WO2017159586A1 - Composition pharmaceutique comprenant un dorzolamide, un timolol et un tensio-actif - Google Patents

Composition pharmaceutique comprenant un dorzolamide, un timolol et un tensio-actif Download PDF

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Publication number
WO2017159586A1
WO2017159586A1 PCT/JP2017/009876 JP2017009876W WO2017159586A1 WO 2017159586 A1 WO2017159586 A1 WO 2017159586A1 JP 2017009876 W JP2017009876 W JP 2017009876W WO 2017159586 A1 WO2017159586 A1 WO 2017159586A1
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Prior art keywords
pharmaceutical composition
salt
composition according
surfactant
timolol
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PCT/JP2017/009876
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English (en)
Japanese (ja)
Inventor
隆司 森本
直樹 松本
貴司 坪井
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参天製薬株式会社
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Publication of WO2017159586A1 publication Critical patent/WO2017159586A1/fr

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    • 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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • the present invention relates to a pharmaceutical composition containing dorzolamide or a salt thereof, timolol or a salt thereof and 0.001 to 5% (w / v) of a surfactant other than benzalkonium chloride and not containing benzalkonium chloride.
  • a surfactant other than benzalkonium chloride and not containing benzalkonium chloride.
  • Dorzolamide which is a carbonic anhydrase inhibitor
  • timolol which is a receptor blocker
  • Patent Document 1 describes that a composition containing both dorzolamide and timolol is particularly useful for the treatment of high intraocular pressure, and a preparation containing dorzolamide and timolol is a Cosopt (registered trademark) ophthalmic solution. It is sold as.
  • the ophthalmic solution needs to have a certain level of antiseptic effect in order to prevent the growth of fungi and the like accompanying repeated use, and the above-mentioned Cosopt (registered trademark) ophthalmic solution has benzalkonium chloride as a preservative. Is blended. However, benzalkonium chloride has cytotoxicity and may cause corneal epithelial damage when the exposure dose increases (Non-patent Document 1. Therefore, from the viewpoint of safety, manufacturing cost, etc., benzalkonium chloride is used. A new ophthalmic solution that does not contain substances is desired.
  • An object of the present invention is to provide a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, while not containing benzalkonium chloride.
  • the amount of the pharmaceutical composition to be contained is controlled so as to approach the amount equivalent to one drop.
  • the inventors have surprisingly found that in a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, 0.001-5% (w / v), although it does not contain benzalkonium chloride. It was found that the amount of one drop of the pharmaceutical composition can be controlled by containing a surfactant other than benzalkonium chloride in (1). Specifically, the present invention provides the following.
  • At least the nonionic surfactant is selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polyethylene glycol monostearate
  • the pharmaceutical composition according to (4), comprising one nonionic surfactant comprising one nonionic surfactant.
  • composition according to (8) wherein the cationic surfactant comprises at least one cationic surfactant selected from the group consisting of chlorhexidine and a salt thereof.
  • composition according to any one of (1) to (14), further comprising hydroxyethyl cellulose.
  • each of the configurations (1) to (22) can be arbitrarily selected and combined in two or more.
  • a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof 0.001 to 5% (w / v) of benzalco, although it does not contain benzalkonium chloride.
  • a surfactant other than nium chloride the amount of one drop of the pharmaceutical composition can be controlled, and it can be brought close to the same drop amount as that of the pharmaceutical composition containing benzalkonium chloride.
  • the contained dorzolamide has the chemical name (4S, 6S) -4-Ethylamino-6-methyl-5, 6-dihydro-4H-thieno [2, 3-b] thiopyran-2- It is a compound represented by sulfonamide 7, 7-dioxide.
  • Dorzolamide is not particularly limited as long as it is commercially available or can be obtained by a known production method.
  • timolol contained is represented by the chemical name (2S) -1-[(1, 1-Dimethylethyl) amino] -3- (4-morpholin-4-yl-1, 2, 5- thiadiazol-3-yloxy) propan-2-ol.
  • Timolol is not particularly limited as long as it is commercially available or can be obtained by a known production method.
  • the contained dorzolamide and timolol may be salts, and are not particularly limited as long as they are pharmaceutically acceptable salts.
