WO2022260050A1 - Liquid preparation of brimonidine - Google Patents

Liquid preparation of brimonidine Download PDF

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Publication number
WO2022260050A1
WO2022260050A1 PCT/JP2022/022997 JP2022022997W WO2022260050A1 WO 2022260050 A1 WO2022260050 A1 WO 2022260050A1 JP 2022022997 W JP2022022997 W JP 2022022997W WO 2022260050 A1 WO2022260050 A1 WO 2022260050A1
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WIPO (PCT)
Prior art keywords
salts
brimonidine
liquid preparation
salt
zinc
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PCT/JP2022/022997
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French (fr)
Japanese (ja)
Inventor
侑美 吉田
Original Assignee
アイ・セラピーズ・エル・エル・シー
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Publication of WO2022260050A1 publication Critical patent/WO2022260050A1/en

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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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • 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
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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 liquid preparations containing brimonidine and/or salts thereof.
  • Brimonidine and its salts are known as ⁇ -2 adrenergic receptor agonists.
  • Human eyes have many ⁇ -2 adrenergic receptors (hereinafter sometimes abbreviated as ⁇ -2 receptors), and ⁇ -2 receptor agonists suppress aqueous humor production and uveal
  • ⁇ -2 receptor agonists are conventionally used for the treatment of glaucoma and ocular hypertension.
  • Agonists of ⁇ -2 receptors also have the effect of causing a reduction in the lumen size of ⁇ -2 receptor concentrating arterioles, particularly terminal arterioles. This action results in vasoconstriction, which can reduce eye redness and increase whiteness, improving the aesthetic appearance of the eye (Patent Document 1: Patent No. 5671459; No. 5738890).
  • Patent Document 3 Japanese Patent Publication No. 2009-533462 describes a composition containing about 1 to 4.5 mM brimonidine and about 2 to 16 mM timolol and having a pH of about 7 to 8.5, It is disclosed that the formation of decomposition products can be suppressed and the stability is improved.
  • Patent Document 4 Japanese Patent Laid-Open No.
  • an aqueous composition containing brimonidine contains an amino compound typified by chlorhexidine, whereby brimonidine in the aqueous composition during high-temperature storage It is disclosed that content reduction can be suppressed.
  • brimonidine and/or its salts as an ophthalmic liquid preparation that alleviates or suppresses ocular hyperemia, it is necessary to have high stability.
  • the present inventors have investigated components that improve the stability of brimonidine and/or salts thereof, and found that at least one anti-inflammatory/constrictor selected from the group consisting of berberine and/or salts thereof and zinc salts can improve the stability of brimonidine and/or salts thereof.
  • One embodiment of the present invention provides an ophthalmic liquid formulation as shown below.
  • the ophthalmic liquid preparation according to item 1 or 2 wherein the concentration of berberine and/or its salt is 0.005 to 0.025 w/v%.
  • the following optical stabilization method is provided.
  • an ophthalmic liquid preparation containing 0.01 to 0.05 w/v% brimonidine and/or a salt thereof, at least one anti-inflammatory agent selected from the group consisting of berberine and/or salts thereof and zinc salts A method for photostabilizing brimonidine and/or its salts in ophthalmic liquid formulations, characterized by incorporating an astringent.
  • At least one selected from the group consisting of berberine and/or salts thereof and zinc salts among antiphlogistic/astringent agents is added to an ophthalmic liquid preparation containing brimonidine and/or salts thereof. can improve stability.
  • brimonidine has the IUPAC name: 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine (5-Bromo-N-(4,5 -dihydro-1H-imidazol-2-yl)quinoxalin-6-amine).
  • concentrations of brimonidine and/or salts thereof are concentrations converted to brimonidine tartrate unless otherwise specified.
  • low-concentration brimonidine refers to brimonidine at a concentration of 0.05 w/v% or less.
  • ophthalmic liquid preparation refers to an aqueous liquid preparation based on water, and refers to ophthalmic preparations, particularly those used for eye drops.
  • photostability refers to the extent to which the content of brimonidine and/or a salt thereof in the ophthalmic liquid formulation is maintained after exposure to a certain amount of light.
  • the term “photostabilization” refers to suppressing a decrease in the content of brimonidine and/or a salt thereof in an ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation, It refers to maintaining a higher residual rate of salt.
  • an ophthalmic liquid preparation containing brimonidine and/or a salt thereof is filled in a colorless glass ampoule, exposed to 600,000 lx hr of white light, and then selected from the group consisting of berberine and/or salts thereof and zinc salts. It means that the content of brimonidine and / or its salt is maintained, that is, the residual rate of brimonidine and / or its salt is higher than when it does not contain at least one anti-inflammatory / astringent agent do.
  • photostabilization method refers to suppressing a decrease in the content of brimonidine and/or a salt thereof in an ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation, It means a method carried out to maintain a higher residual rate of the salt.
  • the term "light stabilizer” refers to suppressing a decrease in the content of brimonidine and/or a salt thereof in an ophthalmic liquid preparation due to exposure to a certain amount of light, and reducing the residual rate of brimonidine and/or a salt thereof. Means an agent that is blended to maintain a higher level.
  • An ophthalmic liquid preparation that is one embodiment of the present invention contains brimonidine and/or a salt thereof, and further contains at least one anti-inflammatory/astringent agent selected from the group consisting of berberine and/or salts thereof and zinc salts. .
  • the salt of brimonidine includes any salt as long as it is a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts of brimonidine include hydrochloride, sulfate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate, succinate, Ascorbate, maleate, methanesulfonate, tartrate and other inorganic carboxylates known to those skilled in the art are included, preferably tartrate.
  • low-concentration brimonidine refers to brimonidine at a concentration of 0.05 w/v% or less.
  • the upper limit of the concentration may be 0.04 w/v% or 0.03 w/v% from the viewpoint of preventing side effects.
  • the lower limit of the concentration is not limited as long as brimonidine is contained, but 0.01 w/v% may be used, and an example is 0.015 w/v%, or 0.02 w/v % may be used.
  • the antiphlogistic/astringent agent can be selected from berberine and/or salts thereof, and zinc salts.
  • Salts of berberine include any salt as long as it is a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts of berberine include chloride, hydrochloride, sulfate, tannate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate. acid salts, succinates, ascorbates, maleates, methanesulfonates, tartrates and other inorganic carboxylates known to those skilled in the art.
  • berberine chloride, berberine sulfate, berberine tannate can be used.
  • Berberine and/or its salts may be hydrates.
  • zinc salts zinc sulfate, zinc lactate, zinc chloride, zinc bromide, zinc iodide, zinc nitrate, zinc phosphate, zinc oxalate, zinc carbonate, zinc acetate can be used.
  • Zinc sulfate and zinc lactate can be used as examples from the viewpoint of blending into eye drops.
  • the zinc salt may be a hydrate.
  • the concentration of the antiphlogistic/astringent agent can be appropriately selected according to its type, and more preferably within the range where it is allowed to be added to eye drops.
  • Berberine and/or its salt can be blended at 0.001 to 0.05 w/v%.
  • the lower limit of the concentration of berberine and/or its salt is, for example, 0.002 w/v%, 0.005 w/v%, or 0.0125 w/v%. can be selected.
  • 0.03 w/v% or 0.025 w/v% can be selected as the upper limit of the concentration of berberine and/or its salt.
  • the concentration of zinc salt can be 0.025 to 0.5 w/v%. From the viewpoint of improving stability and exhibiting anti-inflammatory and astringent effects, it is possible to select, for example, 0.05 w/v%, 0.02 w/v%, or 0.125 w/v% as the lower limit of the zinc salt concentration. can. From the viewpoint of blending into eye drops, 0.3 w/v% or 0.25 w/v% can be selected as the upper limit of zinc and/or its salt concentration.
  • the conjunctiva is a membrane that covers the sclera, which is the white of the eye, and the inner side of the eyelid, and is mainly composed of conjunctival epithelial cells.
  • the epithelial layer of the conjunctiva contains blood vessels, fibrous tissue, and lymphatics.
  • the conjunctiva is in contact with the cornea at the boundary between the white and the iris of the eye, and the cornea and conjunctiva constitute the outermost layer of the eye exposed to the outside world. Since the conjunctiva is exposed to the outside world, it is easily attacked by bacteria and viruses, and inflammation is likely to occur.
  • the active ingredient of the ocularly administered preparation in order for brimonidine and/or a salt thereof to relieve hyperemia, reduce redness of the eye, or whiten the eye, the active ingredient of the ocularly administered preparation must reach capillaries in the conjunctiva to act. It is necessary to
  • the ophthalmic liquid preparation is a water-based liquid preparation, but may further contain any liquid base that can be used for eye drops.
  • the ophthalmic liquid preparation of the present invention is prepared so as to have pH and osmotic pressure acceptable for eye drops.
  • the pH of the ophthalmic liquid preparation can be adjusted to 5.0 to 9.0 using a pH adjusting agent depending on the ingredients, and is 5.5 to 8.5 as an example.
  • pH can be adjusted to 5.0 to 9.0, and pH 5.5 to 8.5 can be selected.
  • a zinc salt when blended into an ophthalmic liquid preparation, precipitation occurs at high pH, so it can be adjusted to pH 5.0 to 7.5. .5 to 6.5 can be selected.
  • the osmotic pressure ratio of the ophthalmic liquid preparation the amounts of ingredients added to the ophthalmic liquid preparation are adjusted so that the ratio is preferably 0.5 to 2.5, more preferably 0.7 to 1.5.
  • the ophthalmic liquid preparation of the present invention is preferably eye drops.
  • the liquid ophthalmic formulation of the present invention may be a liquid formulation that reduces or reduces redness of the eye. Alleviating or suppressing eye redness refers to increasing the whiteness of the white part of the eye and can also be referred to as eye whitening. From the viewpoint of alleviating or suppressing ocular hyperemia, the ophthalmic liquid preparation of the present invention preferably contains a low concentration of brimonidine and/or a salt thereof.
  • Inflammation is one of the causes of hyperemia.
  • brimonidine and/or its salts act via ⁇ -2 receptors to constrict blood vessels and remove hyperemia, but do not remove the cause. Therefore, in ophthalmic liquid preparations containing brimonidine and/or a salt thereof that alleviates or suppresses hyperemia, it is preferable to incorporate an antiphlogistic/astringent from the viewpoint of suppressing the inflammation that is the cause.
  • a light-shielding container can be used for liquid formulations with low photostability.
  • eye drops are intended to be used for a certain period of time after opening. If a light-shielding container is used for the eye drops, it becomes difficult to check the remaining amount or any change in the contents. Therefore, it is desired to use a transparent container for the eye drops. Therefore, it is important to provide formulations with high photostability.
