WO2017057434A1 - Composition aqueuse pharmaceutique - Google Patents

Composition aqueuse pharmaceutique Download PDF

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Publication number
WO2017057434A1
WO2017057434A1 PCT/JP2016/078578 JP2016078578W WO2017057434A1 WO 2017057434 A1 WO2017057434 A1 WO 2017057434A1 JP 2016078578 W JP2016078578 W JP 2016078578W WO 2017057434 A1 WO2017057434 A1 WO 2017057434A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
aqueous pharmaceutical
salt
dorzolamide
chlorobutanol
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PCT/JP2016/078578
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English (en)
Japanese (ja)
Inventor
隆司 森本
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参天製薬株式会社
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Publication of WO2017057434A1 publication Critical patent/WO2017057434A1/fr

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

  • the present invention relates to an aqueous pharmaceutical composition containing dorzolamide or a salt thereof and chlorobutanol.
  • Aqueous pharmaceutical compositions including eye drops require a certain level of preservation efficacy to prevent the growth of fungi and the like.
  • Benzalkonium chloride is water-soluble, chemically stable, and has a high preservative effect compared to other preservatives, so it is generally used in aqueous pharmaceutical compositions.
  • benzalkonium chloride has cytotoxicity, and the possibility of causing corneal epithelial damage increases with increasing exposure (Non-patent Document 1). Therefore, the development of an aqueous pharmaceutical composition that does not contain benzalkonium chloride at all is desired particularly for patients who are hypersensitive to benzalkonium chloride and patients with severe corneal epithelial disorders.
  • chlorobutanol is not as high in preservative effect as benzalkonium chloride, but is relatively improved in safety, so it is used as a preservative for aqueous pharmaceutical compositions.
  • chlorobutanol is easily thermally and photodegraded near neutrality, it is known that it has problems such as a decrease in pH of an aqueous pharmaceutical composition over time and decomposition of active ingredients.
  • the present invention relates to an aqueous pharmaceutical composition containing chlorobutanol, in which pH decrease over time or decomposition of an active ingredient is suppressed, and a pH reduction over time of an aqueous pharmaceutical composition containing chlorobutanol or decomposition of an active ingredient It aims at providing the method etc. which suppress this.
  • the present inventors have found that dorzolamide or a salt thereof suppresses a decrease in pH over time or decomposition of an active ingredient of an aqueous pharmaceutical composition containing chlorobutanol, and has completed the present invention.
  • the present invention is as follows.
  • An aqueous pharmaceutical composition containing dorzolamide or a salt thereof and chlorobutanol containing dorzolamide or a salt thereof and chlorobutanol.
  • aqueous pharmaceutical composition according to any one of (1) to (8), further comprising a buffer (preferably containing citric acid or a salt thereof).
  • aqueous pharmaceutical composition according to any one of (1) to (10), further comprising a surfactant (preferably containing polysorbate 80).
  • aqueous pharmaceutical composition according to any one of (1) to (12), further comprising a therapeutically effective amount of a glaucoma therapeutic agent different from dorzolamide.
  • a method for inhibiting degradation of chlorobutanol comprising adding dorzolamide or a salt thereof to an aqueous pharmaceutical composition containing chlorobutanol.
  • (21) A method for suppressing a decrease in pH of an aqueous pharmaceutical composition over time, wherein dorzolamide or a salt thereof is contained in an aqueous pharmaceutical composition containing chlorobutanol.
  • a method for improving the storage efficacy of an aqueous pharmaceutical composition comprising adding dorzolamide or a salt thereof to an aqueous pharmaceutical composition containing chlorobutanol.
  • each of the configurations (1) to (23) can be arbitrarily selected and combined in two or more.
  • the contained dorzolamide has the chemical name (4S, 6S) -4-Ethylamino-6-methyl-5,6-dihydro-4H-thieno [2,3-b] thiopyran-2 A compound represented by -sulfonamide-7,7-dioxide.
  • the contained dorzolamide may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • Salts include inorganic acid salts, organic acid salts, quaternary ammonium salts, halogen ion salts, alkali metal salts, alkaline earth metal salts, metal salts, organic amine salts, etc. Can be mentioned.
  • inorganic acid salts include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.
  • quaternary ammonium salt examples include salts with methyl bromide, methyl iodide and the like.
  • Salts with halogen ions include salts with chloride ions, bromide ions, iodide ions and the like.
  • Examples of the salt with alkali metal include salts with lithium, sodium, potassium and the like.
  • Examples of the salt with alkaline earth metal include salts with calcium, magnesium and the like.
  • Metal salts include salts with iron, zinc and the like.
  • Salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxy And salts with methyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
  • monohydrochloride (dorzolamide hydrochloride) is particularly preferable.
