Ophthalmic compositions,their preparation and use

PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS

BACKGROUND OF THE INVENTION

The present invention relates to improved ophthalmic formulations, particularly to ophthalmic formulations for anti-inflammatory drugs, and specifically to an improved preservative system for ophthalmic formulations of carboxyl (-CODH¹’) group-containing drugs, especially non-steroidal anti-inflammatory drugs (״NSAIDs).

The formulations of this invention are useful for treating diseases that are either caused by, associated with or accompanied by inflammatory processes, including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy, and conjunctivitis, or any trauma caused by eye surgery or eye injury.

The topical use of NSAIDs, particularly pyrrolo pyrroles, in the treatment of ophthalmic diseases was first taught in U.S. Patent No. 4,454,151, where NSAID compounds (such as those described in U.S. Patents •4,089,969; 4,252,038; 4,087,539 and' 4,097,579) were exemplified in formulation with NaH₂P0^ .H₂0, Na₂HP0₄’H₂0, NaCl, benzalkonium chloride (^,,BAG״) and sterilized water. While the formulations described

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In general, an ophthalmic formulation contains an active compound and various ophthalmologically acceptable excipients, in the form of a solution, an ointment, a suspension, etc. An excipient is ophthalmologically acceptable if it is non-irritating to the eye and if its active ingredient penetrates the blood-aqueous barrier and/or diffuses through the various ocular substructures to the site where it is pharmacologically active. The excipients can include a tonicifier, a preservative, a surfactant, a buffering system, a chelating agent, a viscosity agent as well as other stabilizing agents. Ophthalmic formulations must be sterile, and if intended for multiple dosing regimens, must be preserved with an effective anti-microbial agent.

Organo-mercurials (e.g., thimerosal, phenylmercuric acetate and phenylmercuric nitrate) have been used extensively as the preservative in ophthalmic solutions. These compounds, however, pose difficulties due to potential mercury toxicity as well as poor chemical stability. Benzalkonium chloride, a quaternary ammonium compound, has been widely used in ophthalmic solutions, and is considered to be the preservative of choice.

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However, BAC has typically been considered to be incompatible with anionic drugs (e.g., salicylates or nitrates, etc.), forming insoluble complexes which cause the solution to become cloudy or turbid. Such a complex between the anionic drug and benzalkonium chloride can cause a decrease in the pharmaceutical activity of the anionic drug.

Many NSAIOs (such as ketorolac, indomethacin, flurbiprofen and diclofenac) are being developed for ocular use because of their activity as anti-inflammatory agents including their ability to prevent cystoid macular edema.

In the past, as in the case with other ophthalmic drugs that contain a -COOH group, antiinflammatory solutions of NSAIOs for occular use have proven to be incompatible with quaternary ammonium compounds such as BAC. This incompatibility is due to the fact that the -COOH group can form a complex with the quaternary ammonium compounds, rendering the preservative less available to serve its function, and reducing the activity of the active ingredient. Indomethacin ophthalmic formulations have been prepared, however, these are suspensions, not solutions. Ocufen Ophthalmic solution, an NSAID (flurbiprofen) approved by the FDA for ophthalmic use, incorporates thimerosal (with EDTA) as its preservative system. In U.S. patent 4,454,151 there is a disclosure of an ophthalmic formulation using ketorolac, benzalkonium chloride (as the preservative) and polysorbate 80, however the solution became cloudy or turbid after a short period of time.

It has remained desired to provide a stable, clear, antimicrobially effective ophthalmic formulation with a prolonged shelf life for -COOH group containing ophthalmic drugs, especially NSAIOs, using BAC as the preservative.

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SUMMARY OF THE INVENTION

It has now been discovered that stable, clear and antimicrobially effective, NSAID-containing ophthalmic formulations can be prepared which include a quaternary ammonium preservative. These solutions have an improved shelf life, exhibiting no cloudiness or turbidity over extended periods.

