US 2006O183698A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0183698 A1 Abelson (43) Pub. Date: Aug. 17, 2006

(54) OPHTHALMC FORMULATIONS AND USES Publication Classification THEREOF (51) Int. Cl. A61K 3 1/7034 (2006.01) (75) Inventor: Mark Abelson, Andover, MA (US) A 6LX 3/573 (2006.01) A6II 3L/496 (2006.01) Correspondence Address: A 6LX 3L/95 (2006.01) TOWNSEND AND TOWNSEND AND CREW, (52) U.S. Cl...... 514/35: 514/253.08: 514/171; LLP 514/563; 514/200 TWO EMBARCADERO CENTER (57) ABSTRACT EIGHTH FLOOR Provided by the present invention are compositions or SAN FRANCISCO, CA 94111-3834 (US) formulations suitable for application to a patient's eyes which utilizes a topical ophthalmically-acceptable formula tion comprising a therapeutically-effective amount of an (73) Assignee: ISTA Pharmaceuticals, Inc., Irvine, CA ophthalmically-active antimicrobial agent, and an oph Appl. No.: 11/146,652 thalmically-active anti-inflammatory or steroidal agent in (21) combination with physiologic levels of serum electrolytes in (22) Filed: Jun. 7, 2005 an ophthalmic formulation for the treatment of changes in the normal eye condition. The invention also includes meth Related U.S. Application Data ods of treating patients having an ophthalmic disease, injury or disorder, utilizing the compositions or formula (60) Provisional application No. 60/675,179, filed on Apr. tions. Also provided are kits comprising the compositions or 26, 2005. Provisional application No. 60/577.567, formulations and a means of applying the compositions or filed on Jun. 7, 2004. formulation to the patient's eyes. US 2006/0183698 A1 Aug. 17, 2006

OPHTHALMC FORMULATIONS AND USES from about 14.592 to about 24.32 mg/L. phosphate in a THEREOF concentration from about 85 to about 150 mg/L, and bicar bonate in a concentration from about 1281 to about 2013 CROSS-REFERENCES TO RELATED mg/L. APPLICATIONS 0006 The antimicrobial agent, and anti-inflammatory or 0001. This application claims benefit of priority from steroidal agent of the composition or formulation are used to U.S. Provisional Patent Application 60/577.567, filed Jun. 7, treat or mitigate the injury, disease or disorder. One steroidal 2004, and from U.S. Provisional Patent Application 60/675, agent contemplated in the present invention is 179, filed Apr. 26, 2005 both of which are hereby incorpo whereas a contemplated antimicrobial is tobramycin. rated in their entirety as if fully set forth. 0007. The invention also includes methods of treating patient's having an ophthalmic disease, injury or disorder, BACKGROUND OF THE INVENTION utilizing the compositions or formulations. Further, the 0002 The present invention relates to ophthalmic formu compositions or formulations can be utilized to restore the lations, kits and uses thereof, wherein the formulations normal condition of the eye when the normal condition has utilize physiologic levels of serum electrolytes in conjunc been disrupted or changed. Also provided are kits compris tion with pharmacologically effective doses of an antimi ing the compositions or formulations and a means of apply crobial agent, and an anti-inflammatory or steroidal agent in ing the compositions or formulation to the patient’s eyes. a single formulation for the treatment of ocular disorders, diseases or injuries. Combinations or formulations contain DESCRIPTION OF THE INVENTION ing an antimicrobial agent and an anti-inflammatory agent are available in the ophthalmic art. However, there are 0008. Without being bound by a particular theory, it concerns and expressed reservations in the ophthalmic com appears that the physiology of the injured or diseased eye munity about the safety and efficacy of such prior art more closely resembles the physiology of serum due to the combinations. There continues to be a need for an effective release of vessel contents into the tear film and, as such, the and safe topical ophthalmic pharmaceutical composition of contents are pathological to the condition of the eye. There a or anti-inflammatory agent and a broad spectrum fore, the application of an ophthalmic formulation that antibiotic which, when administered to the eye will not mimics the injured eye condition is a focus of the present inhibit the activity of the antibiotic, or steroidal or anti invention, since the application of Such a formulation does inflammatory components. not shock the already overly-sensitized tissues and is able to gradually restore the eye to a normal condition (i.e. non 0003. Many ophthalmic conditions result in an aberrant inflamed and non-infected State). Such an approach is coun tear film composition. The electrolyte balances and concen terintuitive to conventional therapies, since physicians pres trations in tears can change as a result of a disruption in the ently would not use a formulation that continues the normal eye physiology. For example, when ocular tissue is pathologic condition within the eye. Nevertheless, it is inflamed, serum components leak from the vasculature into important to consider that the addition of a formulation with the tear film. Many of these ophthalmic conditions are electrolytes in “equilibrium' with the electrolytes in the typically treated with antimicrobial and/or steroidal or anti “inflamed eye may provide several advantages when used inflammatory compounds. in conjunction with an antimicrobial and a steroidal or anti-inflammatory agent. Such advantages could include, but SUMMARY OF THE INVENTION are not necessarily limited to, a formulation that is more 0004 The present invention comprises a formulation comfortable to the patient which may result in better patient which mimics the serum components of the injured eye compliance and/or a formulation that promotes faster heal (instead of the normal eye tear physiology) which when used 1ng. in conjunction with an antimicrobial, and anti-inflammatory or steroidal agent in a single formulation assist in restoring DEFINITIONS the injured eye to its normal condition (i.e., non-inflamed 0009 “Ophthalmically-acceptable” means that the for and non-infected State). mulation, active agent, excipient or other material is com 0005 The present invention utilizes physiologic levels of patible with ocular tissue; that is, it does not cause signifi various serum electrolytes in an ophthalmic composition or cant or undue detrimental effects when brought into contact formulation also containing an antimicrobial agent, and an with ocular tissue. In some instances, actives and/or excipi anti-inflammatory or steroidal agent for the treatment of ents of the formulation may cause Some discomfort or various ophthalmic injuries, diseases or disorders. Typically, stinging in the eye; however, those