  • the contained dorzolamide or a salt thereof may take the form of a hydrate or a solvate.
  • the content of dorzolamide or a salt thereof is sufficient to suppress the degradation of the desired chlorobutanol, suppress the pH drop over time of the aqueous pharmaceutical composition, or preserve the storage efficacy of the aqueous pharmaceutical composition.
  • the amount is not particularly limited as long as it is an amount sufficient to improve, but is preferably 0.1 to 5% (w / v), more preferably 0.2 to 3% (w / v), and 0.5 to 2 0.5% (w / v) is more preferred, 1 to 2% (w / v) is even more preferred, and 1% (w / v) is particularly preferred.
  • these values are the content converted into the free dorzolamide.
  • the mass ratio of the content of dorzolamide or a salt thereof to the content of chlorobutanol described below is the desired suppression of degradation of chlorobutanol, suppression of the pH drop over time of the aqueous pharmaceutical composition, or From the viewpoint of improving the storage efficacy of the aqueous pharmaceutical composition, it is preferably 1.0 to 10.0, and more preferably 1.5 to 7.5.
  • these values are mass ratios converted to free dorzolamide.
  • the chlorobutanol contained is a compound represented by the chemical name 1,1,1-Trichloro-2-methyl-2-propanol.
  • the content of chlorobutanol contained is preferably 0.01 to 5% (w / v), more preferably 0.1 to 1% (w / v), and 2 to 0.5% (w / v) is more preferable, and 0.4% (w / v) is particularly preferable.
  • additives for pharmaceuticals can be used as necessary in order to satisfy the requirements as an ophthalmic preparation.
  • a buffer, a thickener, a surfactant, Tonicity agents, antioxidants, pH adjusting agents and the like can be added. These can be used individually by 1 type or in combination of 2 or more types, respectively, and can mix
  • Examples of the buffer that can be used in the aqueous pharmaceutical composition of the present invention include phosphoric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ⁇ -aminocaproic acid And trometamol.
  • Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the citrate includes citric acid. Sodium, disodium citrate and the like can be mentioned.
  • Examples of the acetate include sodium acetate and potassium acetate.
  • Examples of the carbonate include sodium carbonate and sodium bicarbonate.
  • Examples of the tartrate include sodium tartrate, Examples include potassium tartrate. Citric acid or a salt thereof is preferred, and sodium citrate is particularly preferred.
  • the content of the buffer when blending the buffer with the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffer, etc., but is preferably 0.001 to 10% (w / v), 0.01% to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.2 to 2% (w / v) is most preferable.
  • the buffering agent is not included or may be included in less than the above amount from the viewpoint of minimizing the use of the additive.
  • Citric acid or a salt thereof is preferably included in an amount of less than 0.3% (w / v), or not included or less than 0.002% (w / v) in terms of minimizing the use of additives. More preferably, it is contained in an amount of.
  • trometamol is preferably not contained or contained in an amount of less than 0.1% (w / v) from the viewpoint of minimizing the use of the additive.
  • thickening agents include propylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate, and the like, with hydroxyethylcellulose being preferred.
  • the content of the thickening agent in the case where the thickening agent is blended with the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the thickening agent, but is 0.001 to 5% (w / v) Is preferable, 0.01% to 3% (w / v) is more preferable, 0.1 to 2% (w / v) is more preferable, and 0.2 to 1% (w / v) is most preferable.
  • the thickener is not included or may be included in less than the above amount from the viewpoint of minimizing the use of the additive.
  • cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2 -Alkyl imidazoline, 1-hydroxylethyl-2-alkyl imidazoline and the like.
  • anionic surfactant include phospholipids such as lecithin.
  • nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 Polyoxyethylene sorbitan fatty acid esters such as: polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc .; polyoxyl Polyoxyl castor oil such as 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil; polyoxyethylene (16 ) Polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol Polyoxyethylene polyoxypropylene glycol such as polyoxyethylene (20)
  • the content of the surfactant when the surfactant is added to the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant, etc., but is 0.01 to 1% (w / V) is preferable, 0.05 to 0.5% (w / v) is more preferable, and 0.05% to 0.2% (w / v) is particularly preferable.
  • the surfactant is not included or may be included in less than the above amount from the viewpoint of minimizing the use of the additive.
  • Examples of isotonic agents that can be used in the aqueous pharmaceutical composition of the present invention include ionic tonicity agents and nonionic tonicity agents.
  • Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium chloride is preferable.
  • Examples of nonionic tonicity agents include sugar alcohols such as glycerin, propylene glycol, sorbitol, mannitol, xylitol, and mannitol is preferred.
