US008778.999B2

(12) United States Patent (10) Patent No.: US 8,778,999 B2 Hosseini et al. (45) Date of Patent: Jul. 15, 2014

(54) NON-STEROIDAL ANTI-INFLAMMATORY 4,192,827 A 3, 1980 Mueller et al. OPHTHALMC COMPOSITIONS 4,548,990 A 10, 1985 Mueller et al. 4,910,225 A 3/1990 Ogawa et al. 5, 192,535 A 3, 1993 Davis et al. (75) Inventors: Kamran Hosseini, Los Altos, CA (US); 5,221,696 A * 6/1993 Keet al...... 514,786 Lyle Bowman, Pleasanton, CA (US); 5,332,582 A 7/1994 Babcock et al. Erwin C. Si, Alameda, CA (US); 5,558,876 A 9, 1996 Desai et al. Stephen Pham, Sacramento, CA (US) 6,060,463 A * 5/2000 Freeman ...... 51481 8,129,431 B2 3/2012 Sawa et al. 2003/0077302 A1* 4/2003 Claus-Herz et al...... 424/400 (73) Assignee: Insite Vision Incorporated, Alameda, 2003/0143259 A1* 7/2003 Roy et al...... 424/427 CA (US) 2005/0113311 A1* 5/2005 Robledo ...... 514, 19 2006/0171984 A1* 8, 2006 Cromacket al...... 424/423 (*) Notice: Subject to any disclaimer, the term of this 2006/0183698 A1 8/2006 Abelson patent is extended or adjusted under 35 2007,0254.841 A1 11/2007 Ousler et al. U.S.C. 154(b) by 155 days. (Continued) (21) Appl. No.: 12/398,657 FOREIGN PATENT DOCUMENTS (22) Filed: Mar. 5, 2009 EP 1586.316 A1 10, 2005 WO 2008153746 A1 12/2008 (65) Prior Publication Data US 2010/0227928A1 Sep. 9, 2010 OTHER PUBLICATIONS “Comparison of cyclooxygenase inhibitory activity and ocular anti (51) Eikuro, 2006.O1 inflammatory effects of ketorolac tromethamine and bromfenac A6 IK3I/92 3.08: sodium” by Waterbury et al., Curr. Med. Res. Opin. 22, 1133-40 ck A6 IK9/00 (2006.01) (2006). A6 IK 45/06 (2006.01) (Continued) A6 IK 47/32 (2006.01) A61 K 47/34 (2006.01) (52) U.S. Cl. Primary Examiner — Wu-Cheng Winston Shen CPC ...... ( - - - - - st 3/92 in 36 38. 47/34 Assistant Examiner — Theodore R West 2013.01); A61 K9/0048 (2013.01); A6 IK 45/06 (2013.01); A61 K47/32 (2013.01) (74) Attorney, Agent, or Firm — McDermott Will & Emery USPC ...... 514/567; 514/561; 514/557, 514/553, LLP 424/427; 424/78.02 (58) Field of Classification Search (57) ABSTRACT O See application file for complete search history. The disclosure provides compositions and systems for topical (56) Ref Cited ophthalmic application, which include an aqueous mixture of eerees e bromfenac and flowable mucoadhesive polymer, for treating U.S. PATENT DOCUMENTS inflammation and inflammatory conditions of the eye. 2,798,053 A 7, 1957 Brown 4,136,250 A 1/1979 Mueller et al. 21 Claims, 1 Drawing Sheet

Aqueous Humar Bromfenac concentrations Following a Single dose Application & 20

1D 50 i. o

so 28 25 30 Time hours) Aqueous Humor Bromfenac Concentrations Following a Single Dose Application

-- Railoxbrom US 8,778,999 B2 Page 2

(56) References Cited Wagh, V. D. et al., “Formulation and evaluation of ophthalmic insert drug delivery system of forskolin.” Asian Journal of Pharmaceutics, U.S. PATENT DOCUMENTS Oct.-Dec. 2008, pp. 221-224. Saettone et al., “Evaluation of muco-adhesive properties and in vivo 2007/0265341 A1* 11/2007 Dana et al...... 514,560 activity of ophthalmic vehicles based on hyaluronic acid.” Interna 2007/0287749 A1* 12, 2007 Sawa et al. .. 514,567 tional Journal of Pharmaceutics, vol. 51, No. 3 (May 1, 1989) pp. 2008/0039398 A1 2/2008 Ousler et al...... 514/12 203-212. 2008.0070908 A1* 3, 2008 Muller et al...... 514,230.2 Bucci. Jr., F.A. et al., “Comparison of ketorolac 0.4% and bromfenac 2013,0096.199 A1 4/2013 Padilla et al. 0.09% at trough dosing: Aqueous drug absorption and prostaglandin OTHER PUBLICATIONS E2 levels.” J Cataract Refract Surg, vol. 34, Sep. 2008, pp. 1509 1512. "Stability study of azithromycin in ophthalmic preparations” by Baklayan et al., 24-Hour Evaluation of the Ocular Distribution of 14C-Labeled Bromfenac Following Topical Instillation into the Eyes Moreno et al., Brazilian J. Pharma. Sci. 45, 219-26 (2009).* of New Zealand White Rabbits, Journal of Ocular Pharmacology and “Topical Ocular Delivery of NSAIDs” by Ahuja et al., AAPSJournal Therapeutics, vol. 24. No. 4, 2008, pp. 392-398. 10, 229-41 (2008).* Supplementary European Search Report EP Application No. "Ocular Surface Distribution and Pharmacokinetics of a Novel 10749380.1 dated Aug. 20, 2013. Ophthalmic 1% Azithromycin Formulation” by Akpek et al., J. Ocu European Search Report issued in Application No. 10749380.1-1460 lar Pharmacol. Therap. 25, 433-39 (2009).* dated Aug. 20, 2013. Shulman et al., "Comparative evaluation of the short-term bacteri ProlensatM Package Insert, Bausch & Lomb Incorporated. cidal potential of a steroid-antibiotic combination versus steroid in ProlensatM Orange Book Listing. the treatment of chronic bacterial blepharitis and conjunctivitis.” BromdayTM Package Insert, ISTA Pharmaceuticals, Inc., 2010. European Journal of Ophthalmology, vol. 6, No. 4. (1996) pp. 361 367. * cited by examiner U.S. Patent Jul. 15, 2014 US 8,778,999 B2

Aqueous Humor Bromfenac Concentrations Following a Single Dose Application

A 200

150 -O- 0.0456 bromfenac in DuraSite -- Xoror -- radio-Xibrom

O 5 10 15 20 25 30 Time (hours) Aqueous Humor Bromfenac Concentrations Following a Single Dose Application

