Topical ophthalmic acidic drug formulations

Stable, comfortable, preserved, topical, ophthalmic compositions of acidic drugs are disclosed. Methods for their use are also disclosed.

FIELD OF THE INVENTION 
This application is directed to stable and comfortable preserved ophthalmic 
formulations containing an acidic drug. 
BACKGROUND OF THE INVENTION 
Carboxyl containing compounds, including most non-steroidal 
antiinflammatory drugs (NSAIDs), are difficult to formulate into stable, 
preserved, comfortable, ophthalmic compositions. Acidic drugs with 
carboxyl groups are inherently irritating to the eye. In addition, the 
drugs tend to form insoluble complexes with quaternary ammonium 
preservatives, such as benzalkonium chloride (BAC). Many NSAIDs have been 
formulated with other than desirable preservatives (e.g. sorbic acid, 
thimerosol) because the compounds complex with desired preservatives, such 
as, quaternary ammonium compounds, particularly BAC. In addition, it has 
proved difficult to formulate carboxyl containing compounds that are 
comfortable when applied topically to the eye. 
There are ophthalmic products containing acidic drugs. Commonly, these 
drugs are NSAIDs containing a carboxyl group. Examples of these products 
are suprofen (Profenal.RTM., Alcon Laboratories, Inc. which is preserved 
with thimerosol); diclofenac sodium (Voltaren Ophthalmic.TM., Ciba Vision 
Ophthalmics which is preserved with sorbic acid); flurbiprofen sodium 
(Ocufen.RTM., Allergan Medical Optics which is preserved with thimerosol); 
and ketorolac tromethamine (Acular.RTM., Allergan, Inc. which is preserved 
with BAC and Octoxynol 40). 
U.S. Pat. No. 5,110,493 discloses aqueous, ophthalmic, non-steroidal 
anti-inflammatory formulations which include a preservative system formed 
of a quaternary ammonium compound and a nonionic surfactant which is an 
ethoxylated alkyl phenol, such as Octoxynol 10 or 40. 
WO 94/15597 discloses the use of lauralkonium chloride, a C.sub.12 
homologue of BAC, which is compatible with acidic drug entities in 
ophthalmic formulations. 
U.S. Pat. No. 4,960,799 discloses an ophthalmic formulation of a salt of 
ortho-(2,6-dichlorophenyl) aminophenylacetic acid, EDTA, a solubilizer, 
and a bacteriostat. 
EP 0,621,036-A1 discloses ophthalmic formulations of particular arginine 
amides and either cyclodextrin or caffeine. The application discloses that 
the use of cyclodextrin or caffeine improves the arginine amide solubility 
in water and that the caffeine can stabilize the compound in water. 
U.S. Pat. No. 4,559,343 discloses ophthalmic formulations containing NSAIDs 
and a xanthine derivative to reduce ocular discomfort. 
The compositions of the present invention are stable, yet they contain an 
acidic drug and the desired preservative, BAC, or mixtures of at least two 
homologues of BAC. In addition, the compositions are comfortable upon 
topical instillation in the eye. 
SUMMARY OF THE INVENTION 
The present invention is directed to stable, comfortable, and preserved 
topical ophthalmic formulations comprising an acidic drug, Vitamin E 
Tocopherol Polyethylene Glycol 1000 Succinate (TPGS) (Eastman Chemical 
Co., Kingsport, Tenn., BAC, or mixtures of at least two homologues of BAC, 
and caffeine. Types of acidic drugs can include NSAIDs, antibacterials, 
diagnostic agents, antiinfective agents, and prostaglandins. Methods for 
the compositions' use are also disclosed.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
The compositions of the present invention comprise an acidic drug, Vitamin 
E TPGS, BAC, or mixtures of BAC homologues, such as C.sub.12 and C.sub.14 
and caffeine. As used herein the term "acidic" means the drug contains a 
carboxyl moeity or a salt thereof and/or a sulfamide group or a salt 
thereof. 
