WO2002045748A1 - Compositions d'abaissement de la tension oculaire pour administration topique - Google Patents

Compositions d'abaissement de la tension oculaire pour administration topique Download PDF

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Publication number
WO2002045748A1
WO2002045748A1 PCT/JP2001/010549 JP0110549W WO0245748A1 WO 2002045748 A1 WO2002045748 A1 WO 2002045748A1 JP 0110549 W JP0110549 W JP 0110549W WO 0245748 A1 WO0245748 A1 WO 0245748A1
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Prior art keywords
composition according
group
angiotensin
intraocular pressure
antagonist
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PCT/JP2001/010549
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English (en)
Japanese (ja)
Inventor
Takashi Shiokari
Takayuki Kikuchi
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Sankyo Company, Limited
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Priority to AU2002218527A priority Critical patent/AU2002218527A1/en
Publication of WO2002045748A1 publication Critical patent/WO2002045748A1/fr

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    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the present invention relates to a pharmaceutical composition for topical administration that has an excellent intraocular pressure lowering action and is stable even when combined with other drugs.
  • angiotensin II antagonists are known to reduce intraocular pressure by topical administration (EP 795326, EP 631 780, WO 95/21609, WO 91Z1 5206, etc.).
  • topical administration EP 795326, EP 631 780, WO 95/21609, WO 91Z1 5206, etc.
  • the following compounds are known.
  • the present inventors conducted intensive studies on the preparation and pharmacological action of a composition for topical administration of an angiotensin II antagonist, and added boric acid and ethylenediaminetetraacetic acid to the formulation.
  • the present inventors have to solve the problem / perform further studies.
  • a surfactant By adding a surfactant to the above preparation, the combination of active ingredient, boric acid and ethylenediaminetetraacetic acid can be shown.
  • the present invention provides d
  • Angiotensin II antagonist angiotensin II antagonist, boric acids, ethylenediamine E acetic acids, and
  • composition wherein the angiotensin II antagonist is a compound having the following general formula (I) or a pharmaceutically acceptable salt or derivative thereof:
  • composition in which the compound having the general formula (I) is a compound selected from the following: • 4- (1-hydroxy-1-methylethyl) -1-2-propyl-1-1 j4— [2-—tetrazo- 5-yl) phenyl] phenyl 1-methylimidazole-5-carbonic acid,
  • composition wherein the preservative is a paraben
  • composition described above as (1) to (6) further contains at least one compound selected from an adrenergic receptor blocker, a prostaglandin, and a carbonic anhydrase inhibitor. Is also good.
  • compositions preferably,
  • composition wherein the adrenergic receptor blocking agent is bunazosin, timolol, zipradilol, or a pharmacologically acceptable salt or ester thereof;
  • the adrenergic receptor blocker is bunazosin hydrochloride, timolol maleate or A composition that is two pradilol,
  • composition in which the prostaglandins are isopropyl unoprostone, rattanoblast, or a pharmacologically acceptable salt thereof,
  • Another object of the present invention is to provide any one of the above (1) to (6) and (a) to (f) containing a pharmacologically effective amount of an angiotensin II antagonist.
  • composition described in any one of (1) to (6) and (a) to (f) above, and at least one selected from an adrenergic receptor blocker, a prostaglandin, and a carbonic anhydrase inhibitor is described in any one of (1) to (6) and (a) to (f) above, and at least one selected from an adrenergic receptor blocker, a prostaglandin, and a carbonic anhydrase inhibitor.
  • a method for lowering intraocular pressure which comprises administering to a warm-blooded animal (preferably, to a human) at least one compound [particularly, glaucoma (including normal tension glaucoma) or ocular hypertension.
  • glaucoma including normal tension glaucoma
  • ocular hypertension is particularly, glaucoma (including normal tension glaucoma) or ocular hypertension.
  • Boric acids refers to boric acid and substances equivalent to boric acid. Boric acid equivalent material, by dissolving in water shows the compound to produce a borate ion, as such compounds, such as boric anhydride (B 2 0 3), tetraborate (H 2 B 4 0 7), and e ⁇ acid, and pharmacologically acceptable salts of boric anhydride and tetraborate. Preferred are boric acid, boric anhydride, borax and sodium borate decahydrate, particularly preferred is boric acid. .
