Diclofenac and tobramycin formulations for ophthalmic and otic topicaluse

This invention includes a pharmaceutically acceptable formulation of Diclofenac, Tobramycin, a solubility agent and, optionally, excipients, tonicifiers, buffers, viscosity modifying agents, preservatives, and chelating agents, at a pH from greater than 7.0 to about 9. The invention also discloses the use of this pharmaceutically acceptable formulation of an antibiotic and NSAIDs to treat eye and ear conditions accompanied by infection and inflammation.

FIELD OF THE INVENTION 
The present invention relates to medical formulations used in the treatment 
of eye and ear conditions which may be accompanied by infection and 
inflammation. 
BACKGROUND OF THE INVENTION 
In ophthalmology, the use of a combination of an antibiotic and an 
anti-inflammatory drug for the treatment of inflammation associated with 
infection of the anterior ocular segment, especially conjunctivitis, has 
been found useful. For example, Leibowitz HM et al. Human Conjunctivitis. 
Arch Ophthalmol, 1976; 94:1752-6 report that the combination of a 
corticosteroid and an antibiotic is more effective than the antibiotic 
alone in the treatment of bacterial acute conjunctivitis. 
Non-steroid anti-inflammatory drugs (NSAIDs) were introduced to 
ophthalmology as an alternative to corticosteroids. It is presently 
thought that the efficacy of available NSAIDs is comparable to that of the 
weaker corticosteroids. However, NSAIDs lack the adverse side effects 
associated with corticosteroids such as the increase in intraocular 
pressure and the unfavorable immune-suppressant effect that 
corticosteroids have with viral, fungal, tubercular and other types of 
infections. 
In surgical treatment of the anterior segment of the eye, for example, in 
cataract surgery, post-operative inflammation can be reduced by the 
pre-operative and post-operative use of NSAIDs administered to the eye. 
There is a correlation between the blepharoconjunctival microbial flora 
present in the pre-operative stage of cataract surgery and the infectious 
agents isolated from post-operative endooophthalmitis. For this reason, it 
is common practice to sterilize or disinfect the external eye structure, 
both prior to surgery and post-operatively, until there is no longer a 
possibility of infection in the surgical wound, by treatment with an 
antibiotic. A combination of antibiotics and either asteroid or a NSAID is 
also used for treatment of ear infections and ear injuries. This was 
described by Alexander J et al. A new corticosteroid-antibiotic 
preparation in eye and ear infections. General Practitioner Clinical 
Trials 1966; 176:94-96 herein incorporated by reference. 
The use of a combination of asteroid and an antibiotic for treatment of eye 
and ear disorders in veterinary medicine is well known. The same drugs 
used to treat humans are also used to treat animals, since the eye and ear 
disorders that are common in veterinary practice have the same 
physiopathology as human disorders. This is described by Moore CP. 
Conjuntival disorders. In Current Veterinary Therapy, X Small Animal 
Practice. Philadelphia: WB Saunders Company, 1989, herein incorporated by 
reference, Brooks DE. Canine conjunctiva and nictating membrane. In 
Veterinary Ophthalmology. 2nd Ed. Edited by Gelatt KN. Philadelphia: Lea 
and Febiger, 1991, herein incorporated by reference and Macy DW. Diseases 
of the ear. In Textbook of Veterinary Internal Medicine. Diseases of the 
dog and cat. Edited by Ettinger SJ. Philadelphia: Saunders Company, 1989, 
herein incorporated by reference. 
The use of steroidal anti-inflammatory agents with antibiotics in general 
and with Tobramycin in particular is well known. This has been described 
by Cagle et al. in their PCT application WO 89/09057, herein incorporated 
by reference, where Cagle uses the steroids Dexamethasone, Fluoromethalone 
and Fluoromethalone acetate with Tobramycin for treatment of eye 
infections accompanied by inflammation and by Leibowitz HM et al. 1976 as 
previously mentioned. 