  • 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.
  • Examples of the salt with inorganic acid 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.
  • salt of dorzolamide monohydrochloride (dorzolamide hydrochloride) is particularly preferable, and as the salt of timolol, monomaleate (timolol maleate) is particularly preferable.
  • dorzolamide, timolol and salts thereof may take the form of hydrates or solvates.
  • hydrate of timolol hemihydrate is preferable.
  • the content of dorzolamide or a salt thereof is not particularly limited as long as it is a pharmaceutically acceptable amount, but is preferably 0.1 to 5% (w / v), preferably 0.2 to 4% (w / v) is more preferable, 0.3 to 3% (w / v) is more preferable, 0.4 to 2.5% (w / v) is more preferable, and 0.5 to 2% ( w / v) is particularly preferred, with 0.5% (w / v), 1% (w / v) or 2% (w / v) being most preferred.
  • % (w / v) means the mass (g) of the target component (here, Dorzolamide) contained in 100 mL of the pharmaceutical composition of the present invention. The same applies hereinafter unless otherwise specified. Moreover, all% (w / v) described in this specification may be read as% (w / w). “% (W / w)” means the mass (g) of the target component (here, Dorzolamide) contained in 100 g of the pharmaceutical composition of the present invention.
  • the content of timolol or a salt thereof is not particularly limited as long as it is an amount sufficient to exhibit a desired medicinal effect, but is 0.01 to 2% (w / v).
  • 0.05 to 1% (w / v) is more preferable, 0.1 to 0.8% (w / v) is more preferable, and 0.2 to 0.7% (w / v) is even more preferable 0.5% (w / v) is particularly preferable.
  • these values are contents converted to free timolol.
  • the content of dorzolamide or a salt thereof is preferably 0.1 to 10 times, more preferably 0.5 to 8 times, and more preferably 1 to 3 times the content of timolol or a salt thereof from the viewpoint of therapeutic effect and antiseptic effect. More preferably, it is 5 times.
  • the amount of one drop can be obtained despite the absence of benzalkonium chloride. Is reduced.
  • the reason for this is considered that the conventional pharmaceutical composition containing benzalkonium chloride was responsible for the effect of reducing the amount of one drop of the pharmaceutical composition while benzalkonium chloride exerted an antiseptic effect.
  • the surfactant plays a role instead of benzalkonium chloride.
  • the surfactant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is a surfactant that can be used as a pharmaceutical additive.
  • examples of such surfactants include nonionic surfactants, cationic surfactants, and anionic surfactants.
  • nonionic surfactants include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, polyethylene glycol monostearate , Sucrose fatty acid ester, vitamin E TPGS, etc.
  • polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil and polyethylene glycol monostearate And at least one selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, particularly preferably polyoxyethylene sorbitan fatty acid esters.
  • polysorbate 80 polyoxyethylene (20) sorbitan oleate
  • polyoxyethylene sorbitan fatty acid ester examples include polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and the like.
  • polyoxyethylene fatty acid ester examples include polyoxyl 40 stearate.
  • polyoxyethylene hydrogenated castor oil various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, ⁇ 70 are particularly preferred and 60 is most preferred.
  • Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and the like.
  • Ethylene hydrogenated castor oil 60 is preferred.
  • polyoxyethylene castor oil various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 5 to 100, more preferably 20 to 50, and more preferably 30 to 40 Is particularly preferred and 35 is most preferred.
  • polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil and the like, and polyoxyl 35 castor oil is preferred.
  • polyoxyethylene polyoxypropylene glycol polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) And glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol and the like.
  • sucrose fatty acid ester examples include sucrose stearate.
  • Vitamin E TPGS is also called tocopherol polyethylene glycol 1000 succinate.
  • the content of the nonionic surfactant is preferably 0.001 to 5 (w / v), and 0.01 to 2% (w / V) is more preferable, 0.03 to 0.8% (w / v) is more preferable, 0.04 to 0.6% (w / v) is more preferable, and 0.05 to 0.5% ( w / v) is more preferable, 0.07 to 0.4% (w / v) is more preferable, 0.09 to 0.3% (w / v) is particularly preferable, and 0.1 to 0.2%.
