WO2002045748A1

WO2002045748A1 - Ocular tension-lowering compositions for topical administration

Info

Publication number: WO2002045748A1
Application number: PCT/JP2001/010549
Authority: WO
Inventors: Takashi Shiokari; Takayuki Kikuchi
Original assignee: Sankyo Company, Limited
Priority date: 2000-12-05
Filing date: 2001-12-03
Publication date: 2002-06-13
Also published as: AU2002218527A1

Abstract

[Object] To provide compositions for topical administration which are excellent in the effect of lowering ocular tension and highly stable in case of being mixed with other agents. [Means for Resolution] Ocular tension-lowering compositions for topical administration which contain an angiotensin II antagonist, a boric acid compound, ethylenediaminetetraacetic acid and a surfactant.

Description

Description IOP lowering composition for topical administration [Technical field]

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.

[Background technology]

Conventionally, angiotensin II antagonists are known to reduce intraocular pressure by topical administration (EP 795326, EP 631 780, WO 95/21609, WO 91Z1 5206, etc.). For example, the following compounds are known.

[Disclosure of the Invention] formula

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.

It has been found that the addition increases the intraocular pressure lowering effect of an angiotensin II antagonist. However, for this formulation, other drugs [eg, xalatan (trademark)

Product name, Pharmacia Upjohn), pivaleline (product name, Santen) etc.]

I

In this case, the problem a that turbidity occurs was found.

\ 1

The present inventors have to solve the problem / perform further studies. By adding a surfactant to the above preparation, the combination of active ingredient, boric acid and ethylenediaminetetraacetic acid can be shown.

\ 1

Completed the present invention by finding that turbidity can be prevented without hindering the pharmacological effects

-_ I

did. C

I

The present invention provides d

(1) Angiotensin II antagonist, boric acids, ethylenediamine E acetic acids, and

1 /

I

Topical intraocular pressure-lowering composition containing a surfactant 6

\ 1

About.

In the above composition, preferably, (/ \

--1

(2) A composition wherein the angiotensin II antagonist is a compound having the following general formula (I) or a pharmaceutically acceptable salt or derivative thereof:

(I)

Represents a group having

(3) a composition wherein R ¹ is a group having the above structural formula (Ia), (Ib) or (Ic);

(4) A 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,

2-Ethoxy-1-1- [2,-(1H-tetrazol-1-5-yl) biphenyl-1-yl] methyl-1-H-benzimidazole-7-carboxylic acid,

(5) In addition to the above, a composition containing a preservative, and

(6) The composition wherein the preservative is a paraben

Can be mentioned.

The 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.

Of such compositions, preferably,

(a) a composition wherein the adrenergic receptor blocking agent is bunazosin, timolol, zipradilol, or a pharmacologically acceptable salt or ester thereof;

(b) the adrenergic receptor blocker is bunazosin hydrochloride, timolol maleate or A composition that is two pradilol,

(C) A composition in which the prostaglandins are isopropyl unoprostone, rattanoblast, or a pharmacologically acceptable salt thereof,

(d) a composition wherein the prostaglandins are isopropyl unoprostone or latanobrost,

(e) a composition wherein the carbonic anhydrase inhibitor is dorzolamide or a pharmaceutically acceptable salt thereof, and

(f) a composition wherein the carbonic anhydrase inhibitor is tolozolamide hydrochloride,

Can be given.

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. Administering the composition to a warm-blooded animal (preferably to a human), a method of lowering intraocular pressure [especially due to glaucoma (including normotensive glaucoma) or ocular hypertension. A method for reducing elevated intraocular pressure], and

The 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. 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. A method for reducing the increased intraocular pressure. In the present invention,

"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.

For the appropriate amount of `` boric acids '' based on the total volume of the intraocular pressure-lowering composition for topical administration, 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.

The above-mentioned 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). . Also, 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

(For example, 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

(1) 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.

Preferably, 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. Further, 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.

