US 2011 01 05450A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0105450 A1 Chapin et al. (43) Pub. Date: May 5, 2011
(54) OPHTHALMC FORMULATIONS OF Publication Classification FLUTCASONE AND METHODS OF USE (51) Int. Cl. (75) Inventors: Matthew J. Chapin, Amesbury, A6II 3/56 (2006.01) MA (US); George Minno, A6IP27/02 (2006.01) Suwanee, GA (US); Jackie Nice, A6IP37/08 (2006.01) Medford, MA (US); Paul Gomes, Haverhill, MA (US); Mark Barry (52) U.S. Cl...... S14/18O Abelson, Andover, MA (US) (73) Assignee: Aciex Therapeutics, Inc., (57) ABSTRACT Westborough, MA (US) The present invention provides ophthalmic formulations of (21) Appl. No.: 12/794,320 fluticasone that provide a comfortable formulation when instilled in the eye and is effective in the treatment of allergic (22) Filed: Jun. 4, 2010 conjunctivitis and/or allergic conjunctivitis. The invention further provides methods of treating allergic conjunctivitis Related U.S. Application Data and/or allergic conjunctivitis in a Subject in need of Such (60) Provisional application No. 61/184,484, filed on Jun. treatment by topical application of the fluticasone formula 5, 2009. tions of the invention directly to the eye. Patent Application Publication May 5, 2011 Sheet 1 of 22 US 2011/O105450 A1
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This application claims priority under 35 U.S.C. cells. S119(e) to U.S. Provisional Application Ser. No. 61/184,484, 0006. Like allergic conjunctivitis, allergic rhinoconjunc filed Jun. 5, 2009, the contents of which are hereby incorpo tivitis is an allergen-induced, mast cell-mediated response. rated by reference in its entirety. The reaction is triggered when airborne allergens bind to FIELD OF THE INVENTION antibodies attached to the surface of mast cells in the eye and/or nose. Mast cells, in turn, release chemical mediators, 0002 The invention relates to compositions comprising which account for the immediate reaction in sensitized indi fluticasone, alone or in combination with one or more addi viduals exposed to allergen. Some of these mediators, such as tional active agents, and methods for using the same for histamine, directly affect blood vessels and nerves, leading to treating allergic conjunctivitis and allergic rhinoconjunctivi the signs and symptoms of allergic disease. Other released tis. mediators cause the influx of white blood cells to the site, which leads to Sustained symptoms in severe cases and par BACKGROUND OF THE INVENTION ticularly congestion in the nose. 0003. There exists a need for topical ophthalmic pharma 0007 Allergic conjunctivitis and rhinoconjunctivitis may ceutical products to effectively treat allergic conjunctivitis, a also co-exist with other external ocular conditions and dis disorder that presents with both acute allergic symptoms (i.e., eases, such as dry eye, or irritations caused by pollutants or seasonal allergy) and late phase inflammatory reactions (i.e., other causes. This leads to a compromised tear film, which chronic, refractory or persistent allergy), as well as allergic serves to protect the ocular Surface from allergens. rhinoconjunctivitis. It has been estimated that 46% (-70 mil 0008 Currently available treatments for eye allergy lion) of the adult allergy patients in the United States suffer include: drops which can washallergens off the ocular Surface from both the acute and late phase conditions of allergic and act as a barrier for the eye (e.g. artificial tears), drugs conjunctivitis, whereas only 19% suffer from only acute or which block histamine from binding to the histamine recep late phase allergy, respectively. It is estimated that allergic tors (e.g. antihistamines), drugs that block the release of rhinoconjunctivitis (a combination of ocular and nasal symp histamine and other substances from the mast cell (e.g. mast toms) may occur in up to 90% of patients with allergies. The cell stabilizers), drugs with multiple modes of action (e.g. average age of allergy Sufferers—between 20 and 40 years— antihistamine/mast cell stabilizing agents), and drugs that can coincides with the average age of the workforce and the most actively constrict blood vessels thus reducing redness and productive period of an individual's life. Swelling (e.g. vasoconstrictors). The criteria which may be 0004 Both seasonal and perennial allergic conjunctivitis considered in evaluating the appropriateness of an agent for a (ocular allergies) are characterized by itchy, red, Swollen, and patient include: efficacy at onset of action, duration of action, watery eyes. Allergic rhinitis (nasal allergies) manifests as a how well it controls the individual signs and symptoms of runny nose, Sneezing, congestion, and similar symptoms. It ocular allergy, and comfort of the drop when instilled in the can be difficult for a physician to distinguishallergic conjunc eye. The comfort of an ophthalmic product depends on the tivitis from allergic rhinoconjunctivitis because both allergic active pharmaceutical ingredient itself, as well as the nature reactions can occur simultaneously or be triggered by the of the formulation and the vehicle that makes up the product. same types of stimuli. It is further difficult to distinguish acute For example, oral antihistamines have been shown to induce allergic symptoms from late phase symptoms of allergic con decreased tear production and lead to dryness of the ocular junctivitis, as each of these conditions can persist simulta Surface, making the eye Susceptible to irritation by an oph neously or morph back and forth in any given individual. The thalmic product. signs and symptoms of allergic conjunctivitis and allergic 0009. The currently available treatments which contain an rhinoconjunctivitis can significantly impact the quality of life antihistamine or a mast cell stabilizer typically provide relief of patients, from Social interactions, productivity at work and for only acute allergic conjunctivitis and don't address the School, to the ability to perform visual tasks Such as working signs and symptoms of the late phase inflammatory reactions on a computer or reading. (i.e., chronic, refractory, or persistent allergy). 0005 Acute symptoms of allergic conjunctivitis are char 0010 Currently available treatments for allergic rhi acterized by the clinical signs and symptoms of eye itching, noconjunctivitis include eyedrops, nasal sprays, and systemic redness, and Swelling. Late phase or allergic inflammation oral agents. Currently approved anti-allergy eyedrops are reactions of allergic conjunctivitis include redness, lid Swell indicated for ocular allergy and nasal sprays are targeted for ing and tearing, and in some cases itching, as well as the nasal allergy. Systemic agents, while they have indications to predominance of congestion in the nose. Acute allergic Symp treat both nasal and ocular symptoms, several well controlled toms are predominantly caused by the activation of mast cells, clinical trials conducted to ophthalmic standards have shown which when stimulated by an allergen (pollen, dust, dander) that systemic antihistamines are inferior to eyedrops in treat releases a host of substances that produce the signs and Symp ing the ocular signs and symptoms (Spangleret al., Clin. Ther. toms of allergic conjunctivitis (itching, redness, Swelling, and 25(8), 224.5-2267 (2003), are not in fact clinically effective on tearing). Histamine is the primary mediator released and eye allergy, and actually have been shown by objective mea stimulates receptors on nerve endings and blood vessels to Sures to reduce tear production on the eye by 50%, causing produce itching and redness. There are two histamine recep ocular dryness (Ousler et al. Ann Allergy Asthma Immunol. tors that have been identified on the ocular surface. H1 recep November; 93(5):460-4 (2004)). Further studies have shown tors on nerve endings lead to itching, and H1 and H2 receptors that the combination of an eyedrop and nasal steroid is more US 2011/O 105450 A1 May 5, 2011 effective than a systemic agent in treating the ocular and nasal 0015. In a particular embodiment, the formulations signs and symptoms of allergy (Lanier et al. Clin. Ther. 24(7). described herein provide stable formulations comprising flu 1161-1174 (2002)). ticasone as the only active agent, Suitable for ophthalmic use 0011 Fluticasone propionate (S-(fluoromethyl)6.alpha. in a comfortable ophthalmic formulation when instilled 9-difluoro-11.beta., 17-dihydroxy-16.alpha.-methyl-1-3- directly in the eye. The fluticasone alone formulations (i.e., oxoandrosta-1,4-diene-17.beta.-carbothioate, 17-propionate) fluticasone as the only active agent) of the invention, are is an anti-inflammatory corticosteroid described in U.S. Pat. Surprisingly more effective in mitigating the signs and Symp No. 5,676,929, incorporated herein by reference in its toms of ocular allergy Such as ocularitching, redness, chemo entirety. It is known within the art that the acute and chronic sis, lid Swelling, and nasal symptoms associated with ocular use of large doses of corticosteroids, such as fluticasone pro allergy/rhinoconjunctivitis, than conventional antihistamine pionate, may produce serious side effects. Such signs or and/or mast cell stabilizer agents that are typically used to symptoms are generally dose dependent and may include treat allergic conjunctivitis and/or rhinoconjunctivitis. Anti musculoskeletal effects (including osteoporosis, myopathy, histamines and mast cell stabilizers do not effectively block aseptic necrosis of bone), ophthalmic effects (including pos all allergic and pro-inflammatory mediators from the mast terior Subcapsular cataracts, increased intraocular pressure, cell. While antihistamines and mast cell stabilizers may effec and increased risk of infection), gastrointestinal effects (in tively mask itching, they have minimal effects on redness, cluding ulcers, pancreatitis, nausea, vomiting), cardiovascu tearing, Swelling and inflammation. Without intending to be lar effects (hypertension, atherosclerosis), central nervous bound by any theory, fluticasone can effectively halt the tran system effects (pseudotumor cerebri, psychiatric reactions), Scription and production of inflammatory mediators and dermatological effects (hirsutism, redistribution of subcuta down-regulate the production of anti-inflammatory media neous fat, impaired wound healing, thinning of the skin) and tors, thereby treating the signs and symptoms of both acute Suppression of the hypothalamus-pituitary-adrenal axis. Fur and late phase allergic conjunctivitis (i.e., the aggregate dis ther, it is known in the art that chronic use of large doses of ease). fluticasone propionate may result in hypercorticism. 0016. In one embodiment, the fluticasone formulation of 0012. There thus exists a need to develop an effective, the invention comprises a stable ophthalmic formulation of stable yet comfortable and safe fluticasone formulation for fluticasone as the only active ingredient at a concentration of ophthalmic administration for the treatment of allergic con 0.001% to 1.0% (w/v), or any specific value within said range. junctivitis (i.e., the acute phase, the late inflammatory phase, Preferably, fluticasone is present in the formulation at a con or both) and allergic rhinoconjunctivitis. Such formulations centration of 0.001% and 0.2% (w/v), or any specific value for administration directly to the eye would be advantageous within said range. For example, fluticasone is formulated at a over systemic oral formulations and nasal sprays due to direct concentration of 0.001%, 0.005%, 0.01%, 0.015%, 0.025%, local effect, faster action and avoidance of the systemic side or 0.2% (w/v). In a particular embodiment, fluticasone is effects associated with Systemic administration present in the formulationata concentration of 0.005% (w/v). In another particular embodiment, fluticaSone is present in the SUMMARY OF THE INVENTION formulation at a concentration of 0.01% (w/v), and yet in 0013 The present invention provides comfortable topical another embodiment fluticasone is present in the formulation ophthalmic formulations for the treatment of both acute and at a concentration of 0.001% (w/v). late phase signs of allergic conjunctivitis as well as rhinocon 0017. The invention also provides ophthalmic formula junctivitis which contain fluticasone, alone or in combination tions of fluticaSone in combination with one or more active with one or more additional active agents (i.e., fluticasone ingredients including but not limited to an antihistimine Such alone or fluticasone combination formulations), to relieve the as cetirizine, antazoline, astemizole, azelastine, bepotastine, signs and symptoms of allergic conjunctivitis and/or rhi bilastine, brompheniramine, chlorpheniramine, clemastine, noconjunctivitis, particularly ocular itching and/or nasal desloratidine, dexbrompheniramine, diphenhydramine, Symptoms (e.g., itchy, running nose, Sneezing, nasal/sinus