  • the above boric acids can be used alone or in combination of two or more. You can also.
  • the lower limit is 0.5 mg / mL (preferably lmg / mL, preferably More preferably, it is 5 mg / mL, and the upper limit is about 10 Omg / mL (preferably 50 mg / mL, more preferably 20 mgZmL).
  • Ethylenediaminetetraacetic acid refers to ethylenediaminetetraacetic acid and substances equivalent to ethylenediaminetetraacetic acid.
  • a substance equivalent to ethylenediaminetetraacetic acid refers to a compound that produces ethylenediaminetetraacetic acid ions when dissolved in water, and examples of such a compound include pharmacologically acceptable salts of ethylenediaminetetraacetic acid. it can.
  • Preferable examples are ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid disodium dihydrate, ethylenediaminetetraacetic acid trisodium trihydrate, ethylenediaminetetraacetic acid ninatrinium dihydrate, and ethylenediaminetetraacetic acid tetrasodium tetrahydrate. Hydrate may be mentioned, and most preferably ethylenediaminetetraacetate ninatriduminium hydrate.
  • ethylenediamine tetraacetic acid can be used alone or in combination of two or more.
  • the appropriate lower limit of the amount of ⁇ ethylenediaminetetraacetic acid '' based on the total weight of the composition for topical administration of intraocular pressure is 0.0025 mg / mL (Preferably 0.005 mg / mL, more preferably 0.05 mg / mL), and the upper limit is 2 mg_mL (preferably l mg / mL, more preferably 0.5 mgZmL).
  • the appropriate ratio of the amount of “boric acids” to the amount of “ethylenediaminetetraacetic acids” is based on the assumption that the amount of “boric acids” (the amount converted to the weight of boric acid) is 1.
  • the lower limit of the amount of “ethylenediaminetetraacetic acid” (the amount in terms of the weight of disodium ethylenediaminetetraacetate dihydrate) is 0.0000025 (preferably 0.0005, more preferably 0.0005). ), And the upper limit is 0.2 (preferably 0.1, more preferably 0.05).
  • “Surfactant” refers to a surfactant commonly used in ophthalmic preparations. Examples of such surfactants include polyoxyethylene hydrogenated castor oils (eg, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated) Castor oil 40, Polyoxyethylene hardened castor oil 50, Polyoxyethylene hardened castor oil 60, etc.), ether surfactant
  • polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (105) polyoxypropylene (5 ) Glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyalkylene glycols such as polypropylene glycol 2000; polyoxyethylene
  • Polyoxypropylene (1) Cetyl ether, polyoxyethylene (20) Polyoxypropylene (4) Cetyl ether, polyoxyethylene octylphenyl ether, polyoxyethylene nonylphenyl ether, polyoxypropylene Polyoxyalkylene alkyl ethers such as xishylene cetyl ether; polyoxyethylenoleyl ether; polyoxyethylene stearyl ether, etc.), polysorbates (eg, polysorbate 20, polysorbate 60, polysorbate 80, etc.), ester-type surfactant Agents (eg, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbit beeswax, etc.), macrogol (eg, macrogol 200, macrogol 300, macrogol 400, macrogol 400, macrogol 600, macrogol Logol 1540, Macrogol 4000, Macrogol 6000), polyoxyl stearate 40, polyvinyl alcohol (partially saponified), and polyoxyethylene lanolin.
  • polyoxyethylene hydrogenated castor oil polysorbates, macrogol, polyoxyl stearate 40 or polyvinyl alcohol (partially saponified) is used. More preferably, polyoxyethylene hydrogenated castor oil is used. 60, polysorbate 80, macrogol 4000, macrogol 6000, polyoxyl stearate 40 or polyvinyl alcohol (partially saponified) is used.
  • the preferred amount of the surfactant relative to the total volume of the intraocular pressure-lowering composition for topical administration is preferably from 0.1 mg / mL to 1 Omg / mL, more preferably 0.5 mg / mL. mL to 10 mg / mL, more preferably 1 mg ZmL to 5 mg / mL, and most preferably 2 mg / mL to 5 mg / mL.