Acidic drugs which can be formulated according to the present invention 
include NSAIDs, including, but not limited to, diclofenac, bromfenac, 
fiurbiprofen, naproxen, ketorolac, suprofen, ibuprofen, and tolmetin, 
including their pharmaceutically acceptable salts, esters, and prodrugs; 
prostaglandins; antibacterial and antiinfective agents; and diagnostic 
agents. BAC is used to preserve the formulations. The Vitamin E TPGS is 
used to solubilize the acidic drug and reduce ocular discomfort in aqueous 
conditions. The caffeine is added to reduce ocular discomfort, but 
surprisingly, it was found that it acts synergistically with Vitamin E 
TPGS to reduce discomfort and it also potentiates the preservative 
efficacy of BAC. 
In the formulations, the acidic drug is present at concentrations from 
0.001 weight percent (wt. %) to 2.5 wt. %, preferably 0.01 to 1.0 wt. %. 
The Vitamin E TPGS concentration is 0.0001 to 30 wt. %, preferably 0.01 to 
10 wt. %. BAC or its homologue mixtures are present at concentrations from 
0.00001 to 0.02 wt. %, preferably 0.0001 to 0.01 wt. %; and the caffeine 
concentration is from 0.001 to 5.0 wt. %, preferably 0.01 to 1.0 wt. %. 
The compositions of the invention may also contain other components such 
as, but not limited to, those listed below: 
1. Buffers (e.g., phosphate, borate, citrate, acetate, carbonate, 
borate-polyol complexes, etc.); 
2. Tonicity agents (e.g. mannitol, sodium chloride, xylitol, etc.) 
3. Viscosity building agents, e.g., carboxylic polymers like Carbopol.RTM. 
(carbomers), Noveon.RTM. (polycarbophils), etc.; cellulose derivatives 
including alkyl and hydroxyalkyl cellulose like methylcellulose, 
hydroxypropylcellulose, carboxymethylcellulose, etc.; gums like locust 
beam, xanthan, agarose, karaya, guar, etc.; and other polymers including 
but not limited to polyvinyl alcohol, polyvinyl pyrollidone, polyethylene 
glycol, Pluronic.RTM. (Poloxamers), tragacanth, and hyaluronic acid. 
4. Phase-transition polymers for providing sustained and controlled 
delivery of enclosed medicaments to the eye (e.g., alginic acid, 
carrageenans (e.g., Eucheuma), xanthan and locust bean gum mixtures, 
pectins, cellulose acetate phthalate, alkylhydroxyalkyl cellulose and 
derivatives thereof, hydroxyalkylated polyacrylic acids and derivatives 
thereof, poloxamers and their derivatives, etc. The phase-transition in 
these polymers can be mediated by changes in environmental factors such as 
ionic strength, pH, or temperature alone or in combination with other 
factors. 
5. Other excipients include but are not limited to: antioxidants (ascorbic 
acid, sodium metabisulfite, etc.), complexing agents (cyclodextrins and 
derivatives thereof), drug carriers or drug-laden ion exchange carriers, 
such as, Amberlite.RTM. and Duolite.RTM., and some chelating agents. 
The ophthalmic compositions can be administered topically to the eye as 
suspensions, emulsions, ointments, gels, or solutions. The compositions 
may be aqueous or nonaqueous, but are preferably aqueous. The compositions 
may have the drugs incorporated and/or encapsulated in microcapsules, 
nanocapsules, nanoparticles, or liposomes which are dispersed in an 
aqueous or nonaqueous medium. 
The preferred formulation of this invention comprises diclofenac sodium, as 
illustrated in Example 2. 
The following Examples are illustrative, but not limiting: 
Examples 1 and 2 are useful in treating ophthalmic inflammation. The 
formulations are administered 1-4 times daily according to the routine 
discretion of a skilled clinician. 