The use of a NSAID with an antibiotic, however, is not well documented, and 
no combination of a NSAID and an antibiotic has been marketed. Canadian 
Patent Application No. 2,013,188 (Fu et al.), describes an ophthalmic 
formulation comprising an NSAID with Tobramycin in a solution with a 
suitable preservative. The preferred ophthalmic formulation of Fu et al. 
used the NSAID ketorolac tromethamine with the antibiotic Tobramycin. The 
preferred ophthalmic formulation of Fu et al. comprises ketorolac 
tromethamine, Tobramycin, a non-ionic surface active agent, preferably 
Octoxymol 40, and a preservative selected from the group of quaternary 
ammonium compounds. Fu et al. reports that the use of non-ionic surface 
active agents, especially polyoxyethylene alkylphenol surfactants, avoids 
the unacceptable interactions between NSAID and quaternary ammonium 
compounds, wherein the NSAID and quaternary ammonium compound form a 
complex that is either insoluble or retards the absorption of the NSAID. 
However, as will be described in greater detail hereinafter, when we 
attempted to prepare a formulation of Tobramycin and Diclofenac, as 
possibly suggested by Fu et al., we discovered that the formulation of 
Tobramycin and Diclofenac formed a precipitate which would be 
pharmaceutically unacceptable in a formulated product. 
Hence, up until our invention, there still was a need for a 
pharmaceutically acceptable formulation of Tobramycin and Diclofenac for 
ophthalmological and otic use. 
SUMMARY OF THE INVENTION 
The present invention relates to a composition--and method of using the 
composition--which comprises a non-steroidal anti-inflammatory drug, 
Diclofenac, an antibiotic of the aminoglycoside family, Tobramycin, a 
solubility agent and the preservatives, excipients, buffers and 
tonicifiers needed for an acceptable medicament. This composition of the 
present invention is a pharmaceutically acceptable solution; it has an 
acceptable shelf-life and does not form a pharmaceutically unacceptable 
precipitate over its shelf life. This composition can be used to treat eye 
and ear conditions accompanied by infection and inflammation. 
The pathological eye conditions that can be treated with the formulation 
described in the present invention include conjunctivitis, eye trauma 
caused by an accident or surgery, eye inflammation and eye infections. 
The pathological ear infections that can be treated include otitis 
externia, otitis meatus, ear inflammation, ear infections and ear trauma. 
The formulation can also be used in veterinary practice to treat eye and 
ear inflammation and eye and ear trauma in a similar manner to the 
treatment of human eye and ear infections and trauma. 
DEFINITIONS 
The following terms are defined below: 
The term "q.s." means adding a quantity sufficient to achieve a stated 
function, for example, to bring a solution to a desired volume or adjust 
pH to a desired value. 
The term "treatment" or "treating" means any treatment of a disease or 
condition, including: 
(1) prophylaxis-preventing the disease or condition, that is to say, 
causing the clinical symptoms of disease not to develop or occur; 
(2) inhibiting the disease or condition, that is to say, preventing the 
development of clinical symptoms; and 
(3) relieving the disease or condition, that is to say, causing the 
regression of clinical symptoms. 
The term "needs of manufacturing specifications" means the variation in 
concentration range acceptable in good manufacturing process (GMP) in 
order to foresee the possible variations during the production of 
different batches of the product. 
Unless stated to the contrary, the percentages stated hereinafter are 
weight percentages, i.e., grams of material per 100 milliliters of 
solution, or, for hydrogels, grams of material per 100 grams of final 
product. 
The term "Diclofenac" refers to any pharmaceutically acceptable salt, 
ester, isomer, or derivative of ortho-(2,6-dichlorophenyl) aminophenyl 
acetic acid and has the structural formula (I). 
##STR1## 
The term "Tobramycin" refers to any pharmaceutically acceptable salt, 
ester, isomer, or derivative of 
4-[2,6-diamino-2,4,6-trideoxy-alpha-D-glycopyranosyl 
]-6-]3-amino-3-deoxy-alpha-D-glycopyranosyl]-2-deoxystreptamine and has 
the structural formula II. 