doxylamine, ebastine, emedastine, epinastine, fexofenadine, congestion). Surprisingly, once a day dosing of the flutica hydroxy Zine, ketotifen, levocabastine, levocetirizine, lorati sone formulations of the invention is effective to mitigate the dine, meduitazine, mizolastine, norketotifen, olopatadine, symptoms of allergic conjunctivitis and/or rhinoconjunctivi oXatomide, phenindamine, pheniramine, pyrilamine, terfeni tis, particularly ocular itching and/or nasal symptoms (e.g., dine, and triprolidine; a vasoconstrictor Such as naphazoline, itchy, running nose, Sneezing, nasal/sinus congestion). More oxymetazoline, phenylephrine, or tetrahydrozoline; or any Surprisingly, the fluticaSone formulations of the invention do combination thereof. not increase intraocular pressure in the eye after repeated use 0018. The fluticasone combination formulations are effec (e.g., after 14 days in a study population, described herein). tive in further mitigating the symptoms of ocular allergy Such As such the fluticasone formulations of the invention are safe as ocular itching, redness, chemosis, lid Swelling, and nasal for ocular use. symptoms associated with ocular allergy, as well as allergic 0014. The ophthalmic administration of fluticasone using rhinoconjunctivitis. the formulations of the present invention may lower negative 0019 More specifically, the fluticasone combination for systemic side effects usually associated with nasal or sys mulations of the invention (for example without limitation, temic administration of the drug and may increase the effi fluticasone and cetirizine in combination) provide a compre cacy of the drug in the eye. Accordingly, the present invention hensive treatment benefit for both acute and late phase reac provides topical ophthalmic formulations of fluticasone that tions of allergic conjunctivitis that cannot be achieved by the are comfortable when instilled in the eye and effective to use of a single anti-allergic, or other active agent, alone. As mitigate the symptoms of ocular allergy Such as ocular itch previously stated, antihistamines and mast cell stabilizers do ing, redness, chemosis, lid Swelling, and nasal symptoms not effectively block all allergic and pro-inflammatory associated with ocular allergy (e.g., stuffy, runny nose). mediators from the mast cell. Antihistamines and mast cell US 2011/O 105450 A1 May 5, 2011 stabilizers may effectively mask itching but they have mini suitable for use in the methods or formulations of the inven mal effects on redness, tearing, Swelling and inflammation. tion include but are not limited to aqueous polymeric Suspen However, when an antihistamine or mast cell stabilizer is sions comprising one or more polymeric Suspending agents combined with another active agent which can halt the tran including without limitation dextrans, polyethylene glycol, Scription and production of inflammatory mediators and polyvinylpyrolidone, polysaccharide gels, Gelrite R, cellulo down-regulate the production of anti-inflammatory mediator, sic polymers, and carboxy-containing polymer systems. In a Such as a steroid (e.g., fluticaSone), treatment of the signs and particular embodiment, the polymeric Suspending agent com symptoms of acute and late phase allergic conjunctivitis (i.e., prises a crosslinked carboxy-containing polymer (e.g., poly the aggregate disease) is achieved. Likewise, such fluticasone carbophil). In another particular embodiment, the polymeric combination formulations provide a comprehensive treat Suspending agent comprises a polyethylene glycol (PEG). ment benefit for rhinoconjunctivitis that cannot be achieved Examples of cross-linked carboxy-containing polymer sys by the use of a single anti-allergic, or other active agent alone, tems suitable for use in the topical stable ophthalmic flutica for these same reasons. sone formulations of the invention include but are not limited 0020. In one embodiment, the fluticasone combination to Noveon AA-1, Carbopol R, and/or DuraSite R (InSite formulation of the invention comprises a stable ophthalmic Vision). formulation of fluticasone at a concentration of 0.001% to 0024 Optionally, the formulations of the invention con 1.0% (w/v), or any specific value within said range. Prefer tain a preservative. In particular embodiments the preserva ably, fluticaSone is present in the combination formulation at tive is benzalkonium chloride or a derivative thereof (e.g., a concentration of 0.001% and 0.2% (w/v), or any specific PolycuadR), or a stabilized oxychloro complex (e.g., value within said range. For example, fluticasone is formu PuriteR), or sodium perborate, or sorbate. lated at a concentration of 0.001%, 0.005%, 0.01%, 0.015%, 0025. In certain embodiments, the fluticasone alone and 0.025%, or 0.2% (w/v). In a particular embodiment, flutica fluticasone combination formulations of the invention are Sone is present in the combination formulation at a concen formulated in a vehicle comprising 1% Polyethylene Glycol tration of 0.005% (w/v). In another particular embodiment, 400, NF: 0.2% Dibasic Sodium Phosphate, Anhydrous, USP; fluticasone is present in the combination formulation at a 0.25% Hypromellose, USP; 0.1% Polysorbate 80, NF; 1.2% concentration of 0.01% (w/v). to 1.8% Glycerin (or any specific value within said range), 0021. In some embodiments, the fluticasone formulations USP; 0.025% Edetate Disodium, USP; 0.01% Benzalkonium of the invention comprise a tear Substitute. In particular Chloride, NF (pH 7.0). embodiments, the tear substitute is hydroxypropylmethylcel 0026. In one preferred embodiment, the fluticasone for lulose (Hypromellose or HPMC). According to some mulation comprises 0.005% fluticasone, 1% Polyethylene embodiments, the concentration of HPMC ranges from about Glycol 400, NF, 0.2% Dibasic Sodium Phosphate, Anhy 0.1% to about 2% w/v. or any specific value within said range. drous, USP, 0.25% Hypromellose, USP, 0.1% Polysorbate According to some embodiments, the concentration of 80, NF, 1.8% Glycerin, USP, 0.025% Edetate Disodium, USP HPMC ranges from about 0.5% to about 1% w/v. or any and 0.01% Benzalkonium Chloride, NF (pH 7.0). specific value within said range. In a preferred embodiments, 0027. In another preferred embodiment, the fluticasone the concentration of HPMC ranges from about 0.1% to about formulation comprises 0.01% fluticasone, 1% Polyethylene 1.0% w/v., or any specific value within said range (e.g., 0.1- Glycol 400, NF, 0.2% Dibasic Sodium Phosphate, Anhy 0.2%, 0.2-0.3%, 0.3-0.4%, 0.4-0.5%, 0.5-0.6%, 0.6-0.7%, drous, USP, 0.25% Hypromellose, USP; 0.1% Polysorbate 0.7-0.8%, 0.8-0.9%, 0.9-1.0%; about 0.2%, about 0.21%, 80, NF, 1.2% Glycerin, USP, 0.025% Edetate Disodium, USP about 0.22%, about 0.23%, about 0.24%, about 0.25%, about and 0.01% Benzalkonium Chloride, NF (pH 7.0). 0.26%, about 0.27%, about 0.28%, about 0.29%, about 0028. According to some embodiments, the ophthalmic 0.30%, about 0.70%, about 0.71%, about 0.72%, about formulations of the present invention has a viscosity that 0.73%, about 0.74%, about 0.75%, about 0.76%, about ranges from about 10 to about 150 centipoise (cpi), preferably 0.77%, about 0.78%, about 0.79%, about 0.80%, about about 15 to about 120 cpi, even more preferably about 20 to 0.81%, about 0.82%, about 0.83%, about 0.84%, about about 90 cpi (or any specific value within said ranges). 0.85%, about 0.86%, about 0.87%, about 0.88%, about According to a preferred embodiment, the ophthalmic formu 0.89%, or about 0.90%). lations of the present invention has a viscosity that ranges 0022. In another particular embodiment the tear substitute from about 15 cpito about 30 cpi, or any specific value within is carboxymethyl cellulose (CMC). According to some said range (i.e., about 15 cpi, about 16 cpi, about 17 cpi, about embodiments, the concentration of CMC ranges from about 18 cpi, about 19 cpi, about 20 cpi, about 20 cpi, about 22 cpi, 0.1% to about 2% w/v. or any specific value within said range. about 23 cpi, about 24 cpi, about 25 cpi, about 26 cpi, about 27 According to some embodiments, the concentration of CMC cpi, about 28 cpi, about 29 cpi, about 30 cpi). According to ranges from about 0.1% to about 1% w/v. or any specific value another preferred embodiment, the ophthalmic formulations within said range. In a preferred embodiments, the concen of the present invention has a viscosity that ranges from about tration of CMC ranges from about 0.7% to about 0.9% w/v. or 70 cpito about 90 cpi, or any specific value within said range any specific value within said range (i.e., about 0.70%, about (i.e., about 70 cpi, about 71 cpi, about 72 cpi, about 73 cpi, 0.71%, about 0.72%, about 0.73%, about 0.74%, about about 74 cpi, about 75 cpi, about 76 cpi, about 77 cpi, about 78 0.75%, about 0.76%, about 0.77%, about 0.78%, about cpi, about 79 cpi, about 80 cpi, about 81 cpi, about 82 cpi, 0.79%, about 0.80%, about 0.81%, about 0.82%, about about 83 cpi, about 84 cpi, about 85 cpi, about 86 cpi, about 87 0.83%, about 0.84%, about 0.85%, about 0.86%, about cpi, about 88 cpi, about 89 cpi or about 90 cpi). 0.87%, about 0.88%, about 0.89%, or about 0.90%). 0029. The invention also provides methods for the treat 0023. In yet another particular embodiment, the flutica ment of allergic conjunctivitis in a Subject in need of Such Sone formulations of the invention comprise a polymeric, treatment by administering a fluticaSone formulation of the mucoadhesive vehicle. Examples of mucoadhesive vehicles invention (i.e., alone or in combination with one or more US 2011/O 105450 A1 May 5, 2011 active ingredients) directly to the eye of a subject in need of 0041 FIG. 11 is a bar graph summarizing the results such treatment or prevention. Preferably, the formulation of shown in FIGS. 7-10. the invention is administered once a day (q.d.). In certain 0042 FIG. 12 is a line graph comparing the efficacy of embodiments, the methods of the invention (i.e., administra Fluticasone 0.001%, 0.005% and 0.01% as compared to tion of a formulation of the invention directly to the eye) are vehicle in reducing rhinorrhea, assessed on a scale of 0 (none) also effective to treat nasal symptoms associated with allergic to 4 (severe) over time. conjunctivitis. The invention also provides methods of treat 0043 FIG. 13 is a line graph comparing the efficacy of ing and preventing the symptoms of allergic rhinoconjunc Fluticasone 0.001%, 0.005% and 0.01% as compared to tivitis by administering a fluticasone formulation of the vehicle in reducing ear or palate pruritis, assessed on a scale invention (i.e., fluticasone alone or in combination with an of 0 (none) to 4 (severe) over time. additional active agent such as an antihistamine (e.g., without 0044 FIG. 14 is a line graph comparing the efficacy of limitation cetirizine or ketotifen) or a vasoconstrictor (e.g. Fluticasone 0.001%, 0.005% and 0.01% as compared to without limitation, naphazoline or oxymetazoline) directly to vehicle in reducing nasal pruritis, assessed on a scale of 0 the eye of a subject in need of Such treatment or prevention. (none) to 4 (severe) over time. By providing a treatment option in eye drop form, the present 0045 FIG. 15 is a line graph comparing the efficacy of invention will improve quality of life in patients with allergic Fluticasone 0.001%, 0.005% and 0.01% as compared to rhinoconjunctivitis/rhinitis (See e.g., Berger et al., Ann. vehicle on total nasal score, assessed on a scale of 0 (no nasal Allergy Asthma Immunol. October 95(4), 361-71 (2005)). symptoms) to 16 (multiple nasal symptoms) over time. 0030 The invention also provides kits comprising a phar 0046 FIG. 16 is a bar graph summarizing the results maceutical composition of fluticasone formulated for oph shown in FIGS. 12-15. thalmic use and instructions for Such use. Other features and 0047 FIG. 17 is a line graph comparing the efficacy of advantages of the invention will become apparent from the Fluticasone 0.001%, 0.005% and 0.01% as compared to following detailed description and claims. vehicle on PNIF. 0048 FIG. 18 a line graph comparing the drop comfort of BRIEF DESCRIPTION OF THE DRAWINGS Fluticasone 0.001%, 0.005% and 0.01% as compared to 0031 FIGS. 1A and 1B depict a study design (screening vehicle, assessed on a scale of 0 (extremely comfortable) to and evaluation) for testing the efficacy of Fluticasone 10 (extremely uncomfortable) over time. 0.001%, 0.005% and 0.01% as compared to vehicle in reduc 0049 FIG. 19 a line graph comparing the drop comfort of ing ocular and nasal Symptoms of ocular allergy in an allergic Fluticasone 0.001%, 0.005% and 0.01% as compared to conjunctivitis model. vehicle, assessed on a scale of 0 (extremely comfortable) to 0032 FIG. 2 is a line graph comparing the efficacy of 10 (extremely uncomfortable) over time. Fluticasone 0.001%, 0.005% and 0.01% as compared to 0050 FIG. 20 is a chart summarizing the incidence of vehicle in reducing ocularitching assessed on a scale of 0 (no adverse events associated with instillation of Fluticasone itching) to 4 (severe itching) over time. 0.001%, 0.005% and 0.01% in the eye. 0033 FIG. 3 is a line graph comparing the efficacy of 0051 FIG. 21 is a bar graph summarizing the effects of Fluticasone 0.001%, 0.005% and 0.01% as compared to Fluticasone 0.001%, 0.005% and 0.01% as compared to vehicle in reducing conjunctival redness, assessed on a scale vehicle on intraocular pressure. of 0 (no redness) to 4 (severe redness) over time. 0034 FIG. 4 is line graph comparing the efficacy of Flu DETAILED DESCRIPTION ticasone 0.001%, 0.005% and 0.01% as compared to vehicle 0.052 The invention is based, in part, upon the surprising in reducing lidswelling, assessed on a scale of 0 (no Swelling) and upredicatable discovery that stable topical ophthalmic to 3 (severe swelling) over time. formulations of fluticaSone alone (i.e., fluticasone as the only 0035 FIG. 5 is a line graph comparing the efficacy of active agent in the formulation) are both comfortable when Fluticasone 0.001%, 0.005% and 0.01% as compared to applied directly to the eye and effective to treat both the acute vehicle in reducing nasal congestion, assessed on a scale of 0 and late phase reactions of allergic conjunctivitis, as well as (no congestion) to 4 (severe congestion) over time. allergic rhinoconjunctivitis. An even further unexpected find 0036 FIG. 6 is a bar graph summarizing the results shown ing was that the most efficacious dose was not the highest in FIGS. 1-5. concentration tested. Preferably, fluticasone is in the form of 0037 FIG. 7 is a line graph comparing the efficacy of fluticasone propionate or fluticaSone dipropionate. Moreover, Fluticasone 0.001%, 0.005% and 0.01% as compared to the stable topical fluticasone formulations of the invention do vehicle in reducing ciliary redness, assessed on a scale of 0 not increase intraocular pressure in the eye after repeated use (no redness) to 4 (severe redness) over time. and are therefore safe for short term ocular administration. 