  • a colored transparent container can be used instead of the light-shielding container.
  • the ophthalmic liquid preparation of the present invention can contain any component that can be used in eye drops as long as the effects of the present invention are not impaired.
  • optional ingredients such as optional active ingredients and additives may be included.
  • Such optional ingredients include decongestants, focus adjustment function improving agents, antiphlogistic/astringent agents, antihistamines, vitamins, water retention/nutrient ingredients, sulfa agents, preservatives, pH adjusters, isotonic agents, and thickeners. agents, antioxidants, solubilizers, stabilizers, surfactants, fragrances or cooling agents, but are not intended to be limited to these.
  • active ingredients and additives may be used alone from each category, or may be used in combination of multiple types.
  • Optional ingredients are described below, but may be used for effects other than those listed.
  • ethanol which is used as a cooling agent, may be added to liquid ophthalmic formulations as a preservative.
  • the antiphlogistic/astringent agent used in the present invention is listed as an example of an optional ingredient, it does not mean that these ingredients are optional and are included in the ophthalmic liquid preparation of the present invention. It means that other ingredients different from the anti-inflammatory/astringent agent used may be further added for the purpose of anti-inflammatory/astringent.
  • Vitamins are a general term for organic compounds other than carbohydrates, proteins, and lipids that cannot be synthesized in sufficient amounts within the body of an organism, among the nutrients necessary for the survival or growth of an organism in small amounts. Vitamins are roughly classified into water-soluble vitamins and fat-soluble vitamins. Water-soluble vitamins include B vitamins and vitamin C (ascorbic acid). Fat-soluble vitamins include vitamins A, vitamins D, vitamins E, and vitamins K. The standards for approval for manufacturing (importing) of over-the-counter drugs stipulate vitamins to be compounded in eye drops, and from this point of view, vitamins A, B, and E are particularly preferred.
  • Retinol and its related substances can be used.
  • Retinol-related substances also include retinal, retinoic acid, retinyl palmitate, and other retinoids such as isotretinoin, alitretinoin, acitretin, etretinate, adapalene, tazarotene, and bexarotene.
  • Retinol palmitate or retinol acetate is preferable from the viewpoint of formulation as an eye drop.
  • vitamin A acts on epithelial cells to induce their proliferation, they can be added to eye drops for the purpose of protecting the cornea and conjunctiva. It can also be incorporated into eye drops for the treatment of ophthalmic diseases such as night blindness, xeroconjunctiva, xerocornea, and keratomalacia.
  • vitamin B1 thiamine, etc.
  • vitamin B2, vitamin B3 niacin, etc.
  • vitamin B5, vitamin B6, vitamin B7 (biotin, etc.), vitamin B9 (folic acid, etc.), or vitamin B12 can be used.
  • Vitamins include derivative provitamins and pharmaceutically acceptable salts.
  • vitamin B2, B5, B6, or B12 is preferable from the viewpoint of being blended in eye drops.
  • Vitamin B2 As vitamin B2, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, flavin mononucleotide, or pharmaceutically acceptable salts thereof can be used. Salts include sodium salts, potassium salts, and the like. Flavin adenine dinucleotide sodium is preferred from the viewpoint of being blended as eye drops. Vitamin B2 is directly involved in oxidation-reduction, promotes the enzymatic respiration metabolism of corneal/conjunctival cells when used as an eye drop, and has a protective effect on the cornea/conjunctiva. Vitamin B2 may also be incorporated into eye drops to treat keratitis presumably associated with vitamin B2 deficiency or metabolic disorders.
  • Panthenol, pantothenic acid, derivatives thereof, or salts thereof can be used as vitamin B5.
  • Examples include panthenol, pantothenic acid, and derivatives or salts thereof such as pantethine, pantetheine, pantothenyl alcohol, pantothenyl ethyl ether, pantethein pantothenyl alcohol, calcium pantothenate, and sodium pantothenate.
  • Panthenol, calcium pantothenate, or sodium pantothenate is preferable as vitamin B5 from the viewpoint of use as eye drops.
  • vitamin B6 pyridoxal, pyridoxamine, pyridoxine, or pharmaceutically acceptable salts thereof can be used. Pyridoxine hydrochloride is preferred from the viewpoint of use as eye drops. Vitamin B6 is involved in protein metabolism in vivo as a coenzyme for amino acid decarboxylase and aminotransferase, and can be added to eye drops to suppress eye strain.
  • Vitamin B12 is a compound having a structure in which cobalt is coordinated to a choline ring, and specific examples thereof include cyanocobalamin, mecobalamin (methylcobalamin), hydroxocobalamin, adenosylcobalamin, hydroxocobalamin hydrochloride, and hydroxocobalamin acetate. . Vitamin B12 can be incorporated into eye drops for pharmacological effects such as improving eyestrain and asthenopia.
  • tocopherol, tocotrienol, tocophersolan, or derivatives thereof can be used.
  • Tocopherols and tocotrienols may be ⁇ -, ⁇ -, ⁇ -, or ⁇ -, and may be d- or dl-forms. From the viewpoint of use as eye drops, d- ⁇ -tocopherol acetate is an example.
  • Vitamin C includes ascorbic acid or its salts.
  • vitamin D include vitamin D2 (ergosterol, ergocalciferol), D3 (7-dehydrocholesterol), previtamin D3 (cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), ferol), calcitronic acid), vitamin D4 (dihydroergocalciferol), and vitamin D5 (dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol), and the like.
  • Vitamin Ks include phylloquinone (K1), menaquinone (K2), and menadione (K3).
  • Epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, or salts thereof can be used as decongestants.
  • Neostigmine methyl sulfate can be used as a focus adjustment function improving agent.
  • ⁇ -aminocaproic acid or its salts As antiphlogistic/astringent agents, ⁇ -aminocaproic acid or its salts, allantoin, azulene sulfonic acid or its salts, glycyrrhizic acid or its salts, or lysozyme chloride can be used.
  • diphenhydramine hydrochloride or chlorpheniramine maleate can be used as an antihistamine.
  • Amino acids or salts thereof, and sodium chondroitin sulfate can be used as water-retaining and nutritional ingredients.
  • amino acids are blended into ophthalmic liquid preparations for the purpose of improving stability and conjunctival transferability, but the same or different amino acids can also be blended as water-retaining and nutritional ingredients.
  • Amino acids also relate, besides amino acids, to substances having a sulfate group instead of the carboxyl group of amino acids, such as taurine.
  • Amino acids include, by way of example, glycine, alanine, methionine, valine, threonine, glutamine, glutamic acid, asparagine, aspartic acid, cysteine, histidine, isoleucine, leucine, lysine, phenylalanine, tryptophan, arginine, proline, tyrosine, and serine. be done.
  • Amino acids preferably include aspartic acid, methionine, and glycine.
  • Amino acids other than glycine may be L-amino acids, D-amino acids, or DL-amino acids.
  • Sulfamethoxazole, sulfamethoxazole sodium, sufluisoxazole, or sulfisomidine sodium can be used as sulfa drugs.
  • Preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, benzalkonium chloride, chlorobutanol, sodium chlorite, benzododecinium bromide, and chlorhexidine.
  • Gluconate, sorbate, sodium dehydroacetate, benzoate, benzyl alcohol, alkylpolyaminoethylglycine hydrochloride, polyhexamethylene biguanide, boric acid, borax, or the like may be used.
  • pH adjusters examples include buffers such as citrate buffer, acetate buffer, carbonate buffer, borate buffer, and phosphate buffer, as well as hydrochloric acid, acetic acid, boric acid, carbonic acid, sulfuric acid, phosphoric acid, Acids such as citric acid, tartaric acid and bases such as sodium hydroxide, sodium bicarbonate, sodium carbonate, triethanolamine, monoethanolamine can be used.
  • buffers such as citrate buffer, acetate buffer, carbonate buffer, borate buffer, and phosphate buffer
  • hydrochloric acid acetic acid, boric acid, carbonic acid, sulfuric acid, phosphoric acid
  • Acids such as citric acid, tartaric acid and bases such as sodium hydroxide, sodium bicarbonate, sodium carbonate, triethanolamine, monoethanolamine can be used.
  • tonicity agents include sugars and salts
  • salts include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, Sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like can be used.
  • Any monosaccharide or polysaccharide can be used as the saccharide, and glucose, cyclodextrin, xylitol, sorbitol, mannitol, or the like can be used as an example.
  • sodium chondroitin sulfate polyvinyl alcohol, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, hyaluronic acid, polyvinylpyrrolidone, etc. or salts thereof can be used.
  • nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol, and pluronic; polyhydric alcohols such as glycerin or macrogol, and the like can be used.
  • stabilizers examples include polyvinylpyrrolidone, sulfite, monoethanolamine, glycerin, propylene glycol, polyethylene glycol, cyclodextrin, dextran, ascorbic acid, edetate, taurine, or tocopherol.
  • surfactants include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters, and octoxynol; , amphoteric surfactants such as betaine lauryldimethylaminoacetate; anionic surfactants such as alkyl sulfates, N-acyl taurates, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates; or alkylpyridinium Cationic surfactants such as salts, alkylamine salts, benzalkonium salts, benzethonium salts, dialkyldimethylammonium salts, polyhexamethylene biguanide salts, and the like can be used.
  • nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymers
  • benzalkonium salts alkyldiaminoethylglycine salts, polyhexamethylenebiguanide salts, benzethonium salts, dialkyldimethylammonium salts, etc. can be used as bactericidal surfactants.
  • Flavors or cooling agents include menthol, ethanol, camphor, geraniol, borneol, menthol, rhubarb, fennel oil, cool mint oil, spearmint oil, mint water, mint oil, peppermint oil, bergamot oil, eucalyptus oil, or rose oil. etc. may be used.
  • Test Example 1 Measurement of stability of brimonidine tartrate 1. Preparation of test ophthalmic solution Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) were added to and dissolved in purified water, and berberine chloride hydrate was added as appropriate. (Tokyo Chemical Industry Co., Ltd.) or zinc sulfate hydrate (Fuji Film Wako Pure Chemical Industries, Ltd.) was added and dissolved.
  • Photostability test 1 5 mL of the test ophthalmic solution prepared in , is sealed in a glass ampoule, placed in a photostability tester (LT-120A-WCD, manufactured by Nagano Science Co., Ltd.), exposed to white light of 600,000 lx hr, and the degraded product is Obtained.
  • the brimonidine tartrate content of the degraded product and the undegraded product of each test ophthalmic solution of Comparative Examples and Examples was measured by a high-performance liquid chromatography system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below.