  • W / v) is most preferred.
  • cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl- Examples include 2-alkylimidazoline, 1-hydroxyl-2-alkylimidazoline, chlorhexidine or a salt thereof, chlorhexidine or a salt thereof is preferable, and chlorhexidine gluconate is most preferable.
  • the content of the cationic surfactant when the cationic surfactant is blended with the pharmaceutical composition of the present invention is preferably 0.001 to 5 (w / v), and 0.001 to 1% (w / v). ) Is more preferable, 0.001 to 0.1% (w / v) is further preferable, 0.001 to 0.01% (w / v) is particularly preferable, and 0.001 to 0.005% (w / v) v) is most preferred.
  • anionic surfactants include phospholipids, and examples of phospholipids include lecithin.
  • the content of the anionic surfactant when blended with the anionic surfactant in the pharmaceutical composition of the present invention is preferably 0.001 to 5 (w / v), and 0.005 to 2% (w / v). ) Is more preferable, 0.01 to 1% (w / v) is more preferable, and 0.005 to 0.01% (w / v) is particularly preferable.
  • additives can be used as necessary.
  • the additives include high molecular weight polymers, buffers, isotonic agents, stabilizers, antioxidants, preservatives, A pH adjuster or the like can be added.
  • a high molecular weight polymer that can be used as a pharmaceutical additive can be appropriately blended.
  • high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, Examples thereof include carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxy vinyl polymer, polyethylene glycol and the like, and hydroxyethyl cellulose is preferred.
  • the high molecular weight polymer has a viscosity (particularly the viscosity of hydroxyethyl cellulose) in a 1% (w / v) aqueous solution of 50 to 100,000 (mPa ⁇ s) at 25 ° C.
  • a viscosity particularly the viscosity of hydroxyethyl cellulose
  • the viscosity of the high molecular weight polymer is measured for a 1% (w / v) aqueous solution containing only the high molecular weight polymer by a capillary viscometer method using an Oswald viscometer at 25 ° C.
  • the content of the high molecular weight polymer in the case where the high molecular weight polymer is blended with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the high molecular weight polymer, etc., but is 0.001 to 5% (w / v) is preferred, 0.01 to 3% (w / v) is more preferred, 0.1 to 2% (w / v) is more preferred, and 0.2 to 1% (w / v) is most preferred.
  • a buffering agent that can be used as a pharmaceutical additive can be blended.
  • the buffer 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, trometamol, and the like.
  • 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 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 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.
  • an isotonic agent that can be used as a pharmaceutical additive can be appropriately blended.
  • isotonic agents include ionic and nonionic tonicity agents.
  • the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium chloride is preferable.
  • Nonionic tonicity agents include glycerin, propylene glycol, sorbitol, mannitol and the like, with mannitol being preferred.
  • the content of the tonicity agent when blended with the isotonic agent in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of tonicity agent and the like, but is 0.01 to 10% (w / v) is preferred, 0.02 to 7% (w / v) is more preferred, 0.1 to 5% (w / v) is more preferred, 0.5 to 4% (w / v) is particularly preferred, Most preferred is 0.8 to 3% (w / v).
  • a stabilizer that can be used as a pharmaceutical additive can be appropriately blended.
  • stabilizers include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, disodium edetate is preferred, and disodium edetate dihydrate is Particularly preferred.
  • the content of the stabilizer when the stabilizer is added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the stabilizer, etc., but is 0.0001 to 0.5% (w / v ), Preferably 0.0005 to 0.3% (w / v), more preferably 0.001 to 0.1% (w / v), and 0.002 to 0.08% (w / v). ) Is more preferred, 0.003 to 0.05% (w / v) is more preferred, 0.005 to 0.03% (w / v) is particularly preferred, and 0.007 to 0.01% (w / v) v) is most preferred.
  • these values are content calculated based on the mass of the salt of edetic acid or its hydrate.
  • an antioxidant that can be used as a pharmaceutical additive can be appropriately blended.
  • antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
  • the content of the antioxidant when the antioxidant is blended with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the antioxidant and the like, but is 0.0001 to 1% (w / v).