##STR2## 
Tobramycin has a broad spectrum of actions against both Gram positive as 
well as Gram negative organisms, sensitive bacteria include Staphylococcus 
aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Pseudomonas 
aeruginosa, Escherichia coli, Enterobacter aerogenes, Proteus mirabelis, 
Klebsiella pneumoniae, Morganella morganii, Haemophilus infiuenzae, 
Haemophilus aegyptius, Moraxlea lacumata, and Acinetobacter calcoaceticus. 
The terms "tromethamine," "tromethanol," "trometamol," are synonyms of the 
chemical compound trihydroxymethylaminomethane. 
The present invention includes isomers, derivatives and pharmaceutically 
acceptable salts of Diclofenac and Tobramycin. 
A formulation in accordance with the invention will have a shelf-life of at 
least 1 year and preferably 1-2 years. This means that the formulation 
will remain physically stable, that is to say no precipitate will form 
over the shelf life of the formulation, that an effective and potent 
concentration of NSAID and antibiotic will remain at the end of the 
shelf-life and that the formulation will be able to pass the U.S. 
Pharmacopeia's antimicrobial challenge at the end of the formulation shelf 
life. The formulations in accordance with the invention meet these 
requirements. 
DESCRIPTION OF THE INVENTION 
A formulation in accordance with the invention comprises a solution of 
Diclofenac, Tobramycin and a solubility agent to cause Diclofenac and 
Tobramycin to remain in solution for the shelf life of the product. The 
formulations used for treatment of either the eye or ear may be identical. 
Diclofenac or its pharmaceutically acceptable ester, salt, derivative or 
isomer, has a concentration between about 0.001% and about 0.20%, 
preferably from about 0.01% to about 0.15%, more preferably from about 
0.05% to about 0.10% Diclofenac; Tobramycin has a concentration between 
about 0.001% to about 1.0%, preferably from about 0.001% to about 0.50%, 
more preferably from about 0.05% to about 0.40%, and most preferably from 
about 0.10% to about 0.35%. 
The formulations according to the present invention use as solubility 
agents or surfactants, polyoxysorbates, fatty-acid glycerol-polyethylene 
glycol esters or a mixture thereof. These compounds are used at a 
concentration between about 1.0% to about 8.5%, preferably from about 2.0% 
to about 7.5%, more preferably from about 3.0% to about 7.0%. Other 
solubility agents such as Octoxynol 40, Tyloxapol and Pluronics can be 
used as well. The concentration of solubility agent is determined by the 
need to keep the Diclofenac and Tobramycin in solution. For example, a 
solution which contains 0.14% Diclofenac and 0.45% Tobramycin includes 
3.0% solubility agent to maintain the active ingredients in solution at a 
pH of 7.5. 
Diclofenac is a well known NSAID with a safety profile that is well known 
after years of experience with the drug. Diclofenac has good systemic and 
topical efficacy, good systemic and local tolerance and a good topical 
profile. Diclofenac also does not lead to an increase in intraocular 
pressure even when Diclofenac is used extensively. 
Tobramycin is a well known antibiotic with a good safety profile that is 
well known after years of pharmaceutical use in ophthalmology. Tobramycin 
has a broad spectrum of activity and is active against both Gram positive 
and Gram negative bacteria. The sensitivity shown towards Tobramycin by 
most Gram positive and Gram negative bacteria involved in eye and ear 
infections is currently adequate, and Tobramycin seems to have a better 
profile and work better than other antibiotics. 
Tonicity compounds which can be employed are sodium chloride, sodium 
sulfate, glycerol, mannitol, and sorbitol, as well as any other commonly 
used tonicity agent. These components are typically used at a level 
between 0.4% and 7.5%, with the level being selected so as to achieve a 
formulation of appropriate tonicity. 
The formulation also includes pH buffers, such as citrates, borates, 
phosphates, tris(hydroxymethyl)-amino-methane, and amino acids, such as 
glycine, lysine, glutamic acid, arginine, and aspartic acid. These pH 
buffers are introduced into the product to maintain a stable pH and to 
improve product tolerance by the user. The pH buffers are typically used 
at levels between about 0.01% to about 3.0%, preferably from about 0.05% 
to about 2.5%, more preferably from about 0.10% to about 2.0%. 