0038 FIG. 8 is a line graph comparing the efficacy of 0053. The invention also features ophthalmic formula Fluticasone 0.001%, 0.005% and 0.01% as compared to tions of fluticaSone in combination with one or more addi vehicle in reducing episcleral redness, assessed on a scale of tional active ingredients such as an antihistamine (e.g., with 0 (no redness) to 4 (severe redness) over time. out limitation, cetirizine or ketotifen) or a vasoconstrictor 0039 FIG. 9 is a line graph comparing the efficacy of (e.g., without limitation, oxymetazoline or naphazoline). Fluticasone 0.001%, 0.005% and 0.01% as compared to Such fluticasone combination formulations are effective in vehicle in reducing chemosis, assessed on a scale of 0 (none) further mitigating the acute and late phase signs and Symp to 4 (severe) over time. toms of allergic conjunctivitis, Such as ocular itching, red 0040 FIG. 10 is a line graph comparing the efficacy of ness, chemosis, lid Swelling and nasal symptoms. Such for Fluticasone 0.001%, 0.005% and 0.01% as compared to mulations are also effective in mitigating the signs and vehicle in reducing watery eyes, assessed on a scale of 0 symptoms of rhinoconjunctivitis, Such as runny nose, Sneez (none) to 4 (severe) over time. ing, nasal/sinus congestion and red, watery and/or itchy eyes. US 2011/O 105450 A1 May 5, 2011 0054 The comfort, safety, efficacy, solubility, and stabil inserting agents, gels, emulsions, Suspensions and Solid eye ity of the ophthalmic formulations of the invention could not drops and the like, and may be properly selected therefrom. In have been predicted by one skilled in the art. Based on the addition, modifications such as Sustained-releasing, stabiliz known mechanism of action of steroids the skilled artisan ing and easy-absorbing properties and the like may be further would anticipate that the highest dose of steroid would offer applied to such the preparations. These dosage forms are the highest efficacy in reducing the signs and symptoms of sterilized, for example, by filtration through a microorganism allergic conjunctivitis and/or allergic rhinitis. Surprisingly, separating filter, heat sterilization or the like. data presented herein demonstrates that a mid-range dose of 0.058 Aqueous solutions are generally preferred, based on fluticasone (0.005%) was consistently more effective than ease of formulation, as well as a patient's ability to easily both a lower dose offluticasone (0.001%) and a higher dose of administer Such compositions by means of instilling one to fluticasone (0.01%) in reducing both ocular and nasal Symp two drops of the solutions in the affected eyes. However, the toms associated with allergic conjunctivitis (see Example 1). compositions may also be suspensions, Viscous or semi-vis Even more Surprisingly, the mid-range dose of fluticaSone cous gels, or other types of Solid or semisolid compositions. (0.005%) was more comfortable than the lower dose In one embodiment, the fluticasone formulations of the inven (0.001%) and the highest dose (0.01%), with no adverse tion are aqueous formulations. The aqueous formulations of effect on intraocular pressure. The data unexpectedly dem the invention are typically more than 50%, preferably more onstrates that there is an optimal fluticaSone concentration than 75%, and most preferably more than 90% by weight which is both comfortable and safe in the eye, as well as water. In another embodiment, the fluticasone formulations highly efficacious in reducing both ocular and nasal Symp are lyophilized formulations. toms associated with allergic conjunctivitis and rhinitis. Such 0059. In a particular embodiment, the fluticasone formu optimal concentration could not be arrived at by routine opti lations of the invention are formulated as a Suspension. Such mization. formulations generally have a particle size no greater than 30 0055. In some embodiment, the fluticasone formulations um. The skilled artisan would recognize that optimal particle of the invention comprise one or more tear Substitute compo size can be achieved by milling (jet, ball, or other mechanical nents. The fluticasone component provides relief of the Symp sizing), or using techniques such as antisolvent crystalliza toms of allergic conjunctivitis, and the one or more tear Sub tion. Additionally the suspension formulation of the invention stitute component provides ocular surface protection via may include Suspending and dispersing agents to prevent enhancement of the tear film (as evident by increased tear film agglomeration of the particles. For example, without limita break up time), and can act to enhance dwell time on the tion, a suspension formulation of the invention contains flu ocular surface thus increasing duration of activity. An effec ticasone propionate, a phosphate buffer system containing a tive amount of such formulations may be used to treat and/or combination of mono and dibasic phosphate to yield a pH of prevent signs and symptoms associated with acute and/or late 7.0, propylene glycol, polysorbate 80, hypromellose, edetate phase allergic conjunctivitis and/or general eye irritation, and disodium and benzalkonium chloride. can also be used to treat another eye disorder if it contains a drug for that disorder. An effective amount of such formula Active Agents tions may also be used to treat and/or prevent signs and 0060 According to preferred embodiments, there is pro symptoms of allergic rhinoconjunctivitis. Such formulations vided an ophthalmic composition comprising a therapeuti provide a comfortable ophthalmic formulation when instilled cally effective amount of fluticasone, or a pharmaceutically in the eye and have enhanced efficacy and/or duration of acceptable salt or ester thereof. As used herein, "pharmaceu action over formulations of fluticasone that are not combined tically acceptable salts' refer to derivatives of the disclosed with Such other agents. compounds wherein the parent compound is modified by 0056. The superior efficacy of the fluticasone/tear substi making acid or base salts thereof. Examples of pharmaceuti tute formulations is attributed to, among other things, the cally acceptable salts include, but are not limited to, mineral synergistic effect of the combination of ingredients in them. or organic acid salts of basic residues such as amines; alkali or The combination of fluticaSone and tear Substitute, act syn organic salts of acidic residues such as carboxylic acids. The ergistically to provide a longer dwell time of the fluticasone pharmaceutically acceptable salts include the conventional on the ocular surface, thus increasing duration and efficacy of non-toxic salts or the quaternary ammonium salts of the par action, and to prolong the integrity of the tear film thereby ent compound formed, for example, from non-toxic inorganic providing protection of the ocular Surface (e.g., by increasing or organic acids. For example, such conventional non-toxic the tear film break up time and/or the Ocular Protection salts include those derived from inorganic acids such as Index). As such, the compositions of the invention are com hydrochloric, hydrobromic, Sulfuric, Sulfamic, phosphoric, fortable upon instillation into the eye, and may be used for and nitric acids; and the salts prepared from organic acids relief of acute or chronic allergic conjunctivitis and/or rhi Such as acetic, fuoric, propionic, succinic, glycolic, Stearic, noconjunctivitis, and are particularly Suitable for both inter lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, mittent and long term use. hydroxymaleic, phenylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, meth Formulations anesulfonic, ethane disulfonic, oxalic, and isethionic acids. 0057 Preferably, the ophthalmic compositions according 0061 Fluticasone proprionate is the preferred pharmaceu to the present invention are formulated as solutions, Suspen tically acceptable salt. Fluticasone propionate, also known as sions, ointments, emulsions, gels and other dosage forms for S-fluoromethyl-6-O-9-difluoro-11-3-hydroxy-16-O-methyl topical administration (such as an eye drop, an ophthalmic 3-oxoandrosta-1,4-diene-17-f-carbothioate, 17-propionate, ointment, an ophthalmic gel, and the like). For ophthalmic is a synthetic, trifluorinated, corticosteroid having the chemi topical administration, the dosage form of the ophthalmic cal formula CHFOS. It is a white to off-white powder compositions includes solutions, ointments, ophthalmic with a molecular weight of 500.6 g/mol. Fluticasone propi US 2011/O 105450 A1 May 5, 2011 onate is practically insoluble in water (0.14 ug/ml), freely Excipients soluble in dimethyl sulfoxide and dimethyl-formamide, and slightly soluble in methanol and 95% ethanol. 0065. In some embodiments, the fluticasone formulations 0062 According to some embodiments, fluticasone is the of the invention comprise one or more pharmaceutically primary active agent in the formulations of the present inven acceptable excipients. The term excipient as used herein tion. According to some embodiments, the fluticaSoneformu broadly refers to a biologically inactive substance used in lations of the present invention comprise (or consist essen combination with the active agents of the formulation. An tially of) fluticasone as the sole active agent. According to excipient can be used, for example, as a solubilizing agent, a some embodiments, the fluticasone formulations of the present invention comprise (or consist essentially of) flutica stabilizing agent, a surfactant, a demulcent, a Viscosity agent, Sone as the sole anti-allergic agent. Preferably fluticasone is a diluent, an inert carrier, a preservative, a binder, a disinte in the form of fluticasone propionate or fluticasone dipropi grant, a coating agent, a flavoring agent, or a coloring agent. onate. In certain embodiments of the invention, fluticasone is Preferably, at least one excipient is chosen to provide one or formulated at a concentration of 0.001% to 1.0% (w/v), or any more beneficial physical properties to the formulation, Such specific value within said range. Preferably, fluticasone is as increased stability and/or solubility of the active agent(s). present in the formulation at a concentration of 0.001% and A pharmaceutically acceptable excipient is one that has 0.2% (w/v), or any specific value within said range. For been approved by a state or federal regulatory agency for use example, fluticaSone is formulated at a concentration of in animals, and preferably for use in humans, or is listed in the 0.001%, 0.005%, 0.01%, 0.015%, 0.025%, or 0.2% (w/v). In U.S. Pharmacopia, the European Pharmacopia or another a particular embodiment, fluticasone is present in the formu generally recognized pharmacopia for use in animals, and lation at a concentration of 0.005% (w/v). In another particu preferably for use in humans. lar embodiment, fluticasone is present in the formulation at a 0.066 Examples of carriers that may be used in the formu concentration of 0.01% (w/v). lations of the present invention include water, mixtures of 0063. According to