excipients are still the injury, disease or disorder results in an inflammatory considered ophthalmically-acceptable for the purposes of response in and around the eye and/or causes leakage of the this application. In many instances, these irritating compo blood vessels in the eye. The serum electrolytes include nents are removed from the formulations for comfort of the Sodium, potassium, chloride, calcium, magnesium, phos patient. For example, polyvinyl alcohol (PVA) can be elimi phate, and/or bicarbonate in concentrations to match the nated from the formulation ingredients. normal physiologic levels. These levels comprise Sodium in 0010) “Antimicrobial compound' includes those that a concentration from about 3105 to about 3358 mg/L.; effectively kill or mitigate the activity of a microbe. Anti potassium in a concentration from about 136.85 to about microbial includes antibacterial, bacteriostatic, and the like. 207.23 mg/L. chloride in a concentration from about 3368.7 These agents include, but are not limited to: azithromycin, to about 3829.68 mg/L.; calcium in a concentration from tobramycin, gentamicin, ciprofloxacin, norfloxacin, ofloxa about 85 to about 103 mg/L, magnesium in a concentration cin, and sparfloxacin. US 2006/0183698 A1 Aug. 17, 2006

0.011) “Immunosuppressive agent,” and “immunosup the amount of light entering the eye, impairing vision. pressive drug.” refers to any agent which inhibits or prevents Corneal opacification can occur as a result of bacterial, an immune response. Exemplary agents include, but are not fungal or viral infections, or from trauma to the eye. limited to: , cyclosporin A. azathioprine, brequinar, gusperimus, 6-mercaptopurine, mizoribine, rapa 0021 “Diabetic retinopathy' is a complication of diabe mycin, tacrolimus (FK-506), folic acid analogs (e.g. denop tes typically classified into two stages, Non-Proliferative terin, edatrexate, methotrexate, piritrexim, pteropterin, Diabetic Retinopathy (NPDR) and Proliferative Diabetic TomudeX(R), trimetrexate), purine analogs (e.g., cladribine, Retinopathy (PDR). fludarabine, 6-mercaptopurine, thiamiprine, thiaguanine), pyrimidine analogs (e.g., ancitabine, azacitidine, 6-azauri 0022 “Non-Proliferative Diabetic Retinopathy” (NPDR) dine, carmofur, cytarabine, doxifluridine, emitefur, enocit is a complication of diabetes in the early stage of diabetic abine, floXuridine, fluorouracil, gemcitabine, tegafur), fluo retinopathy that occurs when normal blood vessels in the cinolone, , anecortaVe , retina are damaged due to diabetes and Swell and begin to flurometholone, , and prednisilone. leak fluid and small amounts of blood into the eye. 0012 “Nutrient sugar means any sugar that can provide nutrients to cells. Serum Electrolytes 0013 “Therapeutically-effective amount’ means an 0023 The physiologic concentration of electrolytes in amount of active sufficient to prevent, inhibit, or reduce the serum are approximately the following under normal physi level of inflammation, irritation or other abnormal condi ologic conditions: sodium 3105-3358 mg/L. potassium tions in the eye. 136.85-207.23 mg/L. chloride 3368.7-3829.7 mg/L. calcium 85-103 mg/L. magnesium 14.59-24.32 mg/L, phosphate 0014 “Derivative” means any analogs, salts, esters, 85-150 mg/L, and/or bicarbonate 1281-2013 mg/L. There amines, amides, acids and/or alcohols derived from an active are noticeable differences between the electrolyte balances agent of the invention which may be used in place of that found in serum as compared to tears. The greatest difference active agent. between tear electrolytes and serum electrolytes is typically 0015. A "patient' is a vertebrate, preferably mammal, found in the levels of potassium. The concentration of more preferably a human. Mammals include, but are not potassium is typically much lower in serum (3-5 mmol/L) as limited to: humans, rodents, sport animals and pets, such as compared to tears (20-40 mmol/L). rats, dogs, and horses. 0024. According to one aspect of the present invention 0016 "Ocular inflammation' includes, but is not limited there is provided a method of treating a patient's eye to: inflammatory conditions of the palpebral and bulbar wherein its normal condition has been disrupted or changed. conjunctiva, cornea and anterior segment of the globe. The method of this aspect of the invention is effected by 0017 “Eye surface inflammation includes any inflam administering a topical ophthalmic formulation comprising matory disorder involving the ocular Surface. The eye Sur physiologic levels of a serum electrolyte in conjunction with face includes the eyelids, conjunctiva and cornea. “Inflam an antimicrobial, and anti-inflammatory or steroidal agent. A mation” refers to white blood cell or leukocytic infiltration further aspect of the present invention is wherein the topical associated with cellular injury. Eye Surface inflammatory ophthalmic formulation comprising physiologic levels of a disorders treatable by the ophthalmic preparations of the serum electrolyte comprises potassium in a concentration invention are typically manifested by signs and symptoms from about 136.85 to about 207.23 mg/L. A still further Such as eye redness, or irritation. These diseases include, for aspect of the present invention is wherein the topical oph example, meibomianitis, blepharitis conjunctival hyper thalmic formulation comprising physiologic levels of serum emia, eyelid hyperemia, keratitis and ocular rosacea. The electrolytes comprises potassium in a concentration from inflammation of tissue associated with the eye can be the about 136.85 to about 207.23 mg/L. chloride in a concen result of a number of different causes. Whether the cause is tration from about 3368.7 to about 3829.68 mg/L.; calcium bacterial, viral, traumatic, iatrogenic or environmental, in a concentration from about 85 to about 103 mg/L.; inflammation can be painful, damaging to tissues and magnesium in a concentration from about 14.592 to about requires special care. 24.32 mg/L, and phosphate in a concentration from about 85 to about 150 mg/L. A yet still further aspect of the present 0018 “Eye surface dryness” includes, but is not limited invention is wherein the topical ophthalmic formulation to: any ocular disorder resulting in loss of water or Volume comprising physiologic levels of serum electrolytes com from the tear film. Such disorders generally can be charac prises sodium in a concentration from about 3105 to about terized by increased tear film osmolarity and decreased 3358 mg/L. potassium in a concentration from about 136.85 levels of corneal glycogen and conjunctival mucus-contain to about 207.23 mg/L. chloride in a concentration from ing goblet cells. Eye Surface dryness can result from a about 3368.7 to about 3829.68 mg/L. calcium in a concen number of different diseases but is not limited to: meibomian tration from about 85 to about 103 mg/L. magnesium in a gland dysfunction and meibomian gland orifice Stenosis or concentration from about 14.592 to about 24.32 mg/L.; closure. phosphate in a concentration from about 85 to about 150 mg/L, and bicarbonate in a concentration from about 1281 0.019 “Ocular infection' is an abnormal condition caused to about 2013 mg/L. In addition to the methods of treating by bacteria, fungi and viruses. Infections, if not treated, can an eye wherein its normal condition has been disrupted or lead to more severe ocular disorders. changed in a patient, each of the aforementioned formula 0020 “Corneal opacification' consists of a clouding or tions or compositions used in these methods are further scarring of the normally transparent cornea, that diminishes aspects of the present invention. US 2006/01 83698 A1 Aug. 17, 2006

