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USOO630963OB1 (12) United States Patent (10) Patent No.: US 6,309,630 B1 Patel et al. (45) Date of Patent: Oct. 30, 2001

(54) NON-STEROIDAL ANTI-INFLAMMATORY 5,296,228 3/1994 Chang et al...... 424/422 OPHTHALMC SUSPENSIONS 5,340,572 8/1994 Patel et al...... 514/913 (75) Inventors: Rajesh Patel, San Mateo; Lyle M. FOREIGN PATENT DOCUMENTS Bowman, Pleasanton; Peng Shen, 2839752 * 10/1979 (DE). Hayward, all of CA (US) 58-174310 1/1984 (JP). 58-174309 1/1994 (JP). (73) Assignee: Insite Vision Incorporated, Alameda, WO 94/10976 5/1994 (WO). CA (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Weisweiler, P.S. et al., Comparative Comfort of patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. Solution and Indomethacin Suspension Eyedrops, J. Clinical Res. & Drug Dev. 2: 233-239 (Dec. 1988). Vulovic, N. et al. Some Studies into the Properties of (21) Appl. No.: 08/248,500 Indomethacin Suspensions Intended for Ophthalmic Use, (22) Filed: May 24, 1994 Intl. J. of Pharmaceutics 55: 123-128 (Apr. 1989). (51) Int. Cl." ...... S61K 9/10 * cited by examiner (52) U.S. Cl...... 424/78.04 (58) Field of Search ...... 514/913; 424/78.04 Primary Examiner-Peter F. Kulkosky (74) Attorney, Agent, or Firm Arnold & Porter (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Compositions for topical ophthalmic application comprising 4,559,343 12/1985 Han et al...... 514/264 an aqueous mixture of a non-Steroidal anti-inflammatory 4,829,083 5/1989 Doulakas ...... 514/496 agent. The compositions are formulated with a pH and 4,829,088 5/1989 Doulakas ...... 514/567 concentration of agent chosen to maintain at least Some of 4,960,799 10/1990 Nagy ...... 514/567 5,110,493 5/1992 Chering-Chyi et al. ... 514/413 the therapeutic agent of the formulation in Suspension. 5,171,566 * 12/1992 Mizushima et al...... 424/78.04 5,192,535 3/1993 Davis et al...... 424/78.04 23 Claims, No Drawings US 6,309,630 B1 1 2 NON-STEROIDAL ANTI-NFLAMMATORY Most non-Steroidal anti-inflammatory agents, when used OPHTHALMC SUSPENSIONS in a topical Solution, however, Sting upon placement in the BACKGROUND OF THE INVENTION eye. The transient burning and Stinging causes tearing, 1. Field of the Invention which in turn, washes the drug away from the eye, resulting The present invention relates to ophthalmic formulations in reduced bioavailability of the drug. The conventional and more particularly, ophthalmic formulations of nonste Solutions of non-Steroidal anti-inflammatory agents gener roidal anti-inflammatory agents, particularly ally have a pH of 7.0 to about 8.0. This pH level provides Sodium. complete Solubility of the drug, thereby allowing for a high 2. Description of the Related Art 1O concentration of the drug to be immediately available to the cornea. The high concentration of the drug on the eye is essential in the biosynthesis of proS aggravates the burning and Stinging effects of the drug. taglandins which have been shown in many animal models to be mediators of intraocular inflammation. Although Ste The present invention provides topical ophthalmic for mulations containing non-Steroidal anti-inflammatory rioidal compounds have been used to treat Such 15 inflammation, non-Steroidal anti-inflammatory agents, from agents which reduce or eliminate the Stinging and burning the group of drugs known as cyclooxygenase inhibitors, experienced with Solutions of anti-inflammatory agents. have been substituted for steroids because they have not Formulations of the present invention may be useful for shown the same propensity to produce Side-effects in ocular treatment of any condition that may be treated by a non tissueS as ophthalmic Steroids. Non-Steroidal agents are also Steroidal anti-inflammatory agent. widely prescribed to reduce pain and inflammation in a wide Accordingly, it is an object of the invention to provide number of tissues. When used as topical agents in the eye, novel topical ophthalmic formulations containing non they Suppress inflammatory responses and to prevent par Steroidal anti-inflammatory agents. ticular side-effects of Surgical trauma (on the pupil prevent 25 It is a further object of the invention to provide a novel ing Surgical meiosis), fluid accumulating in the back of the method of treating the eye. eye after cataract Surgery (post-Surgical macular edema) and the appearance of inflammatory cells and vessel leakage in SUMMARY OF THE INVENTION the anterior chamber. Topical application of non-Steroidal One embodiment of the present invention is a topical anti-inflammatory agents in the eye also