some embodiments, however, flutica water and water-miscible solvents, such as C- to C, al Sone may be formulated with other active agents as described kanols, vegetable oils or mineral oils comprising from 0.5 to herein. For example, fluticasone may be formulated with one or more additional anti-allergic agents. The term “anti-aller 5% non-toxic water-soluble polymers, natural products. Such genic agent” refers to a molecule or composition that treats as gelatin, alginates, pectins, tragacanth, karaya gum, Xan ocular allergy or reduces a symptom of ocular allergy. The than gum, carrageenin, agar and acacia, starch derivatives, term “ocular allergy” refers to any allergic disease of the eye, such as starch acetate and hydroxypropyl starch, and also e.g., seasonal/perennial ocular allergy, Vernal keratoconjunc other synthetic products, such as polyvinyl alcohol, polyvi tivitis, giant papillary conjunctivitis, perennial ocular allergy nylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, and atopic keratoconjunctivitis. The signs and symptoms of preferably cross-linked polyacrylic acid, such as neutral Car ocular allergies include chemosis, eye itching, tearing, red bopol, or mixtures of those polymers. The concentration of ness and Swelling, and nasal symptoms associated with ocular the carrier is, typically, from 1 to 100000 times the concen allergy (e.g., stuffy, runny nose). Non-limiting examples of tration of the active ingredient. antiallergenic agents include “antihistamines' or drugs which 0067 Further examples of excipients include certain inert block histamine from binding to the histamine receptors, proteins such as albumins; hydrophilic polymers such as “mast cell stabilizers” or drugs that block the release of his polyvinylpyrrolidone; amino acids Such as aspartic acid tamine and other Substances from the mast cell, "drugs with (which may alternatively be referred to as aspartate), multiple modes of action' or drugs that are antiallergenic glutamic acid (which may alternatively be referred to as agents having multiple modes of action (e.g. drugs that are glutamate), lysine, arginine, glycine, and histidine; fatty acids antihistamines and mast cell Stabilizers, drugs with antihista mine, mast cell stabilizing and anti-inflammatory activity, and phospholipids such as alkyl Sulfonates and caprylate; etc.), Steroids, and nonsteroidal anti-inflammatory drugs or Surfactants such as Sodium dodecyl Sulphate and polysorbate; NSAIDS nonionic surfactants such as such as TWEENR), PLURON 0064. In certain embodiments, fluticasone is formulated ICS(R), or a polyethylene glycol (PEG) designated 200, 300, with one or more additional active agents selected from a 400, or 600; a Carbowax designated 1000, 1500, 4000, 6000, mast cell Stabilizer Such as nedocromil, iodoxamide, cro and 10000; carbohydrates such as glucose, Sucrose, mannose, molyn, or cromolyn Sodium; a non-steroidal anti-inflamma maltose, trehalose, and dextrins, including cyclodextrins; tory drug (“NSAID) such as diclofenac or ketorolac polyols such as mannitol and Sorbitol; chelating agents such tromethamine, bromfenac, or nepafenac; a vasoconstrictor as EDTA; and salt-forming counter-ions such as sodium. Such as naphazoline, antolazine, tetrahydrozoline or 0068. In a particular embodiment, the carrier is a poly oxymetazoline; an antihistimine Such as antazoline, astemi meric, mucoadhesive vehicle. Examples of mucoadhesive Zole, azelastine, bepotastine, bilastine, brompheniramine, vehicles suitable for use in the methods or formulations of the chlorpheniramine, clemastine, desloratidine, dexbromphe invention include but are not limited to aqueous polymeric niramine, diphenhydramine, doxylamine, ebastine, emedas Suspensions comprising one or more polymeric Suspending tine, epinastine, fexofenadine, hydroxyzine, ketotifen, levo agents including without limitation dextrans, polyethylene cabastine, levocetirizine, loratidine, meduitazine, glycol, polyvinylpyrolidone, polysaccharide gels, Gelrite R, mizolastine, norketotifen, olopatadine, Oxatomide, phenin cellulosic polymers, and carboxy-containing polymer sys damine, pheniramine, pyrilamine, terfenidine, and triproli tems. In a particular embodiment, the polymeric Suspending dine; or an alpha-adrenergic agonist Such as epinephrine, agent comprises a crosslinked carboxy-containing polymer fenoxazoline, indanazoline, naphazoline, Oxedrine, phenyle (e.g., polycarbophil). In another particular embodiment, the phrine, tefazoline, tetry Zoline, tramaZoline, tymazoline, polymeric Suspending agent comprises polyethylene glycol oxymetazoline, or Xylometazoline. (PEG). Examples of cross-linked carboxy-containing poly US 2011/O 105450 A1 May 5, 2011 mer systems suitable for use in the topical stable ophthalmic any specific value within said range. According to some fluticasone formulations of the invention include but are not embodiments, the concentration of HPMC ranges from about limited to Noveon AA-1, Carbopol R, and/or DuraSite(R) (In 0.6% to about 1% w/v. or any specific value within said range. Site Vision). In a preferred embodiments, the concentration of HPMC 0069. In other particular embodiments, the fluticasone for ranges from about 0.1% to about 1.0% w/v. or any specific mulations of the invention comprise one or more excipients value within said range (i.e., 0.1-0.2%, 0.2-0.3%, 0.3-0.4%, selected from among the following: a tear Substitute, a tonic 0.4-0.5%, 0.5-0.6%, 0.6-0.7%, 0.7–0.8%, 0.8-0.9%, 0.9-1. ity enhancer, a preservative, a solubilizer, a Viscosity enhanc 0%; about 0.2%, about 0.21%, about 0.22%, about 0.23%, ing agent, a demulcent, an emulsifier, a wetting agent, a about 0.24%, about 0.25%, about 0.26%, about 0.27%, about sequestering agent, and a filler. The amount and type of 0.28%, about 0.29%, about 0.30%, about 0.70%, about excipient added is in accordance with the particular require 0.71%, about 0.72%, about 0.73%, about 0.74%, about ments of the formulation and is generally in the range of from 0.75%, about 0.76%, about 0.77%, about 0.78%, about about 0.0001% to 90% by weight. 0.79%, about 0.80%, about 0.81%, about 0.82%, about 0070 According to preferred embodiments, the flutica 0.83%, about 0.84%, about 0.85%, about 0.86%, about Sone formulations of the invention contain a viscosity 0.87%, about 0.88%, about 0.89%, or about 0.90%). enhancing agent or combination of Viscosity enhancing 0075 For example, without limitation, a tear substitute agents, a tonicity agent or combination oftonicity agents, and which comprises hydroxypropyl methyl cellulose is Gen a buffer or combination of buffers. Teal(R) lubricating eye drops. GenTeal(R) (CibaVision No 0071. According to preferred embodiments, the flutica vartis) is a sterile lubricant eye drop containing hydroxypro Sone formulations of the invention contain a demulcent or pylmethyl cellulose 3 mg/g and preserved with sodium combination of demulcents, a tonicity agent or combination perborate. Other examples of an HPMC-based tear are pro oftonicity agents, and a buffer or combination of buffers. vided. 0072 According to preferred embodiments, the flutica 0076. In another preferred embodiment, the tear substitute Sone formulations of the invention contain a demulcent or comprises carboxymethyl cellulose Sodium. For example, combination of demulcents without limitation, the tear substitute which comprises car boxymethyl cellulose sodium is Refresh R. Tears. Refresh(R) Tear Substitutes Tears is a lubricating formulation similar to normal tears, 0073. According to some embodiments, the fluticasone containing a, mild non-sensitizing preservative, stabilised formulations may include an artificial tear substitute. The oxychloro complex (PuriteTM), that ultimately changes into term “tear substitute' refers to molecules or compositions components of natural tears when used. which lubricate, “wet, approximate the consistency of 0077. In a preferred embodiment, the tear substitute, or endogenous tears, aid in natural tear build-up, or otherwise one or more components thereof, is an aqueous Solution hav provide temporary relief of dry eye signs or symptoms and ing a viscosity in a range which optimizes efficacy of Sup conditions upon ocular administration. A variety of tear Sub porting the tear film while minimizing blurring, lid caking, stitutes are known in theart and include, but are not limited to: etc. Preferably, the viscosity of the tear substitute, or one or monomeric polyols, such as, glycerol, propylene glycol, and more components thereof, ranges from about 10 to about 150 ethylene glycol; polymeric polyols such as polyethylene gly centipoise (cpi), preferably about 15 to about 120 cpi, even col; cellulose esters such hydroxypropylmethyl cellulose, more preferably about 20 to about 90 cpi (or any specific carboxymethyl cellulose sodium and hydroxy propylcellu value within said ranges). According to a preferred embodi lose; dextrans such as dextran 70; water soluble proteins such ment, the ophthalmic formulations of the present invention as gelatin: vinyl polymers, such as polyvinyl alcohol, poly has a viscosity that ranges from about 15 cpi to about 30 cpi, vinylpyrrolidone, and povidone; and carbomers, such as car or any specific value within said range (i.e., about 15 cpi, bomer 934P. carbomer 941, carbomer 940 and carbomer about 16 cpi, about 17 cpi, about 18 cpi, about 19 cpi, about 20 974.P. Many such tear substitutes are commercially available, cpi, about 20 cpi, about 22 cpi, about 23 cpi, about 24 cpi, which include, but are not limited to cellulose esters such as about 25 cpi, about 26 cpi, about 27 cpi, about 28 cpi, about 29 Bion Tears(R), CelluviscoR), Genteal(R), OccuCoat(R), Refresh(R), cpi, about 30 cpi). In a particular embodiment, the viscosity of Systane(R), Teargen IIR, Tears Naturale R, Tears Natural II(R), the tear Substitute, or one or more components thereof, is Tears Naturale FreeR), and TheraTears(R); and polyvinyl alco about 20 cpi. According to another preferred embodiment, the hols such as Akwa Tears(R), HypoTears(R, Moisture Eyes.(R), ophthalmic formulations of the present invention has a vis Murine Lubricating R, and Visine Tears(R, Soother. Tear cosity that ranges from about 70 cpi to about 90 cpi, or any Substitutes may also be comprised of paraffins, such as the specific value within said range (i.e., about 70 cpi, about 71 commercially available Lacri-Lube(a) ointments. Other com cpi, about 72 cpi, about 73 cpi, about 74 cpi, about 75 cpi, mercially available ointments that are used as tear Substitutes about 76 cpi, about 77 cpi, about 78 cpi, about 79 cpi, about 80 include Lubrifresh PMR, Moisture Eyes PMR) and Refresh cpi, about 81 cpi, about 82 cpi, about 83 cpi, about 84 cpi, PMCR). about 85 cpi, about 86 cpi, about 87 cpi, about 88 cpi, about 89 0074. In one preferred embodiment of the invention, the cpi or about 90 cpi). tear Substitute comprises hydroxypropylmethyl cellulose 0078 Viscosity may be measured at a temperature of 20° (Hypromellose or HPMC). According to some embodiments, C.+/-1° C. using a Brookfield Cone and Plate Viscometer the concentration of HPMC ranges from about 0.1% to about Model VDV-III Ultra" with a CP40orequivalent Spindle with 2% w/v. or any specific value within said range. According to a shear rate of approximately 22.50+/-approximately 10 some embodiments, the concentration of HPMC ranges from (1/sec), or a Brookfield Viscometer Model LVDV-E with a about 0.5% to about 1.5% w/v., or any specific value within SC4-18 or equivalent Spindle with a shear rate of approxi said range. According to some embodiments, the concentra mately 26+/-approximately 10 (1/sec). Alternatively, viscos tion of HPMC ranges from about 0.1% to about 1% w/v. or ity may be measured at 25°C.+/-1° C. using a Brookfield US 2011/O 105450 A1 May 5, 2011 Cone and Plate Viscometer Model VDV-III Ultra" with a 0.004 to 0.2 M (Molar), preferably 0.04 to 0.1 M. The borate CP40 or equivalent Spindle with a shear rate of approxi buffer (in total) is used at a concentration of 0.02 to 0.8 M, mately 22.50+/-approximately 10 (1/sec), or a Brookfield preferably 0.07 to 0.2 M. Viscometer Model LVDV-E with a SC4-18 or equivalent I0087. Other known buffer compounds can optionally be Spindle with a shear rate of approximately 26+/-approxi added to the lens care compositions, for example, citrates, mately 10 (1/sec). sodium bicarbonate, TRIS, and the like. Other ingredients in 0079. In some embodiments, the tear substitute, or one or the solution, while having other functions, may also affect the more components thereof is buffered to a pH 5.0 to 9.0, buffer capacity. For example, EDTA, often used as a com preferably pH 5.5 to 7.5, more preferably pH 6.0 to 7.0 (or any plexing agent, can have a noticeable effect on the buffer specific value within said ranges), with a suitable salt (e.g., capacity of a solution. phosphate salts). In some embodiments, the tear Substitute I0088 According to some embodiments, the pH of the further comprises one or more ingredients, including without aqueous ophthalmic Solution is at or near physiological pH. limitation, glycerol, propyleneglycerol, glycine, sodium Preferably, the pH of the aqueous ophthalmic solution is borate, magnesium chloride, and Zinc chloride. between about 5.5 to about 8.0, or any specific value within said range. According of some embodiments, the pH of the Salts, Buffers, and Preservatives aqueous ophthalmic solution is between about 6.5 to 7.5, or 0080. The formulations of the present invention may also any specific value within said range (e.g., 6.5., 6.6., 6.7. 