CA2189424C

CA2189424C - Non-steroidal anti-inflammatory ophthalmic suspensions

Info

Publication number: CA2189424C
Application number: CA002189424A
Authority: CA
Inventors: Rajesh Patel; Lyle M. Bowman; Peng Shen
Original assignee: Insite Vision Inc
Current assignee: Sun Pharmaceutical Industries Inc
Priority date: 1994-05-24
Filing date: 1995-05-19
Publication date: 2007-04-10
Anticipated expiration: 2015-05-19
Also published as: AU695699B2; JP4158203B2; US6309630B1; JPH10500684A; WO1995031968A1; EP0764018A1; CA2189424A1; AU2552995A

Abstract

Topical ophthalmic formulations of non-steroidal anti-inflammatory agents, particularly diclofenac sodium, include an aqueous mixture of the agent in formulations with a pH and concentration of agent that maintains at least a therapeutic amount in suspension and a therapeutic amount in solution.

Description

NON-STEROIDAL ANTI-INFLAMMATORY
OPHTHALMIC SUSPENSIONS
BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to ophthalmic formulations and more particularly, ophthalmic formulations of non-steroidal anti-inflammatory agents, particularly diclofenac sodium.
Description of the Related Art Cyclooxygenase is essential in the biosynthesis of prostaglandins which have been shown in many animal models to be mediators of intraocular inflammation. Although sterioidal compounds have been used to treat such inflammation, non-steroidal anti-inflammatory agents, from the group of drugs 1S known as cyclooxygenase inhibitors, have been substituted for steroids because they have not shown the same propensity to produce side-effects in ocular tissues as ophthalmic steroids. Non-steroidal agents are also widely prescribed to reduce pain and inflammation in a wide number of tissues. When used as topical agents in the eye, they suppress inflammatory responses and to prevent particular side-effects of surgical trauma (on the pupil preventing surgical meiosis), fluid accumulating in the back of the eye after cataract surgery (post-surgical macular edema) and the appearance of inflammatory cells and vessel leakage in the anterior chamber. Topical application of non-steroidal anti-inflammatory agents in the eye also appears to relieve some of the itching due to allergic conjunctivitis.
Diclofenac sodium, suprofen, and flurbiprofin are non-steroidal anti-inflammatory agents that have been used for the treatment of postoperative inflammation in patients who have undergone cataract extraction.
Anti-inflammatory agents have in the past been administered in solutions at neutral pH. Injection of anti-inflammatory agents in the form of a suspension has also been proposed. Suspensions have been used for topical ophthalmic applications when the drug is not very soluble. However, when the W095131968 2 ~ g ~ ~ 2 ~~ PCT/US95/06192

-2-drug is soluble, at an acceptable pH, solutions are usually used to avoid potential irritation caused by the particles of a suspension. The following patents illustrate ophthalmic solutions containing non-steroidal anti-inflammatory agents, including diclofenac.
U.S. Patent No. 4,960,799 to Nagy concerns a storage stable aqueous solution of sodium ortho-(2,6-dichlorophenyl) aminophenylacetate acid, which is the chemical name for diclofenac sodium, for topical treatment of ocular inflammation. The solution taught by Nagy has a pH of about 7.0 to 7.8.
U.S. Patent No. 4,829,083 to Doulakas relates to stabilization of mercury-containing preservatives in liquid or gel ophthalmic medicaments with addition of 2-amino-2-hydroxymethyl-1, 3-propanediol or a homologue thereof.
U.S. Patent No. 4,829,088 to Doulakas also relates to an ophthalmic medicament containing diclofenac sodium in aqueous solution. The solution contains 2-amino-2-hydroxymethyl-1, 3-propanediol as a preservative.
U.S. Patent No. 5,110,493 to Cherng-Chyi et al. relates to ophthalmic non-steroidal anti-inflammatory drug formulations containing a quaternary ammonium preservative and a non-ionic surfactant.
Most non-steroidal anti-inflammatory agents, when used in a topical solution, however, sting upon placement in the eye. The transient burning and stinging causes tearing, which in turn, washes the drug away from the eye, resulting in reduced bioavailability of the drug. The conventional solutions of non-steroidal anti-inflammatory agents generally have a pH of 7.0 to about 8Ø
This pH level provides complete solubility of- the drug, thereby allowing for a high concentration of the drug to be immediately available to the cornea. The high concentration of the drug on the eye aggravates the burning and stinging effects of the drug.
The present invention provides topical ophthalmic formulations containing non-steroidal anti-inflammatory agents which reduce or eliminate the , stinging and burning experienced with solutions of anti-inflammatory agents.