appears to relieve ophthalmic composition for treatment of the eye comprising Some of the itching due to allergic conjunctivitis. Diclofenac an aqueous Suspension of a non-Steroidal anti-inflammatory Sodium, , and flurbiprofin are non-Steroidal anti agent, the composition having a pH and concentration of inflammatory agents that have been used for the treatment of agent chosen to ensure that at least Some of the agent is in postoperative inflammation in patients who have undergone 35 Suspension. cataract extraction. The present invention also provides a method for treating Anti-inflammatory agents have in the past been adminis diseases of the eye, including inflammation, by topically tered in Solutions at neutral pH. Injection of anti applying Such Suspensions to eyes in need of treatment. inflammatory agents in the form of a Suspension has also been proposed. Suspensions have been used for topical 40 DETAILED DESCRIPTION OF THE ophthalmic applications when the drug is not very Soluble. INVENTION However, when the drug is Soluble, at an acceptable pH, The present invention provides a composition for treating Solutions are usually used to avoid potential irritation caused the eye topically comprising an aqueous mixture of a by the particles of a Suspension. The following patents 45 non-Steroidal anti-inflammatory agent, wherein the compo illustrate ophthalmic Solutions containing non-Steroidal anti sition has a pH of about 4.0 to about 8.0, preferably about inflammatory agents, including diclofenac. 5.0 to about 6.8, and at least Some of the agent is maintained U.S. Pat. No. 4,960,799 to Nagy concerns a storage stable as a reservoir established in Suspension at the pH of the aqueous Solution of Sodium ortho-(2,6-dichlorophenyl) formulation. The amount established in Suspension may aminophenylacetate acid, which is the chemical name for 50 vary depending on therapeutic needs but it will be at least an diclofenac Sodium, for topical treatment of ocular inflam amount Sufficient to have a therapeutic effect on the eye mation. The solution taught by Nagy has a pH of about 7.0 upon delayed release from the Suspension over a period of to 7.8. time. A Sufficient amount of agent will also be present in U.S. Pat. No. 4,829,083 to Doulakas relates to stabiliza 55 Solution to have an immediate therapeutic effect upon topi tion of mercury-containing preservatives in liquid or gel cal ophthalmic application. Typically, about 80% to about ophthalmic medicaments with addition of 2-amino-2- 90% of the total agent contained in the mixture will be in hydroxymethyl-1,3-propanediol or a homologue thereof. Suspension, but this may vary depending on how much of U.S. Pat. No. 4,829,088 to Doulakas also relates to an the agent is desired for delivery and the duration of delivery ophthalmic medicament containing diclofenac Sodium in 60 desired. The amount of therapeutic agent in Suspension may, aqueous Solution. The Solution contains 2-amino-2- for instance, range from about 70% to about 99% or about hydroxymethyl-1,3-propanediol as a preservative. 10% to about 99% by weight of the total amount of agent U.S. Pat. No. 5,110,493 to Cherng-Chyi et al. relates to contained in the mixture. The compositions will not, ophthalmic non-Steroidal anti-inflammatory drug formula 65 however, have 100% of the agent in Suspension. Some tions containing a quaternary ammonium preservative and a amount will be in solution to provide the immediate thera non-ionic Surfactant. peutic effect. US 6,309,630 B1 3 4 Compositions of the present invention may have a pH of about 4 to about 8 depending on the Solubility characteristics TABLE 3 of the agent. In a preferred embodiment where diclofenac is Percent Flurbiprofen in Suspension the therapeutic agent, a preferred pH range is about 5.0 to Concentration of about 6.8. The concentration of the agent and the pH of the Flurbiprofen in composition will be Selected to ensure that a Sufficient the Formulation amount of the therapeutic agent is in Suspension to provide pH OO1 O1 .1 1.O 5.0 a therapeutic effect upon delayed deliver. In this way, the 4.0 2O 92 99 99 99 portion of the agent in Solution is immediately available for 5.0 O 33 93 99 99 therapeutic effect while the portion in Suspension Serves as 6.O O O O 8O 98 a reservoir and is released slowly over time. 7.0 O O O 24 92