6.8. contain pharmaceutically acceptable salts, buffering agents, 6.9, 7.0. 7.1, 7.2, 7.3, 7.4, 7.5). According to some embodi or preservatives. Examples of Such salts include those pre ments, the pH of the aqueous ophthalmic solution is about 7. pared from the following acids: hydrochloric, hydrobromic, The skilled artisan would recognize that the pH may be Sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, adjusted to a more optimal pH depending on the Stability of boric, formic, malonic, succinic, and the like. the active ingredients included in the formulation. According 0081. Such salts can also be prepared as alkaline metal or to some embodiments, the pH is adjusted with base (e.g., 1N alkaline earth salts, such as Sodium, potassium or calcium Sodium hydroxide) or acid (e.g., 1N hydrochloric acid). salts. Examples of buffering agents include phosphate, cit I0089 For the adjustment of the pH, preferably to a physi rate, acetate, and 2-(N-morpholino)ethanesulfonic acid ological pH, buffers may especially be useful. The pH of the (MES). present solutions should be maintained within the range of 5.5 0082. The fluticasone formulations of the present inven to 8.0, more preferably about 6.0 to 7.5, more preferably tion may include a buffer system. As used in this application, about 6.5 to 7.0 (or any specific value within said ranges). the terms “buffer or “buffer system” is meant a compound Suitable buffers may be added, such as boric acid, sodium that, usually in combination with at least one other com borate, potassium citrate, citric acid, Sodium bicarbonate, pound, provides a buffering system in Solution that exhibits TRIS, and various mixed phosphate buffers (including com buffering capacity, that is, the capacity to neutralize, within binations of NaHPO, NaH2PO and KHPO) and mixtures limits, either acids or bases (alkali) with relatively little or no thereof. Borate buffers are preferred. Generally, buffers will change in the original pH. According to some embodiments, be used in amounts ranging from about 0.05 to 2.5 percent by the buffering components are present from 0.05% to 2.5% weight, and preferably, from 0.1 to 1.5 percent. (w/v) or from 0.1% to 1.5% (w/v). 0090 According to preferred embodiments, the formula I0083 Preferred buffers include borate buffers, phosphate tions of the present invention do not contain a preservative. In buffers, calcium buffers, and combinations and mixtures certain embodiments, the ophthalmic formulations addition thereof. Borate buffers include, for example, boric acid and its ally comprise a preservative. A preservative may typically be salts, for example, sodium borate or potassium borate. Borate selected from a quaternary ammonium compound Such as buffers also include compounds such as potassium tetraborate benzalkonium chloride, benzoxonium chloride or the like. or potassium metaborate that produce borate acid or its salt in Benzalkonium chloride is better described as: N-benzyl-N- Solutions. (C-Cs alkyl)-N,N-dimethylammonium chloride. Further 0084. A phosphate buffer system preferably includes one examples of preservatives include antioxidants such as Vita or more monobasic phosphates, dibasic phosphates and the minA, Vitamin E. Vitamin C, retinyl palmitate, and selenium; like. Particularly useful phosphate buffers are those selected the amino acids cysteine and methionine; citric acid and from phosphate salts of alkali and/or alkaline earth metals. Sodium citrate; and synthetic preservatives such as thimero Examples of suitable phosphate buffers include one or more sal, and alkyl parabens, including for example, methyl para of sodium dibasic phosphate (NaHPO), sodium monobasic ben and propyl paraben. Other preservatives include octade phosphate (NaH2PO4) and potassium monobasic phosphate cyldimethylbenzyl ammonium chloride, hexamethonium (KHPO). The phosphate buffer components frequently are chloride, benzethonium chloride, phenol, catechol, resorci used in amounts from 0.01% or to 0.5% (w/v), calculated as nol, cyclohexanol, 3-pentanol, m-cresol, phenylmercuric phosphate ion. nitrate, phenylmercuric acetate or phenylmercuric borate, 0085. A preferred buffer system is based upon boric acid/ Sodium perborate, sodium chlorite, alcohols, such as chlo borate, a mono and/or dibasic phosphate salt/phosphoric acid robutanol, butyl or benzyl alcohol or phenyl ethanol, guani or a combined boric/phosphate buffer system. For example a dine derivatives, such as chlorohexidine or polyhexamethyl combined boric/phosphate buffer system can be formulated enebiguanide, Sodium perborate, Germal RII, Sorbic acid and from a mixture of Sodium borate and phosphoric acid, or the stabilized oxychloro complexes (e.g., Purite(R). Preferred combination of sodium borate and the monobasic phosphate. preservatives are quaternary ammonium compounds, in par I0086. In a combined boric/phosphate buffer system, the ticular benzalkonium chloride or its derivative such as solution comprises about 0.05 to 2.5% (w/v) of a phosphoric Polycuad (see U.S. Pat. No. 4,407,791), alkyl-mercury salts, acid or its salt and 0.1 to 5.0% (w/v) of boric acid or its salt. parabens and stabilized oxychloro complexes (e.g., Purite(R). The phosphate buffer is used (in total) at a concentration of Where appropriate, a sufficient amount of preservative is US 2011/O 105450 A1 May 5, 2011 added to the ophthalmic composition to ensure protection combination of agents ranges from about 0.6% to about 1% against Secondary contaminations during use caused by bac w/v, or any specific value within said range. According to teria and fungi. Some embodiments, the concentration of viscosity enhancing 0091. In particular embodiments, the fluticasone formula agent or combination of agents ranges from about 0.7% to tions of the invention comprise a preservative selected from about 0.9% w/v. or any specific value within said range (i.e., among the following: benzalkonium chloride, 0.001% to about 0.70%, about 0.71%, about 0.72%, about 0.73%, about 0.05%; benzethonium chloride, up to 0.02%; sorbic acid, 0.74%, about 0.75%, about 0.76%, about 0.77%, about 0.01% to 0.5%; polyhexamethylene biguanide, 0.1 ppm to 0.78%, about 0.79%, about 0.80%, about 0.81%, about 300 ppm; polyduaternium-1 (Omamer M)-0.1 ppm to 200 0.82%, about 0.83%, about 0.84%, about 0.85%, about ppm; hypochlorite, perchlorite or chlorite compounds, 500 0.86%, about 0.87%, about 0.88%, about 0.89%, or about ppm or less, preferably between 10 and 200 ppm); stabilized 0.90%). hydrogen peroxide Solutions, a hydrogen peroxide Source 0096. In certain embodiments, the fluticasone formula resulting in a weight% hydrogen peroxide of 0.0001 to 0.1% tions of the invention comprise ophthalmic demulcents and/ along with a suitable stabilizer; alkyl esters of p-hydroxyben or viscosity enhancing polymers selected from one or more of Zoic acid and mixtures thereof, preferably methyl paraben the following: cellulose derivatives such as carboxymethy and propyl paraben, at 0.01% to 0.5%; chlorhexidine, 0.005% cellulose (0.01 to 5%) hydroxyethylcellulose (0.01% to 5%), to 0.01%; chlorobutanol, up to 0.5%; and stabilized oxy hydroxypropyl methylcellulose or hypromellose (0.01% to chloro complex (Purite(R) 0.001% to 0.5%. 5%), and methylcelluose (0.02% to 5%); dextran 40/70 0092. In another embodiment, the ophthalmic formula (0.01% to 1%); gelatin (0.01% to 0.1%); polyols such as tions of this invention do not include a preservative. Such glycerin (0.01% to 5%), polyethylene glycol 300 (0.02% to formulations would be useful for patients who wear contact 5%), polyethylene glycol 400 (0.02% to 5%), polysorbate 80 lenses, or those who use several topical ophthalmic drops (0.02% to 3%), propylene glycol (0.02% to 3%), polyvinyl and/or those with an already compromised ocular Surface alcohol (0.02% to 5%), and povidone (0.02% to 3%); hyalu (e.g. dry eye) wherein limiting exposure to a preservative may ronic acid (0.01% to 2%); and chondroitin sulfate (0.01% to be more desirable. 2%). 0097. In one preferred embodiment of the invention, the Viscosity Enhancing Agents and Demulcents Viscosity enhancing component comprises hydroxypropylm 0093. In certain embodiments, viscosity enhancing agents ethyl cellulose (Hypromellose or HPMC). HPMC functions may be added to the fluticasone formulations of the invention. to provide the desired level of viscosity and to provide demul Examples of Such agents include polysaccharides, such as cent activity. According to some embodiments, the concen hyaluronic acid and its salts, chondroitin Sulfate and its salts, tration of HPMC ranges from about 0% to about 2% w/v. or dextrans, various polymers of the cellulose family, vinyl any specific value within said range. According to some polymers, and acrylic acid polymers. embodiments, the concentration of HPMC ranges from about 0094. A variety of viscosity enhancing agents are known 0% to about 1.5% w/v. or any specific value within said range. in the art and include, but are not limited to: polyols such as, According to Some embodiments, the concentration of glycerol, glycerin, polyethylene glycol 300, polyethylene HPMC ranges from about 0% to about 0.5% w/v. or any glycol 400, polysorbate 80, propylene glycol, and ethylene specific value within said range. glycol, polyvinyl alcohol, povidone, and polyvinylpyrroli 0098. In another preferred embodiment, the viscosity done; cellulose derivatives such hydroxypropyl methyl cel enhancing component comprises carboxymethyl cellulose lulose (also known as hypromellose and HPMC), carboxym Sodium. ethyl cellulose sodium, hydroxypropyl cellulose, 0099. The viscosity of the ophthalmic formulations of the hydroxyethyl cellulose, and methyl cellulose; dextrans such invention may be measured according to standard methods as dextran 70; water Soluble proteins such as gelatin; car known in the art, Such as use of a viscometer or rheometer. bomers such as carbomer 934P carbomer 941, carbomer 940 One of ordinary skill in the art will recognize that factors such and carbomer 974P; and gums such as HP-guar, or combina as temperature and shear rate may effect viscosity measure tions thereof. Other compounds may also be added to the ment. In a particular embodiment, Viscosity of the ophthalmic formulations of the present invention to increase the Viscosity formulations of the invention is measured at 20°C.--f-1° C. of the carrier. Examples of Viscosity enhancing agents using a Brookfield Cone and Plate Viscometer Model VDV include, but are not limited to: polysaccharides, such as III Ultra" with a CP40 or equivalent Spindle with a shear rate hyaluronic acid and its salts, chondroitin Sulfate and its salts, of approximately 22.50+/-apprx 10 (1/sec), or a Brookfield dextrans, various polymers of the cellulose family; vinyl Viscometer Model LVDV-E with a SC4-18 or equivalent polymers; and acrylic acid polymers. Combinations and mix Spindle with a shear rate of approximately 26+/-apprx 10 tures of the above agents are also suitable. (1/sec)). 