Stabilization of mercury-containing preservatives in ophthalmic medicaments

The invention relates to the stabilization of mercury-containing preservatives in liquid or gel-form ophthalmic medicaments. This stabilization against chemical decomposition after the preservative has become deposited on the inner walls of the plastics containers is achieved by adding to the formulation 2-amino-2-hydroxymethyl-1,3-propanediol or a homologue thereof having up to 10 carbon atoms.

The invention relates to the stabilization of mercury-containing 
preservatives in ophthalmic medicaments, for example eye drops or eye 
gels, by the addition of 2-amino-2-hydroxymethyl-1,3-propanediol 
(trometamol) or a homologue thereof having up to 10 carbon atoms. By means 
of the invention, an increased stability of ophthalmic medicaments 
incorporating mercury-containing preservatives and an improved 
tolerability of these preparations in the eye are achieved. 
Medicaments for the treatment of eye diseases are often formulated in 
liquid form and administered in drop form. In the case of eye drops, there 
is a statutory requirement in most European and other countries that the 
preparations should be preserved, that is to say protected against attack 
by micro-organisms and the subsequent multiplication thereof, by adding a 
component that is capable of preventing or at least checking secondary 
contamination. In addition, ophthalmic medicaments are often formulated in 
gel form and the same requirements as regards preservation apply to gels. 
Specific mercury-containing substances, for example phenyl mercury borate 
(merfen) or the sodium salt of 2-(ethylmercurithio)-benzoic acid 
(thiomersal) have proved to be especially suitable preservatives for use 
in ophthalmic medicaments. 
The mercury-containing preservatives for ophthalmic medicaments have, 
however, various disadvantages. For example, in the course of time they 
become deposited on the surface of the inside of the plastics containers 
in which ophthalmic medicaments are customarily stored. Thus, the content 
of mercury-containing preservative in small plastics bottles made of 
low-pressure polyethylene falls to less than approximately 80% of the 
original content within only a few weeks, and after from 6 months to one 
year there is practically no mercury-containing preservative, or only a 
very small amount, in the eye drop or eye gel formulation. 
A further disadvantage of mercury-containing preservatives is their poor 
stability in aqueous solution. For example, thiomersal, which is used 
especially often owing to its excellent preservative properties, is 
unstable in aqueous solution 
The problem underlying the invention is therefore to provide a liquid or 
gel-form ophthalmic medicament that incorporates a mercury-containing 
preservative and has outstanding stability for a sufficient period of 
storage and use. This problem is solved by the surprising finding that 
stabilization of the mercury-containing preservatives in liquid ophthalmic 
medicaments can be achieved by adding specific aminopolyols. 
The invention therefore relates to an ophthalmic medicament that 
incorporates a mercury-containing preservative, is to be administered in 
drop form or gel form and is characterised in that it contains 
2-amino-2-hydroxymethyl-1,3-propanediol or a homologue thereof having up 
to 10 carbon atoms for the stabilization of the preservative. 
The invention relates also to the use of 
2-amino-2-hydroxymethyl-1,3-propanediol or a homologue thereof having up 
to 10 carbon atoms for the stabilization of mercury-containing 
preservatives in ophthalmic medicaments. 
2-amino-2-hydroxymethyl-1,3-propanediol, which is known under various names 
[tromethamine, tris(hydroxymethyl)-aminomethane, tris, THAM, trisamine, 
tromethane; internationally accepted name trometamol] has the following 
formula: 
##STR1## 
(empirical formula: C.sub.4 H.sub.11 NO.sub.3 molecular weight: 121.14) 
Trometamol is used as a standard in mass analysis and as a buffer for 
microbiological and pharmaceutical purposes. It is also used as an 
emulsifier in cosmetics and as a solution aid in chemistry, especially 
pharmaceutical chemistry. Furthermore, in medicine it is administered 
against acidosis in the form of intravenous injections 
The homologues of 2-amino-2-hydroxymethyl-1,3-propanediol, which can be 
used for the purposes of the invention, can have up to 10 carbon atoms. 
These homologous compounds are formed by the introduction of further 
carbon atoms at one or more positions of the molecular structure shown 
above. The homologues that have from 5 to 7 carbon atoms are preferred. 
Trometamol and its homologues having up to 10, preferably from 5 to 7, 
carbon atoms can also be illustrated by the following formula: 
##STR2## 
in which m, n and o (independently of one another) each represents an 
integer of at least 1 and the sum of m, n and o is in the range of from 3 
to 9, preferably from 3 to 6. 
By the addition of the stabilizer proposed according to the invention, 
mercury-containing preservatives in liquid or gel-form ophthalmic drugs 
are stabilized effectively. It has been found that trometamol, or its 
homologues having up to 10 carbon atoms, prevents the mercury-containing 
preservatives from becoming deposited on the surfaces of the plastics 
containers. The mercury-containing preservative remains in solution for 
several years when the stabiliser proposed according to the invention is 
added. 
The stabilizer proposed according to the invention has the further 
advantage that it suppresses the tendency of certain mercury-containing 
preservatives to decompose in aqueous solution. This advantage is 
demonstrated especially in the case of the preferred preservative 
thiomersal which is not stable in aqueous solution over a prolonged 
period. The stabilization is achieved especially by preventing or 
retarding the adsorption or absorption of the preservative at the inner 
walls of the plastics containers. By adding trometamol, the chemical 
decomposition of the thiomersal in the aqueous ophthalmic formulation can 
be suppressed for a relatively long period so that the preservative is 
available over the entire period in which the preparation is customarily 
stored and used. Furthermore, the stabilizer used according to the 
invention also prevents any cleavage products of thiomersal which may be 
formed, such as ethylmercury salts, from becoming deposited on the walls 
of plastics containers. 
Surprisingly, it has also been found that the tolerability of specific 
ophthalmic medicaments in the eye is improved by the addition of the 
stabilizer proposed according to the invention. This is true, for example, 
of a recently developed preparation for the treatment of relatively severe 
acute or chronically recurrent inflammatory symptoms in the eye that 
contains diclofenac-sodium as non-steroidal anti-inflammatory agent (cf. 
Example 1 below). In that preparation, which contains thiomersal as 
preservative, the addition of trometamol results in a distinct improvement 
in tolerability in the eye. 
The stailizer proposed according to the invention is added to the liquid or 
gel-form ophthalmic medicaments in an amount of from 0.05 to 5%, 
preferably from 0.1 to 1.0%. In that amount, the stabilizer prevents the 
mercury-containing preservative from becoming deposited on the inner walls 
of the plastics containers and thus brings about its desired 
stabilization. The preservative can therefore act in the desired manner 
over a relatively long period against attack by micro-organisms and the 
growth thereof. The preparations can be stored at room temperature and 
meet the requirements demanded in respect of their storability during 
therapeutic use. 
The ophthalmic medicament may contain any active ingredient suitable for 
use in the eye, or mixtures of several active ingredients. In addition to 
the active ingredients mentioned in the Examples there may be mentioned 
especially: spaglumic acid [N-(N'-acetyl-L-.beta.-aspartyl)-L-glutamic 
acid] and gentamicin. 
The following Examples illustrate the invention:

Example 1 
An ophthalmic medicament for the treatment of inflammations that contains 
diclofenac-sodium as non-steroidal anti-inflammatory agent is 
manufactured. Thiomersal is used as preservative and trometamol is used as 
stabilizer. The formulation has the following composition: 
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Constituent Amount 
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diclofenac-sodium 0.1% 
2-(ethylmercurithio)-benzoic acid, 
0.004% 
sodium salt (thiomersal) 
boric acid 1.9% 
trometamol (stabiliser) 
0.6% 
Cremophor EL .RTM. (reaction product 
5.0% 
of castor oil and ethylene 
oxide) (solution aid) 
water for injection purposes 
ad 100% 
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This formulation will keep for from 3 to 5 years at room temperature 
without any significant decrease in the content of preservative being 
observed over that period. 
EXAMPLE 2 
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Constituent Amount 
______________________________________ 
phenyl mercury (II) dihydrogen borate 
0.020 g 
trometamol 0.500 g 
boric acid 1.900 g 
hydroxypropylmethylcellulose 
0.300 g 
water for injection purposes 
97.980 g 
100.700 g 100 ml 
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EXAMPLE 3 
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Constituent Amount 
______________________________________ 
naphazoline nitrate 0.005 g 
zinc sulphate.7 H.sub.2 O 
0.020 g 
boric acid 2.000 g 
trometamol 0.100 g 
witch hazel 4.000 g 
orange flower water 2.000 g 
lavender water 6.000 g 
tincture of euphrasia 
0.080 g 
phenyl mercury (II) dihydrogen borate 
0.002 g 
water for injection purposes 
86.093 g 
100.300 g 100 ml 
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EXAMPLE 4 
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Constituent Amount 
______________________________________ 
chloramphenicol 0.600 g 
polyethylene glycol 400 
10.000 g 
boric acid 0.900 g 
trometamol 0.100 g 
2-(ethylmercurithio)-benzoic acid, 
0.020 g 
sodium salt 
hydroxypropylmethylcellulose 
0.200 g 
prednisolone acetate 
0.500 g 
aluminium hydroxide gel 
1.000 g 
water for injection purposes 
88.780 g 
102.100 g 100 ml 
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The formulations of Examples 2 to 4 have the same long storage life without 
any significant decrease in the content of preservative as the formulation 
of Example 1.