In one aspect of the invention, these compositions include an ophthalmologically effective amount of a NSAID, a quaternary ammonium preservative and a stabilizing amount of an ethoxylated octylphenol as a nonionic surfactant, all in an aqueous vehicle.

Another aspect is an ophthalmic composition including an ophthalmologically effective amount of a NSAID, a quaternary ammonium preservate and a stabilizing amount of an ethoxylated octylphenol as a nonionic surfactant.

Another aspect is an ophthalmic composition including an ophthalmologically effective amount of a NSAID, benzalkonium chloride as a preservative and a stabilizing amount of an ethoxylated octylphenol as a nonionic surfactant.

Another aspect is an ophthalmic composition including an ophthalmologically effective amount of a NSAID, benzalkonium chloride as a preservative and a stabilizing amount of Octoxynol 40 as a nonionic surfactant.

Another aspect is an ophthalmic composition including an ophthalmologically effective amount of ketorolac or an isomer, an ester, or a pharmaceutically acceptable salt thereof, benzalkonium chloride as a preservative and a stabilizing amount of Octoxynol 40 as a nonionic surfactant.

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In another aspect of the invention, methods for treating ophthalmic diseases in mammals using the ־σρ-hthalmic pharmaceutical formulations of the invention are also disclosed. These diseases are those that are either caused by, associated with or accompanied by inflammatory processes, including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy and conjunctivitis, or any trauma caused by eye surgery or eye injury.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions

As used herein, the term NSAID means an ophthalmologically acceptable non-steroidal ¹⁵ anti-inflammatory drug. The NSAID's include, for example, flurbiprofen, ketorolac, diclofenac, indomethacin, and the isomers, esters, and pharmaceutically acceptable salts thereof.

As used herein, the term q.s. means adding a ²⁰ quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

As used herein, the term treatment or treating means any treatment of a disease in a mammal, including:

(i) preventing the disease, that is, causing the ²^ clinical symptoms of the disease not to develop;

(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms.

³⁰ As used herein, the term effective amount means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected.

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As used herein, the term antimicrobially effective means ability to withstand the U.S. Pharmacopia antimicrobial challenge.

As used herein, the term surfactant means a nonionic surfactant, preferably ethoxylated octylphenol compounds as described below.

As used herein, the term quaternary ammonium preservative means a quaternary ammonium compound such as described below.

As used herein, the term stabilizing means keeping a formulation clear and antimicrobially effective for its minimum reasonable shelf life, e.g., at least one year.

Formulations

The formulations of the present invention include an NSAID active agent in an effective amount for ophthalmic treatment, a quaternary ammonium preservative, a stabilizing amount of an ethoxylated octylphenol as a nonionic surfactant, optionally including other excipients such as a chelating agent, a tonicifier, a buffering system, a viscosity agent as well as other stabilizing agents. Ophthalmic solutions and suspensions typically contain an aqueous vehicle rather than an oily vehicle. Ophthalmic formulations must be sterile, and if intended for multiple dosing regimens, must be antimicrobially effective for their minimum reasonable shelf life, e.g., at least one year, and preferably two to three years or more. The ingredients used in the formulations of the present invention are typically commercially available or can be made by methods readily known to those skilled in the art.

Pharmaceutical ophthalmic formulations typically contain an effective amount, e.g., 0.00,1% to 10% wt/vol., preferably 0.002% to 5% wt/vol, most preferably 0.005% to

1% wt/vol of an active ingredient (e.g., the NSAID of the

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26280-FF present invention). The amount of active ingredient will vary with the particular formulation and the disease state for which it is intended. The total concentration of solutes should be such that, if possible, the resulting solution is isotonic with the lacrimal fluid (though this is not absolutely necessary) and has a pH in the range of 6 to 8,

The formulations of the present invention are prepared as solutions incorporating the above-described ingredients within the following approximate ranges:

<td> Ingredient Active Agent Preservative</td><td> Amount 0.001% to 10.0% wt/vol.; 0.001% to 1.0% wt/vol.;</td>

<td> Surfactant</td><td> 0.001% to 1.0% wt/vol.;</td>

<td> Other Excipients Purified Water</td><td> 0% to 10.0% wt/vol.; and q.s. to 100%.</td>

Optional other excipients, such as a chelating agent and

<td> a tonicifier, are used in the proportions:</td><td> following approximate</td>

<td> Ingredient Chelating agent Tonicifier</td><td> Amount 0.01% to 1.0%wt/vol.; q.s. to achieve isotonicity with lacrimal fluid; and</td>

<td> IN NaOH or IN HC1</td><td> q.s. to adjust pH to 6.0 to 8.0.</td>

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In a preferred ophthalmic NSAID solution, the

<td> ingredients are combined in</td><td> the following proportions:</td>

<td> Ingredient</td><td> Amount</td>

<td> NSAID</td><td> 0.002% to 5.0% wt/vol.;</td>

<td> BAG</td><td> 0.002% to 1.0% wt/vol.;</td>

<td> (50% aq. soln.)</td><td></td>

<td> Octoxynol 40</td><td> 0.001% to 1.0% wt/vol.;</td>

<td> (70% aq. soln.)</td><td></td>

<td> EDTA Na₂</td><td> 0.01% to 1.0% wt/vol.;</td>

<td> NaCl</td><td> q.s. for isotonicity with</td>

<td></td><td> lacrimal fluid;</td>

<td> IN NaOH or IN HC1</td><td> q.s. to adjust pH to</td>

<td></td><td> 7.4±0.4; and</td>

<td> Purified Water</td><td> q.s. to 100%.</td>

<td colspan="2"> In another preferred ophthalmic NSAID solution, the</td>

<td> ingredients are combined in</td><td> the following proportions:</td>

<td> Ingredient</td><td> Amount</td>

<td> NSAID</td><td> 0.005% to 1.0% wt/vol.;</td>

<td> BAC</td><td> 0.002% to 1.0% wt/vol.;</td>

<td> (50% aq. soln.)</td><td></td>

<td> Octoxynol 40</td><td> 0.001% to 1.0% wt/vol.;</td>

<td> (70% aq. soln.)</td><td></td>

<td> EDTA Na₂</td><td> 0.01% to 1.0% wt/vol.;</td>

<td> NaCl</td><td> q.s. for isotonicity with</td>

<td></td><td> lacrimal fluid;</td>

<td> IN NaOH or IN HC1</td><td> q.s. to adjust pH to</td>

<td></td><td> 7.4±0.4; and</td>

<td> Purified Water</td><td> q.s. to 100%.</td>

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In a more preferred ophthalmic NSAID solution, the ingredients are combined in the following proportions:

Ingredient Amount

NSAID 0.50% wt/vol.;

BAC 0.02% wt/vol.;

(50% aq. soln.)

Octoxynol 40 0.01% wt/vol.;

(70% aq. soln.) EDTA Na₂ 0.10% wt/vol.;

NaCl q.s. for isotonicity with lacrimal fluid;

IN NaOH or IN HC1 q.s. to adjust pH to 7.4±0.4; and Purified Water q.s. to 100%.

The invention relates primarily to formulations having as the active agent ophthalmologically acceptable drugs (including the isomers, esters and pharmaceutically acceptable salts thereof) that can form a complex with a quaternary ammonium compound, particularly NSAIDs and drugs with a carboxyl group.

NSAIDs useful in the practice of this invention include, for example, ketorolac (and the other compounds described as being ophthalmologically effective in U.S. Patent No. 4,454,151 to Waterbury, issued June 12, 1984, the pertinent portions of which are incorporated herein by reference), indomethacin, flurbiprofen sodium, and diclofenac, including the isomers, esters and pharmaceutically acceptable salts thereof.