0095 According to some embodiments, the concentration of viscosity enhancing agent or combination of agents ranges Tonicity Enhancers from about 0.5% to about 2% w/v. or any specific value within 0100 Tonicity is adjusted if needed typically by tonicity said range. According to some embodiments, the concentra enhancing agents. Such agents may, for example be of ionic tion of Viscosity enhancing agent or combination of agents and/or non-ionic type. Examples of ionic tonicity enhancers ranges from about 0.5% to about 1.5% w/v. or any specific are alkali metal or earth metal halides, such as, for example, value within said range. According to some embodiments, the CaCl, KBr. KC1, LiCl, NaI, NaBr or NaCl, NaSO or boric concentration of viscosity enhancing agent or combination of acid. Non-ionic tonicity enhancing agents are, for example, agents ranges from about 0.5% to about 1% w/v. or any urea, glycerol, Sorbitol, mannitol, propylene glycol, or dex specific value within said range. According to some embodi trose. The aqueous solutions of the present invention are ments, the concentration of Viscosity enhancing agent or typically adjusted with tonicity agents to approximate the US 2011/O 105450 A1 May 5, 2011 osmotic pressure of normallachrymal fluids which is equiva ranges from about 0.0005 to about 0.1% w/v., preferably about lent to a 0.9% solution of sodium chloride or a 2.5% solution 0.005 to about 0.08% w/v, more preferably about 0.06% W/V. of glycerol. An osmolality of about 200 to 1000 mOsm/kg is According to Some embodiments, ZnCl2 ranges from about preferred, more preferably 200 to 500 mOsm/kg, or any spe 0.0005 to about 0.1% w/v., preferably about 0.005 to about cific value within said ranges (e.g., 200 mOsm/kg, 210 0.08% w/v, more preferably about 0.06% W/V. mOsm/kg, 220 mOsm/kg, 230 mOsm/kg, 240 mOsm/kg, 250 0105. According to some embodiments, the ophthalmic mOsm/kg, 260 mOsm/kg, 270 mOsm/kg, 280 mOsm/kg, 290 formulations of the present invention may be adjusted with mOsm/kg, 300 mOsm/kg, 310 mCSm/kg, 320 mOsm/kg, 330 tonicity agents to approximate the osmotic pressure of normal mOsm/kg, 340 mOsm/kg, 350 mOsm/kg, 360 mOsm/kg, 370 lachrymal fluids which is equivalent to a 0.9% solution of mOsm/kg, 380 mOsm/kg, 390 mOsm/kg or 400 mOsm/kg). sodium chloride or a 2.5% solution of glycerol. An osmolality In a particular embodiment, the ophthalmic formulations of of about 225 to 400 mOsm/kg is preferred, more preferably the invention are adjusted with tonicity agents to an osmola 280 to 320 mOSm. lity of ranging from about 240 to 360 mOsm/kg (e.g., 300 mOsm/kg). Solubilizing Agents 0101 The fluticasone formulations of the invention of the 0106 The topical formulation may additionally require present invention may further comprise a tonicity agent or the presence of a solubilizer, in particularif one or more of the combination of tonicity agents. According to some embodi ingredients tend to form a suspension or an emulsion. Suit ments, the fluticaSone formulations of the invention may able solubilizers include, for example, tyloxapol, fatty acid include an effective amount of a tonicity adjusting compo glycerol polyethylene glycol esters, fatty acid polyethylene nent. Among the Suitable tonicity adjusting components that glycol esters, polyethylene glycols, glycerol ethers, a cyclo can be used are those conventionally used in contact lens care dextrin (for example alpha-, beta- or gamma-cyclodextrin, products such as various inorganic salts. Polyols and polysac e.g. alkylated, hydroxyalkylated, carboxyalkylated or alky charides can also be used to adjust tonicity. The amount of loxycarbonyl-alkylated derivatives, or mono- or diglycosyl tonicity adjusting component is effective to provide an osmo alpha-, beta- or gamma-cyclodextrin, mono- or dimaltosyl lality from 200 mOsmol/kg to 1000 mOsmol/kg, or any spe alpha-, beta- or gamma-cyclodextrin or panosyl cific value within said range. cyclodextrin), polysorbate 20, polysorbate 80 or mixtures of 0102 Preferably, the tonicity component comprises a those compounds. In a preferred embodiment, the solubilizer physiologically balanced salt Solution that mimics the min is a reaction product of castor oil and ethylene oxide, for eral composition of tears. According to some embodiments, example the commercial products Cremophor ELR) or Cre tonicity may adjusted by tonicity enhancing agents that mophor RH40R). Reaction products of castor oil and ethylene include, for example, agents that are of the ionic and/or non oxide have proved to be particularly good solubilizers that are ionic type. Examples of ionic tonicity enhancers are alkali tolerated extremely well by the eye. In another embodiment, metal or earth metal halides, such as, for example, CaCl, the solubilizer is tyloxapol or a cyclodextrin. The concentra KBr. KCl, LiCl, NaI, NaBr or NaCl, NaSO or boric acid. tion used depends especially on the concentration of the Non-ionic tonicity enhancing agents are, for example, urea, active ingredient. The amount added is typically Sufficient to glycerol, Sorbitol, mannitol, propylene glycol, or dextrose. solubilize the active ingredient. For example, the concentra 0103) According to some embodiments, the tonicity com tion of the solubilizer is from 0.1 to 5000 times the concen ponent comprises two or more of NaCl, KC1, ZnCl2, CaCl, tration of the active ingredient. and MgCl2 in a ratio that provides an osmolality range as above. According to Some embodiments, the osmolality Demulcifing Agents range of the formulations of the present invention is about 100 to about 1000 mOsm/kg, preferably about 500 to about 1000 0107 The demulcents used in the present invention are mOsm/kg. According to some embodiments, the tonicity used in effective amounts (i.e. “demulcifing amounts”) for component comprises three or more of NaCl, KCl, ZnCl2. providing a demulcifing effect, i.e. Sufficient to lubricating CaCl2, and MgCl2 in a ratio that provides an osmolality range mucous membrane Surfaces and to relieve dryness and irrita of about 100 to about 1000 mOsm/kg, preferably about 500 to tion. Examples of suitable demulcents may include polyvinyl about 1000 mOsm/kg. According to some embodiments, the pyrrolidone, polyvinyl alcohol, polyethylene glycol, and tonicity component comprises four or more of NaCl, KCl, other components such as polyethylene oxide and polyacrylic ZnCl2, CaCl2, and MgCl2 in a ratio that provides an osmola acid, are specifically excluded. In still other embodiments, lity range of about 100 to about 1000 mOsm/kg, preferably other or additional demulcents may be used in combination about 500 to about 1000 mOsm/kg. According to some with glycerin and propylene glycol. For example, polyvinyl embodiments, the tonicity component comprises NaCl, KCl, pyrrolidone, polyvinyl alcohol, may also be used. ZnCl, CaCl, and MgCl, in a ratio that provides an osmola 0108. The specific quantities of demulcents used in the lity range of about 100 to about 1000 mOsm/kg, preferably present invention will vary depending upon the application; about 500 to about 1000 mOsm/kg. however, typically ranges of several demulcents are provided: 0104. According to some embodiments, NaCl ranges from glycerin: from about 0.2 to about 1.5%, but preferably about about 0.1 to about 1% w/v., preferably from about 0.2 to about 1% (w/w); 0.8% w/v. more preferably about 0.39% w/v. According to 0109 propylene glycol: from about 0.2 to about 1.5%, but some embodiments, KCl ranges from about 0.02 to about preferably about 1% (w/w); cellulose derivative: from about 0.5% w/v., preferably about 0.05 to about 0.3% w/v. more 0.2 to about 3%, but preferably about 0.5% (w/w). If addi preferably about 0.14% w/v. According to some embodi tional demulcents are used, they are typically used in quanti ments, CaCl, ranges from about 0.0005 to about 0.1% w/v. ties specified in the over-the-counter monograph, cited above. preferably about 0.005 to about 0.08% w/v, more preferably A preferred cellulose derivative is pharmaceutical grade about 0.06% w/v. According to some embodiments, MgCl, hydroxypropyl methylcellulose (HPMC). US 2011/O 105450 A1 May 5, 2011 Stability 0116. Optionally, the fluticasone formulation comprises 0110. The formulations of the present invention provide one or more tear Substitutes or a mucoadhesive, polymeric for the chemical stability of the formulated fluticasone and compound (e.g., Durasite(R). Where the formulation com other optional active agents of the formulation. “Stability” prises one or more tear substitutes, the tear substitute prefer and 'stable' in this context refers to the resistance of the ably contains hydroxypropylmethyl cellulose or carboxym fluticasone and other optional active agents to chemical deg ethyl cellulose or both. In some embodiments, the radation and physical changes such as settling or precipitation hydroxypropylmethyl cellulose or carboxymethyl cellulose under given manufacturing, preparation, transportation and is present at a concentration of 0.5% to 1% (w/v) (or any storage conditions. The “stable' formulations of the invention specific value within said range) and the resulting viscosity of also preferably retain at least 90%, 95%.98%, 99%, or 99.5% the solution is 60-80 cpi. In a particular embodiment, the of a starting or reference amount under given manufacturing, hydroxypropylmethyl cellulose or carboxymethyl cellulose preparation, transportation, and/or storage conditions. The is present at a concentration of 0.7% to 0.9%. In another amount of fluticaSone and other optional active agents can be particular embodiment, the hydroxypropylmethyl cellulose determined using any art-recognized method, for example, as or carboxymethyl cellulose is present at a concentration of UV-Vis spectrophotometry and high pressure liquid chroma 0.1% to 0.7% and the resulting viscosity of the solution is tography (HPLC). 10-30 cpi. 0111. In certain embodiments, the fluticasone formula 0117 Optionally, the formulation also comprises a preser tions are stable attemperatures ranging from about 20 to 30° vative, preferably benzalkonium chloride at a concentration C. for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, or at least 7 weeks. of from 0.005% to 0.02% (w/v) (or any specific value within In other embodiments, the formulations are stable attempera said range) or its derivative (e.g., PolyguadR), or a stabilized tures ranging from about 20 to 30° C. for at least 1 month, at oxychloro complex (e.g., PuriteR). The pH of the formulation least 2 months, at least 3 months, at least 4 months, at least 5 is between 5.0 and 7.5. For example, the pH of the formula months, at least 6 months, at least 7 months, at least 8 months, tion is 5, 5.5, 6.0, 6.5 or 7.0. at least 9 months, at least 10 months, at least 11 months, or at 0118. In one embodiment, the fluticasone formulation least 12 months. In one embodiment, the formulation is stable comprises fluticasone at 0.001% to 1.0% (w/v), glycerin at for at least 3 months at 20-25°C. 0.1% to 5% (v/v) (e.g., 0.1% to 3% (v/v) or any specific value 0112. In other embodiments, the fluticasone formulations within said range), and water. Optionally, the formulation are stable attemperatures ranging from about 2 to 8°C. for at also comprises benzalkonium chloride at 0.005% to 0.02% least 1 month, at least 2 months, at least 4 months, at least 6 (w/v) or its derivative (e.g., PolycuadR), or a stabilized, oxy months, at least 8 months, at least 10 months, at least 12 chloro complex (e.g., Purite(R). In a particular embodiment, months, at least 14 months, at least 16 months, at least 18 the fluticasone formulation comprises fluticasone at 0.005%, months, at least 20 months, at least 22 months, or at least 24 glycerin at 1.2% to 3% (v/v), and water. In another particular months. In one embodiment, the formulation is stable for at embodiment, the fluticaSone formulation comprises flutica least 2 months at 2 to 8° C. sone at 0.01% (w/v), glycerin at 1.2% to 3% (v/v), and water. 0113. In other embodiments, the fluticasone formulations Optionally, the fluticaSone formulations also comprise ben are stable at temperatures of about -20° C. for at least 1 Zalkonium chloride at 0.01% (w/v) or a stabilized, oxychloro month, at least 2 months, at least 4 months, at least 6 months, complex (e.g., Purite(R). The pH of the formulation is at least 8 months, at least 10 months, at least 12 months, at between 5.0 and 7.5. For example, the pH of the formulation least 14 months, at least 16 months, at least 18 months, at least is 5, 5.5, 6.0, 6.5 or 7.0. 20 months, at least 22 months, or at least 24 months. In one 0119. In yet another particular embodiment, the flutica embodiment, the formulation is stable for at least 6-12 sone formulation comprises fluticasone at 0.001% to 1.0% months at -20°C. (w/v), preferably fluticasone 0.005%, and one or more tear 0114. In a particular embodiment, a fluticasone formula Substitutes or a mucoadhesive, polymeric compound (e.g., tion of the invention is stable attemperatures of about 20-30° Durasite(R). Preferably, the tear substitute preferably contains C. at concentrations up to 0.10% for at least 3 months. In hydroxypropylmethyl cellulose or carboxymethyl cellulose another embodiment, the formulation is stable at tempera or both. In some embodiments, the hydroxypropylmethyl tures from about 2-8°C. at concentrations up to 0.10% for at cellulose or carboxymethyl cellulose is present at a concen least 6 months. tration of 0.5% to 1% (w/v) (or any specific value within said range) and the resulting viscosity of the solution is 60-80 cpi. Examples of Formulations In a particular embodiment, the hydroxypropylmethyl cellu 0115. In a preferred embodiment, the fluticasone formu lose or carboxymethyl cellulose is present at a concentration lation comprises fluticaSone as the only active agent in the of 0.7% to 0.9%. Optionally, the formulation also comprises formulation at 0.001% to 1.0% (w/v), or any specific value a preservative, preferably benzalkonium chloride at a concen within said range. Preferably, fluticasone is present in the tration of from 0.005% to 0.02% (w/v) (or any specific value formulation at a concentration of 0.001% and 0.2% (w/v), or within said range) or stabilized oxychloro complex (Purite(R). any specific value within said range. For example, fluticaSone The pH of the formulation is between 5.0 and 7.5. For is formulated at a concentration of 0.001%, 0.005%, 0.01%, example, the pH of the formulation is 5, 5.5, 6.0, 6.5 or 7.0. 