  • angiotensin II antagonist is preferably a compound having the following general formula (I) or a pharmacologically acceptable salt or derivative thereof:
  • R 1 represents the following structural formula (Ia), (Ib), (Ic), (Id), (Ie) or (If)
  • the “pharmacologically acceptable salt” means that the compound of the above general formula (I), boric acid, etc. and diethylenediaminetetraacetic acid can be converted into a salt by reacting with a base. Show the salt.
  • Examples of such salts include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; metal salts such as aluminum salt and iron salt; and ammonium salt.
  • Inorganic salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, dalcosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methyldalcamin salt, guanidine salt, getylamine salt, Triethylamine salt, dicyclohexylamine salt, N, ⁇ '-dibenzylethylenediamine salt, black mouth pro-force salt, pro-force salt, diethanolamine salt, ⁇ -benzylphenethylamine salt, Perazine salt, tetramethylammonium salt, tris (hydroxymethyl) amino methane salt And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.
  • amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspart
  • it is an alkali metal salt, and more preferably, it is a sodium salt or magnesium salt.
  • Boric acids, ethylenediaminetetraacetic acids, and the compounds of the above general formula (I) and their pharmacologically acceptable salts absorb moisture by being left in the air or by recrystallization. However, there is a case where water is adsorbed or a hydrate is formed, and such a hydrate is also included in the present invention.
  • a pharmacologically acceptable derivative of the compound of the above general formula (I) is defined as a derivative obtained by modifying a compound having a hydroxyl group and / or a carboxyl group when the compound (I) has a hydroxyl group and / or a carboxyl group.
  • derivatives refers to “hydroxyl-based esters”, “hydroxyl-based ethers”, “carboxy-based esters”, and “carboxy-based amides”. Wherein each ester residue, ether residue or amide residue is a "general protecting group” or a "protection that can be cleaved in vivo by a biological method such as hydrolysis.” Group ".
  • General protecting group refers to chemicals such as hydrogenolysis, hydrolysis, electrolysis, and photolysis. Means a protecting group that can be cleaved by a standard method.
  • An “aralkyl group” such as a lower alkyl group substituted by one to three aryl groups in which the ring is substituted; vinyloxy Carbonyl, "alkenylcarbonyl O alkoxycarbonyl group” such as ⁇ Lil O alkoxycarbonyl; benzyl
  • “general protecting group” for the “ester based on a carboxy group” preferably, methyl, ethyl, propyl, isopropyl, n-butyl, isoptyl, s-butyl, tert-butyl, n- Pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, "Lower alkyl groups" such as 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl; vinyl, 2-propenyl, 1-methyl-2-propenyl , 2-methyl-
  • 3-pentenyl 1-methyl-3-pentenyl, 2-methyl-1-pentenyl, 4-pentenyl, 1-methyl_4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-to "Lower alkenyl groups" such as xenyl, 5-hexenyl; ethynyl, 2'-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-1-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butul, 1-ethyl-3-butynyl,
  • 2-pentynyl 1-methyl-1-2-pentynyl, 3-pentynyl, 1-methyl-13-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-1-pentynyl, 2-methyl-4-1-pentynyl, "Lower alkynyl groups" such as 2-hexynyl, 3-hexynyl, 4-hexyl, 5-hexynyl; trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2, 2, 2 _ trichloroethyl, 2, 2, 2— trifluoroethyl, 2 —Halogeno lower alkyls, such as bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromomethyl; 2-hydroxyhexyl, 2,3-dihydroxypropyl,
  • Protecting group that can be cleaved in vivo by a biological method such as hydrolysis means a protective compound that is cleaved in a human body by a biological method such as hydrolysis and is a base compound or its pharmacologically.