Preservatives useful in the formulations of the present invention include quaternary ammonium compounds, such as cetyltrimethylammonium bromide, cetylpyridinium chloride and benzalkonium chloride, preferably, benzalkonium chloride.

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The nonionic surfactants useful in the formulations of the present invention are preferably ethoxylated octylphenol compounds, such as octylphenoxypoly(ethyleneoxy)ethanols, more preferably, a homologous series of surfactants sold under the trade name Igepal CA with a numerical suffix indicating the mole ratio of ethylene oxide to octylphenol, the ratio being 3 to 40. Examples include Octoxynol 9, Octoxynol 12, Octoxynol 13, and Octoxynol 40, and most preferably Octoxynol 40, manufactured and sold by GAF under the trade name Igepal CA897 (a 70% aqueous solution of Octoxynol 40).

Among the optional excipients, the chelating agents useful in the formulations of the present invention include 8-hydroxyquinoline sulfate, citric acid, and 15 preferably disodium edetate. Under certain conditions, the chelating agent may also enhance the anti-microbial effect due to its ability to render essential metal ions unavailable to the microbes.

Buffering systems optionally useful in the formulations of the present invention are based on, for example, citrate, borate, or phosphate.

Tonicifiers optionally useful in the formulations of the present invention include dextrose, potassium chloride and/or sodium chloride, preferably sodium 25 chloride.

Viscosity agents optionally useful in the formulations □f the present invention include the cellulose derivatives such as hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and 30 hydroxyethylcellulose.

Other optional excipients useful in the formulations of the present invention include stabilizing agents such as antioxidants, e.g., sodium metabisulfate and ascorbic acid, depending on the NSAID used.

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These formulations are prepared by dissolving the solutes (e.g., the NSAID, the preservative, the surfactant, the chelating agent, and the buffering agent) in a suitable quantity of water, adjusting the pH to about 6 to 8, preferably 6.8 to 8.0 and most preferably 7.4, making a final volume adjustment to 100% with additional water, and sterilizing the preparation using any suitable method known to those in the art.

It has been discovered that ophthalmic formulations incorporating the preservative system of the invention are physically stable (i.e., remain clear) and functionally stable (i.e., remain antimicrobially effective) for at least the minimum reasonable shelf life of such products.

Preferred Formulations

The preferred preservative system of the invention includes a quaternary ammonium preservative and a stabilizing amount of a nonionic surfactant.

The preferred ophthalmic formulation of the invention includes a NSAID active agent in an effective amount for ophthalmic treatment and an antimicrobially effective amount of the above-described preferred preservative system.

The preferred preservative of the invention is benzalkonium chloride.

The preferred surfactant of the invention is Octoxynol 40, especially when combined with benzalkonium chloride as the preservative.

The preferred chelating agent of the invention is disodium edetate, especially when combined with benzalkonium chloride as the preservative and Octoxynol 40 as the nonionic surfactant.

The preferred ophthalmic solutions of the invention include a NSAID, benzalkonium chloride, Octoxynol 40 and disodium edetate.

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A preferred ophthalmic NSAID ingredients are combined in the Ingredient

NSAID

BAC (50% aq, soln.) Octoxynol 40 (70% aq. soln.) EDTA Na₂

NaCl

IN NaOH or IN HC1

Purified Water

Another preferred ophthalmic NSAID ingredients are combined in the Ingredient

NSAID

BAC (50% aq. soln.) Octoxynol 40 (70% aq. soln.)

EDTA Na₂

NaCl

IN NaOH or IN HC1

Purified Water solution, the following proportions;

Amount

0.002% to 5.0% wt/vol 0.002% to 1.0% wt/vol.

0.001% to 1.0% wt/vol.