0.015%, 0.025%, or 0.2% (w/v). In a particular embodiment, I0120 In still another particular embodiment, the flutica fluticasone is present in the formulation at a concentration of sone formulations of the invention are formulated in a vehicle 0.005% (w/v). In another particular embodiment, fluticasone comprising 1% Polyethylene Glycol 400, NF; 0.2% Dibasic is present in the formulation at a concentration of 0.01% Sodium Phosphate, Anhydrous, USP; 0.25% Hypromellose, (w/v). USP; 0.1% Polysorbate 80, NF; 1.2% to 1.8% Glycerin (or US 2011/O 105450 A1 May 5, 2011 any specific value within said range), USP; 0.025%. Edetate 0.126 The formulations of the present invention containan Disodium, USP; 0.01% Benzalkonium Chloride, NF (pH amount of fluticaSone, and optionally one or more additional 7.0). active ingredients (for example without limitation a vasocon 0121. In a certain embodiment, the fluticasone formula strictor Such as naphazoline or oxymetazoline, or an antihis tion comprises 0.005% fluticasone, 1% Polyethylene Glycol tamine Such as cetirizine or ketotifen), in an amount that is 400, NF, 0.2% Dibasic Sodium Phosphate, Anhydrous, USP effective for the intended use (i.e., to mitigate the signs and 0.25% Hypromellose, USP, 0.1% Polysorbate 80, NF, 1.8% symptoms of allergic conjunctivitis and/or rhinoconjunctivi Glycerin, USP, 0.025% Edetate Disodium, USP, and 0.01% tis). In certain embodiments, once a day administration of the Benzalkonium Chloride, NF (pH 7.0). formulations of the present invention is effective to mitigate the symptoms of allergic conjunctivitis and/or rhinoconjunc 0122. In yet another certain embodiment, the fluticasone tivitis. However, particular dosages are also selected based on formulation comprises 0.01% fluticasone, 1% Polyethylene a number of factors including the age, sex, species and con Glycol 400, NF, 0.2% Dibasic Sodium Phosphate, Anhy dition of the subject. Effective amounts can also be extrapo drous, USP, 0.25% Hypromellose, USP; 0.1% Polysorbate lated from dose-response curves derived from in vitro test 80, NF, 1.2% Glycerin, USP, 0.025% Edetate Disodium, USP systems or from animal models. and 0.01% Benzalkonium Chloride, NF (pH 7.0). 0127. The term “effective amount’ means an amount of fluticasone that is Sufficient to eliminate or reduce a symptom Methods of Use of allergic conjunctivitis and/or rhinoconjunctivitis. In cer tain embodiments, the effective amount is the amount suffi 0123. The fluticasone formulations of the invention are cient for the treatment or prevention of allergic conjunctivitis useful for the treatment and prevention of the signs and Symp and/or rhinoconjunctivitis. “Treatment” in this context refers toms of both the acute phase (i.e., seasonal) and late phase to reducing or ameliorating at least one symptom of allergic inflammatory reactions (i.e., chronic, persistent or refractory) conjunctivitis and/or rhinoconjunctivitis. “Prevention” in this of allergic conjunctivitis, such as ocular itching, redness, and context refers to a reduction in the frequency of, or a delay in eyelid Swelling, as well as associated nasal symptoms. The the onset of symptoms associated with allergic conjunctivitis formulations of the invention are also useful for the treatment and/or rhinoconjunctivitis, relative to a Subject who does not and prevention of the signs and symptoms of allergic rhi receive the composition. The effective amount of fluticasone noconjunctivitis, such as itchy, running nose, Sneezing, nasal/ and other active agents in the formulation will depend on sinus congestion, and red, watery and/or itchy eyes. absorption, inactivation, and excretion rates of the drug as 0.124. The invention provides methods of treating or pre well as the delivery rate of the compound from the formula venting allergic conjunctivitis and/or allergic rhinoconjunc tion. Particular dosages may also vary with the severity of the tivitis in a subject in need thereof comprising topically admin condition to be alleviated. It is to be further understood that istering directly to the eye surface of the Subject a an for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the ophthalmic formulation comprising an effective amount of professional judgment of the person administering or Super fluticasone. In certain embodiments, the administration of vising the administration of the compositions. Typically, a fluticasone directly to the eye of a subject in need of treatment dosing regimen will be determined using techniques known or prevention of allergic conjunctivitis and/or rhinoconjunc to one skilled in the art. tivitis is also effective to mitigate or reduce one or more nasal symptoms associated with the either allergy (e.g., itchy, run I0128. Examples of dosing regimens that can be used in the ning nose, Sneezing and/or nasal/sinus congestion). Topical methods of the invention include, but are not limited to, once administration of the ophthalmic formulations directly to the daily, twice daily, three times, and four times daily. In certain eye of a Subject will significantly reduce nasal signs and embodiments, the method comprises administering a flutica symptoms via drainage from the ocular Surface into the nasal sone formulation of the invention directly to the eye of the cavity through the nasolacrimal duct (See e.g., Abelson et al., Subject once a day. In some embodiments, the administration Clin. Ther. 25(3),931-947 (2003); Spangler et al., Clin. Ther. is 2 to 4 times a day. 25 (8), 224.5-2267 (2003); and Crampton et al., Clin Ther. I0129. In certain embodiments, once a day administration November; 24(11):1800-8 (2002)). Furthermore, signifi (q.d.) is effective to mitigate the symptoms of ocular and/or cantly less active agent is required to treat the nasal symptoms nasal allergy. However, particular dosages may also be when instilled through the eye of a subject as compared to selected based on a number of factors including the age, sex, administration through the nose of the Subject. For example, species and condition of the Subject. Effective amounts can each spray of Flonase R (commercially available nasal spray also be extrapolated from dose-response curves derived from comprising fluticaSone) delivers 50 micrograms of flutica in vitro test systems or from animal models. Sone to the nasal cavity to treat allergic rhinitis and allergic 0.130. The combined use of several active agents formu rhinoconjunctivitis. In contrast, one drop of a 0.005% fluti lated into the compositions of the present invention may casone ophthalmic formulation (i.e., 2.5 micrograms in a 500 reduce the required dosage for any individual component microliter drop) has been shown to significantly reduce nasal because the onset and duration of effect of the different com symptoms associated with ocular allergy when topically ponents may be complimentary. In Such combined therapy, administered directly to the eye (see Example 1 herein). As the different active agents may be delivered together or sepa Such, the methods of the present invention are more optimal rately, and simultaneously or at different times within the day. than the currently available treatment options for nasal Symp I0131. In a particular embodiment, a formulation compris toms of allergic conjunctivitis and allergic rhinoconjunctivi ing fluticaSone as the only active agent in the formulation is tis. administered to the eye of a subject in need of treatment or 0.125. The subject is preferably a human, but may be prevention of an allergic conjunctivitis and/or rhinoconjunc another mammal, for example a dog, a cat, a horse, a rabbit, a tivitis once daily (q.d.). In certain embodiments, the flutica mouse, a rat, or a non-human primate. Sone formulation is administered two to four times a day. US 2011/O 105450 A1 May 5, 2011 0132) Surprisingly the fluticasone alone formulations as single dose products creates a risk of microbial contamination described herein were more effective at relieving ocular itch of the single dose product and an associated risk of ocular ing and associated nasal symptoms of allergic conjunctivitis infection if a contaminated composition is applied to the eyes. than could be predicted. Even more surprising was the finding that a lower dose fluticasone was more effective at relieving 0.137 While the formulations of this invention are prefer ocularitching and associated nasal symptoms of allergic con ably formulated as “ready for use’ aqueous solutions, alter junctivitis than a higher dose of fluticasone, when adminis native formulations are contemplated within the scope of this tered directly to the eye. For example, as described in the invention. Thus, for example, the active ingredients, Surfac Examples, the efficacy of 0.005% fluticasone was more effi tants, salts, chelating agents, or other components of the cacious than the higher dose 0.01% fluticasone. ophthalmic solution, or mixtures thereof, can be lyophilized 0133. In another particular embodiment, cetirizine is for or otherwise provided as a dried powder or tablet ready for mulated with one or more of naphazoline, oxymetazoline dissolution (e.g., in deionized, or distilled) water. Because of cetirizine or ketotifen, and administered to the eye of a subject the self-preserving nature of the solution, sterile water is not in need of treatment or prevention of allergic conjunctivitis required. and/or rhinoconjunctivitis once daily (q.d.). In certain 0.138 Sterility or adequate antimicrobial preservation may embodiments, the combination formulation is administered be provided as part of the present formulations. Since certain two to four times a day. formulations of the present invention are intended to be administered ophthalmically, it is preferred that they be free Packaging of pathogenic organisms. A benefit of a sterile liquid Suspen sion is that it reduces the possibility of introducing contami 0134. The formulations of the present invention may be nants into the individual when the Suspension formulation is packaged as either a single dose product or a multi-dose administered to the eye, thereby reducing the chance of an product. The single dose product is sterile prior to opening of opportunistic infection. Processes which may be considered the package and all of the composition in the package is for achieving sterility may include any appropriate steriliza intended to be consumed in a single application to one or both tion steps known in the art. In one embodiment, the drug eyes of a patient. The use of an antimicrobial preservative to Substance (e.g., fluticasone) is produced under sterile condi maintain the Sterility of the composition after the package is tions, the micronization is performed in a sterile environment, opened is generally unnecessary. and the mixing and packaging is conducted under sterile 0135 Multi-dose products are also sterile prior to opening conditions. In alternative embodiment, the formulations of of the package. However, because the container for the com the present invention may be sterile filtered and filled in vials, position may be opened many times before all of the compo including unit dose vials providing sterile unit dose formula sition in the container is consumed, the multi-dose products tions which are used in a nasal spray device for example. Each must have sufficient antimicrobial activity to ensure that the unit dose vial may be sterile and is suitably administered compositions will not become contaminated by microbes as a without contaminating other vials or the next dose. In one result of the repeated opening and handling of the container. alternative embodiment, one or more ingredients in the The level of antimicrobial activity required for this purpose is present formulation may be sterilized by Steam, gamma radia well known to those skilled in the art, and is specified in tion or prepared using or mixing sterile steroidal powder and official publications, such as the United States Pharmaco other sterile ingredients where appropriate. Also, the formu poeia (“USP) and corresponding publications in other coun lations may be prepared and handled understerile conditions, tries. Detailed descriptions of the specifications for preserva or may be sterilized before or after packaging. tion of ophthalmic pharmaceutical products against microbial contamination and the procedures for evaluating the preser Kits vative efficacy of specific formulations are provided in those 0.139. The present invention provides a pharmaceutical publications. In the United States, preservative efficacy stan pack or kit comprising one or more containers filled with a dards are generally referred to as the “USP PET require liquid or lyophilized fluticasone formulation of the invention ments. (The acronym "PET stands for “preservative efficacy (i.e., a formulation comprising fluticasone alone or in com testing.) bination with an additional active agent as described herein). 