15 The various non-Steroidal anti-inflammatory drugs have The Solubility of non-Steroidal anti-inflammatory agents different solubilities at a given pH. These differences in is pH dependent, i.e., normally the higher the pH, the higher Solubility are known or can be ascertained with techniques the solubility of the drug in the formulation. For instance, familiar to those of ordinary skill in the art. The amount of below a pH of about 6.8, as in the present invention, a non-Steroidal anti-inflammatory agent in Suspension for use formulation containing 1% diclofenac Sodium, has virtually in the present compositions will therefore vary depending, all of the diclofenac in Suspension. Formulating the com for example, on the Specific agent or drug chosen, the dosage required, the desired release profile (the degree of Sustained position as a Suspension rather than as a Solution inhibits release), the condition for which the drug is administered immediate contact between the drug and tissues of the eye and the pH of the composition. Generally, however, it is and in that way reduces the Stinging and burning Sensation 25 preferred to have formulations with about 70%-99% of the experienced when a Solution of Such drugs places all of the total NSAI in Suspension although other amounts may be drug in immediate contact with the ocular tissues. used (such as 10%-99%), so long as at least some of the agent is in Suspension; that is an amount Sufficient to have AS demonstrated by Tables 1, 2 and 3, the percentage of a therapeutic effect during delayed release. AS previously explained, a therapeutic amount must also be in Solution. diclofenac Sodium, Suprofen, and flurbiprofen in Suspension The total amount of therapeutic agent, or drug, is present in is dependent on concentration and pH. Thus, by providing at the composition in an amount effective to treat the Selected least Some of the diclofenac in Suspension, via pH control, target condition. For inflammation of the eye, the concen lower transient burning and Stinging would be observed tration will generally be about 0.001 to about 5.0% by when administered to patients. 35 weight of the composition. Preferably, the drug is about 0.005 to about 3.0% by weight of the composition, and more TABLE 1. preferably about 0.1 to about 1.0% by weight of said Percent Diclofenac Sodium in Suspension composition. These same ranges of drug concentrations are 40 believed to be appropriate for treating a wide range of Concentration of conditions that require therapeutic treatment as well as Diclofenac Sodium inflammation. in the Formulation Non-Steroidal anti-inflammatory agents as used herein are pH OO1 O1 .1 1.O intended to mean any non-narcotic analgesic/nonsteroidal 3.7 1OO 1OO 1OO 1OO 45 anti-inflammatory compound useful as a cyclooxygenase 4.0 99 99 99 99 inhibitor. Preferably the non-steroidal anti-inflammatory 4.6 90 99 99 99 agent is one or more of to the following: , 5.2 2O 92 99 99 5.9 O 50 95 99 , benzofenac, bucloxic acid, butibufen, 6.3 O O 76 98 , cicloprofen, cinmetacin, clidanac, clopirac, 6.5 O O 35 93 50 diclofenac, , , , fenclorac, 7.3 O O O 64 , fentia Zac, , fura profen, flurbiprofen, furobufen, furofenac, , ibufenac, indomethacin, , isoxepac, ketroprofen, lactorolac, TABLE 2 lonazolac, metiaZinic, , , , 55 OXepinac, , , piraZolac, protizinic acid, Percent Suprofen in Suspension , Suprofen, , , and Zomepi Concentration of rac. Preferably, the agent is Selected from the group con Suprofen in Sisting of diclofenac, Suprofen, and flurbiprofen Sodium and the Formulation 60 mixtures thereof. More preferably, the non-steroidal anti pH OO1 O1 .1 1.O 5.0 inflammatory agent is diclofenac Sodium. 4.0 O O 77 98 99 The pH and concentration of the agent in the formulation 5.0 O O 45 95 99 are Selected to provide Sufficient drug in Solution to begin 6.O O O O 54 95 effective therapeutic treatment but at least Some in Suspen 7.0 O O O O 68 65 Sion 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 US 6,309,630 B1 S 6 6.8, but at a level Sufficient to establish the desired suspen can also be used in addition to or instead of Sodium chloride Sion amount of non-Steroidal anti-inflammatory agent. to achieve OSmolalities within the above-Stated ranges. Sug The composition may be formulated as an aqueous SuS ars like mannitol, dextrose, glucose or other polyols may be pension. The composition may contain water Soluble poly added to adjust OSmolarity. merS or water insoluble polymers as the Suspending agent. The amounts of insoluble lightly crosslinked polymer Examples of Such Soluble polymers are cellulosic polymers particles, the pH, and the osmotic preSSure chosen from like hydroxypropyl methylcellulose. Water insoluble poly within the above-stated ranges will be correlated with each mers are preferably crosslinked carboxy-Vinyl polymers. It other and with the