  • the content of the tonicity agent when the isotonic agent is blended with the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the tonicity agent and the like, but is 0.01 to 10% (w / V) is preferable, 0.02% to 7% (w / v) is more preferable, 0.1 to 5% (w / v) is more preferable, and 0.5 to 4% (w / v) is particularly preferable 0.8 to 3% (w / v) is most preferable.
  • the tonicity agent is not included in the case of, for example, an ionic tonicity agent, or may be included in less than the above amount, and is included in the case of a sugar alcohol. Preferably, it is included in an amount of less than 0.1% (w / v).
  • antioxidants examples include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
  • the content of the antioxidant when the antioxidant is mixed with the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the antioxidant, etc., but is 0.0001 to 1% (w / v) Is preferable, 0.0005% to 0.1% (w / v) is more preferable, 0.001 to 0.02% (w / v) is further preferable, and 0.005 to 0.01% (w / v) is preferable. ) Is most preferred.
  • the antioxidant is not included or may be included in less than the above amount from the viewpoint of minimizing the use of the additive.
  • pH adjusting agent examples include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the like.
  • the pH adjusting agent may not be included from the viewpoint of minimizing the use of the additive.
  • the pH of the aqueous pharmaceutical composition of the present invention is preferably 4.0 to 8.0, more preferably 5.0 to 6.0, and even more preferably 5.1 to 5.8.
  • the 14-day average pH fall value by storage at 60 degreeC is 0.046 / day or less.
  • the average pH drop value for 14 days by storage at 60 ° C. is more preferably 0.046 / day or less, further preferably 0.040 / day or less, most preferably 0.035 / day or less, and 0.030 / day or less.
  • the lower limit of the 14-day average pH lowering value when the pH is 5.0 or more is not particularly limited, but may be 0.005 or more.
  • preservatives examples include benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, sodium edetate, boric acid, sorbic acid, and the like.
  • boric acid is preferably not contained or contained in an amount of less than 0.1% (w / v) from the viewpoint of minimizing the use of additives.
  • the preservative may not be included from the viewpoint of minimizing the use of the additive.
  • Dorzolamide or a salt thereof in the aqueous pharmaceutical composition of the present invention may be contained as an active ingredient (for example, a therapeutic agent for glaucoma or high intraocular pressure), a chlorobutanol stabilizer, a temporal pH inhibitor, an aqueous pharmaceutical composition It may be contained as an agent for improving the preservation effect of the product.
  • the aqueous pharmaceutical composition of the present invention may contain an active ingredient different from dorzolamide or a salt thereof.
  • the aqueous pharmaceutical composition of the present invention may contain only dorzolamide or a salt thereof as an active ingredient.
  • the aqueous pharmaceutical composition of the present invention can further contain another therapeutic agent for glaucoma or ocular hypertension in a therapeutically effective amount within a range that does not impair the effects of the present invention.
  • the aqueous pharmaceutical composition of the present invention may not contain any of ketotifen fumarate, chlorpheniramine maleate, and aminocaproic acid from the viewpoint of minimizing the components used, and specifically, glaucoma as an active ingredient. Or it may contain only the therapeutic agent for ocular hypertension.
  • Examples of other glaucoma therapeutic agents that can be contained in the aqueous pharmaceutical composition of the present invention include prostaglandin preparations, ⁇ blockers, ⁇ blockers, parasympathomimetic agents and the like.
  • ⁇ -blockers such as timolol or a salt thereof, carteolol or a salt thereof, betaxolol or a salt thereof, nipradilol or a salt thereof are preferable, timolol or a salt thereof is more preferable, and timolol maleate is particularly preferable.
  • the active ingredient contained in the aqueous pharmaceutical composition of the present invention may consist only of dorzolamide or a salt thereof and timolol or a salt thereof.
  • the aqueous pharmaceutical composition of the present invention is useful as a therapeutic agent for glaucoma or ocular hypertension. Because the causes of chronic diseases are diverse and the treatment is long-lasting, many drugs for glaucoma with different mechanisms of action are often used in combination, so it is necessary to consider the toxicity of cumulative additives other than the active ingredient. is there. However, since the aqueous pharmaceutical composition of the present invention can impart sufficient storage efficacy even with a minimum of additives as described above, the above problem can be suppressed.
  • the dosage is not particularly limited as long as it is sufficient to achieve the desired drug effect, but it is preferable to instill 1 to 3 drops at a time, 1 to 3 times a day. More preferably, 1 to 2 drops per day, 1-2 times per day, most preferably 1 drop per day, 2 times per day.
  • the aqueous pharmaceutical composition of the present invention is excellent in suppressing degradation of chlorobutanol, suppressing pH decrease over time, and improving storage efficiency. Therefore, a light-shielding container is preferable, but it is housed in a non-light-shielding container. You can also The non-light-shielding property includes not only transparent but also opaque as long as light can be transmitted.
