of chlorous acid and / or a salt thereof means chlorous acid in an aqueous solution containing chlorous acid and / or a salt thereof and boric acid and / or a salt thereof. And / or means a method performed to suppress a decrease in the content of chlorous acid and / or its salt and to maintain a stable content of chlorous acid and / or its salt.
  • the notation such as "decrease in the content of brimonidine and / or a salt thereof” means that the content of brimonidine in the aqueous solution decreases after storage for a certain period of time.
  • brimonidine measured under the following conditions. When the residual rate of and / or its salt is less than 99.0%, it can be said that "decrease in the content of brimonidine and / or its salt” is observed.
  • ⁇ Measurement conditions for residual rate of brimonidine and / or its salt> An aqueous solution containing brimonidine and / or a salt thereof is prepared and immediately stored at 60 ° C. for 2 weeks under light-shielded conditions. The concentration of brimonidine and / or its salt in the aqueous solution immediately after preparation and after storage for 2 weeks is measured by HPLC, and the residual ratio of brimonidine and / or its salt is calculated according to the following formula.
  • the notation such as "suppressing the decrease in the content of brimonidine and / or its salt” can suppress the decrease in the brimonidine content of the aqueous solution after storage for a certain period of time as compared with the aqueous solution before storage. Point to that. For example, when the residual rate of the brimonidine and / or its salt is 99.0% or more, it can be said that "the decrease in the content of brimonidine and / or its salt is suppressed".
  • the term "method for stabilizing the content of brimonidine and / or a salt thereof” refers to an aqueous solution containing brimonidine and / or a salt thereof and a boric acid and / or a salt thereof. It means a method performed to suppress a decrease in content and maintain a stable content of brimonidine and / or a salt thereof.
  • Chlorous acid and its salts are used as preservatives in the pharmaceutical field because they are highly safe and have excellent preservative effects.
  • the present inventor puts an aqueous solution containing chlorous acid and its salt, boric acid and / or its salt in a gas-sterilized container, and the content of chlorous acid and its salt decreases over time. It was found that it occurs. Such a decrease in the content of chlorous acid and / or a salt thereof will reduce the preservative effect of chlorous acid and / or a salt thereof.
  • an aqueous solution containing chlorous acid and / or a salt thereof, boric acid and / or a salt thereof, and brimonidine and / or a salt thereof is contained in a gas-sterilized container. It has been found that a decrease in the content of chlorous acid and / or a salt thereof can be suppressed, and the preservation effect of chlorous acid and / or a salt thereof can be stably maintained.
  • the present invention comprises a container in which an aqueous solution containing chlorous acid and / or a salt thereof, boric acid and / or a salt thereof, brimonidine and / or a salt thereof is gas-sterilized.
  • a pharmaceutical product that is contained.
  • One aspect of the present invention solves the problem of suppressing a decrease in the content of chlorous acid and / or a salt thereof in an aqueous solution containing chlorous acid and / or a salt thereof and boric acid and / or a salt thereof. Will be done.
  • aqueous solution of the present invention Another aspect of the aqueous solution of the present invention is that the aqueous solution containing chlorous acid and / or a salt thereof and boric acid and / or a salt thereof suppresses a decrease in the content of brimonidine and / or a salt thereof.
  • the problem is solved.
  • the pharmaceutical product of the present invention will be described.
  • the aqueous liquid agent used in the present invention contains chlorous acid and / or a salt thereof.
  • the salt of chlorous acid is not particularly limited as long as it is pharmaceutically acceptable and can generate chlorate ion (ClO 2 - ion) in an aqueous solution, but sodium chlorate and chlorous acid are not particularly limited.
  • Chlorous acid alkali metal salts such as potassium; chlorous acid alkaline earth metal salts such as calcium chlorate and magnesium chlorate; copper chlorate, lead chlorate, ammonium chlorate and the like can be mentioned.
  • chlorous acid or a salt thereof may be used alone, or these may be used in combination.
  • chlorous acid and its salts preferably chlorous acid alkali metal salt, more preferably sodium chlorite can be mentioned.