0.01% to 1.0% wt/vol.; q.s. for isotonicity with lacrimal fluid; q.s. to adjust pH to 7.4±0.4; and q.s. to 100%.

solution, the following proportions: Amount

0.005% to 1.0% wt/vol 0.002% to 1.0% wt/vol.

0.001% to 1.0% wt/vol.;

0.01% to 1.0% wt/vol.; q.s. for isotonicity with lacrimal fluid; q.s. to adjust pH to 7.4±0.4; and q.s. to 100%.

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A preferred ophthalmic NSAID solution has the following formulation:

<td colspan="2"> Ingredient</td><td rowspan="2"> Amount 0.50% wt/vol.</td>

<td></td><td> NSAID</td>

<td> 5</td><td> BAC</td><td> 0.02% wt/vol.</td>

<td> 10</td><td> (50% aq. soln.) Octoxynol 40 (70% aq. soln.) EDTA Na₂ NaCI</td><td> 0.01% wt/vol. 0.10% wt/vol. q.s. for isotonicity</td>

<td> 15</td><td> IN NaOH or IN HC1 Purified Water</td><td> with lacrimal fluid q.s. to adjust pH to 7.4+0.4 q.s. to 100%</td>

Most preferred is the ophthalmic solution according to the above formulation wherein the NSAID is Ketorolac Tromethamine or an isomer thereof.

Utility and Administration

This invention is directed to NSAID ophthalmic formulations and a method useful for treating ophthalmic diseases in mammals. These diseases are either caused by, associated with or accompanied by inflammatory 25 processes, including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy and conjunctivitis, or any trauma caused by eye surgery or eye injury.

The method of this invention is both curative and 30 preventative. Where applied, for example, pre-surgically or immediately post-traumatically, i.e. before inflammation develops, it prevents development of inflammation. When applied directly to> the eye suffering from any of the named ophthalmic diseases, it supresses 35 already developed inflammatory processes.

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Ophthalmic formulations are typically administered by topical application to the eyelids or for instillation into the space (cul-de-sac) between the eyeball and the eyelids, of topically applied ophthalmic solutions, suspensions or ointments, or by subconjunctival injection.

The dosage level will, of course, depend on the concentration of the drops, the condition of the subject and the individual magnitude of responses to treatment. However, typical dosage ranges might be about 2 to 10 drops of 0.5% solution of active ingredient per day.

For a more detailed discussion of ophthalmic formulations, their preparation and administration, see Remington’s Pharmaceutical Sciences, 15th Ed., pages 1489-1504, (1975).

Testing

Ophthalmic formulations such as the solutions of the present invention are typically tested for physical stability, chemical stability, and preservative efficacy, both when they are first manufactured and after a fixed period of time (e.g., after two years). They are generally considered to be safe and clinically acceptable if proven to be well tolerated in the eye.

Physical stability is determined by observation of a solution after expiration of a fixed period of time. A solution is considered to be physically stable if its appearance (e.g., color and clarity) does not change and if the pH remains constant, within acceptable limits. Chemical stability involves a routine chemical analysis of the solution, to be sure that its active ingredient and the excipients have not changed after a fixed period of time.

Preservative efficacy is tested by the procedure described in the U.S. Pharmacopia Compendiary, whereby a

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EXAMPLES

The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as a limitation on the scope of the invention, but merely as being illustrative and representative thereof.

EXAMPLE 1

This example illustrates the preparation of a representative pharmaceutical formulation for ophthalmic administration containing the NSAID Ketorolac Tromethamine.

Ingredient

Ketorolac Tromethamine

BAC (50% aq. soln.)

Octoxynol 40 (70% aq. soln.)

EDTA Na₂

NaCl

Amount

0.50% wt/vol.

0.02% wt/vol.

0.01% wt/vol.

0.10% wt/vol.

0.79% wt/vol.

The above ingredients are mixed, adding purified water until they are dissolved, the pH is adjusted to 7.4^0.4 and the balance of the formulation is made up with purified water, adding a quantity sufficient to make 100% volume. The solution is then sterilized.