  • the residual ratio (%) of brimonidine tartrate was calculated according to the formula shown below.
  • brimonidine tartrate content The brimonidine tartrate content of each test ophthalmic solution before deterioration and deteriorated product was measured using a high performance liquid chromatography (HPLC) method under the following conditions.
  • HPLC high performance liquid chromatography
  • Detector UV absorption photometer (measurement wavelength: 264 nm)
  • Mobile Phase Dissolve 5.175 g of ammonium dihydrogen phosphate in 900 mL of water and add 100 mL of acetonitrile for liquid chromatography. Flow rate: about 1 mL/min
  • brimonidine tartrate 0.025 w/v % berberine chloride hydrate or 0.25 w/v % zinc sulfate hydrate was added to a test ophthalmic solution containing brimonidine tartrate at a concentration of 0.01-0.05 w/v %.
  • the formulation improved the photostability of brimonidine tartrate.
  • brimonidine tartrate By blending 0.005 to 0.025 w/v% berberine chloride hydrate into a test ophthalmic solution containing brimonidine tartrate at a concentration of 0.01 w/v% or 0.05 w/v%, brimonidine The photostability of tartrate was improved.
  • brimonidine tartrate By adding 0.05-0.25 w/v% zinc sulfate hydrate to a test ophthalmic solution containing brimonidine tartrate at a concentration of 0.01 w/v% or 0.05 w/v%, brimonidine tartrate The photostability of the salt was improved.

Abstract

The purpose of the present invention is to improve the stability of a liquid preparation for ophthalmic use that comprises brimonidine and/or a salt thereof. The present inventors found that the stability can be improved by adding an anti-inflammatory and astringent agent. Based on this finding, provided is a liquid preparation for ophthalmic use that comprises brimonidine and/or a salt thereof and an anti-inflammatory and astringent agent.

Description

ブリモニジンの液体製剤Liquid formulation of brimonidine
　本発明はブリモニジン及び／又はその塩を含有する液体製剤に関する。 The present invention relates to liquid preparations containing brimonidine and/or salts thereof.
　ブリモニジン及びその塩は、α－２アドレナリン受容体アゴニストとして知られている。ヒトの眼は、多くのα－２アドレナリン受容体（以下、α－２受容体と略す場合がある）を有しており、α－２受容体のアゴニストは、眼房水産生抑制と共にぶどう膜強膜流出路を介した眼房水の流出を促進することによって、眼圧を低下させる作用を有する。この作用に基づき、α－２受容体アゴニストは、従来、緑内障や高眼圧症の治療に使用されている。また、α－２受容体のアゴニストは、α－２受容体集中細動脈、特に終末細動脈の内腔サイズの低減を引き起こす作用を有する。この作用により、血管収縮が生じ、目の赤みを低減し、そして白みを増加させ、眼の審美的外観を改善することができる（特許文献１：特許第５６７１４５９号公報；特許文献２：特許第５７３８８９０号公報）。 Brimonidine and its salts are known as α-2 adrenergic receptor agonists. Human eyes have many α-2 adrenergic receptors (hereinafter sometimes abbreviated as α-2 receptors), and α-2 receptor agonists suppress aqueous humor production and uveal This medicine has the effect of lowering intraocular pressure by promoting the outflow of aqueous humor through the scleral outflow tract. Based on this action, α-2 receptor agonists are conventionally used for the treatment of glaucoma and ocular hypertension. Agonists of α-2 receptors also have the effect of causing a reduction in the lumen size of α-2 receptor concentrating arterioles, particularly terminal arterioles. This action results in vasoconstriction, which can reduce eye redness and increase whiteness, improving the aesthetic appearance of the eye (Patent Document 1: Patent No. 5671459; No. 5738890).
　ブリモニジン及び／又はその塩と、チモロール及び／又はその塩を併用した製剤について、製剤安定性に着目した製剤化技術が検討されている。例えば、特許文献３（特表２００９－５３３４６２号公報）には、約１～４．５ｍＭのブリモニジン及び約２～１６ｍＭのチモロールを含有し、ｐＨが約７～８．５である組成物は、分解生成物の生成を抑制でき、安定性が向上していることが開示されている。また、特許文献４（特開２０１７－２２２７０７号公報）には、ブリモニジン及び／又はその塩、並びにブリンゾラミド及び／又はその塩を含む点眼薬を、波長３６０～４６０ｎｍの光の最大透過率が６７％以下であり、且つ波長６００～６８０ｎｍの光の最大透過率が７８％以下である透明収容体に収容することにより、ブリモニジン及び／又はその塩の光暴露による分解を抑制でき、製剤安定性を確保できることが開示されている。さらに、特許文献５（特開２０２０－３３２９０号公報）には、ブリモニジンを含有する水性組成物に、クロルヘキシジンに代表されるアミノ化合物を含有せしめることにより、水性組成物中のブリモニジンの高温保存時の含量低下を抑制できることが開示されている。 For formulations that combine brimonidine and/or its salts with timolol and/or its salts, formulation techniques focusing on formulation stability are being investigated. For example, Patent Document 3 (Japanese Patent Publication No. 2009-533462) describes a composition containing about 1 to 4.5 mM brimonidine and about 2 to 16 mM timolol and having a pH of about 7 to 8.5, It is disclosed that the formation of decomposition products can be suppressed and the stability is improved. Further, Patent Document 4 (Japanese Patent Laid-Open No. 2017-222707) describes eye drops containing brimonidine and/or its salts and brinzolamide and/or its salts with a maximum transmittance of 67% for light with a wavelength of 360 to 460 nm. and the maximum transmittance of light with a wavelength of 600 to 680 nm is 78% or less. It reveals what it can do. Furthermore, in Patent Document 5 (Japanese Patent Application Laid-Open No. 2020-33290), an aqueous composition containing brimonidine contains an amino compound typified by chlorhexidine, whereby brimonidine in the aqueous composition during high-temperature storage It is disclosed that content reduction can be suppressed.
　点眼薬として製剤化する際には、１又は複数の有効成分とともに、周知の添加物が添加される。製剤化にあたり有効成分や添加物を任意に組み合わせることができるわけでなく、有効成分間の相性、有効成分と添加物との相性を鑑みて、製剤全体としての安定性、有効性、安全性などを評価する必要がある。 When formulating eye drops, well-known additives are added along with one or more active ingredients. It is not possible to arbitrarily combine active ingredients and additives in formulations, and in consideration of the compatibility between active ingredients and the compatibility between active ingredients and additives, the stability, efficacy, safety, etc. of the formulation as a whole need to be evaluated.
特許第５６７１４５９号公報Japanese Patent No. 5671459 特許第５７３８８９０号公報Japanese Patent No. 5738890 特表２００９－５３３４６２号公報Japanese Patent Publication No. 2009-533462 特開２０１７－２２２７０７号公報JP 2017-222707 A 特開２０２０－３３２９０号公報Japanese Patent Application Laid-Open No. 2020-33290
　ブリモニジン及び／又はその塩を目の充血を緩和又は抑制する眼科用液体製剤として製剤化するためには、高い安定性を有している必要がある。 In order to formulate brimonidine and/or its salts as an ophthalmic liquid preparation that alleviates or suppresses ocular hyperemia, it is necessary to have high stability.
　そこで、本発明者らが、ブリモニジン及び／又はその塩の安定性を向上する成分について、検討したところ、ベルベリン及び／又はその塩、及び亜鉛塩からなる群から選ばれる少なくとも１の消炎・収れん剤を配合することで、ブリモニジン及び／又はその塩の安定性を向上できることを見出した。 Therefore, the present inventors have investigated components that improve the stability of brimonidine and/or salts thereof, and found that at least one anti-inflammatory/constrictor selected from the group consisting of berberine and/or salts thereof and zinc salts can improve the stability of brimonidine and/or salts thereof.
　本発明の一実施形態として、下記に示す眼科用液体製剤を提供する。
［１］０．０１ｗ／ｖ％～０．０５ｗ／ｖ％のブリモニジン及び／又はその塩、並びにベルベリン及び／又はその塩、及び亜鉛塩からなる群から選ばれる少なくとも１の消炎・収れん剤を含有する眼科用液体製剤。
［２］前記ベルベリン及び／又はその塩が、ベルベリン硫酸塩である、項目１に記載の眼科用液体製剤。
［３］ベルベリン及び／又はその塩の濃度が、０．００５～０．０２５ｗ／ｖ％である、項目１又は２に記載の眼科用液体製剤。
［４］ｐＨが、５．０～９．０である、項目１～３のいずれか一項に記載の眼科用液体製剤。
［５］前記亜鉛塩が、乳酸亜鉛又は硫酸亜鉛である、項目１に記載の眼科用液体製剤。
［６］前記亜鉛塩の濃度が、０．０５～０．２５ｗ／ｖ％である、項目１又は４に記載の眼科用液体製剤。
［７］ｐＨが５．０～７．０である、項目１、５及び６のいずれか一項に記載の眼科用液体製剤。 One embodiment of the present invention provides an ophthalmic liquid formulation as shown below.
[1] 0.01 w/v% to 0.05 w/v% of brimonidine and/or salts thereof, berberine and/or salts thereof, and at least one anti-inflammatory agent selected from the group consisting of zinc salts ophthalmic liquid formulations.
[2] The ophthalmic liquid preparation according to Item 1, wherein the berberine and/or its salt is berberine sulfate.
[3] The ophthalmic liquid preparation according to item 1 or 2, wherein the concentration of berberine and/or its salt is 0.005 to 0.025 w/v%.
[4] The ophthalmic liquid preparation according to any one of items 1 to 3, which has a pH of 5.0 to 9.0.
[5] The ophthalmic liquid preparation according to item 1, wherein the zinc salt is zinc lactate or zinc sulfate.
[6] The ophthalmic liquid preparation according to item 1 or 4, wherein the zinc salt has a concentration of 0.05 to 0.25 w/v%.
[7] The ophthalmic liquid preparation according to any one of items 1, 5 and 6, which has a pH of 5.0 to 7.0.
　また、本発明の一実施形態として、下記に示す光安定化方法を提供する。
［８］　０．０１～０．０５ｗ／ｖ％のブリモニジン及び／又はその塩を含有する眼科用液体製剤において、ベルベリン及び／又はその塩、及び亜鉛塩からなる群から選ばれる少なくとも１の消炎・収れん剤を配合することを特徴とする、眼科用液体製剤中におけるブリモニジン及び／又はその塩の光安定化方法。 Further, as one embodiment of the present invention, the following optical stabilization method is provided.