  • a polyethylene container a polypropylene container, a polyethylene terephthalate container etc. are mentioned, for example.
  • the aqueous pharmaceutical composition of the present invention is not limited to a cold place and may be stored at room temperature.
  • the room temperature refers to, for example, 1 to 30 ° C., and may be more than 15 ° C. and 30 ° C. or less.
  • the aqueous pharmaceutical composition of the present invention may be contained in any of a multi-dose container, a single-use unit dose container, or a PFMD (Preservative Free Multi Dose) container.
  • PFMD Preservative Free Multi Dose
  • the dosage form of the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical product, but an eye drop is particularly preferable and can be produced according to a usual method in the technical field.
  • Formulation Example A typical formulation example of the present invention is shown below.
  • the amount of each component is the content in 1 mL of the formulation.
  • a desired composition can be obtained by appropriately adjusting the types and blending amounts of dorzolamide, chlorobutanol and additives in Preparation Examples 1 and 2.
  • Example 1 (in 1 mL) Dorzolamide hydrochloride 11.13mg Chlorobutanol 4.00mg Sodium citrate hydrate 3.00mg Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Water for injection Appropriate amount pH 5.65 The mass ratio of dorzolamide to chlorobutanol is 2.5.
  • Example 2 Preparations of Example 2, Example 3, Comparative Example 1, and Comparative Example 2 were prepared in the same manner as the preparation method of Example 1.
  • Example 2 (in 1 mL) Dorzolamide hydrochloride 11.13mg Timolol maleate 6.83mg Chlorobutanol 4.00mg Sodium citrate hydrate 3.00mg Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Water for injection Appropriate amount pH 5.64 The mass ratio of dorzolamide to chlorobutanol is 2.5.
  • Example 3 (in 1 mL) Dorzolamide hydrochloride 11.13mg Timolol maleate 6.83mg Chlorobutanol 4.00mg Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Water for injection Appropriate amount pH 5.68 The mass ratio of dorzolamide to chlorobutanol is 2.5.
  • Example 1 Example 2, Example 3, Comparative Example 1 and Comparative Example 2 were filled in a glass ampule and stored at 60 ° C. for 2 weeks in the dark. During storage, the pH of each sample was measured immediately after preparation preparation (day 0) and 14 days after preparation.
  • Table 1 shows the test results.
  • the test result of Table 1 shows the pH value at each measurement point.
  • Day 0 is the value immediately after preparation preparation.
  • the 0-14 day change and the daily change (0-14 day) (also expressed as the 14-day average pH drop) are calculated as follows.
  • Example 1 As shown in Table 1, the pH values of Comparative Example 1 and Comparative Example 2 not containing dorzolamide or a salt thereof both decreased over time, whereas those containing dorzolamide or a salt thereof and chlorobutanol were reduced.
  • the formulation of Example 1 suppressed the decrease in pH over time.
  • the preparation of Example 2 containing timolol in dorzolamide or a salt thereof and chlorobutanol further suppressed the decrease in pH over time.
  • water-based pharmaceutical composition of this invention is an aqueous
  • citric acid or a salt thereof is not essential, although it contributes to suppression of pH decrease over time. It has been suggested.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition aqueuse pharmaceutique qui comprend du chlorobutanol et qui supprime la diminution du pH avec le temps et la dégradation des principes actifs. Cette composition aqueuse pharmaceutique comprend du dorzolamide ou un sel de celui-ci et du chlorobutanol. Le pH de la composition est de préférence situé dans la plage allant de 4,0 à 8,0. De plus, la diminution moyenne du pH, après 14 jours de conservation à 60 °C, est de préférence inférieure ou égale à 0,046/jour. Le dorzolamide ou un sel de celui-ci est de préférence le chlorhydrate de dorzolamide.
PCT/JP2016/078578 2015-09-28 2016-09-28 Composition aqueuse pharmaceutique WO2017057434A1 (fr)

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JP2003192583A (ja) * 2001-12-25 2003-07-09 Taisho Pharm Ind Ltd 消炎点眼剤
JP2004256519A (ja) * 2003-02-07 2004-09-16 Senju Pharmaceut Co Ltd クロロブタノール含有人工涙液
JP2005187383A (ja) * 2003-12-25 2005-07-14 Lion Corp 眼科用組成物
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JP2016166198A (ja) * 2015-03-06 2016-09-15 興和株式会社 水性組成物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019210288A (ja) * 2018-06-05 2019-12-12 千寿製薬株式会社 水性液剤
WO2019235456A1 (fr) * 2018-06-05 2019-12-12 千寿製薬株式会社 Agent liquide aqueux

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