-3-Formulations of the present invention may be useful for treatment of any condition that may be treated by a non-steroidal anti-inflammatory agent.
Accordingly, it is an object of the invention to provide novel topical ophthalmic formulations containing non-steroidal anti-inflammatory agents.
It is a further object of the invention to provide a novel method of treating the eye.
SUMMARY OF THE INVENTION
One embodiment of the present invention is a topical ophthalmic composition for treatment of the eye comprising an aqueous suspension of a non-steroidal anti-inflammatory agent, the composition having a pH and concentration of agent chosen to ensure that at least some of the agent is in suspension.
The present invention also provides a method for treating diseases of the eye, including inflammation, by topically applying such suspensions to eyes in need of treatment.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a composition for treating the eye topically comprising an aqueous mixture of a non-steroidal anti-inflammatory agent, wherein the composition has a pH of about 4.0 to about 8.0, preferably about 5.0 to about 6.8, and at least some of the agent is maintained as a reservoir established in suspension at the pH of the formulation. The amount established in suspension may vary depending on therapeutic needs but it will be at least an amount sufficient to have a therapeutic effect on the eye upon delayed release from the suspension over a period of time. A sufficient amount of agent will also be present in solution to have an immediate therapeutic effect upon topical ophthalmic application. Typically, about 80% to about 90% of the total agent contained in the mixture will be in suspension, but this may vary depending on how much of the agent is desired for delivery and the duration of delivery

-4-desired. The amount of therapeutic agent in suspension may, for instance, range from about 70% to about 99% or about 10% to about 99% by weight of the total , amount of agent contained in the mixture. The compositions will not, however, have 100% of the agent in suspension. Some amount will be in solution to provide the immediate therapeutic effect.
Compositions of the present invention may have a pH of about 4 to about 8 depending on the solubility characteristics of the agent. In a preferred embodiment where the diclofenac is the therapeutic agent, a preferred pH range is about 5.0 to about 6.8. The concentration of the agent and the pH of the composition will be selected to ensure that a sufficient amount of the therapeutic agent is in suspension to provide a therapeutic effect upon delayed delivery.
In this way, the portion of the agent in solution is immediately available for therapeutic effect while the portion in suspension serves as a reservoir and is released slowly over time.
The solubility of non-steroidal anti-inflammatory agents is pH
dependent, i.e., normally the higher the pH, the higher the solubility of the drug in the formulation. For-instance, below a pH of about 6.8, as in the present invention, a formulation containing 1% diclofenac sodium , has virtually all of the diclofenac in suspension. Formulating the composition as a suspension rather than as a solution inhibits immediate contact between the drug and tissues of the eye and in that way reduces the stinging and burning sensation experienced when a solution of such drugs places all of the drug in immediate contact with the ocular tissues.
As demonstrated by Tables 1, 2 and 3, the percentage of diclofenac sodium, suprofen, and flurbiprofen in suspension is dependent on concentration and pH. Thus, by providing at least some of the diclofenac in suspension, via pH
control, lower transient burning and stinging would be observed when administered to patients.

WO 95/31968 218 9 4 2 4 PCT~595/06192

-5-Percent Diclofenac Sodium in Suspension Concentration pH of Diclofenac Sodium in the Formulation .001 .Ol .1 1.0 3.7 100 100 100 100 4.0 99 99 99 99 4.6 90 99 99 99 5.2 20 92 99 99 5.9 0 50 95 99

6.3 0 0 76 98 6.5 0 0 35 93

7.3 0 0 0 64 PercentSuprofen m Suspension Concentration pH of Suprofen in the Formulation .001 .Ol .1 1.0 5.0 4.0 0 0 77 98 99 5.0 0 0 45 95 gg 6.0 0 0 0 54 95 7.0 0 0 0 0 68 Percent Flurbiprofen in Suspension Concentration of Flurbiprofen in the Formulation pH .001 .Ol .1 1.0 5.0 4.0 20 92 99 99 99 5.0 0 33 93 99 99 6.0 0 0 0 80 98 7.0 0 0 0 24 92 The various non-steroidal anti-inflammatory drugs have different solubilities at a given pH. These differences in solubility are known or can be ascertained with techniques familiar to those of ordinary skill in the art.
The amount of non-steroidal anti-inflammatory agent in suspension for use in the present compositions will therefore vary depending, for example, on the specific agent or drug chosen, the dosage required, the desired release profile (the degree of sustained release), the condition for which the drug is administered and the pH
of the composition. Generally, however, it is preferred to have formulations with about 70% - 99% of the total hISAI in suspension although other amounts may be used (such as 10% - 99%), so long as at least some of the agent is in suspension;
that is an amount sufficient to have a therapeutic effect during delayed release.
As previously explained, a therapeutic amount must also be in solution. The total amount of therapeutic agent, or drug, is present in the composition in an amount effective to treat the selected target condition. For inflammation of the eye, the concentration will generally be about 0.001 to about 5.0% by weight of the composition. Preferably, the drug is about 0.005 to about 3.0% by weight of the composition, and more preferably about 0.1 to about 1.0% by weight of said composition. These same ranges of drug concentrations are believed to be