[8] In an ophthalmic liquid preparation containing 0.01 to 0.05 w/v% brimonidine and/or a salt thereof, at least one anti-inflammatory agent selected from the group consisting of berberine and/or salts thereof and zinc salts A method for photostabilizing brimonidine and/or its salts in ophthalmic liquid formulations, characterized by incorporating an astringent.
　また、本発明の一実施形態として、下記に示す光安定化剤を提供する。
［９］　　０．０１～０．０５ｗ／ｖ％のブリモニジン及び／又はその塩を含有する眼科用液体製剤に使用される、ブリモニジン及び／又はその塩の光安定化剤であって、ベルベリン及び／又はその塩、及び亜鉛塩からなる群から選ばれる少なくとも１の消炎・収れん剤を含有する、前記光安定化剤。 Moreover, as one embodiment of the present invention, the following photostabilizer is provided.
[9] A photostabilizer for brimonidine and/or its salts for use in ophthalmic liquid formulations containing 0.01-0.05 w/v% brimonidine and/or its salts, comprising berberine and/or or a salt thereof, and at least one anti-inflammatory/astringent agent selected from the group consisting of zinc salts.
　本発明によれば、ブリモニジン及び／又はその塩を含む眼科用液体製剤に対し、消炎・収れん剤のうち、ベルベリン及び／又はその塩、及び亜鉛塩からなる群から選ばれる少なくとも１を添加することで、安定性を向上することができる。 According to the present invention, at least one selected from the group consisting of berberine and/or salts thereof and zinc salts among antiphlogistic/astringent agents is added to an ophthalmic liquid preparation containing brimonidine and/or salts thereof. can improve stability.
　本明細書において使用される用語は、特に言及しない限り、当該分野で通常用いられる意味で用いられることが理解される。従って、他に定義されない限り、本明細書中で使用されるすべての専門用語及び科学技術用語は、本発明の属する分野の当業者によって一般的に理解されるのと同じ意味を有する。本明細書で特定される数値範囲は、その下限値及び上限値を含むものとする。 It is understood that the terms used in this specification have the meanings commonly used in the field unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Numerical ranges specified herein are intended to be inclusive of their lower and upper limits.
（定義）
　本明細書において、「ブリモニジン」は、ＩＵＰＡＣ名：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（５－Ｂｒｏｍｏ－Ｎ－（４，５－ｄｉｈｙｄｒｏ－１Ｈ－ｉｍｉｄａｚｏｌ－２－ｙｌ）ｑｕｉｎｏｘａｌｉｎ－６－ａｍｉｎｅ）の化合物を指す。また、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。 (definition)
As used herein, "brimonidine" has the IUPAC name: 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine (5-Bromo-N-(4,5 -dihydro-1H-imidazol-2-yl)quinoxalin-6-amine). In addition, in the present specification, concentrations of brimonidine and/or salts thereof are concentrations converted to brimonidine tartrate unless otherwise specified.
　本明細書において、「低濃度のブリモニジン」とは、０．０５ｗ／ｖ％以下の濃度のブリモニジンを指す。 As used herein, "low-concentration brimonidine" refers to brimonidine at a concentration of 0.05 w/v% or less.
　本明細書において、「眼科用液体製剤」とは、水を基剤とする水性液体製剤であり、眼科用製剤、特に点眼に用いられる製剤を指す。 As used herein, the term "ophthalmic liquid preparation" refers to an aqueous liquid preparation based on water, and refers to ophthalmic preparations, particularly those used for eye drops.
　本明細書において、「光安定性」とは、眼科用液体製剤を一定量の光に曝露した後の製剤中のブリモニジン及び／又はその塩の含量が維持された度合いを指す。 As used herein, "photostability" refers to the extent to which the content of brimonidine and/or a salt thereof in the ophthalmic liquid formulation is maintained after exposure to a certain amount of light.
　本明細書において、「光安定化」とは、眼科用液体製剤中の一定量の光の曝露による眼科用液体製剤中のブリモニジン及び／又はその塩の含量低下を抑制し、ブリモニジン及び／又はその塩の残存率をより高く維持することをいう。一例としてブリモニジン及び／又はその塩を含有する眼科用液体製剤を無色ガラスアンプルに充填し、白色光６０万ｌｘ・ｈｒに曝露した後に、ベルベリン及び／又はその塩、及び亜鉛塩からなる群から選ばれる少なくとも１の消炎・収れん剤を含有していない場合と比較して、ブリモニジン及び／又はその塩の含量が維持されていること、すなわちブリモニジン及び／又はその塩の残存率がより高いことを意味する。 As used herein, the term “photostabilization” refers to suppressing a decrease in the content of brimonidine and/or a salt thereof in an ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation, It refers to maintaining a higher residual rate of salt. As an example, an ophthalmic liquid preparation containing brimonidine and/or a salt thereof is filled in a colorless glass ampoule, exposed to 600,000 lx hr of white light, and then selected from the group consisting of berberine and/or salts thereof and zinc salts. It means that the content of brimonidine and / or its salt is maintained, that is, the residual rate of brimonidine and / or its salt is higher than when it does not contain at least one anti-inflammatory / astringent agent do.
　本明細書において、「光安定化方法」とは、眼科用液体製剤中の一定量の光の曝露による眼科用液体製剤中のブリモニジン及び／又はその塩の含量低下を抑制し、ブリモニジン及び／又はその塩の残存率をより高く維持するために行われる方法を意味する。 As used herein, the term "photostabilization method" refers to suppressing a decrease in the content of brimonidine and/or a salt thereof in an ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation, It means a method carried out to maintain a higher residual rate of the salt.
　本明細書において、「光安定化剤」とは、一定量の光の曝露による眼科用液体製剤中のブリモニジン及び／又はその塩の含量低下を抑制し、ブリモニジン及び／又はその塩の残存率をより高く維持するために配合される剤を意味する。 As used herein, the term "light stabilizer" refers to suppressing a decrease in the content of brimonidine and/or a salt thereof in an ophthalmic liquid preparation due to exposure to a certain amount of light, and reducing the residual rate of brimonidine and/or a salt thereof. Means an agent that is blended to maintain a higher level.
（好ましい実施形態の説明）
　以下に本発明の好ましい実施形態を説明する。以下に提供される実施形態は、本発明のよりよい理解のために提供されるものであり、本発明の範囲は以下の記載に限定されるべきでないことが理解される。従って、当業者は、本明細書中の記載を参酌して、本発明の範囲内で適宜改変を行うことができることは明らかである。また、以下の実施形態は単独でも使用されあるいはそれらを組み合わせて使用することができることが理解される。 (Description of the preferred embodiment)
Preferred embodiments of the present invention are described below. The embodiments provided below are provided for a better understanding of the invention, and it is understood that the scope of the invention should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present invention in light of the description in this specification. It is also understood that the following embodiments can be used singly or in combination.
　本発明の一実施形態である眼科用液体製剤は、ブリモニジン及び／又はその塩を含有し、さらにベルベリン及び／又はその塩、及び亜鉛塩からなる群から選ばれる少なくとも１の消炎・収れん剤を含む。 An ophthalmic liquid preparation that is one embodiment of the present invention contains brimonidine and/or a salt thereof, and further contains at least one anti-inflammatory/astringent agent selected from the group consisting of berberine and/or salts thereof and zinc salts. .
　ブリモニジンの塩としては、医薬として許容される塩であれば任意の塩が挙げられる。ブリモニジンの医薬として許容される塩として、塩酸塩、硫酸塩、リン酸塩、酢酸塩、クエン酸塩、シュウ酸塩、マロン酸塩、サリチル酸塩、リンゴ酸塩、フマル酸塩、コハク酸塩、アスコルビン酸塩、マレイン酸塩、メタンスルホン酸塩、酒石酸塩および当業者に周知の他の無機カルボン酸塩が挙げられ、好ましくは酒石酸塩である。 The salt of brimonidine includes any salt as long as it is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of brimonidine include hydrochloride, sulfate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate, succinate, Ascorbate, maleate, methanesulfonate, tartrate and other inorganic carboxylates known to those skilled in the art are included, preferably tartrate.
　本発明において、低濃度のブリモニジンとは、０．０５ｗ／ｖ％以下の濃度のブリモニジンを指す。一例として、濃度の上限は、副作用を予防する観点から０．０４ｗ／ｖ％、又は０．０３ｗ／ｖ％であってもよい。濃度の下限は、ブリモニジンが含有される限り限定されないが、０．０１ｗ／ｖ％が用いられてもよく、一例として本剤の効果を鑑み、０．０１５ｗ／ｖ％、又は０．０２ｗ／ｖ％が用いられてもよい。 In the present invention, low-concentration brimonidine refers to brimonidine at a concentration of 0.05 w/v% or less. As an example, the upper limit of the concentration may be 0.04 w/v% or 0.03 w/v% from the viewpoint of preventing side effects. The lower limit of the concentration is not limited as long as brimonidine is contained, but 0.01 w/v% may be used, and an example is 0.015 w/v%, or 0.02 w/v % may be used.
　本発明において消炎・収れん剤としては、ベルベリン及び／又はその塩、及び亜鉛塩から選択されうる。ベルベリンの塩としては、医薬として許容される塩であれば任意の塩が挙げられる。ベルベリンの医薬として許容される塩として、塩化物、塩酸塩、硫酸塩、タンニン酸塩、リン酸塩、酢酸塩、クエン酸塩、シュウ酸塩、マロン酸塩、サリチル酸塩、リンゴ酸塩、フマル酸塩、コハク酸塩、アスコルビン酸塩、マレイン酸塩、メタンスルホン酸塩、酒石酸塩および当業者に周知の他の無機カルボン酸塩が挙げられる。一例として、塩化ベルベリン、硫酸ベルベリン、タンニン酸ベルベリンが使用されうる。ベルベリン及び／又はその塩は、水和物であってもよい。亜鉛塩として、硫酸亜鉛、乳酸亜鉛、塩化亜鉛、臭化亜鉛、ヨウ化亜鉛、硝酸亜鉛、リン酸亜鉛、シュウ酸亜鉛、炭酸亜鉛、酢酸亜鉛が使用されうる。点眼剤へ配合する観点から、一例として硫酸亜鉛、乳酸亜鉛が使用されうる。亜鉛塩は、水和物であってもよい。 In the present invention, the antiphlogistic/astringent agent can be selected from berberine and/or salts thereof, and zinc salts. Salts of berberine include any salt as long as it is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of berberine include chloride, hydrochloride, sulfate, tannate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate. acid salts, succinates, ascorbates, maleates, methanesulfonates, tartrates and other inorganic carboxylates known to those skilled in the art. As an example, berberine chloride, berberine sulfate, berberine tannate can be used. Berberine and/or its salts may be hydrates. As zinc salts zinc sulfate, zinc lactate, zinc chloride, zinc bromide, zinc iodide, zinc nitrate, zinc phosphate, zinc oxalate, zinc carbonate, zinc acetate can be used. Zinc sulfate and zinc lactate can be used as examples from the viewpoint of blending into eye drops. The zinc salt may be a hydrate.