EXAMPLE 1 
______________________________________ 
Ingredients Concentration (% wt./vol.) 
______________________________________ 
NSAID 0.1-2.5 
HPMC 0.05-1.0 
Tromethamine 0.1-1.2 
Boric Acid 0.01-1.0 
Vit E TPGS 0.1-5.0 
Caffeine 0.01-2.0 
Mannitol 2.0-4.4 
Benzalkonium Chloride 
0.005-0.01 
or its homologue mixtures 
Disodium EDTA 0.01-0.1 
HCl/NaOH q.s. to pH 7.4 
Purified Water q.s. 100% 
______________________________________ 
Compounding Procedure: 
To a tared glass vessel containing purified water, first caffeine is added. 
The solution is stirred until the caffeine dissolves. Next, the rest of 
the ingredients are added in the order given below and each ingredient is 
completely dissolved by stirring before the next one is added. 
NSAID 
Vitamin E TPGS 
Tromethamine 
Boric acid 
Disodium EDTA 
Benzalkonium chloride 
Mannitol 
HPMC 
The formulation is then brought to 95% of its final weight. The pH is 
adjusted to about 7-7.4 using NaOH or HCl. The final weight is adjusted to 
100% with purified water. The formulation's tonicity is 300 mOsms. 
______________________________________ 
Ingredients Concentration (% w/w) 
______________________________________ 
Diclofenac Sodium 
0.1 
HPMC 0.1 
Tromethamine 1.2 
Boric Acid 0.6 
Vit E TPGS 2.0 
Caffeine 0.2 
Mannitol 4.2 
Benzalkonium Chloride 
0.01 
Disodium EDTA 0.1 
HCl/NaOH q.s. pH 7.4 
Purified Water q.s. 100% 
______________________________________ 
Compounding Procedure: 
A. Preparing 10% Vitamin E TPGS stock solution 
Deionized water (70% of final weight of TPGS stock solution) was taken in a 
large beaker and brought to boiling with heat. The required quantity of 
Vitamin E TPGS was added in small proportions under stirring. Final weight 
was adjusted to 100% with additional d.i. water after all of Vitamin E 
TPGS had gone in solution. 
B. Preparing 2% HPMC (Hydroxypropyl methyl cellulose) stock solution 
HPMC wad added in small proportions under constant stirring into a beaker 
containing deionized water which was 70% of final weight of HPMC stock 
solution. Final weight was adjusted to 100% with additional d.i. water 
after all of the added FIPMC had dissolved completely. 
C. Ingredients were added in the order suggested below and each ingredient 
was dissolved completely under constant stirring before the next one was 
added: 
0.2 g of caffeine was weighed in a tared vessel containing a stir bar and 
d.i. water which is 40% of final weight. Then 0.1 g of diclofenac, 20 g of 
10% Vitamin E TPGS stock solution, 1.2 g of tromethamine, 0.6 g of boric 
acid, 0.1 g of disodium EDTA, 0.01 g of BAC, 4.2 g of mannitol and 5 g of 
2% HPMC stock solution were added sequentially. Weight was adjusted to 95% 
of final weight with d.i. water. Next, pH was measured and if necessary, 
it was adjusted to 7.4 with 0.1N NaOH or 0.1N HCl. Finally weight was 
adjusted to 100 g with additional d.i. water. 
Example 3 
______________________________________ 
Examples of other NSAID and prostaglandin formulations 
Formulation % weight by volume 
Ingredient A B C D E F 
______________________________________ 
Caffeine 0.2 0.2 0.2 0.2 0.2 0.2 
Flurbiprofen 0.03 -- -- -- -- -- 
Bromfenac -- 0.05 -- -- -- -- 
Suprofen -- -- 0.25 
-- -- -- 
Suprofen -- -- -- 0.25 -- -- 
Prostaglandin 
-- -- -- -- 0.1 -- 
(PGE.sub.2) 
Prostaglandin 
-- -- -- -- -- 0.1 
(PGF.sub.2.alpha.) 