B 400 -- 0.09% Brorfenac in Durasite -- Xibrom -- Radio-Xibrom 300

200

O

-- - O 5 10 15 20 25 30 Time (hours) US 8,778,999 B2 1. 2 NON-STEROIDAL ANTI-NFLAMMATORY the flowable mucoadhesive polymer is in an amount of about OPHTHALMC COMPOSITIONS 0.5% to about 1.5% by weight of the composition and the bromfenac is in an amount of about 0.005% to about 0.5% by FIELD OF THE INVENTION weight of the composition. In another related embodiment, bromfenac is in an amount of about 0.01% to about 0.2% by The present invention relates to ophthalmic formulations: weight of the composition. In another related embodiment, more particularly to ophthalmic formulations of nonsteroidal the bromfenac in an amount of about 0.045% to about 0.09% anti-inflammatory agents; more particularly the present by weight of the composition. In a related embodiment, the invention relates to ophthalmic formulations of bromfenac. bromfenac is retained in or carried with the flowable mucoad 10 hesive polymer. In another related embodiment, the flowable BACKGROUND OF THE INVENTION mucoadhesive polymer is a carboxy-containing polymer. In another related embodiment, the carboxy-containing poly In topical administration of medicaments to the eye, a mer is polycarbophil or DuraSite(R). In another related variety of factors can be important, among them: comfort, embodiment, the bromfenac is in an amount of about 0.01% control, consistency and accuracy of dosage, type and time of 15 to about 0.09% by weight of the composition. In another any vision interference, ease of administration, and timing of related embodiment, the polymer is in an amount of about delivery. Prior ophthalmic delivery systems for bromfenac 0.8% to about 1.0% by weight of the composition. In another have suffered drawbacks in one or more of those areas. related embodiment, the composition has a pH of about 7.4 to about 8.5. In another related embodiment, the composition SUMMARY OF THE INVENTION has a pH of about 8.3. In another related embodiment, the viscosity of the composition is in the range of about 1,000 to It is an object of the invention to provide a novel compo about 2,000 cps. In another related embodiment, the viscosity sition of bromfenac that can overcome any of the above of the composition is about 1,500 cps. drawbacks. In another aspect, the invention relates to a process for The present invention provides topical ophthalmic formu 25 therapeutic treatment of the eye of a mammal including: (a) lations containing a non-steroidal anti-inflammatory agent, providing an ophthalmic composition having bromfenac in a bromfenac, and a flowable mucoadhesive polymer. It has therapeutically effective amount of about 0.005% to about been discovered that the composition of the invention not 0.5% by weight of the composition and a flowable mucoad only facilitates a slow release of bromfenac overalong period hesive polymer in an amount of about 0.5% to about 1.5% by of time, but also unexpectedly facilitates a high absorption 30 weight of the composition; (b) administering said composi and retention of bromfenac by the aqueous humor of the eye tion to the eye of a mammal in need thereof to treat inflam as compared with other bromfenac formulations currently mation or inflammatory conditions of the eye. In another available on the market. related embodiment, the bromfenac is retained in or carried In one aspect, the present invention relates to an oph with the flowable mucoadhesive polymer. In another related thalmic composition including a flowable mucoadhesive 35 embodiment, the flowable mucoadhesive polymer is a car polymer and a therapeutically effective amount of bro boxy-containing polymer. In another related embodiment, mfenac, wherein the composition has a viscosity formulated the carboxy-containing polymer is polycarbophil or Dur for administration to the eye of a mammal in drop form. In aSite(R). In another related embodiment, bromfenac is in an another related embodiment, bromfenac is retained in or car amount of about 0.01% to about 0.2% by weight of the com ried with the flowable mucoadhesive polymer. In another 40 position. In another related embodiment, the bromfenac in an related embodiment, the flowable mucoadhesive polymer is a amount of about 0.01% to about 0.09% by weight of the sustained release delivery system. In another related embodi composition. In another related embodiment, the bromfenac ment, the flowable mucoadhesive polymer is a carboxy-con in an amount of about 0.045% to about 0.09% by weight of taining polymer, Such as polycarbophil or DuraSite(R). In the composition. In another related embodiment, the polymer another embodiment, the ophthalmic composition further 45 is in an amount of about 0.8% to about 1.0% by weight of the includes a therapeutically effective amount of ketorolac. In composition. In another related embodiment, the composi another related embodiment, the mucoadhesive polymer is in tion has a pH of about 7.4 to about 8.5. In another related an amount of about 0.5% to about 1.5% by weight of the embodiment, the composition has a pH of about 8.3. In composition. In another related embodiment, the polymer is another related embodiment, the viscosity of the composition in an amount of about 0.8% to about 1.0% by weight of the 50 is in the range of about 1,000 to about 2,000 cps. In another composition. In another related embodiment, bromfenac is in related embodiment, the viscosity of the composition is about an amount of about 0.005% to about 0.5% by weight of the 1,500 cps. composition. In another related embodiment, bromfenac is in In another aspect, the invention relates to a composition or an amount of about 0.01% to about 0.2% by weight of the method for combination therapy of the eye of a mammal composition. In another related embodiment, the bromfenac 55 including: an ophthalmic composition having a therapeuti in an amount of about 0.045% to about 0.09% by weight of cally effective amount of bromfenac, a therapeutically effec the composition. In another related embodiment, the compo tive amount of ketorolac and a flowable mucoadhesive poly sition has a pH of about 7.4 to about 8.5. In another related mer such as DuraSite(R), wherein the composition has a embodiment, the composition has a pH of about 8.3. In Viscosity formulated for administration to the eye of a mam another related embodiment, the viscosity of the composition 60 mal in drop form. In another aspect, the invention relates to a is in the range of about 1,000 to about 2,000 centipoises (cps). composition or method for combination therapy of the eye of In another related embodiment, the viscosity of the compo a mammal including: an ophthalmic composition having a sition is about 1,500 cps. therapeutically effective amount of bromfenac, a flowable In another aspect, the invention relates to a Sustained mucoadhesive polymer such as DuraSite(R) and one or more release bromfenac delivery system, including a flowable 65 additional non-steroidal anti-inflammatory agent Such as, for mucoadhesive polymer and a therapeutically effective example, a therapeutically effective amount of ketorolac. In amount of bromfenac in an ophthalmic composition; wherein an embodiment, ketorolac is included in the composition of US 8,778,999 B2 3 4 the invention in an amount of about 0.01% to about 1% by higher efficacy in treating inflammation of the eye (Bucci et weight of the composition. In another embodiment, ketorolac al., J. Cataract Refract Surg. 34(9): 1509-12 (2008)). is included in the composition of the invention in an amount Non-steroidal anti-inflammatory agents are known to of about 0.4% to about 0.5% by weight of the composition. In inhibit cyclooxygenases, enzymes associated with pain and another aspect, the invention relates to a composition or inflammation in mammals. Cyclooxygenases are essential in method for combination therapy of the eye of a mammal the biosynthesis of prostaglandins, which have been shown in including: an ophthalmic composition having a therapeuti many animal models to be mediators of intraocular inflam cally effective amount of bromfenac, a flowable mucoadhe mation. Although steroidal compounds have been used to sive polymer such as DuraSite(R) and one or more steroidal treat such inflammation, non-steroidal anti-inflammatory anti-inflammatory agent. In another aspect, the invention 10 agents from the group of drugs known as cyclooxygenase inhibitors have been substituted for steroids because they relates to a composition or method for combination therapy of have not shown the same propensity to produce side-effects in the eye of a mammal including: an ophthalmic composition ocular tissues as compared to ophthalmic steroids. Non-Ste having a therapeutically effective amount of bromfenac, a roidal agents are also widely prescribed to reduce pain and flowable mucoadhesive polymer such as DuraSite R and one 15 inflammation in a wide number of tissues. When used as or more antibacterial agent. In an embodiment, relating to any topical agents in the eye, they suppress inflammatory of the above aspects, the invention relates to a composition or responses and have been shown to prevent particular side method for combination therapy of the eye of a mammal effects of Surgical trauma (on the pupil preventing Surgical including: an ophthalmic composition having a therapeuti meiosis), fluid accumulating in the back of the eye after cally effective amount of bromfenac, a flowable mucoadhe cataract Surgery (post-Surgical macular edema) and the sive polymer such as DuraSite(R) and an additional therapeu appearance of inflammatory cells and vessel leakage in the tically active agent selected from the group consisting of anterior chamber. Topical application of non-steroidal anti antibacterial antibiotic agent, synthetic antibacterial agent, inflammatory agents in the eye also appears to relieve Some of antifungal antibiotic agent, synthetic antifungal agent, anti the itching due to allergic conjunctivitis. Diclofenac sodium, neoplastic agent, steroidal anti-inflammatory agent, non-ste 25 Suprofen, and flurbiprofin are non-steroidal anti-inflamma roidal anti-inflammatory agent, anti-allergic agent, glau tory agents that have been used for the treatment of postop coma-treating agent, antiviral agent and anti-mycotic agent. erative inflammation in patients who have undergone cataract It is to be understood that both the foregoing general extraction. description and the following detailed description are exem Bromfenac is a non-steroidal anti-inflammatory agent plary and explanatory only and are not restrictive of the inven 30 commonly used to treat patients who have undergone cataract tion, as claimed. removal. The chemical structure of bromfenac is disclosed in U.S. Pat. No. 4,910,225, which is hereby incorporated in its BRIEF DESCRIPTION OF THE DRAWINGS entirety by reference. A sterile ophthalmic solution of bro mfenac as sodium salt equivalent to 0.09% bromfenac free FIG. 1A shows the differences in aqueous humor concen 35 acid is currently marketed as Xibrom R) by ISTA/Senju Phar tration of bromfenac as a factor of time following a single maceuticals with a recommended dosing schedule of 1 drop dose application of 0.045% bromfenac in DuraSite(R), per 12 hours. However, Xibrom R) has been shown not to Xibrom R) and radioactively