8 218 9 4 2 4 pCTIUS95/06192 appropriate for treating a wide range of conditions that require therapeutic treatment as well as inflammation.
Non-steroidal anti-inflammatory agents as used herein are intended to mean any non-narcotic analgesic/non-steroidal anti-inflammatory compound useful as a cyclooxygenase inhibitor. Preferably the non-steroidal anti-inflammatory agent is one or more of the following: aspirin, benoxaprofen, benzofenac, bucloxic acid, butibufen, carprofen, cicloprofen, cinxnetacin, clidanac, clopirac, diclofenac, etodolac, fenbufen, fenclofenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, flurbiprofen, furobufen, furofenac, ibuprofen, ibufenac, indomethacin, indoprofen, isoxepac, ketroprofen, lactorolac, lonazolac, metiazinic, miroprofen, naproxen, oxaprozin, oxepinac, phenacetin, pirprofen, pirazolac, protizinic acid, sulindac, suprofen, tiaprofenic acid, tolmetin, and zomepirac. Preferably, the agent is selected from the group consisting of diclofenac, suprofen, and flurbiprofen sodium and mixtures thereof.
More preferably, the non-steroidal anti-inflammatory agent is diclofenac sodium.

The pH and concentration of the agent in the formulation are selected to provide sufficient drug in solution to begin effective therapeutic treatment but at least some in suspension to serve as a depot for the agent which delays release of that agent over time. The pH of the aqueous mixture may be about 4.0 to about 8.0 and preferably, about 5.0 to about 6.8, but at a level sufficient to establish the desired suspension amount of non-steroidal anti-inflammatory agent.

The composition may be formulated as an aqueous suspension.
The composition may contain water soluble polymers or water insoluble polymers as the suspending agent. Examples of such soluble polymers are cellulosic polymers like hydroxypropyl methylcellulose. Water insoluble polymers are preferably crosslinked carboxy-vinyl polymers. It is important to note, however, that the present invention requires the drug to be in suspension without reference to whether the polymer is or is not in suspension.

A preferred form of the invention incorporates insoluble polymers to provide a gel or liquid drops which release the drug over time. Preferably, the polymer is about 0.1 to about 6.5%, more preferably about 1.0 to about 1.3% by weight based on the total weight of the suspension of a crosslinked carboxy-containing polymer. Suitable carboxy-containing polymers for use in the present invention and method for making them are described in U.S. Patent No.
5,192,535 to Davis et al. These polymer carriers include lightly crosslinked carboxy-containing polymers (such as polycarbophil, or Carbopols~), dextran, cellulose derivatives, polyethylene glycol 400 and other polymeric demulcents such as polyvinylpyrolidone, polysaccaride gels and Gelrite~. A carboxy-containing polymer system known by the tradename DuraSite~, containing polycarbophil, is a sustained release topical ophthalmic delivery system that releases the drug at a controlled rate, may also be used.
Aqueous mixtures of this invention may also contain amounts of suspended lightly crosslinked polymer particles ranging from about 0.1% to about 6.5% by weight, and preferably from about 0.5% to about 4.5% by weight, based on the total weight of the aqueous suspension. They will preferably be prepared using pure, sterile water, preferably deionized or distilled, having no physiologically or ophthalmologically harmful constituents, and will be adjusted to a pH of from about 4.0 to about 6.8, and preferably from about 5.5 to about 6.5, using any physiologically and ophthalmologically acceptable pH adjusting acids, bases or buffers, e.g., acids such as acetic, boric, citric, lactic, phosphoric, hydrochloric, or the like, bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, THAM
(trishydroxymethylamino-methane), or the like and salts and buffers such as citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
When formulating the aqueous suspensions, their osmotic pressure (~t) may be adjusted to from about 10 milliosmolar (mOsM) to about 400 mOsM,

-9-using appropriate amounts of physiologically and ophthalmologically acceptable salts. Sodium chloride is preferred to approximate physiologic fluid, and amounts of sodium chloride ranging from about 0.01% to about 1% by weight, and preferably from about 0.05°!° to about 0.45% by weight, based on the total weight of the aqueous suspension, will give osmolalities within the above-stated ranges. Equivalent amounts of one or more salts made up of cations such as potassium, ammonium and the like and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium bisulfate, ammonium sulfate, and the like can also be used in addition to or instead of sodium chloride to achieve osmolalities within the above-stated ranges. Sugars like mannitol, dextrose, glucose or other polyols may be added to adjust osmolarity.
The amounts of insoluble lightly crosslinked polymer particles, the pH, and the osmotic pressure chosen from within the above-stated ranges will be correlated with each other and with the degree of crosslinking to give aqueous suspensions having viscosities ranging from about 500 to about 100,000 centipoise, and preferably from about 5,000 to about 30,000 or about 5,000 to about 20,000 centipoise, as measured at room temperature (about 25°C) using a BrookfieldTM Digital LVT Viscometer equipped with a number 25 spindle and a small sample adapter at 12 rpm. Formulations of the present invention should have a viscosity that is suited for the selected route of administration.
Viscosity up to about 30,000 = drop. About 30,000 to about 100,000 centipoise is an advantageous viscosity range for ophthalmic administration in ribbon form.
When water soluble polymers are used, such as hydroxypropyl methylcellulose, the viscosity will typically be about 10 to about 400 centipoises, more typically about 10 to about 200 centipoises or about 10 to about 25 centipoises.
The composition of the present invention will ordinarily contain surfactants and, if desired, adjuvants, including additional medicaments, buffers, antioxidants, tonicity adjusters, preservatives, thickeners or viscosity modifiers, W0 95131968 , PCTIUS95106192 1