  • a protective group that forms an acceptable salt is administered to a laboratory animal such as a rat or mouse by intravenous injection, and then the body fluid of the animal is examined to determine the source. Can be determined by the ability to detect the compound or a pharmacologically acceptable salt thereof,
  • protecting group which can be cleaved in vivo by a biological method such as hydrolysis in the "ester based on a hydroxyl group” and "ether based on a hydroxyl group", preferably, formyloxymethyl, Acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, pa'relyloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyxetil, 1-acetoxicetyl, 1 —Propionyloxyxetil, 1—Butyriloxyxetil, 1—Pivaloyloxicetyl, 1—Norelyloxexyl, 1 Isovaleryloxixyl, 1—Hexanoylox Quixetil, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxyp Pill, 1-Bivaloyloxypropyl, 1-Norely
  • Lower alkyl group such as lower alkyl group; methoxycarbonyloxymethyl, ethoxycarbonyl Oxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyl Kishiro Cicarboxyloxymethyl, cyclohexyloxycarponyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl , 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethy
  • the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester based on a carboxy group” preferably, methoxethyl, 11-ethoxyl, 1 1-Methyl-1-methoxyl, 1- (Isopropoxy) ethyl, 2-Methoxyl, 2-Ethoxyl, 1,1_dimethyl 1-Methoxyethyl, Ethoxymethyl, n-Propoxymethyl, Isopropoxymethyl, lower alkoxy lower alkyl groups such as n-butoxymethyl and t-butoxymethyl; lower alkoxylated lower alkoxy lower alkyl groups such as 2-methoxyethoxymethyl; "Alkyl lower” such as "aryl” oxy "lower alkyl” such as phenoxymethyl, halogenated lower alkoxy such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl “
  • lower alkyl refers to C-6 straight-chain or branched-chain alkyl, preferably methyl, ethyl, propyl, isopropyl or butyl, and more preferably methyl or ethyl. Is shown.
  • lower alkoxy indicates a C _ 4 linear or branched alkoxy, preferably denotes main butoxy, ethoxy, Purobokishi, isopropoxy or butoxy, more preferably shows a main butoxy or ethoxy.
  • adrenergic receptor blocker refers to ⁇ blocker, /? Blocker or ⁇ 9 blocker.
  • blocker refers to preferably ⁇ 1 blocker, particularly preferably bunazosin or a pharmacologically acceptable salt thereof, and most preferably bunazosin hydrochloride.
  • the blocking agent particularly preferably represents timolol or a pharmacologically acceptable salt or derivative thereof, and most preferably timolol maleate.
  • the ⁇ . / 9 blocker particularly preferably represents nipradilol or a pharmaceutically acceptable salt or derivative thereof, and most preferably nipradilol.
  • Prostaglandins include naturally occurring prostaglandins such as prostaglandin F 2 ⁇ ; or derivatives of prostaglandins such as isopropyl unoprostone and latanoprost; or pharmacologically thereof. It represents an acceptable salt, particularly preferably isopropyl unoprostone or latanobustone, or a pharmacologically acceptable salt thereof, and most preferably isopropyl unoprostone or latanobustone.
  • carbonic anhydrase inhibitor particularly preferably refers to dorzolamide or a pharmacologically acceptable salt thereof, and most preferably tolzolamide hydrochloride.
  • adrenergic receptor blockers In the description of “adrenergic receptor blockers”, “prostaglandins” and “prostaglandins”, “pharmacologically acceptable salts” and “pharmacologically acceptable derivatives” are as defined above. Is shown.
  • angiotensin II antagonists include, for example, ⁇ 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 And the like, and these compounds can be easily produced according to a known method.
  • adrenergic receptor blocker for example, compounds disclosed in GB 1253710, GB 1398455, EP 42299, etc. can be employed.These compounds can be easily produced according to known methods. Can be.
  • prostaglandins for example, compounds disclosed in EP 289349 and WO 90/2553 can be adopted, and these compounds can be easily produced according to a known method. Can be.
  • the intraocular pressure lowering composition for topical administration of the present invention comprises an angiotensin II antagonist, boric acids, It can be prepared according to a conventional method using ethylenediaminetetraacetic acid and a surfactant (and, if desired, further using an adrenergic receptor blocker, a prostaglandin, and a carbonic anhydrase inhibitor).
  • a pharmacologically acceptable carrier can be used in addition to the above components.