degree of crosslinking to give acqueous is important to note, however, that the present invention Suspensions having Viscosities ranging from about 500 to requires the drug to be in Suspension without reference to about 100,000 centipoise, and preferably from about 5,000 whether the polymer is or is not in Suspension. to about 30,000 or about 5,000 to about 20,000 centipoise, A preferred form of the invention incorporates insoluble as measured at room temperature (about 25 C.) using a polymers to provide a gel or liquid drops which release the Brookfield Digital LVT Viscometer equipped with a number drug over time. Preferably, the polymer is about 0.1 to about 15 25 Spindle and a 13R Small Sample adapter at 12 rpm. 6.5%, more preferably about 1.0 to about 1.3% by weight Formulations of the present invention should have a ViscoS based on the total weight of the Suspension of a crosslinked ity that is Suited for the Selected route of administration. carboxy-containing polymer. Suitable carboxy-containing Viscosity up to about 30,000-drop. About 30,000 to about polymers for use in the present invention and method for 100,000 centipoise is an advantageous Viscosity range for making them are described in U.S. Pat. No. 5,192,535 to ophthalmic administration in ribbon form. Davis et al. which is hereby incorporated by reference and When water soluble polymers are used, such as hydrox relied upon. These polymer carriers include lightly ypropyl methylcellulose, the Viscosity will typically be crosslinked carboxy-containing polymers (Such as about 10 to about 400 centipoises, more typically about 10 polycarbophil, or Carbopols(E), dextran, cellulose 25 to about 200 centipoises or about 10 to about 25 centipoises. derivatives, polyethylene glycol 400 and other polymeric The composition of the present invention will ordinarily demulcents Such as polyvinylpyrolidone, polysaccaride gels contain Surfactants and, if desired, adjuvants, including and Gelrite(R). A carboxy-containing polymer System known additional medicaments, buffers, antioxidants, tonicity by the tradename DuraSite(R), containing polycarbophil, is a adjusters, preservatives, thickenerS or Viscosity modifiers, Sustained release topical ophthalmic delivery System that and the like. Additives in the formulation may desirably releases the drug at a controlled rate, may also be used. include sodium chloride, EDTA (disodium edetate), and/or Aqueous mixtures of this invention may also contain BAK (benzalkonium chloride) or sorbic acid. amounts of Suspended lightly crosslinked polymer particles Non-Steroidal anti-inflammatory agents are non-Steroidal ranging from about 0.1% to about 6.5% by weight, and 35 Substances used in treating or ameliorating a disease or preferably from about 0.5% to about 4.5% by weight, based medical condition. They include drugs intended to treat on the total weight of the aqueous Suspension. They will therapeutically conditions of the eye itself or the tissue preferably be prepared using pure, Sterile water, preferably Surrounding the eye and drugs administered via the oph deionized or distilled, having no physiologically or ophthal thalmic route to treat therapeutically a local condition other mologically harmful constituents, and will be adjusted to a 40 than that involving the eye. The ophthalmic medicaments pH of from about 4.0 to about 6.8, and preferably from about will typically be incorporated in the topical delivery Systems 5.5 to about 6.5, using any physiologically and ophthalmo of this invention in therapeutically active amounts compa logically acceptable pH adjusting acids, bases or buffers, rable to amounts administered in other dosage forms, usu e.g., acids Such as acetic, boric, citric, lactic, phosphoric, 45 ally in amounts ranging from about 0.001% to about 5% by hydrochloric, or the like, bases Such as Sodium hydroxide, weight, and preferably from about 0.1% to about 1% by Sodium phosphate, Sodium borate, Sodium citrate, Sodium weight, based on the total weight of the formulation. Thus, acetate, sodium lactate, THAM (trishydroxymethylamino for example, about 0.1% to about 1.0% by weight of the methane), or the like and salts and bufferS Such as citrate/ anti-inflammatory non-Steroidal compound can be adminis dextrose, Sodium bicarbonate, ammonium chloride and mix 50 tered to the eye in this manner. tures of the aforementioned acids and bases. The viscous gels that result from fluid eyedrops delivered When formulating the aqueous Suspensions, their OSmotic by means of the aqueous Suspensions of this invention pressure (t) may be adjusted to from