-10-and the like. Additives in the formulation may desirably include sodium chloride, EDTA (disodium edetate), and/or BAK (benzalkonium chloride) or sorbic acid.
Non-steroidal anti-inflammatory agents are non-steroidal substances used in treating or ameliorating a disease or medical condition.
They include drugs intended to treat therapeutically conditions of the eye itself or the tissue surrounding the eye and drugs administered via the ophthalmic route to treat therapeutically a local condition other than that involving the eye. The ophthalmic medicaments will typically be incorporated in the topical delivery systems of this invention in therapeutically active amounts comparable to amounts administered in other dosage forms, usually in amounts ranging from about 0.001% to about 5% by weight, and preferably from about 0.1% to about 1%
by weight, based on the total weight of the formulation. Thus, for example, about 0.1% to about 1.0% by weight of the anti-inflammatory non-steroidal compound can be administered to the eye in this manner.
The viscous gels that result from fluid eyedrops delivered by means of the aqueous suspensions of this invention typically have residence times in the eye ranging from about 2 to about 12 hours, e.g., from about 3 to about 6 hours.
The agents contained in these drug delivery systems will be released from the gels at rates that depend on such factors as the drug itself and its physical form, the extent of drug loading and the pH of the system, as well as on any drug delivery adjuvants, such as ion exchange resins compatible with the ocular surface, which may also be present. Preferably, the aqueous suspensions provide sustained concentration of the non-steroidal anti-inflammatory agent of between 10'$~and 10''l M, and more preferably between 10-~ and 10~ M, in the aqueous or treated tissue of the eye for at least two hours, preferably at least three hours.
Ophthalmic suspensions of the present invenrion may be formulated so that they retain the same or substantially the same viscosity in the eye that they had prior to administration to the eye. Alternatively, ophthalmic suspensions of ~e present invention may be formulated so that there is increased gelation upon

-11-contact with tear fluid. For instance, when a formulation containing DuraSite~
is administered to the eye at a lower pH, the DuraSite~ system swells upon contact with tears. This gelation or increase in gelation leads to entrapment of the ' suspended drug particles, thereby extending the residence time of the composition in the eye. The drug is released slowly as the suspended particles dissolve over time as the solubility of the drug is higher in the tear fluid.
All these events eventually lead to increased patient comfort, increase in the time the drug is in contact with the eye tissues, thereby increasing the extent of drug absorption and duration of action of the formulation in the eye.
Although described above in the context of viscous aqueous polymeric suspensions containing non-steroidal anti-inflammatory in solution and in suspension, the compositions of this invention can be formulated in any other suitable manner. For example, diclofenac sodium may be dissolved and added by sterile filtration to a preparation containing sodium chloride, hydroxypropyl methyl cellulose and surfactant. This mixture may then be adjusted to the appropriate pH by known techniques, for example by the addition of sodium hydroxide. Other methods will be apparent to one skilled in the art.
In general, ophthalmic formulations suitable for topical ophthalmic administration may be formulated and administered in accordance with techniques familiar to persons skilled in the art. The finished formulations are preferably stored in opaque or brown containers to protect them from light exposure, and under an inert atmosphere. These aqueous suspensions can be packaged in preservative-free, single-dose non-reclosable containers. This permits a single dose of the medicament to be delivered to the eye as a drop or ribbon, with the container then being discarded after use. Such containers eliminate the potential for preservative-related irritation and sensitization of the corneal epithelium, as has been observed to occur particularly from ophthalmic medicaments containing mercurial preservatives. Multiple dose containers can also be used, if desired, particularly since the relatively low viscosities of the aqueous suspensions of this invention permit constant, accurate dosages to be

- 12-administered dropwise to the eye as many times each day as necessary. In those suspension where preservatives are to be included, suitable preservatives are chlorobutanol, polyquat, benzalkonium chloride, cetyl bromide, sorbic acid and the like. ' In order that those skilled in the art can more fully appreciate aspects of this invention, the following Tables and examples are set forth.
These examples are given solely for purposes of illustration and should not be considered as expressing limitations.