10% Vitamin E 
20.0 20.0 15.0 20.0 25.0 25.0 
TPGS Stock Soln. 
tromethamine 1.0 1.0 1.2 1.2 1.0 1.0 
boric acid 0.6 0.6 0.6 0.6 0.6 0.6 
Disodium EDTA 
0.05 0.05 0.05 
0.05 0.05 
0.05 
Benzalkonium 0.01 0.01 -- 0.01 0.01 
-- 
Chloride (BAC) 
C12 and C14 -- -- 0.01 
-- -- 0.01 
homologues of BAC 
(80:20) 
Mannitol 4.2 4.2 3.8 3.8 4.0 4.0 
2% HPMC Stock 
15.0 15.0 15.0 15.0 15.0 15.0 
Soln. 
0.1N NaOH or 0.1N 
7.4 7.4 7.4 7.4 7.4 7.4 
HCl to adjust pH 
Deionized water qs to 
100 100 100 100 100 100 
______________________________________ 
Compounding Procedure: 
Formulations A-F are prepared by adding caffeine to a tared glass vessel 
containing deionized water. The solution is stirred until caffeine is 
dissolved. Next, the remaining ingredients are added sequentially as 
listed and after the previous ingredient has completely dissolved. The 
solution is then brought to 95% of final weight with water and the pH is 
adjusted to 7.4. The final weight is then made 100% with water. 
EXAMPLE 4 
A simplified preservative efficacy screen based on the United States 
Pharmacopeia (USP) XXII, 1990 Antimicrobial Preservative Effectiveness 
standards was performed against Staphylococcus aureus for the compositions 
shown in the following table. The screen entailed challenging the 
formulations with the gram-positive bacteria, S. aureus, and sampling at 7 
and 14 days. The initial preservative efficacy test for the formulations 
had indicated that the formulations had poor preservation only against S. 
aureus, whereas the formulations exhibited appropriate preservative 
efficacy according to USP against the other organisms such as 
gram-negative (Pseudomonas aeruginosa) and fungi (Aspergillus niger) at 7 
and 14 days. 
______________________________________ 
Formulation 
Ingredient A B C D 
______________________________________ 
Caffeine 0.0 0.2 0.75 
1.25 
Diclofenac Sodium 
0.1 0.1 0.1 0.1 
Vitamin E TPGS 1.5 1.5 1.5 1.5 
Tromethamine 1.2 1.2 1.2 1.2 
Boric acid 0.6 0.6 0.6 0.6 
Disodium EDTA 0.1 0.1 0.1 0.1 
BAC 0.01 0.01 0.01 
0.01 
Mannitol 4.4 4.4 3.8 3.2 
HPMC 0.1 0.1 0.1 0.1 
NaOH or HCl, qs to 
7.4 7.4 7.4 7.4 
adjust pH to 
Purified Water, qs to 
100 100 100 100 
______________________________________ 
According to the USP preservative efficacy standards for S. aureus, a 
formulation has to exhibit a minimum of 3.0 log reduction on day 14 and no 
increase in count between 14 to 28 days. FIG. 1 shows the results for the 
S. aureus screen for the formulations in the above table. The formulations 
had similar compositions except for the varying concentrations of caffeine 
from 0.0% to 1.25%. As shown in FIG. 1, the higher the caffeine 
concentration in the formulation the higher was the S. aureus log 
reduction value. The figure also shows that the required 3.0 log reduction 
is achieved by 7 days at higher caffeine concentration rather than on 14 
days. 
The formulation of Example 2 above showed the S. aureus log reduction 
values of 3.1 and 5.1 on days 7 and 14, respectively, when the S. aureus 
screen was performed. 
Thus, surprisingly caffeine was found to potentiate the preservative 
efficacy of BAC in the formulations of the invention.