labeled bromfenac (radio-Xi provide a good control of prostaglandin-mediated inflamma brom R) to the eye of a mammal at time zero. tion when compared to ketorolac (another NSAID) partly due FIG. 1B shows the differences in aqueous humor concen 40 to its concentration drop in the eye after twelve hours, con tration of bromfenac as a factor of time following a single sistent with its on-label dosing schedule (Bucci et al., J. Cata dose application of 0.09% bromfenac in DuraSite(R), ract Refract Surg. 34(9): 1509-12 (2008)). Xibrom R) and radioactively labeled bromfenac (radio-Xi It is an object of the invention to provide novel topical brom R) to the eye of a mammal at time zero. ophthalmic formulations containing bromfenac and a flow 45 able mucoadhesive polymer that reduce the required dosing DETAILED DESCRIPTION OF THE INVENTION of bromfenac to, for example, once per day administration while facilitating the absorption and retention of a higher The present invention generally relates to topical oph concentration of bromfenac in the eye and/or its related or thalmic formulations containing bromfenac, a non-steroidal Surrounding tissues such as, for example, retina to treat pros anti-inflammatory agent (NSAID), and a flowable mucoad 50 taglandin-mediated inflammation or inflammatory condi hesive polymer. Not only have the applicants found that the tions of the eye. compositions of the invention facilitate a slow release of As used herein the term “ophthalmic composition” refers bromfenac over a longer period of time, but they have also to a composition intended for application to the eye or its unexpectedly discovered that the compositions of the inven related or Surrounding tissues such as, for example, eyelid. tion facilitate a higher absorption and retention of bromfenac 55 The term also includes compositions intended to therapeuti by the aqueous humor of the eye as compared to other bro cally treat conditions of the eye itself or the tissues surround mfenac formulations. ing the eye and compositions administered via the ophthalmic The increased absorption and retention of bromfenac in the route to treat therapeutically a local condition other than that eye, provided by the compositions of the present invention, involving the eye. The ophthalmic composition can be allow Subjects to apply fewer doses (e.g., once per day) of 60 applied topically or by other techniques, known to persons bromfenac to treat the affected eye. Reduced dosing increases skilled in the art, such as injection to the eye or its related convenience of using the bromfenac formulation, while a tissues. Examples of suitable topical administration to the eye higher absorption and retention of bromfenac in the eye include administration in eye drops and by spray formula increases the efficacy of bromfenac in treating inflammation tions. A further suitable topical administration route is by and inflammatory conditions of the eye. In general, it has been 65 Subconjunctival injection. The agents can also be provided to shown that control over dosing and concentration of NSAIDs the eye periocularly or retro-orbitally. Although it is an advan delivered to the aqueous humor has been correlated to a tage of the invention that intracameral administration is not US 8,778,999 B2 5 6 required, this and other routes of administration are not out pain, redness, Swelling, wateriness and itchiness of the eye or side the scope of the invention. its Surrounding tissues. Exogenous agents or events include, As used herein the term “flowable mucoadhesive polymer but are not limited to, infection, injury, radiation, Surgery or refers to a carboxy-containing polymer, e.g., lightly damage to the eye or its surrounding tissues, which initiate crosslinked polymers of acrylic acid or the like, having an biochemical reactions leading to an inflammation. An ocular optimal in vivo mucosal absorption rate, safety, degradability disease is one caused by vascular leakage in the eye or by and flowability for an eye drop. The flowable mucoadhesive inflammation in the eye. Examples of conditions related to polymers used in the present invention are water insoluble, inflammation in the eye include, but are not limited to the water-Swellable, biodegradable polymer carriers including following: Surgical trauma; dry eye; allergic conjunctivitis; lightly crosslinked carboxy-containing polymers such as 10 viral conjunctivitis; bacterial conjunctivitis; blepharitis; ante polycarbophil (Noveon R AA-1, Lubizol Corp., Wickliffe, rioruveitis; injury from a chemical; radiation orthermal burn; Ohio) or other Carbopol R polymers (Lubizol Corp., Wick or penetration of a foreign body, signs and symptoms of eye liffe, Ohio). Suitable carboxy-containing polymers for use in problems (e.g., pain in or around the eye, redness especially the present invention and methods for making them are accompanied by pain in the eye (with or without movement), described in U.S. Pat. No. 5,192,535 to Davis et al. which is 15 extreme light sensitivity, halos (colored circles or halos hereby incorporated in its entirety by reference. A suitable around lights), bulging (protrusion) of the eye or Swelling of carboxy-containing polymer system for use in the present eye tissues, discharge, crusting or excessive tearing: eyelids invention is known by the tradename DuraSite R (InSite stuck together, especially upon awakening, blood inside the Vision Inc., Alameda, Calif.), containing polycarbophil. front of the eye (on the colored part) or white of the eye); which is a Sustained release topical ophthalmic delivery sys cataracts; pain and inflammation associated with wearing tem that releases drug at a controlled rate. DuraSite(R) encom contact lenses; corneal conditions (e.g., conjunctival tumor pass lightly crosslinked polymers that are prepared by Sus excision, conjunctivitis (“Pink Eye''), cornea edema after pension or emulsion polymerizing at least about 90% by cataract Surgery, corneal clouding, corneal transplantation, weight of a carboxyl-containing monoethylenically unsatur corneal ulcer, dry eye syndrome, dystrophies, conditions ated monomer such as acrylic acid with from about 0.1% to 25 associated with excimer laser phototherapeutic keratectomy, about 5% by weight of a polyfunctional, or difunctional, herpes simplex keratitis, keratoconus, pterygium, recurrent crosslinking agent Such as divinyl glycol (3,4-dihydroxy-1, erosion syndrome); eye movement disorders; glaucoma, ocu 5-hexadiene), having a particle size of not more than about 50 lar oncology, oculoplastics (e.g., cosmetic Surgery, enucle um in equivalent spherical diameter, when formulated with an ation, eyelid and orbit injuries, ectropion, entropion, graves ophthalmic medicament, e.g., bromfenac, into Solutions or 30 disease, involuntary eyelid blinking); conditions associated Suspensions in aqueous medium in which the amount of poly with refractive Surgery; and retinal conditions. mer ranges from about 0.5% to about 1.5% by weight, based As used herein the term "sustained release delivery sys on the total weight of the aqueous Suspension, the pH is from tem” or 'sustained release composition” refers to a composi about 7.4 to about 8.5, and the osmotic pressure (osmolality tion comprising a flowable mucoadhesive polymer—which is or tonicity) is from about 10 mCsM to about 400 mOsm, 35 a carboxy-containing polymer Such as polycarbophil and provide new topical ophthalmic medicament delivery sys DuraSite(R), as described in U.S. Pat. No. 5,192,535 which tems having suitably low viscosities which permit them to be facilitates a Sustained release of bromfenac. Such composi easily administered to the eye in drop form, and hence be tions may include other biologically active agents besides comfortably administrable in consistent, accurate dosages. bromfenac. Typically, the Sustained release compositions of The compositions of the invention containing DuraSite(R) will 40 the invention can contain from about 0.005% (w/w) to about rapidly gel in the eye after coming into contact with the eye's 0.5% of bromfenac (free acid). In an embodiment, the range tear fluid to a substantially greater viscosity than that of the of bromfenac loading is between about 0.01% (w/w) to about originally-introduced Suspension or solution and thus remain 0.2%. In another embodiment, the range of bromfenac load in place for prolonged periods of time to provide Sustained ing is between about 0.045% (w/w) to about 0.09%. The release of the ophthalmic medicament. 45 Sustained release delivery systems or compositions of this As used herein the term “retained in or carried with or invention can be formed into many shapes such as a solution, "retaining or carrying embraces generally all ways that bro a gel, a film, a pellet, a rod, a filament, a cylinder, a disc, a mfenac can be associated with the flowable mucoadhesive wafer, nanoparticles or a microparticle. A "microparticle' as polymer. For example, bromfenac can be in aqueous Solution defined herein, comprises a blend polymer component having dispersed throughout the polymer. A bromfenac concentra 50 a diameter of less than about one millimeter and having tion of up to about 0.09% will be in solution mixed with or bromfenac dispersed therein. A microparticle can have a dispersed throughout the flowable mucoadhesive polymer spherical, non-spherical or irregular shape. Typically, the carrier. Bromfenac can also be in Suspension with the poly microparticle will be of a size suitable for injection. In one mer depending on its concentration. For example, when bro embodiment, the size range for microparticles is from about mfenac is used in an amount more than about 0.36% by 55 one to about 50 microns in diameter. weight of the composition, some of the bromfenac can be in As defined herein, a Sustained release of a biologically Suspension with the polymer carrier while an amount of up to active agent is a release of the biologically active agent (e.g., about 0.36% of bromfenac will still be in solution and mixed bromfenac) from a Sustained release delivery system or com with the polymer carrier. position. The release occurs over a period which is longer As used herein the term “inflammation or inflammatory 60 than that period during which a therapeutically significant conditions of the eye” refers to an ocular disease or any amount of the biologically active agent would be available inflammatory condition of the eye and external tissues Sur following direct administration of a solution of the biologi rounding eye, e.g., eyelid, influenced by various exogenous or cally active agent. In one embodiment, a Sustained release endogenous agents or events. Endogenous factors include, occurs over a period of greater than six to twelve hours such but are not limited to, inflammatory chemokines, cytokines, 65 as about twenty-four hours or longer. A Sustained release of mediators, nuclear transcription factors, antigens, autogens biologically active agent can be a continuous or a discontinu or hormones that can cause acute or chronic inflammation, ous release, with relatively constant or varying rates of US 8,778,999 B2 7 8 release. The continuity of release and level of release can be A further aspect of the present invention is a therapeutic affected by the type of polymer composition used (e.g., method wherein said