COMPONENTS Example Example Example Example Example Didofenac 0.01 1.0 0.01 1.0 0.01 Sodium NoveonTM AA-1 - - 13 1.3 1.3 Hydroxypropyl 0.2 0.2 - - -Methylcellulose Edetate Sodium0.1 0.1 0.1 0.1 0.1 Sodium Chloride0.7 0.7 0.7 0.7 -M~tol - - - - -Dextrose - - - - 2.s o-Phosphoric - - - - -Acid Sodium Borate - - - - -PluronicTM 0-~ 0.2 0.05 0.2 0.05 Sodium q.s. to q.s. to q.s. to q.s. to q.s. to Hydroxide pH 6 pH 6 pH 6 pH 6 pH 6 Purified Waterq.s. to q.s. to q.s. to q.s. to q.s. to 100% 100% 100% 100% 100%

-13-TABLE 4 ( continued) COMPONENT'S Example Example Example Example Example Diclofenac 1.0 0.01 1.0 0.01 1.0 Sodium Noveon AA-1 1.3 1.3 1.3 1.3 1.3 Hydroxypropyl- - - -Methylcellulose Edetate Sodium0.1 0.1 0.1 0.1 0.1 Sodium Chloride- - - OS OS

Mannitol _ _ _ 1 .\ 1 Dextrose 2.8 - - _ _ o-Phosphoric - OS 0.5 - -Acid Sodium Borate- 0.5 0.5 - -Pluronic F1270.2 0.05 0.2 O.DS 0.2 Sodium q.s. to q.s. to q.s. to q.s. to q.s. to Hy~oxide pH 6 pH 6 pH 6 pH 6 pH 6 Purified Waterq.s. to q.s. to q.s. to q.s. to q.s. to 100% 100% 100% 100% 100%

COMPOSITION Example Example Example Example Suprofen 1.0 20 - _ Flurbiprofen - - 1.0 0.1 Sodium Noveon AA-1 1.3 L3 1.3 1.3 Edetate Sodium0.1 0.1 0.1 0.1 Sodium ChlorideOS 0.5 OS 0.5 Mannitol 1 1 1 1 Pluronic F127 0.2 0.05 02 0.05 Sodium Hydroxideq.s. to q.s. to q.s. to q.s. to pH 6 pH 6 pH 6 pH 6 Pied Water q.s. to q.s_ to q.s. to q.s. to 100% 100% I00ib 100%

2~8942~

-14-Epl~s 1-2 Hydroxypropylmethyl cellulose, sodium chloride, edetate sodium (EDTA), and surfactants are dissolved in a beaker containing approximately 1/3 ' of the final weight of water and stirred for 10 minutes with an overhead stirrer.
The solution is sterilized by autoclaving at 121 °C for 20 minutes.
Diclofenac sodium is dissolved separately in approximately 1/2 of the final weight of water and added by sterile filtration (.22 gm filter) and stirred for 10 minutes to form a mixture. The mixture is adjusted to pH 6.0 with lON sodium hydroxide, brought to final weight with water by sterile filtration and aseptically filled into unit-dose containers. The viscosity of compositions of Examples 1 and 2 will be about 10 up to about 200 centipoises, preferably about 10 to about 25 centipoises.
Example Noveon AA-1 is slowly dispersed into a beaker containing approximately 1/3 of the final weight of water and stirred for 1.5 hrs. with an overhead stirrer. Noveon AA-1 is an acrylic acid polymer available from B.F.
Goodrich. Edetate sodium (EDTA) and sodium chloride are then added to the polymer solution and stirred for 10 minutes after each addition. The polymer suspension is at a pH of about 3.0-3.5. The mixture is sterilized by autoclaving at 121°C for 20 minutes. Diclofenac sodium is dissolved separately in approximately 1/2 of the final weight of water, added to the polymer mixture by sterile filtration (0.22 ~m filter) and stirred for 10 minutes. The mixture is adjusted to pH 6.0 with lON sodium hydroxide, brought to final weight with water and surfactant by sterile filtration and aseptically filled into unit-dose containers.
Noveon AA-1 is slowly dispersed into a beaker containing approximately 1/3 of the final weight of water and stirred for 1.5 hrs. with an

-15-overhead stirrer. Noveon AA-1 is an acrylic acid polymer available from B.F.
Goodrich. Edetate sodium (EDTA) is then added to the polymer suspension and stirred for 10 minutes. The polymer suspension is at a pH of about 3.0-3.5.
The mixture is sterilized by autoclaving at 121 °C for 20 minutes. Dextrose is dissolved in 1/10 of the final weight of water and sterile filtered (0.22 ~m filter) in to the polymer suspension and stirred for 10 minutes. Diclofenac sodium is dissolved separately in approximately 1/2 of the final weight of water, added to the polymer mixture by sterile filtration and stirred for 10 minutes. The mixture is adjusted to pH 6.0 with lON sodium hydroxide, brought to final weight with wafer and surfactant by sterile filtration and aseptically filled into unit-dose containers.
Noveon AA-1 is slowly dispersed into a beaker containing approximately 1/3 of the final weight of water and stirred for 1.5 hrs. with an overhead stirrer. Noveon AA-1 is an acrylic acid polymer available from B.F.
Goodrich. Edetate sodium (EDTA), o-phosphoric acid, and sodium borate are then added to the polymer suspension and stirred for 10 minutes after each addition. The polymer solution is at a pH of about 3.0-3.5. The mixture is sterilized by autoclaving at 121° for 20 minutes. Didofenac sodium is dissolved separately in approximately 1/2 of the final weight of water, added to the polymer mixture by sterile filtration (0.22 llm filter) and stirred for 10 minutes.
The mixture is adjusted to pH 6.0 with lON sodium hydroxide, brought to final weight with water and surfactant by sterile filtration and aseptically filled into unit=dose containers.
< Ex~ In es 9-10 Noveon AA-1 is slowly dispersed into a beaker containing approximately 1/3 of the final weight of water and stirred for 1.5 hrs. with an