Other NSAIDs or their isomers, salts or esters, such as those described above, can be used as the active

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EXAMPLE 2

This example illustrates the preparation of a representative pharmaceutical formulation for ophthalmic administration containing the NSAID Ketorolac Tromethamine.

<td> Ingredient</td><td> Amount</td>

<td> Ketorolac Tromethamine</td><td> 0.50% wt/vol</td>

<td> BAC</td><td> 0.02% wt/vol</td>

<td> (50% aq. soln.)</td><td></td>

<td> Octoxynol 40</td><td> 0.02% wt/vol</td>

<td> (70% aq. soln.)</td><td></td>

<td> EDTA Na₂</td><td> 0.20% wt/vol</td>

<td> NaCl</td><td> 0.79% wt/vol</td>

The above ingredients are mixed, adding purified water until they are dissolved, the pH is adjusted to 7.4^0.4 and the balance of the formulation is made up with purified water, adding a quantity sufficient to make 100% volume. The solution is then sterilized.

Other NSAIDs or their isomers, salts or esters, such as those described above, can be used as the active compound in the preparation of the formulation of this example.

EXAMPLE 3

This example illustrates the preparation of a representative pharmaceutical formulation for ophthalmic

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26280-FF administration containing the NSAID Ketorolac

Tromethamine.

<td> Ingredient</td><td> Amount</td>

<td> Ketorolac Tromethamine BAC (50% aq. soln.) Octoxynol 40</td><td> 0.10% wt/vol. 0.004% wt/vol. 0.004% wt/vol.</td>

<td> (70% aq. soln.) EDTA Na₂ NaCl</td><td> 0.05% wt/vol. 0.88% wt/vol.</td>

The above ingredients are mixed, adding purified water until they are dissolved, the pH is adjusted to 7.410.4 and the balance of the formulation is made up with purified water, adding a quantity sufficient to make 100% volume. The solution is then sterilized.

Other NSAIDs their isomers, salts or esters, such as those described above, can be used as the active compound in the preparation of the formulation of this example.

EXAMPLE 4

This example illustrates the preparation of a representative pharmaceutical formulation for ophthalmic administration containing the NSAID flurbiprofen sodium.

Ingredient

Flurbiprofen Sodium BAC (50% aq. soln.)

Octoxynol 40 (70% aq. soln.)

EDTA Na₂

NaCl

The above ingredients are

Amount

0.03% wt/vol.

0.02% wt/vol.

0.01% wt/vol.

0.10% wt/vol.

0.90% wt/vol.

mixed, adding purified

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7.410.4 and the balance of the formulation is made up with purified water, adding a quantity sufficient to make

100% volume. The solution is then sterilized.

Other ophthalmic drugs and NSAIDs, such as those described above, can be used as the active compound in the preparation of the formulation of this example.

EXAMPLE 5 10 ———

Physical stability of the formulations of the present invention is measured by preparing clear formulations, in the concentrations shown in the table below, sealing them in sterilized containers, and 15 observing the clarity of the solution after a period of one month and again after five months. Solutions that remain clear are considered stable in this procedure.

The formulations of the present invention have proven to be stable when tested in accordance with the 20 above procedure. Formulations using surfactants other than the nonionic surfactants of the invention did not remain clear and were not stable.

Three surfactants were evaluated for their ability to dissolve the ketorolac - benzalkonium chloride complex 25 and maintain a physically clear solution over an extended period of time. The three surfactants tested were: Octoxynol 40; Polysorbate 80 (Tween 80); and MyrJ 52 Two concentrations of each surfactant were incorporated into the ophthalmic formulation, and these were placed at 30 various temperatures for future visual observations.