ocular disease, injury or disorder is monomer ratios, molecular weight, and varying combina caused by Surgery, physical damage to the eye, glaucoma, tions of polymers), agent loading, and/or selection of excipi macular degeneration, or diabetic retinopathy. The formula ents to produce the desired effect. tion of bromfenac, in accordance with the compositions or As used herein the term “treating or “treatment” refers to methods of the invention, can be used to treat retina condi reducing, ameliorating reversing, alleviating, inhibiting the tions (e.g., macular edema, macular degeneration, etc.) since progress of, or preventing a disease or a medical condition of topical application of the inventive compositions results in the eye itself or the tissue Surrounding the eye or the Symp high concentrations of the drug, i.e., bromfenac, in the retina. toms associated therewith. The term also encompasses pro 10 A still further aspect of the present invention is to use the phylaxis, therapy and cure. The Subject receiving “treatment.” bromfenac formulations of the invention to treat ocular dis or whom undergoes “treating is any mammal in need of such ease, injury or disorder wherein the ocular disease, injury or treatment for (eye-related inflammation or inflammatory con disorder is one caused by vascular leakage in the eye or by ditions), including primates, in Such as humans, and other 15 inflammation in the eye. Examples of conditions related to mammals such as equines, cattle, Swine and sheep; and poul inflammation in the eye include, but are not limited to the try and domesticated mammals and pets in general. following: Surgical trauma; dry eye; allergic conjunctivitis; The term “therapeutically effective amount’ as used herein viral conjunctivitis; bacterial conjunctivitis; blepharitis; ante means that the amount of a composition elicits a beneficial rioruveitis; injury from a chemical; radiation orthermal burn; biological or medicinal response in a tissue, system, animal or injury from penetration of a foreign body, pain in or around human. For example, a therapeutically effective amount of a the eye, redness especially accompanied by pain in the eye; composition of the invention is a dose which leads to a clini light sensitivity; seeing halos (colored circles or halos around cally detectable improvement or treatment (as defined above) lights); bulging (protrusion) of the eye; Swelling of eye tis of the eye of a Subject Suffering from an inflammatory eye Sues; discharge, crusting or excessive tearing; eyelids stuck condition or disease. 25 together, blood inside the front of the eye (on the colored part) As used herein, the term “about” refers to an approxima or white of the eye); cataracts; pain and inflammation asso tion of a stated value within an acceptable range, e.g. +/-5% ciated with wearing contact lenses; corneal-associated con of the stated value. dition; conjunctival tumor excision; conjunctivitis known as It is an aspect of the present invention to provide novel Pink Eye; cornea edema after cataract Surgery; corneal cloud ophthalmic compositions for treating inflammation and 30 ing; corneal transplantation; corneal ulcer, dry eye syndrome; inflammatory conditions of the eye; Such compositions dystrophies; condition associated with excimer laser photo include bromfenac and a flowable mucoadhesive polymer to therapeutic keratectomy; herpes simplex keratitis; keratoco increase the retention of bromfenac in the eye for a longer nus; pterygium; recurrent erosion syndrome; eye movement period of time. disorder, glaucoma, ocular oncology: oculoplastic condition It is a further aspect of the invention to provide a novel 35 resulted from cosmetic Surgery, enucleation, eyelid and orbit sustained release delivery system for bromfenac, which injuries, ectropion, entropion, graves' disease, involuntary includes bromfenac and a flowable mucoadhesive polymer. It eyelid blinking; condition associated with refractive Surgery; is an object of this invention to provide a novel Sustained and retinal condition. release delivery system for topical ophthalmic delivery of Retinal conditions include, but are not limited to, age bromfenac. 40 related macular degeneration, AIDS-related ocular disease A further aspect of this invention is to provide novel bro (e.g., CMV retinitis), birdshot retinochoroidopathy (BR), mfenac compositions and Sustained release ophthalmic deliv choroidal melanoma, coats disease, cotton wool spots, dia ery systems suitable for administration at intervals of once betic retinopathy, diabetic macular edema, cystoid macular daily or less often, e.g., once per every two to three days. edema, lattice degeneration, macular disease (e.g., macular Yet another aspect of this invention is to provide a method 45 degeneration, hereditary macular dystrophy, macular edema, for convenient therapeutic treatment using a composition or a macular hole, macular pucker, central serous chorioretinopa delivery system including bromfenac and a flowable mucoad thy), ocular histoplasmosis syndrome (OHS), posterior vitre hesive polymer, which has a prolonged release time for bro ous detachment, retinal detachment, retinal artery obstruc mfenac while facilitating a high absorption and retention of tion, retinal vein occlusion, retinoblastoma, retinopathy of bromfenac in the eye over the release-time period. 50 prematurity (ROP), retinitis pigmentosa, retinoschisis (ac A still further aspect of this invention is to provide novel quired and X-linked), Stargardt’s disease, toxoplasmosis (af methods for treating, ameliorating or reducing inflammation fecting retina) and uveitis. or inflammatory conditions of the eye by providing a compo Bromfenac is a non-steroidal anti-inflammatory agent sition or a delivery system containing bromfenac and a flow which has the structural formula of able mucoadhesive polymer, which has a prolonged release 55 time for bromfenac, while facilitating a high absorption and retention of bromfenac by the eye over the release time O NH2 period. According to one aspect of the present invention there is OH provided a method of treating inflammation or inflammatory 60 conditions of the eye or an ocular disease, injury or disorder in a patient by administering a topical ophthalmic formula Br tion described herein. Furthermore the method may include a dosing regime of once, to two times daily administration into The above compound to be used in accordance with the said eye to treat the pain and/or inflammation associated with 65 invention may be in a salt form or a hydrated form or both. said ocular disease, injury or disorder. In one embodiment, The salt forms include alkali metal salts such as sodium salt the dosing is once a day bromfenac formulation. and potassium salt, alkaline earth metal salts such as calcium US 8,778,999 B2 9 10 salt and magnesium salt, among others, and any salt may of bromfenac is in Suspension to provide a therapeutic effect suitably be used, provided that it can attain the object of the upon delayed deliver. In this way, the portion of the agent in invention. The hydrated forms include monohydrate, ses solution is immediately available for therapeutic effect, while quihydrate (1.5 H2O), dihydrate, pentahydrate and any other the portion in Suspension serves as a reservoir and is released hydrate forms may suitably be used, provided that it can attain 5 slowly over time. the object of the invention. In Some embodiments, according to any of the above The present invention also provides kits including a com aspects of the invention, the flowable mucoadhesive polymer position having bromfenac and a flowable mucoadhesive content of the composition of the invention is about 0.5% to polymer for application to the eye of a mammal. The kit about 1.5% by weight of the composition. In other embodi further includes instructions for how use the composition, eye 10 ments, the flowable mucoadhesive polymer content of the dropper and other useful paraphernalia for topical delivery to composition of the invention is about 0.8% to about 1.0% by the eye. weight of the composition. In another embodiment, the flow In one embodiment, according to any of the above aspects able mucoadhesive polymers of the invention are crosslinked of the invention, the composition of the invention has a pH of carboxy-vinyl polymers as carboxy-containing polymers. about 7.4 to about 8.5: in other embodiments the pH is about 15 Suitable carboxy-containing polymers for use in the present 83. invention and method for making them are described in U.S. In one embodiment, according to any of the above aspects Pat. No. 5,192,535 to Davis et al. which is hereby incorpo of the invention, the bromfenac content of the compositions rated, in its entirety, by reference and relied upon. These of the invention is about 0.005% to about 0.5% by weight of polymer carriers include lightly crosslinked carboxy-con the composition. In another embodiment, the bromfenac con taining polymers such as polycarbophil, or Carbopols(R), dex tent of the compositions is about 0.01% to about 0.2% by tran, cellulose derivatives, polyethylene glycol 400 and other weight of the composition. In another embodiment, the bro polymeric demulcents such as polyvinylpyrolidone, polysac mfenac content of the compositions is about 0.01% to about caride gels and Gelrite(R). In another embodiment, a carboxy 0.09% by weight of the composition. In another embodiment, containing polymer system known by the tradename Dur the bromfenac content of the compositions is about 0.045% to 25 aSite(R) is used. DuraSite(R) is a lightly crosslinked polymer about 0.09% by weight of the composition containing polycarbophil which is a Sustained release topical In one embodiment, according to any of the above aspects ophthalmic delivery system that releases the drug at a con of the invention, the viscosity of the compositions of the trolled rate. invention is in the range of about 1,000 to about 2,000 cps. In The lightly crosslinked polymers of acrylic acid or the like another embodiment, the viscosity of the composition of the 30 used in practicing this inventionare, in general, well known in invention is about 1,500 cps. When formulated as a topical the art. In one embodiment such polymers are ones prepared ophthalmic delivery system, the viscosity of the composition from at least about 90% or from about 95% to about 99.9% by of the invention is desirably in a range Suitable for adminis weight, based on the total weight of monomers present, of one tration to the eye in drop form, Such as a viscosity from about or more carboxyl-containing monoethylenically unsaturated 1,000 to about 2,000 cps. 35 monomers. Acrylic acid is a carboxyl-containing monoethyl In one embodiment, according to any of the above aspects enically unsaturated monomer, but other unsaturated, poly of the invention, the bromfenac is retained in or carried with merizable carboxyl-containing monomers, such as meth the flowable mucoadhesive polymer. The flowable mucoad acrylic acid, ethacrylic acid, ..beta.-methylacrylic acid hesive polymer increases the retention of bromfenac in the (crotonic acid), cis-alpha.-methylcrotonic acid (angelic eye for a longer period of time. In another embodiment, the 40 acid), trans-alpha.-methylcrotonic acid (tiglic acid), alpha.- entire bromfenac content of the composition of the invention butylcrotonic acid, alpha.-phenylacrylic acid, alpha.-benzy is in aqueous Solution. lacrylic acid, alpha.-cyclohexylacrylic acid, ..beta.-pheny In one embodiment, according to any of the above aspects lacrylic acid (cinnamic acid), coumaric acid of the invention, a percentage of bromfenac content of the (o-hydroxycinnamic acid), umbellic acid (p-hydroxycou compositions of the invention is in aqueous solution with the 45 maric acid), and the like can be used in addition to or instead polymer while the remaining bromfenac remains in Suspen of acrylic acid. sion with the polymer. In another embodiment, the bromfenac Such polymers are crosslinked by using a small percent mixed with the polymer carrier can be in Suspension to act as age, i.e., less than about 5%, such as from about 0.5% or from a reservoir established in suspension at the pH of the formu about 0.1% to about 5%, or from about 0.2% to about 1%, lation. The amount established in Suspension may vary 50 based on the total weight of monomers present, of a polyfunc depending on therapeutic needs, but it will be at least an tional crosslinking agent. Included among Such crosslinking amount Sufficient to have a therapeutic effect on the eye upon agents are non-polyalkenyl polyether difunctional crosslink delayed release from the Suspension over a period of time. A ing monomers such as divinyl glycol; 2.3-dihydroxyhexa-1, Sufficient amount of agent will also be present in Solution to 5-diene; 2,5-dimethyl-1,5-hexadiene; divinylbenzene; N.N- have an immediate therapeutic effect upon topical ophthalmic 55 diallylacrylamide: N,N-diallylmethacrylamide and the like. application. For example, about 80% to about 90% of the total Also included are polyalkenyl polyether crosslinking agents bromfenac contained in the mixture will be in suspension, but containing two or more alkenyl ether groupings per molecule, this may vary depending on how much of the agent is desired or alkenyl ether groupings containing terminal H. C=C- for sustained delivery and the duration of delivery desired. groups, prepared by etherifying a polyhydric alcohol contain The amount of bromfenac in Suspension may, for instance, 60 ing at least four carbon atoms and at least three hydroxyl range from about 70% to about 99% or about 10% to about groups with an alkenyl halide such as allyl bromide or the 99% by weight of the total amount of bromfenac contained in like, e.g., polyallyl Sucrose, polyallyl pentaerythritol, or the the mixture. The compositions will not, however, have 100% like: see, e.g., Brown U.S. Pat. No. 2,798,053, which incor of bromfenac in Suspension. Some amount will be in Solution porated herein by reference in its entirety. Diolefinic non to provide the immediate therapeutic effect. In certain 65 hydrophilic macromeric crosslinking agents having molecu embodiments, the concentration of bromfenac and the pH of lar weights of from about 400 to about 8,000, such as the composition is selected to ensure that a sufficient amount insoluble di- and polyacrylates and methacrylates of diols and US 8,778,999 B2 11 12 polyols, diisocyanate-hydroxyalxyl acrylate or methacrylate When formulating the composition of the invention as reaction products, and reaction products of isocyanate termi either an aqueous solution or an aqueous Suspension, the nated prepolymers derived from polyester diols, polyether osmolality can be adjusted to from about 10 mCsm/kg to diols or polysiloxane diols with hydroxyalkylmethacrylates, about 400 mOsm/kg, using appropriate amounts of physi and the like, can also be used as the crosslinking agents; see, ologically and ophthalmologically acceptable salts. Sodium e.g., Mueller et al. U.S. Pat. Nos. 4,192,827 and 4,136,250, chloride approximates physiologic fluid, and amounts of which incorporated herein by reference in its entirety. sodium chloride ranging from about 0.01% to about 1% by The lightly crosslinked polymers can of course be made weight, or from about 0.05% to about 0.45% by weight, based from a carboxyl-containing monomer or monomers as the on the total weight of the aqueous Suspension, provide osmo sole monoethylenically unsaturated monomer present, 10 lalities within the above-stated ranges. Equivalent amounts of together with a crosslinking agent or agents. They can also be one or more salts made up of cations such as potassium, polymers in which up to about 40%, or from about 0% to ammonium and the like and anions such as chloride, citrate, about 20% by weight, of the carboxyl-containing monoeth ascorbate, borate, phosphate, bicarbonate, Sulfate, thiosul ylenically unsaturated monomer or monomers has been fate, bisulfate, sodium bisulfate, ammonium sulfate, and the replaced by one or more non-carboxyl-containing monoeth 15 like can also be used in addition to or instead of Sodium ylenically unsaturated monomers containing only physi chloride to achieve osmolalities within the above-stated ologically and ophthalmologically innocuous Substituents, ranges. Sugars like mannitol, dextrose, glucose or other poly including acrylic and methacrylic acid esters such as methyl ols may be added to adjust the osmolality. methacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexy The amounts of flowable mucoadhesive polymer, the pH, lacrylate, octyl methacrylate, 2-hydroxyethyl-methacrylate, and the osmotic pressure chosen from within the above-stated 3-hydroxypropylacrylate, and the like, vinyl acetate, N-vi ranges are correlated with one another and with the degree of nylpyrrolidone, and the like; see Mueller et al. U.S. Pat. No. crosslinking of the polymer to give aqueous solutions or 4.548,990, which incorporated herein by reference in its Suspensions having Viscosities ranging from about 1,000 to entirety, for a more extensive listing of such additional mono about 2,000 or 5,000 to about 20,000 cps respectively, as ethylenically unsaturated monomers. In one embodiment, 25 measured at room temperature (about 25°C.) using a Brook polymers are lightly crosslinked acrylic acid polymers field Digital LVT Viscometer equipped with a number 25 wherein the crosslinking monomer is 2,3-dihydroxyhexa-1, spindle and a 13R Small sample adapter at 12 rpm. The com 5-diene or 2,3-dimethylhexa-1,5-diene. positions of the present invention have a viscosity that is The lightly crosslinked polymers used in practicing this suited for the selected route of administration. Alternatively, invention are prepared by Suspension or emulsion polymer 30 the viscosity can be 1000 to 3400 cps as measured with a izing the monomers, using conventional free radical polymer Brookfield cone and plate viscosity DV-II+ with the spindle ization catalysts, to a dry particle size of not more than about No. CP-52 at 6 rpm. 50 um in equivalent spherical diameter; e.g., to provide dry In one embodiment, according to any of the above aspects polymer particles ranging in size from about 1 to about 30 um, of the invention, the compositions of the present invention or from about 3 to about 20 Lum, in equivalent spherical 35 ordinarily contain one or more Surfactants and, if desired, one diameter. In general. Such polymers will range in molecular or more adjuvants, including additional medicaments, buff weight estimated to be about 25,000 to about 4,000,000, or ers, antioxidants, tonicity adjusters, preservatives, thickeners about 500,000 to about 2,000,000. or viscosity modifiers, and the like. Additives in the formu According to any of the above aspects of the invention, the lation may desirably include sodium chloride, EDTA (diso composition of the invention is an aqueous mixture that can 40 dium edetate), and BAC (benzalkonium chloride) or sorbic also contain amounts of Suspended lightly crosslinked poly acid, or both. mer particles ranging from about 0.5% to about 1.5% by Compositions delivered by means of the sustained release weight, or from about 0.8% to about 1.0% by weight, based medicament delivery system of this invention typically have on the total weight of the aqueous mixture. The aqueous residence times in the eye ranging from about 8 to about 24 mixture can be an aqueous Solution of bromfenac and a flow 45 hours. The bromfenac contained in these compositions is able mucoadhesive polymer or an aqueous Suspension of released from the composition at rates that depend on Such bromfenac and a flowable mucoadhesive polymer. In certain factors as bromfenac itself and its physical form, the extent of embodiments, the composition of the invention is prepared drug loading and the pH of the system, as well as on any drug using pure, Sterile water, such as deionized or distilled, having delivery adjuvants, such as ion exchange resins compatible no physiologically or ophthalmologically harmful constitu 50 with the ocular surface, which may also be present in the ents, and is adjusted to a pH of from about 7.4 to about 8.5, in composition. In one embodiment, according to any of the some embodiments from about 8.2 to about 8.4, and in other aspects of the present invention, the composition of the inven embodiments to a pH of about 8.3 using any physiologically tion provides a Sustained concentration of bromfenac of and ophthalmologically acceptable pH adjusting acid, base or between 10 and 10 M, in another embodiment between buffer, e.g., acids such as acetic, boric, citric, lactic, phospho 55 107 and 10M, in the aqueous or treated tissue of the eye for ric, hydrochloric, or the like, bases such as sodium hydroxide, at least two hours, and in certain embodiments, at least three Sodium phosphate, Sodium borate, Sodium citrate, sodium hours. In another embodiment, the composition of the inven acetate, sodium lactate, THAM (trishydroxymethylamino tion provides Sustained concentration of bromfenac of methane), or the like and salts and buffers such as citrate/ between 10 and 10 M, or between 107 and 10M, in the dextrose, sodium bicarbonate, ammonium chloride and mix 60 aqueous or treated tissue of the eye for at least two hours, or tures of the aforementioned acids and bases. For example, at least three hours. bromfenac or its salt at may be dissolved and added by sterile Ophthalmic compositions of the present invention may be filtration to a preparation containing Sodium chloride, Dur formulated so that they retain the same or substantially the aSite(R) and surfactant. This mixture may then be adjusted to same Viscosity in the eye that they had prior to administration the appropriate pH by known techniques, for example by the 65 to the eye. Alternatively, ophthalmic suspensions of the addition of sodium hydroxide. Other methods will be appar present invention may beformulated so that there is increased ent to one skilled in the art. gelation upon contact with tear fluid. For instance, when a US 8,778,999 B2 13 14 formulation containing DuraSite(R) is administered to the eye, Unless the intended purpose of use is affected adversely, the DuraSite R system swells upon contact with tears. This the ophthalmic formulation of the present invention can fur gelation or increase in gelation leads to a slower release rate ther comprise one or more additional therapeutically-active of bromfenac, thereby extending the residence time of the agents. Specific therapeutically-active agents include, but are composition in the eye. These events eventually leads to not limited to: antibacterial antibiotics, synthetic antibacteri increased patient comfort, increase in the time bromfenac is als, antifungal antibiotics, synthetic antifungals, antineoplas in contact with the eye tissues, thereby increasing the extent tic agents, steroidal anti-inflammatory agents, non-steroidal of drug absorption and duration of action of the formulation in anti-inflammatory agents, anti-allergic agents, glaucoma the eye. treating agents, antiviral agents, and anti-mycotic agents. 10 Further contemplated are any derivatives of the therapeuti In an embodiment, according to any of the above aspects of cally-active agents which may include, but not be limited to: the invention, the invention relates to a composition or analogs, salts, esters, amines, amides, alcohols and acids method for combination therapy of the eye of a mammal derived from an agent of the invention and may be used in including: an ophthalmic composition having a therapeuti place of an agent itself. cally effective amount of bromfenac, a therapeutically effec 15 Examples of the antibacterial antibiotics include, but are tive amount of ketorolac and a flowable mucoadhesive poly not limited to: aminoglycosides (e.g., amikacin, apramycin, mer such as DuraSite(R), wherein the composition has a arbekacin, bambermycins, butirosin, dibekacin, dihydros Viscosity formulated for administration to the eye of a mam treptomycin, fortimicin(s), gentamicin, isepamicin, kanamy mal in drop form. In an embodiment, ketorolac is included in cin, micronomicin, neomycin, neomycin undecylenate, the composition of the invention in an amount of about 0.01% netilmicin, paromomycin, ribostamycin, Sisomicin, spectino to about 1% by weight of the composition. In another embodi mycin, Streptomycin, tobramycin, trospectomycin), ment, ketorolac is included in the composition of the inven amphenicois (e.g., azidamfenicol, chloramphenicol, florfeni tion in an amount of about 0.4% to about 0.5% by weight of col, thiamphenicol), ansamycins (e.g., rifamide, rifampin, the composition. In another embodiment, the invention rifamycin SV, rifapentine, rifaximin), beta.-lactams (e.g., car relates to a composition or method for combination therapy of 25 bacephems (e.g., loracarbef), carbapenems (e.g., biapenem, the eye of a mammal including: an ophthalmic composition imipenem, meropenem, panipenem), cephalosporins (e.g., having a therapeutically effective amount of bromfenac, a cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, flowable mucoadhesive polymer such as DuraSite R and one cefazolin, cefcapene pivoxil, cefclidin, cefdinir, cefditoren, or more additional non-steroidal anti-inflammatory agent cefepime, cefetamet, cefixime, cefimenoxime, cefodizime, Such as, for example, ketorolac. In another embodiment, the 30 cefonicid, cefoperaZone, ceforanide, cefotaxime, cefotiam, invention relates to a composition or method for combination cefoZopran, cefpimizole, cefpiramide, cefpirome, cefpo therapy of the eye of a mammal including: an ophthalmic doxime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazi composition having a therapeutically effective amount of dime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriax bromfenac, a flowable mucoadhesive polymer such as Dur one, cefuroxime, ceifuZonam, cephacetrile Sodium, aSite Randone or more steroidal anti-inflammatory agent. In 35 cephalexin, cephaloglycin, cephaloridine, cephalosporin, another embodiment, the invention relates to a composition or cephalothin, cephapirin Sodium, cephradine, pivoefalexin), method for combination therapy of the eye of a mammal cephamycins (e.g., cefbuperaZone, cefimetazole, cefininox, including: an ophthalmic composition having a therapeuti cefotetan, cefoxitin), monobactams (e.g., aztreonam, caru cally effective amount of bromfenac, a flowable mucoadhe monam, tigemonam), oxacephems, flomoxef, moxalactam), sive polymer such as DuraSite(R) and one or more antibacterial 40 penicillins (e.g., amdinocillin, amdinocillin pivoxil, amox agent. In another embodiment, relating to any of the above icillin, amplicillin, apalcillin, aspoxicillin, azidocillin, aZlocil aspects, the invention relates to a composition or method for lin, bacampicillin, benzylpenicillinic acid, benzylpenicillin combination therapy of the eye of a mammal including: an Sodium, carbenicillin, carindacillin, clometocillin, cloxacil ophthalmic composition having a therapeutically effective lin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacil amount of bromfenac, a flowable mucoadhesive polymer 45 lin, hetacillin, lenampicillin, metampicillin, methicillin such as DuraSite(R) and an additional therapeutically active Sodium, mezlocillin, nafcillin Sodium, oxacillin, penamecil agent selected from the group consisting of antibacterial anti lin, penethamate hydriodide, penicilling benethamine, peni biotic agent, synthetic antibacterial agent, antifungal antibi cilling benzathine, penicilling benzhydrylamine, penicilling otic agent, Synthetic antifungal agent, antineoplastic agent, calcium, penicilling hydrabamine, penicilling potassium, steroidal anti-inflammatory agent, non-steroidal anti-inflam 50 penicilling procaine, penicillinn, penicillino, penicillin V, matory agent, anti-allergic agent, glaucoma-treating agent, penicillin V benzathine, penicillin V hydrabamine, penimepi antiviral agent and anti-mycotic agent. cycline, phenethicillin potassium, piperacillin, pivampicillin, In one embodiment, according to any of the above aspects propicillin, quinacillin, Sulbenicillin, Sultamicillin, talampi of the invention, the compositions of the invention can cillin, temocillin, ticarcillin), other (e.g., ritipenem), lincosa include, in addition to bromfenac, one or more other active 55 mides (e.g., clindamycin, lincomycin), macrollides (e.g., ingredients such as other NSAIDs. Suitable NSAIDs for com azithromycin, carbomycin, clarithromycin, dirithromycin, bination therapy are, for example, aspirin, benoxaprofen, erythromycin, erythromycin acistrate, erythromycineStolate, benzofenac, bucloxic acid, butibufen, carprofen, cicloprofen, erythromycin glucoheptonate, erythromycin lactobionate, cinmetacin, clidanac, clopirac, diclofenac, diflupredinate, erythromycin propionate, erythromycin Stearate, josamycin, etodolac, fenbufen, fenclofenac, fenclorac, fenoprofen, fen 60 leucomycins, midecamycins, miokamycin, oleandomycin, tiazac, flunoxaprofen, furaprofen, flurbiprofen, furobufen, primycin, rokitamycin, rosaramicin, roXithromycin, spira furofenac, ibuprofen, ibufenac, indomethacin, indoprofen, mycin, troleandomycin), polypeptides (e.g., amphomycin, isoxepac, ketorolac, ketroprofen, lactorolac, lonazolac, bacitracin, capreomycin, colistin, enduracidin, enviomycin, metiazinic, miroprofen, nepafenac, naproxen, norketotifen, fusafungine, gramicidin s, gramicidin(s), mikamycin, poly oxaprozin, oxepinac, phenacetin, pirprofen, piraZolac, protiz 65 myxin, pristinamycin, ristocetin, teicoplanin, thiostrepton, inic acid, Sulindac, Suprofen, tiaprofenic acid, tolmetin, and tuberactinomycin, tyrocidine, tyrothricin, Vancomycin, vio Zomepirac. mycin, Virginiamycin, Zinc bacitracin), tetracyclines (e.g., US 8,778,999 B2 15 16 apicycline, chlortetracycline, clomocycline, demeclocycline, neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin, doxycycline, guamecycline, lymecycline, meclocycline, viridin). Examples of the synthetic antifungals include, but methacycline, minocycline, oxytetracycline, penimepicy are not limited to: allylamines (e.g., butenafine, naftifine, cline, pipacycline, rollitetracycline, Sancycline, tetracycline), terbinafine), imidazoles (e.g., bifonazole, butoconazole, and others (e.g., cycloserine, mupirocin, tuberin). chlordantoin, chlormidazole, clotrimazole, econazole, enil Examples of the synthetic antibacterials include, but are conazole, fenticonazole, flutrimazole, isoconazole, keto not limited to: 2,4-diaminopyrimidines (e.g., brodimoprim, conazole, lanoconazole, miconazole, omoconazole, oxicona tetroxoprim, trimethoprim), nitrofurans (e.g., furaltadone, Zole nitrate, Sertaconazole, Sulconazole, tioconazole), furazolium chloride, nifuradene, nifuratel, nifurfoline, thiocarbamates (e.g., tolciclate, tolindate, tolnaftate), triaz nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin), quino 10 lones and analogs (e.g., cinoxacin, ciprofloxacin, clinafloxa oles (e.g., fluconazole, itraconazole, Saperconazole, tercona cin, difloxacin, enoxacin, fleroxacin, flumequine, grepafloxa Zole) others (e.g., acrisorcin, amorolfine, biphenamine, bro cin, lomefloxacin, miloxacin, nadifloxacin, nalidixic acid, mosalicylchloranilide, buclosamide, calcium propionate, norfloxacin, ofloxacin, oxolinic acid, paZufloxacin, pefloxa chlorphenesin, ciclopirox, cloxyquin, coparaffinate, diamt cin, pipemidic acid, piromidic acid, roSoxacin, rufloxacin, 15 hazole dihydrochloride, exalamide, flucytosine, halethazole, sparfloxacin, temafloxacin, to Sufloxacin, trovafloxacin), Sul hexetidine, loflucarban, nifuratel, potassium iodide, propi fonamides (e.g., acetyl Sulfamethoxypyrazine, benzylsulfa onic acid, pyrithione, Salicylanilide, sodium propionate, Sul mide, chloramine-b, chloramine-t, dichloramine-t, n. Sup.2- bentine, tenonitrozole, triacetin, ujothion, undecylenic acid, formylsulfisomidine, n. Sup.4-beta.-d- Zinc propionate). glucosylsulfanilamide, mafenide, 4'-(methylsulfamoyl) In general, ophthalmic formulations Suitable for topical Sulfanilanilide, noprylsulfamide, phthalylsulfacetamide, ophthalmic administration can be formulated and adminis phthalylsulfathiazole, Salazosulfadimidine, Succinylsul tered in accordance with techniques familiar to persons fathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpy skilled in the art. The finished formulations are stored in ridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, Sulfadi opaque or brown containers to protect them from light expo cramide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole, 25 Sure, and under an inert atmosphere. These compositions can Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic acid, Sul be packaged in preservative-free, single-dose non-reclosable/ farnerazine, Sulfameter, Sulfamethazine, Sulfamethizole, Sul reclosable containers or kits. This permits a single dose of the famethomidine, Sulfamethoxazole, Sulfamethoxypyridazine, medicament to be delivered to the eye as a drop, with the Sulfametrole, Sulfamidocchrysoidine, Sulfamoxole, Sulfanil container then being discarded after use. Such containers amide, 4-sulfanilamidosalicylic acid, n. Sup.4-Sulfanilylsulfa 30 nilamide, Sulfanily lurea, n-sulfanilyl-3,4-Xylamide, Sulfanit eliminate the potential for preservative-related irritation and rah, sulfaperine, sulfaphenazole, sulfaproxyline, sensitization of the corneal epithelium, as has been observed Sulfapyrazine, Sulfapyridine, Sulfasomizole, Sulfasymazine, to occur particularly from ophthalmic medicaments contain Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomidine, ing mercurial preservatives. Multiple dose containers can also Sulfisoxazole) sulfones (e.g., acedapsone, acediasulfone, 35 be used, if desired, particularly since the relatively low vis acetosulfone sodium, dapsone, diathymosulfone, glucosul cosities of the compositions of this invention permit constant, fone