WO2022260050A1 - Préparation liquide de brimonidine - Google Patents

Préparation liquide de brimonidine Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
salts
brimonidine
liquid preparation
salt
zinc
Prior art date
Application number
PCT/JP2022/022997
Other languages
English (en)
Japanese (ja)
Inventor
侑美 吉田
Original Assignee
アイ・セラピーズ・エル・エル・シー
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by アイ・セラピーズ・エル・エル・シー filed Critical アイ・セラピーズ・エル・エル・シー
Publication of WO2022260050A1 publication Critical patent/WO2022260050A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—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.

Landscapes

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

Abstract

Le but de la présente invention est d'améliorer la stabilité d'une préparation liquide à usage ophtalmique qui comprend de la brimonidine et/ou un sel de celle-ci. Les présents inventeurs ont découvert que la stabilité peut être améliorée par ajout d'un agent anti-inflammatoire et astringent. Sur la base de cette découverte, l'invention concerne une préparation liquide à usage ophtalmique qui comprend de la brimonidine et/ou un sel de celle-ci et un agent anti-inflammatoire et astringent.
PCT/JP2022/022997 2021-06-07 2022-06-07 Préparation liquide de brimonidine WO2022260050A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021095257 2021-06-07
JP2021-095257 2021-06-07

Publications (1)

Publication Number Publication Date
WO2022260050A1 true WO2022260050A1 (fr) 2022-12-15

Family

ID=84425077

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/022997 WO2022260050A1 (fr) 2021-06-07 2022-06-07 Préparation liquide de brimonidine

Country Status (2)

Country Link
JP (1) JP2022187495A (fr)
WO (1) WO2022260050A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004203836A (ja) * 2002-12-26 2004-07-22 Rohto Pharmaceut Co Ltd 眼科用局所適用製剤
JP2005247798A (ja) * 2004-03-08 2005-09-15 Zeria Pharmaceut Co Ltd 点眼剤
JP2005298364A (ja) * 2004-04-07 2005-10-27 Rohto Pharmaceut Co Ltd アズレン含有水性液剤
JP2008154810A (ja) * 2006-12-25 2008-07-10 Lion Corp 眼科用剤
WO2017099207A1 (fr) * 2015-12-10 2017-06-15 千寿製薬株式会社 Produit pharmaceutique ophtalmique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004203836A (ja) * 2002-12-26 2004-07-22 Rohto Pharmaceut Co Ltd 眼科用局所適用製剤
JP2005247798A (ja) * 2004-03-08 2005-09-15 Zeria Pharmaceut Co Ltd 点眼剤
JP2005298364A (ja) * 2004-04-07 2005-10-27 Rohto Pharmaceut Co Ltd アズレン含有水性液剤
JP2008154810A (ja) * 2006-12-25 2008-07-10 Lion Corp 眼科用剤
WO2017099207A1 (fr) * 2015-12-10 2017-06-15 千寿製薬株式会社 Produit pharmaceutique ophtalmique

Also Published As

Publication number Publication date
JP2022187495A (ja) 2022-12-19

Similar Documents

Publication Publication Date Title
US9119827B2 (en) Ophthalmic composition
US20120095097A1 (en) Ophthalmic composition
JP7076183B2 (ja) ビタミンａを含有するエマルション点眼液
WO2012100109A2 (fr) Goutte ophtalmique thérapeutique comprenant de la doxycycline et un agent stabilisant
JP2013181020A (ja) 眼科用組成物
JP2015067607A (ja) 複数の成分を配合した点眼剤
WO2022260050A1 (fr) Préparation liquide de brimonidine
JP2005162747A (ja) 眼科用組成物
JP2013256462A (ja) ビタミンａ類を含有する水性組成物
WO2021235527A1 (fr) Préparation liquide contenant de la brimonidine
WO2015041193A1 (fr) Composition ophtalmique pour lentilles de contact souples zwitterioniques
JP6213715B2 (ja) 多成分配合点眼剤
WO2022075472A1 (fr) Préparation liquide de brimonidine
JP6449773B2 (ja) 陰イオン性ソフトコンタクトレンズ用眼科用組成物
WO2021221074A1 (fr) Préparation liquide contenant de la brimonidine
JP5838718B2 (ja) ソフトコンタクトレンズ用眼科組成物及び吸着抑制方法
WO2022097731A1 (fr) Préparation liquide ophtalmique
JP2009161456A (ja) 眼科用組成物
WO2013047373A1 (fr) Formulation aqueuse contenant un chlorite
JP4470393B2 (ja) 安定である点眼剤
JP2024007419A (ja) コンタクトレンズ用眼科組成物
TWI712429B (zh) 水性醫藥組成物
WO2023079427A1 (fr) Compositions ophtalmiques et procédés associés
KR20220068131A (ko) 세티리진 및 토코페솔란을 포함하는 안과용 조성물
KR20220089106A (ko) 도르졸라마이드 또는 폴리소르베이트80을 유효성분으로 포함하는 점안용 조성물

Legal Events

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

Ref document number: 22820229

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE