Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-10
2004-08-17
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S566000, C424S660000
Reexamination Certificate
active
06777436
ABSTRACT:
The present invention relates to a novel medical composition for topical administration showing excellent intraocular tension lowering activity.
BACKGROUND OF THE INVENTION
It has been well known that angiotensin II antagonists lower intraocular tension when topically administered (EP 795326 (and U.S. Pat No. 5,925,664), EP 631780, WO 95/21609, WO 91/15206, etc.). In particular, the following compounds are known as representative drugs.
SUMMARY OF THE INVENTION
As the result of various investigation on preparations and pharmacologies of topical compositions containing angiotensin II antagonists, the present inventors have found that the intraocular tension lowering activity of angiotensin II antagonists can be reinforced by adding one or more boric acids and one or more ethylenediamine tetraacetic acids to the composition.
The present invention relates to:
(1) an intraocular tension lowering topical composition containing an angiotensin II antagonist, a boric acid and an ethylenediamine tetraacetic acid.
Said composition preferably is
(2) a composition in which the angiotensin II antagonist is a compound of the following general formula (I) or a pharmacologically acceptable salt or derivative thereof:
wherein R
1
represents a group of the following structure (Ia), (Ib), (Ic), (Id), (Ie) or (If):
(3) a composition in which R
1
represents a group of the structure (Ia), (Ib) or (Ic);
(4) a composition in which the compound of general formula (I) is a compound selected from 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl) phenyl]phenyl}methylimidazole-5-carboxylic acid and 2-ethoxy-1-[2′-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl-1H-benzimidazole-7-carboxylic acid;
(5) a composition additionally containing a preservative; and
(6) a composition in which the preservative is a paraben.
Further, another object of the present invention is to provide a method of lowering intraocular tension which comprises administering a composition as described in any one of (1) to (6) above containing a pharmacologically effective amount of an angiotensin II antagonist to a warm-blooded animal (preferably human). In particular, it is to provide a method of lowering intraocular tension caused by glaucoma (including glaucoma with normal intraocular tension) or ocular hypertension.
In the present invention, “boric acid” includes boric acid and compounds which function equivalent to a boric acid. A substance equivalent to boric acid is a compound that gives rise to borate ion when dissolved in water. Examples of such compounds are boric anhydride (B
2
O
3
), tetraboric acid (H
2
B
4
O
7
), as well as pharmacologically acceptable salts of boric acid, boric anhydride, and tetraboric acid. Boric acid, boric anhydride, borax and sodium borate decahydrate are preferred. Boric acid is more preferred.
These boric acids may be used singly or in combination of two or more members.
“Ethylenediamine tetraacetic acid” includes ethylenediamine tetraacetic acid and compounds which function equivalent to ethylenediamine tetraacetic acid. A substance equivalent to ethylenediamine tetraacetic acid is a compound that gives rise to an ethylenediamine tetraacetate ion when dissolved in water. Such compounds include pharmacologically acceptable salts of ethylenediamine tetraacetic acid, and appropriate examples thereof are ethylenediamine tetraacetic acid, disodium ethylenediamine tetraacetate dihydrate, trisodium ethylenediamine tetraacetate trihydrate, disodium ethylenediamine tetraacetate dihydrate, and tetrasodium ethylenediamine tetraacetate tetrahydrate. Disodium ethylenediamine tetraacetate dihydrate is most preferred.
These ethylenediamine tetraacetic acids may be used singly or in combination of two or more members.
“Angiotensin II antagonists” preferably mean the compounds of the following general formula (I) or pharmacologically acceptable salts or derivatives thereof:
wherein R
1
represents a group of the following structures (Ia), (Ib), (Ic), (Id), (Ie) or (If):
More preferably, the compound is 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid and 2-ethoxy-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-benzimidazole-7-carboxylic acid, or a pharmacologically acceptable salt or derivative thereof.
“Pharmacologically acceptable salts” mean those salts that may be prepared by reacting the compound of general formula (I) above, boric acids, or ethylenediamine tetraacetic acids with a base. Examples of such salts include metal salts including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc., alkaline earth metal salts such as calcium salts, magnesium salts, etc., aluminium salts and ferrous salts, etc.; amine salts including inorganic salts such as ammonium salts, etc., organic salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, tris(hydroxymethyl)aminomethane salts, etc.; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, aspartic acid salts, etc. Of them, alkali metal salts are preferred, and sodium salts and potassium salts are more preferred.
Boric acids, ethylenediamine tetraacetic acids, and the compounds of the general formula (I) above or their pharmacologically acceptable salts may occasionally absorb water so that the absorbed water is incorporated, ie they become a hydrate, by allowing them to stand in the air or during recrystallization. Such hydrates are included in the present invention.
When the compound (i) has hydroxyl groups and/or carboxyl groups, such a compound can be converted into its derivatives by modifying those groups. So, pharmaceutically acceptable derivatives of the compound of the general formula (I) above mean such derivatives. Such derivatives include “esters of hydroxyl groups”, “ethers of hydroxyl groups”, “esters of carboxyl groups” and “amides of carboxyl groups” and the residues of such ester, ether or amide groups include “general protecting groups” or “protecting groups capable of being cleaved by biological means like hydrolysis within living bodies”.
“General protecting groups” mean protecting groups capable of being cleaved by chemical methods such as hydrogenation, hydrolysis, electrolysis, photolysis, etc.
“General protecting groups” comprising the residue of “esters of hydroxyl groups” and “ethers of hydroxyl groups” preferably mean aliphatic acyl groups (preferably lower aliphatic acyl groups having 1 to 6 carbon atoms) including alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, heneicosanoyl, etc., halogeno-alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc., lower alkoxyalkylcarbonyl groups such as methoxyacetyl, etc., unsaturated alkylcarbonyl groups such as acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E)-2-methyl-2-butenoyl etc.; aromatic acyl groups including arylcarbonyl groups such as benzoyl, &agr;-naphthoyl, &bgr;-naphthoyl, etc., halogenoarylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl, etc., lower alkylarylcarbonyl groups such as 2,4,6-trimethylbenzoyl, 4-toluoyl, etc., lower alkoxyarylcarbonyl groups such as 4-anisoyl, etc., nitroarylcarbonyl groups such as 4-n
Shiokari Takashi
Yokoyama Tomihisa
Frishauf Holtz Goodman & Chick P.C.
Sankyo Company Limited
Spivack Phyllis G.
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