The “angiotensin II antagonist” is preferably a compound having the following general formula (I) or a pharmacologically acceptable salt or derivative thereof:

[Wherein, R ¹ represents the following structural formula (Ia), (Ib), (Ic), (Id), (Ie) or (If)

A group having the formula:

More preferably,

• 4- (1-hydroxyl-methylethyl) 1- 2-propyl- 1- 1- [2- (tetrazol-5-yl) phenyl] phenyl! Methylimidazole-5-carboxylic acid,

• 2-ethoxy-11- [2,1- (1H-tetrazole-5-yl) biphenyl-2-yl, methyl-1H-benzimidazole-7-carboxylic acid, Or a pharmacologically acceptable salt or derivative thereof.

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, Ν'-dibenzylethylenediamine salt, black mouth pro-force salt, pro-force salt, diethanolamine salt, Ν-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. Preferably, 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. The term “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.

As the “general protecting group” for the “ester based on hydroxyl group” and the “ether based on hydroxyl group”, preferably, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, norrelyl, isono Reryl, Octanoyl, Nonanoyl, Decanoyl, 3-Methylnonanoyl, 8-Methylnonanoyl, 3-Ethyloktanoyl, 3,7-Dimethyloctanoyl, Pendecanoyl, Dodecanoyl, Tridecanoyl, Tetradecanoyl, Tetradecanol, Hepentacanyl, Tetradecanol Pentadecanoyl, 14'-Methylpentadecanoyl, 13, 13-Dimethyltilde toradecanol, Heptadecanoyl, 15-Methylhexadecanoyl, Octadecanoyl, 1—Methylheptadecanoyl, Nonadecanol, Alkanoyl groups such as eicosanoyl, henicosanoyl, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl; lower alkoxyalkylcarbonyl groups such as methoxyacetyl, and alcohol An "aliphatic acyl group" such as an unsaturated alkylcarbonyl group such as propiooloyl, methacryloyl, crotonyl, isocrotonyl, (E) -2-methyl-2-butenoyl (preferably having 1 to 6 carbon atoms); Lower aliphatic acyl group.); Arylcarbonyl groups such as benzoyl, mono-naphthyl, mono-naphthyl, 2-bromobenzoyl, halogenated aryl-carbonyl groups such as 4-bromobenzoyl, 2, 4, 6 — trimethylbenzoyl, 4 torr Lower alkylated arylcarbonyl groups such as oil, lower alkoxylated arylcarbonyl groups such as 4-anisyl, 4-nitronitrosilyl groups such as 4-nitrobenzoyl, 2-nitrobenzoyl, “Aromatic acyl groups” such as lower alkoxycarbonylylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl and arylalkylcarbonyl groups such as 4-phenylbenzoyl; methoxycarbonyl Ethoxycarbonyl, butoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t--poxycarbonyl, lower alkoxycarbonyl such as isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2—Halogen or trimethylsilylethoxycarbonyl Lower alkoxy force substituted by lower alkylsilyl group “Alkoxycarbonyl group” such as luponyl group; tetrahydropyran-1-yl, 3-bromotetrahydropyran-2-yl, 4-methoxyethoxyhydropyran-1-4-yl, tetrahydropyropyran-12-yl, 4-methyl A "tetrahydrodrobilanyl or tetrahydrothiopyranyl group" such as toxicoxytetrahydropyropyran-14-yl; a "tetrahydrofuranyl or tetrahydrothiofuranyl group" such as tetrahydrofuran-12-yl or tetrahydrofurothiofuran-12; trimethylsilyl, triethylsilyl, Tri-lower 'alkylsilyl groups such as isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenyl “Silyl groups” such as tri-lower alkylsilyl groups in which one or two alkyl groups have been replaced by aryl groups, such as nilbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylpropylsilyl; methoxymethyl, 1 Lower alkoxymethyl groups such as, 1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxy such as 2-methoxyethoxymethyl “Alkoxymethyl group” such as methyl group, halogeno lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; 1-ethoxyxyl, 1- (isopropoxy) ethyl Lower alkoxylated tyl group, 2,2,2-tri "Substituted ethyl groups" such as halogen groups such as chloroethyl; such as benzyl, di-naphthylmethyl, /? _ Naphthylmethyl, diphenylmethyl, triphenylmethyl, di-naphthyldiphenylmethyl, 9-thrylmethyl Lower alkyl groups substituted with 1 to 3 aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxybenzyl Lower alkyl, lower alkoxy, nitro., Such as methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, aryl, halogen, cyano, aryl 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 O carboxymethyl Cal Poni le, 4- main Toki One or two lower alkoxy or diethoxy, such as cibenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 212-pentoxybenzyloxycarbonyl, 4-nitrobenzoyloxycarbonyl; An "aralkyloxycarbonyl group" which may be substituted on the aryl group by a mouth group can be mentioned.