Antimicrobial, and Anti-Inflammatory or Steroidal include, but are not limited to: antibacterial antibiotics, Agents synthetic antibacterials, antifungal antibiotics, synthetic 0025) The topical ophthalmic formulation of the present antifungals, antineoplastic agents, steroidal anti-inflamma invention comprises physiologic levels of a serum electro tory agents, non-steroidal anti-inflammatory agents, anti lyte, an antimicrobial agent, and an anti-inflammatory or allergic agents, glaucoma-treating agents, antiviral agents, steroidal agent. The antimicrobial compound of the present and anti-mycotic agents. Further contemplated are any invention is selected from, but not limited to the following derivatives of the therapeutically-active agents which may antimicrobial classes: aminoglycoside, fluoroquinolone, include, but not be limited to: analogs, salts, esters, amines, tetralide, or cephalosporin and their ophthalmically-accept amides, alcohols and acids derived from an agent of the able derivatives. The antimicrobial compound of the present invention and may be used in place of an agent itself. invention is selected from, but not limited to: tobramycin, 0030) Examples of the antibacterial antibiotics include, gentamicin, ciprofloxacin, norfloxacin, ofloxacin, and/or but are not limited to: aminoglycosides (e.g., amikacin, sparfloxacin; or their ophthalmically-acceptable derivatives. apramycin, arbekacin, bambermycins, butirosin, dibekacin, The anti-inflammatory compound of the present invention is dihydrostreptomycin, fortimicin(s), gentamicin, isepamicin, selected from, but not limited to: diclofenac, bromfenac, kanamycin, micronomicin, neomycin, neomycin unde dexamethasone and prednisolone. The steroidal compound cylenate, netilmicin, paromomycin, ribostamycin, Sisomi of the present invention is selected from, but not limited to: cin, spectinomycin, streptomycin, tobramycin, trospectomy prednisolone, dexamethasone, , beta cin), amphenicols (e.g., azidamfenicol, chloramphenicol, methasone, and/or . For example, ocular ste florfenicol, thiamphenicol), ansamycins (e.g., rifamide, roids are added when indicated in inflammatory conditions rifampin, rifamycin SV, rifapentine, rifaximin), f-lactams of the palpebral and bulbar conjunctiva, cornea and anterior (e.g., carbacephems (e.g., loracarbef), carbapenems (e.g., segment of the globe such as allergic conjunctivitis, acne biapenem, imipenem, meropenem, panipenem), cepha rosacea, superficial punctuate keratitis, herpes Zoster kerati losporins (e.g., cefaclor, cefadroxil, cefamandole, cefatriz tis, cyclitis, and where the inherent risk of steroid use in ine, cefazedone, cefazolin, cefcapene pivoxil, cefclidin, cef certain infective conjunctivides is accepted to obtain a dinir, cefditoren, cefepime, cefetamet, cefixime, dimunition in edema and inflammation. Ocular are cefmenoxime, cefodizime, cefonicid, cefoperaZone, cefo also indicated in surgical trauma, anterior uveitis and corneal ranide, cefotaxime, cefotiam, cefoZopran, ce?pimizole, cef injury from chemical, radiation or thermal burns, or pen piramide, ce?pirome, cefpodoxime proxetil, cefprozil, etration of foreign bodies. The antimicrobial agent of the cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, present invention is indicated where the risk of Superficial ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefu ocular infection is high or where there is an expectation that Zonam, cephacetrile sodium, cephalexin, cephaloglycin, potentially dangerous numbers of bacteria will be present in cephaloridine, cephalosporin, cephalothin, cephapirin the eye. sodium, cephradine, piveefalexin), cephamycins (e.g., cef buperazone, cefimetazole, cefininox, cefotetan, cefoxitin). Conditions/Diseases monobactams (e.g., aztreonam, carumonam, tigemonam). 0026. According to one aspect of the present invention oxacephems, flomoxe?, moxalactam), penicillins (e.g., there is provided a method of treating an ocular disease, amdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin, injury or disorder in a patient. The method of this aspect of apalcillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, the invention is effected by administering a topical oph benzylpenicillinic acid, benzylpenicillin sodium, carbenicil thalmically-acceptable formulation comprising therapeuti lin, carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin, cally-effective amounts of antimicrobial, and anti-inflam lenampicillin, metampicillin, methicillin sodium, meZlocil matory or steroidal agents in combination with physiologic lin, nafcillin sodium, oxacillin, penamecillin, penethamate levels of serum electrolytes to a subject in need thereof. hydriodide, penicilling benethamine, penicilling benza 0027) A further aspect of the present invention is wherein thine, penicilling benzhydrylamine, penicilling calcium, said ocular disease, injury or disorder is caused by Surgery, penicilling hydrabamine, penicilling potassium, penicillin physical damage to the eye, glaucoma, macular degenera g procaine, penicillinn, penicillino, penicillin V, penicillin tion, or diabetic retinopathy. A still further aspect of the v benzathine, penicillin V hydrabamine, penimepicycline, present invention is wherein the ocular disease, injury or phenethicillin potassium, piperacillin, pivampicillin, propi disorder is one caused by vascular leakage in the eye or by cillin, quinacillin, sulbenicillin, Sultamicillin, talampicillin, inflammation in the eye. temocillin, ticarcillin), other (e.g., ritipenem), lincosamides (e.g., clindamycin, lincomycin), macrollides (e.g., azithro 0028. Examples of conditions related to inflammation in mycin, carbomycin, clarithromycin, dirithromycin, erythro the