sodium, Solasulfone, Succisulfone, Sulfanilic acid, p-sul accurate dosages to be administered dropwise to the eye as fanilylbenzylamine, Sulfoxone sodium, thiazolsulfone), and many times each day as necessary. In those Suspensions others (e.g., clofoctol, hexedine, methenamine, methenamine where preservatives are to be included, suitable preservatives anhydromethylene-citrate, methenamine hippurate, meth 40 are chlorobutanol, polyguat, benzalkonium chloride, cetyl enamine mandelate, methenamine Sulfosalicylate, nitroXo bromide, sorbic acid and the like. line, taurolidine, Xibornol). Another embodiment of the present invention includes the Examples of the steroidal anti-inflammatory agents method of treating ocular inflammation and/or pain in a include, but are not limited to: 21-acetoxypregnenolone, patient in need with one of the ophthalmic formulations alclometasone, algestone, amcinonide, beclomethasone, 45 described above, wherein said inflammation and/or pain is betamethasone, budesonide, chloroprednisone, clobetasol, caused by Surgical trauma, and wherein said treatment com clobetaSone, clocortolone, cloprednol, corticosterone, corti prises treating the patient once, or twice a day. An additional Sone, cortivaZol, deflazacort, desonide, desoximetaSone, dex embodiment of the present invention includes the method of amethasone, diflorasone, diflucortolone, difluprednate, enox treating ocular pain and/or inflammation in a patient in need olone, fluazacort, flucloronide, flumethasone, flunisolide, 50 thereof, wherein said inflammation and accompanying pain is fluocinolone acetonide, fluocinonide, fluocortin butyl, fluo the result of cataract Surgery or one of many refractive eye cortolone, fluorometholone, fluperolone acetate, filupred Surgical techniques, and wherein said treatment comprises nidene acetate, fluprednisolone, flurandrenolide, fluticasone treating the patient once or twice daily with a formulation propionate, formocortal, halcinonide, halobetasol propi herein. onate, halometaSone, halopredone acetate, hydrocortamate, 55 An additional embodiment of the present invention hydrocortisone, loteprednol etabonate, maZipredone, includes the method of treating ocular pain and/or inflamma medrysone, meprednisone, methylprednisolone, mometa tion in a patient in need thereof, wherein said inflammation Sone furoate, paramethasone, prednicarbate, prednisolone, and accompanying pain is the result of allergic, viral or bac prednisolone 25-diethylamino-acetate, prednisolone sodium terial conjunctivitis, and wherein said treatment comprises phosphate, prednisone, prednival, prednylidene, rimexolone, 60 treating the patient with any of the disclosed formulations. tiXocortol, triamcinolone, triamcinolone acetonide, triamci An additional embodiment of the present invention nolone benetonide, and triamcinolone hexacetonide. includes a method treating ocular pain and/or inflammation Examples of the antifungal antibiotics include, but are not associated with allergic, viral or bacterial conjunctivitis with limited to: polyenes (e.g., amphotericin b, candicidin, den one of the topical ophthalmic formulations of the invention. nostatin, filipin, fungichromin, hachimycin, hamycin, lucen 65 An additional embodiment may include one or more addi Somycin, mepartricin, natamycin, nystatin, pecilocin, peri tional active ingredients as part of the formulation, Such addi mycin), others (e.g., azaserine, griseofulvin, oligomycins, tional actives may include, but are not limited to, antihista US 8,778,999 B2 17 18 mines and/or antibacterials and/or antimicrobial compounds, degeneration, macular disease, macular degeneration, heredi to further assist with the treatment of the conjunctivitis con tary macular dystrophy, macular edema, macular hole, macu dition. lar pucker, central serous chorioretinopathy, ocular histoplas An additional embodiment of the present invention mosis syndrome (OHS), posterior vitreous detachment, includes a method for treating an eye wherein its normal retinal detachment, retinal artery obstruction, retinal vein condition has been disrupted or changed comprising admin occlusion, retinoblastoma, retinopathy of prematurity (ROP), istering to said eye one to six times daily the formulation or retinitis pigmentosa, retinoschisis (acquired and X-linked), composition of the invention. An additional embodiment of Stargardt’s disease, toxoplasmosis of retina or uveitis. the present invention includes a method for treating postop In order that those skilled in the art can more fully appre erative inflammation and/or pain in patients who have under 10 ciate aspects of this invention, the following Tables and gone cataract extraction comprising the once, twice or up to examples are set forth. These examples are given solely for six times daily administration of a selected formulation into purposes of illustration and should not be considered as the effected eye. expressing limitations. For example, in one embodiment, the methods of the inven tion encompass a process for therapeutic treatment of an 15 EXAMPLE 1. inflammatory condition of the eye in a mammal including: (a) providing an ophthalmic composition comprising bromfenac Polycarbophil (Noveon RAA-1) was slowly dispersed into in an amount of about 0.005% to about 0.5% by weight of the a citrate buffer solution containing dissolved EDTA and composition and a flowable mucoadhesive polymer in an sodium chloride at approximately 50% of the final batch size. amount of about 0.5% to about 1.5% by weight of the com The resulting dispersion, which had a pH of about 3.0 to 3.5, position; (b) administering said composition to the eye of a was stirred with an overhead stirrer until visibly well mammal in need thereof to treat inflammation or inflamma hydrated. The mixture was sterilized by autoclaving at 121° tory conditions of the eye. In a related embodiment, the oph C. for 20 minutes. The pH was then brought up to approxi thalmic composition further includes a therapeutically active mately 4.0 to 4.4 with 2N sodium hydroxide. Bromfenac agent selected from the group consisting of antibacterial anti 25 Sodium was dissolved in a mannitol Solution containing dis biotic agent, synthetic antibacterial agent, antifungal antibi solved benzalkonium chloride and Poloxamer 407 at approxi otic, synthetic antifungal agent, antineoplastic agent, steroi mately 20% of the final batch size. The resulting solution was dal anti-inflammatory agent, non-steroidal anti-infaimatory then sterile filtered (0.22 um filter) in to the polymer disper agent, anti-allergic agent, glaucoma-treating agent, antiviral sion and stirred for 10 minutes. The pH of the bromfenac agent and anti-mycotic agent. In another related embodiment, 30 polymer dispersion was brought to 8.3 with 2N sodium wherein the non-steroidal anti-inflammatory agent is ketoro hydroxide. Sterile make up water was added to the formula lac. In an embodiment, ketorolac is included in the composi tion to final weight and mixed for at least 5 minutes. The tion of the invention in an amount of about 0.01% to about 1% formulation was aseptically filled into 5 ml bottles. SeeTable by weight of the composition. In another embodiment, 1 for formulation composition. ketorolac is included in the composition of the invention in an 35 amount of about 0.4% to about 0.5% by weight of the com TABLE 1 position. The inflammatory conditions for which the compositions Composition of Bromfenac Formulations and methods of the invention can be use are, but not limited to, Concentration (% ww Surgical trauma; dry eye; allergic conjunctivitis; viral con 40 junctivitis; bacterial conjunctivitis; blepharitis; anterior uvei Excipient Low Strength Mid Strength High Strength tis; injury from a chemical; radiation or thermal burn; injury Bromfenac O.045 O.09 O.36 from penetration of a foreign body, pain in or around the eye, Polycarbophil O.9 O.9 O.9 redness especially accompanied by pain in the eye; light Citric acid O.2 O.2 O.2 sensitivity; seeing halos (colored circles or halos around 45 Citric acid O.2 O.2 O.2 Sodium chloride O.14 O.14 O.14 lights); bulging (protrusion) of the eye; Swelling of eye tis Sodium chloride O.1 O.1 O.1 Sues; discharge, crusting or excessive tearing; eyelids stuck Poloxamer 407 O.1 O.1 O.1 together, blood inside the front of the eye (on the colored part) Manitol 1.O 1.O 1.O or white of the eye; cataracts; pain and inflammation associ Sodium hydroxide, 2N q.S. to pH 8.3 q.S. to pH 8.3 q.S. to pH 8.3 ated with wearing contact lenses; corneal-associated condi 50 Water q.S. to 100% q.S. to 100% q.S. to 100% tion; conjunctival tumor excision; conjunctivitis known as Pink Eye; cornea edema after cataract Surgery; corneal cloud ing; corneal transplantation; corneal ulcer, dry eye syndrome; EXAMPLE 2 dystrophies; condition associated with excimer laser photo therapeutic keratectomy; herpes simplex keratitis; keratoco 55 In this example, the formulations of 0.09% and 0.045% nus; pterygium; recurrent erosion syndrome; eye movement bromfenac in DuraSite(R), prepared according to Example 1, disorder, glaucoma, ocular oncology: oculoplastic condition were compared with Xibrom R and Radio-Xibrom R) in pro resulted from cosmetic Surgery, enucleation, eyelid and orbit viding bromfenac to the aqueous humor of the eye in pig injuries, ectropion, entropion, graves disease, involuntary mented rabbits (n=6). In a first experiment, separately, the eyelid blinking; condition associated with refractive Surgery; 60 formulation of 0.09% bromfenac in DuraSite(R), XibromR) and retinal condition. and Radio-Xibrom R. (C carbon 14 labeled bromfenac in The retinal condition for which the compositions and Xibrom from literature reference JOURNAL OF OCULAR methods of the invention can be used are, but not limited to, PHARMACOLOGY AND THERAPEUTICS, 24(2), 2008, macular degeneration, AIDS-related ocular disease, CMV 392-398) were topically administered to pigmented rabbits in retinitis, birdshot retinochoroidopathy (BR), choroidal mela 65 the amount of 1 dropper eye (approximately equal to about 25 noma, coats disease, cotton wool spots, diabetic retinopathy microliters per eye). Xibrom was administered to one eye and diabetic macular edema, cystoid macular edema, lattice the bromfenac DuraSite solution to the other. The concentra US 8,778,999 B2 19 20 tions of bromfenac in the aqueous humor of the eye were TABLE 2-continued determined by removing the aqueous humor and measuring concentrations by LCMS (see FIG. 1A). In a second experi Compositions and Target Attributes of NSAID Formulations ment, the bromfenac concentrations provided by 1 drop per O.09% eye of the formulation of 0.045% bromfenac in DuraSite(R), O.09% BF- O.4% KT- BFAO.4% Xibrom R) and Radio-Xibrom R) were separately monitored DuraSite DuraSite KT - DuraSite for 24 hours (see FIG. 1B). The results indicated that the Edetate disodium O.1 O.1 O.1 exemplary formulations of the invention unexpectedly facili dihydrate tated a high absorption and retention of bromfenac by the Sodium chloride O45 O45 O.45 10 Poloxamer 407 O.2 NA NA aqueous humor of the eye as compared with other XibromR) Octoxynol 40 NA 0.4 0.4 and Radio-Xibrom R. 2N sodium hydroxide q.S. to pH 8.3 q.S. to pH 7.4 q.S. to pH 8.3 Water q.S. to 100% q.S. to 100% q.S. to 100% EXAMPLE 3 Attribute TargetValue