-16-overhead stirrer. Noveon AA-I is an acrylic acid polymer available from B.F.
Goodrich. Edetate sodium (EDTA), sodium chloride and mannitol are then added to the polymer suspension and stirred for 10 minutes after each addition. The polymer solution is at a pH of about 3.0-3.5. The mixture is sterilized by ' autoclaving at 121° for 20 minutes. Diclofenac sodium is dissolved separately in approximately 1 /2 of the final weight of water, added to the polymer mixture by sterile filtration (0.22 ~m filter) and stirred for 10 minutes. The mixture is adjusted to pH 6.0 with 10N sodium hydroxide, brought to final weight with water and surfactant by sterile filtration and aseptically filled into unit-dose containers.
Fxam~I_PS 1I-14 _ Noveon AA-1 is slowly dispersed into a beaker containing approximately 1/3 of the final weight of water and stirred for 1.5 hrs. with an overhead stirrer. Noveon AA-1 is an acrylic acid polymer available from B.F.
Goodrich. Edetate sodium (EDTA), sodium chloride and mannitol are then added to the polymer suspension and stirred for 10 minutes after each addition. The polymer solution is at a pI-i of about 3.0-3.5. The mixture is sterilized by autoclaving at 121° for 20 minutes. Suprofen or Flurbiprofen sodium is dissolved separately in approximately 1/2 of the final weight of water and the pH is adjusted to 7-8 with sodium hydroxide and it is then added to the polymer mixture by sterile filtration (0.22 ltm filter) and stirred for 10 minutes.
The mixture is adjusted to pH 6.0 with lON sodium hydroxide, brought to final weight with water and surfactant by sterile filtration and aspectically filled into unit-dose containers.
The above discussion of this invention is directed primarily to preferred embodiments and practices thereof. It will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts described herein can easily be made or may be learned by practice

-17-of the invention, without departing from the spirit and scope of the invention as defined by the following claims.

Claims

CLAIMS:

1. A composition for topical ophthalmic application comprising an aqueous preparation of a non-steroidal anti-inflammatory agent, said composition being formulated with a pH of from 4.0 to 6.8, having a portion of the non-steroidal anti-inflammatory agent in suspension and a therapeutic amount of the non-steroidal anti-inflammatory agent of the formulation in solution, wherein said non-steroidal anti-inflammatory agent is selected from the group con-sisting of aspirin.TM., benoxaprofen, benzofenac, bucloxic acid, butibufen, carprofen, ciclopro-fen, cinmetacin, clidanac, clopirac, etodolac, fenbufen, fenclofenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, flurbiprofen, furobufen, furofenac, ibuprofen, ibufenac, indoprofen, isoxepac, ketoprofen, lactorolac, lonazolac, metiazinic, miroprofen, naproxen, oxaprozin, oxepinac, phenacetin, pirprofen, pirazolac, protizinic acid, sulindac, suprofen, tiaprofenic acid, tolmetin, and zomepirac.

2. A composition as recited in claim 1, wherein said composition comprises from 0.001 to 5.0 % by weight of said non-steroidal anti-inflammatory agent.

3. A composition as recited in claim 1 or 2, wherein said non-steroidal anti-inflam-matory agent is selected from the group consisting of: aspirin.TM., benoxaprofen, benzofenac, bucloxic acid, butibufen, carprofen, cicloprofen, cinmetacin, clidanac, clopirac, etodolac, fenbufen, fenclofenac, fenclorac, fentiazac, flunoxaprofen, furaprofen, furobufen, furofenac, ibufenac, indoprofen, isoxepac, lactorolac, lonazolac, metiazinic, miroprofen, oxaprozin, oxepinac, phenacetin, pirprofen, pirazolac, protizinic acid, sulindac, tiaprofenic acid, and zomepirac.

4. A composition as recited in any one of claims 1 to 3, wherein the composition main-tains from 70% to 99% of said non-steroidal anti-inflammatory agent in suspension, and a therapeutic amount of the non-steroidal anti-inflammatory agent of the formulation in solution.

A composition as recited in any one of claims 1 to 4, wherein said composition further comprises a polymer suspending agent.

6. A composition according to claim 5, wherein said polymer is water soluble and the viscosity of the composition is from 10 to 400 centipoises.

7. A composition according to claim 5, wherein said polymer is water insoluble.

8. A composition as recited in claim 7, wherein said polymer is in an amount of about 0.1 to about 1.3% by weight of the suspension.

9. A composition according to claim 7, wherein said polymer is a lightly crosslinked carboxy-containing polymer.

10. A composition according to claim 9, having a viscosity of about 500 to about 100,000 centipoises.

11. A composition according to claim 9, having a viscosity up to about 30,000 centi-poises.

12. A composition according to claim 9, having a viscosity of about 5,000 to about 20,000 centipoises.

13. A composition according to claim 8, wherein said composition increases in gelation upon contact with tear fluid.

14. A composition according to any one of claims 1 to 13, that results in the sustained release of said non-steroidal anti-inflammatory agent over time.