The formulation typically includes viscosity modifying agents, which 
improve the residence time of the product where it is applied. Typical 
examples of viscosity modifying agents would include polyvinyl alcohol, 
polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, 
hydroxyethylcellulose, carboxymethylcellulose and 
hydroxypropylmethylcellulose. These compounds are typically used at levels 
between about 0.01% to about 10.0%, preferably from about 0.05% to about 
5% and more preferably from about 0.10% to about 3%. The amount of the 
viscosity modifying agent should be selected so as to obtain a formulation 
with the desired residence time. 
Chelating agents are used in the formulation to eliminate heavy metals and 
improve the action of the preservative. Examples of chelating agents would 
include citric acid, ethylene diaminetetraacetic acid (EDTA), EDTA sodium 
salts, and ethylene glycol-bis(.beta.-aminoethyl ether) 
N,N,N',N'-tetraacetic acid (EGTA). These compounds are used at a 
concentration between about 0.01% to about 3.0%, preferably from about 
0.05% to about 2.0%, and most preferably from about 0.10% to about 1.0%. 
Preservatives, used to inhibit microbial contamination of the product when 
it is dispensed in multidose containers, can include: quaternary ammonium 
derivatives, (benzalkonium chloride, benzylammonium chloride, cetylmethyl 
ammonium bromide, cetylpyridinium chloride), benzethonium chloride, 
organomercury compounds (Thimerosal, phenylmercury acetate, phenylmercury 
nitrate), methyl and propyl p-hydroxy-benzoates and salts thereof, 
betaphenylethyl alcohol, benzyl alcohol, phenylethyl alcohol and 
phenoxyethanol. The formulation according to the invention can also 
include mixtures of the preservatives. These compounds are used at 
effective concentrations, typically from about 0.005% to about 5.0%, 
depending on the preservative(s) selected. The mount of the preservative 
used should be enough so that the solution is physically stable, i.e. a 
precipitate is not formed, and antibacterially effective, that is the 
formulation with preservative can pass the U.S. Pharmacopeia antimicrobial 
challenge by a panel of microbes. 
The formulation can, as an option, include excipients normally used to 
obtain pharmaceutical hydrogels. These excipients would include 
poly(hydroxymethylmethacrylate), poly(N-vinylpyrrolidone), polyvinyl 
alcohol and acrylic acid polymers such as Carbopol. These compounds are 
typically used at levels between 0.01% and 25.0%, preferably 0.05% to 15%, 
more preferably 0.10% to 7%. 
The pH of the formulation is chosen so that the formulation remains as a 
stable, clear and transparent solution. The pH can vary from more than 7.0 
to about 9, preferably from about 7.5 to about 9, and most preferably 8.4. 
To adjust the pH of the formulation to the desired value, the use of acids 
such as hydrochloric acid or sulfuric acid or bases such as sodium or 
potassium hydroxide can be used with the pH buffers. 
Otic formulations are similar to ophthalmic formulations and the 
formulations can be used interchangeably. If one were to specifically 
formulate an otic formulation, one would use more excipient to form a more 
viscous solution. Hydrogel forming excipients, as was previously 
described, would be the preferred excipients. 
The formulations represented by the invention are physically stable, remain 
clear and transparent for a useful shelf-life of one to two years and 
remain antimicrobially effective for the useful shelf life of the product. 
For a more detailed discussion of ophthalmic formulations, their 
preparation and administration, see Remington's Pharmaceutical Sciences, 
17th Ed., 1985; 1553-1566, herein incorporated by reference. The otic 
formulations can be substantially the same as the ophthalmic formulations. 
The present invention will become more readily apparent from the 
comparative examples and working examples which follow.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
COMATIVE EXAMPLE A 
Under the conditions described by Fu et al, a formulation comprising 0.3% 
Tobramycin, 0.5% Ketorolac tromethamine, 0.01% benzalkonium chloride (BAC) 
and 0.01% Octoxynol 40 (70% aqueous solution) at pH 7.4 was prepared and 
yielded a clear, transparent and ophthalmologically useful solution. 