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<td rowspan="2"></td><td rowspan="2"> Octo; 0.004%</td><td rowspan="2"> &lt;ynol 40 0.02%</td><td colspan="2"> Tween 80</td><td colspan="2"> Myrj 52</td>

<td> 0.0055%</td><td> 0.01%</td><td> 0.0015%</td><td> 0.01%</td>

<td> 1 month</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 60°C</td><td> clear</td><td> clear</td><td> clear</td><td> clear</td><td> clear</td><td> clear</td>

<td> 40°C</td><td> clear</td><td> clear</td><td> very</td><td> very</td><td> turbid</td><td> turbid</td>

<td></td><td></td><td></td><td> turbid</td><td> turbid</td><td></td><td></td>

<td> RT</td><td> clear</td><td> clear</td><td> turbid</td><td> turbid</td><td> clear</td><td> clear</td>

<td> 4-40°C</td><td> clear</td><td> clear</td><td> turbid</td><td> turbid</td><td> clear</td><td> clear</td>

month

<td> 60°C</td><td> clear</td><td> clear</td><td> clear</td><td> clear</td><td> clear</td><td> clear</td>

<td> 40°C</td><td> clear</td><td> clear</td><td> turbid</td><td> turbid</td><td> turbid</td><td> turbid</td>

<td> RT</td><td> clear</td><td> clear</td><td> turbid</td><td> turbid</td><td> turbid</td><td> turbid</td>

<td></td><td> At the</td><td> 5 month</td><td colspan="2"> time period it</td><td colspan="2"> was apparent that</td>

the Octoxynol 40 surfactant was superior to the other two surfactants. At 5 months, Tween 80 and Myrj 52 displayed turbidity when stored at RT. The presence of turbidity suggested the inability to solubilize a precipitate formation between the Ketorolac moiety and benzalkonium chloride.

A further study has shown a 2 year shelf life for the ophthalmic formulation. Precipitate formation and turbidity are not a problem with this formulation. Preservative efficacy is maintained throughout the 2 year shelf life.

EXAMPLE 6

Preservative efficacy of the formulations of the present invention is measured by preparing formulations, e.g., according to the foregoing Examples, and subjecting them to the U.S. Pharmacopia antimicrobial challenge.

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The formulations of the present invention demonstrate preservative efficacy when tested in accordance with the above procedure.

EXAMPLE 7

The objective of this clinical efficacy study was to compare the effectiveness and safety of ketorolac with a control solution in reducing inflammation following cataract removal and intraocular lens implantation. All patients underwent an extracapsular cataract extraction with intraocular lens implantation 1 day following initiation of treatment.

Ophthalmic examinations were performed preoperatively (within 3 weeks of surgery) and during the first week (postoperative days 1 to 3), second week (postoperative days 4 through 12), and third week (postoperative days 15 through 27) of treatment. Particular attention was given to signs and symptoms consistent with inflammation. Among the ocular characteristics assessed on a scale of none, mild, moderate, or severe were: lid edema, corneal edema, conjunctival injections, ciliary flush, and the presence of cells and flare in the anterior chamber.

Fluorophotometry: Anterior segment inflammation (i.e., iritis, cyclitis, iridocyclitis) is by definition a disruption of the blood-aqueous barrier. When inflammation is present, a careful slit lamp examination will reveal cells and flare within the anterior chamber of the eye. The clinical grading of cells and flare is a measure of degree of anterior segment inflammation; but consistent grading of these observations is difficult, even by experts.

Ocular fluorophotometry is based on the fact that the blood-aqueous barrier becomes permeable to

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The fluorophotometry data were analyzed using the Wilcoxon Rank Sum Test or analysis of variance (ANOVA) of rank-transformed data by calculating the percentage difference in fluorescein concentration between the patient’s two eyes, according to the formula:

Percent difference = [(fluorescein concentration of operated eye - fluorescein concentration of unoperated eye)/fluorescein concentration of unoperated eye] x 100.

This calculation allowed and corrected for any interpatient variation in the timing and concentration of fluorescein administered.