　消炎・収れん剤の濃度は、その種類に応じて適宜選択することができ、より好ましくは点眼剤への配合が許容されている範囲で選択することができる。ベルベリン及び／又はその塩としては、０．００１～０．０５ｗ／ｖ％で配合することができる。安定性の向上及び消炎・収れん効果を発揮する観点から、ベルベリン及び／又はその塩の濃度の下限として、例えば０．００２ｗ／ｖ％、０．００５ｗ／ｖ％、又は０．０１２５ｗ／ｖ％を選択することができる。点眼剤へ配合する観点から、ベルベリン及び／又はその塩の濃度の上限として０．０３ｗ／ｖ％、又は０．０２５ｗ／ｖ％を選択することができる。亜鉛塩の濃度としては、０．０２５～０．５ｗ／ｖ％で配合することができる。安定性の向上及び消炎・収れん効果を発揮する観点から、亜鉛塩の濃度の下限として、例えば０．０５ｗ／ｖ％、０．０２ｗ／ｖ％、又は０．１２５ｗ／ｖ％を選択することができる。点眼剤へ配合する観点から、亜鉛及び／又はその塩の濃度の上限として０．３ｗ／ｖ％、又は０．２５ｗ／ｖ％を選択することができる。 The concentration of the antiphlogistic/astringent agent can be appropriately selected according to its type, and more preferably within the range where it is allowed to be added to eye drops. Berberine and/or its salt can be blended at 0.001 to 0.05 w/v%. From the viewpoint of improving stability and exhibiting anti-inflammatory and astringent effects, the lower limit of the concentration of berberine and/or its salt is, for example, 0.002 w/v%, 0.005 w/v%, or 0.0125 w/v%. can be selected. From the viewpoint of blending into eye drops, 0.03 w/v% or 0.025 w/v% can be selected as the upper limit of the concentration of berberine and/or its salt. The concentration of zinc salt can be 0.025 to 0.5 w/v%. From the viewpoint of improving stability and exhibiting anti-inflammatory and astringent effects, it is possible to select, for example, 0.05 w/v%, 0.02 w/v%, or 0.125 w/v% as the lower limit of the zinc salt concentration. can. From the viewpoint of blending into eye drops, 0.3 w/v% or 0.25 w/v% can be selected as the upper limit of zinc and/or its salt concentration.
　結膜は、白目である強膜上を覆い、かつ瞼の内側を覆う膜であり、結膜上皮細胞から主に構成される。結膜の上皮層には血管、繊維組織、リンパ管が含まれる。結膜は白目と黒目の境界で角膜と接しており、角膜と結膜は外界にさらされる目の最外層を構成する。結膜は外界にさらされていることから、細菌やウイルスなどに侵されやすく、炎症が生じやすい。また炎症が起こっていない場合であっても、寝不足や目の酷使により、目に酸素や栄養を供給するために血流量が増えて充血する。本発明においてブリモニジン及び／又はその塩が、充血緩和、目の赤みの低減又は白化という作用を発揮するためには、点眼投与された製剤の有効成分が、結膜内の毛細血管に到達して作用することが必要となる。 The conjunctiva is a membrane that covers the sclera, which is the white of the eye, and the inner side of the eyelid, and is mainly composed of conjunctival epithelial cells. The epithelial layer of the conjunctiva contains blood vessels, fibrous tissue, and lymphatics. The conjunctiva is in contact with the cornea at the boundary between the white and the iris of the eye, and the cornea and conjunctiva constitute the outermost layer of the eye exposed to the outside world. Since the conjunctiva is exposed to the outside world, it is easily attacked by bacteria and viruses, and inflammation is likely to occur. Also, even when inflammation does not occur, due to lack of sleep or overuse of the eyes, blood flow increases to supply oxygen and nutrients to the eyes, resulting in congestion. In the present invention, in order for brimonidine and/or a salt thereof to relieve hyperemia, reduce redness of the eye, or whiten the eye, the active ingredient of the ocularly administered preparation must reach capillaries in the conjunctiva to act. It is necessary to
　本発明において眼科用液体製剤は、水を基剤とする水性液体製剤であるが、点眼薬に使用しうる任意の液体基剤をさらに含んでいてもよい。本発明の眼科用液体製剤は、点眼薬として許容されるｐＨ、浸透圧を有するように調製される。眼科用液体製剤のｐＨは、配合成分に応じてｐＨ調整剤を使用して５．０～９．０に調整することができ、一例として５．５～８．５である。眼科用液体製剤にベルベリン及び／又はその塩を配合する場合、ｐＨ５．０～９．０に調整することができ、さらにはｐＨ５．５～８．５を選択することができる。一方、眼科用液体製剤に亜鉛塩を配合する場合、高ｐＨでは析出が生じるため、５．０～７．５に調整することができ、一例として、ｐＨ５．０～７．０、さらにはｐＨ５．５～６．５を選択することができる。眼科用液体製剤の浸透圧比の一例として、好ましくは０．５～２．５、より好ましくは０．７～１．５になるように眼科用液体製剤に添加する成分量を調節される。 In the present invention, the ophthalmic liquid preparation is a water-based liquid preparation, but may further contain any liquid base that can be used for eye drops. The ophthalmic liquid preparation of the present invention is prepared so as to have pH and osmotic pressure acceptable for eye drops. The pH of the ophthalmic liquid preparation can be adjusted to 5.0 to 9.0 using a pH adjusting agent depending on the ingredients, and is 5.5 to 8.5 as an example. When blending berberine and/or a salt thereof in an ophthalmic liquid preparation, pH can be adjusted to 5.0 to 9.0, and pH 5.5 to 8.5 can be selected. On the other hand, when a zinc salt is blended into an ophthalmic liquid preparation, precipitation occurs at high pH, so it can be adjusted to pH 5.0 to 7.5. .5 to 6.5 can be selected. As an example of the osmotic pressure ratio of the ophthalmic liquid preparation, the amounts of ingredients added to the ophthalmic liquid preparation are adjusted so that the ratio is preferably 0.5 to 2.5, more preferably 0.7 to 1.5.
　本発明の眼科用液体製剤は、好ましくは点眼薬である。本発明の眼科用液体製剤は、目の充血を緩和するまたは抑制する液体製剤であってもよい。目の充血を緩和するまたは抑制するとは、白目部分の白みを増加させることを言い、目のホワイトニングともいうことができる。目の充血を緩和するまたは抑制する観点から、本発明の眼科用液体製剤は、低濃度のブリモニジン及び／又はその塩を含むことが好ましい。 The ophthalmic liquid preparation of the present invention is preferably eye drops. The liquid ophthalmic formulation of the present invention may be a liquid formulation that reduces or reduces redness of the eye. Alleviating or suppressing eye redness refers to increasing the whiteness of the white part of the eye and can also be referred to as eye whitening. From the viewpoint of alleviating or suppressing ocular hyperemia, the ophthalmic liquid preparation of the present invention preferably contains a low concentration of brimonidine and/or a salt thereof.
　充血の原因の一つとして炎症が挙げられる。一方で、ブリモニジン及び／又はその塩は、α－２受容体を介して作用し、血管を収縮して充血を除去するものであり、原因を取り除くわけではない。したがって、充血を緩和又は抑制するブリモニジン及び／又はその塩を含有する眼科用液体製剤において、原因である炎症を抑制する観点で、消炎・収れん剤を配合することが好ましい。 Inflammation is one of the causes of hyperemia. On the other hand, brimonidine and/or its salts act via α-2 receptors to constrict blood vessels and remove hyperemia, but do not remove the cause. Therefore, in ophthalmic liquid preparations containing brimonidine and/or a salt thereof that alleviates or suppresses hyperemia, it is preferable to incorporate an antiphlogistic/astringent from the viewpoint of suppressing the inflammation that is the cause.
　光安定性の低い液体製剤については、遮光容器を用いることができる。しかしながら、点眼薬は開封後、一定の期間にわたって使用されるものである。点眼薬として遮光容器を用いると、残存量や内容物の異変の確認が難しくなることから、点眼薬は透明容器を使用することが望まれている。したがって、光安定性の高い製剤の提供が重要になる。また、遮光容器の代わりに着色された透明容器を用いることもできる。 A light-shielding container can be used for liquid formulations with low photostability. However, eye drops are intended to be used for a certain period of time after opening. If a light-shielding container is used for the eye drops, it becomes difficult to check the remaining amount or any change in the contents. Therefore, it is desired to use a transparent container for the eye drops. Therefore, it is important to provide formulations with high photostability. Also, a colored transparent container can be used instead of the light-shielding container.
　本発明の眼科用液体製剤は、点眼薬に使用しうる任意の成分を、本発明の効果を損なわない範囲で含有することができる。本発明の有効成分であるブリモニジン酒石酸塩とは別に、任意の有効成分及び添加物などの任意的成分を含んでもよい。このような任意的成分としては、充血除去剤、ピント調節機能改善剤、消炎・収れん剤、抗ヒスタミン剤、ビタミン類、保水・栄養成分、サルファ剤、保存剤、ｐＨ調整剤、等張化剤、増粘剤、抗酸化剤、溶解補助剤、安定化剤、界面活性剤、香料または清涼化剤などが挙げられるが、これらに限定されることを意図するものではない。これらの有効成分及び添加剤は、それぞれ各カテゴリーの中から１種類のみを用いてもよいし、複数の種類を組み合わせて使用することができる。以下に、任意的成分を説明するが、列挙された作用以外の作用を目的として使用されてもよい。例えば清涼化剤として用いられるエタノールは、保存剤として眼科用液体製剤に添加されていてもよい。本発明において使用される消炎・収れん剤が、任意的成分の一例として列挙されているが、これらの成分が任意的に用いられることを意味するものではなく、本発明の眼科用液体製剤に含まれる消炎・収れん剤とは異なる他の成分が消炎・収れんの目的でさらに配合されうることを意味する。 The ophthalmic liquid preparation of the present invention can contain any component that can be used in eye drops as long as the effects of the present invention are not impaired. In addition to brimonidine tartrate, which is the active ingredient of the present invention, optional ingredients such as optional active ingredients and additives may be included. Such optional ingredients include decongestants, focus adjustment function improving agents, antiphlogistic/astringent agents, antihistamines, vitamins, water retention/nutrient ingredients, sulfa agents, preservatives, pH adjusters, isotonic agents, and thickeners. agents, antioxidants, solubilizers, stabilizers, surfactants, fragrances or cooling agents, but are not intended to be limited to these. These active ingredients and additives may be used alone from each category, or may be used in combination of multiple types. Optional ingredients are described below, but may be used for effects other than those listed. For example, ethanol, which is used as a cooling agent, may be added to liquid ophthalmic formulations as a preservative. Although the antiphlogistic/astringent agent used in the present invention is listed as an example of an optional ingredient, it does not mean that these ingredients are optional and are included in the ophthalmic liquid preparation of the present invention. It means that other ingredients different from the anti-inflammatory/astringent agent used may be further added for the purpose of anti-inflammatory/astringent.