about 10 milliosmolar typically have residence times in the eye ranging from about (mC)SM) to about 400 mOSM, using appropriate amounts of 55 2 to about 12 hours, e.g., from about 3 to about 6 hours. The physiologically and ophthalmologically acceptable Salts. agents contained in these drug delivery Systems will be Sodium chloride is preferred to approximate physiologic released from the gels at rates that depend on Such factors as fluid, and amounts of Sodium chloride ranging from about the drug itself and its physical form, the extent of drug 0.01% to about 1% by weight, and preferably from about loading and the pH of the System, as well as on any drug 0.05% to about 0.45% by weight, based on the total weight 60 delivery adjuvants, Such as ion eXchange resins compatible of the aqueous Suspension, will give oSmolalities within the with the ocular Surface, which may also be present. above-Stated ranges. Equivalent amounts of one or more Preferably, the aqueous Suspensions provide Sustained con Salts made up of cations Such as potassium, ammonium and centration of the non-Steroidal anti-inflammatory agent of the like and anions Such as chloride, citrate, ascorbate, 65 between 10 and 10" M, and more preferably between borate, phosphate, bicarbonate, Sulfate, thiosulfate, 107 and 10 M, in the aqueous or treated tissue of the eye bisulfate, Sodium bisulfate, ammonium Sulfate, and the like for at least two hours, preferably at least three hours. US 6,309,630 B1 7 8 Ophthalmic Suspensions of the present invention may be In general, ophthalmic formulations Suitable for topical formulated So that they retain the Same or Substantially the ophthalmic administration may be formulated and adminis Same Viscosity in the eye that they had prior to administra tered in accordance with techniques familiar to perSons tion to the eye. Alternatively, ophthalmic Suspensions of the skilled in the art. The finished formulations are preferably present invention may be formulated So that there is Stored in opaque or brown containers to protect them from increased gelation upon contact with tear fluid. For instance, light exposure, and under an inert atmosphere. These acque when a formulation containing DuraSite(E) is administered to the eye at a lower pH, the DuraSite(R) system swells upon ous Suspensions can be packaged in preservative-free, Single-dose non-reclosable containers. This permits a Single contact with tears. This gelation or increase in gelation leads 1O to entrapment of the Suspended drug particles, thereby dose of the medicament to be delivered to the eye as a drop extending the residence time of the composition in the eye. or ribbon, with the container then being discarded after use. The drug is released slowly as the Suspended particles Such containers eliminate the potential for preservative dissolve over time as the solubility of the drug is higher in related irritation and Sensitization of the corneal epithelium, the tear fluid. All these events eventually lead to increased 15 as has been observed to occur particularly from ophthalmic patient comfort, increase in the time the drug is in contact medicaments containing mercurial preservatives. Multiple with the eye tissues, thereby increasing the extent of drug dose containers can also be used, if desired, particularly absorption and duration of action of the formulation in the Since the relatively low Viscosities of the aqueous Suspen eye. Sions of this invention permit constant, accurate dosages to Although described above in the context of Viscous aque be administered dropwise to the eye as many times each day ous polymeric Suspensions containing non-Steroidal anti as necessary. In those Suspensions where preservatives are to inflammatory in Solution and in Suspension, the composi be included, Suitable preservatives are chlorobutanol, tions of this invention can be formulated in any other 25 polyguat, benzalkonium chloride, cetyl bromide, Sorbic acid Suitable manner. For example, diclofenac Sodium may be and the like. dissolved and added by Sterile filtration to a preparation containing Sodium chloride, hydroxypropyl methyl cellulose In order that those skilled in the art can more fully and Surfactant. This mixture may then be adjusted to the appreciate aspects of this invention, the following Tables appropriate pH by known techniques, for example by the and examples are set forth. These examples are given Solely addition of sodium hydroxide. Other methods will be appar for purposes of illustration and should not be considered as ent to one skilled in the art. expressing limitations.