However, when 0.3% Tobramycin, 0.5% sodium Diclofenac, 0.01% benzalkonium 
chloride (BAC) and 0.01% Octoxynol 40 (70% aqueous solution) was 
formulated under the conditions described by Fu et al., that formulation 
yielded a cloudy solution with suspended particles that was not 
pharmaceutically acceptable. 
COMATIVE EXAMPLE B 
The experiment of Example A was repeated using 0.3% Tobramycin, 0.1% sodium 
Diclofenac (the concentration normally used in ophthalmology), 0.01% 
benzalkonium chloride (BAC) and 0.01% Octoxynol 40 (70% aqueous solution) 
at pH 7.4. This formulation again yielded a cloudy solution with suspended 
particles that was not pharmaceutically acceptable. The presence of 
suspended particles is due to the formation of an insoluble complex 
between Diclofenac and Tobramycin, which was identified by thin-layer 
chromatography (TLC), HPLC, infra-red spectroscopy (FIG. 1) and DSC (FIG. 
2), as will be discussed in greater detail in the following comparative 
example. 
COMATIVE EXAMPLE C 
A formulation was prepared using 0.1% sodium Diclofenac, 0.3% Tobramycin, 
0.01% benzalkonium chloride, 1.0% Octoxynol 40 (70% aqueous solution) and 
the pH was adjusted to 8.0. As comparative controls, two more formulations 
were prepared, one with sodium Diclofenac as the active ingredient and the 
other formulation with Tobramycin as the active ingredient. Samples of the 
three formulations were stored at 4.degree. C. and 22.degree. C. with the 
formation of precipitate being followed. The storage temperature of 
4.degree. C. was intended to represent a critical storage condition from 
the point of view of the appearance of a precipitate, but realistic from 
the point of view of the environmental conditions which a preparation may 
encounter during its shelf life as a pharmaceutical product. After 41 days 
at 4.degree. C., the formulation of Diclofenac and Tobramycin developed a 
precipitate, while the formulations of Diclofenac alone or Tobramycin 
alone did not develop a precipitate. None of the formulations at 
22.degree. C. developed a precipitate after 7.5 months. 
The precipitate formed was separated and then analyzed by thin layer 
chromatography (TLC), HPLC and Infra-Red (IR) spectroscopy. The analysis 
detected the presence of Diclofenac and Tobramycin. The IR spectrum (FIG. 
1) of the precipitate shows the characteristic bands of sodium Diclofenac 
and Tobramycin that are not found in the spectrum of the separate 
compounds. The analysis by differential scanning calorimetry (DSC) (FIG. 
2) of the precipitate shows a profile clearly different from the profile 
obtained from the individual compounds as well as the profile obtained 
from the simple physical mixing of sodium Diclofenac and Tobramycin. 
The results obtained show different solubility behavior between Ketorolac 
and Diclofenac, showing the existence of an interaction between sodium 
Diclofenac and Tobramycin. The special characteristics of Diclofenac have 
been disclosed by Kriwet K and Muller-Goyman C. Binary Diclofenac 
Diethylamine Water systems: micelies, vesicles and lyotropic liquid 
crystals. Eur J Pharm Biopharm 1993; 39(6):234-238; and Winiwarter S and 
Roth HJ. The top ten NSAIDs. Pharmaceutica Acta Helvetica 1994; 
68:181-189, both herein incorporated by reference. 
However, the appearance of a precipitate within 3 days, at 22.degree. C., 
was observed with a formulation that contained 0.15% sodium Diclofenac, 
0.45% Tobramycin, 1.0% Octoxynol 40 (70% aqueous solution) and 0.01% 
benzyl ammonium chloride (BAC) at a pH of 8.0. These concentrations, which 
are within the concentrations claimed by Fu et al., were chosen because it 
is considered that these concentrations are the maximums at which a 
formulation of Diclofenac and Tobramycin could be found within the normal 
concentrations used in ophthalmology 0.1% Diclofenac and 0.3% Tobramycin. 