  • the carrier used is not particularly limited as long as it is used for preparing a preparation usually applied to the eye.
  • Inert diluents include, for example, aqueous solvents such as water, Ringer's solution, isotonic saline, castor oil, olive oil, sesame oil, soybean oil, liquid paraffin, propylene glycol, / 9-year-old cutyldodecanol And other oily solvents.
  • aqueous solvents such as water, Ringer's solution, isotonic saline, castor oil, olive oil, sesame oil, soybean oil, liquid paraffin, propylene glycol, / 9-year-old cutyldodecanol And other oily solvents.
  • preservative examples include parabens such as methyl paraben, ethyl paraben, propyl paraben, and butyl paraben, benzalkonium chloride, chlorhexidine, benzethonium chloride, benzyl alcohol, sorbic acid and salts thereof, thimerosal, and chlorobutanol. be able to.
  • parabens, benzalcodium chloride, and benzethonium chloride are used.
  • parabens are used in combination with boric acids and ethylenediaminetetraacetate, an excellent preservative action can be obtained. In this respect, parabens are most preferred.
  • tonicity agent examples include sodium chloride, mannitol, sorbitol, glycerin and the like.
  • buffer examples include phosphate, acetate, citrate and the like.
  • pH adjuster examples include hydrochloric acid, acetic acid, and sodium hydroxide.
  • ointment base examples include petrolatum, plastibase (trademark), and liquid paraffin.
  • viscosity agent examples include methylcellulose, carmellose and salts thereof, hydroxyshethylcellulose, sodium alginate, propyloxyvinyl polymer, and polyvinylpyrrolidone.
  • a gel for example, carboxyvinyl polymer, methyl cellulose, sodium alginate, hydroxypropylcellulose, ethylene maleic anhydride polymer and the like can be used.
  • the formulation of the composition for topical administration of the present invention has a lower limit of 0.1 mg / mL (preferably 0.1 mg / mL) and an upper limit of 100 mg / mL (preferably 5 mg / mL).
  • the dose of the composition of the present invention varies depending on the disease state and the like. For example, when the composition of the present invention is used as an eye drop, one to several drops, preferably one or two drops (one drop of About 50 L) can be administered about 1 to 6 times a day.
  • composition of the present invention can be administered to a warm-blooded animal. Preferably, it is administered to a human.
  • a topical intraocular pressure-lowering composition containing an angiotensin II antagonist, boric acids, ethylenediaminetetraacetic acids, and a surfactant in one dosage unit, These components can be administered separately and almost simultaneously.
  • Compound A [2- (tetrazol-5-yl) phenyl] phenyl 1-methylimidazole-5-capillonic acid (hereinafter referred to as “Compound A”) was added, and 1 mo 1 / L aqueous sodium hydroxide solution was further added. About 7.5 mL was added and stirred. After adjusting the pH to 7.0 using an aqueous sodium hydroxide solution (concentration: lmo 1 / L), water for injection was added to adjust the total volume to 100 mL.
  • This solution was sterile-filtered using a membrane filter made of MILLIPORE [Hydrophilic Durapo 7 (material: hydrophilic polyvinylidene difluoride), 0.2 (hereinafter referred to as “GV”)]. An eye drop was prepared.
  • the solution was aseptically filtered using GV to prepare eye drops.
  • This solution was aseptically filtered using GV to prepare an eye drop.
  • composition for topical administration of the present invention the following composition was prepared, and in the test examples described later, the composition was compared with the composition of the above example.
  • the solution was aseptically filtered using GV to prepare eye drops.
  • the solution was aseptically filtered using GV to prepare eye drops.
  • This solution was aseptically filtered using GV to prepare an eye drop.
  • intraocular pressure was measured every 30 minutes.
  • the intraocular pressure drop width was calculated from the measured values of the intraocular pressure in the group in which the test composition was instilled and the control group.
  • ⁇ MP '' indicates methylparaben
  • ⁇ PP '' indicates propylparaben
  • "EDTA'2Na” indicates disodium ethylenediaminetetraacetate 'dihydrate.