eye include, but are not limited to the following: Surgical mycin, erythromycin acistrate, erythromycin estolate, eryth trauma, dry eye, allergic conjunctivitis, viral conjunctivitis, romycin glucoheptonate, erythromycin lactobionate, bacterial conjunctivitis, blepharitis, anterior uveitis, injury erythromycin propionate, erythromycin stearate, josamycin, from a chemical, radiation or thermal burn, or penetration of leucomycins, midecamycins, miokamycin, oleandomycin, a foreign body. primycin, rokitamycin, rosaramicin, roXithromycin, spira mycin, troleandomycin), polypeptides (e.g., amphomycin, Additional Actives bacitracin, capreomycin, colistin, enduracidin, enviomycin, 0029. Unless the intended purpose of use is affected fusafungine, gramicidins, gramicidin(s), mikamycin, poly adversely, the ophthalmic formulation of the present inven myxin, pristinamycin, ristocetin, teicoplanin, thiostrepton, tion may further comprise one or more additional therapeu tuberactinomycin, tyrocidine, tyrothricin, Vancomycin, vio tically-active agents. Specific therapeutically-active agents mycin, virginiamycin, zinc bacitracin), tetracyclines (e.g., US 2006/0183698 A1 Aug. 17, 2006

apicycline, chlortetracycline, clomocycline, demeclocy hexetidine, loflucarban, nifuratel, potassium iodide, propi cline, doxycycline, guamecycline, lymecycline, meclocy onic acid, pyrithione, Salicylanilide, Sodium propionate, cline, methacycline, minocycline, oxytetracycline, penime Sulbentine, tenonitrozole, triacetin, ujothion, undecylenic picycline, pipacycline, rollitetracycline, sancycline, acid, Zinc propionate). tetracycline), and others (e.g., cycloserine, mupirocin, 0034) Examples of the antineoplastic agents include, but tuberin). are not limited to: antineoplastic antibiotics and analogs (e.g., 0031 Examples of the synthetic antibacterials include, aclacinomycins, actinomycin f, anthramycin, azaserine, but are not limited to: 2,4-diaminopyrimidines (e.g., brodi bleomycins, cactinomycin, carubicin, carZinophilin, chro moprim, tetroxoprim, trimethoprim), nitrofurans (e.g., fural momycins, dactinomycin, daunorubicin, 6-diazo-5-oxo-L- tadone, fuirazolium chloride, nifuradene, nifuratel, nifurfo norleucine, doxorubicin, epirubicin, idarubicin, menogaril. line, nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin), mitomycins, mycophenolic acid, nogalamycin, olivomy quinolones and analogs (e.g., cinoxacin, ciprofloxacin, cines, peplomycin, pirarubicin, plicamycin, porfiromycin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine, puromycin, streptonigrin, Streptozocin, tubercidin, Zinosta grepafloxacin, lomefloxacin, miloxacin, nadifloxacin, nali tin, Zorubicin), antimetabolites exemplified by folic acid dixic acid, norfloxacin, ofloxacin, oxolinic acid, paZufloxa analogs (e.g., denopterin, edatrexate, methotrexate, piritr cin, pefloxacin, pipemidic acid, piromidic acid, roSoxacin, exim, pteropterin, TomudeX(R), trimetrexate), purine analogs rufloxacin, sparfloxacin, temafloxacin, to Sufloxacin, trova (e.g., cladribine, fludarabine, 6-mercaptopurine, thiami floxacin), Sulfonamides (e.g., acetyl sulfamethoxypyrazine, prine, thioguanine), pyrimidine analogs (e.g., ancitabine, benzylsulfamide, chloramine-b, chloramine-t, dichloramine aZacitidine, 6-azauridine, carmofur, cytarabine, doxifluri t, n-formylsulfisomidine, n-?3-d-glucosylsulfanilamide, dine, emitefur, enocitabine, floXuridine, fluorouracil, gem mafenide, 4'-(methylsulfamoyl)sulfanilanilide, noprylsulfa citabine, tagafur). mide, phthalylsulfacetamide, phthalylsulfathiazole, Salazo Sulfadimidine. Succinylsulfathiazole, Sulfabenzamide, Sul 0035 Examples of the steroidal anti-inflammatory agents facetamide, Sulfachlorpyridazine, Sulfachrysoidine, include, but are not limited to: 21-acetoxypregnenolone, Sulfacytine, Sulfadiazine, Sulfadicramide, Sulfadimethoxine, , algestone, , beclomethasone, Sulfadoxine, Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sul , , , , falene, Sulfaloxic acid, Sulfamerazine, Sulfameter, Sulfamet , , , corticosterone, corti hazine, Sulfamethizole, Sulfamethomidine, Sulfamethox Sone, , , , , aZole, Sulfamethoxypyridazine, Sulfametrole, dexamethasone, , , , Sulfamidocchrysoidine, Sulfamoxole, Sulfanilamide, 4-sulfa enoXolone, , flucloronide, flumethasone, nilamidosalicylic acid, n-sulfanilylsulfanilamide, sulfanily , acetonide, , lurea, n-sulfanillyl-3,4-Xylamide, Sulfanitran, Sulfaperine, butyl, , fluorometholone, acetate, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, Sulfapyri acetate, , flurandrenolide, flu dine, Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathio ticasone propionate, , , halobetasol urea, Sulfatolamide, Sulfisomidine, Sulfisoxazole) Sulfones propionate, , acetate, hydrocor (e.g., acedapsone, acediasulfone, acetosulfone sodium, dap tamate, , etabonate, Sone, diathymosulfone, glucosulfone sodium, Solasulfone, , medrysone, , methylpredniso Succisulfone, Sulfanilic acid, p-sulfanilylbenzylamine, Sul lone, furoate, , , foXone sodium, thiazolsulfone), and others (e.g., clofoctol, prednisolone, prednisolone 25-diethylamino-acetate, pred hexedine, methenamine, methenamine anhydromethylene nisolone sodium phosphate, , prednival, pred citrate, methenamine hippurate, methenamine mandelate, nylidene, , , triamcinolone, triamcino methenamine Sulfosalicylate, nitroxoline, taurolidine, lone acetonide, triamcinolone benetonide, and triamcinolone xibornol). hexacetonide. 0032 Examples of the antifungal antibiotics include, but 0036) Examples of the non-steroidal anti-inflammatory are not limited to: polyenes (e.g., amphotericin b, candici agents include, but are not limited to: aminoarylcarboxylic din, dennostatin, filipin, fungichromin, hachimycin, hamy acid derivatives (e.g., enfenamic acid, etofenamate, flufe cin, lucensomycin, mepartricin, natamycin, nystatin, pecilo namic acid, isonixin, meclofenamic acid, mefenamic acid, cin, perimycin), others (e.g., azaserine, griseofulvin, niflumic acid, talniflumate, terofenamate, tolfenamic acid), oligomycins, neomycin undecylenate, pyrrolnitrin, siccanin, arylacetic acid derivatives (e.g., aceclofenac, acemetacin, alclofenac, amfenac, amtolimetin guacil, bromfenac, bufex tubercidin, viridin). amac, cinmetacin, clopirac, diclofenac sodium, etodolac, 0033 Examples of the synthetic antifungals include, but felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, are not limited to: allylamines (e.g., butenafine, naftifine, indomethacin, isofeZolac, isoxepac, lonazolac, metiazinic terbinafine), imidazoles (e.g., bifonazole, butoconazole, acid, mofeZolac, oxametacine, piraZolac, proglumetacin, chlordantoin, chlormiidazole, clotrimazole, econazole, enil Sulindac, tiaramide, tolmetin, tropesin, Zomepirac), arylbu