TABLE 4 COMPONENTS Example 1 Example 2 Example 3 Example 4 Example 5

Diclofenac Sodium O.O1 1.O O.O1 1.O O.O1 Noveon AA-1 1.3 1.3 1.3 Hydroxypropyl O.2 O.2 Methylcellulose Edetate Sodium O1 O.1 O1 O.1 O1 Sodium Chloride O.7 O.7 O.7 O.7 Mannitol Dextrose 2.8 o-Phosphoric Acid Sodium Borate Pluronic F127 O.OS O.2 O.05 O.2 O.05 Sodium Hydroxide q.S. to pH 6 q.s. to pH 6 q.S. to pH 6 q.S. to pH 6 q.S. to pH 6 Purified Water q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% Example 6 Example 7 Example 8 Example 9 Example 10

Diclofenac Sodium Noveon AA-1 13 1.3 1.3 1.3 1.3 Hydroxypropyl Methylcellulose Edetate Sodium O1 O.1 O1 O.1 O1 Sodium Chloride 0.5 0.5 Mannitol 1. 1. Dextrose 2.8 o-Phosphoric Acid 0.5 0.5 Sodium Borate 0.5 0.5 Pluronic F127 O.2 O.OS O.2 O.OS O.2 Sodium Hydorxide q.S. to pH 6 q.s. to pH 6 q.S. to pH 6 q.S. to pH 6 q.S. to pH 6 Purified Water q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% US 6,309,630 B1 9 10

TABLE 5 COMPOSITION Example 11 Example 12 Example 13 Example 14 Suprofen 1.O 2.O Flurbiprofen Sodium 1.O Noveon AA-1 1.3 1.3 1.3 1.3 Edetate Sodium O.1 O1 O1 Sodium Chloride 0.5 0.5 0.5 0.5 Mannitol 1. 1. 1. 1. Pluronic F127 O.2 O.OS O.2 O.05 Sodium Hydroxide q.S. to pH 6 q.S. to pH 6 q.S. to pH 6 q.s. to pH 6 Purified Water q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

EXAMPLES 1-2 15 final weight with water and surfactant by sterile filtration Hydroxypropylmethyl cellulose, Sodium chloride, edatate and aseptically filled into unit-dose containers. sodium (EDTA), and surfactants are dissolved in a beaker EXAMPLES 7-8 containing approximately /3 of the final weight of water and stirred for 10 minutes with an overhead stirrer. The Solution Noveon AA-1 is slowly dispersed into a beaker containing is sterilized by autoclaving at 121 C. for 20 minutes. approximately /3 of the final weight of water and stirred for Diclofenac Sodium is dissolved Separately in approximately 1.5 hrs. with an overhead stirrer. Noveon AA-1 is an acrylic % of the final weight of water and added by sterile filtration acid polymer available from B.F. Goodrich. Edetate sodium (0.22 um filter) and stirred for 10 minutes to form a mixture. (EDTA), o-phosphoric acid, and Sodium borate are then The mixture is adjusted to pH 6.0 with 10N Sodium 25 added to the polymer Suspension and Stirred for 10 minutes hydroxide, brought to final weight with water by sterile after each addition. The polymer Solution is at a pH of about filtration and aseptically filled into unit-dose containers. The 3.0-3.5. The mixture is sterilized by autoclaving at 121 for viscosity of compositions of Examples 1 and 2 will be about 20 minutes. Diclofenac Sodium is dissolved separately in 10 up to about 200 centipoises, preferably about 10 to about approximately 72 of the final weight of water, added to the 25 centipoises. polymer mixture by sterile filtration (0.22 um filter) and stirred for 10 minutes. The mixture is adjusted to pH 6.0 EXAMPLES 3-4 with 10N Sodium hydroxide, brought to final weight with Noveon AA-1 is slowly dispersed into a beaker containing water and Surfactant by Sterile filtration and aseptically filled approximately /3 of the final weight of water and stirred for 35 into unit-dose containers. 