  • the concentration of chlorous acid and / or a salt thereof in the aqueous liquid preparation used in the present invention may be appropriately set in consideration of the degree of preservation effect to be imparted to the aqueous liquid preparation, and is, for example, 0.0001 to 1w. / V%, preferably 0.001 to 0.1 w / v%, more preferably 0.002 to 0.05 w / v%, and particularly preferably 0.005 to 0.02 w / v%.
  • the concentration of chlorous acid and / or a salt thereof used in the aqueous liquid preparation is a concentration converted to sodium chlorite unless otherwise specified.
  • the aqueous liquid preparation used in the present invention contains 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 used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but is not particularly limited, but is an alkali metal salt such as borosand, sodium salt, potassium salt; calcium salt, magnesium salt and the like. Alkaline earth metal salts; aluminum salts; organic amine salts such as triethylamine, triethanolamine, morpholin, piperazine, pyrrolidine and the like can be mentioned.
  • the salt of boric acid may be in the form of a hydrate, such as borax. These boric acid salts may be used alone or in combination of two or more.
  • boric acid and its salt may be selected and used alone, or two or more of these may be used in combination.
  • boric acid and salts thereof preferably at least one of boric acid and borax, and more preferably at least one of orthoboric acid and borax can be mentioned.
  • boric acid and / or a salt thereof used in the present invention a combination of boric acid and borax can be mentioned.
  • boric acid and borax are used in combination, these ratios are not particularly limited, but for example, boric acid is 1 to 100 parts by mass, preferably 20 to 80 parts by mass, and more preferably 20 to 80 parts by mass per 100 parts by mass of boric acid. 40 to 60 parts by mass.
  • the concentration of boric acid and / or a salt thereof in the aqueous solution used in the present invention is, for example, 0.01 to 10 w / v% w / v%, preferably 0. 1 to 2 w / v%, more preferably 0.1 to 1 w / v%, and particularly preferably 0.1 to 0.5 w / v%.
  • the concentration of boric acid and / or a salt thereof is the concentration converted to boric acid.
  • the aqueous solution used in the present invention contains brimonidine and / or a salt thereof.
  • brimonidine and / or a salt thereof reduces the content of chlorous acid and / or a salt thereof that occurs when chlorous acid and / or a salt thereof and boric acid and / or a salt thereof coexist in an aqueous solution. It is a component that contributes to suppression.
  • the salt of brimonidine is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts and inorganic acid salts.
  • examples of the organic acid salt include tartrate salt and acetate.
  • examples of the inorganic acid salt include hydrochloride and the like.
  • brimonidine or a salt thereof may be in the form of a solvate such as a hydrate.
  • brimonidine tartrate is preferably used because it has been marketed as a pharmaceutical product and its safety has been established.
  • brimonidine or a salt thereof may be used alone, or these may be used in combination.
  • the concentration of brimonidine and / or a salt thereof in the aqueous liquid preparation used in the present invention is, for example, 0.05 to 0.5 w / v%, preferably 0.05 to 0.3 w / v%, and more preferably 0. 05 to 0.2 w / v%, particularly preferably 0.08 to 0.12 w / v%.
  • the concentration of brimonidine and / or a salt thereof is the concentration converted to brimonidine tartrate unless otherwise specified.
  • the aqueous liquid agent used in the present invention may contain a metal chloride.
  • the metal chloride can play a role as an isotonic agent or the like.
  • the metal chloride is not particularly limited as long as it is pharmaceutically acceptable, but for example, chlorides of alkali metals such as sodium chloride and potassium chloride; chlorides of alkaline earth metals such as magnesium chloride and calcium chloride. ; Zinc chloride, iron chloride and the like can be mentioned. These metal chlorides may be in the form of hydrates. Among these metal chlorides, sodium chloride, potassium chloride, magnesium chloride and calcium chloride are preferable.
  • These metal chlorides may be used alone or in combination of two or more.
  • a preferred embodiment of the aqueous liquid agent used in the present invention is that it contains at least sodium chloride as a metal chloride.