conazole, fenticonazole, flutrimazole, isoconazole, keto tyric acid derivatives (e.g., bumadizon, butibufen, fenbufen, conazole, lanoconazole, , omoconazole, oxi Xenbucin), arylcarboxylic acids (e.g., clidanac, ketorolac, conazole nitrate, Sertaconazole, Sulconazole, tioconazole), tinoridine), arylpropionic acid derivatives (e.g., alminopro thiocarbamates (e.g., tolciclate, tolindate, tolnaftate), triaz fen, benoxaprofen, bermoprofen, bucloxic acid, carprofen, oles (e.g., fluconazole, itraconazole, Saperconazole, tercona fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibu Zole) others (e.g., acrisorcin, amorolfine, biphenamine, bro proxam, indoprofen, ketoprofen, loxoprofen, naproxen, mosalicylchloranilide, buclosamide, calcium propionate, oxaprozin, piketoprolen, pirprofen, pranoprofen, protizinic chlorphenesin, ciclopirox, cloxyquin, coparaflinate, diamt acid, Suprofen, tiaprofenic acid, Ximoprofen, Zaltoprofen), hazole dihydrochloride, exalamide, flucytosine, halethazole, pyrazoles (e.g., difenamizole, epirizole), pyrazolones (e.g., US 2006/0183698 A1 Aug. 17, 2006 apaZone, benzpiperylon, feprazone, mofebutaZone, mora acceptable formulation comprising physiologic levels of Zone, oxyphenbutaZone, phenylbutaZone, pipebuZone, pro serum electrolytes in combination with a therapeutically pyphenaZone, ramifenaZone, SuXibuZone, thiazolinobuta effective amount of an ophthalmically-active antimicrobial, Zone), salicylic acid derivatives (erg., acetaminosalol, and an ophthalmically-active anti-inflammatory or steroidal aspirin, benorylate, bromosaligenin, calcium acetylsalicy agent to treat an ocular disease, injury or disorder comprises: late, diflunisal, etersalate, fendosal, gentisic acid, glycol sodium in a concentration from about 3105 to about 3358 salicylate, imidazole salicylate, lysine acetylsalicylate, mg/L, potassium in a concentration from about 136.85 to mesalamine, morpholine Salicylate, 1-naphthyl salicylate, about 207.23 mg/L. chloride in a concentration from about olsalazine, parsalmide, phenyl acetylsalicylate, phenyl sali 3368.7 to about 3829.68 mg/L. calcium in a concentration cylate, Salacetamide, salicylamide o-acetic acid, Salicylsul from about 85 to about 103 mg/L. magnesium in a concen furic acid, Salsalate, SulfaSalazine), thiazinecarboxamides tration from about 14.592 to about 24.32 mg/L. phosphate in (e.g., ampiroxicam, droxicam, isoxicam, lornoxicam, piroxi a concentration from about 85 to about 150 mg/L, and cam, tenoxicam), E-acetamidocaproic acid, S-adenosylme bicarbonate in a concentration from about 1281 to about thionine, 3-amino-4-hydroxybutyric acid, amixetrine, 2013 mg/L. bendazac, benzydamine, C.-bisabolol, bucolome, difenpira mide, ditazol, emorfaZone, fepradinol, guaiaZulene, nabu Viscosity/Osmolality/pH metone, nimeSulide, oxaceprol, paranyline, perisoxal, pro quaZone, Superoxide dismutase, tenidap, and Zileuton. 0042. The ophthalmic formulation when in an aqueous or non-aqueous form may also contain, but not be limited to: 0037 Examples of anti-allergic agents include, but are Suspending agents (e.g., polyvinyl pyrrolidone, glycerin not limited to: tranilast, ketotifen fumarate, pheniramine, monostearate, Sorbitan esters, lanolin alcohols) and dispers diphenhydramine hydrochloride, and sodium cromoglicate. ing agents (e.g., Surfactants such as tyloxapol and polysor 0038 Examples of glaucoma-treating agents include, but bate 80, ionic polymers such as Sodium alginate) in addition are not limited to: pilocarpine hydrochloride, latanoprost, to the agents listed above, to ensure that the ophthalmic timolol, and isopropylunoprostone. formulation is satisfactorily dispersed in a uniform micro particulate suspension. 0.039 Examples of antiviral agents include, but are not limited to: idoxuridine, acyclovir, and trifluorouridine. 0043. When the ophthalmic formulation is in the form of an aqueous Suspension or solution, a non-aqueous Suspen 0040 Examples of anti-mycotic agents include, but are sion or solution, or a gel or ointment it is preferable to use not limited to: pimaricin, fluconazole, miconazole, ampho a pH modifier to make the formulation have a pH between tericin B, flucytosine, and itraconazole. about 4 and 8, more preferably between about 6.8 to about 7.5. A preferred pH modifier is hydrochloric acid, sulfuric Methods acid, boric acid, Sodium hydroxide or any other ophthalmi 0041 According to one aspect of the present invention cally-acceptable pH modifier. there is provided a method of treating a patient's eye 0044 According to a further aspect of the present inven wherein its normal condition has been disrupted or changed. tion a topical ophthalmically-acceptable formulation com The method of this aspect of the invention is effected by prising physiologic levels of serum electrolytes in combi administering a topical ophthalmically-acceptable formula nation with a therapeutically-effective amount of an tion comprising physiologic levels of serum electrolytes in ophthalmically-active antimicrobial and an ophthalmically combination with a therapeutically-effective amount of an active anti-inflammatory or steroidal agent to treat an ocular ophthalmically-active antimicrobial, and an ophthalmically disease, injury or disorder may further comprise an oph active anti-inflammatory or steroidal agent to treat an ocular thalmically-acceptable excipient which modulates the osmo disease, injury or disorder. A further aspect of the present lality of the formulation from about 200 to about 500 invention is wherein the topical ophthalmically-acceptable mOsm/Kg, preferably from about 250 to about 400 mOsm/ formulation comprising physiologic levels of serum electro Kg, and more preferably from about 280 to about 320 lytes in combination with a therapeutically-effective amount mOsm/Kg. Examples of osmolality excipients include, but of an ophthalmically-active antimicrobial, and an oph are not limited to: dextrose, sodium chloride, potassium thalmically-active anti-inflammatory or steroidal agent to chloride, glycerin, various buffers and the like. treat an ocular disease, injury or disorder comprises potas sium in a concentration from about 136.85 to about 207.23 Sugars mg/L. A still further aspect of the present invention is wherein the topical ophthalmically-acceptable formulation 0045. It is further contemplated by the present invention comprising physiologic levels of serum electrolytes in com that a topical ophthalmically-acceptable formulation com bination with a therapeutically-effective amount of an oph prising physiologic levels of serum electrolytes in combi thalmically-active antimicrobial, and an ophthalmically-ac nation with a therapeutically-effective amount of an oph