0136. The use of a single dose packaging arrangement In one embodiment, the formulation is an aqueous formula eliminates the need for an antimicrobial preservative in the tion of fluticasone. In one embodiment, the formulation is compositions, which is a significant advantage from a medi lyophilized. In preferred embodiments the liquid or lyo cal perspective, because conventional antimicrobial agents philized formulation is sterile. In one embodiment, the kit utilized to preserve ophthalmic compositions (e.g., benzalko comprises a liquid or lyophilized formulation of the inven nium chloride) may cause ocular irritation, particularly in tion, in one or more containers, and one or more other pro patients suffering from dry eye conditions or pre-existing phylactic or therapeutic agents (e.g., fluticasone in combina tion with an additional active agent Such as naphazoline, ocular irritation. However, the single dose packaging arrange oxymetazoline, cetirizine or ketotifen) useful for the treat ments currently available. Such as Small Volume plastic vials ment of allergic conjunctivitis and/or allergic rhinoconjunc prepared by means of a process known as “form, fill and seal'. tivitis. The one or more other prophylactic or therapeutic have several disadvantages for manufacturers and consumers. agents may be in the same container as the fluticaSone or in The principal disadvantages of the single dose packaging one or more other containers. Preferably, the fluticasone is systems are the much larger quantities of packaging materials formulated at a concentration of from about 0.05% (w/v) to required, which is both wasteful and costly, and the inconve about 1.0% (w/v) and is suitable for topical ocular adminis nience for the consumer. Also, there is a risk that consumers tration. In some embodiments, fluticasone is formulated with will not discard the single dose containers following applica an additional active agent such as oxymetazoline, naphazo tion of one or two drops to the eyes, as they are instructed to line, cetirizine or ketotifen, as described herein. In certain do, but instead will save the opened container and any com embodiments, the kit contains the fluticasone in unit dosage position remaining therein for later use. This improper use of form. US 2011/O 105450 A1 May 5, 2011 0140. In certain embodiments, the kit further comprises 0147 Conjunctival redness was also subjectively assessed instructions for use in the treatment of allergic conjunctivitis on a scale of 0 (no redness) to 4 (severe redness). As shown in and/or allergic rhinoconjunctivitis (e.g., using the fluticaSone FIG. 3, Fluticasone 0.001%, 0.005% and 0.01% were about formulations of the invention alone or in combination with equally effective in reducing conjunctival redness over a 20 another prophylactic or therapeutic agent), as well as side minute period as compared to vehicle alone. effects and dosage information for one or more routes of 0148 Lidswelling was subjectively assessed on a scale of administration. Optionally associated with Such container(s) 0 (no lid swelling) to 3 (severe lid swelling). As shown in FIG. is a notice in the form prescribed by a governmental agency 4, Fluticasone 0.001% and 0.005% were each more effective than Fluticasone 0.01% at reducing lid swelling over a 20 regulating the manufacture, use or sale of pharmaceuticals or minute period as compared to vehicle alone. biological products, which notice reflects approval by the 0149 Nasal Congestion was subjectively assessed on a agency of manufacture, use or sale for human administration. scale of 0 (no congestion) to 4 (severe congestion). As shown While the instructional materials typically comprise written in FIG.5, Fluticasone 0.001%, 0.005% and 0.01% were about or printed materials they are not limited to such. Any medium equally effective in reducing nasal congestion over a 30 capable of storing Such instructions and communicating them minute period as compared to vehicle alone. to an end user is contemplated by this invention. Such media 0150. A summary of the results of the primary ocular include, but are not limited to electronic storage media (e.g., endpoint assessments is shown in FIG. 6. As shown in FIG. 6, magnetic discs, tapes, cartridges, chips), optical media (e.g. the reduction in conjunctival redness by Fluticasone 0.005% CDROM), and the like. Such media may include addresses to and 0.01% and the reduction in lid swelling by Fluticasone internet sites that provide such instructional materials. 0.001% were each statistically significant (p<0.05). 0141. In another embodiment, this invention provides kits Secondary Ocular Endpoints for the packaging and/or storage and/or use of the formula 0151 Ciliary Redness, episcleral redness, chemosis and tions described herein, as well as kits for the practice of the watery eyes were assessed in each Subject at visit 4B. methods described herein. The kits can be designed to facili 0152 Ciliary redness was assessed on a scale of 0 (no tate one or more aspects of shipping, use, and storage. redness) to 4 (severe redness). As shown in FIG. 7. Flutica 0142. All publications and patents mentioned herein are sone 0.001%, 0.005% and 0.01% were each significantly hereby incorporated by reference in their entirety as if each effective in reducing ciliary redness over a 20 minute period individual publication or patent was specifically and indi as compared to vehicle alone (p<0.05 for each Fluticasone vidually indicated to be incorporated by reference. concentration). 0153 Episcleral redness was assessed on a scale of 0 (no EXAMPLES redness) to 4 (severe redness). As shown in FIG. 8, Flutica sone 0.001%, 0.005% and 0.01% each reduce episcleral red 0143. The invention is further defined by reference to the ness over a 20 minute period as compared to vehicle alone. following examples, which are not meant to limit the scope of 0154 Chemosis was assessed on a scale of 0 (none) to 4 the present invention. It will be apparent to those skilled in the (extreme). As shown in FIG.9, Fluticasone 0.001%, 0.005% art that many modifications, both to the materials and meth and 0.01% were each significantly effective in reducing ods, may be practiced without departing from the purpose and chemosis over a 20 minute period. interest of the invention. 0155 Watery eyes were also subjectively assessed on a scale of 0 (not watery) to 4 (extremely watery). As shown in Example 1 FIG. 10, Fluticasone 0.001% and 0.05% were each more effective than Fluticasone 0.01% in reducing watery eyes Fluticasone Prevents Ocular and Nasal Symptoms over a 20 minute period, as compared to vehicle alone. Associated with Allergic Conjunctivitis 0156 A summary of the secondary ocular endpoints 0144. A placebo controlled, double-blind study was con assessed is shown in FIG. 11. As shown in FIG. 10, the ducted to evaluate the efficacy of Fluticasone 0.001% (N=16), reduction in ciliary redness by all three concentrations of Fluticasone 0.005% (N=16), Fluticasone 0.01% (N=15).com Fluticasone, the reduction in episcleral redness by Flutica pared to vehicle alone (N=15). Subjects underwent 2 screen sone 0.005%, and the reduction of watery eyes by Fluticasone ing visits (allergentitration and confirmation) followed by 2 0.05% were each statistically significant (p<0.05). drug evaluation visits, as indicated in the study design shown Secondary Nasal Endpoints in FIGS. 1A and 1B. At the drug evaluation visits, one drop of masked study medication was instilled in each eye and ocular 0157 Rhinorrhea, ear or palate pruritis, nasal pruritis were allergic assessments were taken. Eight hours later the Subjects assessed in each Subject at visit 4B using a scale of 0 (none) to were challenged with allergen and primary and secondary 4 (extreme) for each endpoint. 0158. As shown in FIGS. 12 and 14, Fluticasone 0.001%, ocular and nasal endpoints were assessed, as well as safety of 0.005% and 0.01% each had a clinically significant effect in the formulations. The results are presented in FIGS. 2-21. reducing rhinorrhea and nasal pruritis, respectively, over a 20 Primary Ocular Endpoints minute period as compared to vehicle alone. Shown in FIG. 13, Fluticasone 0.001%, 0.005% and 0.01% were each had an 0145 Ocular itching, conjunctival redness, lid swelling, effect in reducing ear and palate pruritis as compared to and nasal congestion were assessed in each Subject during vehicle alone. visit 4B. 0159. Total nasal scores were assessed on a scale of 0-16. 0146 Ocular itching was subjectively assessed on a scale As shown in FIG. 15, Fluticasone 0.001%, 0.005% and of 0 (no itching) to 4 (severe itching). As shown in FIG. 2, 0.01%, each Surprisingly had a clinically significant effect on Fluticasone 0.001%, 0.005% and 0.01% were about equally total nasal score when administered directly to the eye of each effective in reducing ocular itching over a 7 minute time Subject. A Summary of the nasal endpoints assessed is shown period as compared to vehicle alone. in FIGS. 16 and 17. US 2011/O 105450 A1 May 5, 2011 Safety a demulcifing agent at a concentration of between 0.2% 0160 Intraocular pressure, drop comfort and adverse and 5.0% (w/v); events such as blurry vision, conjunctival hemorrhage, dry glycerin; and eye, site pain and/or irritation and headache, were assessed a buffer system comprising one or more of aborate buffer, for each subject. phosphate buffer, or calcium buffer. 0161 Drop comfort was subjectively assessed on a scale 2. The ophthalmic formulation of claim 1, wherein flutica of 0 (extremely comfortable) to 10 (extremely uncomfort Sone and is present in the formulation at a concentration of able) during visit 2 and visit 3. As shown in FIGS. 18 and 19. 0.001% to 0.2% (w/v). Fluticasone 0.01 was highly uncomfortable upon instillation 3. The ophthalmic formulation of claim 2, wherein the as compared to Fluticasone 0.001% and 0.005%, and as com concentration of fluticasone is 0.005% (w/v). pared to vehicle alone. The comfort of Fluticasone 0.001% 4. The ophthalmic composition of claim 1, wherein the and 0.005% were comparable to the comfort of the vehicle demulcifing agent contains hydroxypropylmethylcellulose. control. 5. The ophthalmic composition of claim 1, wherein the 0162. A summary of the total percentage of subjects who composition comprises a preservative. experienced adverse events such as blurry vision, conjuncti 6. The ophthalmic formulation of claim 5, wherein the Val hemorrhage, dry eye, site pain and/or irritation, and head preservative is benzalkonium chloride or a derivative thereof, ache, is shown in FIG. 20. or a stabilized, oxychloro complex. 0163 The effect of each concentration of Fluticasone on 7. The ophthalmic composition of claim 1, wherein the intraocular pressure (IOP) as compared to vehicle alone is composition does not comprise a preservative. shown in FIG. 21. 8. The ophthalmic formulation of claim 1, wherein the pH 0164. The results demonstrate that a single drop of either of the composition is 5 to 7.0. Fluticasone 0.001%, 0.005% or 0.01% was effective to pre 9. The ophthalmic formulation of claim 1, wherein the vent both ocular and nasal symptoms associated with allergic formulation is an aqueous formulation, an ointment, an oil, a conjunctivitis. However, when taking all primary and second Suspension, an emulsion, or incorporated in a drug delivery ary endpoints into consideration, the mid-strength Flutica device. sone 0.005% was the most efficacious in relieving both ocular 10. The ophthalmic formulation of claim 9, wherein the and nasal symptoms, and was shown to be more comfortable formulation is in an aqueous formulation. than Fluticasone 0.001% and Fluticasone 0.01%, with no 11. A topical ophthalmic formulation comprising 0.005% adverse effect on intraocular pressure. fluticasone, 1% Polyethylene Glycol 400, NF, 0.2% Dibasic Sodium Phosphate, Anhydrous, USP, 0.25% Hypromellose, EQUIVALENTS USP, 0.1% Polysorbate 80, NF, 1.8% Glycerin, USP, 0.025% 0.165 Those skilled in the art will recognize, or be able to Edetate Disodium, USP, and 0.01% Benzalkonium Chloride, ascertain using no more than routine experimentation, many wherein the formulation has a pH 7.0. equivalents to the specific embodiments of the invention 12. A method for treating allergic conjunctivitis by topi described herein. Such equivalents are intended to be encom cally administering to the eye of a Subject in need of Such passed by the following claims. treatment an ophthalmic formulation comprising the oph What is claimed is: thalmic formulation of claim 1. 1. A topical ophthalmic formulation comprising: 13. A method for treating allergic rhinoconjunctivitis by fluticasone, or a pharmaceutically acceptable salt or ester topically administering to the eye of a Subject in need of Such thereof, wherein the fluticasone is present at a concen treatment an ophthalmic formulation comprising the oph tration of between 0.001% and 1.0% (w/v), wherein thalmic formulation of claim 1. fluticasone is the sole antiallergic agent in the composi tion; c c c c c