  • aqueous liquid agent used in the present invention it is more preferable to use a combination of an alkali metal chloride and an alkaline earth metal chloride as the metal chloride.
  • an alkali metal chloride and an alkaline earth metal chloride As the metal chloride, sodium chloride, potassium chloride, magnesium chloride, and calcium chloride may be used in combination.
  • the concentration of metal chloride in the aqueous liquid agent used in the present invention is, for example, 0.01 to 2 w / v%, preferably 0.05 to 1 w / v%, and more preferably 0. 1 to 0.9 w / v% can be mentioned.
  • the concentration of the metal chloride is the concentration converted into an anhydride when the metal chloride is a hydrate.
  • sodium chloride is 0. 01 to 2 w / v%, preferably 0.05 to 1 w / v%, more preferably 0.1 to 0.6 w / v%, particularly preferably 0.5 to 0.6 w / v%; 0 potassium chloride 0.01-2 w / v%, preferably 0.05-1 w / v%, more preferably 0.1-0.5 w / v%, particularly preferably 0.1-0.2 w / v%; magnesium chloride 0.001 to 0.2 w / v%, preferably 0.005 to 0.05 w / v%, more preferably 0.005 to 0.02 w / v%; and calcium chloride 0.001 to 0.2 w / v%.
  • V% preferably 0.005 to 0.05 w / v%, more
  • the aqueous liquid agent used in the present invention in one embodiment further comprises an isotonic agent other than metal chloride, a polyhydric alcohol, a surfactant, a thickener, a chelating agent, if necessary.
  • Buffering agents other than boric acid and salts thereof, preservatives other than chlorous acid and / or salts thereof, stabilizers, pH adjusters and other additives may be contained.
  • the tonicity agent (other than metal chloride) is not particularly limited as long as it is pharmaceutically acceptable, but for example, polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, polyethylene glycol; sodium acetate, acetate.
  • polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, polyethylene glycol; sodium acetate, acetate.
  • metal salts such as potassium, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.
  • 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 alone or in combination of two or more.
  • the surfactant is not particularly limited as long as it is pharmaceutically acceptable, and for example, tyroxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy.
  • Nonionic surfactants such as Nol
  • Amphoteric surfactants such as alkyldiaminoethylglycine, betaine lauryldimethylaminoacetate
  • alkyl sulfates N-acyl taurine salts
  • polyoxyethylene alkyl ether phosphates polyoxyethylene alkyl
  • Anionic surfactants such as ether sulfate
  • cationic surfactants such as alkylpyridinium salt and alkylamine salt can be mentioned. These surfactants may be used alone or in combination of two or more.
  • the thickener is not particularly limited as long as it is pharmaceutically acceptable, but for example, it has high water solubility such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate.
  • Polymers Cellulose such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and the like can be mentioned. 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, and for example, edetic acid, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1, Examples thereof include 1-diphosphonic acid, polyphosphoric acid, metaphosphate, hexametaphosphate, 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 alone or in combination of two or more.
  • the buffer (other than boric acid and salts thereof) is not particularly limited as long as it is pharmaceutically acceptable, and for example, a phosphate buffer, a Tris buffer, a citrate buffer, a tartrate buffer, and an acetate buffer. Agents, amino acid buffers and the like. These buffers may be used alone or in combination of two or more.
  • the preservative (other than chlorhexidine and / or a salt thereof) is not particularly limited as long as it is pharmaceutically acceptable, and for example, sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl paraoxybenzoate, etc.
  • These preservatives or preservatives may be used alone or in combination of two or more.
  • the stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyvinylpyrrolidone, sulfites, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, and dibutylhydroxytoluene. Can be mentioned. These stabilizers may be used alone or in combination of two or more.
  • the pH adjuster is not particularly limited as long as it is pharmaceutically acceptable, and is, for example, an acid such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide. , Hosand, triethanolamine, monoethanolamine, sodium hydrogen carbonate, sodium carbonate and other alkalis. These pH adjusters may be used alone or in combination of two or more.