tive anti-inflammatory or Steroidal agent to treat an ocular thalmically-active antimicrobial, and an ophthalmically disease, injury or disorder comprises: potassium in a con active anti-inflammatory or steroidal agent to treat an ocular centration from about 136.85 to about 207.23 mg/L. chloride disease, injury or disorder may further comprise from about in a concentration from about 3368.7 to about 3829.68 10 to about 1500 mg/L, and more preferred from about 700 mg/L.; calcium in a concentration from about 85 to about 103 to about 1250 mg/L of a nutrient sugar. In yet a further mg/L. magnesium in a concentration from about 14.592 to contemplation of the present invention the nutrient Sugar of about 24.32 mg/L, and phosphate in a concentration from the formulation is a monosaccharide, oligosaccharide or about 85 to about 150 mg/L. A yet still further aspect of the polysaccharide. Examples of the nutrient Sugars include, but present invention is wherein the topical ophthalmically are not limited to: dextrose, fructose, galactose, glucose, US 2006/0183698 A1 Aug. 17, 2006 mannose, N-acetyl-galactosamine, N-acetyl-glucosamine, 0052. In another aspect of this invention, the ophthalmic N-acetyl-neuraminic acid, and xylose. In yet still a further formulation may be incorporated in a carrier system, which contemplation of the invention provides that the nutrient may be water, gel or ointment base. In still another aspect of Sugar of the present formulation is dextrose at a concentra this invention, said carrier system is a clear and stable tion from about 700 to about 1250 mg/L. pharmaceutical preparation, Suitable for ocular treatment. Excipients Kits 0046) The formulation may contain various excipients 0053. The present invention also provides for an oph incorporated ordinarily, Such as buffering agents (e.g., phos thalmic kit comprising a composition for use in a topical phate buffers, borate buffers, citrate buffers, tartarate buffers, ophthalmic formulation comprising a topical ophthalmi acetate buffers, amino acids, sodium acetate, sodium citrate cally-acceptable formulation comprising a therapeutically and the like), isotonicity agents (e.g., saccharides Such as effective amount of an ophthalmically-active antimicrobial, Sorbitol, glucose and mannitol, polyhydric alcohols such as and an ophthalmically-active anti-inflammatory or steroidal glycerin, concentrated glycerin, polyethylene glycol and agent in combination with physiologic levels of serum propylene glycol, salts such as Sodium chloride), preserva electrolytes and a means to apply the composition to the eye. tives or antiseptics (e.g., benzalkonium chloride, benzetho The ophthalmic kits may contain an application means nium chloride, p-oxybenzoates such as methyl p-oxyben which is an eye dropper, an eye cup, an eye spray or gel Zoate or ethyl p-oxybenzoate, benzyl alcohol, phenethyl ointment tube and can comprise a single dose or a multi dose alcohol, Sorbic acid or its salt, thimerosal, chlorobutanol, of the composition or formulation in a single container. other quaternary amines and the like), Solubilizing aids or stabilizing agents (e.g., cyclodextrins and their derivatives, Administration water-soluble polymers such as polyvinyl pyrrolidone, or 0054 The ophthalmic composition or formulation of the carbomer, surfactants such as polysorbate 80 (Tween 80)), present invention may be administered to a patient which is pH modifiers (e.g., hydrochloric acid, acetic acid, phospho or may be suffering from an ophthalmic injury, disease or ric acid, Sodium hydroxide, potassium hydroxide, ammo disorder (e.g., human, rat, mouse, rabbit, dog, cat, cattle, nium hydroxide and the like), thickening agents (e.g., horse, monkey). The ophthalmic composition or formulation hydroxyethyl cellulose, hydroxypropyl cellulose, methyl of the present invention also can be administered to a patient cellulose, hydroxypropylmethyl cellulose, carboxymethyl following ophthalmic Surgery. The composition or formu cellulose and their salts), chelating agents (e.g., sodium lation is given in an amount sufficient to cure, treat, or at edetate, Sodium citrate, condensed sodium phosphate) and least partially arrest the symptoms or complications of the the like. Descriptions of compounds used in standard oph Surgery, injury, disease or disorder. Amounts effective for thalmic formulations may be found in, for example, Rem this use will depend on the severity and course of the ington's Pharmaceutical Sciences, latest edition, Mack Pub Surgery, injury, disease or disorder, the patient's health status lishing Co. Easton, Pa. and response to the composition or formulation, and the 0047. Non-limiting examples of the contemplated excipi judgment of the treating physician. ents include a buffer, osmotic agent, demulcent, Surfactant, 0055. The formulation of the present invention and its emollient, tonicity agent, and/or a preservative component. subsequent administration is within the skill of those in the art. Dosing is dependent on severity and responsiveness of Preparations the disease state to be treated, with the course of treatment lasting from one day to several months, or until a cure is 0.048. The formulation for ophthalmic conditions accord effected or a diminution of the disease state is achieved. ing to the present invention can be mixed with a ophthalmi Optimal dosing schedules can be calculated from measure cally acceptable carrier, excipient or diluent and formulated ments of drug accumulation in the body of the patient. by a known method into a composition or formulation in various dosage forms such as injection solutions, eye drops EXAMPLES and ophthalmic gels or ointments, and it is especially preferred to be used in a topical dosage form, preferably an 0056 Having now generally described the invention, the eye drop formulation in solution or Suspension form or an same will be more readily understood through reference to ophthalmic gel or ointment. the following examples which are provided by way of illustration, and are not intended to be limiting of the present 0049. The ophthalmic formulation may for example be invention, unless specified. aqueous formulations such as aqueous eye drops, aqueous Suspension eye drops, viscous eye drops and solubilized eye Example 1 drops as well as non-aqueous formulations such as non aqueous eye drops and non-aqueous Suspension eye drops, 0057 Electrolyte Component: or an ophthalmic gel or ointment. 0050. The eye drop formulation in the form of an aqueous Electrolyte 1 - Sodium about 3200 mg/L.; Suspension preferably contains Sodium citrate as a buffering Electrolyte 2 - Potassium about 160 mg/L. agent, glycerin and/or propylene glycol as an isotonicity Electrolyte 3 - Chloride about 3500 mg/L.; agent and polyvinyl pyrrolidone as a Suspending agent. Electrolyte 4 - Calcium about 95 mg/L.; Electrolyte 5 - Magnesium about 20 mg/L.; 0051. The ophthalmic ointment may employ an ointment Electrolyte 6 - Phosphate about 120 mg/L, and base known per se, such as purified lanolin, petrolatum, Electrolyte 7 - Bicarbonate about 1650 mg/L plastibase, liquid paraffin, polyethylene glycol and the like. US 2006/01 83698 A1 Aug. 17, 2006