As the “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-

2-'probenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 1-ethyl-2-butenyl, 3-butenyl,

1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-1-2-pentenyl, 2-methyl-1-2-pentenyl,

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, 3-hydroxypropyl, 3, A hydroxy "lower alkyl group" such as 4-dihydroxybutyl or 4-hydroxybutyl; a "lower aliphatic acyl" such as acetylmethyl; a "lower alkyl group"; the "aralkyl group"; and the "silyl group" Can be mentioned.

"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. Whether such a derivative is or not 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,

As the "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-Norelyloxypropyl, 1-Isonorelyloxypropyl, 1-Hexanolyloxypropyl, 1-Acetoxybutyl, 1 Peptyl pionyloxyptyl, 1 Butyrylo Such as xyloxybutyl, 1-bivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl (“Lower aliphatic acryl” oxy) “lower alkyl group”, cyclopentyl carbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyshetyl, 1-cyclohexylcarbonyl Shechill, 1-sh 1-("cycloalkyl" carbonyloxy) "lower alkyl" such as 1-cyclopentylcarbonyloxybutyl, 1-cyclopentylcarbonyloxybutyl, 1-cyclopentylcarbonyloxybutyl and 1-cyclohexylcarbonyloxypropyl 1- (Aromatic acyl) oxy such as benzyl group, benzoyloxymethyl, etc. 1- (Acyloxy) 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) ethyl, 1— (dimethyl) 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyl) propyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl (2 loxy) propyl, 1 (cyclopentyloxyl) Bonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) Propyl, 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1_ (isobutoxycarbonyl) 1- (pentyloxycarbonyloxy) propyl., 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1 (propoxycarbonyloxy) butyl, 1 Isopropoxycarbonyl O carboxy) butyl le, 1- (butoxycarbonyl O carboxymethyl) butyl, 1- (isobutoxycarbonyl O (Xy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy) pentyl, 1- (methoxycarbonyloxy) hexyl, 1_ (ethoxycarbonyloxy) hexyl (Lower alkoxycarbonyloxy) alkyl group; (5-phenyl-2-oxo1-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -12-oxo-1; I, 3 —Dioxolen-14-yl] methyl, [5- (4-methoxyphenyl) -12-oxo-1,3, -dioxolen-4-yl] .methyl, [5- (4-fluorophenyl) 1-2— Oxo-1, 3-Dioxolen-41-yl] methyl, [5- (4-chlorophenyl) _2-oxo-1, 3-Dioxolen-4-1] methyl, (2-oxo-1) (1, 3—dioxolen-4-1) Methyl, (5-methyl-2-oxo-1,4-dioxylene-4-yl) methyl, (5-ethyl-2-oxo-1,1,3-dioxolen-1-yl) methyl, (5-propyl-1-methyl) 2-oxo-1,3-dioxolen-4-yl) methyl, (5-isopropyl-1-2-oxo-1,3-dioxolen-4-yl) methyl, (5-butyl-1-2-oxo-1,3) “Carboxyoxyalkyl group” such as oxodioxorenylmethyl group such as —dioxolen-1-4-yl) methyl; “phthalidyl group” such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl; "Lower aliphatic acyl group": the above "aromatic acyl group": "half ester salt residue of succinic acid": "phosphate ester salt residue": "ester forming residue of amino acid and the like": livamoyl group : 1 or 2 low And a carbamoyl group substituted with a quaternary alkyl group: and “11 (acyloxy) alkyloxycarbonyl group” such as bivaloyloxymethyloxycarbonyl group. Xyalkyl group ". '