  • concentration of these additives may be appropriately set according to the type of additive used, the characteristics to be imparted to the aqueous liquid agent, and the like.
  • the aqueous liquid agent used in the present invention can have a desired buffering action by containing boric acid and / or a salt thereof, as one embodiment of the aqueous liquid agent used in the present invention, boric acid and / or its salt is used. An embodiment that does not contain a buffer other than a salt can be mentioned.
  • chlorous acid is one embodiment of the aqueous liquid agent used in the present invention.
  • the aqueous solution used in the first embodiment may contain a pharmacological component other than brimonidine and / or a salt thereof, if necessary.
  • pharmacological components include carbonate dehydration enzyme inhibitors such as dorzolamide; prostaglandins such as tafluprost, latanoprost and isopropylunoprost; parasympathomimetics such as pyrocarpine hydrochloride; anticholineresterases such as distigmine bromide.
  • Drugs such as dipivefrine hydrochloride; ⁇ 1 blockers such as betaxolol hydrochloride; ⁇ blockers such as timolol maleate; ⁇ 1 / ⁇ blockers such as niplazirol and levobnorol hydrochloride; bunazosin hydrochloride, etc. Examples include ⁇ 1 blockers.
  • These pharmacological components may be used alone or in combination of two or more. The concentration of these pharmacological components may be appropriately set according to the type of the pharmacological component to be used, the medicinal effect to be imparted, and the like.
  • the aqueous liquid preparation used in the present invention contains brimonidine and / or a salt thereof as a direct active ingredient for glaucoma, and substantially does not contain other active ingredients.
  • the pH of the aqueous liquid agent used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include pH 5.0 to 9.0. If the aqueous solution used in the first embodiment is an ophthalmic composition such as an eye drop or an eyewash, the pH is set from the viewpoint of further alleviating irritation to the eye that can be applied to the ocular mucosa. , Preferably 5.5 to 8.5, more preferably 6.0 to 8.0, and even more preferably 6.5 to 7.5.
  • the osmotic pressure of the aqueous liquid agent used in the present invention is not particularly limited as long as it can be applied to the intended use.
  • the osmotic pressure is 250 to 350 mOsm / kg.
  • the osmotic pressure ratio of the aqueous liquid agent used in the present invention is not particularly limited as long as it can be applied to the intended use.
  • the osmotic pressure ratio may be 0.85 to 1.15. From the viewpoint of alleviating eye irritation, 0.9 to 1.1 is preferable, and 1.0 is more preferable.
  • Preparation form for formulation of aqueous liquid used in the present invention is not particularly limited, an aqueous solution form, suspension form, may be any of emulsion-like, etc., preferably include aqueous solutions form.
  • the aqueous liquid preparation used in the present invention is prepared into pharmaceutical compositions for various purposes such as ophthalmology, dentistry, otolaryngology, dermatology, etc., and is used as a topically administered preparation.
  • a composition for ophthalmology, dentistry, otolaryngology, or dermatology can be mentioned, and an aqueous liquid preparation for ophthalmology is preferable.
  • aqueous solution for ophthalmology examples include eye drops, injections, and the like. Among these, eye drops are preferably mentioned.
  • aqueous solution used in the present invention can suppress the production of aqueous humor and reduce the intraocular pressure, and thus is used in the present invention.
  • the aqueous solution to be used it is provided as an eye drop, and glaucoma can be suitably used for therapeutic purposes.
  • one drop may be instilled once or multiple times a day. Further, in one aspect of the aqueous liquid preparation used in the present invention, one drop at a time is instilled twice a day.
  • the aqueous liquid agent used in the present invention may be produced according to a known preparation method according to its use, and is produced, for example, by the method described in the 17th revised Japanese Pharmacopoeia general rules for preparation. be able to.
  • the method for producing an aqueous solution used in the present invention comprises chlorous acid and / or a salt thereof, boric acid and / or a salt thereof, brimonidine and / or a salt thereof, and the like. It comprises the step of blending the other ingredients into a pharmaceutically acceptable aqueous medium.