-continued -continued Antibiotic Component: Benzalkonium Chloride about 0.005% Tobramycin about 0.30% 1N. Sodium Hydroxide about 0.05 mL. Citric Acid about 0.25% Boric Acid about 0.30% pH about 7.2 0.058 Anti-Inflammatory Component: oSmolality (mCSm/kg) about 290

Prednisolone Acetate about 1% Example 4 Other Ingredients: 0063 Electrolyte Component: Hydroxypropyl methylcellulose E4M about 0.3% Polysorbate 80 about 0.05% Benzalkonium Chloride about 0.005% 1N. Sodium Hydroxide about 0.05 mL. Citric Acid about 0.25% Electrolyte 1 - Sodium about 3200 mg/L.; Boric Acid about 0.30% Electrolyte 2 - Potassium about 160 mg/L. pH about 7.2 Electrolyte 3 - Chloride about 3500 mg/L.; oSmolality (mCSm/kg) about 290 Electrolyte 4 - Calcium about 95 mg/L.; Electrolyte 5 - Magnesium about 20 mg/L.; Electrolyte 6 - Phosphate about 120 mg/L, and Electrolyte 7 - Bicarbonate about 1650 mg/L Example 2 0059 Electrolyte Component: 0064 Antibiotic Component:

Potassium about 160 mg/L. Tobramycin about 0.30% Anti-Inflammatory Component: Prednisolone Acetate about 1% 0065 Anti-Inflammatory Component: 0060 Antibiotic Component:

Dexamethasone about 1% Other Ingredients: Tobramycin about 0.30% Other Ingredients: Hydroxypropyl methylcellulose E4M about 0.3% Polysorbate 80 about 0.05% Hydroxypropyl methylcellulose E4M about 0.3% Benzalkonium Chloride about 0.005% Polysorbate 80 about 0.05% 1N. Sodium Hydroxide about 0.05 mL. Benzalkonium Chloride about 0.005% Citric Acid about 0.25% 1N. Sodium Hydroxide about 0.05 mL. Boric Acid about 0.30% Citric Acid about 0.25% pH about 7.2 Boric Acid about 0.30% oSmolality (mCSm/kg) about 290 pH about 7.2 oSmolality (mCSm/kg) about 290 0066. A further non-limiting example of a tobramycin and prednisolone electrolyte formulation with ranges is Example 3 provided below: 0061 Electrolyte Component: 0067 Prednisolone Acetate about 0.9 to about 1.1%/ Tobramycin about 0.2 to about 0.4% Ophthalmic Suspen sion Quantitative Composition

Potassium about 160 mg/L. Antibiotic Component: Gentamicin about 0.30% Pharmaceutical Raw Materials Grade mg/mL Prednisolone Acetate USP About 9 to About 11 0062 Anti-Inflammatory Component: Tobramycin USP About 2 to About 4 Hydroxypropyl methyl- USP About 2 to About 4 cellulose E4M Polysorbate 80 NF About 0.4 to About 0.6 Dexamethasone about 1% Potassium Chloride USP About 0.25 to About 0.3 Other Ingredients: Calcium Chloride Di- USP About 0.28 to About 0.35 hydrate Hydroxypropyl methylcellulose E4M about 0.3% Magnesium Chloride USP About 0.1 to About 0.15 Polysorbate 80 about 0.05% Hexahydrate US 2006/0183698 A1 Aug. 17, 2006

0.077 Finished Drug Product Specifications -continued

Pharmaceutical Test Test Methods Specifications Raw Materials Grade mg/mL Appearance USP Off white to slightly straw Sodium Phosphate Dibasic, USP About 0.1 to About 0.2 yellow Suspension pH USP 791. About 5 to About 8 Anhydrous Osmolality USP 785 About 250 to About Benzalkonium Chloride NF About 0.05 to About 0.055 400 mCSm/Kg Sodium Chloride USP About 4 to About 6 Prednisolone *TM-OO158 About 8 to About 12 Acetate Assay mg/mL Sodium Borate Decahydrate NF About 4 to About 5 Tobramycin Assay *TM-00160 About 2 to about 4 mg/mL. Sodium Sulfate Deca- USP About 3.5 to About 4.0 Benzalkonium *TM-OO161 About 0.04 to about 0.06 hydrate Chloride Assay mg/mL Sulfuric Acid NF To adjust pH Prednisolone *TM-OO166 a. < or = About 4 Lim: Acetate Particle About 95% to 99.0% by Purified Water USP Q.S. to volume Size Distribution volume. b. < or = About 6 Im: About 99% to 99.9% by volume 0068 A further non-limiting example of a prepared tobra Sterility **TM 200508204-01 No growth within About 14 mycin and prednisolone electrolyte formulation is provided days below: 0078 All references cited herein, including patents, 0069 Prednisolone Acetate 1.0%/Tobramycin 0.3% Oph patent applications, arid publications, are hereby incorpo thalmic Suspension Quantitative Composition rated by reference in their entireties, whether previously specifically incorporated or not. 0079. Having now fully described this invention, it will Pharmaceutical be appreciated by those skilled in the art that the same can Raw Materials Grade mg/mL be performed within a wide range of equivalent parameters, Prednisolone Acetate USP 1.O.OOO concentrations, and conditions without departing from the Tobramycin USP 3.OOOO spirit and scope of the invention and without undue experi Hydroxypropyl methylcellulose E4M USP 3.OOOO mentation. Polysorbate 80 NF O.SOOO Potassium Chloride USP 0.2750 Calcium Chloride Dihydrate USP O.31SO 0080 While this invention has been described in connec Magnesium Chloride Hexahydrate USP O.12SO tion with specific embodiments thereof, it will be understood Sodium Phosphate Dibasic, Anhydrous USP O.1500 that it is capable of further modifications. This application is Benzalkonium Chloride NF 0.0525 intended to cover any variations, uses, or adaptations of the Sodium Chloride USP 5.0500 invention following, in general, the principles of the inven Sodium Borate Decahydrate NF 4...SOOO Sodium Sulfate Decahydrate USP 3.8000 tion and including Such departures from the present disclo Sulfuric Acid NF To adjust pH Sure as come within known or customary practice within the Purified Water USP Q.S. to volume art to which the invention pertains and as may be applied to the essential features hereinbefore set forth. 0070 A non-limiting example of the manufacturing preparation for the above tobramycin and prednisolone What is claimed is: electrolyte formulation is provided below: 1. A topical ophthalmic formulation comprising: 0071 1. Reduce the particle size of the prednisolone (a) physiologic levels of serum electrolytes; acetate to the specified size range; (b) an antimicrobial compound; and 0072 2. Sterilize the prednisolone acetate; (c) an anti-inflammatory or steroidal compound. 0073. 3. Combine, mix and then sterilize the tobramy 2. The formulation of claim 1 wherein (a), (b) and (c) are cin and the excipient ingredients; in a single topical ophthalmic formulation. 3. The formulation of claim 1 wherein said antimicrobial 0074 4. Aseptically combine and mix the sterile pre compound is an aminoglycoside, fluoroquinolone, tetralide, disolone acetate with the sterile mixture of the tobra and/or cephalosporin or their ophthalmically-acceptable mycin and the other ingredients; and derivatives. 4. The formulation of claim 1 wherein the antimicrobial 0075 5. Aseptically fill the final suspension into the compound is tobramycin, gentamicin, ciproflaxacin, nor container/closure system. floxacin, ofloxacin, and/or sparfloxacin; or their ophthalmi cally-acceptable derivatives. 0.076 The release specifications for the above prepared 5. The formulation of claim 1 wherein said antimicrobial tobramycin and prednisolone electrolyte formulation are compound is tobramycin or its ophthalmically-acceptable provided below: derivatives. US 2006/0183698 A1 Aug. 17, 2006