  • 0.0005 to 0.1% (w / v) is more preferable, 0.001 to 0.02% (w / v) is more preferable, and 0.005 to 0.010% (w / v) is more preferable.
  • a preservative that can be used as a pharmaceutical additive can be appropriately blended.
  • preservatives include benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, edetic acid, and salts thereof.
  • salts of edetic acid include monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, disodium edetate is preferred, and disodium edetate is particularly preferred. .
  • the content of the preservative when blended with the preservative in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the preservative, etc., but is preferably 0.0001 to 3% (w / v), 0 .0005 to 1% (w / v) is more preferable, 0.001 to 0.5% (w / v) is more preferable, and 0.005 to 0.1% (w / v) is most preferable.
  • edetic acid or a salt thereof may be added to the pharmaceutical composition as a stabilizer.
  • edetic acid or a salt thereof is included in the pharmaceutical composition of the present invention
  • 0.0001 to 0.5% (w / V) is preferable, 0.0005 to 0.3% (w / v) is more preferable, 0.001 to 0.1% (w / v) is further preferable, and 0.002 to 0.08% (w / V) is more preferable, 0.003 to 0.05% (w / v) is more preferable, 0.005 to 0.03% (w / v) is particularly preferable, and 0.007 to 0.01% ( w / v) is most preferred.
  • These values are those values as the total amount of edetic acid and its salt contained in the pharmaceutical composition of the present invention, and are calculated based on the mass of the salt of edetic acid or its hydrate.
  • a pH adjuster that can be used as a pharmaceutical additive can be appropriately blended.
  • the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like, and citric acid is preferable.
  • the pharmaceutical composition of the present invention particularly preferably contains hydroxyethyl cellulose as a high molecular weight polymer, citric acid or a salt thereof as a buffering agent, and edetic acid or a salt thereof as a preservative.
  • the content of each component is 0.001 to 5% (w / v) for hydroxyethyl cellulose, 0.001 to 10% (w / v) for citric acid or a salt thereof, edetic acid or a salt thereof Is preferably 0.0001 to 0.5% (w / v), 0.01 to 3% (w / v) of hydroxyethylcellulose, 0.01 to 5% (w / v) of citric acid or a salt thereof.
  • edetic acid or a salt thereof is more preferably 0.001 to 0.1% (w / v), hydroxyethyl cellulose is 0.1 to 2% (w / v), citric acid or a salt thereof More preferably, 0.1 to 3% (w / v), edetic acid or a salt thereof is 0.003 to 0.05% (w / v), and hydroxyethyl cellulose is 0.2 to 1% (w / v). v) 0.2 to 2% (w / w) citric acid or salt thereof ), And most preferably edetic acid or a salt thereof is 0.007 ⁇ 0.01% (w / v).
  • the pH of the pharmaceutical composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and is preferably 3.0 to 8.0. From the viewpoint of the stability of dorzolamide, 3.0 to 6.0 is preferable. More preferably, 4.0 to 6.0 is more preferable, 5.0 to 6.0 is more preferable, 5.5 to 6.0 is particularly preferable, and 5.5 to 5.8 is most preferable.
  • the osmotic pressure ratio (with respect to physiological saline) of the pharmaceutical composition of the present invention can be adjusted as appropriate, but is preferably 0.1-2.4, more preferably 0.7 to 2.1, and 0.9 to 1.1 is particularly preferred and about 1 is most preferred.
  • the viscosity of the pharmaceutical composition of the present invention can be adjusted as appropriate, but it is preferably 50 to 700 (mPa ⁇ s) at 25 ° C. using a capillary viscometer method using an Oswald viscometer, preferably 55 to More preferably, it is 500 (mPa ⁇ s), more preferably 60 to 300 (mPa ⁇ s), particularly preferably 65 to 200 (mPa ⁇ s), and 65 to 170 (mPa ⁇ s). ) Is most preferred.
  • the pharmaceutical composition of the present invention is preferably a colorless and clear, slightly viscous, sterile aqueous pharmaceutical composition, particularly preferably an eye drop composition (eye drop).