　ビタミン類とは、生物の生存又は生育に微量に必要な栄養素のうち、その生物の体内で十分な量を合成できない炭水化物・タンパク質・脂質以外の有機化合物の総称である。ビタミン類は、水溶性ビタミン類と、脂溶性ビタミン類に大別される。水溶性ビタミン類としては、ビタミンＢ類及びビタミンＣ（アスコルビン酸）が挙げられる。脂溶性ビタミンとしては、ビタミンＡ類、ビタミンＤ類、ビタミンＥ類、及びビタミンＫ類が挙げられる。一般用医薬品製造（輸入）承認基準では、点眼薬に配合されるビタミン類が規定されており、この観点から、特にビタミンＡ類、ビタミンＢ類、又はビタミンＥ類が好ましい。 Vitamins are a general term for organic compounds other than carbohydrates, proteins, and lipids that cannot be synthesized in sufficient amounts within the body of an organism, among the nutrients necessary for the survival or growth of an organism in small amounts. Vitamins are roughly classified into water-soluble vitamins and fat-soluble vitamins. Water-soluble vitamins include B vitamins and vitamin C (ascorbic acid). Fat-soluble vitamins include vitamins A, vitamins D, vitamins E, and vitamins K. The standards for approval for manufacturing (importing) of over-the-counter drugs stipulate vitamins to be compounded in eye drops, and from this point of view, vitamins A, B, and E are particularly preferred.
　ビタミンＡ類としては、レチノール、及びその関連物質が使用されうる。レチノール関連物質として、レチナール、レチノイン酸、パルミチン酸レチノールやその他のレチノイド、例えばイソトレチノイン、アリトレチノイン、アシトレチン、エトレチナート、アダパレン、タザロテン、及びベキサロテン等も挙げられる。点眼薬として配合する観点からパルミチン酸レチノール、又は酢酸レチノールが好ましい。ビタミンＡ類は上皮細胞に作用し増殖を誘導することから、角膜や結膜保護等を目的として点眼薬に配合されうる。夜盲症、結膜乾燥症、角膜乾燥症、角膜軟化症等の眼科系疾患の治療のためにも点眼薬に配合されうる。 As vitamin A, retinol and its related substances can be used. Retinol-related substances also include retinal, retinoic acid, retinyl palmitate, and other retinoids such as isotretinoin, alitretinoin, acitretin, etretinate, adapalene, tazarotene, and bexarotene. Retinol palmitate or retinol acetate is preferable from the viewpoint of formulation as an eye drop. Since vitamin A acts on epithelial cells to induce their proliferation, they can be added to eye drops for the purpose of protecting the cornea and conjunctiva. It can also be incorporated into eye drops for the treatment of ophthalmic diseases such as night blindness, xeroconjunctiva, xerocornea, and keratomalacia.
　ビタミンＢ類としては、ビタミンＢ１（チアミン等）、ビタミンＢ２、ビタミンＢ３（ナイアシン等）、ビタミンＢ５、ビタミンＢ６、ビタミンＢ７（ビオチン等）、ビタミンＢ９（葉酸等）、又はビタミンＢ１２が使用されうる。ビタミン類には、誘導体であるプロビタミンや医薬として許容される塩を包含する。ビタミンＢ類の中でも、特に点眼薬に配合される観点から、ビタミンＢ２、Ｂ５、Ｂ６、又はＢ１２が好ましい。 As the B vitamins, vitamin B1 (thiamine, etc.), vitamin B2, vitamin B3 (niacin, etc.), vitamin B5, vitamin B6, vitamin B7 (biotin, etc.), vitamin B9 (folic acid, etc.), or vitamin B12 can be used. . Vitamins include derivative provitamins and pharmaceutically acceptable salts. Among B vitamins, vitamin B2, B5, B6, or B12 is preferable from the viewpoint of being blended in eye drops.
　ビタミンＢ２としてはリボフラビン、リン酸リボフラビン、酪酸リボフラビン、酢酸リボフラビン、フラビンアデニンジヌクレオチド、フラビンモノヌクレオチド、又は薬学的に許容されるそれらの塩等が使用されうる。塩としては、ナトリウム塩、及びカリウム塩等が挙げられる。点眼薬として配合される観点からフラビンアデニンジヌクレイオチドナトリウムが好ましい。ビタミンＢ２は、酸化還元に直接関与し、点眼薬として使用されると角膜・結膜細胞の酵素呼吸代謝を促進し、角膜・結膜の保護作用を有する。またビタミンＢ２は、ビタミンＢ２欠乏または代謝障害が関与すると推定される角膜炎に対して治療のために点眼薬に配合されうる。 As vitamin B2, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, flavin mononucleotide, or pharmaceutically acceptable salts thereof can be used. Salts include sodium salts, potassium salts, and the like. Flavin adenine dinucleotide sodium is preferred from the viewpoint of being blended as eye drops. Vitamin B2 is directly involved in oxidation-reduction, promotes the enzymatic respiration metabolism of corneal/conjunctival cells when used as an eye drop, and has a protective effect on the cornea/conjunctiva. Vitamin B2 may also be incorporated into eye drops to treat keratitis presumably associated with vitamin B2 deficiency or metabolic disorders.
　ビタミンＢ５としてはパンテノール、パントテン酸又はそれらの誘導体又はそれらの塩が使用されうる。一例として、パンテノール、パントテン酸の他に、誘導体又はそれらの塩として、パンテチン、パンテテイン、パントテニールアルコール、パントテニールエチルエーテル、パンテテインパントテニールアルコール、パントテン酸カルシウム、及びパントテン酸ナトリウム等が挙げられる。点眼薬として使用される観点から、ビタミンＢ５としてはパンテノール、パントテン酸カルシウム、又はパントテン酸ナトリウムが好ましい。 Panthenol, pantothenic acid, derivatives thereof, or salts thereof can be used as vitamin B5. Examples include panthenol, pantothenic acid, and derivatives or salts thereof such as pantethine, pantetheine, pantothenyl alcohol, pantothenyl ethyl ether, pantethein pantothenyl alcohol, calcium pantothenate, and sodium pantothenate. . Panthenol, calcium pantothenate, or sodium pantothenate is preferable as vitamin B5 from the viewpoint of use as eye drops.
　ビタミンＢ６としては、ピリドキサール、ピリドキサミン、ピリドキシン又はそれらの医薬として許容される塩が使用されうる。点眼薬として使用される観点から、ピリドキシン塩酸塩が好ましい。ビタミンＢ６は、生体内でアミノ酸脱炭酸酵素及びアミノ基転移酵素の補酵素として、タンパク質の代謝に関わっており、眼精疲労の抑制のために点眼薬に配合されうる。 As vitamin B6, pyridoxal, pyridoxamine, pyridoxine, or pharmaceutically acceptable salts thereof can be used. Pyridoxine hydrochloride is preferred from the viewpoint of use as eye drops. Vitamin B6 is involved in protein metabolism in vivo as a coenzyme for amino acid decarboxylase and aminotransferase, and can be added to eye drops to suppress eye strain.
　ビタミンＢ１２はコリン環にコバルトが配位した構造を有する化合物であり、具体的には、シアノコバラミン、メコバラミン（メチルコバラミン）、ヒドロキソコバラミン、アデノシルコバラミン、塩酸ヒドロキソコバラミン、及び酢酸ヒドロキソコバラミン等が挙げられる。ビタミンＢ１２は疲れ目や眼精疲労の改善等の薬理作用のために点眼薬に配合されうる。 Vitamin B12 is a compound having a structure in which cobalt is coordinated to a choline ring, and specific examples thereof include cyanocobalamin, mecobalamin (methylcobalamin), hydroxocobalamin, adenosylcobalamin, hydroxocobalamin hydrochloride, and hydroxocobalamin acetate. . Vitamin B12 can be incorporated into eye drops for pharmacological effects such as improving eyestrain and asthenopia.
　ビタミンＥ類としては、トコフェロール、トコトリエノール、トコフェルソラン、又はそれらの誘導体が使用されうる。トコフェロール及びトコトリエノールは、α－、β－、γ－、δ－のいずれであってもよく、また、ｄ体、ｄｌ体のいずれであってもよい。点眼薬として使用される観点から、一例として酢酸ｄ－α－トコフェロールが挙げられる。 As vitamin E, tocopherol, tocotrienol, tocophersolan, or derivatives thereof can be used. Tocopherols and tocotrienols may be α-, β-, γ-, or δ-, and may be d- or dl-forms. From the viewpoint of use as eye drops, d-α-tocopherol acetate is an example.
　ビタミンＣとしては、アスコルビン酸又はその塩が挙げられる。ビタミンＤ類としては、ビタミンＤ２（エルゴステロール、エルゴカルシフェロール）、Ｄ３（７－デヒドロコレステロール）、プレビタミンＤ３（コレカルシフェロール、２５－ヒドロキシコレカルシフェロール、カルシトリオール（１，２５－ジヒドロキシコレカルシフェロール）、カルシトロン酸）、ビタミンＤ４（ジヒドロエルゴカルシフェロール）、及びビタミンＤ５（ジヒドロタキステロール・カルシポトリオール・タカルシトール・パリカルシトール）等が挙げられる。ビタミンＫ類としては、フィロキノン（Ｋ１）、メナキノン（Ｋ２）、及びメナジオン（Ｋ３）が挙げられる。 Vitamin C includes ascorbic acid or its salts. Examples of vitamin D include vitamin D2 (ergosterol, ergocalciferol), D3 (7-dehydrocholesterol), previtamin D3 (cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), ferol), calcitronic acid), vitamin D4 (dihydroergocalciferol), and vitamin D5 (dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol), and the like. Vitamin Ks include phylloquinone (K1), menaquinone (K2), and menadione (K3).
　充血除去剤としては、エピネフリン、エフェドリン、テトラヒドロゾリン、ナファゾリン、フェニレフリン、メチルエフェドリン、又はそれらの塩が使用されうる。 Epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, or salts thereof can be used as decongestants.