1.5 hrs. with an overhead stirrer. Noveon AA-1 is an acrylic EXAMPLES 9-10 acid polymer available from B.F. Goodrich. Edetate sodium (EDTA) and sodium chloride are then added to the polymer Noveon AA-1 is slowly dispersed into a beaker containing Solution and stirred for 10 minutes after each addition. The approximately /3 of the final weight of water and stirred for polymer suspension is at a pH of about 3.0-3.5. The mixture 40 1.5 hrs. with an overhead stirrer. Noveon AA-1 is an acrylic is sterilized by autoclaving at 121 C. for 20 minutes. acid polymer available from B.F. Goodrich. Edetate sodium Diclofenac Sodium is dissolved Separately in approximately (EDTA), sodium chloride and mannitol are then added to the % of the final weight of water, added to the polymer mixture polymer Suspension and Stirred for 10 minutes after each by sterile filtration (0.22 um filter) and stirred for 10 45 addition. The polymer solution is at a pH of about 3.0-3.5. minutes. The mixture is adjusted to pH 6.0 with 10N sodium The mixture is sterilized by autoclaving at 121 for 20 hydroxide, brought to final weight with water and Surfactant minutes. Diclofenac Sodium is dissolved separately in by sterile filtration and aseptically filled into unit-dose approximately 72 of the final weight of water, added to the containers. polymer mixture by sterile filtration (0.22 um filter) and 50 stirred for 10 minutes. The mixture is adjusted to pH 6.0 EXAMPLE 5-6 with 10N Sodium hydroxide, brought to final weight with Noveon AA-1 is slowly dispersed into a beaker containing water and Surfactant by Sterile filtration and aseptically filled approximately /3 of the final weight of water and stirred for into unit-dose containers. 1.5 hrs. with an overhead stirrer. Noveon AA-1 is an acrylic 55 acid polymer available from B.F. Goodrich. Edetate sodium EXAMPLES 11-14 (EDTA) is then added to the polymer Suspension and stirred Noveon AA-1 is slowly dispersed into a beaker containing for 10 minutes. The polymer suspension is at a pH of about approximately /3 of the final weight of water and stirred for 3.0-3.5. The mixture is sterilized by autoclaving at 121 C. 1.5 hrs. with an overhead stirrer. Noveon AA-1 is an acrylic for 20 minutes. Dextrose is dissolved in /10 of the final 60 acid polymer available from B.F. Goodrich. Edetate sodium weight of water and sterile filtered (0.22 um filter) in to the (EDTA), sodium chloride and mannitol are then added to the polymer Suspension and Stirred for 10 minutes. Diclofenac polymer Suspension and Stirred for 10 minutes after each Sodium is dissolved separately in approximately 72 of the addition. The polymer solution is at a pH of about 3.0-3.5. final weight of water, added to the polymer mixture by 65 The mixture is sterilized by autoclaving at 121 for 20 sterile filtration and stirred for 10 minutes. The mixture is minutes. Suprofen or Flurbiprofen sodium is dissolved sepa adjusted to pH 6.0 with 10N Sodium hydroxide, brought to rately in approximately 72 of the final weight of water and US 6,309,630 B1 11 12 the pH is adjusted to 7–8 with sodium hydroxide and it is inflammatory agent, Said composition having a pH of about then added to the polymer mixture by sterile filtration (0.22 4.0 to about 6.8, and containing from about 0.1% to about um filter) and stirred for 10 minutes. The mixture is adjusted 6.5% by weight based on the total weight of the suspension to pH 6.0 with 10N Sodium hydroxide, brought to final of a crosslinked carboxyl-containing polymer, and wherein weight with water and surfactant by sterile filtration and 5 a therapeutic amount of about 10%-99% of said agent is in aspectically filled into unit-dose containers. Suspension and a therapeutic amount of Said agent is in The above discussion of this invention is directed prima Solution. rily to preferred embodiments and practices thereof. It will 13. A composition as recited in claim 12 wherein Said be readily apparent to those skilled in the art that further agent is Selected from the group consisting of diclofenac, changes and modifications in actual implementation of the Suprofen, flurbiprofen and mixtures thereof. concepts described herein can easily be made or may be 14. A composition as recited in claim 13 wherein Said learned by practice of the