  • the pharmaceutical composition of the present invention can be placed in a unit dose type eye drop container or a multi dose type eye drop container, and preferably in a multi dose type eye drop container.
  • a unit dose type eye drop container is an eye drop container that can be used once
  • a multi dose type eye drop container is an eye drop container that can be freely opened and closed for the purpose of using it multiple times.
  • PFMD Preservative Free Multi Dose
  • eye drop containers made from a product made from polyethylene (PE), a product made from polypropylene (PP), a product made from polyethylene terephthalate (PET), etc. can be used.
  • the outer diameter of the dropping port of the eye drop container is preferably 2.0 to 4.5 mm, more preferably 2.5 to 4.0 mm, and most preferably 3.0 to 3.6 mm.
  • the amount of one drop of the pharmaceutical composition may vary depending on the diameter of the dropping port of the eye drop container, but is preferably 28 to 36 ⁇ L, more preferably 29 to 35 ⁇ L, and most preferably 30 to 34 ⁇ L. . Alternatively, it is preferably 28 to 36 mg, more preferably 29 to 35 mg, and most preferably 30 to 34 mg.
  • the amount of one drop of the present pharmaceutical composition can be measured by, for example, pressing the container body in the same manner as using normal eye drops and dropping one drop, and then measuring the mass with a balance.
  • the eye drop container is turned upward, the cap is removed, the eye drop container is pointed directly down, the container body is pushed as slowly as possible (for example, 2 to 5 seconds, preferably about 3 seconds), and the balance is placed on the balance.
  • Drop a drop on the saucer After dropping one drop, the force applied to the container body is relaxed while holding the container downward.
  • the mass of one drop of the composition of the present invention can be measured.
  • the volume of the drop amount of the composition of the present invention can be easily calculated from the measured mass of the drop amount of the composition of the present invention and the specific gravity of the pharmaceutical composition.
  • the same conditions for example, the same temperature, the same eye drop container, the same dropping condition (for example, the angle of inclination of the eye drop container at the time of dropping, the container The force and time applied to the body part, and the same method for measuring the mass of a single drop) are compared with each other.
  • the dosage form of the 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.
  • the pharmaceutical composition of the present invention is useful as a therapeutic agent for glaucoma or ocular hypertension.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is administered, there is no particular limitation on the dosage as long as it is sufficient to achieve a desired drug effect, but it is preferable to instill 1 to 3 drops at a time, 1 to 5 times a day, More preferably, 1 to 2 drops per day, 2 to 4 times per day, and most preferably 1 drop per day, 3 times per day.
  • the pharmaceutical composition of the present invention is useful for contact lenses (wearers).
  • the type of contact lens to be applied is not particularly limited, and specific examples include hard contact lenses, soft contact lenses, and the like, and oxygen permeable contact lenses may be used.
  • Examples of the soft contact lens include a hydrous soft contact lens, a non-hydrous soft contact lens, and a (nonionic) silicone hydrogel soft contact lens.
  • composition of the present invention controls the use of the pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment of glaucoma or ocular hypertension and the amount of one drop of the pharmaceutical composition of the present invention. It is also applied to the method.
  • the method for controlling the drop amount of the pharmaceutical composition of the present invention comprises 0.001-5% (w / w) of a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof and not containing benzalkonium chloride. v) containing a surfactant other than benzalkonium chloride.
  • the drop amount of the pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof and not containing benzalkonium chloride can be controlled.
  • the pharmaceutical composition containing benzalkonium chloride can be controlled to be close to the amount of one drop.
  • the amount of one drop increases when the pharmaceutical composition does not contain benzalkonium chloride.
  • control of the drop amount of the pharmaceutical composition means that the drop amount of the pharmaceutical composition is controlled in the downward direction (that is, control in the direction of decreasing the drop amount of the pharmaceutical composition).
  • 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.
  • the desired composition can be obtained by appropriately adjusting the types and blending amounts of dorzolamide, timolol and surfactant in Formulation Examples 1 and 2 and the pH.