15. A composition for topical treatment of the eye comprising: an aqueous suspension of a non-steroidal anti-inflammatory agent, said composition having a pH of about 4.0 to about 6.8, and containing from about 0.1% to about 6.5% by weight based on the total weight of the suspension of a crosslinked carboxyl-containing polymer, wherein 10% - 99%
of the non-steroidal anti-inflammatory agent is in suspension, and a therapeutic amount of the non-steroidal anti-inflammatory agent is in solution, and wherein said non-steroidal anti-inflam-matory agent is not indomethacin.

16. A composition according to claim 15, wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac, suprofen, flurbiprofen and mix-tures thereof.

17. A composition according to claim 16, wherein said non-steroidal anti-inflammatory agent is diclofenac.

18. A composition according to claim 17, wherein said diclofenac is present in an amount from about 0.1 to about 1.0% by weight of the composition.

19. A composition as recited in claim 15, wherein said polymer comprises from about 0.1 to about 1.3% by weight of the suspension of a polymeric suspending agent.

20. A composition according to claim 15, having a viscosity up to about 30,000 centi-poises.

21. A composition according to claim 15, having a viscosity of about 5,000 to about 20,000 centipoises.

22. A method for preparing a topical ophthalmic composition for use in the treatment of eye inflammation, said composition comprising an aqueous suspension of non-steroidal anti-inflammatory agent, the method involving formulating the composition at a pH
of from 4.0 to 6.8 and concentration of the non-steroidal anti-inflammatory agent of from 0.001 % to 5.0% by weight of the composition which maintains from 70% to 99% of the non-steroidal anti-inflammatory agent in suspension, and a therapeutic amount of the non-steroidal anti-inflammatory agent in solution, wherein said non-steroidal anti-inflammatory agent is not indomethacin.

23. A method for preparing a topical ophthalmic composition for use in the treatment of eye inflammation, said composition comprising an aqueous suspension of non-steroidal anti-inflammatory agent, the method involving formulating the composition at a pH
of from 4.0 to 6.8 and concentration of the non-steroidal anti-inflammatory agent of from 0.005% to 3.0% by weight of the composition which maintains from 70% to 99% of the non-steroidal anti-inflammatory agent in suspension, and a therapeutic amount of the non-steroidal anti-inflammatory agent in solution, wherein said non-steroidal anti-inflammatory agent is not indomethacin.

24. A method for preparing a topical ophthalmic composition for use in the treatment of eye inflammation, said composition comprising an aqueous suspension of non-steroidal anti-inflammatory agent, the method involving formulating the composition at a pH
of from 5.0 to 6.8 and concentration of the non-steroidal anti-inflammatory agent of from 0.001 % to 5.0% by weight of the composition which maintains from 70% to 99% of the non-steroidal anti-inflammatory agent in suspension, and a therapeutic amount of the non-steroidal anti-inflammatory agent in solution, wherein said non-steroidal anti-inflammatory agent is not indomethacin.

25. A method for preparing a topical ophthalmic composition for use in the treatment of eye inflammation, said composition comprising an aqueous suspension of a non-steroidal anti-inflammatory agent, the method involving formulating the composition at a pH of from 5.0 to 6.8 and a concentration of the non-steroidal anti-inflammatory agent of from 0.005%
to 3.0% by weight of the composition which maintains from 70% to 99% of the non-ster-oidal anti-inflammatory agent in suspension, and a therapeutic amount of the non-steroidal anti-inflammatory agent in solution, wherein said non-steroidal anti-inflammatory agent is not indomethacin.

26. A method for preparing a topical ophthalmic composition for use in the treatment of eye inflammation, said composition comprising an aqueous suspension of diclofenac, the method involving formulating the composition at a pH of from 5.0 to 6.8 and a concentration of diclofenac of from 0.001 % to 5.0% by weight of the composition which maintains from 70% to 99% of diclofenac in suspension, and a therapeutic amount of diclofenac in solution.

27. A method for preparing a topical ophthalmic composition for use in the treatment of eye inflammation, said composition comprising an aqueous suspension of diclofenac, the method involving formulating the composition at a pH of from 5.0 to 6.8 and a concentration of diclofenac of from 0.1 to 1% by weight of the composition which maintains from 70% to 99% of diclofenac in suspension, and a therapeutic amount of diclofenac in solution.

28. A method according to any one of claims 22 to 25, wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of aspirin.TM., benoxaprofen, benzofenac, bucloxic acid, butibufen, carprofen, cicloprofen, cinmetacin, clidanac, clopirac, etodolac, fenbufen, fenclofenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, furobufen, furofenac, buprofen, ibufenac, indoprofen, isoxepac, ketroprofen, lactorolac, lonazolac, metiazinic, miroprofen, naproxen, oxaprozin, oxepinac, phenacetin, pirprofen, pirazolac, protizinic acid, sulindac, tiaprofenic acid, tolmetin, zomepirac and mixtures thereof.