  • “Pharmaceutically acceptable aqueous medium” means a pharmaceutically acceptable aqueous medium, and examples thereof include purified water.
  • the compounding order of each component is not particularly limited, and may be sequentially compounded in any order, or may be compounded at the same time.
  • a sterilization treatment step such as filtration sterilization, dry heat sterilization, electron beam sterilization, gamma ray sterilization may be performed, if necessary.
  • the pharmaceutical product of the present invention is contained in a container in which the aqueous solution is sterilized with a gas such as ethylene oxide gas or hydrogen peroxide gas (hereinafter, may be abbreviated as "gas sterilization container”).
  • a gas such as ethylene oxide gas or hydrogen peroxide gas
  • the type of gas used in gas sterilization is not particularly limited, and examples thereof include ethylene oxide gas, hydrogen peroxide gas, and a mixed gas of these with carbon dioxide and the like. Among these, ethylene oxide gas is preferable.
  • the conditions for sterilization using ethylene oxide gas are not particularly limited as long as the container is sufficiently sterilized.
  • the ethylene oxide concentration is 100 to 1000 mg / L, preferably 400 to 700 mg / L.
  • Temperature is 20 to 70 ° C., preferably 40 to 50 ° C.; Relative humidity is 30 to 100%, preferably 45 to 85%; Treatment time is 1 to 8 hours, preferably 3 to 5 hours. ..
  • the material of the gas sterilization container used in the present invention is not particularly limited and may be made of plastic or glass, but plastic is preferable.
  • the constituent resin thereof is not particularly limited, but for example, polyolefins such as polyethylene and polypropylene; polyesters such as polyethylene terephthalate and polybutylene terephthalate; polystyrene, acrylonitrile butadiene styrene, polycarbonate and polymethacryl.
  • plastics such as methyl acid and ethylene vinyl alcohol copolymers.
  • polyolefins are preferable, polypropylene or polyethylene is more preferable, and polypropylene is particularly preferable, from the viewpoint of more effectively suppressing the decrease in the content of chlorous acid and / or a salt thereof.
  • gas sterilization container used in the present invention may be transparent, translucent, or opaque, and may be colorless or colored.
  • the gas sterilization container used in the present invention may be either a multi-dose type container or a unit-dose type container, and a preferred embodiment is a multi-dose type container. Since the multi-dose container is used repeatedly, it is required to have a desired storage effect. However, the aqueous liquid agent used in the present invention has a storage effect with chlorous acid and / or a salt thereof. It is equipped and is suitable for storage in a multi-dose type container.
  • the gas sterilization container used in the present invention may be in the form of an eye drop container, an eye wash container, or the like, depending on the use of the aqueous liquid agent to be contained.
  • chlorous acid and / or chlorous acid in an aqueous solution containing chlorous acid and / or a salt thereof and boric acid and / or a salt thereof in an aqueous solution containing chlorous acid and / or a salt thereof and boric acid and / or a salt thereof.
  • an aqueous solution containing chlorous acid and / or a salt thereof, boric acid and / or a salt thereof, and brimonidine and / or a salt thereof which is a method for stabilizing the content of the salt thereof, in a gas sterilization container.
  • a method for stabilizing the content of chlorous acid and / or a salt thereof which comprises a step.
  • the type and concentration of chlorous acid and / or a salt thereof, the type and concentration of boric acid and / or a salt thereof, the type and concentration of brimonidin and / or a salt thereof, and other compounds blended in an aqueous solution are as described in the column of "3. Pharmaceutical products”.
  • the gas sterilization container used in the method of the present invention is also as described in the column of "3. Pharmaceutical products”.
  • Method for Stabilizing the Content of Brimonidin and / or its Salt As an embodiment of the present invention, the content of brimonidin and / or its salt in an aqueous solution containing brimonidine and / or its salt and chlorous acid and / or its salt is determined. A method for stabilizing brimonidine and / or a salt thereof, boric acid and / or a salt thereof, and an aqueous solution containing chlorous acid and / or a salt thereof in a gas sterilization vessel. / Or provide a method for stabilizing the salt content thereof.