　ピント調節機能改善剤としては、メチル硫酸ネオスチグミンが使用されうる。 Neostigmine methyl sulfate can be used as a focus adjustment function improving agent.
　消炎・収れん剤としては、ε－アミノカプロン酸又はその塩、アラントイン、アズレンスルホン酸又はその塩、グリチルリチン酸又はその塩、又は塩化リゾチームが使用されうる。 As antiphlogistic/astringent agents, ε-aminocaproic acid or its salts, allantoin, azulene sulfonic acid or its salts, glycyrrhizic acid or its salts, or lysozyme chloride can be used.
　抗ヒスタミン剤としては、塩酸ジフェンヒドラミン、又はマレイン酸クロルフェニラミンが使用されうる。 As an antihistamine, diphenhydramine hydrochloride or chlorpheniramine maleate can be used.
　保水・栄養成分としては、アミノ酸類又はその塩、コンドロイチン硫酸エステルナトリウムが使用されうる。本発明においてアミノ酸類は、安定性の向上及び結膜移行性の向上を目的として眼科用液体製剤に配合されるが、保水・栄養成分として同一又は異なるアミノ酸類を配合することもできる。アミノ酸類とは、アミノ酸以外に、アミノ酸のカルボキシル基の代わりに硫酸基を有する物質、例えばタウリンにも関する。アミノ酸としては、一例として、グリシン、アラニン、メチオニン、バリン、トレオニン、グルタミン、グルタミン酸、アスパラギン、アスパラギン酸、システイン、ヒスチジン、イソロイシン、ロイシン、リシン、フェニルアラニン、トリプトファン、アルギニン、プロリン、チロシン、及びセリンが挙げられる。アミノ酸としては、好ましくはアスパラギン酸、メチオニン、及びグリシンが挙げられる。グリシンを除くアミノ酸は、Ｌ体のアミノ酸であってもよいし、Ｄ体のアミノ酸であってもよいし、又はＤＬ体のアミノ酸であってもよい。 Amino acids or salts thereof, and sodium chondroitin sulfate can be used as water-retaining and nutritional ingredients. In the present invention, amino acids are blended into ophthalmic liquid preparations for the purpose of improving stability and conjunctival transferability, but the same or different amino acids can also be blended as water-retaining and nutritional ingredients. Amino acids also relate, besides amino acids, to substances having a sulfate group instead of the carboxyl group of amino acids, such as taurine. Amino acids include, by way of example, glycine, alanine, methionine, valine, threonine, glutamine, glutamic acid, asparagine, aspartic acid, cysteine, histidine, isoleucine, leucine, lysine, phenylalanine, tryptophan, arginine, proline, tyrosine, and serine. be done. Amino acids preferably include aspartic acid, methionine, and glycine. Amino acids other than glycine may be L-amino acids, D-amino acids, or DL-amino acids.
　サルファ剤としては、スルファメトキサゾール、スフファメトキサゾールナトリウム、スフルイソキサゾール、又はスルフイソミジンナトリウムが使用されうる。 Sulfamethoxazole, sulfamethoxazole sodium, sufluisoxazole, or sulfisomidine sodium can be used as sulfa drugs.
　保存剤としては、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、硫酸オキシキノリン、ベンザルコニウム塩化物、クロロブタノール、亜塩素酸ナトリウム、ベンゾドデシニウム臭化物、クロルヘキシジングルコン酸塩、ソルビン酸塩、デヒドロ酢酸ナトリウム、安息香酸塩、ベンジルアルコール、アルキルポリアミノエチルグリシン塩酸塩、ポリヘキサメチレンビグアニド、ホウ酸、又はホウ砂などが使用されうる。 Preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, benzalkonium chloride, chlorobutanol, sodium chlorite, benzododecinium bromide, and chlorhexidine. Gluconate, sorbate, sodium dehydroacetate, benzoate, benzyl alcohol, alkylpolyaminoethylglycine hydrochloride, polyhexamethylene biguanide, boric acid, borax, or the like may be used.
　ｐＨ調整剤としては、クエン酸緩衝剤、酢酸緩衝剤、炭酸緩衝剤、ホウ酸緩衝剤、リン酸緩衝剤などの緩衝剤とともに、例えば、塩酸、酢酸、ホウ酸、炭酸、硫酸、リン酸、クエン酸、酒石酸などの酸や、水酸化ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、トリエタノールアミン、モノエタノールアミンなどの塩基が使用されうる。 Examples of pH adjusters include buffers such as citrate buffer, acetate buffer, carbonate buffer, borate buffer, and phosphate buffer, as well as hydrochloric acid, acetic acid, boric acid, carbonic acid, sulfuric acid, phosphoric acid, Acids such as citric acid, tartaric acid and bases such as sodium hydroxide, sodium bicarbonate, sodium carbonate, triethanolamine, monoethanolamine can be used.
　等張化剤としては、糖類や塩類が挙げられ、塩類としては、亜硫酸水素ナトリウム、亜硫酸ナトリウム、塩化カリウム、塩化カルシウム、塩化ナトリウム、塩化マグネシウム、酢酸カリウム、酢酸ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、チオ硫酸ナトリウム、硫酸マグネシウム、リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウムなどが用いられうる。糖類としては、任意の単糖類又は多糖類を使用することができ、一例としてグルコース、シクロデキストリン、キシリトール、ソルビトール、又はマンニトール等を使用することができる。 Examples of tonicity agents include sugars and salts, and salts include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, Sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like can be used. Any monosaccharide or polysaccharide can be used as the saccharide, and glucose, cyclodextrin, xylitol, sorbitol, mannitol, or the like can be used as an example.
　増粘剤としては、コンドロイチン硫酸ナトリウム、ポリビニルアルコール、カルボキシビニルポリマー、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、アルギン酸、ヒアルロン酸、ポリビニルピロリドンなど又はそれらの塩が使用されうる。 As a thickening agent, sodium chondroitin sulfate, polyvinyl alcohol, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, hyaluronic acid, polyvinylpyrrolidone, etc. or salts thereof can be used.
　溶解補助剤としては、ポリオキシエチレンソルビタンモノオレエート、ポリオキシエチレン硬化ヒマシ油、チロキサポール、プルロニック等の非イオン性界面活性剤；グリセリン、又はマクロゴール等の多価アルコール等が使用されうる。 As solubilizers, nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol, and pluronic; polyhydric alcohols such as glycerin or macrogol, and the like can be used.
　安定化剤としては、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、グリセリン、プロピレングリコール、ポリエチレングリコール、シクロデキストリン、デキストラン、アスコルビン酸、エデト酸塩、タウリン、又はトコフェロール等が使用されうる。 Examples of stabilizers that can be used include polyvinylpyrrolidone, sulfite, monoethanolamine, glycerin, propylene glycol, polyethylene glycol, cyclodextrin, dextran, ascorbic acid, edetate, taurine, or tocopherol.
　界面活性剤としては、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塩、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；又はアルキルピリジニウム塩、アルキルアミン塩、ベンザルコニウム塩、ベンゼトニウム塩、ジアルキルジメチルアンモニウム塩、ポリヘキサメチレンビグアニド塩等の陽イオン界面活性剤等が使用されうる。特にベンザルコニウム塩、アルキルジアミノエチルグリシン塩、ポリヘキサメチレンビグアニド塩、ベンゼトニウム塩、又はジアルキルジメチルアンモニウム塩等は殺菌性界面活性剤として使用されうる。 Examples of surfactants include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters, and octoxynol; , amphoteric surfactants such as betaine lauryldimethylaminoacetate; anionic surfactants such as alkyl sulfates, N-acyl taurates, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates; or alkylpyridinium Cationic surfactants such as salts, alkylamine salts, benzalkonium salts, benzethonium salts, dialkyldimethylammonium salts, polyhexamethylene biguanide salts, and the like can be used. In particular, benzalkonium salts, alkyldiaminoethylglycine salts, polyhexamethylenebiguanide salts, benzethonium salts, dialkyldimethylammonium salts, etc. can be used as bactericidal surfactants.
　香料又は清涼化剤としては、メントール、エタノール、カンフル、ゲラニオール、ボルネオール、メントール、リュウノウ、ウイキョウ油、クールミント油、スペアミント油、ハッカ水、ハッカ油、ペパーミント油、ベルガモット油、ユーカリ油、又はローズ油等が使用されうる。 Flavors or cooling agents include menthol, ethanol, camphor, geraniol, borneol, menthol, rhubarb, fennel oil, cool mint oil, spearmint oil, mint water, mint oil, peppermint oil, bergamot oil, eucalyptus oil, or rose oil. etc. may be used.
　本明細書において言及される全ての文献はその全体が引用により本明細書に取り込まれる。 All documents referred to in this specification are hereby incorporated by reference in their entirety.
　以下に説明する本発明の実施例は例示のみを目的とし、本発明の技術的範囲を限定するものではない。本発明の技術的範囲は特許請求の範囲の記載によってのみ限定される。本発明の趣旨を逸脱しないことを条件として、本発明の変更、例えば、本発明の構成要件の追加、削除及び置換を行うことができる。 The examples of the present invention described below are for illustrative purposes only and do not limit the technical scope of the present invention. The technical scope of the present invention is limited only by the description of the claims. Modifications of the present invention, such as additions, deletions and replacements of constituent elements of the present invention, can be made without departing from the gist of the present invention.
［試験例１］ブリモニジン酒石酸塩の安定性の測定
１．試験点眼液の調製
　精製水にホウ酸（富士フイルム和光純薬株式会社）及びブリモニジン酒石酸塩（Ｈｉｎｅｗｙ　Ｐｈａｒｍａ．　Ｔｅｃｈ．　Ｃｏ．，　Ｌｔｄ．）を添加して溶解し、さらに適宜ベルベリン塩化物水和物（東京化成工業株式会社）または硫酸亜鉛水和物（富士フイルム和光純薬株式会社）を添加して溶解した。溶解後、ｐＨ調整剤（塩酸又は水酸化ナトリウム水溶液）によりｐＨを調整し、表１～５に示す組成の溶液を調製し、比較例１～６並びに実施例１～２２の試験点眼液を得た。なお、表中の数値は、ｐＨと残存率を除きｗ／ｖ％である。 [Test Example 1] Measurement of stability of brimonidine tartrate 1. Preparation of test ophthalmic solution Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) were added to and dissolved in purified water, and berberine chloride hydrate was added as appropriate. (Tokyo Chemical Industry Co., Ltd.) or zinc sulfate hydrate (Fuji Film Wako Pure Chemical Industries, Ltd.) was added and dissolved. After dissolution, the pH was adjusted with a pH adjuster (hydrochloric acid or aqueous sodium hydroxide solution) to prepare solutions having the compositions shown in Tables 1 to 5 to obtain test ophthalmic solutions of Comparative Examples 1 to 6 and Examples 1 to 22. rice field. Numerical values in the table are w/v% except for pH and residual rate.