On the other hand, as 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 “Alkyl group”; “lower alkoxy” carbonyl such as methoxycarbonylmethyl “lower alkyl group”; “cyano“ lower alkyl group ”such as cyanomethyl and 2-cyanoethyl;“ “lower alkyl” such as methylthiomethyl and ethylthiomethyl “Alkyl” thiomethyl group ”;“ aryl ”thiomethyl group such as phenylthiomethyl and naphthylthiomethyl;“ optionally substituted with halogen ”such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl "Lower alkyl" sulfonyl "low Alkyl group ";" Aryl "sulfonyl" lower alkyl group "such as 2-benzenesulfonylethyl and 2-toluenesulfonylethyl; the above-mentioned" 1- (acyloxy) "lower alkyl group"";"A lower alkyl group"; a "carboxyalkyl group" such as carboxymethyl; and an "amino acid amide-forming residue" such as phenylalanine. .

In the above, “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.

The term "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.

The term “adrenergic receptor blocker” refers to << blocker, /? Blocker or << 9 blocker. The term "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 Ω. / 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 2α; 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.

The term “carbonic anhydrase inhibitor” particularly preferably refers to dorzolamide or a pharmacologically acceptable salt thereof, and most preferably tolzolamide hydrochloride.

In the description of “adrenergic receptor blockers”, “prostaglandins” and “prostaglandins”, “pharmacologically acceptable salts” and “pharmacologically acceptable derivatives” are as defined above. Is shown.

[Embodiment of the invention]

Examples of “angiotensin II antagonists” include, for example, Ρ 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.

As the “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.

As the “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.

As the “carbonic anhydrase inhibitor”, for example, compounds disclosed in EP 296879 can be employed, and these compounds can be easily produced according to a known method. 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). , Water-based eye drops, aqueous suspension eye drops, non-aqueous eye drops such as non-aqueous eye drops and non-aqueous suspension eye drops, gels, eye softeners, etc. it can. When preparing such a preparation, 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.For example, an inert diluent, a preservative, an isotonic agent, a buffer, a pH adjuster And ointment, ointment base and the like.

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.

Examples of the preservative 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. Preferably, parabens, benzalcodium chloride, and benzethonium chloride are used.

Since parabens are used in combination with boric acids and ethylenediaminetetraacetate, an excellent preservative action can be obtained. In this respect, parabens are most preferred.

Examples of the tonicity agent include sodium chloride, mannitol, sorbitol, glycerin and the like.

Examples of the buffer include phosphate, acetate, citrate and the like.

Examples of the pH adjuster include hydrochloric acid, acetic acid, and sodium hydroxide.

Examples of the ointment base include petrolatum, plastibase (trademark), and liquid paraffin. Examples of the viscosity agent include methylcellulose, carmellose and salts thereof, hydroxyshethylcellulose, sodium alginate, propyloxyvinyl polymer, and polyvinylpyrrolidone.

When a gel is prepared, 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). Omg / mL) and may contain an angiotensin II antagonist. 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.

The composition of the present invention can be administered to a warm-blooded animal. Preferably, it is administered to a human.

In the present invention, it is most preferable to administer 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.

[Best Mode for Carrying Out the Invention]

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

[Example]

[Example 1] Eye drops

33 mg of methylparaben and 18 mg of propylparaben were dissolved by heating in 70 mL of water for injection and cooled to room temperature.After cooling to room temperature, 1 g of boric acid, 5 mg of disodium ethylenediaminetetraacetate dihydrate and 0.2 g of 0.2 g of Polysorbate 80 was added and dissolved.

To this solution was added 2 g of 4_ (1-hydroxy-1-methylethyl) -1-2-propyl JP01 / 10549

19

11-I 4- [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.