invention, without departing from agent is diclofenac. the Spirit and Scope of the invention as defined by the 15 15. A composition as recited in claim 14 wherein said following claims. We claim: diclofenac is about 0.1 to about 1.0% be weight of the 1. A composition for topical ophthalmic application com composition. prising: an aqueous mixture of a non-Steroidal anti 16. A composition as recited in claim 9 wherein said inflammatory agent, Said composition being formulated with polymer is about 0.1 to about 1.3% by weight of the a pH and concentration of agent which maintains at least a Suspension. therapeutic amount of the non-Steroidal anti-inflammatory 17. A composition as recited in claim 14 having a vis agent of the formulation in Suspension and a therapeutic cosity of about 5,000 to about 30,000 centipoises. amount of the non-Steroidal anti-inflammatory agent of the 18. A composition as recited in claim 15 having a vis formulation in Solution. 25 cosity of about 5,000 to about 20,000 centipoises. 2. A composition as recited in claim 1 wherein the pH is 19. A method for treating the eye comprising the Step of: about 4.0 to about 8.0. applying to an eye an amount of an aqueous Suspension of 3. A composition as recited in claim 1 wherein the pH is diclofenac effective to treat the eye, Said composition having about 5.0 to about 6.8. a pH of about 5.0 to about 6.8 and a concentration of 4. A composition as recited in claim 2 wherein the diclofenac wherein about 70%-99% of said diclofenac is in non-Steroidal anti-inflammatory agent is Selected from the Suspension and the remainder is in Solution. group consisting of diclofenac, Suprofen, and flurbiprofen 20. A method for treating eye inflammation comprising: and mixtures thereof. topically applying to an eye an aqueous mixture of a 5. A composition as recited in claim 3 wherein the 35 non-Steroidal anti-inflammatory agent formulated with a pH non-Steroidal anti-inflammatory agent is diclofenac. and concentration of agent which maintains at least a 6. A composition as recited in claim 5 wherein the therapeutic amount of the non-Steroidal anti-inflammatory diclofenac is about 0.1 to about 1% by weight of said agent in Suspension and a therapeutic amount of the non composition and about 70%-99% of said diclofenac is in Steroidal anti-inflammatory agent of the formulation in Suspension. 40 Solution, whereby the therapeutic amount of the agent in 7. A composition as recited in claim 2 wherein Said Solution has an immediate therapeutic effect, and the thera composition further comprises a polymer Suspending agent. peutic amount of agent in Suspension has a therapeutic effect 8. A composition as recited in claim 7 wherein said by release from the Suspension over a period of time. polymer is water Soluble and the Viscosity of Said compo 45 21. A method for treating eye inflammation according to sition is about 10 to about 400 centipoises. claim 20 wherein the non-Steroidal anti-inflammatory agent 9. A composition as recited in claim 7 wherein said is diclofenac. polymer is water insoluble. 22. A method for treating eye inflammation according to 10. A composition as recited in claim 9 wherein said claim 21 wherein the diclofenac is about 0.1 to about 1% by polymer is a lightly crosslinked carboxy-containing poly 50 weight of the formulation and about 70%-99% of said C. diclofenac is in Suspension. 11. A composition as recited in claim 10 wherein the 23. A method for treating eye inflammation according to viscosity of the composition is about 500 to about 100,000 claim 22 wherein the formulation is administered at a pH of centipoises. 55 about 5.0 to about 6.8. 12. A composition for topical treatment of the eye com prising: an aqueous Suspension of a non-Steroidal anti