２．光安定性試験
　１．で調製された試験点眼液５ｍＬをガラスアンプルに封入し、光安定性試験装置（ＬＴ－１２０Ａ－ＷＣＤ、ナガノサイエンス株式会社製）に入れ、白色光６０万ｌｘ・ｈｒに暴露させ、劣化品を得た。比較例及び実施例の各試験点眼液についての劣化品及び劣化前品のブリモニジン酒石酸塩含量を、以下に示す条件で高速液体クロマトグラフシステム（ＨＰＬＣ、島津製作所社製）によって測定した。以下に示す算出式に従ってブリモニジン酒石酸塩の残存率（％）を算出した。
Figure JPOXMLDOC01-appb-M000001
 2. Photostability test 1 . 5 mL of the test ophthalmic solution prepared in , is sealed in a glass ampoule, placed in a photostability tester (LT-120A-WCD, manufactured by Nagano Science Co., Ltd.), exposed to white light of 600,000 lx hr, and the degraded product is Obtained. The brimonidine tartrate content of the degraded product and the undegraded product of each test ophthalmic solution of Comparative Examples and Examples was measured by a high-performance liquid chromatography system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below. The residual ratio (%) of brimonidine tartrate was calculated according to the formula shown below.
Figure JPOXMLDOC01-appb-M000001
３．ブリモニジン酒石酸塩含量の測定
　各試験点眼液の劣化前品及び劣化品について、高速液体クロマトグラフィー（ＨＰＬＣ）法を以下の条件で用いて、ブリモニジン酒石酸塩含量を測定した。
　　カラム：　　　内径４．６ｍｍ×長さ１５ｃｍ　オクタデシルシリル化シリカゲル（「ＡＡ１２Ｓ０５－１５０６ＷＴ」ワイエムシィ社製）
　　検出器：　　　紫外吸光光度計（測定波長：２６４ｎｍ）
　　カラム温度：　４０℃
　　移動相：　　　リン酸二水素アンモニウム５．１７５ｇを９００ｍＬの水に溶かし、液体クロマトグラフィー用アセトニトリル１００ｍＬを加える。
　　流速：　　　　約１ｍＬ／ｍｉｎ 3. Measurement of brimonidine tartrate content The brimonidine tartrate content of each test ophthalmic solution before deterioration and deteriorated product was measured using a high performance liquid chromatography (HPLC) method under the following conditions.
Column: 4.6 mm inner diameter × 15 cm length octadecylsilylated silica gel (“AA12S05-1506WT” manufactured by YMC)
Detector: UV absorption photometer (measurement wavelength: 264 nm)
Column temperature: 40°C
Mobile Phase: Dissolve 5.175 g of ammonium dihydrogen phosphate in 900 mL of water and add 100 mL of acetonitrile for liquid chromatography.
Flow rate: about 1 mL/min
Figure JPOXMLDOC01-appb-T000002
 　０．０１～０．０５ｗ／ｖ％の濃度のブリモニジン酒石酸塩を含む試験点眼液に、０．０２５ｗ／ｖ％のベルベリン塩化物水和物又は０．２５ｗ／ｖ％の硫酸亜鉛水和物を配合することにより、ブリモニジン酒石酸塩の光安定性が向上した。
Figure JPOXMLDOC01-appb-T000002
 0.025 w/v % berberine chloride hydrate or 0.25 w/v % zinc sulfate hydrate was added to a test ophthalmic solution containing brimonidine tartrate at a concentration of 0.01-0.05 w/v %. The formulation improved the photostability of brimonidine tartrate.
Figure JPOXMLDOC01-appb-T000003
 　０．０２５ｗ／ｖ％のブリモニジン酒石酸塩を含む試験点眼液に、０．００５～０．０２５ｗ／ｖ％のベルベリン塩化物水和物又は０．０５～０．２５ｗ／ｖ％の硫酸亜鉛水和物を配合することにより、ブリモニジン酒石酸塩の光安定性が向上した。
Figure JPOXMLDOC01-appb-T000003
 Test eye drops containing 0.025 w/v % brimonidine tartrate, 0.005-0.025 w/v % berberine chloride hydrate or 0.05-0.25 w/v % zinc sulfate hydrate The photostability of brimonidine tartrate was improved by compounding
Figure JPOXMLDOC01-appb-T000004
 　０．０１ｗ／ｖ％又は０．０５ｗ／ｖ％の濃度のブリモニジン酒石酸塩を含む試験点眼液に、０．００５～０．０２５ｗ／ｖ％のベルベリン塩化物水和物を配合することにより、ブリモニジン酒石酸塩の光安定性が向上した。
Figure JPOXMLDOC01-appb-T000004
 By blending 0.005 to 0.025 w/v% berberine chloride hydrate into a test ophthalmic solution containing brimonidine tartrate at a concentration of 0.01 w/v% or 0.05 w/v%, brimonidine The photostability of tartrate was improved.
Figure JPOXMLDOC01-appb-T000005
 　０．０１ｗ／ｖ％又は０．０５ｗ／ｖ％の濃度のブリモニジン酒石酸塩を含む試験点眼液に、０．０５～０．２５ｗ／ｖ％の硫酸亜鉛水和物を配合することにより、ブリモニジン酒石酸塩の光安定性が向上した。
Figure JPOXMLDOC01-appb-T000005
 By adding 0.05-0.25 w/v% zinc sulfate hydrate to a test ophthalmic solution containing brimonidine tartrate at a concentration of 0.01 w/v% or 0.05 w/v%, brimonidine tartrate The photostability of the salt was improved.
Figure JPOXMLDOC01-appb-T000006
 　０．０２５ｗ／ｖ％の濃度のブリモニジン酒石酸塩及び０．０２５ｗ／ｖ％のベルベリン塩化物水和物又は０．２５ｗ／ｖ％の硫酸亜鉛水和物を含む試験点眼液において、ｐＨを変化させた。ベルベリン塩化物水和物を配合した場合には５．５～８．５において、ブリモニジン酒石酸塩の光安定性が向上した。硫酸亜鉛水和物を配合した場合には、５．５～６．５において、ブリモニジン酒石酸塩の光安定性が向上した。一方、硫酸亜鉛水和物を配合し、高ｐＨとすると析出を形成した。
Figure JPOXMLDOC01-appb-T000006
 In test ophthalmic solutions containing brimonidine tartrate at a concentration of 0.025 w/v % and 0.025 w/v % berberine chloride hydrate or 0.25 w/v % zinc sulfate hydrate, the pH was varied. rice field. The photostability of brimonidine tartrate was improved from 5.5 to 8.5 when berberine chloride hydrate was incorporated. The photostability of brimonidine tartrate was improved between 5.5 and 6.5 when zinc sulfate hydrate was incorporated. On the other hand, when zinc sulfate hydrate was formulated and high pH was applied, a precipitate was formed.

Claims (7)

  1. 　０．０１ｗ／ｖ％～０．０５ｗ／ｖ％のブリモニジン及び／又はその塩、並びにベルベリン及び／又はその塩、及び亜鉛塩からなる群から選ばれる少なくとも１の消炎・収れん剤を含有する眼科用液体製剤。 0.01 w/v% to 0.05 w/v% of an ophthalmic agent containing at least one anti-inflammatory/astringent agent selected from the group consisting of brimonidine and/or its salts, berberine and/or its salts, and zinc salts liquid formulation.
  2. 　前記ベルベリン及び／又はその塩が、ベルベリン硫酸塩である、請求項１に記載の眼科用液体製剤。 The ophthalmic liquid preparation according to claim 1, wherein the berberine and/or its salt is berberine sulfate.
  3. 　ベルベリン及び／又はその塩の濃度が、０．００５～０．０２５ｗ／ｖ％である、請求項１又は２に記載の眼科用液体製剤。 The ophthalmic liquid preparation according to claim 1 or 2, wherein the concentration of berberine and/or its salt is 0.005 to 0.025 w/v%.
  4. 　ｐＨが、５．０～９．０である、請求項１～３のいずれか一項に記載の眼科用液体製剤。 The ophthalmic liquid preparation according to any one of claims 1 to 3, which has a pH of 5.0 to 9.0.
  5. 　前記亜鉛塩が、乳酸亜鉛又は硫酸亜鉛である、請求項１に記載の眼科用液体製剤。 The ophthalmic liquid preparation according to claim 1, wherein the zinc salt is zinc lactate or zinc sulfate.
  6. 　前記亜鉛塩の濃度が、０．０５～０．２５ｗ／ｖ％である、請求項１又は４に記載の眼科用液体製剤。 The ophthalmic liquid preparation according to claim 1 or 4, wherein the zinc salt has a concentration of 0.05 to 0.25 w/v%.
  7. 　ｐＨが５．０～７．０である、請求項１、５及び６のいずれか一項に記載の眼科用液体製剤。 The ophthalmic liquid preparation according to any one of claims 1, 5 and 6, which has a pH of 5.0 to 7.0.
PCT/JP2022/022997 2021-06-07 2022-06-07 Liquid preparation of brimonidine WO2022260050A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004203836A (en) * 2002-12-26 2004-07-22 Rohto Pharmaceut Co Ltd Ophthalmic preparation for topical application
JP2005247798A (en) * 2004-03-08 2005-09-15 Zeria Pharmaceut Co Ltd Eye drop
JP2005298364A (en) * 2004-04-07 2005-10-27 Rohto Pharmaceut Co Ltd Aqueous solution containing azulene
JP2008154810A (en) * 2006-12-25 2008-07-10 Lion Corp Ophthalmic agent
WO2017099207A1 (en) * 2015-12-10 2017-06-15 千寿製薬株式会社 Ophthalmic drug product

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004203836A (en) * 2002-12-26 2004-07-22 Rohto Pharmaceut Co Ltd Ophthalmic preparation for topical application
JP2005247798A (en) * 2004-03-08 2005-09-15 Zeria Pharmaceut Co Ltd Eye drop
JP2005298364A (en) * 2004-04-07 2005-10-27 Rohto Pharmaceut Co Ltd Aqueous solution containing azulene
JP2008154810A (en) * 2006-12-25 2008-07-10 Lion Corp Ophthalmic agent
WO2017099207A1 (en) * 2015-12-10 2017-06-15 千寿製薬株式会社 Ophthalmic drug product

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