15 Bromfenac Assay O.09% NA O.09% The formulation of 0.09% bromfenac in DuraSite R, pre Ketorolac NA O.4% O.4% Tromethamine Assay pared according to Example 1, was ophthalmically adminis pH 8.3 7.4 8.3 tered to pigmented rabbits in the same manner as Example 2. Viscosity 1500 cps 1500 cps 1500 cps TID for a period of 14 days. At the end of the 14-day period, Osmolality 290 mOsm/kg 290 mOsm/kg 290 mOsm/kg rabbits were sacrificed in accordance with the related regula tory and NIH guidelines for animal studies, and the concen tration of bromfenac was measured using LCMS. In this EXAMPLE 5 experiment, the retina was separated from the choroid and tissue concentrations of bromfenac were measured. The con Polycarbophil (Noveon RAA-1) was slowly dispersed into centration of bromfenac in the retina tissue from this 0.09% 25 a citrate buffer solution containing dissolved EDTA and brom fenrac formulation on average, was found to be 34+10.4 sodium chloride at approximately 50% of the final batch size. ng per gram of tissue. The resulting dispersion, which had a pH of about 3.0 to 3.5, was stirred with an overhead stirrer until visibly well EXAMPLE 4 hydrated. The mixture was sterilized by autoclaving at 121° C. for 20 minutes. The pH was then brought up to approxi Polycarbophil (Noveon RAA-1) was slowly dispersed into 30 mately 4.0 to 4.4 with 2N sodium hydroxide. Bromfenac a citrate buffer solution containing dissolved EDTA and Sodium and additional medicament was dissolved in a man sodium chloride at approximately 50% of the final batch size. nitol Solution containing dissolved benzalkonium chloride The resulting dispersion, which had a pH of about 3.0 to 3.5, and Poloxamer 407 at approximately 20% of the final batch was stirred with an overhead stirrer until visibly well size. The resulting solution was then sterile filtered (0.22 um 35 filter) in to the polymer dispersion and stirred for 10 minutes. hydrated. The mixture was sterilized by autoclaving at 121° The pH of the bromfenac drug-polymer dispersion was C. for 20 minutes. The pH was then brought up to approxi brought up to 8.0 with 2N sodium hydroxide. Sterile make up mately 4.0 to 4.4 with 2N sodium hydroxide. Bromfenac water was added to the formulation to final weight and mix for sodium (BF) and ketrolac tromethamine (KT) were dissolved at least 5 minutes. The formulation was aseptically filled into in a mannitol Solution containing dissolved benzalkonium 40 5 ml bottles containers. See Table 3 for formulation compo chloride and Poloxamer 407 at approximately 20% of the sition. final batch size. The resulting solution was then sterile filtered (0.22 um filter) in to the polymer dispersion and stirred for 10 minutes. The pH of the bromfenac-ketorolac tromethamine TABLE 3 polymer dispersion was brought to 8.3 with 2N sodium Compositions of Bromfenac with Additional Medicaments hydroxide. Sterile make up water was added to the formula 45 tion to final weight and mixed for at least 5 minutes. The Excipient Concentration (%) formulation was aseptically filled into 5 ml bottles containers. Bromfenac O.09 O.09 O.09 See Table 2 for composition and target attributes of the for Tobramycin O.3 mulations. Dexamethasone O.12S 50 phosphate Doxycycline HCL O.3 TABLE 2 Polycarbophil O.9 O.9 O.9 Benzalkonium chloride O.OOS O.OO6 O.OO6 Compositions and Target Attributes of NSAID Formulations Citric acid O.2 O.2 O.2 Sodium citrate O.14 O.14 O.14 O.09% 55 dihydrate O.09% BF- O.4% KT- BFAO.4% Mannitol 1.O 1.O 1.O DuraSite DuraSite KT - DuraSite Edetate disodium O.1 O.1 O.1 dihydrate Excipient Concentration (% w/w) Sodium chloride O.45 O45 O45 Poloxamer 407 O.2 O.2 O.2 Bromfenac O.09 NA O.09 60 2N sodium hydroxide q.S. to pH 8.0 q.S. to pH 8.0 q.S. to pH 8.0 Ketorolac NA 0.4 0.4 Water q.S. to 100% q.S. to 100% q.S. to 100% Tromethamine Polycarbophil O.9 O.9 O.9 Benzalkonium chloride O.OOS O.OO6 O.OO6 The embodiments within the specification provide an illus Citric acid O.2 O.2 O.2 Sodium citrate O.14 O.14 O.14 tration of embodiments of the invention and should not be dihydrate 65 construed to limit the scope of the invention. The skilled Mannitol 1.O 1.O 1.O artisan readily recognizes that many other embodiments are encompassed by the invention. US 8,778,999 B2 21 22 We claim: 10. The ophthalmic composition of claim 1, wherein the 1. A topical ophthalmic composition formulated for appli composition comprises from about 0.01 to 0.09 bromfenac by cation to the eye, said composition comprising a therapeuti weight of the composition. cally effective amount of bromfenac and a flowable 11. The ophthalmic composition of claim 10 wherein the crosslinked carboxy-containing polycarbophil mucoadhe composition has a pH of about 8.3. sive polymer, wherein the composition has a viscosity in the 12. An ophthalmic composition comprising a therapeuti range of about 1,000 to about 3,400 cps and a pH of about 7.4 cally effective amount of bromfenac, a therapeutically effec to about 8.5. tive amount of ketorolac and a flowable crosslinked carboxy 2. The ophthalmic composition according to claim 1, containing polycarbophil mucoadhesive polymer, wherein wherein the composition further comprises a therapeutically 10 the composition has a viscosity in the range of about 1,000 to about 3,400 cps and is formulated for administration effective amount of ketorolac. to the eye of a mammal in drop form, and 3. The ophthalmic composition according to claim 1, the composition has a pH of about 7.4 to about 8.5. wherein the flowable mucoadhesive polymer is in an amount 13. An ophthalmic composition comprising a therapeuti of about 0.5% to about 1.5% by weight of the composition. 15 cally effective amount of bromfenac and a flowable mucoad 4. The ophthalmic composition according to claim 1, hesive polymer, wherein: wherein bromfenac is in an amount of about 0.005% to about the composition has a viscosity in the range of about 1,000 0.5% by weight of the composition. to about 3,400 cps and is formulated for administration 5. The ophthalmic composition according to claim 1, to the eye of a mammal in drop form, wherein the composition further comprises an additional the composition further comprises at least one additional therapeutically active agent selected from the group consist non-steroidal anti-inflammatory agent, ing of antibacterial antibiotic agent, synthetic antibacterial the flowable mucoadhesive polymer is a crosslinked car agent, antifungal antibiotic agent, synthetic antifungal agent, boxy-containing polycarbophil, and antineoplastic agent, steroidal anti-inflammatory agent, non the composition has a pH of about 7.4 to about 8.5. steroidal anti-inflammatory agent, anti-allergic agent, glau 25 14. An ophthalmic composition comprising a therapeuti coma-treating agent, antiviral agent and anti-mycotic agent. cally effective amount of bromfenac and a flowable mucoad 6. The ophthalmic composition according to claim 5. hesive polymer, wherein: wherein the additional therapeutic active agent is a non-ste the composition has a viscosity in the range of about 1,000 roidal anti-inflammatory agent selected from the group con to about 3,400 cps and is formulated for administration sisting of aspirin, benoxaprofen, benzofenac, bucloxic acid, 30 to the eye of a mammal in drop form, butibufen, carprofen, cicloprofen, cinmetacin, clidanac, clo the composition further comprises at least one steroidal pirac, diclofenac, diflupredinate, etodolac, fenbufen, fen anti-inflammatory agent, clofenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, the flowable mucoadhesive polymer is a crosslinked car furaprofen, flurbiprofen, furobufen, furofenac, ibuprofen, boxy-containing polycarbophil, and ibufenac, indomethacin, indoprofen, isoxepac, ketorolac, ket 35 the composition has a pH of about 7.4 to about 8.5. roprofen, lactorolac, lonazolac, metiazinic, miroprofen, 15. An ophthalmic composition comprising a therapeuti naproxen, oxaprozin, oxepinac, phenacetin, pirprofen, pira cally effective amount of bromfenac and a flowable mucoad Zolac, protizinic acid, Sulindac, Suprofen, tiaprofenic acid, hesive polymer, wherein: tolimetin, and Zomepirac. the composition has a viscosity in the range of about 1,000 7. The ophthalmic composition according to claim 6. 40 to about 3,400 cps and is formulated for administration wherein the additional non-steroidal anti-inflammatory agent to the eye of a mammal in drop form, is ketorolac. the composition further comprises at least one antibacterial 8. The ophthalmic composition according to claim 5. agent, wherein the additional therapeutic active agent is a steroidal the flowable mucoadhesive polymer is a crosslinked car anti-inflammatory agent selected from the group consisting 45 boxy-containing polycarbophil, and of 21-acetoxypregnenolone, alclometasone, algestone, amci the composition has a pH of about 7.4 to about 8.5. nonide, beclomethasone, betamethasone, budesonide, chlo 16. A method for therapeutic treatment of an inflammatory roprednisone, clobetasol, clobetaSone, clocortolone, clopred condition of the eye in a mammal comprising nol, corticosterone, cortisone, cortivaZol, deflazacort, administering the composition of claim 1 to the eye of a desonide, desoximetaSone, dexamethasone, diflorasone, 50 mammal in need thereof to treat inflammation or inflam diflucortolone, difluprednate, enoxolone, fluazacort, fluclo matory conditions of the eye. ronide, flumethasone, flunisolide, fluocinolone acetonide, 17. The method for therapeutic treatment of an inflamma fluocinonide, fluocortin butyl, fluocortolone, fluo tory condition of the eye in a mammal according to claim 16. rometholone, fluperolone acetate, fluprednidene acetate, flu wherein the ophthalmic composition further comprises a prednisolone, flurandrenolide, fluticasone propionate, for 55 therapeutically active agent selected from the group consist mocortal, halcinonide, halobetasol propionate, ing of antibacterial antibiotic agent, synthetic antibacterial halometaSone, halopredone acetate, hydrocortamate, hydro agent, antifungal antibiotic, synthetic antifungal agent, anti cortisone, loteprednol etabonate, maZipredone, medrysone, neoplastic agent, steroidal anti-inflammatory agent, non-ste meprednisone, methylprednisolone, mometaSone furoate, roidal anti-inflammatory agent, anti-allergic agent, glau paramethasone, prednicarbate, prednisolone, prednisolone 60 coma-treating agent, antiviral agent and anti-mycotic agent. 25-diethylamine-acetate, prednisolone sodium phosphate, 18. The method for therapeutic treatment of an inflamma prednisone, prednival, prednylidene, rimexolone, tiXocortol, tory condition of the eye in a mammal according to claim 17. triamcinolone, triamcinolone acetonide, triamcinolone bene wherein the therapeutically active agent is ketorolac. tonide, and triamcinolone hexacetonide. 19. The method for therapeutic treatment of an inflamma 9. The topical ophthalmic composition of claim 1, wherein 65 tory condition of the eye in a mammal according to claim 16. the viscosity of the composition is in the range of about 1,000 wherein the inflammatory condition is selected from the to about 2,000 cps. group consisting of inflammatory conditions associated with US 8,778,999 B2 23 24 Surgical trauma; dry eye; allergic conjunctivitis; viral con wherein the inflammatory condition is associated with a reti junctivitis; bacterial conjunctivitis; blepharitis; anterior uvei nal condition. tis; injury from a chemical; radiation or thermal burn; injury 21. The method for therapeutic treatment of an inflamma from penetration of a foreign body; pain in or around the eye; tory condition of the eye in a mammal according to claim 20, redness and pain in the eye; light sensitivity; seeing colored 5 wherein the retinal condition is selected from the group con circles or halos around lights; protrusion of the eye; Swelling sisting of age related macular degeneration, AIDS-related of eye tissues; discharge, crusting or excessive tearing; eye ocular disease, CMV retinitis, birdshot retinochoroidopathy lids stuck together; blood on the colored part or white of the (BR), choroidal melanoma, coats disease, cotton wool spots, eye; cataracts; wearing contact lenses; corneal-associated diabetic retinopathy diabetic macularedema, cystoid macular condition; conjunctival tumor excision; conjunctivitis; cor 10 neal edema associated with cataract Surgery; corneal cloud edema, lattice degeneration, macular disease, macular degen ing; corneal transplantation; corneal ulcer, dry eye syndrome; eration, hereditary macular dystrophy, macular edema, macu dystrophies; excimer laser phototherapeutic keratectomy; lar hole, macular pucker, central serous chorioretinopathy, herpes simplex keratitis; keratoconus; pterygium; recurrent ocular histoplasmosis syndrome (OHS), posterior vitreous erosion syndrome; eye movement disorder, glaucoma, ocular 15 detachment, retinal detachment, retinal artery obstruction, tumor, ocuplastic Surgery; enucleation; eyelid or orbit inju retinal vein occlusion, retinoblastoma, retinopathy of prema ries: ectropion; entropion; graves disease; involuntary eyelid turity (ROP), retinitis pigmentosa, acquired or X-linked reti blinking; refractive Surgery; and retinal condition. noschisis, Stargardt’s disease, toxoplasmosis of retina and 20. The method for therapeutic treatment of an inflamma uveitis. tory condition of the eye in a mammal according to claim 16.