The concentration of 0.15% Diclofenac and 0.45% Tobramycin would take into 
account the needs of manufacturing specifications, the potential need for 
overdosing because of the instability of the Diclofenac and/or the 
Tobramycin, and the concentration of the formulated product due to 
evaporative losses from the containers normally used to store these 
products. 
For the purpose of determining the conditions under which a precipitate 
occurs, the concentration of sodium Diclofenac, the concentration of 
Octoxymol 40 (70% aqueous solution) and the pH of the final solution was 
varied while the concentration of benzalkonium chloride (BAC) (0.01%) and 
Tobramycin (0.3%) was held constant. The concentration of sodium 
Diclofenac was varied between 0.05 and 0.5%, the concentration of 
Octoxynol 40 (70% aqueous solution) was varied from 0.01% to 1.0%. The pH 
values of 6, 7 and 8 were studied. The rest of the components needed for 
an acceptable ophthalmological medicament were used at the concentrations 
described in Fu et al., herein incorporated by reference. The initial 
experimental approach corresponded to a factorial design 3.sup.3, and, as 
results were observed, new formulations were developed for the purpose of 
exploring the conditions that yielded clear and transparent solutions of 
sodium Diclofenac and Tobramycin. Based on these experiments, the use of 
high concentrations of surface active agent and alkaline conditions were 
found to provide the best conditions for obtaining clear and transparent 
solutions. 
We discovered that after 7 months of storage in a refrigerator, clear and 
transparent solutions were obtained only from the following formulations: 
______________________________________ 
% Octoxynol 40 
% sodium Diclofenac 
pH (70% aqueous solution) 
______________________________________ 
0.05 6 1.0 
0.05 7 1.0 
0.05 8 0.5 
0.05 8 1.0 
______________________________________ 
We also discovered that after 7 months storage at 22.degree. C., clear and 
transparent solutions were obtained only from the following experimental 
conditions: 
______________________________________ 
% Octoxynol 40 
% sodium Diclofenac 
pH (70% aqueous solution) 
______________________________________ 
0.05 6 1.0 
0.05 7 1.0 
0.05 7 0.5 
0.05 8 0.25 
0.05 8 0.5 
0.05 8 1.0 
0.10 8 1.0 
______________________________________ 
The other formulations studied did not provide clear and transparent 
solutions because a precipitate was obtained either on mixing or during 
storage. The following formulations yielded a precipitate either on mixing 
or during storage: 
______________________________________ 
% Octoxynol 40 
% sodium Diclofenac 
pH (70% aq. soln.) 
______________________________________ 
0.5 8 1.0 
0.5 7 1.0 
0.5 6 1.0 
0.05 8 0.01 
0.05 7 0.01 
0.05 6 0.01 
0.5 8 0.01 
0.5 7 0.01 
0.5 6 0.01 
0.25 8 0.01 
0.25 8 0.5 
0.25 8 1.0 
0.5 8 0.5 
0.05 6 0.5 
0.1 8 0.5 
0.1 7 1.0 
0.1 6 1.0 
0.05 7 0.25 
0.05 6 0.25 
______________________________________ 
It is noteworthy that Fu et al. prefer a pH of 7.4.+-.0.4 for their 
formulations, and that even with the greatest concentration of surface 
active agent described (1.0% Octoxynol 40), a pharmaceutically acceptable, 
clear and transparent solution cannot be obtained with a concentration of 
0.1% sodium Diclofenac and 0.3% Tobramycin at a pH of 7. 
As a result of these experiments, we discovered the preferred conditions 
(pH between 8 and 9; high concentration of solubility agent) necessary to 
obtain a pharmaceutically acceptable solution of Diclofenac and 
Tobramycin, thus overcoming the precipitation problems of the Fu et al 
formulations. The discovered conditions also permit including in the 
formulation quaternary ammonium compounds as preservatives, since these 
same conditions also inhibit the unacceptable interaction between 
Diclofenac and the quaternary ammonium compounds. 