  • a decrease in the content of brimonidine and / or a salt thereof can be suppressed, and brimonidine and / or a salt thereof can be suppressed. It becomes possible to provide an aqueous liquid agent that can stably maintain the above.
  • the type and concentration of brimonidin and / or a salt thereof, the type and concentration of boric acid and / or a salt thereof, the type and concentration of chloric acid and / or a salt thereof, and other compounds compounded in an aqueous solution are as described in the column of "3. Pharmaceutical products”.
  • the gas sterilization container used in the method of the present invention is also as described in the column of "3. Pharmaceutical products”.
  • orthoboric acid was used as the boric acid.
  • Test Example 1 1. Manufacture of ophthalmic pharmaceutical products 1-1. Preparation of ophthalmic solution According to the composition shown in Table 1, sodium chlorite (content 80% by weight), boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, brimonidine tartrate, sodium chloride were added to purified water. , Potassium chloride, calcium chloride hydrate, and magnesium chloride were added in a predetermined amount and dissolved, and the pH was adjusted to 7.1 with sodium hydroxide or hydrochloric acid to obtain an ophthalmic solution.
  • EOG sterilization container made of polypropylene eye dropper
  • EB sterile container by electron beam irradiation the polypropylene
  • the EOG sterilization container used was sterilized under the conditions of an ethylene oxide concentration of 400 to 700 mg / L, a temperature of 40 to 50 ° C., a relative humidity of 45 to 85%, and a treatment time of 3 hours or more.
  • the EB sterilization container used was sterilized by irradiating an electron beam with 60 kGy. Each sterilization condition satisfies the sterility guarantee level in the sterilization validation standard (Yaksik Faculty No. 0215 No. 13).
  • the chlorine dioxide concentration in the aqueous solution immediately after preparation and after storage for 14 days was measured by the iodine titration method shown below to calculate the residual rate (%) of chlorine dioxide.
  • ⁇ Iodine titration method 10 mL of a 2-weight potassium iodide aqueous solution and 10 mL of 0.5 mol / L hydrochloric acid were accurately weighed and shaken. After accurately adding 25 mL of each aqueous solution to this solution and allowing it to stand for 5 minutes, 0.01 mol according to the "2.50 titration end point detection method" of the "general test method" of the 17th revised Japanese Pharmacopoeia. / L Titrated with sodium thiosulfate solution.
  • the end point of titration was the time when 2 mL of the starch test solution was added when the color of the solution changed to pale yellow and the color of the solution changed from dark blue to colorless.
  • the chlorine dioxide concentration of each aqueous solution was determined according to the following formula, and the residual rate of chlorine dioxide was calculated. The calculated residual rate of chlorine dioxide was taken as the residual rate of sodium chlorite.
  • Table 1 shows the results obtained.
  • An aqueous solution containing sodium chlorite and a phosphate buffer (disodium hydrogen phosphate and sodium dihydrogen phosphate) has a high residual rate of sodium chlorite after storage even when stored in an EOG sterilization container. No problem of reducing the content of sodium chlorite was observed (Reference Examples 1 and 2).
  • sodium chlorite after storage may be stored in either an EB sterilization container or an EOG sterilization container.
  • the residual rate of sodium chlorite was low, and a decrease in the content of sodium chlorite was observed (Comparative Examples 1 and 3).
  • an aqueous solution containing sodium chlorite, boric acid, borax, and brimonidine tartrate was stored in an EOG sterilization container, the residual rate of sodium chlorite after storage was high, and chlorite.
  • Example 2 Although the decrease in sodium content was suppressed (Example 1), the decrease in sodium chlorite content was not suppressed when stored in an EB sterilized container. In addition, except that the sodium chlorite concentration was increased to 16 mg / 100 mL, even if the aqueous solution had the same composition as in Example 1, the content of sodium chlorite could be reduced by storing it in an EOG sterilization container. It was suppressed (Example 2). Even when the aqueous liquid agent having the same composition as that of Example 1 was stored in an EOG sterilized polyethylene container, the residual rate of sodium chlorite was as high as 97.7%.