Compound A

[Example 2] Eye drops

33 mg of methyl parapen and 18 mg of propyl paraben were dissolved in 70 mL of water for injection under heating, cooled to room temperature, and lg of boric acid, 5 mg of ethylenediaminetetraacetic acid sodium dihydrate and 0.2 g of poly (vinyl acetate) were dissolved. Oxyethylene hydrogenated castor oil 60 was added and dissolved.

2 g of Compound A was added to this solution, and about 7.5 mL of a lmo 1 / L aqueous sodium hydroxide solution was further added, followed by stirring. 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 amount to 10 OmL.

The solution was aseptically filtered using GV to prepare eye drops.

[Example 3] Eye drops

lg boric acid, 5 mg disodium ethylenediaminetetraacetate dihydrate, 0.2 110549

20 g of polysorbate 80 and 10 mg of 50% benzalkonium chloride solution were dissolved in 70 mL of water for injection with stirring.

2 g of Compound A was added to this solution, and about 7.5 mL of an Imo1 / L aqueous sodium hydroxide solution was further added, followed by stirring. After adjusting the pH to 7.0 using an aqueous sodium hydroxide solution (concentration: lmo1 / L), water for injection was added to adjust the total amount to 10 OmL.

This solution was aseptically filtered using GV to prepare an eye drop.

[Example 4] Eye drops

lg boric acid, 5 mg ethylenediamine disodium disodium acetate dihydrate, 0.2 g polyoxyethylene hydrogenated castor oil 60 and 1 Omg of a 50% benzalkonium chloride solution in 7 OmL of water for injection. Dissolve with stirring. '

2 g of Compound A was added to this solution, and about 7.5 mL of a lmo1 / L aqueous sodium hydroxide solution was further added, followed by stirring. After adjusting the pH to 7.0 using an aqueous sodium hydroxide solution (concentration: lmo1 / L), water for injection was added to adjust the total amount to 10 OmL.

The solution was aseptically filtered using GV to prepare eye drops. [Comparative example]

In order to evaluate the 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.

[Comparative Example 1]

6. 6 mg of methylparaben and 3.6 mg of propylparaben were dissolved by heating in 14 ml of water for injection.

To this solution, 0.1 g of compound A and 166.2 mg of sodium chloride were added, and about 0.4 ml of a 1 mol / L aqueous sodium hydroxide solution was added thereto to dissolve with stirring. After adjusting the pH to 7.0 using an aqueous sodium hydroxide solution (concentration: lmol / L), water for injection was added to adjust the total amount to 2 Om1. The solution was aseptically filtered using GV to prepare eye drops. [Comparative Example 2]

6.6 mg of methylparaben and 3.6 mg of propylparaben were dissolved by heating in 14 ml of water for injection, cooled to room temperature, and 1 mg of disodium ethylenediamine tetraacetate dihydrate was added to dissolve.

To this solution, 0.1 g of Compound A and 166.2 mg of sodium chloride were added, and about 0.4 ml of a 1 ml / L aqueous sodium hydroxide solution was added thereto, followed by stirring and dissolution. After adjusting the pH to 7.0 using an aqueous sodium hydroxide solution (concentration: 1 mo1 / L), water for injection was added to adjust the total volume to 2 Oml.

The solution was aseptically filtered using GV to prepare eye drops.

[Comparative Example 3]

6.6 mg of methylparaben and 3.6 mg of propylparaben were dissolved by heating in 14 ml of water for injection, cooled to room temperature, and dissolved by adding 0.2 g of boric acid.

To this solution were added 0.1 g of compound A and 61 mg of sodium chloride, and about 0.4 ml of lmol / L aqueous sodium hydroxide solution was added thereto to dissolve with stirring. The pH was adjusted to 7.0 using an aqueous sodium hydroxide solution (concentration: lmo1 / L), and water for injection was added to adjust the total volume to 20 ml.

The solution was aseptically filtered using GV to prepare eye drops.

[Comparative Example 4]

6.6 mg of methylparaben and 3.6 mg of propylparaben were dissolved by heating in 14 ml of water for injection, cooled to room temperature, and then cooled to room temperature with 0.2 g of boric acid and 1 mg of ethylenediamine tetraacetate. Was added and dissolved.