29. A method according to any one of claims 22 to 25, wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of aspirin.TM., benoxaprofen, benzofenac, bucloxic acid, butibufen, carprofen, cicloprofen, cinmetacin, clidanac, clopirac, etodolac, fenbufen, fenclofenac, fenclorac, fentiazac, flunoxaprofen, furaprofen, furobufen, furofenac, ibufenac, indoprofen, isoxepac, lactorolac, lonazolac, metiazinic, miroprofen, oxaprozin, oxepinac, phenacetin, pirprofen, pirazolac, protizinic acid, sulindac, tiaprofenic acid and zomepirac.

30. A method according to any one of claims 22 to 25, wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac, suprofen, flurbi-profen and mixtures thereof.

31. A method according to any one of claims 22 to 25, wherein the non-steroidal anti-inflammatory agent is diclofenac.

32. Use of a topical ophthalmic composition in the treatment of eye inflammation, the composition comprising an aqueous suspension of a non-steroidal anti-inflammatory agent and being formulated with a pH of from 4.0 to 6.8 and a concentration of the non-steroidal anti-inflammatory agent of from 0.001 to 5.0% by weight of the composition which main-tains from 70% to 99% of tile non-steroidal anti-inflammatory agent in suspension, and a therapeutic amount of the non-steroidal anti-inflammatory agent in solution, wherein said non-steroidal anti-inflammatory agent is not indomethacin.

33. Use of a topical ophthalmic composition in the treatment of eye in inflammation, the composition comprising an aqueous suspension of a non-steroidal anti-inflammatory agent and being formulated with a pH of from 5.0 to 6.8 and a concentration of the non-steroidal anti-inflammatory agent of from 0.005 to 3.0% by weight of the composition which main-tains from 70% to 99% of the non-steroidal anti-inflammatory agent in suspension, and a therapeutic amount of the non-steroidal anti-inflammatory agent in solution, wherein said non-steroidal anti-inflammatory agent is not indomethacin.

34. Use of topical ophthalmic composition in the treatment of eye inflammation, the composition comprising an aqueous suspension of diclofenac and being formulated with a pH of from 4.0 to 6.8 and a concentration of diclofenac of from 0.001 to 5% by weight of the composition which maintains from 70% to 99% of diclofenac in suspension, and a therapeu-tic amount of diclofenac in solution.

35. Use of a topical ophthalmic composition in the treatment of eye inflammation, the composition comprising an aqueous suspension of diclofenac and being formulated with a pH of form 5.0 to 6.8 and a concentration of diclofenac of from 0.1 to 1 % by weight of the composition which maintains from 70% to 99% of diclofenac in suspension, and a therapeu-tic amount of diclofenac in solution.

36. Use according to claim 32 or 33, wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of aspirin.TM., benoxaprofen, benzofenac, bucloxic acid, butibufen, carprofen, cicloprofen, cinmetacin, clidanac, clopirac, etodolac, fenbufen, fenclo-fenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, furobufen, furofenac, ibuprofen, ibufenac, indoprofen, isoxepac, ketoprofen, lactorolac, lonazolac, metiazinic, miroprofen, naproxen, oxaprozin, oxepinac, phenacetin, pirprofen, pirazolac, protizinic acid, sulindac, tiaprofenic acid, tolmetin, and zomepirac.

37. Use according to claim 32 or 33, wherein the non-steroidal anti-inflammatory agent comprises more than one of: aspirin TM, benoxaprofen, benzofenac, bucloxic acid, butibufen, carprofen, cicloprofen, cinmetacip, clidanac, clopirac, diclofenac, etodolac, fenbufen, fenclo-fenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, flurbiprofen, furobufen, furofenac, ibuprofen, ibufenac, indoprofen, isoxepac, ketoprofen, lactorolac, lonazolac, metiazinic, miroprofen, naproxen, oxaprozin, oxepinac, phenacetin, pirprofen, pirazolac, protizinic acid, sulindac, suprofen, tiaprofenic acid, tolmetin and zomepirac.

38. Use according to claim 32 or 33, wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac, suprofen, flurbiprofen and mixtures thereof.

39. Use according to claim 32 or 33, wherein the non-steroidal anti-inflammatory agent is diclofenac, and wherein said diclofenac is present from 0.1 to 1% by weight of the composition.

40. A composition for topical treatment of the eye comprising: an aqueous suspension of a non-steroidal anti-inflammatory agent, said composition having a pH of about 4.0 to about 6.8, wherein 10% - 99% of the non-steroidal anti-inflammatory agent is in suspension, and a therapeutic amount of the non-steroidal anti-inflammatory agent is in solution, and wherein said non-steroidal anti-inflammatory agent is not indomethacin.

41. A composition according to claim 40 wherein said pH is from 5.0 to 6.8.

42. A composition according to claim 41, wherein said non-steroidal anti-inflammatory agent is diclofenac, suprofen, or flurbiprofen.