It is well known that combinations of antibiotics and antiinflammatory 
agents intended for topical application are often used to treat different 
external organs of the body; for example, formulations intended for the 
topical treatment of the eye are also used for topical treatment of the 
ear, and, therefore, a combination of antibiotics with an NSAID would be 
analogously used. 
The following formulations are given as representative examples of the 
compositions included in the present invention, and they should not be 
considered as restrictions of the scope of the present invention. 
EXAMPLE 
______________________________________ 
COMPOSITION AMOUNT PER 100 ml. 
______________________________________ 
Sodium Diclofenac 0.100 g. 
Tobramycin 0.300 g. 
Benzalkonium chloride 
0.010 g. 
Polysorbate 80 3.000 g. 
Boric acid 0.900 g. 
Sodium tetraborate 0.450 g. 
EDTA Na.sub.2 0.100 g. 
NaCl q.s. 300 m0smol/kg 
HCl and/or NaOH q.s. 
pH 8.4 .+-. 0.4 
Purified water q.s. 
100 ml. 
______________________________________ 
To prepare an ophthalmic solution, 80% of the water of the formulation was 
put into a suitable container, and the benzalkonium chloride, boric acid, 
sodium tetraborate, EDTA Na.sub.2, NaCl, Polysorbate 80, Tobramycin and 
sodium Diclofenac were added. The pH was adjusted with HCl and/or NaOH to 
8.4.+-.0.4, water was added to 100 ml., and the resulting solution was 
filtered through a previously sterilized 0.22 micron filtration system. 
The obtained solution was dispensed into suitable containers which had 
been previously sterilized. 
EXAMPLE 
______________________________________ 
COMPOSITION AMOUNT PER 100 ml. 
______________________________________ 
Sodium Diclofenac 0.100 g. 
Tobramycin 0.300 g. 
Benzalkonium chloride 
0.010 g. 
Polysorbate 20 3.000 g. 
Boric acid 0.900 g. 
Sodium tetraborate 0.450 g. 
EDTA Na.sub.2 0.100 g. 
NaCl q.s. 300 m0smol/kg 
HCl and/or NaOH q.s. 
pH 8.4 .+-. 0.4 
Purified water q.s. 
100 ml. 
______________________________________ 
To prepare an ophthalmic solution, 80% of the water of the formulation was 
put into a suitable container, and benzalkonium chloride, boric acid, 
sodium tetraborate, EDTA Na.sub.2, NaCl, Polysorbate 20, Tobramycin and 
sodium Diclofenac were added. The pH was adjusted with HCl and/or NaOH to 
8.4.+-.0.4, water was added to adjust the volume to 100 ml, and the 
resulting solution was filtered through a previously sterilized 0.22 
micron filtration system. The obtained solution was dispensed into 
suitable containers which had been previously sterilized. 
EXAMPLE 
______________________________________ 
COMPOSITION AMOUNT PER 100 ml. 
______________________________________ 
Sodium Diclofenac 0.100 g. 
Tobramycin 0.300 g. 
Benzalkonium chloride 
0.010 g. 
Glycerol-polyethyleneglycol 
3.500 g. 
ricinoleate 
Tromethamine 0.600 g. 
EDTA Na.sub.2 0.100 g. 
NaCl q.s. 300 m0smol/kg 
H.sub.2 SO.sub.4 and NaOH q.s. 
pH 8.4 .+-. 0.4 
Purified water q.s. 
100 ml. 
______________________________________ 
To prepare an ophthalmic solution, 80% of the water of the formulation was 
put into a suitable container, and benzalkonium chloride, Tromethamine, 
EDTA Na.sub.2, NaCl, glycerol-polyethyleneglycol ricinoleate, Tobramycin 
and sodium Diclofenac were added. The pH was adjusted with H.sub.2 
SO.sub.4 and/or NaOH to 8.4.+-.0.4, the volume was adjusted to 100 ml with 
water, and the resulting solution was filtered through a previously 
sterilized 0.22 micron filtration system. The obtained solution was 
dispensed into suitable containers which had been previously sterilized. 