To this solution were added 0.1 g of Compound A and 61 mg of sodium chloride, and about 0.4 ml of lmol / L aqueous sodium hydroxide solution was added thereto, followed by stirring to dissolve. Adjust the pH to 7.0 using sodium hydroxide aqueous solution (concentration: lmo1 / L), then use for injection Water was added to adjust the total volume to 2 Oml.

This solution was aseptically filtered using GV to prepare an eye drop.

[Comparative Example 5]

33 mg of methylparaben and 18 mg of propylparaben were dissolved by heating in 70 mL of water for injection, cooled to room temperature, and dissolved by adding 1 g of boric acid and 5 mg of disodium ethylenediaminetetraacetate dihydrate. .

2 g of Compound A was added to this solution, and about 7.5 mL of Imo 1ZL aqueous sodium hydroxide solution was further added, followed by stirring. The pH was adjusted to 7.0 using an aqueous sodium hydroxide solution (concentration: lmo1 / L), and water for injection was added to adjust the total volume to 10 OmL.

This solution was aseptically filtered using GV to prepare an eye drop. [Comparative Example 6],

1 g of boric acid, 5 mg of sodium diammonium tetradiaminate tetrahydrate and 10 mg of a 50% benzalkonium chloride solution were dissolved in 7 OmL of water for injection with stirring. '

2 g of Compound A was added to this solution, and about 7.5 mL of ImolZL sodium hydroxide aqueous solution was further added, followed by stirring. The pH was adjusted to 7.0 using an aqueous sodium hydroxide solution (concentration: lmo1 / L), and water for injection was added to adjust the total volume to 10 OmL.

This solution was aseptically filtered using GV to prepare an eye drop. [Test example]

Hereinafter, the effects of the present invention will be specifically described with reference to test examples.

[Test Example 1] Intraocular pressure reduction test

Using a New Zealand White White Heron weighing 2 to 3 kg, a model for increasing intraocular pressure was created according to the method of Kurihara et al. (Ophthalmic Pharmacology, pp. 62-64, Vol. 4, 1990). Then, the effect of lowering intraocular pressure of the test composition was examined. That is, after the whole rabbit was anesthetized with urethane, the intraocular pressure was measured using a tonometer (Alcon Applanation Pneumatonography).

After instilling a local anesthetic in the eyes of a heron, 0.1 ml of 5% aqueous sodium chloride was injected into the vitreous via a 30 gauge injection needle. It was confirmed that the intraocular pressure had risen 30 minutes after the injection, and the test composition 50/1 was instilled (the control group was instilled with physiological saline).

After instillation, intraocular pressure was measured every 30 minutes. The intraocular pressure drop width (mmHg) was calculated from the measured values of the intraocular pressure in the group in which the test composition was instilled and the control group.

The results are shown in Table 1. (Note that the formulation of each composition used in this test is as shown in Table 2.) Table 1. Hypotensive effect

Table 2. Formulation of each composition (mg / mL)

(In the above table, `` MP '' indicates methylparaben, `` PP '' indicates propylparaben, "EDTA'2Na" indicates disodium ethylenediaminetetraacetate 'dihydrate. Further, in order to adjust the pH of each of the above compositions to 7.0, an appropriate amount of sodium hydroxide or hydrochloric acid was used. )

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.

On the other hand, 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.

The 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.

[Test Example 2] Stability test when compounded with other agents

2 mL of the eye drops prepared in Example 1, Example 2 or Comparative Example 5 and 2 mL of various eye drops (commercially available) were mixed, and the appearance (color tone, precipitation, turbidity) was visually observed. evaluated. The eye drops of Comparative Example 5 were Ecolicin. (Trade name, Santen), Kisaratan (trade name, Fal Macia Upjohn), Bivalephrine (trade name, Santen), Petbutik (trade name, Japanese Archon) and When mixed with Sankova (trade name, Santen), cloudiness and precipitation occurred. In contrast, the eye drops of Example 1 and Example 2 showed no change in appearance when mixed with any of the above.