129 patients began treatment for 21 days with either ketorolac or vehicle. In this study, the ketorolac formulation used was that illustrated in Example 1 above. During the first week 118 patients and during the second week 110 patients were evaluated for postoperative inflammation with ophthalmic examinations and fluorophotometry. During the third week, 83 patients were evaluated with ophthalmic examinations alone. At 2 weeks ketorolac provide significantly greater anti-inflammatory activity than the vehicle as measured

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26280-FF by fluorophotometry (p = 0.019). When patients were excluded who had greater than 40% difference in fluorescein concentration between eyes at baseline, the p-value during week 2 rose to 0.06. In addition, the vehicle-treated patients had more ocular inflammation seen on slit lamp examination, e.g., eyelid edema (p = 0.001), conjunctival injection (p = 0.001), and Descemet folds (p = 0.002) than did the ketorolac-treated patients. Finally, there were significantly more complaints (p = 0.01) and more severe complaints consistent with ocular inflammation (photophobia, iritis, conjunctival injection) in the vehicle-treated group than in the ketorolac-treated group.

In summary, ketorolac solutions proved significantly superior to vehicle in treating postoperative inflammation as quantitated by fluorophotometry, by routine slit lamp examination, by patients having fewer and milder adverse events, and by infrequent need of additional corticosteroid therapy to control inflammation.

EXAMPLE 8

This was a double-blind, parallel comparison with vehicle to evaluate the efficacy of ketorolac 0.5% ophthalmic solution in reducing signs and symptoms of allergic conjunctivitis. Ketorolac 0.5% solution or a vehicle solution of the same pH and tonicity were instilled four times daily into the eyes of patients with allergic conjunctivitis (ocular itching with and without eosinophils seen on conjunctival scrapings) for 7 days.

Thirty patients with allergic conjunctivitis participated in the study. Following admission to the study, patients reported to the investigator for baseline, mid-week, and final one-week examinations. At each of these visits, patients received ophthalmic

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26280-FF examinations (visual acuity, external eye exam using slit lamp biomicroscopy, measurement of intraocular pressure and undilated ophthalmoscopic examination). Laboratory tests included a conjunctival scraping performed at baseline and the final exam.

All patients completed the study. There were no adverse events or toxicities in patients treated with vehicle while stinging on one occasion was reported from ketorolac 0.5% ophthalmic solution. Ketorolac treatment was associated with a decrease in free eosinophilic granules as compared to vehicle (p = 0.025 Fisher's Exact Test, two-tailed).

The results of this study show that ketorolac 0.5% ophthalmic solution applied four times daily for seven days produces a decrease in eosinophilic granules as compared to vehicle in the treatment of allergic conjunctivitis.

EXAMPLE 9

This study was a double-blind, paired comparison design trial to evaluate the tolerance of ketorolac 0.5% ophthalmic solution and its vehicle in 26 healthy subjects. Solutions were instilled three times daily for 21 days. Complete ophthalmic examinations were done pretreatment and on days 3, 10, 17, 24 (2 days after ending treatment), and 45 (23 days after ending treatment). No statistically significant difference in symptoms (burning, stinging, itchiness, scratchiness, photophobia) or signs (tearing, ocular discharge, conjunctival vasodilation, chemosis, keratitis, fluorescein staining, Rose Bengal staining) was found between ketorolac and vehicle.

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EXAMPLE 10

An ocular formulation containing 5 mg/ml ketorolac tromethamine was administered at a dose of 0.1 ml/eye every one-half hour for a total of 12 doses to both eyes of 6 New Zealand albino rabbits. The formulation contained benzalkonium chloride as the preservative system. Two additional groups of animals served as saline and vehicle controls, respectively.

Eyes were examined after the last dose was administered and on days 1, 2, 3, and 6 following dosing. Results indicated that no eye irritation or toxicity resulted from ketorolac tromethamine administration.

While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are Intended to be within the scope of the claims appended hereto.