  • Test Example 2 1. Manufacture of ophthalmic pharmaceutical products 1-1. Preparation of ophthalmic solution According to the composition shown in Table 2, sodium chlorite (content 80% by weight), boric acid, borax, brimonidine tartrate, sodium chloride, potassium chloride, calcium chloride hydrate, magnesium chloride are added to purified water. Was dissolved in a predetermined amount, and the pH was adjusted to 7.1 with sodium hydroxide or hydrochloric acid to obtain an ophthalmic solution.
  • the EOG sterilization vessel polypropylene or polyethylene eyedropper
  • EB sterile container made of polypropylene eye dropper
  • each sample medicinal product for eye drops
  • the EOG sterilization container used was sterilized under the conditions of an ethylene oxide concentration of 400 to 700 mg / L, a temperature of 40 to 50 ° C., a relative humidity of 45 to 85%, and a treatment time of 3 hours or more.
  • the EB sterilization container used was sterilized by irradiating an electron beam with 60 kGy. Each sterilization condition satisfies the sterility guarantee level in the sterilization validation standard (Yaksik Faculty No. 0215 No. 13).
  • the concentration of brimonidine tartrate in the aqueous solution immediately after preparation and after storage for 14 days was measured by a high performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and the brimonidine tartrate was measured according to the formula shown below.
  • the survival rate (%) was calculated.
  • Detector Ultraviolet absorptiometer (measurement wavelength: 264 nm)
  • Column A stainless steel tube having an inner diameter of 4.6 mm and a length of 7.5 cm was filled with 3.5 ⁇ m of ODS silica gel for high performance liquid chromatography (Symmetry C18 column, manufactured by Waters).
  • Column temperature Constant temperature around 25 ° C
  • Mobile phase 2.3 g of potassium dihydrogen phosphate and 47.5 mg of sodium 1-heptane sulfonate were dissolved in 830 mL of water, and the pH was adjusted to 3.0 using phosphoric acid.
  • 84 mL of acetonitrile and 84 mL of methanol were mixed with this liquid, and water was added to make 1 L.
  • Flow velocity Approximately 1 mL / min

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Abstract

Le but de la présente invention concerne une technologie associée à un produit pharmaceutique qui comprend un liquide aqueux contenant de l'acide chloreux et/ou un sel correspondant et de l'acide borique et/ou un sel correspondant et qui peut supprimer une diminution de la teneur en acide chloreux et/ou en sel correspondant.　L'invention concerne également un produit pharmaceutique formé par réception, dans un récipient soumis à un traitement de stérilisation au gaz, d'un liquide aqueux qui comprend de l'acide chloreux et/ou un sel correspondant, de l'acide borique et/ou un sel correspondant et de la brimonidine et/ou un sel correspondant.
PCT/JP2020/015338 2020-02-19 2020-04-03 Produit pharmaceutique WO2021166274A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011063625A (ja) * 2004-12-09 2011-03-31 Santen Pharmaceut Co Ltd 分子内にフッ素原子を有するプロスタグランジン含有製品
WO2019026992A1 (fr) * 2017-08-03 2019-02-07 参天製薬株式会社 Composition médicinale contenant de la chlorhexidine
JP2019178083A (ja) * 2018-03-30 2019-10-17 参天製薬株式会社 点眼用水溶液

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011063625A (ja) * 2004-12-09 2011-03-31 Santen Pharmaceut Co Ltd 分子内にフッ素原子を有するプロスタグランジン含有製品
WO2019026992A1 (fr) * 2017-08-03 2019-02-07 参天製薬株式会社 Composition médicinale contenant de la chlorhexidine
JP2019178083A (ja) * 2018-03-30 2019-10-17 参天製薬株式会社 点眼用水溶液

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Aiphagan Ophthalmic Solution 0.1%, Package Insert", COMPOSITION/ATTRIBUTES, 2019 *

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