6. The formulation of claim 1 wherein said anti-inflam 18. The topical formulation of claim 1 wherein the matory compound is diclofenac, bromfenac, dexamethasone formulation is an aqueous, non-aqueous, gel, or ointment and/or prednisolone or their ophthalmically-acceptable formulation. derivatives. 19. A composition for use in a topical ophthalmic formu 7. The formulation of claim 1 wherein said anti-inflam lation comprising: matory compound is prednisolone or its ophthalmically acceptable derivatives. about 9 to about 11 mg/ml of prednisolone acetate; 8. The formulation of claim 1 wherein said steroidal about 2 to about 4 mg/ml of tobramycin; compound is prednisolone, dexamethasone, fluorimetholone, beta-methasone, and/or corticosterone or their ophthalmi about 0.25 to about 0.30 mg/ml of potassium chloride: cally-acceptable derivatives. about 0.28 to about 0.35 mg/ml of calcium chloride 9. The formulation of claim 1 wherein said steroidal dihydrate; compound is prednisolone or its ophthalmically-acceptable about 0.1 to about 0.15 mg/ml of magnesium chloride derivatives. hexahydrate; 10. The formulation of claim 1 which comprises potas sium in a concentration from about 136.85 to about 207.23 about 0.1 to about 0.2 mg/ml of sodium phosphate diba mg/L. sic, anhydrous; and 11. The formulation of claim 1 which comprises the about 4 to about 6 mg/ml of sodium chloride. following ranges of electrolytes: 20. The topical formulation of claim 19 further compris potassium in a concentration from about 136.85 to about ing: 207.23 mg/L.; about 2 to about 4 mg/ml of hydroxypropyl methylcellu chloride in a concentration from about 3368.7 to about lose E4M; and 3829.68 mg/L. about 0.4 to about 0.6 mg/ml of Polysorbate 80. calcium in a concentration from about 85 to about 103 21. The topical formulation of claim 20 further compris mg/L. ing: magnesium in a concentration from about 14.592 to about about 4 to about 5 mg/ml of sodium borate decahydrate; 24.32 mg/L, and and phosphate in a concentration from about 85 to about 150 about 3.5 to about 4 mg/ml of sodium sulfate decahydrate. mg/L. 22. The topical formulation of claim 21 further compris 12. The formulation of claim 1 which comprises the ing about 0.05 to about 0.055 mg/ml of benzalkonium following ranges of electrolytes: chloride. 23. The topical formulation of claim 1 comprising: sodium in a concentration from about 3105 to about 3358 mg/L. about 10 mg/ml of prednisolone acetate; potassium in a concentration from about 136.85 to about about 3 mg/ml of tobramycin; 207.23 mg/L.; about 0.275 mg/ml of potassium chloride; chloride in a concentration from about 3368.7 to about about 0.315 mg/ml of calcium chloride dihydrate; 3829.68 mg/L. about 0.125 mg/ml of magnesium chloride hexahydrate; calcium in a concentration from about 85 to about 103 mg/L. about 0.15 mg/ml of Sodium phosphate dibasic, anhy drous; and magnesium in a concentration from about 14.592 to about 24.32 mg/L. about 5.05 mg/ml of sodium chloride. 24. The topical formulation of claim 23 further compris phosphate in a concentration from about 85 to about 150 ing: mg/L, and about 3.0 mg/ml of hydroxypropyl methylcellulose E4M; bicarbonate in a concentration from about 1281 to about and 2013 mg/L. about 0.5 mg/ml of Polysorbate 80. 13. The formulation of claim 1 further comprising an 25. The topical formulation of claim 24 further compris ophthalmically-acceptable excipient. ing: 14. The formulation of claim 13 wherein the excipient is a buffer, osmotic agent, demulcent, Surfactant, emollient, about 4.5 mg/ml of sodium borate decahydrate; and tonicity agent, and/or preservative component. about 3.8 mg/ml of sodium sulfate decahydrate. 15. The formulation of claim 14 wherein said preservative 26. The formulation of claim 25 wherein the osmolality of component is benzalkonium chloride. the formulation is from about 200 to about 500 mOsm/Kg. 16. The formulation of claim 14 wherein the osmolality of 27. The formulation of claim 26 wherein the osmolality of the formulation is from about 200 to about 500 mOsm/Kg. the formulation is from about 250 to about 400 mOsm/Kg. 17. The formulation of claim 14 wherein the osmolality of 28. An ophthalmic kit comprising the composition of the formulation is from about 250 to about 400 mOsm/Kg. claim 1 and a means to apply the composition to the eye. US 2006/0183698 A1 Aug. 17, 2006

29. An ophthalmic kit comprising the formulation of 35. The method of claim 33 wherein the ocular disease, claim 19 and a means to apply the formulation to the eye. injury or disorder is one which results in vascular leakage in 30. An ophthalmic kit comprising the formulation of the eye or by inflammation in the eye. claim 23 and a means to apply the formulation to the eye. 36. The method of claim 35 wherein the inflammation in the eye is caused by Surgical trauma, dry eye, an allergic, 31. The kit of claim 28 wherein the application means is viral, or bacterial infection, injury from a chemical, radiation an eye dropper, an eye cup, an eye spray or gel ointment or thermal burn, or penetration of a foreign body. tube. 37. A method of treating an eye wherein its normal 32. The kit of claim 29 further comprising a single dose condition has been disrupted or changed comprising admin or a multi dose of the formulation in a single container. istering to said eye the composition of claim 1. 33. A method of treating an ocular disease, injury or 38. A method of treating an eye wherein its normal disorder comprising administering the formulation of claim condition has been disrupted or changed comprising admin 1 to a patient in need of Such treatment. istering to said eye the formulation of claim 19. 34. The method of claim 33 wherein the ocular disease, 39. A method of treating an eye wherein its normal injury or disorder is caused by Surgery, physical damage to condition has been disrupted or changed comprising admin the eye, glaucoma, diabetic retinopathy, and/or macular istering to said eye the formulation of claim 23. degeneration. k k k k k