EXAMPLE 
______________________________________ 
SUBSTANCE AMOUNT PER 100 ml. 
______________________________________ 
Sodium Diclofenac 0.100 g. 
Tobramycin 0.300 g. 
Benzalkonium chloride 
0.010 g. 
Polysorbate 80 3.000 g. 
Hydroxypropylmethylcellulose 
0.300 g. 
Boric acid 0.900 g. 
Sodium tetraborate 0.450 g. 
EDTA NaCl.sub.2 0.100 g. 
NaCl q.s. 300 m0smol/kg 
HCl and/or NaOH q.s. 
pH 8.4 .+-. 0.4 
Purified water q.s. 100 ml. 
______________________________________ 
To prepare an ophthalmic solution, 80% of the water of the formulation was 
put in a suitable container, and benzalkonium chloride, 
hydroxypropylmethylcellulose, boric acid, sodium tetraborate, EDTA 
Na.sub.2, NaCl, Polysorbate 80, Tobramycin and sodium Diclofenac were 
added. The pH was adjusted with HCl and/or NaOH to 8.4.+-.0.4, the volume 
was adjusted to 100 ml with water, and the resulting solution was filtered 
through a previously sterilized 0.22 micron filtration system. The 
obtained solution was dispensed in suitable containers which had been 
previously sterilized. 
EXAMPLE 
______________________________________ 
SUBSTANCE AMOUNT PER 100 ml. 
______________________________________ 
Sodium Diclofenac 0.100 g. 
Tobramycin 0.300 g. 
Benzalkonium chloride 
0.010 g. 
Polysorbate 20 3.000 g. 
Hydroxyethylcellulose 
0.500 g. 
Boric acid 0.900 g. 
Sodium tetraborate 
0.450 g. 
EDTA Na.sub.2 0.100 g. 
NaCl q.s. 300 m0smol/kg 
HCl and/or NaOH q.s. 
pH 8.0 .+-. 0.4 
Purified water q.s. 
100 ml. 
______________________________________ 
To prepare an ophthalmic solution, 80% of the water of the formulation was 
put into a suitable container, and benzalkonium chloride, 
hydroxyethylcellulose, boric acid, sodium tetraborate, EDTA Na.sub.2, 
NaCl, Polysorbate 20, Tobramycin and sodium Diclofenac were added. The pH 
was adjusted with HCl and/or NaOH to 8.4.+-.0.4, the volume was adjusted 
to 100 ml with water, and the resulting solution was filtered through a 
previously sterilized 0.22 micron filtration system. The obtained solution 
was dispensed into suitable containers which had been previously 
sterilized. 
EXAMPLE 
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SUBSTANCE AMOUNT PER 100 ml. 
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Sodium Diclofenac 0.100 g 
Tobramycin 0.300 g. 
Benzalkonium chloride 
0.010 g. 
Polysorbate 80 5.000 g. 
Boric acid 0.900 g. 
Sodium tetraborate 0.450 g. 
EDTA Na.sub.2 0.100 g. 
NaCl q.s. 300 m0smol/kg 
HCl and/or NaOH q.s. 
pH 7.5 .+-. 0.4 
Purified water q.s. 
100 ml. 
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To prepare an ophthalmic solution, 80% of the water of the formulation was 
put into a suitable container, and the benzalkonium chloride, boric acid, 
sodium tetraborate, EDTA Na.sub.2, NaCl, Polysorbate 80, Tobramycin and 
sodium Diclofenac were added. The pH was adjusted to 7.5.+-.0.4 with HCl 
and/or NaOH, water was added to 100 ml., and the resulting solution was 
filtered through a previously sterilized 0.22 micron filtration system. 
The obtained solution was dispensed into suitable containers which had 
been previously sterilized. 
Although certain presently preferred examples and embodiments of the 
invention have been described herein, it will be apparent to those skilled 
in the art to which the invention pertains that variations and 
modifications of the described examples and embodiments may be made 
without departing from the spirit and scope of the invention. Accordingly, 
it is intended that the invention be limited only to the extent required 
by the appended claims and the applicable rules of law.