  • Viscosity measurement test Preparation of test preparation ⁇ Preparation of preparation containing benzalkonium chloride (BAK-containing preparation)> Hydroxyethyl cellulose (0.95 g) was dissolved in sterilized purified water and autoclaved (121 ° C., 30 minutes) to give a 0.95% (w / w) hydroxyethyl cellulose solution. Also, dorzolamide hydrochloride (2.7825 g), timolol maleate (1.77075 g), sodium citrate hydrate (0.735 g) and D-mannitol (7.5 g) were dissolved in sterile purified water. A 5 times concentrated liquid A was obtained.
  • a 10% (w / v) benzalkonium chloride solution was diluted with sterilized purified water to obtain a 0.5% benzalkonium chloride solution.
  • To 12 mL of 2.5-fold concentrated solution A 0.3 mL of 0.5% (w / v) benzalkonium chloride solution was added, and further 15 g of 0.95% (w / w) hydroxyethyl cellulose solution was added and stirred. . Then, 1N sodium hydroxide was added to adjust the pH to 5.65.
  • a solution containing BAK (benzalkonium chloride) was prepared by adding sterilized purified water to adjust the total amount to 30 g. The prepared solution (5 mL) was put in a polyethylene eye drop container (outer diameter of nozzle tip; 3.2 mm) to prepare BAK-containing preparation 1.
  • BAK-containing preparation 2 was prepared in the same manner as the preparation method for BAK-containing preparation 1.
  • test method At room temperature, the eye drop container of each preparation was turned upward, the cap was removed, the eye drop container was pointed directly down, the container body was slowly pushed with the thumb and forefinger for about 3 seconds, and placed on a semi-micro balance. A drop was dropped on the saucer. After dropping one drop, the force applied to the container body was loosened while holding the container downward. The amount of each drop was measured by measuring the mass with a semi-micro balance. All tests for each formulation were performed under the same conditions.
  • the amount of one drop of the preparations of Examples 1 to 9 containing benzalkonium chloride was the same as that of the BAK-containing preparation 1 and the BAK-containing preparation 2. From this result, it is found that a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof does not contain benzalkonium chloride, so that a drop of the pharmaceutical composition can be reduced by including a surfactant. It has been found that it can approach an amount equivalent to a drop amount of a pharmaceutical composition containing nium chloride. In addition, from the comparison of Examples 4, 5, 8 and 9, it was found that polysorbate 80 was particularly excellent as the surfactant.

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Abstract

L'invention a pour objet de réguler une goutte d'une composition pharmaceutique qui comprend un dorzolamide ou un sel de celui-ci et un timolol ou un sel de celui-ci, et qui ne comprend pas de chlorure de benzalkonium. Selon l'invention, une goutte de la composition pharmaceutique est régulée du fait que 0,001 à 5%(w/v) d'un tensio-actif autre qu'un chlorure de benzalkonium est compris dans cette composition pharmaceutique comprenant un dorzolamide ou un sel de celui-ci et un timolol ou un sel de celui-ci, et ne comprenant pas de chlorure de benzalkonium. De préférence, le tensio-actif inclut au moins un tensio-actif choisi dans un groupe constitué d'un ester d'acide gras de polyoxyéthylène sorbitanne, d'un ester d'acide gras de polyoxyéthylène, d'une huile de ricin hydrogénée polyoxyéthylène, d'une huile de ricin polyoxyéthylène, d'un polyéthylène glycol d'acide monostéarique et d'une chlorhexidine ou d'un sel de celle-ci.
PCT/JP2017/009876 2016-03-14 2017-03-13 Composition pharmaceutique comprenant un dorzolamide, un timolol et un tensio-actif WO2017159586A1 (fr)

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WO2021237096A1 (fr) * 2020-05-21 2021-11-25 Graybug Vision, Inc. Implants durables et microparticules pour une thérapie oculaire à long terme

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JP6603785B2 (ja) * 2017-12-08 2019-11-06 千寿製薬株式会社 水溶性高分子を含む水性液剤
TW202245794A (zh) * 2021-02-15 2022-12-01 日商參天製藥股份有限公司 包含熊去氧膽酸或其鹽之水性醫藥組合物

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WO2021237096A1 (fr) * 2020-05-21 2021-11-25 Graybug Vision, Inc. Implants durables et microparticules pour une thérapie oculaire à long terme

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