That is, by adding the surfactant, the stability when blended with another agent was improved.

[Test Example 3] Stability test when compounded with other agents

2 mL of the eye drops prepared in Example 3, Example 4 or Comparative Example 6 and 2 mL of various eye drops (commercially available) were mixed, and the appearance (color, precipitate, turbidity) was visually observed. evaluated. The eye drops of Comparative Example 6 were Kisalatan (trade name, Pharmacia Upjohn), Pivale When mixed with furin (trade name, Santen), Petobutik (trade name, Alcon Japan) and Sankova (trade name, Santen), cloudiness and sedimentation occurred. In contrast, the eye drops of Example 3 and Example 4 showed no change in appearance when mixed with any of the above.

That is, similarly to the results of Test Example 2, the addition of a surfactant improved the stability when blended with another agent.

[Possibility of industrial use]

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.

Claims

1. An intraocular pressure-reducing composition for topical administration, comprising an angiotensin II antagonist, boric acids, ethylenediaminetetraacetic acids, and a surfactant.

2. In Claim 1, the 7-angiotensin II antagonist is represented by the following general formula (I):

Or a pharmacologically acceptable salt or derivative thereof having the formula:

A group having the formula:

3. The composition according to claim 2, wherein R ¹ is a group having the structural formula (Ia), (Ib), or (Ic).

4. A composition according to claim 2, wherein the compound having the general formula (I) is a compound selected from the following: • 4— (1-hydroxy-1-methylethyl) -1-2-propyl-1-—4— [2- (tetrazo-1-yl) phenyl] phenyl i-methylimidazole-5-carbonic acid,

• 2-Ethoxy 1-11 [2,1 (1H-tetrazole-1-5-yl) biphen-2-4- 4-yl] methyl-1H-benzimidazole-1 7-hydrorubonic acid.

5. The composition according to any one of claims 1 to 4, further comprising a preservative.

6. The composition according to claim 5, wherein the preservative is a paraben.

7. The method according to any one of claims 1 to 6, further comprising at least one selected from an adrenergic receptor blocker, a prostaglandin, and a carbonic anhydrase inhibitor. A composition containing a compound.

8. The composition according to claim 7, wherein the adrenergic receptor blocking agent is bunazosin, timolol, nipradilol, or a pharmaceutically acceptable salt or derivative thereof.

9. The composition according to claim 7, wherein the adrenergic receptor blocking agent is bunazosin hydrochloride, timolol maleate or dibradirol.

10. The composition according to any one of claims 7 to 9, wherein the prostaglandins are isopropyl unoprostone, rattanoblast, or a pharmacologically acceptable salt thereof.

11. The composition according to any one of claims 7 to 9, wherein the prostaglandins are isopropylpropylunoprostone or rattanobrost.

12. The composition according to any one of claims 7 to 11, wherein the carbonic anhydrase inhibitor is dorzolamide or a pharmaceutically acceptable salt thereof.

13. The composition according to any one of claims 7 to 11, wherein the carbonic anhydrase inhibitor is tolozolamide hydrochloride.

14. The composition according to any one of claims 1 to 13 containing a pharmacologically effective amount of an angiotensin II antagonist, a warm-blooded animal. A method of lowering intraocular pressure that consists of administering.

15. The composition according to any one of claims 1 to 13 containing a pharmacologically effective amount of an angiotensin II antagonist is administered to a human. A method of lowering intraocular pressure.

16. A composition according to any one of claims 1 to 13 containing a pharmacologically effective amount of an angiotensin II antagonist, the composition according to any one of claims 1 to 13, which is used for a warm-blooded animal. A method of reducing intraocular pressure that has been raised due to glaucoma or ocular hypertension.

17. The composition according to any one of claims 1 to 13 containing a pharmacologically effective amount of an angiotensin II antagonist is administered to a human. A method of reducing intraocular pressure that has been raised due to glaucoma or ocular hypertension.