  • compositions 2 to 4 From the results of compositions 2 to 4, it is clear that when boric acid or ethylenediaminetetraacetic acid alone is used in combination with an angiotensin II antagonist, the degree of decrease in intraocular pressure is hardly affected.
  • Composition 1 containing boric acid and ethylenediaminetetraacetic acid showed a remarkable intraocular pressure lowering effect as compared with Compositions 2 to 4. That is, as is clear from Table 1, the combination of boric acid and ethylenediaminetetraacetic acid markedly enhanced the intraocular pressure lowering effect of the angiotensin II antagonist.
  • composition of the present invention further contains a surfactant in the composition of Comparative Example 4, and is expected to have a remarkable intraocular pressure lowering effect as in Comparative Example 4.
  • Example 1 and Example 2 showed no change in appearance when mixed with any of the above.
  • Example 3 and Example 4 showed no change in appearance when mixed with any of the above.
  • the intraocular pressure-lowering composition for topical administration according to the present invention has an excellent intraocular pressure-lowering effect and weak side effects, and thus has an increased intraocular pressure due to glaucoma (including normal tension glaucoma) and ocular hypertension. Can be effectively lowered, and since it has good stability even when mixed with other drugs, it can be used in combination with other eye drops and the like, and better treatment with drugs can be achieved.

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Abstract

L'invention concerne des compositions pour administration topiques présentant un excellent effet d'abaissement de la tension oculaire, et très stables lorsqu'elles sont mélangées avec d'autres agents. L'invention concerne également des compositions d'abaissement de la tension oculaire pour administration topique contenant un antagoniste de l'angiotensine II, un composé d'acide borique, un acide éthylène diamine tétraacétique, et un tensioactif.
PCT/JP2001/010549 2000-12-05 2001-12-03 Compositions d'abaissement de la tension oculaire pour administration topique WO2002045748A1 (fr)

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AU2002218527A AU2002218527A1 (en) 2000-12-05 2001-12-03 Ocular tension-lowering compositions for topical administration

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003063879A1 (fr) * 2002-01-29 2003-08-07 Santen Pharmaceutical Co., Ltd. Remedes contre le glaucome contenant de la bunazosine et des prostaglandines
WO2004091659A1 (fr) * 2003-04-15 2004-10-28 Sankyo Company, Limited Medicament destine a la prevention ou au traitement des maladies oculaires angiogeniques

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WO1991015206A1 (fr) * 1990-04-05 1991-10-17 E.I. Du Pont De Nemours And Company Traitement du glaucome et de l'hypertension oculaire a l'aide d'imidazoles en tant qu'antagonistes de recepteur d'angiotensine-ii
EP0480745A2 (fr) * 1990-10-12 1992-04-15 Merck & Co. Inc. Dihydrothiénothiopène-2-sulfonamides substitués et leurs dioxydes
EP0631780A1 (fr) * 1993-07-02 1995-01-04 Takeda Chemical Industries, Ltd. Utilisation d'un antagoniste de l'angiotensine-II comme un agent oculaire hypotenseur
WO1995021609A1 (fr) * 1994-02-08 1995-08-17 Ciba-Geigy Ag Antagonistes de l'angiotensine ii destines au traitement du glaucome normotensif
EP0795326A1 (fr) * 1994-03-16 1997-09-17 Sankyo Company Limited Reducteur de tension oculaire
WO1998041208A1 (fr) * 1997-03-17 1998-09-24 Novartis Ag Compositions et procedes pour reduire l'hypertension oculaire

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WO1991015206A1 (fr) * 1990-04-05 1991-10-17 E.I. Du Pont De Nemours And Company Traitement du glaucome et de l'hypertension oculaire a l'aide d'imidazoles en tant qu'antagonistes de recepteur d'angiotensine-ii
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WO2003063879A1 (fr) * 2002-01-29 2003-08-07 Santen Pharmaceutical Co., Ltd. Remedes contre le glaucome contenant de la bunazosine et des prostaglandines
WO2004091659A1 (fr) * 2003-04-15 2004-10-28 Sankyo Company, Limited Medicament destine a la prevention ou au traitement des maladies oculaires angiogeniques

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