Pharmaceutical composition for topical ophthalmic use having improved local tolerability

The composition comprises from 0.1 to 3 moles of free lysine for each mole of an active ingredient selected from bendazac, 5-OH bendazac and the salts thereof with pharmaceutically acceptable organic and inorganic bases.

This invention relates to a pharmaceutical composition for topical 
ophthalmic use having improved local tolerability, which comprises from 
0.1 to 3 moles of free lysine for each mole of an active ingredient 
selected from bendazac, 5-OH bendazac and the salts thereof with 
pharmaceutically acceptable organic and inorganic bases. 
U.S. Pat. No. 4,451,477 and European patent application A-0191520 disclose 
some pharmaceutical dosage forms for topical ophthalmic use containing 
bendazac or 5-OH bendazac or a salt thereof with a physiologically 
acceptable organic or inorganic base, respectively. Lysine salt is cited 
in both said documents. 
Furthermore, the aforementioned US patent teaches that oral absorption of 
bendazac lysinate is higher than that of bendazac; no advantage, however, 
is disclosed in connection with topical ophthalmic administration. 
Finally, the aforementioned European patent application does not disclose 
any peculiar beneficial action of 5-OH bendazac lysinate with respect to 
5-OH bendazac or any other salt thereof. 
An extensive clinical use of a commercially available collyrium containing 
bendazac lysinate, also known as bendaline, proved that in some 
hypersensitive patients bendazac lysinate causes burning sensation and 
reddenings. 
The extent and the occurence of said symptoms are not prejudicial to the 
use of said collyrium in the most part of cases. Since, however, said 
collyrium is used in the treatment of cataract, this involving long 
therapy periods and a greater propensity of the sick eye to phenomena of 
local reactivity, elimination of said symptoms is still a significant goal 
.

We have now found that addition of lysine dramatically improves 
tolerability of a collyrium containing one of the aforementioned active 
ingredients. 
It is therefore an object of this invention to provide a pharmaceutical 
composition for topical ophthalmic use containing at least one active 
ingredient selected from bendazac, 5-OH bendazac and the salts thereof 
with pharmaceutically acceptable organic and inorganic bases, 
characterized in that said composition contains from 0.1 to 3 moles of 
free lysine for each mole of said active ingredient. 
In this description and in the appended claims, the expression "free 
lysine" is used to mean lysine not salified by bendazac or 5-OH bendazac. 
Thus, when bendazac or 5-OH bendazac are used as starting material in the 
preparation of the pharmaceutical composition of this invention, from 1.1 
to 4 moles of lysine are added to each mole of said active ingredients 
because one mole is needed for salifying the active ingredient itself. 
Preferably, the composition of this invention contains from 0.2 to 2.5 
moles of free lysine. More preferably it will contain from 0.5 to 2 moles 
of free lysine. 
Examples of suitable salts of bendazac and 5-OH bendazac are sodium, 
potassium, methylamine, isopropylamine, hexylamine, diethyl amine, 
ethanolamine, 2-hydroxymethyl-2-amino-1,3-propanediol, arginine and lysine 
salts. Typical examples of preferred salts are lysine and arginine salts. 
The dosage forms of this invention are preferably liquid, such as 
solutions, or semiliquid, such as creams. Aqueous solutions are a typical 
example of a preferred dosage form. 
In addition to usual excipients, the dosage forms of this invention may 
contain preservatives, stabilizers, humectants, emulsifiers, buffers and 
the like. 
The composition of this invention may also contain other ophthalmologic 
active ingredients and are prepared and sterilized according to known 
techniques. 
A collyrium containing 0.5% by weight of bendazac lysinate is currently 
used in the treatment of cataract. In some patients having hypersensitive 
eyes, this collyrium causes local irritation consisting in burning 
sensation and reddening. In 20 of these patients a comparison test between 
the commercially available bendazac lysinate collyrium (A) and a collyrium 
modified by mere addition of lysine (B) was carried out. The two 
collyriums had the following compositions: 
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Collyrium A 
Bendazac lysinate 0.500 g 
Boric acid 1.000 g 
Borax 0.135 g 
Hydroxypropylmethylcellulose 
0.500 g 
Potassium chloride 0.310 g 
Sterilized purified water up to 
100 ml 
Collyrium B 
Bendazac lysinate 0.500 g 
Lysine 0.188 g 
Boric acid 0.380 g 
Potassium chloride 0.810 g 
Hydroxypropylmethylcellulose 
0.500 g 
Sterilized purified water up to 
100 ml 
______________________________________ 
The test was carried out in double blindness conditions. 
The subjects hypersensitive to bendaline (bendazac lysinate) were divided 
into two homogeneous groups. Three drops of one of the two collyriums were 
instilled in one eye of each subject while 3 drops of a physiological 
saline solution were instilled in the other eye. After some hours the test 
was repeated by instilling the other collyrium, while still applying 
physiological saline solution to the other eye. The results show that 
collyrium B is almost indistinguishable from physiological saline solution 
while collyrium A causes reddening and burning sensation. 
Similar results were obtained with a collyrium containing: 0.5 g of 
bendazac lysinate, 0.157 g of Lysine, 0.480 g of boric acid, 0.76 g of 
potassium chloride, 0.5 g of hydroxypropylmethylcellulose, and sterilized 
purified water up to 100 ml. 
Lysine was tested at lower concentrations also, obtaining a less effective 
but still appreciable protective action. At higher concentrations lysine 
is well tolerated and excellent local tolerability was observed.